Preparation method of 8, 8-difluoro-2, 6-diazaspiro [3.4] octane compound

Abstract

The invention provides a preparation method of an 8, 8-difluoro-2, 6-diazaspiro [3.4] octane compound, which is characterized in that the 8, 8-difluoro-2, 6-diazaspiro [3.4] octane compound is synthesized by a one- Specifically, the invention provides a preparation method of a compound shown in a formula II, which comprises the following steps: in an organic solvent, under the action of a catalyst and in the presence of alkali and hydrogen, a compound shown in a formula I is subjected to cyclization reaction to obtain the compound shown in the formula II, R1 is C1-6 alkyl-O-CO-, the catalyst is a subgroup metal catalyst, and the alkali is organic alkali. The preparation method provided by the invention is high in yield, high in efficiency and good in application prospect. # imgabs0 #

Description

Technical Field

[0001] The invention relates to a method for preparing 8,8-difluoro-2,6-diazaspiro[3.4]octane compounds. Background Art

[0002] Spiro compounds have special physical and chemical properties due to their unique chemical structure. As a drug intermediate, spiro compounds have been widely used in the synthesis of drugs.

[0003] Fluorine atoms have the characteristics of strong electronegativity, small atomic radius and good metabolic stability. In recent years, they have become atoms frequently introduced in medicinal chemistry and material chemistry, greatly improving the properties of the original molecules. Among them, fluorinated spiro compounds have attracted particular attention in the field of medicinal chemistry and have become a hot segment in current drug research and development.

[0004] 8,8-Difluoro-2,6-diazaspiro[3.4]octane has been used in the research of various drug molecules in recent years, for example, as a molecular fragment of LRRK2 degrader in WO2022198112, as a molecular fragment of KRAS G12D inhibitor in WO2022105855, and as a molecular fragment of KRAS G12C inhibitor used by Amgen in WO2022083569. However, there are few literature reports on the synthesis method of this fragment. Summary of the invention

[0005] The technical problem to be solved by the present invention is to overcome the defect that there are few types of existing 8,8-difluoro-2,6-diazaspiro[3.4]octane compound synthesis methods. Therefore, the present invention provides a preparation method of 8,8-difluoro-2,6-diazaspiro[3.4]octane compounds. The preparation method provided by the present invention has high yield, high efficiency and good application prospects.

[0006] The present invention solves the above technical problems through the following technical solutions.

[0007] The present invention provides a method for preparing a compound of formula II, comprising the following steps: in an organic solvent, in the presence of a catalyst, a base and hydrogen, subjecting the compound of formula I to a cyclization reaction to obtain a compound of formula II;

[0008] ;

[0009] R1 is C 1-6 Alkyl-O-CO-;

[0010] The catalyst is a subgroup metal catalyst, and the base is an organic base.

[0011] In one embodiment, in the cyclization reaction, the organic solvent is an alcohol solvent, such as methanol.

[0012] In one embodiment, the reaction pressure of the cyclization reaction is 2-7 atm, for example 5 atm.

[0013] In one embodiment, in R1, the C 1-6 The alkyl group is methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl or tert-butyl, for example, R1 is tert-butyloxycarbonyl (Boc).

[0014] In one embodiment, the catalyst is a subgroup metal catalyst (eg, a palladium catalyst and / or a nickel catalyst), such as palladium carbon (eg, 5% palladium carbon) or Raney nickel.

[0015] In one embodiment, the organic base is an amine compound, such as triethylamine, diisopropylethylamine or DBU (1,8-diazabicyclo[5.4.0]undec-7-ene). Preferably, the organic base is a bicyclic amidine amine compound (such as DBU).

[0016] In one embodiment, the mass volume ratio of the compound represented by formula I to the organic solvent is 30-200 g / L, such as 40-110 g / L, preferably 100 g / L, 53 g / L or 106.5 g / L.

[0017] In one embodiment, the mass ratio of the compound represented by formula I to the catalyst is (20-5):1, for example (15-8):1, preferably 10.6:1.

[0018] In one embodiment, when the organic base is triethylamine or diisopropylethylamine, the molar ratio of the compound represented by formula I to the organic base is (0.5-6):1, for example (0.5-2):1, preferably 1:1.

[0019] In one embodiment, when the organic base is DBU, the molar ratio of the compound represented by formula I to the organic base is (0.1-25):1, for example (0.5-10):1, preferably 1:1, 20:1 or 10:1.

[0020] In one embodiment, the cyclization reaction temperature is 45-80°C, such as 60-70°C, preferably 50°C, 65°C.

[0021] The progress of the cyclization reaction can be monitored by conventional methods in the art, such as LCMS, and preferably the reaction endpoint is when the compound represented by formula I is no longer converted or the compound represented by formula II is no longer generated. The reaction time can be 1-24 hours, for example 16 hours.

[0022] In one embodiment, the cyclization reaction comprises the following post-treatment steps: after the reaction is completed, filtering (e.g., filtration on diatomaceous earth), concentrating, adding an ester solvent (e.g., ethyl acetate), washing (e.g., washing with hydrochloric acid solvent, water, and saturated brine in sequence), and concentrating (preferably concentrating and then purifying on a silica gel column) to obtain the compound represented by formula II.

[0023] In one embodiment, the cyclization reaction comprises the following steps: in a hydrogen atmosphere, the reaction pressure is 2-7atm, the compound represented by the formula I, the organic solvent, the catalyst and the mixture of the organic base are subjected to the cyclization reaction, after the reaction is completed, the reaction is filtered (for example, diatomaceous earth filtration), concentrated, an ester solvent is added, washed, and concentrated to obtain the compound represented by the embodiment formula II.

[0024] In one embodiment, the raw materials for the cyclization reaction are the compound represented by formula I, the organic solvent, the catalyst, the base and the hydrogen.

[0025] In one embodiment, the preparation method of the compound represented by formula II further comprises the following steps: in a polar organic solvent, in the presence of copper powder, coupling reaction is carried out on the compound represented by formula SM1 and the compound represented by formula SM2 to obtain the compound represented by formula I;

[0026] ;

[0027] R1 is as defined in any embodiment of the present invention.

[0028] In one embodiment, in the coupling reaction, the polar organic solvent is an ether solvent or a sulfoxide solvent, preferably a sulfoxide solvent. The ether solvent is, for example, tetrahydrofuran, and the sulfoxide solvent is, for example, dimethyl sulfoxide.

[0029] In one embodiment, the coupling reaction is carried out in a protective gas, such as an inert gas (eg, nitrogen).

[0030] In one embodiment, the mass volume ratio of the compound represented by formula SM1 to the organic solvent is 100-200 g / L, preferably 100-150 g / L, preferably 137.5 g / L.

[0031] In one embodiment, the molar ratio of the compound represented by formula SM1 to the copper powder is 1:(1-10), for example 1:(2-4), preferably 1:2.3 or 1:6.

[0032] In one embodiment, the molar ratio of the compound represented by formula SM1 to the compound represented by formula SM2 is 1:(1-5), for example 1:(1.5-3), preferably 1:1.8 or 1:3.

[0033] In one embodiment, the coupling reaction temperature is 10-70°C, such as 30-40°C or 15-25°C, preferably 35°C or 20°C.

[0034] In one embodiment, the compound represented by formula SM2 is added under a protective gas atmosphere, such as nitrogen. The temperature for adding the compound represented by formula SM2 can be 30-40°C or 15-25°C, such as 35°C or 20°C.

[0035] The reaction progress of the coupling reaction can be monitored by conventional methods in the art, such as LCMS, and preferably the reaction endpoint is when the compound represented by the formula SM1 is no longer converted or the compound represented by the formula I is no longer generated. The reaction time can be 1-24 hours, such as 4 hours, 20 hours.

[0036] In one embodiment, the coupling reaction comprises the following post-treatment steps: after the reaction is completed, extraction (for example, the reaction solution is cooled to room temperature, quenched by adding ice water, and extracted with methyl tert-butyl ether), washing (for example, washing the organic phase with water), removing the solution (for example, concentrating the solution), and purification to obtain the compound represented by formula I.

[0037] In one embodiment, the coupling reaction comprises the following steps: in an atmosphere of protective gas (such as nitrogen), the compound represented by the formula SM2 is subjected to the coupling reaction with a mixture of the polar organic solvent, the copper powder and the compound represented by the formula SM1; after the reaction is completed, extraction, washing, removal of the solution, and purification are performed to obtain the compound represented by the formula I.

[0038] In one embodiment, the raw materials for the cyclization reaction are the compound represented by the formula SM1, the compound represented by the formula SM2, the polar organic solvent and the copper powder.

[0039] The present invention provides a method for preparing a compound of formula III, comprising the following steps: in an organic solvent, in the presence of a reducing agent, subjecting the compound of formula II to a reduction reaction to obtain a compound of formula III;

[0040] ;

[0041] R1 is C 1-6 Alkyl-OCO-;

[0042] The reducing agent is a borane compound, a borohydride and / or a metal hydride.

[0043] In one embodiment, the borane compound is borane (BH3).

[0044] In one embodiment, the borohydride is sodium borohydride.

[0045] In one embodiment, the metal hydride is lithium aluminum hydride.

[0046] In one embodiment, the organic solvent is an ether solvent, and the reducing agent is borane (BH3), sodium borohydride or lithium aluminum hydride.

[0047] In one embodiment, the organic solvent is an ether solvent, and the ether solvent is preferably tetrahydrofuran.

[0048] In one embodiment, in R1, the C 1-6 The alkyl group is methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl or tert-butyl, for example, R1 is tert-butyloxycarbonyl (Boc).

[0049] In one embodiment, the borane is used in the form of borane tetrahydrofuran reagent, preferably 0.5-1.1 mol / L (molar volume concentration based on borane) borane tetrahydrofuran reagent, for example 1 mol / L borane tetrahydrofuran reagent.

[0050] In one embodiment, the reduction reaction is carried out in a protective gas, such as an inert gas (eg, nitrogen).

[0051] In one embodiment, when the reducing agent is lithium aluminum hydride, the mass volume ratio of the compound represented by formula II to the organic solvent is 25-200 g / L, preferably 80-120 g / L, such as 30-80 g / L, and another example is 50 g / L.

[0052] In one embodiment, when the reducing agent is lithium aluminum hydride, the molar ratio of the reducing agent to the compound represented by formula II is 1:1-2:1, preferably 1.05:1-1.5:1, for example 1.1:1.

[0053] In one embodiment, when the reducing agent is lithium aluminum hydride, the temperature for adding the lithium aluminum hydride is 0-10°C, for example, 5°C.

[0054] In one embodiment, when the reducing agent is lithium aluminum hydride, the reaction temperature is room temperature (eg, 10-30° C.).

[0055] In one embodiment, when the reducing agent is lithium aluminum hydride, the method comprises the following post-treatment steps: after the reaction is completed, water and a base (for example, water, an aqueous NaOH solution and water) are added at 0-10° C., dried (for example, dried with anhydrous sodium sulfate), filtered, and washed (for example, washed with tetrahydrofuran) to obtain the compound represented by formula III.

[0056] In one embodiment, the compound represented by formula II is used in the form of an ether solution of the compound represented by formula II, and the ether solvent may be tetrahydrofuran. Preferably, the molar volume ratio of the compound represented by formula II and the ether solvent is (3-4.5):10 mol / L, for example 38.1:100 mol / L.

[0057] In one embodiment, the temperature of the ether solution of the compound represented by Formula II when added to the reduction reaction is 0°C.

[0058] In one embodiment, when the reducing agent is lithium aluminum hydride, the reduction reaction comprises the following steps: adding an ether solution of the compound represented by formula II to a mixture of the lithium aluminum hydride and the ether solvent in nitrogen, and carrying out the reduction reaction at room temperature. After the reaction is completed, water and alkali are added at 0-10°C, and the mixture is dried, filtered, and washed to obtain the compound represented by formula III.

[0059] In one embodiment, when the reducing agent is borane, the mass volume ratio of the compound represented by formula II to the organic solvent is 50-150 g / L, preferably 90-120 g / L, for example 100 g / L or 67.6 g / L.

[0060] In one embodiment, when the reducing agent is borane, the molar ratio of the compound represented by formula II to the reducing agent is (0.1-5):1, preferably (0.5-1.5):1, for example 0.8:1.

[0061] In one embodiment, when the reducing agent is borane, the reduction reaction is carried out by heating to reflux.

[0062] In one embodiment, when the reducing agent is borane, the following post-treatment steps are included: after the reaction is completed, the temperature is lowered, the reaction is quenched (for example, methanol is added to quench), concentrated, and purified to obtain a compound represented by formula III.

[0063] In a certain embodiment, when the reducing agent is borane, the reduction reaction comprises the following steps: adding the borane tetrahydrofuran solution to the compound represented by formula II and the ether solvent mixture, carrying out the reduction reaction under nitrogen protection, and after the reaction is completed, cooling, quenching the reaction, concentrating, and purifying to obtain the compound represented by formula III.

[0064] In one embodiment, when the reducing agent is sodium borohydride, the mass volume ratio of the compound represented by formula II to the organic solvent is 50-150 g / L, preferably 90-120 g / L, for example 100 g / L.

[0065] In one embodiment, when the reducing agent is sodium borohydride, the molar ratio of the compound represented by formula II to the reducing agent is 1:(1-10), preferably 1:(3-7), for example 1:5.

[0066] In one embodiment, when the reducing agent is sodium borohydride, the reduction reaction is carried out in the presence of an organic acid, such as trifluoroacetic acid.

[0067] In one embodiment, when the reducing agent is sodium borohydride, the reduction reaction is carried out by heating to reflux.

[0068] In one embodiment, when the reducing agent is sodium borohydride, the following post-treatment steps are included: after the reaction is completed, the temperature is lowered, the reaction is quenched (for example, by adding water), extracted (for example, by adding ethyl acetate for extraction), concentrated, and purified to obtain a compound represented by formula III.

[0069] In a certain embodiment, when the reducing agent is sodium borohydride, the reduction reaction comprises the following steps: adding the sodium borohydride to the compound represented by formula II and the ether solvent mixture, adding an organic acid, and carrying out the reduction reaction under nitrogen protection. After the reaction is completed, cooling, quenching the reaction, concentrating, and purifying to obtain the compound represented by formula III.

[0070] The progress of the reduction reaction can be monitored by conventional methods in the art, such as LCMS, and preferably the reaction endpoint is when the compound represented by formula II is no longer converted or the compound represented by formula III is no longer generated. The reaction time can be 1-24 hours, such as 4 hours or 16 hours.

[0071] In one embodiment, the raw materials for the reduction reaction are the ether solvent, the reducing agent and the compound represented by formula II.

[0072] In a certain embodiment, preferably, the method for preparing the compound represented by formula III further comprises the method for preparing the compound represented by formula II described in any embodiment of the present invention.

[0073] The present invention provides a method for preparing a compound of formula I, comprising the following steps: in a polar organic solvent, in the presence of copper powder, coupling a compound of formula SM1 with a compound of formula SM2 to obtain a compound of formula I;

[0074] ;

[0075] R1 is as defined in any embodiment of the present invention.

[0076] Preferably, the polar organic solvent is a sulfoxide solvent, such as DMSO.

[0077] Preferably, the coupling reaction temperature is 30-40°C or 15-25°C (eg 35°C or 20°C).

[0078] Preferably, in the coupling reaction, the polar organic solvent, the copper powder, the compound represented by formula SM1, the compound represented by formula SM2, and the reaction conditions and operation of the coupling reaction are as described in any embodiment of the present invention.

[0079] The present invention provides a compound represented by formula I;

[0080]

[0081] R1 is as defined in any embodiment of the present invention.

[0082] Preferably, the compound represented by formula I is .

[0083] The present invention provides a compound represented by formula II;

[0084]

[0085] R1 is as defined in any embodiment of the present invention.

[0086] Preferably, the compound represented by formula II is .

[0087] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0088] The reagents and raw materials used in the present invention are commercially available.

[0089] The positive progressive effect of the present invention is that the preparation method provided by the present invention has high reaction yield, high efficiency and good application prospect. DETAILED DESCRIPTION

[0090] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0091] Example 1 Preparation of Compound I:

[0092]

[0093] Condition 1:

[0094] 3-(Nitromethylene)azetidine-1-carboxylic acid tert-butyl ester (11 g, 51.5 mmol) and copper powder (7.5 g, 118.5 mmol) were dissolved in THF (80 mL). Under nitrogen protection, difluoroethyl bromoacetate (18.8 g, 92.5 mmol) was added dropwise at 35°C and reacted at 65°C for 20 hours. The reaction solution was cooled to room temperature, poured into ice water (100 mL), extracted with methyl tert-butyl ether (50 mL*2), the organic phases were combined, washed with water, concentrated to remove the solvent, and the crude product was purified by silica gel column chromatography to obtain compound I as a yellow oil (7.6 g, yield: 46%).

[0095] LCMS: M+1=339, 1H-NMR (400 MHz, CDCl3) δ ppm: 5.10 (s, 2H), 4.29 (q, J= 7.2 Hz, 2H), 4.20 (d, J = 9.7 Hz, 2H), 3.90 (d, J = 9.7 Hz, 2H), 1.46 (s,9H), 1.33 (t, J = 7.2 Hz, 3H).

[0096] Condition 2:

[0097] 3-(Nitromethylene)azetidine-1-carboxylic acid tert-butyl ester (11 g, 51.5 mmol) and copper powder (7.5 g, 119 mmol) were dissolved in DMSO (80 mL). Under nitrogen protection, difluoroethyl bromoacetate (18.8 g, 92.5 mmol) was added dropwise at 35°C and reacted at 35°C for 20 hours. The reaction solution was cooled to room temperature, poured into ice water (100 mL), extracted with methyl tert-butyl ether (50 mL*2), and the organic phases were combined, washed with water, and concentrated to remove the solvent to obtain compound I as a yellow oil (12.1 g, yield: 67%).

[0098] Condition 3:

[0099] 3-(Nitromethylene)azetidine-1-carboxylic acid tert-butyl ester (11 g, 51.5 mmol) and copper powder (19.63 g, 309 mmol) were dissolved in DMSO (80 mL). Under nitrogen protection, difluoroethyl bromoacetate (31.4 g, 154.4 mmol) was added dropwise at 35°C and reacted at 35°C for 4 hours. The reaction solution was cooled to room temperature, poured into ice water (100 mL), extracted with methyl tert-butyl ether (50 mL*2), and the organic phases were combined, washed with water, and concentrated to remove the solvent to obtain compound I as a yellow oil (15.3 g, yield: 85%).

[0100] Condition 4:

[0101] 3-(Nitromethylene)azetidine-1-carboxylic acid tert-butyl ester (11 g, 51.5 mmol) and copper powder (19.63 g, 309 mmol) were dissolved in DMSO (80 mL). Under nitrogen protection, difluoroethyl bromoacetate (31.4 g, 154.4 mmol) was added dropwise at 20°C and reacted at 20°C for 4 hours. The reaction solution was cooled to room temperature, poured into ice water (100 mL), extracted with methyl tert-butyl ether (50 mL*2), and the organic phases were combined, washed with water, and concentrated to remove the solvent to obtain compound I as a yellow oil (17.1 g, yield: 95%).

[0102] Condition 5:

[0103] 3-(Nitromethylene)azetidine-1-carboxylic acid tert-butyl ester (220 g, 1.03 mol) and copper powder (150 g, 2.37 mol) were dissolved in DMSO (1.6 L). Under nitrogen protection, difluoroethyl bromoacetate (376 g, 1.85 mol) was added dropwise at 20°C and reacted at 20°C for 4 hours. The reaction solution was cooled to room temperature, poured into 2 L of ice water, extracted with methyl tert-butyl ether (1 L*2), and the organic phases were combined, washed with water, and concentrated to remove the solvent to obtain compound I as a yellow oil (349 g, yield: 97%).

[0104] Example 2 Preparation of Compound II:

[0105]

[0106] Condition 1:

[0107] A solution of compound I (10.6 g, 31.4 mmol) in methanol (200 mL) was added to a high-pressure hydrogenation autoclave, and 5% palladium carbon (1 g) and triethylamine (3.2 g, 31.4 mmol) were added. After replacing the hydrogen, the mixture was reacted at 5 atm and 65 °C for 16 hours, and the reaction was monitored to be complete. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated to remove the solvent, ethyl acetate (100 mL) was added, and the mixture was washed with 1 mol / L hydrochloric acid, water, and saturated brine. The organic phase was dried and concentrated, and the crude product was purified by silica gel column chromatography to obtain compound II (6.17 g, yield 75%).

[0108] LCMS: M+1=263.

[0109] Condition 2:

[0110] A solution of compound I (10.6 g, 31.4 mmol) in methanol (200 mL) was added to a high-pressure hydrogenation autoclave, and 5% palladium carbon (1 g) and triethylamine (0.32 g, 3.14 mmol) were added. After replacing the hydrogen, the mixture was reacted at 65°C at 5 atm for 16 hours, and the reaction was monitored to be complete. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated to remove the solvent, ethyl acetate (100 mL) was added, and the mixture was washed with 1 mol / L hydrochloric acid, water, and saturated brine. The organic phase was dried and concentrated, and the crude product was purified by silica gel column chromatography to obtain compound II (1.07 g, yield 13%).

[0111] Condition 2:

[0112] A solution of compound I (10.6 g, 31.4 mmol) in methanol (200 mL) was added to a high-pressure hydrogenation autoclave, and 5% palladium carbon (1 g) and DBU (4.78 g, 31.4 mmol) were added. After replacing the hydrogen, the mixture was reacted at 50°C for 16 hours at 5 atm, and the reaction was monitored to be complete. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated to remove the solvent, ethyl acetate (100 mL) was added, and the mixture was washed with 1 mol / L hydrochloric acid, water, and saturated brine. The organic phase was dried and concentrated, and the crude product was purified by silica gel column chromatography to obtain compound II (6.94 g, yield 84%).

[0113] Condition 3:

[0114] A solution of compound I (10.6 g, 31.4 mmol) in methanol (200 mL) was added to a high-pressure hydrogenation autoclave, and 5% palladium carbon (1 g) and DBU (0.478 g, 3.14 mmol) were added. After replacing the hydrogen, the mixture was reacted at 50°C for 16 hours at 5 atm, and the reaction was monitored to be complete. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated to remove the solvent, ethyl acetate (100 mL) was added, and the mixture was washed with 1 mol / L hydrochloric acid, water, and saturated brine. The organic phase was dried and concentrated, and the crude product was purified by silica gel column chromatography to obtain compound II (6.99 g, yield 85%).

[0115] Condition 4:

[0116] A solution of compound I (10.6 g, 31.4 mmol) in methanol (200 mL) was added to a high-pressure hydrogenation autoclave, and 5% palladium carbon (1 g) and DBU (0.239 g, 1.57 mmol) were added. After replacing the hydrogen, the mixture was reacted at 50°C for 16 hours at 5 atm, and the reaction was monitored to be complete. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated to remove the solvent, ethyl acetate (100 mL) was added, and the mixture was washed with 1 mol / L hydrochloric acid, water, and saturated brine. The organic phase was dried and concentrated, and the crude product was purified by silica gel column chromatography to obtain compound II (6.95 g, yield 85%).

[0117] Condition 5:

[0118] A methanol (200 mL) solution of compound I (10.6 g, 31.4 mmol) was added to a high-pressure hydrogenation autoclave, and 5% palladium on carbon (1 g) was added. After replacing the hydrogen, the reaction was carried out at 50 °C under 5 atm for 16 hours. The reaction of the raw materials was monitored to be complete, and no obvious product was generated.

[0119] Condition 6:

[0120] A methanol (2 L) solution of compound I (213 g, 628 mmol) was added to a high-pressure hydrogenation reactor, and Raney nickel (20 g) and DBU (3.17 g, 31.4 mmol) were added. After replacing the hydrogen, the reaction was carried out at 50 ° C for 16 hours at 5 atm, and the reaction was monitored to be complete. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to remove the solvent. Ethyl acetate (2 L) was added, and the mixture was washed with 1 mol / L hydrochloric acid, water, and saturated brine. The organic phase was dried and concentrated to obtain compound II (153 g, yield 93%), which can be directly used in the next step.

[0121] LCMS: M+1=263.

[0122] Example 3 Synthesis of Compound III:

[0123]

[0124] Condition 1:

[0125] Lithium aluminum hydride (1.59 g, 41.9 mmol) was added to dry tetrahydrofuran (100 mL) under stirring, and the temperature was lowered to 0°C under nitrogen protection. A tetrahydrofuran solution (100 mL) of compound II (10 g, 38.1 mmol) was slowly added dropwise to the lithium aluminum hydride solution, keeping the temperature not exceeding 10°C. After the addition, the reaction was stirred at room temperature for 4 hours, and the reaction was complete by LCMS. The reaction solution was cooled, and water (1.59 g), 15% sodium hydroxide aqueous solution (1.59 g) and water (4.8 g) were added dropwise in sequence, and the temperature did not exceed 10°C. After the addition, it was stirred for 30 minutes, anhydrous sodium sulfate was added to dry, stirred for 1 hour, filtered, and the filter cake was rinsed with tetrahydrofuran. The filtrates were combined and concentrated to obtain compound III (7.6 g, yield 80%).

[0126] LCMS: M+1=249. 1 H-NMR (400 MHz, DMSO) δ 4.22 (d, J = 9.2 Hz, 2H), 3.75 (d, J = 9.2 Hz, 2H), 3.35 (s, 2H), 2.28 (t, J = 13.6 Hz, 2H), 1.50 (s, 9H).

[0127] Condition 2:

[0128] Under stirring, slowly add borane tetrahydrofuran (1M, 48.0 mL) solution to a tetrahydrofuran solution (100 mL) of compound II (10 g, 38.1 mmol). After the addition, reflux under nitrogen for 16 hours. LCMS detected that the reaction was complete. The reaction solution was cooled, methanol (10 mL) was added dropwise to quench, stirred for 30 minutes, concentrated, and the crude product was purified by silica gel column chromatography to obtain compound III (5.6 g, yield 59%).

[0129] LCMS: M+1=249.

[0130] Condition 3:

[0131] Sodium borohydride (7.19 g, 191 mmol) was added in batches to a tetrahydrofuran solution (100 mL) of compound II (10 g, 38.1 mmol) under stirring. After the addition, trifluoroacetic acid (17.3 g, 152 mmol) was added dropwise at room temperature under stirring. After the addition, the mixture was refluxed under nitrogen for 4 hours. The reaction was complete when detected by LCMS. The reaction solution was cooled, quenched by adding water (100 mL), extracted with ethyl acetate, dried and concentrated, and the crude product was purified by silica gel column chromatography to obtain compound III (4.8 g, yield 51%). LCMS: M+1=249.

Claims

1. A method for preparing a compound represented by formula II, characterized in that: The method comprises the following steps: in an organic solvent, in the presence of a catalyst, a base and hydrogen, subjecting the compound of formula I to a cyclization reaction to obtain a compound of formula II; ； R1 is C 1-6 Alkyl-O-CO-; The catalyst is a subgroup metal catalyst, and the base is an organic base.

2. The method for preparing the compound of formula II as claimed in claim 1, characterized in that: It meets one or more of the following conditions: (1) The organic solvent is an alcohol solvent, such as methanol; (2) The reaction pressure of the cyclization reaction is 2-7 atm, for example 5 atm; (3) In R1, the C 1-6 Alkyl is methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl or tert-butyl, for example, R1 is tert-butyloxycarbonyl; (4) The catalyst is a palladium catalyst and / or a nickel catalyst, such as palladium carbon or Raney nickel, and the palladium carbon is, for example, a 5% palladium carbon catalyst; (5) The organic base is an amine compound, preferably a bicyclic amidine compound, such as triethylamine, diisopropylethylamine or DBU; (6) The mass volume ratio of the compound represented by formula I to the organic solvent is 30-200 g / L, for example 40-110 g / L, preferably 100 g / L, 53 g / L or 106.5 g / L; (7) The mass ratio of the compound represented by formula I to the catalyst is (20-5):1, for example (15-8):1, preferably 10.6:1; (8) The cyclization reaction temperature is 45-80°C, for example 60-70°C, preferably 50°C or 65°C; (9) The raw materials for the cyclization reaction are the compound represented by formula I, the organic solvent, the catalyst, the base and the hydrogen; (10) The cyclization reaction preferably comprises the following post-treatment steps: after the reaction is completed, filtering, concentrating, adding an ester solvent, washing, and concentrating to obtain the compound represented by formula II, wherein the ester solvent is, for example, ethyl acetate.

3. The method for preparing the compound of formula II as claimed in claim 2, characterized in that: It meets one or more of the following conditions: (1) When the organic base is triethylamine or diisopropylethylamine, the molar ratio of the compound represented by formula I to the organic base is (0.5-6):1, for example (0.5-2):1, preferably 1:1; Alternatively, when the organic base is DBU, the molar ratio of the compound represented by formula I to the organic base is (0.1-25):1, for example (0.5-10):1, preferably 1:1, 20:1 or 10:1; (2) The cyclization reaction preferably comprises the following steps: in a hydrogen atmosphere at a reaction pressure of 2-7 atm, subjecting the compound represented by formula I, the organic solvent, the catalyst and the mixture of the organic base to the cyclization reaction; after the reaction is completed, filtering, concentrating, adding an ester solvent, washing and concentrating to obtain the compound represented by formula II.

4. The method for preparing the compound of formula II as claimed in claim 1, characterized in that: The preparation method of the compound represented by formula II further comprises the following steps: in a polar organic solvent, in the presence of copper powder, coupling reaction is performed on the compound represented by formula SM1 and the compound represented by formula SM2 to obtain the compound represented by formula I; ； R1 is as described in claim 1.

5. The method for preparing the compound of formula II as claimed in claim 4, characterized in that: It meets one or more of the following conditions: (1) The polar organic solvent is an ether solvent or a sulfoxide solvent, preferably a sulfoxide solvent, such as tetrahydrofuran, and such as dimethyl sulfoxide; (2) The coupling reaction is carried out in a protective gas, such as nitrogen; (3) The mass volume ratio of the compound represented by formula SM1 to the organic solvent is 100-200 g / L, preferably 100-150 g / L, for example 137.5 g / L; (4) The molar ratio of the compound represented by formula SM1 to the copper powder is 1:(1-10), preferably 1:(2-4), for example 1:2.3 or 1:6; (5) The molar ratio of the compound represented by formula SM1 to the compound represented by formula SM2 is 1:(1-5), preferably 1:(1.5-3), for example 1:1.8 or 1:3; (6) The coupling reaction temperature is 10-70°C, such as 30-40°C or 15-25°C, preferably 35°C or 20°C; (7) The addition of the compound represented by the formula SM2 is carried out under a protective gas atmosphere, such as nitrogen, and the addition temperature of the compound represented by the formula SM2 can be 30-40°C or 15-25°C, such as 35°C or 20°C; (8) The coupling reaction comprises the following post-treatment steps: after the reaction is completed, extraction, washing, removal of the solution, and purification to obtain the compound represented by formula I; (9) The coupling reaction comprises the following steps: in a protective gas atmosphere, subjecting the compound represented by the formula SM2 to the coupling reaction with a mixture of the polar organic solvent, the copper powder and the compound represented by the formula SM1, and after the reaction is completed, extracting, washing, removing the solution, and purifying to obtain the compound represented by the formula I; (10) The raw materials for the cyclization reaction are the compound represented by the formula SM1, the compound represented by the formula SM2, the polar organic solvent and the copper powder.

6. A method for preparing a compound represented by formula III, characterized in that: The method comprises the following steps: in an organic solvent, in the presence of a reducing agent, subjecting the compound represented by formula II to a reduction reaction to obtain a compound represented by formula III; ； R1 as claimed in claim 1 or 2; The reducing agent is a borane compound, a borohydride and / or a metal hydride.

7. The preparation method according to claim 6, characterized in that: It meets one or more of the following conditions: (1) The borane compound is borane; (2) The borohydride is sodium borohydride; (3) The metal hydride is lithium aluminum hydride; (4) The organic solvent is an ether solvent, and the ether solvent is preferably tetrahydrofuran; (5) The borane is preferably used in the form of a borane tetrahydrofuran reagent, preferably a 0.5-1.1 mol / L borane tetrahydrofuran reagent, such as a 1 mol / L borane tetrahydrofuran reagent; (6) The reduction reaction is carried out in a protective gas, such as nitrogen; (7) When the reducing agent is lithium aluminum hydride, the mass volume ratio of the compound represented by formula II to the organic solvent is 25-200 g / L, preferably 80-120 g / L, for example 30-80 g / L, and for example 50 g / L; (8) When the reducing agent is lithium aluminum hydride, the molar ratio of the reducing agent to the compound represented by formula II is 1:1-2:1, preferably 1.05:1-1.5:1, for example 1.1:1; (9) When the reducing agent is lithium aluminum hydride, the temperature for adding the lithium aluminum hydride is 0-10°C, for example, 5°C; (10) When the reducing agent is lithium aluminum hydride, the reaction temperature is room temperature; (11) When the reducing agent is lithium aluminum hydride, the method comprises the following post-treatment steps: after the reaction is completed, water and alkali are added at 0-10° C., and the mixture is dried, filtered, and washed to obtain the compound represented by formula III; (12) The compound of formula II is used in the form of an ether solution of the compound of formula II, wherein the ether solvent may be tetrahydrofuran, and preferably the molar volume ratio of the compound of formula II to the ether solvent is (3-4.5):10 mol / L, for example 38.1:100 mol / L; (13) The temperature of the ether solution of the compound represented by formula II when added to the reduction reaction is 0°C; (14) When the reducing agent is lithium aluminum hydride, the reduction reaction comprises the following steps: adding an ether solution of the compound represented by formula II to a mixture of the lithium aluminum hydride and the ether solvent in nitrogen, and carrying out the reduction reaction at room temperature. After the reaction is completed, adding water and alkali at 0-10°C, drying, filtering, and washing to obtain the compound represented by formula III.

8. The preparation method according to claim 6, characterized in that: It meets one or more of the following conditions: (1) When the reducing agent is borane, the mass volume ratio of the compound represented by formula II to the organic solvent is 50-150 g / L, preferably 90-120 g / L, for example 100 g / L or 67.6 g / L; Alternatively, when the reducing agent is sodium borohydride, the mass volume ratio of the compound represented by formula II to the organic solvent is 50-150 g / L, preferably 90-120 g / L, for example 100 g / L; (2) When the reducing agent is borane, the molar ratio of the compound represented by formula II to the reducing agent is (0.1-5):1, preferably (0.5-1.5):1, for example 0.8:1; Alternatively, when the reducing agent is sodium borohydride, the molar ratio of the compound represented by formula II to the reducing agent is 1:(1-10), preferably 1:(3-7), for example 1:5; (3) When the reducing agent is borane, the reduction reaction is heated to reflux; Alternatively, when the reducing agent is sodium borohydride, the reduction reaction is carried out by heating to reflux; (4) When the reducing agent is sodium borohydride, the reduction reaction is carried out in the presence of an organic acid, such as trifluoroacetic acid; (5) When the reducing agent is borane, the process comprises the following post-treatment steps: after the reaction is completed, cooling, quenching the reaction, concentrating, and purifying to obtain a compound represented by formula III; Alternatively, when the reducing agent is sodium borohydride, the method comprises the following post-treatment steps: after the reaction is completed, cooling, quenching the reaction, extracting, concentrating, and purifying to obtain a compound represented by formula III; (6) When the reducing agent is borane, the reduction reaction comprises the following steps: adding the borane tetrahydrofuran solution to a mixture of the compound represented by Formula II and an ether solvent, carrying out the reduction reaction under nitrogen protection, and after the reaction is completed, cooling, quenching the reaction, concentrating, and purifying to obtain a compound represented by Formula III; Alternatively, when the reducing agent is sodium borohydride, the reduction reaction comprises the following steps: adding the sodium borohydride to a mixture of the compound represented by formula II and an ether solvent, adding an organic acid, and performing the reduction reaction under nitrogen protection, cooling after the reaction, quenching the reaction, concentrating, and purifying to obtain a compound represented by formula III; (7) The raw materials for the reduction reaction are the ether solvent, the reducing agent and the compound represented by formula II; (8) The method for preparing the compound of formula III further comprises the following step: preparing the compound of formula II according to the method for preparing the compound of formula II as described in any one of claims 1 to 5.

9. A method for preparing a compound of formula I, characterized in that: The method comprises the following steps: in a polar organic solvent, in the presence of copper powder, coupling a compound represented by formula SM1 with a compound represented by formula SM2 to obtain a compound represented by formula I; ； R1 is as described in claim 1 or 2; the operation and reaction conditions of the coupling reaction are as described in any one of claims 4 or 5; Preferably, the polar organic solvent is a sulfoxide solvent, such as DMSO; and / or the coupling reaction temperature is 15-25°C, such as 20°C.

10. A compound of formula I or a compound of formula II; in, R1 as claimed in claim 1 or 2; Preferably, the compound represented by formula I is ; Preferably, the compound represented by formula II is .

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