Preparation method and intermediate of compound with anti-androgen receptor activity

Abstract

The invention provides a method for preparing a compound shown in a formula (I), which comprises the following steps: 1) reacting a compound III with a compound IV to obtain a compound II; and 2) the compound II is subjected to an oxidation reaction to obtain a compound I, and the reaction formula is shown in the specification. The method can be used for preparing a series of compounds with anti-androgen receptor activity, and is suitable for large-scale production. The invention also provides an intermediate compound III and a compound II.

Description

[0001] The present invention claims priority from a prior application filed on March 29, 2024, entitled “A method for preparing a compound having anti-androgen receptor activity and its intermediates” and application number 202410376345.0. The contents of the above-mentioned prior application are incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of medicinal chemistry, and in particular relates to a method for preparing a compound having anti-androgen receptor activity. Background Art

[0003] Androgen receptor is a ligand-dependent trans-transcriptional regulatory protein that is widely distributed in various tissues of the body and participates in various physiological regulatory functions of androgens. Its relationship with diseases has become an increasingly hot topic of research.

[0004] The action of androgens on androgen receptors is associated with many diseases or conditions, such as androgen-dependent cancers, female virilization, and acne. Compounds that reduce the signaling effects of androgens through androgen receptors and / or reduce androgen receptor concentrations are useful in treating diseases or conditions in which androgen receptors play a role.

[0005] CN116969828A discloses a compound with anti-androgen receptor activity (as shown in Formula I), and also provides a method for preparing the compound, which has high cost and very low yield.

[0006]

[0007] Therefore, it is of great significance to develop a preparation method with high yield and suitable for industrial application. Summary of the Invention

[0008] The purpose of the present invention is to provide a method for preparing a compound (Formula I) having anti-androgen receptor activity and an intermediate compound thereof.

[0009] The present invention provides the following technical solutions:

[0010] A method for preparing compound I, comprising the following steps:

[0011] 1) Compound III reacts with compound IV to obtain compound II,

[0012] 2) Compound II is subjected to oxidation reaction to obtain compound I,

[0013] The reaction formula is as follows:

[0014]

[0015] Wherein, R1, R2, R3, and R4 are independently selected from substituted or unsubstituted C 1-12 Alkyl, preferably substituted or unsubstituted C 1-6 Alkyl; when a substituent is present, the substituent is one or more, independently selected from deuterium, halogen, *=O, hydroxyl, amino, C 1-12 Alkyl, C 1-12 Alkoxy, etc.

[0016] For example, R1, R2, R3, and R4 are independently selected from methyl, ethyl, propyl, isopropyl, butyl, deuterated methyl, deuterated ethyl, and deuterated propyl, wherein the deuterated group represents that one, two, three or more hydrogen atoms are replaced by deuterium atoms; more preferably, R1, R2, R3, and R4 independently represent methyl or deuterated methyl (CD3).

[0017] represents a substituted or unsubstituted ring system as follows: C 3-20 Cycloalkyl, C 4-20 Cycloalkenyl, 3-20 membered heterocyclic ring, C 3-20 Cycloalkyl and C 3-20 Spirocyclic rings formed by connecting cycloalkyl groups, C 3-20 A spiro ring formed by connecting a cycloalkyl group and a 3-20-membered heterocyclic group, or a spiro ring formed by connecting a 3-20-membered heterocyclic group and a 3-20-membered heterocyclic group; preferably, represents a substituted or unsubstituted 3-7 membered carbocyclic or heterocyclic ring, or a spirocyclic ring formed by connecting a 3-7 membered carbocyclic or heterocyclic ring to a 3-7 membered carbocyclic or heterocyclic ring; when a substituent is present, the substituent is one or more independently selected from deuterium, halogen, Hydroxyl, amino, C 1-12 Alkyl or cycloalkyl, etc.

[0018] Preferably, Can be selected from the following groups: More preferably, Can be selected from the following groups:

[0019] In some embodiments, Compound 1 is selected from the following compounds:

[0020]

[0021] Preferably, compound I is selected from the following compounds:

[0022]

[0023] More preferably, compound I is selected from the following compounds:

[0024]

[0025] In some embodiments, in step 1), the reaction is carried out in the presence of a non-nucleophilic base reagent, and the non-nucleophilic base reagent is selected from one of lithium bistrimethylsilylamide (LHMDS), lithium diisopropylamide (LDA), sodium bistrimethylsilylamide (NaHMDS), potassium bistrimethylsilylamide (KHMDS), magnesium diisopropylamide, and potassium diisopropylamide, preferably LDA or LHMDS.

[0026] In some embodiments, in step 1), the reaction is carried out in the presence of a Lewis acid and a base, wherein the Lewis acid is selected from titanium tetrachloride, boron trifluoride, trifluoromethyl lanthanum sulfate, diphenyl trifluoroacetate, aluminum trichloride, ferric chloride, zinc chloride, magnesium bromide, and the like; preferably, the Lewis acid is titanium tetrachloride and / or zinc chloride. The base is selected from triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]-5-nonene (DBN), pyridine, 4-dimethylaminopyridine, N-methylmorpholine, tetramethylethylenediamine, and the like; preferably, the base is triethylamine or pyridine. Further optionally, the reaction is carried out in the presence of a Lewis acid, a base, and an organosilicon reagent. The organosilicon reagent may be trimethylchlorosilane (TMSCl), trimethylsilyl trifluoromethanesulfonate (TMSOTf), and the like.

[0027] In some embodiments, in step 2), the oxidant of the oxidation reaction is selected from Dess-Martin periodinane (DMP), 2-iodoacetylbenzoic acid (IBX), iodobenzene diacetate, Jones reagent, PCC reagent, PDC reagent, chromium trioxide, peroxide, etc. Preferably, the oxidant is selected from DMP, IBX, PCC.

[0028] The present invention further provides a method for preparing compound VII and compound III.

[0029] The present invention provides a method for preparing compound VII, comprising the following steps:

[0030] 1) Compound VIIa is subjected to halogenation reaction to obtain compound VIIb,

[0031] 2) Compound VIIb reacts with metal Mg to obtain compound VIIc,

[0032] 3) Compound VIc reacts with compound VId to obtain compound VI.

[0033] The reaction formula is as follows:

[0034]

[0035] Wherein, X represents a halogen selected from Br, Cl, and I; R6 represents a group that is easily reacted with a Grignard reagent and leaves, for example, R6 can be Preferably, R6 is selected from etc., more preferably, R6 is

[0036] Wherein, R7 can be substituted at any position of the benzene ring, wherein R7 is selected from H, D, halogen, hydroxyl, amino, C 1-12 Alkyl, C 1-12 Alkoxy, deuterated C 1-12 Alkyl, deuterated C 1-12 Alkoxy; preferably, R7 can be substituted at one or more positions on the benzene ring, wherein R7 is selected from H, D, C 1-4 Alkyl, C 1-4 Alkoxy, deuterated C 1-4 Alkyl, deuterated C 1-4 Alkoxy.

[0037] In some embodiments, in step 1), the halogenating agent of the halogenation reaction is selected from N-bromosuccinimide (NBS), bromine, N-chlorosuccinimide (NCS), trimethylchlorosilane, N-chloroisopropylamine, N-iodosuccinimide (NIS), I2, etc., preferably NBS, NCS, NIS, I2; more preferably NBS.

[0038] Furthermore, the present invention provides a method for preparing compound III, comprising the steps of:

[0039] 1) Compound IIIa is subjected to halogenation reaction to obtain compound IIIb,

[0040] 2) Compound IIIb reacts with metal Mg to obtain compound IIIc,

[0041] 3) Compound IIIc reacts with compound V to produce compound III.

[0042] The reaction formula is as follows:

[0043]

[0044] Among them, R1, R2, The definitions are as described above; X represents a halogen selected from Br, Cl, I; R6 represents a group that is easily reacted with a Grignard reagent and leaves, for example, R6 can be Preferably, R6 is selected from etc., preferably, R6 is The halogenation reagent is the same as described above.

[0045] In some embodiments, the method for preparing Compound V comprises the steps of:

[0046] 1) Compound Va is subjected to chlorination reaction to obtain compound Vb,

[0047] 2) Compound Vb and compound VI undergo condensation reaction to obtain compound V,

[0048] The reaction formula is as follows:

[0049]

[0050] in, R6 is defined as above.

[0051] The present invention also provides a method for preparing compound IV, comprising the steps of:

[0052] 1) Compound IVa is subjected to chlorination reaction to obtain compound IVb,

[0053] 2) Compound IVb reacts with compound VI to obtain compound IVc,

[0054] 3) Compound IVc is subjected to reduction reaction to obtain compound IV,

[0055]

[0056] R3, R4, and R6 are as defined above.

[0057] In some embodiments, in step 1), the chlorination agent for the chlorination reaction can be selected from thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, preferably thionyl chloride;

[0058] In some embodiments, in step 3), the reaction is carried out under the action of a reducing agent, which can be selected from lithium aluminum hydride, sodium borohydride, potassium borohydride, and diisobutylaluminum hydride, preferably lithium aluminum hydride.

[0059] The present invention also provides a method for preparing Compound I, comprising the steps of:

[0060] 1) Compound IIIa reacts in the presence of NBS to obtain compound IIIb,

[0061] 2) Compound IIIb reacts with metal Mg to obtain compound IIIc,

[0062] 3) Compound IIIc reacts with compound V to produce compound III.

[0063] 4) Compound III reacts with compound IV to obtain compound II,

[0064] 5) Compound II is subjected to oxidation reaction to obtain compound I,

[0065] The reaction formula is as follows:

[0066]

[0067] The present invention also provides intermediate compounds for preparing compound I, including intermediate compound II and intermediate compound III.

[0068] Specifically, the present invention provides an intermediate compound II,

[0069]

[0070] Among them, R1, R2, R3, R4, The definitions are as above.

[0071] In some embodiments, compound II is selected from the following compounds:

[0072]

[0073] Preferably, compound II is selected from the following compounds:

[0074]

[0075] More preferably, compound II is selected from the following compounds:

[0076]

[0077] Specifically, the present invention also provides an intermediate compound III,

[0078]

[0079] Among them, R1, R2, Definitions are the same as above.

[0080] In some embodiments, compound III is selected from the following compounds:

[0081]

[0082] Preferably, compound III is selected from the following compounds:

[0083]

[0084] More preferably, compound III is selected from the following compounds:

[0085]

[0086] The present invention also provides the use of Compound II and / or Compound III in preparing Compound I having anti-androgen receptor activity.

[0087] The present invention provides Compound III and Compound II, important intermediates of Compound I, and methods for preparing Compound III and Compound II. Furthermore, the present invention provides the use of the intermediates Compound II and Compound IV in the preparation of Compound V, which has anti-androgen receptor activity. Furthermore, the method for preparing Compound I provided by the present invention has the advantages of being environmentally friendly, convenient post-processing, low cost, high yield, and suitability for industrial production applications.

[0088] Another aspect of the present invention provides a method for preparing Compound VII. Compound VII is an important organic synthesis intermediate, for example, it can be used to synthesize curcumin, curcumin analogs, or curcumin derivatives. Compound VII contains a double bond and a carbonyl structure and is of great value in the field of organic synthesis. Compared with the prior art, the method for preparing Compound VII provided by the present invention has the advantages of simple operation, high yield, low by-products, simple purification, and wide substrate applicability. DETAILED DESCRIPTION

[0089] The present invention is described in detail below by way of examples. The methods in the examples are for illustrative purposes only and do not constitute any limitation of the present invention. Unless otherwise specified, the materials used in the examples are commercially available or can be prepared by theories known in the art or by reference to known methods. In the examples, the completion of the reaction was monitored by HPLC, and the mass percentage of the compound was obtained by area normalization. Unless otherwise specified, the percentages of the solutions used in the examples are all the mass percentages of the solutes contained.

[0090] Example 1: Preparation of Compound V-6

[0091]

[0092] Method 1: Stir 4,4-difluorocyclohexanecarboxylic acid (Va-6, 70.5 g, 429 mmol), dichloromethane (210 ml) and DMF (2 g) at 0-5°C, add dropwise a dichloromethane solution (70 ml) of thionyl chloride (68.4 g, 575 mmol), and react at room temperature for 3 h. Concentrate the reaction solution to obtain crude compound Vb-6.

[0093] N,O-dimethylhydroxylamine hydrochloride (46.1 g, 472 mmol) was added to dichloromethane (280 ml), and triethylamine (95.5 g, 944 mmol) was added with stirring. The temperature was lowered to 10°C, and a dichloromethane solution (70 ml) of crude compound Vb-6 was added dropwise, maintaining the temperature below 20°C. After the addition was complete, the mixture was stirred at room temperature for 3-4 hours. Water and 3M hydrochloric acid were added to adjust the pH to 3-4. After separation, the organic phase was washed with sodium bicarbonate solution and concentrated to obtain compound V-6 (86.4 g) with a yield of 97.1%.

[0094] Method 2: Referring to the above method, thionyl chloride was replaced with an equal molar amount of oxalyl chloride to prepare compound V-6 (84.6 g) with a yield of 95.1%.

[0095] Referring to the above method 1, N,O-dimethylhydroxylamine hydrochloride was replaced with an equimolar amount of azetidine hydrochloride (44.1 g, 472 mmol) to obtain the compound azetidin-1-yl (4,4-difluorocyclohexyl)methanone (79.6 g) with a yield of 83.0%.

[0096] Example 2: Preparation of Compound III-6

[0097]

[0098] Method 1: Dissolve compound IIIa-6 (100 g, 480 mmol) and triethylamine (2.4 g, 24 mmol) in dichloromethane (150 ml). Add N-bromosuccinimide (89.7 g, 504 mmol) portionwise with stirring at room temperature. After reacting for 3 h, wash with water, dry over sodium sulfate, and concentrate to obtain the crude product. Column chromatography (petroleum ether:ethyl acetate = 7:1) afforded IIIb-6 (94.6 g) as a pale yellow solid in a 70% yield.

[0099] Under nitrogen, stir at room temperature. Suspend magnesium turnings (10.2 g, 418.3 mmol) in tetrahydrofuran (50 ml) and add 1,2-dibromoethane (4.2 g, 22.4 mmol) dropwise. After 30 minutes of reaction, add IIIb-6 (10 g, 41.1 mmol) and heat to 45-50°C for 30 minutes. Then, add a solution of IIIb-6 (80 g, 329.1 mmol) in tetrahydrofuran (550 ml) dropwise. After the addition is complete, continue the reaction at 45-50°C for 2 hours to obtain a tetrahydrofuran solution of IIIc-6.

[0100] Under nitrogen protection, compound V-6 (47.9 g, 231 mmol) prepared in Example 1 and tetrahydrofuran (50 ml) were stirred at -10 to -5°C, and the tetrahydrofuran solution (600 ml) of the Grignard reagent IIIc-6 was added dropwise. After the addition was complete, the mixture was brought to room temperature and reacted for 1 hour. Saturated ammonium chloride solution (1000 ml) was added. The liquids were separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over sodium sulfate, and concentrated. Compound III-6 (38.0 g) was obtained by column chromatography in a yield of 53%.

[0101] Method 2: Referring to the above method, when preparing Grignard reagent compound IIIc-6, the reaction solvent tetrahydrofuran was replaced with an equal volume of diethyl ether to finally obtain compound III-6 (33.0 g) with a yield of 46%.

[0102] Method 3: Referring to the above method, when preparing compound III-6, the compound V-6 in step 3 was replaced by an equimolar amount of azetidin-1-yl (4,4-difluorocyclohexyl) ketone prepared in Example 1 to finally obtain compound III-6 (31.5 g) with a yield of 44%.

[0103] 1 H NMR (400MHz, CDCl3) δ7.579(d,J=15.9Hz,1H),7.160(dd,J=8.4,2.0Hz,1H),7.080(d,J=2.0Hz,1H),6.884(d,J=8.3H z,1H),6.696(d,J=15.9Hz,1H),3.934(s,3H),3.928(s,3H),2.93–2.56(m,1H),2.37–2.09(m,2H),2.08–1.70(m,6H).

[0104] Example 3: Preparation of Compound IV-6

[0105]

[0106] Compound IIIa-6 (100 g, 480 mmol) was dissolved in dichloromethane (420 ml) and stirred. DMF (2 ml) was added, and then dichlorothionyl (68.6 g, 576 mmol) was added dropwise. The reaction was continued for 3 hours until the system became a clear and transparent light yellow solution. The solution was directly concentrated and dried to obtain a light yellow solid crude compound IVb-6, which was directly used in the next reaction.

[0107] N,O-dimethylhydroxylamine hydrochloride (56.2 g, 576 mmol) and dichloromethane (600 ml) were placed in a reaction flask and stirred. N-methylmorpholine (117.5 g, 1161 mmol) was added, and a solution of compound IVb-6 in dichloromethane (1000 ml) was added dropwise at below 10°C, with the temperature controlled below 20°C during the addition process. After completion of the addition, the system was naturally warmed to room temperature and stirred for two hours. 500 ml of water was added for washing, and the organic phase was separated. The organic phase was washed with water and separated. The organic phase was concentrated and the solvent was replaced with methyl tert-butyl ether. After all the dichloromethane was removed, the remaining amount of methyl tert-butyl ether solvent was reduced to 250 ml. The mixture was stirred at room temperature overnight, then at 10°C for 2 hours. The mixture was filtered to obtain crude compound IVc-6 as an off-white solid in a yield of 78%, which was used directly in the next reaction.

[0108] Lithium aluminum hydride (16.5 g, 435 mmol) was dissolved in tetrahydrofuran (500 ml) and stirred at -30°C. A solution of compound IVc-6 (164.5 g, 655 mmol) in tetrahydrofuran (1300 ml) was slowly added to the bottle, with the temperature kept below -10°C during the addition. After completion, the mixture was stirred until the reaction was complete. The reaction solution was slowly added to a mixed solvent of 1500 ml of ice-water and 50 ml of 12N HCl. After stirring, 1500 ml of ethyl acetate was added and the mixture was stirred to separate. The aqueous phase was washed once with ethyl acetate, and the organic phases were combined. The organic phase was washed sequentially with 1500 ml of sodium bicarbonate solution, 1500 ml of pure water, and 1500 ml of 7% NaCl solution. The organic phase was concentrated and dried to a yellow oily liquid. While hot, add 100 ml of ethyl acetate and 50 ml of n-heptane, stir at 45°C, and slowly drip 150 ml of n-heptane into the flask. After complete dripping, stir at room temperature overnight. The system was then stirred at 5°C for 1 hour, filtered, and washed with 50 ml of a 1:4 ethyl acetate:n-heptane solution. Air-drying afforded compound IV-6 (80.6 g) as a pale yellow solid in a 64% yield.

[0109] Example 4: Preparation of Compound II-6

[0110]

[0111] Under nitrogen, compound III-6 (10 g, 32.2 mmol) and tetrahydrofuran (60 ml) were stirred at -78°C. Lithium diisopropylamide (35.4 ml, 33.4 mmol) was dissolved in tetrahydrofuran (30 ml) and added dropwise to the reaction system, controlling the internal temperature not to exceed -65°C. After the addition, the mixture was stirred at -70 to -75°C for 1.5 hours. A solution of compound IV-6 (6.2 g, 32.2 mmol) in tetrahydrofuran (30 ml) was added dropwise to the system, controlling the temperature not to exceed -65°C. After the addition, the mixture was stirred for 2 hours. The temperature was then raised to 0°C, and the reaction solution was poured into a 0°C saturated citric acid solution. The mixture was extracted twice with 30 ml of ethyl acetate, concentrated, and subjected to column chromatography (ethyl acetate: petroleum ether = 1:10 to 1:3) to obtain compound II-6 (2.9 g) in an 18% yield.

[0112] 1 H NMR (400MHz, CDCl3) δ7.70 (d, J=15.4Hz, 1H), 7.20 (dd, J=8.4, 2.0Hz, 1H), 7.1 5(d,J=15.5Hz,1H),7.07(d,J=2.0Hz,1H),6.95–6.86(m,3H),6.80(d,J=8.0Hz ,1H),6.53(d,J=15.7Hz,1H),6.01(dd,J=15.7,7.9Hz,1H),4.30(d,J=7.9Hz, 1H),3.93(s,3H),3.90(s,3H),3.88(s,3H),3.85(s,3H),2.30–1.50(m,8H).MS m / z:503.25[M+H] + .

[0113] Example 5: Preparation of Compound II-6

[0114] Under nitrogen conditions, compound III-6 (13.7 g, 44 mmol) and dichloromethane (140 ml) were placed at -30 ° C and stirred, and a solution of titanium tetrachloride (9.2 g, 48.4 mmol) in dichloromethane (30 ml) was added dropwise, and then triethylamine (9.7 g, 96.8 mmol) was added dropwise to the system. The temperature was controlled not to exceed -30 ° C. After the dropwise addition was completed, the mixture was kept warm and stirred for 1 hour, and the temperature was lowered to -78 ° C. The dichloromethane (30 ml) solution of compound IV-6 (7.7 g, 40 mmol) was added dropwise. After the dropwise addition was completed, the mixture was kept warm and stirred for 0.5 hour. The reaction solution was poured into 250 ml of ice water, separated, the aqueous phase was back-extracted with 100 ml of dichloromethane, the organic phases were combined, concentrated, and column chromatography (ethyl acetate: petroleum ether = 1:4~3:1) was performed to obtain compound II-6 (7.7 g) with a yield of 38%.

[0115] Example 6: Preparation of Compound I-6

[0116]

[0117] Compound II-6 (7.7 g, 15.3 mmol) was dissolved in dichloromethane (77 ml), and DMP (6.48 g, 15.3 mmol) was added in batches at -5°C. The temperature was controlled not to exceed 10°C, and the mixture was stirred for 0.5 h. The reaction solution was poured into a silica gel column and purified by pure dichloromethane column chromatography to obtain compound I-6 (6.1 g) with a yield of 79.2%.

[0118] 1 H NMR (400MHz, CDCl3) δ7.71(d,J=15.4Hz,2H),7.14(d,J=8.3Hz,2H),7.09–6.96(m,2H),6.85( d,J=8.4Hz,2H),6.72(d,J=15.4Hz,2H),3.91(s,12H),2.45–2.18(m,4H),2.12–1.91(m,4H). 19 F NMR(376MHz,CDCl3)δ-97.28.MS m / z:501.27[M+H] + .

[0119] Example 7: Preparation of Compound I-6

[0120]

[0121] Under nitrogen, compound III-6 (31.0 g, 100 mmol) and dichloromethane (300 ml) were stirred at -30°C. A solution of titanium tetrachloride (20.8 g, 110 mmol) in dichloromethane (60 ml) was added dropwise. After the addition was complete, TMSCl (0.54 g, 5.0 mmol) was added. Triethylamine (22.3 g, 220 mmol) was added dropwise to the system, and the temperature was controlled not to exceed -30°C. After the addition was complete, the system was stirred at -30°C for 1 hour. The temperature was lowered to -78°C, and a solution of compound IV-6 (15.4 g, 80 mmol) in dichloromethane (50 ml) was added dropwise. After the addition was complete, the system was stirred at this temperature for 0.5 hour. The reaction solution was poured into 450 ml of ice water, separated, and the aqueous phase was extracted with 180 ml of dichloromethane. The organic phases were combined, anhydrous sodium sulfate was added, and the mixture was dried by adsorption on silica gel. The mixture was filtered to obtain a dichloromethane solution of crude compound II-6.

[0122] Under stirring conditions, Dess-Martin periodinane (DMP) (67.9 g, 160 mmol) was added to a dichloromethane solution of the crude compound II-6. The temperature was controlled not to exceed 20°C and stirred for 0.5 h. Sodium bicarbonate solution (76 ml, 6%) was then added dropwise to the system. After the addition was complete, the mixture was stirred for 30 min. The reaction solution was filtered through diatomaceous earth and separated. Silica gel was added to the organic phase and stirred. The organic phase was filtered and the mother liquor was concentrated. Pure dichloromethane was passed through a silica gel column and concentrated to obtain compound I-6 (20.0 g) with a yield of 50%.

[0123] Example 8: Preparation of Compound III-10

[0124]

[0125] Referring to the preparation method 1 of Example 1, Va-6 was replaced with spiro[3,3]heptane-2-carboxylic acid.

[0126] Spiro[3.3]heptane-2-carboxylic acid (70.0 g, 500 mmol), dichloromethane (210 ml) and DMF (2 g) were stirred at 0-5°C, and a dichloromethane solution (90 ml) of thionyl chloride (77.3 g, 650 mmol) was added dropwise. The mixture was reacted at room temperature for 3 h. The reaction solution was concentrated to obtain the crude compound spiro[3,3]heptane-2-carbonyl chloride.

[0127] N,O-Dimethylhydroxylamine hydrochloride (53.65 g, 550 mmol) was added to dichloromethane (300 ml), and triethylamine (111.3 g, 1.1 mol) was added with stirring. The temperature was lowered to 10°C, and a dichloromethane solution (90 ml) of the crude compound Vb-6 was added dropwise, maintaining the temperature below 20°C. After the addition was complete, the mixture was stirred at room temperature for 4 hours. Water and 3M hydrochloric acid were added to adjust the pH to 3-4. After separation, the organic phase was washed with sodium bicarbonate solution and concentrated to obtain compound V-10 (75.1 g) with a yield of 82%.

[0128] Under nitrogen, compound V-10 (42.3 g, 231 mmol) and tetrahydrofuran (50 ml) were stirred at -10 to -5°C. A tetrahydrofuran solution (600 ml) of Grignard reagent IIIc-6 prepared according to the method of Example 2 was added dropwise. After the addition was complete, the mixture was allowed to react at room temperature for 1.5 hours. Saturated ammonium chloride solution (1000 ml) was added. The liquids were separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over sodium sulfate, and concentrated. Compound III-10 (27.1 g) was obtained by column chromatography in a 41% yield.

[0129] 1H NMR (400MHz, CDCl3) δ7.443(d,J=16.1Hz,1H),7.118(dd,J=8.3,2.0Hz,1H),7.059(d,J=2.0Hz,1H),6.868(d,J=8.3Hz,1H),6.547(d,J=16.1Hz ,1H),3.917(s,3H),3.915(s,3H),3.426(q,J=8.6Hz,1H),2.369–2.163 (m,4H),2.139–2.040(m,2H),1.955–1.867(m,2H),1.866–1.746(m,2H).

[0130] Example 9: Preparation of Compound I-10

[0131]

[0132] Under nitrogen, compound III-10 (1.6 g, 5.5 mmol) and dichloromethane (10 ml) were stirred at -30 ° C. A solution of titanium tetrachloride (970 mg, 5.11 mmol) in dichloromethane (2 ml) was added dropwise. After the addition was complete, TMSCl (27 mg) was added. Triethylamine (1 g, 10 mmol) was added dropwise to the system, and the temperature was controlled not to exceed -30 ° C. After the addition was complete, the mixture was stirred at -30 ° C for 1 hour. The temperature was lowered to -78 ° C, and a solution of compound IV-6 (890 mg, 4.6 mmol) in dichloromethane (12 ml) was added dropwise. After reacting for 30 minutes, 0.5 M hydrochloric acid (50 ml) was added to quench the reaction. The liquid was separated, the aqueous phase was extracted with 100 ml of dichloromethane, the organic phases were combined, anhydrous sodium sulfate was added and dried by adsorption on silica gel, and filtered to obtain a dichloromethane solution of crude compound II-10.

[0133] Under stirring conditions, DMP (5.3 g, 12.5 mmol) was added to the dichloromethane solution of the crude compound II-10. The temperature was controlled not to exceed 20°C and stirred for 0.5 h. Sodium bicarbonate solution (76 ml, 6%) was then added dropwise to the system. After completion of the addition, the mixture was stirred for 15 min. The reaction solution was filtered through diatomaceous earth and separated. Silica gel was added to the organic phase and stirred. The organic phase was filtered and the mother liquor was concentrated. Pure dichloromethane was passed through a silica gel column and concentrated to obtain compound I-10 (1.0 g) with a yield of 47%.

[0134] 1H NMR (400MHz, CDCl3) δ7.568(d,J=15.9Hz,2H),7.109(dd,J=8.3,2.1Hz,2H),6.996(d,J=2.1Hz,2H),6.823(d,J=8.3Hz ,2H),6.522(d,J=15.9Hz,2H),3.890(s,6H),3.887(s,6H),2.730(s,4H),2.022–1.900(m,4H),1.860–1.672(m,2H).MS m / z:477.30[M+H] + .

[0135] Example 10: Preparation of Compound III-11

[0136]

[0137] 2,2-Difluorocyclopropanecarboxylic acid (52.4 g, 429 mmol), dichloromethane (210 ml) and DMF (2 g) were stirred at 0-5°C, and a dichloromethane solution (70 ml) of thionyl chloride (68.4 g, 575 mmol) was added dropwise. The mixture was reacted at room temperature for 3 h. The reaction solution was concentrated to obtain a crude compound for later use.

[0138] N,O-Dimethylhydroxylamine hydrochloride (46.13 g, 472 mmol) was added to dichloromethane (280 ml), and triethylamine (95.52 g, 944 mmol) was added with stirring. The temperature was lowered to 10°C, and a dichloromethane solution (70 ml) of the crude compound was added dropwise, maintaining the temperature below 20°C. After the addition was complete, the mixture was stirred at room temperature for 3-4 hours. Water and 3M hydrochloric acid were added to adjust the pH to 3-4. After separation, the organic phase was washed with sodium bicarbonate solution and concentrated to obtain compound V-11 (60.2 g) in a yield of 85%.

[0139] Under nitrogen, compound V-11 (40.0 g, 230 mmol) and tetrahydrofuran (50 ml) were stirred at -10 to -5°C. A tetrahydrofuran solution (600 ml) of Grignard reagent IIIc-6 prepared according to the method of Example 2 was added dropwise. After the addition was complete, the mixture was allowed to react at room temperature for 1 hour. Saturated ammonium chloride solution (1000 ml) was added. The liquids were separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over sodium sulfate, and concentrated. Compound III-11 (27.8 g) was obtained by column chromatography in a yield of 45%.

[0140] 1H NMR (400MHz, DMSO-d6) δ7.738(d,J=16.2Hz,1H),7.392(d,J=2.0Hz,1H),7.318(dd,J=8.3,2.0Hz,1H),7.039(d,J=16.1Hz,1H),7.0 34(d,J=8.4Hz,1H),3.824(s,3H),3.815(s,3H),3.548(ddd,J=14.2,10.6,7.9Hz,1H),2.210–2.052(m,1H),2.046–1.862(m,1H).MS m / z:269.12[M+H] + .

[0141] The above embodiments are merely examples of the technical solutions of the present invention. Those skilled in the art may make further combinations and improvements based on the present invention, which shall fall within the scope of protection of the present invention as long as they do not violate the concept of the present invention.

Claims

1. A method for preparing a compound of formula I, comprising the following steps: 1) Compound III reacts with compound IV to obtain compound II, 2) Compound II is subjected to oxidation reaction to obtain compound I, The reaction formula is as follows: Wherein, R1, R2, R3, and R4 are independently selected from substituted or unsubstituted C 1-12 Preferably, R1, R2, R3, R4 are independently selected from substituted or unsubstituted C 1-6 Alkyl; when substituents are present, the substituents are one or more, independently selected from deuterium, halogen, Hydroxyl, amino, C 1-12 Alkyl, C 1-12 Alkoxy, etc.; preferably, R1, R2, R3, R4 are independently selected from methyl, ethyl, propyl, isopropyl, butyl, deuterated methyl, deuterated ethyl, deuterated propyl; represents a substituted or unsubstituted ring system as follows: C 3-20 Cycloalkyl, C 4-20 Cycloalkenyl, 3-20 membered heterocyclic ring, C 3-20 Cycloalkyl and C 3-20 Spirocyclic rings formed by connecting cycloalkyl groups, C 3-20 A spiro ring formed by connecting a cycloalkyl group with a 3-20 membered heterocyclic group, or a spiro ring formed by connecting a 3-20 membered heterocyclic group with a 3-20 membered heterocyclic group; preferably represents a substituted or unsubstituted 3-7 membered carbocyclic or heterocyclic ring, or a spirocyclic ring formed by connecting a 3-7 membered carbocyclic or heterocyclic ring to a 3-7 membered carbocyclic or heterocyclic ring; when a substituent is present, the substituent is one or more independently selected from deuterium, halogen, Hydroxyl, amino, C 1-12 Alkyl or cycloalkyl, etc.; Preferably, Selected from the following groups: More preferably, Selected from the following groups:

2. The method of claim 1 , wherein in step 1), the reaction is carried out in the presence of a non-nucleophilic alkaline reagent selected from the group consisting of lithium bistrimethylsilylamide, lithium diisopropylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide, magnesium diisopropylamide, and potassium diisopropylamide.

3. The method of claim 1 , wherein in step 1), the reaction is carried out in the presence of a Lewis acid and a base, wherein the Lewis acid is selected from titanium tetrachloride, boron trifluoride, trifluoromethyl lanthanum sulfate, diphenyl trifluoroacetate, aluminum chloride, ferric chloride, zinc chloride, and magnesium bromide; and the base is selected from triethylamine, tripropylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]-5-nonene, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, and tetramethylethylenediamine.

4. The method of claim 1, wherein in step 2), the reaction is carried out in the presence of an oxidant selected from Dess-Martin periodinane, 2-iodoacylbenzoic acid, iodobenzene diacetate, Jones reagent, PCC reagent, PDC reagent, chromium trioxide, and peroxide.

5. The method according to claim 1, wherein the preparation method of compound III comprises the steps of: 1) Compound IIIa is subjected to halogenation reaction to obtain compound IIIb, 2) Compound IIIb reacts with metal Mg to obtain compound IIIc, 3) Compound IIIc reacts with compound V to produce compound III. The reaction formula is as follows: in, R1, R2, The definition is the same as that of claim 1; X represents a halogen selected from Br, Cl, I; R6 represents a group that is easily reacted with a Grignard reagent and leaves, and R6 is Preferably, selected from 6. The method of claim 1, wherein the preparation method of compound IV comprises the steps of: 1) Compound IVa is subjected to chlorination reaction to obtain compound IVb, 2) Compound IVb and compound VI are subjected to condensation reaction to obtain compound IVc, 3) Compound IVc is subjected to reduction reaction to obtain compound IV, in: In step 1), the chlorination agent for the chlorination reaction is selected from thionyl chloride, oxalyl chloride, phosphorus oxychloride, and phosphorus pentachloride; In step 2), R6 in compound VI is Preferably, selected from In step 3), the reaction is carried out under the action of a reducing agent, which is selected from lithium aluminum hydride, sodium borohydride, potassium borohydride, and diisobutylaluminum hydride.

7. The method of claim 5, wherein the preparation method of compound V comprises the steps of: 1) Compound Va is subjected to chlorination reaction to obtain compound Vb, 2) Compound Vb and compound VI undergo condensation reaction to obtain compound V, The reaction formula is as follows: in, The definition is the same as that of claim 1; the definition of R6 is the same as that of claim 5.

8. A method for preparing Compound I, comprising the steps of: 1) Compound IIIa reacts in the presence of NBS to obtain compound IIIb, 2) Compound IIIb reacts with metal Mg to obtain compound IIIc, 3) Compound IIIc reacts with compound V to produce compound III. 4) Compound III reacts with compound IV to obtain compound II, 5) Compound II is subjected to oxidation reaction to obtain compound I, The reaction formula is as follows:

9. Compound II, in, R1, R2, R3, R4, Same definition as claim 1.

10. Compound III, in, R1, R2, Same definition as claim 1.

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