Tyk2 inhibitor and preparation method for intermediates thereof

Abstract

The present invention provides a TyK2 inhibitor and a preparation method for intermediates thereof, and particularly relates to preparation for a compound I and an intermediate compound IV and compound V thereof. The compound I and the intermediates thereof prepared by means of the method involve a mild reaction, simple post-treatment, high purity and yield.

Description

A preparation method of TyK2 inhibitor and its intermediate

[0001] This application claims priority to Chinese patent application CN202311773442.5, filed on December 22, 2023. This application incorporates the entire text of the aforementioned Chinese patent application. Technical Field

[0002] The present invention belongs to the field of medical technology, and specifically relates to the preparation of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide and its intermediates. Background Art

[0003] The compound 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (hereinafter referred to as "Compound I") has the following structural formula:

[0004] Compound I is a Tyk2 inhibitor used to treat autoimmune and autoinflammatory diseases. Unlike known JAK inhibitors, Compound I selectively binds to the pseudokinase binding domain (JH2) of TyK2, inhibiting TyK2 kinase activity through a molecular allosteric mechanism. Its inhibitory ability against JAK1-3 is relatively weak, effectively reducing the adverse reactions caused by JAK kinase 1-3 inhibition.

[0005] WO2023102085A1 discloses a method for preparing compound I: (1) 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (compound III) and 4,6-dichloropyridazine-3-carboxylic acid ethyl ester (compound IIa) are stirred in toluene at 110°C in the presence of 2,2,6,6-tetramethylpiperidine until the reaction is complete, and then cooled to about 20°C. Toluene and water are added, stirred for 1 hour, and then filtered. The filter cake is washed twice with toluene and then washed twice with water, and dried under reduced pressure at about 50°C to obtain solid 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxylic acid ethyl ester (compound IVa) with a yield of 80%. (2) 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxylic acid ethyl ester (Compound IVa) was reacted with trideuteromethylamine hydrochloride in tetrahydrofuran at room temperature in the presence of lithium bis(trimethylsilyl)amide. After the reaction was completed, 2:1 (v / v) water / saturated ammonium chloride aqueous solution was slowly added to quench the reaction. The layers were separated and the upper layer was evaporated to dryness to obtain a solid compound 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino]-N-(methyl-d3)pyridazine-3-carboxamide ( Compound Va) with a yield of 75%. (3) 6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]amino]-N-(methyl-d3)pyridazine-3-carboxamide (Compound Va) was reacted with cyclopropanecarboxamide in the presence of potassium carbonate, palladium acetate, and Josiphos ligand at about 75°C in acetonitrile and toluene. The reaction mixture was then cooled to about 20°C and quenched by slowly adding a 3:1 (v / v) water / saturated aqueous ammonium chloride solution. The mixture was filtered, the filter cake was washed twice with water, and the solid was dried under reduced pressure at about 80°C to obtain Compound I with a yield of 80%.

[0006] The first step of the preparation method is carried out in toluene at a relatively high temperature of 110°C. The second step requires very strict control of the moisture content of the reaction system. When the reaction system contains moisture, the following impurity 1 is generated, which hinders the formation of the corresponding product through the amine transesterification reaction of the substrate. The third step uses a mixed solvent, which is not conducive to solvent recovery and reuse. Furthermore, the post-processing of all three steps is relatively cumbersome and generates a large amount of wastewater. Summary of the Invention

[0007] The first aspect of the present invention provides a method for preparing compound V:

[0008] Deuterated methylamine hydrochloride is mixed with an inorganic base in a solvent, and then compound IV and an organic base are added to react to generate compound V. The reaction is as follows:

[0009] Where R is C 1-6 Alkyl or aryl, X2 is Cl, Br, I or sulfonate, and the organic base is a non-nucleophilic organic base that does not contain metal ions.

[0010] In some embodiments, the preparation of Compound V is carried out in a closed container.

[0011] In some embodiments, R is selected from methyl, ethyl, and X2 is Cl.

[0012] In some embodiments, the compound IV is compound IVa, the compound V is compound Va, and the structures of compound IVa and compound Va are shown below:

[0013] In some embodiments, the inorganic base may be optionally dissolved in water first to prepare an aqueous solution containing the inorganic base.

[0014] In some embodiments, the inorganic base is selected from one or more of LiOH, NaOH, KOH, Ca(OH)2, Ba(OH)2, Na2CO3, K2CO3, NaHCO3, KHCO3, NaNH2, NH3·H2O. In some embodiments, the inorganic base is selected from NaOH or KOH.

[0015] In some embodiments, the inorganic base is a 50% (w / w) sodium hydroxide solution, which is prepared by mixing equal amounts of water and sodium hydroxide.

[0016] In some embodiments, the molar ratio of deuterated methylamine hydrochloride to the inorganic base is 1:1 to 1.5.

[0017] In some embodiments, the molar ratio of deuterated methylamine hydrochloride to the inorganic base is 1:1 to 1.2.

[0018] In some embodiments, the non-nucleophilic organic base containing no metal ions is selected from one or more of DIEA, DBU, DBN, DMAP, 2,6-di-tert-butylpyridine, urea, and thiourea. In some embodiments, the non-nucleophilic organic base containing no metal ions is selected from one or more of DBU, DIEA, DMAP, urea, and thiourea.

[0019] In some embodiments, the molar ratio of compound IV to the non-nucleophilic organic base containing no metal ions is 1:0.001 to 0.5. In some embodiments, the molar ratio of compound IV to the non-nucleophilic organic base containing no metal ions is 1:0.01 to 0.5. In some embodiments, the molar ratio of compound IV to the non-nucleophilic organic base containing no metal ions is 1:0.01 to 0.3. In some embodiments, the molar ratio of compound IV to the non-nucleophilic organic base containing no metal ions is 1:0.05 to 0.15.

[0020] In some embodiments, the solvent is selected from one or more of THF, DMF, methanol, ethanol, propanol, isopropanol, 1,4-dioxane, and water. In some embodiments, the solvent is selected from one or more of THF, ethanol, and water. In some embodiments, the solvent is selected from ethanol. In some embodiments, the solvent is selected from THF. In some embodiments, the solvent is selected from a mixed solvent of THF and water.

[0021] In some embodiments, the mass volume ratio of the compound IV to the solvent is 1:5 to 20. In some embodiments, the mass volume ratio of the compound IV to the solvent is 1:10 to 15.

[0022] In some embodiments, the molar ratio of Compound IV to deuterated methylamine hydrochloride is 1:1 to 1.5. In some embodiments, the molar ratio of Compound IV to deuterated methylamine hydrochloride is 1:1 to 1.3.

[0023] In some embodiments, the reaction temperature of the reaction of Compound IV with deuterated methylamine hydrochloride is 20°C to 40°C.

[0024] In some embodiments, the reaction temperature of the reaction of Compound IV with deuterated methylamine hydrochloride is 20°C to 35°C.

[0025] In some preferred embodiments, the preparation method of compound V further includes the preparation of compound IV, and the preparation method of compound IV comprises the following steps: compound II reacts with compound III to obtain compound IV, and the reaction is as follows

[0026] Where R is C 1-6 Alkyl or aryl, X1 and X2 are independently Cl, Br, I or sulfonate.

[0027] In some embodiments, the compound II reacts with the compound III in a protic solvent under the action of an organic base to generate the compound IV, wherein the organic base is a non-nucleophilic organic base that does not contain metal ions.

[0028] In some embodiments, R is selected from methyl and ethyl, and X1 and X2 are Cl.

[0029] In some embodiments, the compound II is compound IIa, and the compound IV is compound IVa. The structures of compound IIa and compound IVa are shown below:

[0030] In some embodiments, the protic solvent is an aliphatic alcohol containing 1-6 carbon atoms.

[0031] In some embodiments, the protic solvent is selected from methanol, ethanol, and isopropanol.

[0032] In some embodiments, the protic solvent is ethanol.

[0033] In some embodiments, the non-nucleophilic organic base containing no metal ions is selected from one or more of DIEA, DBU, DBN, DMAP, 2,6-di-tert-butylpyridine, urea, and thiourea. In some embodiments, the non-nucleophilic organic base containing no metal ions is selected from one or more of DBU, DIEA, DMAP, urea, and thiourea. In some embodiments, the non-nucleophilic organic base containing no metal ions is selected from DBU or DIEA.

[0034] In some embodiments, the molar ratio of compound III to compound II is 1:1 to 1.5. In some embodiments, the molar ratio of compound III to compound II is 1:1 to 1.3.

[0035] In some embodiments, the molar ratio of compound III to the non-nucleophilic organic base containing no metal ions is 1:1 to 3. In some embodiments, the molar ratio of compound III to the non-nucleophilic organic base containing no metal ions is 1:2 to 3.

[0036] In some embodiments, the mass volume ratio of the compound III to the protic solvent is 1:5-20.

[0037] In some embodiments, the mass volume ratio of the compound III to the protic solvent is 1:8-15.

[0038] In some embodiments, the reaction temperature of the reaction of Compound II and Compound III is 60-85°C.

[0039] In some embodiments, the reaction temperature of the reaction of Compound II and Compound III is 65-80° C. In some preferred embodiments, the preparation method of Compound V is prepared using Compound II and Compound III as starting materials using a one-pot process, specifically comprising the following steps: Compound II reacts with Compound III in a protic solvent under the action of a non-nucleophilic organic base that does not contain metal ions, and after the reaction is complete, the same base is added, and then deuterated methylamine or a salt thereof is added to continue the reaction to produce Compound V.

[0040] The protic solvent, the non-nucleophilic organic base containing no metal ions, the reaction ratio and the reaction conditions are all as described above.

[0041] In some preferred embodiments, when the preparation method of compound V adopts the above-mentioned one-pot method from compound II and compound III as starting materials, the molar ratio of the deuterated methylamine or its salt to compound IV, and the molar ratio of the added base to compound IV are both the theoretical molar ratios to compound IV, and the ratios are as described above.

[0042] The above method is used to prepare compound V or compound Va, and the amount of non-nucleophilic organic base used is greatly reduced, thereby reducing costs. Moreover, because the non-nucleophilic organic base used does not contain metal ions, the water requirement in the reaction system is not high compared to LiHMDS. The above preparation method can be carried out in a mixed solvent containing water, the reaction is mild, impurities are less generated, and post-processing is simple. After the reaction is completed, there is no need to add an aqueous ammonium chloride solution for quenching. Solid compound V or compound Va can be directly obtained by cooling and crystallization, with high purity and yield.

[0043] The second aspect of the present invention provides a method for preparing Compound I:

[0044] Compound V reacts with cyclopropaneamide in a non-polar organic solvent under the action of a base, a palladium catalyst and a phosphine ligand, and the reaction is as follows:

[0045] wherein X2 is independently Cl, Br, I or sulfonate.

[0046] In some embodiments, X2 is Cl.

[0047] In some embodiments, the base is selected from an inorganic base, an organic base, or a mixture of the two.

[0048] In some embodiments, the base is selected from a mixture of inorganic bases and organic bases.

[0049] In some embodiments, the non-polar solvent is a single solvent.

[0050] In some embodiments, the inorganic base is selected from one or more of LiOH, NaOH, KOH, Ca(OH)2, Ba(OH)2, Na2CO3, K2CO3, NaHCO3, KHCO3, NaNH2, NH3·H2O, K3PO3, and K2HPO3. In some embodiments, the inorganic base is selected from K2CO3 or K3PO3.

[0051] In some embodiments, the molar ratio of the compound V to the inorganic base is 1:1 to 3. In some embodiments, the molar ratio of the compound V to the inorganic base is 1:1.5 to 2.5.

[0052] In some embodiments, the organic base is a non-nucleophilic organic base that does not contain metal ions. In some embodiments, the non-nucleophilic organic base that does not contain metal ions is selected from one or more of DIEA, DBU, DBN, DMAP, 2,6-di-tert-butylpyridine, urea, and thiourea. In some embodiments, the non-nucleophilic organic base that does not contain metal ions is selected from one or more of DBU, DIEA, DMAP, urea, and thiourea. In some embodiments, the non-nucleophilic organic base that does not contain metal ions is selected from DBU and DIEA.

[0053] In some embodiments, the molar ratio of the compound V to the non-nucleophilic organic base containing no metal ions is 1:1 to 5. In some embodiments, the molar ratio of the compound V to the non-nucleophilic organic base containing no metal ions is 1:2 to 3.

[0054] In some embodiments, the palladium catalyst is selected from Pd(OAc)2, PdCl2(MeCN)2, Pd2(dba)3, Pd(dba)2, [(allyl)PdCl]2, [(crotyl)PdCl]2. In some embodiments, the palladium catalyst is Pd(OAc)2. In some embodiments, the molar ratio of the compound V to the palladium catalyst is 1:0.005 to 0.1. In some embodiments, the molar ratio of the compound V to the palladium catalyst is 1:0.01 to 0.05.

[0055] In some embodiments, the phosphine ligand is selected from Josiphos ligands and Xantphos ligands. In some embodiments, the Josiphos ligand can be (R)-N,N-dimethyl-1-((S)-2-diphenylphosphino)ferrocene)ethylamine or (R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocene]ethyldi-tert-butylphosphine. In some embodiments, the Xantphos ligand is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. In some embodiments, the molar ratio of Compound V to the phosphine ligand is 1:0.01 to 0.1. In some embodiments, the molar ratio of Compound V to the phosphine ligand is 1:0.02 to 0.05.

[0056] In some embodiments, the molar ratio of compound V to cyclopropanamide is 1:1 to 5. In some embodiments, the molar ratio of compound V to cyclopropanamide is 1:1 to 4. In some embodiments, the molar ratio of compound V to cyclopropanamide is 1:1 to 3. In some embodiments, the molar ratio of compound V to cyclopropanamide is 1:1 to 2. In some embodiments, the molar ratio of compound V to cyclopropanamide is 1:1 to 1.5. In some embodiments, the molar ratio of compound V to cyclopropanamide is 1:1 to 1.3.

[0057] In some embodiments, the non-polar organic solvent is an ether solvent, an aromatic solvent, or an ester solvent. In some embodiments, the non-polar organic solvent is selected from DME and toluene. In some embodiments, the mass-to-volume ratio of Compound V to the non-polar organic solvent is 1:5-20, and in some embodiments, the mass-to-volume ratio of Compound V to the non-polar organic solvent is 1:10-15. In some embodiments, the reaction temperature is 70°C to 110°C.

[0058] In some embodiments, the preparation of Compound I further comprises the preparation of Compound V; in some embodiments, the preparation method of Compound V is as described in the first aspect of the present invention.

[0059] The third aspect of the present invention provides a method for preparing compound IV, comprising the following steps:

[0060] Compound II reacts with compound III in a protic solvent under the action of an organic base to generate compound IV. The reaction is as follows:

[0061] Where R is C 1-6 An alkyl or aryl group, X1 and X2 are independently Cl, Br, I or sulfonate, and the organic base is a non-nucleophilic organic base that does not contain metal ions.

[0062] In some embodiments, R is selected from methyl and ethyl, and X1 and X2 are Cl.

[0063] In some embodiments, the compound II is compound IIa, and the compound IV is compound IVa. The structures of compound IIa and compound IVa are shown below:

[0064] In some embodiments, the preparation of compound IV or compound IVa involves the selection of organic base and protic solvent, the amount of each component, the ratio, reaction temperature, etc. as described in the preparation method of compound IV or compound IVa in the first aspect of the present invention.

[0065] The method for preparing compound IV or compound IVa has a mild reaction and simple post-treatment. No water washing is required. Solid compound IV or compound IVa can be directly obtained by cooling and crystallization, with high purity and yield. Moreover, the solvent used is a single alcohol solvent, which is easy to recycle and reuse, does not generate wastewater, and is environmentally friendly.

[0066] The fourth aspect of the present invention provides a method for preparing compound I.

[0067] The following steps are involved:

[0068] (1) Preparation of Compound IVa

[0069] Compound IIa reacts with compound III in an alcohol solvent under the action of an organic base to generate compound IVa. The reaction is as follows:

[0070] (2) Preparation of Compound Va

[0071] Deuterated methylamine hydrochloride is mixed with an inorganic base in a solvent, and then compound IVa and an organic base are added to react to generate compound Va. The reaction is as follows:

[0072] (3) Preparation of Compound I

[0073] Compound Va reacts with cyclopropaneamide in a non-polar organic solvent in the presence of a base, a palladium catalyst, and a phosphine ligand to produce compound I, as follows:

[0074] In some embodiments, the selection of organic base, amount of each component, ratio, reaction temperature, etc. involved in the preparation of compound IVa in step (1) are the same as those described in the preparation method of compound IV or compound IVa in the first aspect of the present invention.

[0075] In some embodiments, the alcohol solvent in step (1) is selected from methanol, ethanol, and isopropanol.

[0076] In some embodiments, the mass volume ratio of compound III to the alcohol solvent in step (1) is 1:5-20.

[0077] In some embodiments, the mass volume ratio of compound III to the alcohol solvent in step (1) is 1:8-15.

[0078] In some embodiments, the preparation of compound Va in step (2) is carried out in a closed container, and the selection of inorganic base, organic base and solvent, the amount of each component, the ratio, reaction temperature, etc. are all as described in the preparation method of compound V or compound Va of the first aspect of the present invention.

[0079] In some embodiments, the organic bases in steps (1) to (2) are all non-nucleophilic organic bases that do not contain metal ions. In some embodiments, the organic bases in steps (1) to (2) are the same.

[0080] In some embodiments, the selection of inorganic base, organic base, palladium catalyst, phosphine ligand and non-polar organic solvent involved in the preparation of compound I in step (3), the amount of each component, the ratio, reaction temperature, etc. are all as described in the preparation method of compound I in the second aspect of the present invention.

[0081] In some embodiments, after the reaction of step (1), step (2) and step (3) is complete, the corresponding solid compounds IVa, Va and I can be obtained by cooling and crystallizing. The obtained corresponding solid compounds can be further purified by conventional methods such as recrystallization.

[0082] In some embodiments, the present invention also provides a method for preparing compound I starting from compound IVa or compound Va, and the reaction is as described above.

[0083] Compound I prepared by the above method has mild reaction, simple post-treatment, and high purity and yield. DETAILED DESCRIPTION

[0084] The following specific embodiments are further detailed descriptions of this invention. The examples are for illustration only and should not be considered as limiting the present invention in any way.

[0085] Unless otherwise defined herein, scientific and technical terms used herein have the same meanings as commonly understood by those skilled in the art.

[0086] In the present invention, "C 1-6"Alkyl" refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. This includes, but is not limited to, methyl, ethyl, propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.

[0087] The "aryl group" in the present invention refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 carbon atoms in the ring portion, such as phenyl and naphthyl, each of which may be substituted.

[0088] In the present invention, "sulfonate" refers to a group having the general formula -OSO2R3, where R3 can be optionally an alkyl group or an aryl group, including, but not limited to, methanesulfonate, ethanesulfonate, and toluenesulfonate.

[0089] Compound II and Compound III used in the present invention can be purchased or prepared by methods disclosed in existing literature such as CN110475774. The units of mass and volume in the present invention are g / mL unless otherwise specified.

[0090] The abbreviations used in the present invention are explained as follows: DIEA: N,N-diisopropylethylamine DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DMAP: dimethylaminopyridine DBN: 9,9-dimethylxanthene DME: ethylene glycol dimethyl ether LiHMDS: lithium bis(trimethylsilyl)amide IPA: isopropyl alcohol THF: tetrahydrofuran w / w: mass to mass ratio

[0091] The specific embodiments are as follows:

[0092] Comparative Example 1: Preparation of Compound IVa, reacted according to the method of Example 28 of WO2023102085A1

[0093] 1.98 mL of 2,2,6,6-tetramethylpiperidine, 2.60 g of Compound IIa, and 2 g of Compound III were added to 11 mL of toluene and stirred at 110°C until the reaction was complete. The reaction solution was cooled to 20°C, and toluene and water were added to terminate the reaction. The reaction was stirred for 1 hour and filtered. The filter cake was rinsed with toluene and water and dried at 50°C to obtain 2.92 g of solid Compound IVa. The yield was 76.7% and the purity was 98.27%.

[0094] Comparative Example 2: Preparation of Compound IVa

[0095] 2.60 g of compound IIa, 2 g of compound III, and 3.16 g of DIEA were added to 20 mL of toluene. The reaction temperature was raised to 110°C and stirred until complete. The temperature was then lowered to 25-35°C. 30 mL of water was added to the system to adjust the pH to 6-7. The filter cake was rinsed with a small amount of toluene and dried to obtain 2.81 g of solid compound IVa. The yield was 73.8% and the purity was 96.14%.

[0096] Example 1: Preparation of Compound IVa

[0097] 90.91 g of Compound IIa, 70 g of Compound III, and 110.75 g of DIEA were added to 700 mL of ethanol. The reaction temperature was raised to 78°C and stirred until complete. The reaction was then cooled to 25-35°C. The crystals were separated and filtered. The filter cake was rinsed with a small amount of ethanol and dried to obtain 107.01 g of solid Compound IVa. The yield was 80.3% and the purity was 99.49%.

[0098] Example 2: Preparation of Compound IVa

[0099] 11.36g of compound IIa, 10g of compound III, and 15.82g of DIEA were added to 100mL of IPA. The reaction temperature was raised to 80°C and stirred until complete. The reaction was then cooled to 0-5°C. The crystals were separated and filtered. The filter cake was rinsed with a small amount of IPA and dried to obtain 16.03g of solid compound IVa. The yield was 84.2% and the purity was 97.39%.

[0100] Example 3: Preparation of Compound IVa

[0101] 11.36 g of compound IIa, 10 g of compound III, and 15.82 g of DIEA were added to 100 mL of methanol. The reaction temperature was raised to reflux and stirred until complete. The reaction was then cooled to 25-35°C. The crystals were separated and filtered. The filter cake was rinsed with a small amount of methanol and dried to obtain 15.88 g of solid compound IVa. The yield was 83.4% and the purity was 99.27%.

[0102] Example 4: Preparation of Compound IVa

[0103] 11.91 g of compound IIa, 10 g of compound III, and 18.64 g of DBU were added to 100 mL of ethanol, the reaction temperature was raised to 80°C, and the reaction was stirred until completion. The reaction was filtered, and the filter cake was rinsed with ethanol and dried to obtain 15.42 g of compound IVa with a yield of 81.0% and a purity of 98.85%.

[0104] Comparative Example 3: Preparation of Compound Va

[0105] The reaction was carried out according to the method of Example 31 of WO2023102085A1

[0106] 5.6 mL of LiHMDS, 2 g of compound IVa, and 0.408 g of deuterated methylamine hydrochloride were added to 20 mL of THF and reacted at 20°C until completion. 30 mL of a 2:1 (v / v) water / saturated ammonium chloride aqueous solution was slowly added to terminate the reaction. The layers were separated, and the upper organic phase was evaporated to dryness to obtain 1.43 g of solid compound Va with a yield of 73.8% and a purity of 98.07%.

[0107] Example 5: Preparation of Compound Va

[0108] 14 g of deuterated methylamine hydrochloride and 10 mL of a 50% (w / w) NaOH solution were added to 700 mL of THF and stirred in a sealed container at 0-10°C for 2 h. Then, 70 g of Compound IVa and 2.57 g of DBU were added, and the mixture was allowed to react in a sealed container at 30°C. After the reaction, 2100 mL of water was added and stirred for 0.5 h. The THF was removed by distillation under reduced pressure, and the mixture was filtered and dried to obtain 67 g of solid Compound Va. The yield was 98.8% and the purity was 99.10%.

[0109] Example 6: Preparation of Compound Va

[0110] 0.40 g of deuterated methylamine hydrochloride and 0.32 g of KOH were added to 20 mL of ethanol and stirred at 0-10°C under sealed conditions for 1 hour. Then, 2 g of Compound IVa and 0.07 g of DIEA were added and reacted in a sealed condition at 30°C. After the reaction, 60 mL of water was added, stirred for 0.5 hour, filtered, and dried to obtain 1.81 g of solid Compound Va. The yield was 93.4% and the purity was 95.17%.

[0111] Example 7: Preparation of Compound Va

[0112] 0.40 g of deuterated methylamine hydrochloride and 0.30 mL of 50% (w / w) NaOH solution were added to 20 mL of THF and stirred at 0-10°C under sealed conditions for 1 hour. Then, 2 g of Compound IVa and 0.06 g of DMAP were added and the mixture was allowed to react at 30°C under sealed conditions. After the reaction, 60 mL of water was added and stirred for 0.5 hour. The THF was removed by distillation under reduced pressure, and the mixture was filtered and dried to obtain 1.80 g of solid Compound Va. The yield was 92.8% and the purity was 95.85%.

[0113] Example 8: Preparation of Compound Va

[0114] 0.40 g of deuterated methylamine hydrochloride and 0.28 mL of 50% (w / w) NaOH solution were added to 20 mL of THF and stirred in a sealed container at 0-10°C for 2 h. Then, 2 g of Compound IVa and 0.03 g of urea were added and the mixture was allowed to react in a sealed container at 35°C. After the reaction, 60 mL of water was added and stirred for 0.5 h. The THF was removed by distillation under reduced pressure, and the mixture was filtered and dried to obtain 1.79 g of solid Compound Va. The yield was 92.3% and the purity was 95.94%.

[0115] Example 9: Preparation of Compound Va

[0116] 0.44 g of deuterated methylamine hydrochloride and 0.30 mL of a 50% w / w NaOH solution were added to 30 mL of THF and stirred at 0-10°C under sealed conditions for 2 h. Then, 2 g of Compound IVa and 0.06 g of thiourea were added and the mixture was allowed to react at 30°C under sealed conditions. After the reaction, 80 mL of water was added and stirred for 0.5 h. The THF was removed by distillation under reduced pressure, and the mixture was filtered and dried to obtain 1.73 g of solid Compound Va. The yield was 89.2% and the purity was 96.99%.

[0117] Comparative Example 4: Preparation of Compound I

[0118] The reaction was carried out according to the method of Example 32 of WO2023102085A1

[0119] 2g of compound Va, 1.12g of cyclopropaneamide, and 3.4g of K2CO3 were added to 9.2mL of acetonitrile and 15.2mL of toluene. The reaction mixture was purged with nitrogen. 36mg of Pd(OAc)2 and 62mg of (R)-N,N-dimethyl-1-((S)-2-diphenylphosphino)ferrocene)ethylamine were added. The reaction mixture was purged with nitrogen. The temperature was raised to 75°C and stirred. If the reaction was not complete, an additional 36mg of Pd(OAc)2 and 62mg of (R)-N,N-dimethyl-1-((S)-2-diphenylphosphino)ferrocene)ethylamine were added. The reaction was continued at 75°C until complete. The temperature was then lowered to 20°C and 28mL of a 3:1 (v / v) water / saturated ammonium chloride aqueous solution was slowly added to terminate the reaction. The mixture was filtered, the filter cake was rinsed with water, and then dried at 50°C to obtain 1.41g of solid compound I. The yield was 62.4% and the purity was 99.15%.

[0120] Example 10: Preparation of Compound I

[0121] 9 g of compound Va, 2.44 g of cyclopropaneamide, 8.26 g of K3PO4, 7.72 g of DIEA, 67 mg of Pd(OAc)2, and 0.31 g of (R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocene]ethyldi-tert-butylphosphine) were added to 90 mL of toluene, the temperature was raised to 110°C, and the mixture was stirred until the reaction was complete. The temperature was then lowered to 30-35°C, 27 mL of water was added, and the pH was adjusted to 7 with 2N HCl. The mixture was stirred for 30 min, and filtered and dried to obtain 9.16 g of compound I with a yield of 90.1% and a purity of 98.18%.

[0122] Example 11: Preparation of Compound I

[0123] 4.70 g of compound Va, 1.27 g of cyclopropaneamide, 2.81 g of K2CO3, 4.74 g of DBU, 0.14 g of Pd(OAc)2, and 0.13 g of (R)-N,N-dimethyl-1-((S)-2-diphenylphosphino)ferrocene)ethylamine were added to DME (105 ml, 15 V), the temperature was raised to 80°C, and the mixture was stirred until the reaction was complete. The temperature was then lowered to 30-35°C, filtered, and the filter cake was rinsed with DME, then slurried with water, filtered, and dried to obtain 4.44 g of compound I with a yield of 83.7% and a purity of 98.18%.

[0124] Example 12: Preparation of Compound I

[0125] 2 g of compound Va, 0.54 g of cyclopropaneamide, 1.13 g of K2CO3, 1.76 g of DIEA, 30 mg of Pd(OAc)2, and 0.12 g of (R)-N,N-dimethyl-1-((S)-2-diphenylphosphino)ferrocene)ethylamine were added to 20 mL of toluene. The temperature was raised to 110°C and stirred until the reaction was complete. The mixture was then cooled to 30-35°C, and 30 mL of water was added with stirring. The pH was adjusted to approximately 7 with 2N HCl. The mixture was filtered, and the filter cake was rinsed with a small amount of toluene and dried to obtain 1.95 g of solid compound I. The yield was 86.4%, and the purity was 97.83%.

[0126] Example 13: Preparation of Compound I

[0127] 2g of compound Va, 540mg of cyclopropaneamide, 1.83g of K3PO4, 2.02g of DBU, 60mg of Pd(OAc)2, and 0.28g of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene were added to 20mL of toluene. The temperature was raised to 110°C and stirred until the reaction was complete. The temperature was then lowered to room temperature, 20mL of water was added, and the mixture was stirred for 30 minutes. The mixture was filtered, and the filter cake was rinsed with toluene and dried to obtain 1.91g of solid compound I. The yield was 84.6% and the purity was 96.96%.

[0128] Although this application has been described with reference to exemplary embodiments, it should be understood that this application is not limited to the disclosed exemplary embodiments. Various adjustments or variations may be made to the exemplary embodiments of this application specification without departing from the scope or spirit of this application. The scope of the claims should be based on the broadest interpretation so as to encompass all modifications and equivalent structures and functions.

Claims

1. A method for preparing compound V, comprising the following steps: Deuterated methylamine hydrochloride is mixed with an inorganic base in a solvent, and then compound IV and an organic base are added to react to generate compound V. The reaction is as follows: in, R is C 1-6 The organic base is an alkyl or aryl group, X2 is Cl, Br, I or sulfonate, and the organic base is a non-nucleophilic organic base that does not contain metal ions.

2. The preparation method according to claim 1, characterized in that: The R is selected from methyl and ethyl, preferably R is ethyl; X2 is Cl.

3. The preparation method according to claim 1, characterized in that: The compound IV is compound IVa, the compound V is compound Va, and the structures of compound IVa and compound Va are shown below:

4. The preparation method according to any one of claims 1 to 3, characterized in that: The inorganic base may be optionally dissolved in water first to prepare an aqueous solution containing the inorganic base.

5. The preparation method according to any one of claims 1 to 4, characterized in that: The inorganic base is selected from one or more of LiOH, NaOH, KOH, Ca(OH)2, Ba(OH)2, Na2CO3, K2CO3, NaHCO3, KHCO3, NaNH2, NH3·H2O, preferably one or more of NaOH and KOH.

6. The preparation method according to any one of claims 1 to 5, characterized in that: The non-nucleophilic organic base containing no metal ions is selected from one or more of DIEA, DBU, DBN, DMAP, 2,6-di-tert-butylpyridine, urea, and thiourea, preferably one or more of DIEA, DBU, DMAP, urea, and thiourea.

7. The preparation method according to any one of claims 1 to 6, characterized in that: The molar ratio of the compound IV to the non-nucleophilic organic base containing no metal ions is 1:0.001-0.5; preferably 1:0.01-0.3; more preferably 1:0.05-0.

15.

8. The preparation method according to any one of claims 1 to 7, characterized in that: The molar ratio of the compound IV to deuterated methylamine hydrochloride is 1:1 to 1.5, preferably 1:1 to 1.

3.

9. The preparation method according to any one of claims 1 to 8, characterized in that: The molar ratio of the deuterated methylamine hydrochloride to the inorganic base is 1:1 to 1.5, preferably 1:1 to 1.

2.

10. The preparation method according to any one of claims 1 to 9, characterized in that: The solvent is selected from one or more of THF, DMF, methanol, ethanol, propanol, isopropanol, 1,4-dioxane and water; preferably one or more of ethanol, THF and water.

11. The preparation method according to any one of claims 1 to 10, characterized in that: Also included is the preparation of compound IV, the reaction is as follows: Where R is C 1-6 Alkyl or aryl, X1 and X2 are independently Cl, Br, I or sulfonate.

12. The preparation method according to claim 11, characterized in that: The R is methyl or ethyl, preferably ethyl; X1 and X2 are independently Cl.

13. The preparation method according to any one of claims 11 to 12, characterized in that: The compound II is compound IIa, and the compound IV is compound IVa. The structures of the compound IIa and compound IVa are shown below: 。 14. The preparation method according to any one of claims 11 to 13, characterized in that: The compound II reacts with the compound III in a protic solvent under the action of an organic base to generate the compound IV.

15. The preparation method according to claim 14, characterized in that: The organic base is a non-nucleophilic organic base that does not contain metal ions.

16. The preparation method according to claim 15, characterized in that: The non-nucleophilic organic base containing no metal ions is selected from DIEA, DBU, DBN, DMAP, 2,6-di-tert-butylpyridine, urea, thiourea, preferably one or more of DBU, DMAP, urea, thiourea, more preferably DBU and DIEA.

17. The preparation method according to any one of claims 15 to 16, characterized in that: The molar ratio of the compound III to the non-nucleophilic organic base containing no metal ions is 1:1-3, preferably 1:2-3.

18. The preparation method according to any one of claims 14 to 17, characterized in that: The protic solvent is an aliphatic alcohol containing 1 to 6 carbon atoms, preferably methanol, ethanol, or isopropanol.

19. The preparation method according to any one of claims 11 to 18, characterized in that: The molar ratio of compound III to compound II is 1:1 to 1.5, preferably 1:1 to 1.

3.

20. The preparation method according to any one of claims 1 to 19, characterized in that: The compound V is further used to prepare compound I, and the structure of compound I is as follows: 。 21. The preparation method according to claim 20, characterized in that: The compound V reacts with cyclopropaneamide in a non-polar organic solvent under the action of a base, a palladium catalyst and a phosphine ligand to generate the compound I, and the reaction is as follows: Among them, X2 is Cl, Br, I or sulfonate, preferably X2 is Cl.

22. The preparation method according to claim 21, characterized in that: The base is selected from an inorganic base, an organic base or a mixture of the two; preferably a mixture of the two.

23. The preparation method according to claim 22, characterized in that: The inorganic base is selected from one or more of LiOH, NaOH, KOH, Ca(OH)2, Ba(OH)2, Na2CO3, K2CO3, NaHCO3, KHCO3, NaNH2, NH3·H2O, K3PO3, and K2HPO3; preferably K2CO3 and K3PO3.

24. The preparation method according to any one of claims 22 to 23, characterized in that: The molar ratio of the compound V to the inorganic base is 1:1-3; preferably, the molar ratio of the compound V to the inorganic base is 1:1.5-2.

5.

25. The preparation method according to any one of claims 22, characterized in that: The organic base is a non-nucleophilic organic base that does not contain metal ions.

26. The preparation method according to claim 25, characterized in that: The non-nucleophilic organic base containing no metal ions is selected from DIEA, DBU, DBN, DMAP, 2,6-di-tert-butylpyridine, urea, and thiourea, preferably one or more of DIEA, DBU, DMAP, urea, and thiourea, and more preferably DBU and DIEA.

27. The preparation method according to any one of claims 25 to 26, characterized in that: The molar ratio of the compound V to the non-nucleophilic organic base containing no metal ions is 1:1-5; preferably, the molar ratio of the compound V to the non-nucleophilic organic base containing no metal ions is 1:2-3.

28. The preparation method according to any one of claims 21 to 27, characterized in that: The palladium catalyst is selected from Pd(OAc)2, PdCl2(MeCN)2, Pd2(dba)3, Pd(dba)2, [(allyl)PdCl]2, [(crotyl)PdCl]2. Pd(OAc)2 is preferred.

29. The preparation method according to any one of claims 21 to 28, characterized in that: The molar ratio of the compound V to the palladium catalyst is 1:0.005-0.1, preferably 1:0.01-0.

05.

30. The preparation method according to any one of claims 21 to 29, characterized in that: The phosphine ligand is selected from Josiphos ligand and Xantphos ligand.

31. The preparation method according to claim 30, characterized in that: The Josiphos ligand is selected from (R)-N,N-dimethyl-1-((S)-2-diphenylphosphino)ferrocene)ethylamine, (R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocene]ethyldi-tert-butylphosphine; the Xantphos ligand is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

32. The preparation method according to any one of claims 21 to 31, characterized in that: The molar ratio of the compound V to the phosphine ligand is 1:0.01-0.1, preferably 1:0.02-0.

05.

33. The preparation method according to any one of claims 21 to 32, characterized in that: The non-polar organic solvent is a single solvent, and the non-polar organic solvent is selected from ether solvents, aromatic solvents, and ester solvents; preferably DME and toluene.

34. A preparation of compound IV, comprising the following steps: Compound II reacts with compound III in a protic solvent under the action of an organic base to generate compound IV, and the reaction is as follows: Where R is C 1-6 Alkyl or aryl, X1 and X2 are independently Cl, Br, I or sulfonate, and the organic base is a non-nucleophilic organic base without metal ions.

35. The preparation method according to claim 34, characterized in that: The R is methyl or ethyl, preferably ethyl.

36. The preparation method according to any one of claims 34 to 35, characterized in that: Said X1 and X2 are independently Cl.

37. The preparation method according to any one of claims 34 to 36, characterized in that: The compound II is compound IIa, and the compound IV is compound IVa. The structures of the compound IIa and compound IVa are shown below: 。 38. The preparation method according to any one of claims 34 to 37, characterized in that: The protic solvent is an aliphatic alcohol containing 1 to 6 carbon atoms; preferably methanol, ethanol, isopropanol, and more preferably ethanol.

39. The preparation method according to any one of claims 34 to 38, characterized in that: The non-nucleophilic organic base containing no metal ions is selected from DIEA, DBU, DBN, DMAP, 2,6-di-tert-butylpyridine, urea, thiourea, preferably one or more of DBU, DMAP, urea, thiourea, more preferably DBU and DIEA.

40. The preparation method according to any one of claims 34 to 39, characterized in that: The molar ratio of the compound III to the compound II is 1:1 to 1.5, preferably 1:1 to 1.

3.

41. The preparation method according to any one of claims 34 to 40, characterized in that: The molar ratio of the compound III to the non-nucleophilic organic base containing no metal ions is 1:1-3, preferably 1:2-3.

42. The preparation method according to any one of claims 34 to 41, characterized in that: The mass volume ratio of the compound III to the protic solvent is 1:5-20, preferably 1:8-15.

43. The preparation method according to any one of claims 34 to 42, characterized in that: The reaction temperature of the compound II and the compound III is 60-85°C, preferably 65-80°C.

44. A method for preparing compound I, comprising the following steps: Compound V reacts with cyclopropaneamide in a non-polar organic solvent under the action of a base, a palladium catalyst and a phosphine ligand, and the reaction is as follows: Wherein, X2 is independently Cl, Br, I or sulfonate.

45. The preparation method according to claim 44, characterized in that: The X2 is Cl.

46. ​​The preparation method according to any one of claims 44 to 45, characterized in that: The non-polar solvent is a single solvent.

47. The preparation method according to any one of claims 44 to 46, characterized in that: The base is selected from an inorganic base, an organic base or a mixture of the two; preferably, the base is selected from a mixture of an inorganic base and an organic base.

48. The preparation method according to claim 47, characterized in that: The inorganic base is selected from one or more of LiOH, NaOH, KOH, Ca(OH)2, Ba(OH)2, Na2CO3, K2CO3, NaHCO3, KHCO3, NaNH2, NH3·H2O, K3PO3, and K2HPO3; preferably, the inorganic base is selected from K2CO3 or K3PO3.

49. The preparation method according to any one of claims 47 to 48, characterized in that: The molar ratio of the compound V to the inorganic base is 1:1-3; preferably 1:1.5-2.

5.

50. The preparation method according to claim 47, characterized in that: The organic base is a non-nucleophilic organic base that does not contain metal ions.

51. The preparation method according to claim 50, characterized in that: The non-nucleophilic organic base containing no metal ions is selected from one or more of DIEA, DBU, DBN, DMAP, 2,6-di-tert-butylpyridine, urea, and thiourea; preferably, the non-nucleophilic organic base containing no metal ions is selected from one or more of DBU, DIEA, DMAP, urea, and thiourea; more preferably, the non-nucleophilic organic base containing no metal ions is selected from DBU and DIEA.

52. The preparation method according to any one of claims 50 to 51, characterized in that: The molar ratio of the compound V to the non-nucleophilic organic base containing no metal ions is 1:1-5, preferably 1:2-3.

53. The preparation method according to any one of claims 44 to 52, characterized in that: The palladium catalyst is selected from Pd(OAc)2, PdCl2(MeCN)2, Pd2(dba)3, Pd(dba)2, [(allyl)PdCl]2, [(crotyl)PdCl]2; preferably, the palladium catalyst is Pd(OAc)2.

54. The preparation method according to any one of claims 44 to 53, characterized in that: The molar ratio of the compound V to the palladium catalyst is 1:0.005-0.1, preferably 1:0.01-0.

05.

55. The preparation method according to any one of claims 44 to 54, characterized in that: The phosphine ligand is selected from Josiphos ligand and Xantphos ligand.

56. The preparation method according to claim 55, characterized in that: The Josiphos ligand is selected from (R)-N,N-dimethyl-1-((S)-2-diphenylphosphino)ferrocene)ethylamine, (R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocene]ethyldi-tert-butylphosphine; the Xantphos ligand is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

57. The preparation method according to any one of claims 44 to 56, characterized in that: The molar ratio of the compound V to the phosphine ligand is 1:0.01-0.1; preferably 1:0.02-0.05.

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