A method for preparing 8,8-difluoro-2,6-diazaspiro[3.4]octane compounds

Abstract

The application provides a preparation method of 8,8-difluoro-2,6-diazaspiro[3.4]octane compounds. Specifically provided is a preparation method of a compound shown in formula II, which comprises the following steps: performing a cyclization reaction on a compound shown in formula I in an organic solvent under the action of a catalyst, in the presence of a base and hydrogen to obtain the compound shown in formula II, R1 is C 1‑6 alkyl-O-CO-, the catalyst is a secondary group metal catalyst, and the base is an organic base. The preparation method provided by the application has high yield and high efficiency, and has good application prospect.

Description

TECHNICAL FIELD

[0001] The application relates to a preparation method of 8,8-difluoro-2,6-diazaspiro[3.4]octane compounds. BACKGROUND

[0002] Spiral compounds have special physical and chemical properties due to their unique chemical structure. As a drug intermediate, spiral compounds have been widely used in the synthesis process 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 original molecules. Among them, fluorinated spiral compounds, especially in the field of medicinal chemistry, have attracted attention and become a popular 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, such as a molecular fragment used as an LRRK2 degrading agent in WO2022198112, a molecular fragment used as a KRAS G12D inhibitor in WO2022105855, and a molecular fragment used by AstraZeneca to synthesize KRAS G12C inhibitors in WO2022083569. However, there are few documents on the synthesis method of this segment. SUMMARY

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

[0006] The present application solves the above technical problems by the following technical solutions.

[0007] The present application provides a preparation method of a compound shown in formula II, which comprises the following steps: performing a cyclization reaction on a compound shown in formula I in an organic solvent in the presence of a catalyst, a base and hydrogen to obtain a compound shown in formula II.

[0008] ;

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

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

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

[0012] In one embodiment, the cyclization reaction is carried out at a pressure of 2-7 atm, such as 5 atm.

[0013] In one embodiment, R1is C(O)NR2R3, wherein R2and R3are each independently H or alkyl, such as methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl or t-butyl, such as t-butoxycarbonyl (Boc). 1-6 alkyl is methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl or t-butyl, such as R1is t-butoxycarbonyl (Boc).

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

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

[0016] In one embodiment, the mass to volume ratio of the compound of 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 of formula I to the catalyst is (20-5):1, such as (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 of formula I to the organic base is (0.5-6):1, such as (0.5-2):1, preferably 1:1.

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

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

[0021] The progress of the cyclization reaction can be monitored using conventional methods in the art, such as LCMS, preferably using the absence of further conversion of the compound of formula I or the absence of further production of the compound of formula II as the end point of the reaction. The reaction time can be 1-24 h, such as 16 h.

[0022] In one embodiment, the cyclization reaction comprises the following work-up procedure: after the reaction is completed, the reaction mixture is filtered (e.g. celite filtration), concentrated, an ester solvent (e.g. ethyl acetate) is added, and the mixture is washed (e.g. with hydrochloric acid, water, and saturated brine) and concentrated (preferably followed by purification on a silica gel column) to obtain the compound of formula II.

[0023] In one embodiment, the cyclization reaction comprises the following procedure: the mixture of the compound of formula I, the organic solvent, the catalyst, and the organic base is subjected to the cyclization reaction in the presence of hydrogen at a pressure of 2-7 atm, and after the reaction is completed, the reaction mixture is filtered (e.g. celite filtration), concentrated, an ester solvent is added, and the mixture is washed and concentrated to obtain the compound of formula II.

[0024] In one embodiment, the cyclization reaction comprises the following procedure: the mixture of the compound of formula I, the organic solvent, the catalyst, and the organic base is subjected to the cyclization reaction in the presence of hydrogen at a pressure of 2-7 atm, and after the reaction is completed, the reaction mixture is filtered (e.g. celite filtration), concentrated, an ester solvent is added, and the mixture is washed and concentrated to obtain the compound of formula II.

[0025] In one embodiment, the method for preparing the compound of formula II further comprises the following procedure: the compound of formula SM1 is coupled with the compound of formula SM2 in the presence of copper powder in a polar organic solvent to obtain the compound of formula I.

[0026] ;

[0027] R1is as defined in any one of the embodiments.

[0028] In one embodiment, the polar organic solvent in the coupling reaction is an ether solvent or a sulfoxide solvent, preferably a sulfoxide solvent, and 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, for example, an inert gas (e.g. nitrogen).

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

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

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

[0033] In one aspect, the coupling reaction is carried out at a temperature of 10-70 °C, such as 30-40 °C or 15-25 °C, preferably 35 °C or 20 °C.

[0034] In one aspect, the addition of the compound of formula SM2 is carried out under a protective atmosphere, such as nitrogen. The compound of formula SM2 can be added at a temperature of 30-40 °C or 15-25 °C, such as 35 °C or 20 °C.

[0035] The progress of the coupling reaction can be monitored by conventional methods in the art, such as LCMS, preferably with the end point of the reaction being no further conversion of the compound of formula SM1 or no further formation of the compound of formula I. The reaction time can be 1-24 h, such as 4 h, 20 h.

[0036] In one aspect, the coupling reaction comprises the following work-up steps after the reaction is completed: extraction (e.g. the reaction mixture is cooled to room temperature and quenched by addition to ice water, extraction with methyl tert-butyl ether), washing (e.g. the organic phase is washed with water), removal of the solution (e.g. the solution is concentrated), and purification to obtain the compound of formula I.

[0037] In one aspect, the coupling reaction comprises the following steps: the mixture of the compound of formula SM2, the polar organic solvent, the copper powder, and the compound of formula SM1 is subjected to the coupling reaction in a protective atmosphere (e.g. nitrogen), after which the reaction is extracted, washed, the solution is removed, and the compound of formula I is purified.

[0038] In one aspect, the starting materials for the cyclization reaction are the compound of formula SM1, the compound of formula SM2, the polar organic solvent, and the copper powder.

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

[0040] ;

[0041] R1is C 1-6 alkyl-OCO-;

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

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

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

[0045] In one aspect, 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 aluminium hydride.

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

[0048] In one embodiment, R1is C 1-6 alkyl is methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl or tert-butyl, for example R1is tert-butyloxycarbonyl (Boc).

[0049] In one embodiment, the borane is used as borane tetrahydrofuran reagent, preferably 0.5-1.1 mol / L (molar volume concentration of 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, for example an inert gas (e.g. nitrogen).

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

[0052] In one embodiment, when the reducing agent is lithium aluminium hydride, the molar ratio of the reducing agent to the compound of 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 aluminium hydride, the lithium aluminium hydride is added at a temperature of 0-10 °C, for example 5 °C.

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

[0055] In one embodiment, when the reducing agent is lithium aluminium hydride, the reaction is followed by a work-up procedure comprising adding water and a base (e.g. water, aqueous NaOH and water) at a temperature of 0-10 °C, drying (e.g. drying over anhydrous sodium sulphate) and filtering to obtain the compound of formula III.

[0056] In one embodiment, the compound of formula II is used as an ether solution of the compound of formula II, the ether solvent can be tetrahydrofuran, 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.

[0057] In one embodiment, the temperature at which the ether solution of the compound of Formula II is added to the reducing agent is 0 °C.

[0058] In one embodiment, when the reducing agent is lithium aluminum hydride, the reduction reaction comprises the steps of: adding the ether solution of the compound of Formula II to a mixture of lithium aluminum hydride and the ether solvent under nitrogen, and conducting the reduction reaction at room temperature. After the reaction is complete, water and base are added at 0-10 °C, and the compound of Formula III is obtained by drying, filtering, and washing.

[0059] In one embodiment, when the reducing agent is borane, the mass / volume ratio of the compound of 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 of 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 conducted with heating to reflux.

[0062] In one embodiment, when the reducing agent is borane, the reduction reaction comprises the steps of: adding the borane solution in tetrahydrofuran to a mixture of the compound of Formula II and the ether solvent, conducting the reduction reaction under nitrogen, and after the reaction is complete, cooling, quenching the reaction, concentrating, and purifying to obtain the compound of Formula III.

[0063] In one embodiment, when the reducing agent is borane, the reduction reaction comprises the steps of: adding the borane solution in tetrahydrofuran to a mixture of the compound of Formula II and the ether solvent, conducting the reduction reaction under nitrogen, and after the reaction is complete, cooling, quenching the reaction, concentrating, and purifying to obtain the compound of Formula III.

[0064] In one embodiment, when the reducing agent is sodium borohydride, the mass / volume ratio of the compound of 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 of 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 conducted in the presence of an organic acid, for example trifluoroacetic acid.

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

[0068] In one aspect, when the reducing agent is sodium borohydride, the method comprises the following post-treatment steps: after the reaction is completed, the reaction is quenched (e.g., by adding water), extracted (e.g., by adding ethyl acetate), concentrated, and purified to obtain the compound of formula III.

[0069] In one aspect, when the reducing agent is sodium borohydride, the method comprises the following steps: the sodium borohydride is added to the mixture of the compound of formula II and the ether solvent, an organic acid is added, and the reaction is carried out under nitrogen protection; after the reaction is completed, the reaction is quenched, concentrated, and purified to obtain the compound of formula III.

[0070] The progress of the reaction can be monitored by conventional methods in the art, such as LCMS, and preferably, the reaction is terminated when the compound of formula II is not converted or the compound of formula III is no longer generated. The reaction time can be 1-24 h, such as 4 h or 16 h.

[0071] In one aspect, the raw materials for the reaction are the ether solvent, the reducing agent, and the compound of formula II.

[0072] In one aspect, preferably, the method for preparing the compound of formula III further comprises the method for preparing the compound of formula II according to any aspect of the present application.

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

[0074] ;

[0075] R1is as defined in any aspect of the present application.

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

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

[0078] Preferably, in the coupling reaction, the polar organic solvent, the copper powder, the compound of formula SM1, the compound of formula SM2, the reaction conditions and operations of the coupling reaction are as described in any aspect of the present application.

[0079] The present application provides a compound of formula I;

[0080]

[0081] R1is as defined in any aspect of the application.

[0082] Preferably, the compound of Formula I is .

[0083] The application provides a compound of Formula II;

[0084]

[0085] R1is as defined in any aspect of the application.

[0086] Preferably, the compound of Formula II is .

[0087] Without departing from the common general knowledge, the above preferred conditions can be combined in any way, to give the various preferred embodiments of the application.

[0088] The reagents and materials used in the application are commercially available.

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

[0090] The application will be further described by way of examples, but the application is not limited to the examples. The experimental methods in the following examples, if not specified, are selected according to the conventional methods and conditions, or according to the instructions of the goods.

[0091] Example 1 Preparation of compound I:

[0092]

[0093] Condition 1:

[0094] tert-Butyl 3-(nitromethylidene)azetidine-1-carboxylate (11 g, 51.5 mmol) and copper powder (7.5 g, 118.5 mmol) were dissolved in THF (80 mL), and ethyl difluorobromoacetate (18.8 g, 92.5 mmol) was added dropwise under nitrogen protection at 35°C, and reacted at 65°C for 20 hours. The reaction liquid 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 in 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] tert-Butyl 3-(nitromethylidene)azetidine-1-carboxylate (11 g, 51.5 mmol) and copper powder (7.5 g, 119 mmol) were dissolved in DMSO (80 mL), and ethyl difluorobromoacetate (18.8 g, 92.5 mmol) was added dropwise at 35°C under nitrogen protection, 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), the organic phases were combined, washed with water, and the solvent was removed by concentration to obtain compound I as a yellow oil (12.1 g, yield: 67%).

[0098] Condition 3:

[0099] tert-Butyl 3-(nitromethylidene)azetidine-1-carboxylate (11 g, 51.5 mmol) and copper powder (19.63 g, 309 mmol) were dissolved in DMSO (80 mL), and ethyl difluorobromoacetate (31.4 g, 154.4 mmol) was added dropwise at 35°C under nitrogen protection, 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), the organic phases were combined, washed with water, and the solvent was removed by concentration to obtain compound I as a yellow oil (15.3 g, yield: 85%).

[0100] Condition 4:

[0101] tert-Butyl 3-(nitromethylidene)azetidine-1-carboxylate (11 g, 51.5 mmol) and copper powder (19.63 g, 309 mmol) were dissolved in DMSO (80 mL), and ethyl difluorobromoacetate (31.4 g, 154.4 mmol) was added dropwise at 20°C under nitrogen protection, 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), the organic phases were combined, washed with water, and the solvent was removed by concentration to obtain compound I as a yellow oil (17.1 g, yield: 95%).

[0102] Condition 5:

[0103] Compound I (220 g, 1.03 mol) and copper powder (150 g, 2.37 mol) were dissolved in DMSO (1.6 L), and ethyl difluorobromoacetate (376 g, 1.85 mol) was added dropwise under nitrogen protection at 20 °C, and reacted at 20 °C for 4 h. The reaction solution was cooled to room temperature, poured into 2 L of ice water, extracted with methyl tert-butyl ether (1 L*2), 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 kettle, 5% palladium-carbon (1 g) and triethylamine (3.2 g, 31.4 mmol) were added, and after replacement of hydrogen, the reaction was carried out at 5 atm at 65 °C for 16 h, and the reaction was monitored to completion. The reaction solution was filtered through celite, the filtrate was concentrated to remove the solvent, ethyl acetate (100 mL) was added, washed with 1 mol / L hydrochloric acid, washed with 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 kettle, 5% palladium-carbon (1 g) and triethylamine (0.32 g, 3.14 mmol) were added, and after replacement of hydrogen, the reaction was carried out at 5 atm at 65 °C for 16 h, and the reaction was monitored to completion. The reaction solution was filtered through celite, the filtrate was concentrated to remove the solvent, ethyl acetate (100 mL) was added, washed with 1 mol / L hydrochloric acid, washed with 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 kettle, 5% palladium on carbon (1 g) and DBU (4.78 g, 31.4 mmol) were added, after replacement of hydrogen, reaction was carried out at 5 atm for 16 hours at 50 °C, the reaction was monitored to be complete. The reaction solution was filtered through celite, the filtrate was concentrated to remove the solvent, ethyl acetate (100 mL) was added, washed with 1 mol / L hydrochloric acid, water, saturated brine, the organic phase was dried and concentrated, 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 kettle, 5% palladium on carbon (1 g) and DBU (0.478 g, 3.14 mmol) were added, after replacement of hydrogen, reaction was carried out at 5 atm for 16 hours at 50 °C, the reaction was monitored to be complete. The reaction solution was filtered through celite, the filtrate was concentrated to remove the solvent, ethyl acetate (100 mL) was added, washed with 1 mol / L hydrochloric acid, water, saturated brine, the organic phase was dried and concentrated, 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 kettle, 5% palladium on carbon (1 g) and DBU (0.239 g, 1.57 mmol) were added, after replacement of hydrogen, reaction was carried out at 5 atm for 16 hours at 50 °C, the reaction was monitored to be complete. The reaction solution was filtered through celite, the filtrate was concentrated to remove the solvent, ethyl acetate (100 mL) was added, washed with 1 mol / L hydrochloric acid, water, saturated brine, the organic phase was dried and concentrated, the crude product was purified by silica gel column chromatography to obtain compound II (6.95 g, yield 85%).

[0117] Condition 5:

[0118] A solution of compound I (10.6 g, 31.4 mmol) in methanol (200 mL) was added to a high-pressure hydrogenation kettle, 5% palladium on carbon (1 g) was added, after replacement of hydrogen, reaction was carried out at 5 atm for 16 hours at 50 °C, the reaction was monitored to be complete. The reaction solution was filtered through celite, the filtrate was concentrated to remove the solvent, ethyl acetate (100 mL) was added, washed with 1 mol / L hydrochloric acid, water, saturated brine, the organic phase was dried and concentrated, the crude product was purified by silica gel column chromatography to obtain compound II (6.94 g, yield 84%).

[0119] Condition 6:

[0120] A solution of compound I (213 g, 628 mmol) in methanol (2 L) was added to a high pressure hydrogenation vessel, Raney nickel (20 g) and DBU (3.17 g, 31.4 mmol) were added, and the reaction was stirred at 50 °C under 5 atm of hydrogen for 16 h after purging with hydrogen. The reaction was monitored for completion. The reaction was filtered through celite, and the filtrate was concentrated to remove the solvent. Ethyl acetate (2 L) was added, and the mixture was washed with 1 M HC1, water, and saturated brine. The organic layer was dried and concentrated to give compound II (153 g, 93% yield), which was used directly 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) with stirring under nitrogen protection, and the temperature was lowered to 0 °C. A solution of compound II (10 g, 38.1 mmol) in tetrahydrofuran (100 mL) was added slowly to the lithium aluminum hydride solution, keeping the temperature below 10 °C. After the addition was complete, the reaction was stirred at room temperature for 4 h, and LCMS was used to monitor the reaction. The reaction was cooled, and water (1.59 g), 15% aqueous sodium hydroxide (1.59 g), and water (4.8 g) were added sequentially, keeping the temperature below 10 °C. After the addition was complete, the mixture was stirred for 30 min, dried with anhydrous sodium sulfate, stirred for 1 h, filtered, and the filter cake was washed with tetrahydrofuran. The filtrates were combined and concentrated to give compound III (7.6 g, 80% yield).

[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] To a solution of compound II (10 g, 38.1 mmol) in tetrahydrofuran (100 mL) was added dropwise a solution of borane tetrahydrofuran (1 M, 48.0 mL) slowly under stirring. After addition, the reaction was refluxed under nitrogen for 16 hours, which was monitored by LCMS. The reaction was cooled and quenched by dropwise addition of methanol (10 mL), which was stirred for 30 minutes. The reaction mixture was concentrated and the crude product was purified by silica gel column chromatography to give compound III (5.6 g, yield 59%).

[0129] LCMS: M+1 = 249.

[0130] Condition 3:

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

Claims

1. A method for preparing a compound of formula II, characterized in that, It includes the following steps: in an organic solvent, in the presence of a catalyst, base and hydrogen, the compound shown in Formula I undergoes a cyclization reaction to obtain the compound shown in Formula II; ； R1 is C 1-6 Alkyl-O-CO-; The alkali is an organic alkali; The catalyst is a palladium catalyst and / or a nickel catalyst, and the organic base is DBU.

2. The method for preparing the compound of formula II as described in claim 1, characterized in that, It satisfies one or more of the following conditions: (1) The organic solvent is an alcohol solvent; (2) The reaction pressure of the cyclization reaction is 2-7 atm; (3) In R1, the C 1-6 The alkyl group is methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, or tert-butyl; (4) The catalyst is palladium on carbon or Raney nickel; (5) The mass-to-volume ratio of the compound shown in Formula I to the organic solvent is 30-200 g / L; (6) The mass ratio of the compound shown in Formula I to the catalyst is (20-5):1; (7) The cyclization reaction temperature is 45-80℃.

3. The method for preparing the compound of formula II as described in claim 2, characterized in that, It satisfies one or more of the following conditions: (1) The alcohol solvent is methanol; (2) The reaction pressure of the cyclization reaction is 5 atm; (3) R1 is tert-butyloxycarbonyl; (4) The palladium on carbon is a 5% palladium on carbon catalyst; (5) The mass-to-volume ratio of the compound shown in Formula I to the organic solvent is 40-110 g / L; (6) The mass ratio of the compound shown in Formula I to the catalyst is (15-8):1; (7) The cyclization reaction temperature is 60-70℃.

4. The method for preparing the compound represented by Formula II as described in claim 2, characterized in that, It satisfies one or more of the following conditions: (1) The mass-to-volume ratio of the compound shown in Formula I to the organic solvent is 100 g / L, 53 g / L or 106.5 g / L; (2) The mass ratio of the compound shown in Formula I to the catalyst is 10.6:1; (3) The cyclization reaction temperature is 50℃ or 65℃.

5. The method for preparing the compound of formula II as described in claim 1, characterized in that, The cyclization reaction includes the following post-processing steps: after the reaction is completed, the mixture is filtered, concentrated, an ester solvent is added, washed, and concentrated to obtain the compound shown in Formula II, wherein the ester solvent is ethyl acetate.

6. The method for preparing the compound of formula II as described in claim 1, characterized in that, When the organic base is DBU, the molar ratio of the compound shown in Formula I to the organic base is (0.1-25):

1.

7. The method for preparing the compound represented by Formula II as described in claim 6, characterized in that, When the organic base is DBU, the molar ratio of the compound shown in Formula I to the organic base is (0.5-10):

1.

8. The method for preparing the compound represented by Formula II as described in claim 6, characterized in that, When the organic base is DBU, the molar ratio of the compound shown in Formula I to the organic base is 1:1, 20:1, or 10:

1.

9. The method for preparing the compound of formula II as described in claim 1, characterized in that, The cyclization reaction comprises the following steps: in a hydrogen atmosphere, at a reaction pressure of 2-7 atm, a mixture of the compound shown in Formula I, the organic solvent, the catalyst, and the organic base is subjected to the cyclization reaction. After the reaction is completed, the mixture is filtered, concentrated, an ester solvent is added, washed, and concentrated to obtain the compound shown in Formula II.

10. The method for preparing the compound of formula II as described in claim 1, characterized in that, The preparation method of the compound shown in Formula II further includes the following steps: in a polar organic solvent, in the presence of copper powder, the compound shown in Formula SM1 and the compound shown in Formula SM2 are coupled to obtain the compound shown in Formula I. ； R1 is as described in claim 1.

11. The method for preparing the compound represented by Formula II as described in claim 10, characterized in that, It satisfies one or more of the following conditions: (1) The polar organic solvent is an ether solvent or a sulfoxide solvent; (2) The coupling reaction is carried out in a protective gas, namely nitrogen; (3) The mass-to-volume ratio of the compound represented by formula SM1 to the polar organic solvent is 100-200 g / L; (4) The molar ratio of the compound shown in formula SM1 to the copper powder is 1:(1-10). (5) The molar ratio of the compound shown in formula SM1 to the compound shown in formula SM2 is 1:(1-5); (6) The coupling reaction temperature is 10-70℃; (7) The compound shown in formula SM2 is added under a protective atmosphere, and the protective atmosphere is nitrogen.

12. The method for preparing the compound of formula II as described in claim 10, characterized in that, The coupling reaction includes the following post-processing steps: after the reaction is completed, extraction, washing, removal of solution, and purification are performed to obtain the compound shown in Formula I.

13. The method for preparing the compound represented by Formula II as described in claim 10, characterized in that, The coupling reaction comprises the following steps: in a protective atmosphere, the compound represented by formula SM2 is subjected to the coupling reaction with a mixture of the polar organic solvent, the copper powder and the compound represented by formula SM1. After the reaction is completed, the mixture is extracted, washed, the solution is removed, and purified to obtain the compound represented by formula I.

14. The method for preparing the compound of formula II as described in claim 11, characterized in that, It satisfies one or more of the following conditions: (1) The polar organic solvent is a sulfoxide solvent; (2) The mass-to-volume ratio of the compound represented by formula SM1 to the polar organic solvent is 100-150 g / L; (3) The molar ratio of the compound shown in formula SM1 to the copper powder is 1:(2-4); (4) The molar ratio of the compound shown in formula SM1 to the compound shown in formula SM2 is 1:(1.5-3). (5) The coupling reaction temperature is 30-40℃ or 15-25℃; (6) The compound shown in formula SM2 is added at a temperature of 30-40℃ or 15-25℃.

15. The method for preparing the compound of formula II as described in claim 11, characterized in that, It satisfies one or more of the following conditions: (1) The ether solvent is tetrahydrofuran; (2) The sulfoxide solvent is dimethyl sulfoxide; (3) The mass-to-volume ratio of the compound represented by formula SM1 to the polar organic solvent is 137.5 g / L; (4) The molar ratio of the compound represented by formula SM1 to the copper powder is 1:2.3 or 1:6; (5) The molar ratio of the compound shown in formula SM1 to the compound shown in formula SM2 is 1:1.8 or 1:3; (6) The coupling reaction temperature is 35℃ or 20℃; (7) The compound shown in formula SM2 is added at a temperature of 35°C or 20°C.

16. A method for preparing a compound of Formula III, characterized in that, It includes the following steps: The compound shown in Formula II is prepared by the method for preparing the compound shown in Formula II according to any one of claims 1-15; In an organic solvent, in the presence of a reducing agent, the compound shown in Formula II is reduced to obtain the compound shown in Formula III; ； R1 is as described in any one of claims 1-3; The reducing agent is a borane compound, a borohydride, and / or a metal hydride.

17. The preparation method according to claim 16, characterized in that, It satisfies one or more of the following conditions: (1) The borane compound is a borane; (2) The borohydride is sodium borohydride; (3) The metal hydride is lithium aluminum hydride; (4) The organic solvent is an ether solvent; (5) The reduction reaction is carried out in a protective gas.

18. The preparation method according to claim 17, characterized in that, It satisfies one or more of the following conditions: (1) When the reducing agent is lithium aluminum hydride, the mass-to-volume ratio of the compound shown in Formula II to the organic solvent is 25-200 g / L; (2) When the reducing agent is lithium aluminum hydride, the molar ratio of the reducing agent to the compound shown in Formula II is 1:1-2:1; (3) When the reducing agent is lithium aluminum hydride, the lithium aluminum hydride is added at a temperature of 0-10℃; (4) When the reducing agent is lithium aluminum hydride, the reaction temperature is room temperature.

19. The preparation method according to claim 17, characterized in that, When the reducing agent is lithium aluminum hydride, the following post-processing steps are included: after the reaction is completed, water and alkali are added at 0-10°C, the mixture is dried, filtered, and washed to obtain the compound shown in Formula III.

20. The preparation method according to claim 16, characterized in that, The compound represented by Formula II is used in the form of an ether solution of the compound represented by Formula II.

21. The preparation method according to claim 20, characterized in that, The temperature at which the ether solution of the compound shown in Formula II is added to the reduction reaction is 0°C.

22. The preparation method according to claim 17, characterized in that, It satisfies one or more of the following conditions: (1) The ether solvent is tetrahydrofuran; (2) The borane is used in the form of a 0.5-1.1 mol / L boranetetrahydrofuran reagent; (3) The reduction reaction is carried out in nitrogen.

23. The preparation method according to claim 17, characterized in that, It satisfies one or more of the following conditions: (1) When the reducing agent is lithium aluminum hydride, the mass-to-volume ratio of the compound shown in Formula II to the organic solvent is 80-120 g / L; (2) When the reducing agent is lithium aluminum hydride, the molar ratio of the reducing agent to the compound shown in Formula II is 1.05:1-1.5:1; (3) When the reducing agent is lithium aluminum hydride, the lithium aluminum hydride is added at a temperature of 5°C.

24. The preparation method according to claim 20, characterized in that, The compound represented by Formula II is used in the form of an ether solution of the compound represented by Formula II, wherein the ether solvent is tetrahydrofuran.

25. The preparation method according to claim 20, characterized in that, The compound shown in Formula II is used in the form of an ether solution of the compound shown in Formula II, wherein the molar volume ratio of the compound shown in Formula II to the ether solvent is (3-4.5):10 mol / L.

26. The preparation method according to claim 17, characterized in that, The borane is used in the form of a 1 mol / L boranetetrahydrofuran reagent.

27. The preparation method according to claim 17, characterized in that, It satisfies one or more of the following conditions: (1) When the reducing agent is lithium aluminum hydride, the mass-to-volume ratio of the compound shown in Formula II to the organic solvent is 30-80 g / L; (2) When the reducing agent is lithium aluminum hydride, the molar ratio of the reducing agent to the compound shown in Formula II is 1.1:

1.

28. The preparation method according to claim 20, characterized in that, The compound represented by Formula II is used in the form of an ether solution of the compound represented by Formula II, wherein the molar volume ratio of the compound represented by Formula II to the ether solvent is 38.1:100 mol / L.

29. The preparation method according to claim 17, characterized in that, When the reducing agent is lithium aluminum hydride, the mass-to-volume ratio of the compound represented by Formula II to the organic solvent is 50 g / L.

30. The preparation method according to claim 17, characterized in that, It satisfies one or more of the following conditions: (1) When the reducing agent is borane, the mass-to-volume ratio of the compound of formula II to the organic solvent is 50-150 g / L; Alternatively, when the reducing agent is sodium borohydride, the mass-to-volume ratio of the compound represented by Formula II to the organic solvent is 50-150 g / L; (2) When the reducing agent is borane, the molar ratio of the compound shown in Formula II to the reducing agent is (0.1-5):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). (3) When the reducing agent is borane, the reduction reaction is carried out by heating 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.

31. The preparation method according to claim 30, characterized in that, It satisfies one or more of the following conditions: (1) When the reducing agent is borane, the mass-to-volume ratio of the compound of formula II to the organic solvent is 90-120 g / L; Alternatively, when the reducing agent is sodium borohydride, the mass-to-volume ratio of the compound of Formula II to the organic solvent is 90-120 g / L; (2) When the reducing agent is borane, the molar ratio of the compound shown in Formula II to the reducing agent is (0.5-1.5):1; Alternatively, when the reducing agent is sodium borohydride, the molar ratio of the compound shown in Formula II to the reducing agent is 1:(3-7). (3) When the reducing agent is sodium borohydride, the reduction reaction is carried out in the presence of an organic acid, which is trifluoroacetic acid.

32. The preparation method according to claim 30, characterized in that, It satisfies one or more of the following conditions: (1) When the reducing agent is borane, the mass-to-volume ratio of the compound of formula II to the organic solvent is 100 g / L or 67.6 g / L; Alternatively, when the reducing agent is sodium borohydride, the mass-to-volume ratio of the compound represented by Formula II to the organic solvent is 100 g / L; (2) When the reducing agent is borane, the molar ratio of the compound shown in Formula II to the reducing agent is 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 1:5.

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