Synthetic methods applied to heterocyclic intermediates that are KRAS inhibitors

Abstract

The present application provides a compound of formula II and a method for preparing a compound of formula I, i.e., 2-isopropyl-4-methylpyridin-3-amine, using the compound of formula II. The compound of formula I can be used to synthesize KRAS inhibitors. The raw materials involved in the method of the present application are readily available and inexpensive, and the operation is easy and simple, achieving economy and environmental protection, and facilitating industrial production.

Description

[Technical field]

[0001] Related Applications This application claims priority from Chinese Patent Application No. 2019108588762, filed on September 11, 2019. This application references the full text of the above Chinese patent application.

[0002] The present application relates to the field of pharmaceutical synthesis, in particular to synthetic methods applied to heterocyclic intermediates of KRAS inhibitors. [Background technology]

[0003] KRAS mutation is very common in human cancer (about 30%). It is one of the most common tumor-driving genes, with a high incidence in lung cancer, colon cancer, and pancreatic cancer. However, it is difficult to design KRAS inhibitors because there is no drug-binding pocket in KRAS mutant protein.

[0004] Amgen achieved a historic breakthrough by announcing Phase I clinical results of the small molecule KRAS inhibitor AMG510 at the 2019 ASCO Annual Meeting, highlighting the importance of 2-isopropyl-3-amino-4-methylpyridine (Compound I) as an essential fragment of AMG510.

[0005] So far, few related patents have been reported. The main synthetic route in the patent is that of the innovator Amgen (WO2018217651): [ka] It is.

[0006] In Example 40 of WO2018217651 (page 235), high catalyst loadings and expensive palladium catalysts and zinc reagents are used in the coupling reaction. On the other hand, compound XI is not commercially available. Its synthesis is reported in the Journal für Praktische Chemie (Leipzig) paper (331 (1989), 369-374) in 46% yield. [ka]

[0007] To improve the synthesis of compound I, the synthetic route needs to be redesigned to change the expensive transition metal catalyzed cross-coupling reaction, especially to avoid the amino group in the substrate that impairs the activity of the cross-coupling catalyst. Furthermore, if the cross-coupling reaction can be eliminated, the raw material cost of this pharmaceutical intermediate can be effectively reduced. Summary of the Invention [Problem to be solved by the invention]

[0008] The first objective of the present application is to provide compounds of formula II, V and VI, their preparation methods and applications to intermediates of KRAS inhibitors.

[0009] Another object of the present application is to provide a process for the preparation of the compounds of formula I.

[0010] In order to solve the above problems, the present application provides the following technical scheme.

[0011] In one aspect, the present application provides a compound of formula II: [ka] , Formula V: [ka] , and Formula VI: [ka] The present invention provides a compound of the formula:

[0012] In Formula V, the double bond of the dimethylamine group is in the Z configuration, the E configuration, or a mixture of the Z and E configurations.

[0013] The present application provides a compound as an intermediate for the preparation of a KRAS inhibitor, the structure of which is represented by Formula II: [ka] , Formula V: [ka] , and Formula VI: [ka] As shown in.

[0014] In another aspect, the present application provides a method for the synthesis of a compound of formula I from a compound of formula II, comprising decarboxylation of a compound of formula II by a rearrangement reaction: [ka] to provide.

[0015] In one scheme herein, the synthesis of a compound of formula I comprises the steps of: Compound II reacts under Hofmann rearrangement conditions to produce compound I. The Hofmann rearrangement conditions include a mixture of NaOBr and water.

[0016] Here, NaOBr can be used in the form of an aqueous NaOBr solution prepared by adding Br2 to a mixture of NaOH and water, where the mass ratio of NaOH to Br2 is 0.9:1, and the mass ratio of NaOH to water in the mixture of NaOH and water is 0.3:1.

[0017] The molar ratio of compound II to NaOBr is (0.8-1.2): 1, for example, (0.9-1.1): 1. When the aqueous NaOBr solution prepared in the above step is used, the mass ratio of compound II to Br2 is 1:1.

[0018] The mixed system can be obtained by adding NaOBr to a mixture of compound II and water. The addition method is dropwise. The addition temperature is -10 to 10°C, such as 0°C. In the mixture of compound II and water, the mass ratio of compound II to water is 0.5:1.

[0019] In the mixed system, the mass ratio of the total amount of water (including the water in the aqueous NaOBr solution when the aqueous NaOBr solution is used) to compound II is 7:1.

[0020] The reaction temperature for the rearrangement reaction is 10 to 100°C, for example, room temperature (10 to 30°C) to 80°C.

[0021] The progress of the rearrangement reaction can be monitored by conventional testing methods in the art (e.g., TLC, HPLC, or NMR), and the reaction reaches an end point when compound II disappears or no further reaction occurs. The reaction time is 1 to 5 hours.

[0022] The work-up is included in the synthesis method, and includes the following steps: after the rearrangement reaction is completed, the reaction mixture is extracted with an organic solvent. The resulting organic phase is then rinsed, concentrated, isolated and purified. The organic solvent for extraction is ethyl acetate. The rinse solution is saturated brine. The isolation and purification method is silica gel column chromatography, for example, column chromatography using ethyl acetate and n-heptane (volume ratio 1:2) as eluent.

[0023] In one embodiment of the present invention, the synthesis of a compound of formula II comprises the steps of hydrolyzing compound III in an acid to obtain compound II: [ka] Includes.

[0024] The conditions and procedures for the hydrolysis reaction can be conventional conditions and procedures for such reactions in the art, and in the present application, the following are preferred: The acid is concentrated sulfuric acid, for example 98% concentrated sulfuric acid. The mass ratio of acid to compound III is 2.25:1. The hydrolysis temperature is 105°C.

[0025] The progress of the hydrolysis reaction can be monitored by conventional testing methods in the art (e.g., TLC, HPLC, or NMR), and the reaction reaches an end point when compound III disappears or no further reaction occurs. The reaction time is 1 to 5 hours.

[0026] A work-up is included in the synthesis method, which includes adding water after the hydrolysis reaction is completed, adjusting the pH to 10-11, filtering and drying to obtain compound II. The pH is adjusted using 50% aqueous sodium hydroxide solution. The product of compound II can be used directly in the rearrangement reaction.

[0027] In one solution in the present application, the synthesis method includes Schemes 1 and 2.

[0028] Scheme 1 shows the steps of the Kumada coupling reaction of compound IV with isopropyl Grignard reagent in the presence of N-methyl-pyrrolidone and iron catalyst in an organic solvent: [ka] Includes.

[0029] The conditions and procedures for the Kumada coupling reaction can be conventional conditions and procedures for such reactions in the art, and in the present application, the following are preferred: The organic solvent is an ether solvent such as tetrahydrofuran. The amount of the organic solvent does not need to be limited as long as it does not affect the reaction. For example, the mass-to-volume ratio of compound IV to the organic solvent is 0.03 to 0.04 g / mL. The mass ratio of N-methyl-pyrrolidone to compound IV is 9.5:1. The iron catalyst is iron(III) acetylacetonate. The mass ratio of the iron catalyst to the compound IV is 1:(2-2.2). The isopropyl Grignard reagent is isopropyl magnesium chloride. The isopropyl Grignard reagent can be used in the form of a solution. The solvent of the solution is an organic solvent such as an ether solvent. For example, it is a 1.0 to 2.5 mol / L tetrahydrofuran solution. The volume to mass ratio of the isopropyl Grignard reagent to compound IV is (2.6-4.4:1). The reaction temperature for the Kumada coupling is 0 to 10°C.

[0030] The progress of the Kumada coupling can be monitored by conventional testing methods in the art (e.g., TLC, HPLC, or NMR), and the reaction reaches an end point when compound IV disappears or no further reaction occurs. The reaction time can be 0.2 to 5 hours.

[0031] The synthesis method includes a work-up, which includes adding aqueous citric acid and saturated aqueous sodium bicarbonate to the reaction mixture after the Kumada coupling reaction is completed, and extracting with an organic solvent. The organic phase is then washed, concentrated, isolated, and purified. The organic solvent for extraction is an ester solvent such as ethyl acetate. The isolation and purification method is silica gel column chromatography, for example, column chromatography using ethyl acetate and n-heptane (volume ratio 1:6) as the eluent. The product of compound III can be directly used in the hydrolysis reaction.

[0032] Scheme 2 illustrates the cyclization of compound V with an ammonia source in an organic solvent to give compound III: [ka] Includes.

[0033] In Scheme 2, the cyclization reaction is the reaction of compound V with an ammonia source, followed by an intramolecular substitution reaction to produce compound III.

[0034] The conditions and procedures for the cyclization reaction can be conventional for such reactions in the art, and in the present application, the following are preferred: The organic solvent is an alcohol solvent such as methanol. The amount of the organic solvent does not need to be limited as long as it does not affect the reaction. For example, the mass-to-volume ratio of compound V to the organic solvent is 0.03 to 0.04 g / mL. The ammonia source can be ammonia, ammonium acetate, ammonium chloride; for example, when the ammonia source is ammonium acetate, the mass ratio of ammonium acetate to compound V is (3-4):1, for example, 3.67:1. The reaction temperature for the cyclization reaction is 0 to 50°C, for example, 20 to 30°C.

[0035] The progress of the cyclization reaction can be monitored by conventional testing methods in the art (e.g., TLC, HPLC, or NMR), and the reaction reaches an end point when compound V disappears or no further reaction occurs. The reaction time is 1 to 10 days, for example 5 days.

[0036] Workup is included in this synthesis method, and workup includes the following steps: after the cyclization reaction is completed, the reaction mixture is concentrated, isolated and purified to obtain the product of compound III. The isolation and purification method is silica gel column chromatography, for example, column chromatography using ethyl acetate and n-heptane (volume ratio 1:6) as eluent. The product of compound III can be directly used in hydrolysis reaction.

[0037] In another solution of the present application, scheme 2 comprises the following steps:

[0038] In step (1), compound VII is condensed with acetone in the presence of alkaline aluminum oxide in an organic solvent to give compound VI.

[0039] In step (2), compound VI is condensed with N,N-dimethylformamide dimethyl sulfate condensate (DMF-DMS) in the presence of acetic anhydride and triethylamine in an organic solvent to give compound V. [ka]

[0040] The conditions and operations for the condensation reaction in steps (1) and (2) can be conventional conditions and operations for such reactions in the art, and in the present application, the following are preferred:

[0041] The organic solvent used in step (1) is an aromatic solvent such as toluene. The amount of the organic solvent in step (1) does not need to be limited as long as it does not affect the reaction. For example, the mass-to-volume ratio of compound VII to the organic solvent can be 0.10 to 0.20 g / mL. In the step (1), the mass ratio of the alkaline aluminum oxide to the compound VII is (2-4):1, for example, 2.3:1. The reaction temperature for the condensation reaction in the step (1) is 0 to 50°C, for example, 20 to 30°C.

[0042] In step (1), the progress of the condensation reaction can be monitored by conventional testing methods in the art (e.g., TLC, HPLC, or NMR), and the reaction reaches an end point when compound VII disappears or no further reaction occurs. The reaction time is 0.5 to 2 days, for example 1 day.

[0043] A work-up of step (1) is included in the synthetic method, which includes the steps of filtering the reaction mixture after the condensation reaction is complete, rinsing the filter cake with an organic solvent, and combining the filtrates and using them directly in step (2).

[0044] The organic solvent used in step (2) is an aromatic solvent such as toluene. In step (2), the mass ratio of N,N-dimethylformamide dimethyl sulfate condensate (DMF-DMS) to compound VII is (2-4):1, for example, 3:1. In step (2), the mass ratio of acetic anhydride to compound VII is (0.1-0.4):1, for example, 0.18:1. In step (2), the volume to mass ratio of triethylamine to compound VII is 1 to 2 mL / g, for example, 1.5 mL / g. The reaction temperature for the condensation reaction in the step (2) is 0 to 50°C, for example, 0 to 10°C or 20 to 30°C.

[0045] In one scheme, step (2) includes a step of successively adding acetic anhydride and triethylamine to a mixture of compound VI obtained in step (1) and N,N-dimethylformamide dimethyl sulfate condensate to carry out a condensation reaction. The addition temperature is 0 to 10°C for acetic anhydride and 20 to 30°C for triethylamine.

[0046] The progress of the condensation reaction in step (2) can be monitored by a conventional test method in the art (e.g., TLC, HPLC, or NMR), and the reaction reaches an end point when compound VI disappears or no further reaction occurs. The reaction time is 5 to 24 hours, for example 20 hours.

[0047] Work-up is included in the procedure of step (2), after the condensation reaction is completed, water is added to the reaction mixture, stirred for 5 hours, the layers are separated, the aqueous phase is extracted with an organic solvent, the organic phases are combined, condensed and purified to obtain the product of compound V. The organic solvent for extraction is dichloromethane. The isolation and purification method is silica gel column chromatography, for example, column chromatography using ethyl acetate and n-heptane (volume ratio 1:6) as the eluent. The product of compound V can be directly used for the cyclization reaction.

[0048] In another embodiment, the present application provides a method for the synthesis of compound II, comprising coupling compound IV to produce compound III, and then hydrolyzing compound III. The method comprises the steps of: [ka] Includes.

[0049] The conditions and procedures for the coupling reaction and hydrolysis reaction can be those for the corresponding reactions described above.

[0050] In a particular coupling reaction embodiment for synthesizing compound III, an iron catalyst is used in the Kumada coupling, with compound IV and an isopropyl Grignard reagent being the reactants.

[0051] In another scheme, the present application provides a method for the synthesis of compound II, the method comprising the steps of: [ka] the condensation reaction of compound VII with acetone to produce compound VI, the condensation reaction of compound VI to produce compound V, then the cyclization reaction of compound V to lead compound III, and finally the hydrolysis reaction of compound III to produce compound II.

[0052] The conditions and procedures for the condensation, cyclization, and hydrolysis reactions can be those for the corresponding reactions described above.

[0053] In a particular embodiment of the synthesis of compound V by condensation of compound VI, compound VI and N,N-dimethylformamide dimethyl acetal (DMF-DMA) or N,N-dimethylformamide dimethyl sulfate condensate (DMF-DMS) are used as reactants in the condensation reaction. In the synthesis of compound III via compound V, the cyclization reaction comprises reacting compound V with an ammonia source, followed by an intramolecular substitution reaction to produce compound III. More preferably, the ammonia source is selected from ammonia, ammonium acetate, and ammonium chloride.

[0054] Compared with the prior art, the method for synthesizing the compound of formula I in this application has the following advantages: 1. Raw materials are easily available and inexpensive. 2. The operation is simple, and the process is easy for scale-up and industrial production. 3. Safer and more environmentally friendly. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0055] The following embodiments describe the implementation of the present application, and those skilled in the art should understand that these specific embodiments only show the implementation technical solutions selected to achieve the objectives of the present application, and do not limit the technical solutions. According to the teachings of the present application, the improvements of the technical solutions of the present application combined with the prior art are obvious, and all of them belong to the protection scope of the present application.

[0056] The operating conditions adopted in the embodiments can be further adjusted according to specific requirements, and the undefined operating conditions are usually those in conventional experiments.

[0057] Among them, the known chemical reagents used in the following embodiments are all commercially available chemical reagents.

[0058] In the exemplary implementation of the present disclosure, those skilled in the art can also make modifications to the synthetic pathway, for example, modify specific reaction conditions or adjust certain steps or some steps of the synthetic pathway as necessary. Modifications made without departing from the gist of the present application are within the protection scope of the present application.

[0059] Example 1 [ka]

[0060] To a 500 mL three-neck flask was added compound IV (6.0 g), THF (150 mL), NMP (57 mL), and Fe(acac)3 (2.77 g). The reaction mixture was refilled with nitrogen three times and cooled to 0-10 °C. i PrMgCl was added dropwise to the reaction mixture at 0-10°C. After stirring for 30 min, the reaction was quenched with aqueous citric acid (60 mL, 0.5 mol / L), followed by the addition of saturated aqueous NaHCO3 (60 mL) and EtOAc (60 mL). The layers were separated. The aqueous layer was extracted with EtOAc (60 mL). The organic phases were combined and concentrated under reduced pressure. Column chromatography purification (EtOAc:n-heptane=1:6) afforded compound 3 (3.59 g) as an oily liquid in 57% yield.

[0061] Compound III 1 H NMR: 1 H NMR (400MHz, DMSO-d6) δ8.63(d,J=5.1Hz,1H),7.35(dd,J=5.0,0.8Hz,1H),3.41(m,J=6.8Hz,1H),2.50(s,J=0.6Hz,3H),1.27(d,J=6.8Hz,6H).

[0062] MS for compound III: [M+H] + =161.1.

[0063] Example 2 [ka]

[0064] To compound III (3.0 g) in a 50 mL reaction flask was added concentrated sulfuric acid (6.76 g) dropwise. The mixture was heated to 105° C. and stirred for 4 hours. After completion of the reaction, the reaction was cooled to 70-75° C. Water (6 g) was added to the reaction. After 30 minutes, the reaction was cooled to 0-10° C. Water (21 g) and 50% aqueous sodium hydroxide were added to adjust the pH of the reaction mixture to 10-11. After 30 minutes, the mixture was filtered. The cake was dried at 50° C. to give an off-white solid (2.5 g, 75% yield).

[0065] Compound II 1 H NMR: 1 H NMR (400MHz, DMSO-d6) δ8.38(d,J=4.9Hz,1H),7.90(s,1H),7.63(s,1H),7.08(d,J=4.7Hz,1H),3.14(m,1H),2.26(s,3H),1.20(d,J=6.8Hz,6H).

[0066] MS for compound II: [M+H] + =179.1.

[0067] Example 3: [ka]

[0068] To a mixture of sodium hydroxide (0.45 g) and water (1.5 mL) in a 25 mL round-bottom flask A, Br2 (0.5 g) was added dropwise in an ice-water bath. After stirring at room temperature for 10 min, the resulting aqueous NaOBr solution was added to a mixture of compound II (0.5 g) and water (1 mL) in a 25 mL round-bottom flask B in an ice-water bath. After stirring at room temperature for 1.5 h, water (1 mL) was added. The reaction mixture was heated to 80 °C and stirred for 1.5 h. After completion of the reaction, the reaction was cooled to 20-30 °C and EtOAc (10 mL) was added. The layers were separated. The aqueous phase was extracted with EtOAc (10 mL). The combined organic phase was washed with saturated brine (10 mL) and concentrated. The crude product was purified by column chromatography (EtOAc:n-heptane=1:2) to give compound I (140 mg, 33% yield) as a pale yellow oily liquid.

[0069] Compound I 1 H NMR: 1 H NMR (400MHz, DMSO-d6) δ7.67(d,J=4.7Hz,1H),6.78(d,J=4.6,0.8Hz,1H),4.72(s,2H),3.19(m,1H),2.08(s,3H),1.15(d,J=6.7Hz,6H).

[0070] Compound I MS: [M+H] + =151.2.

[0071] Example 4: [ka]

[0072] To a mixture of compound VII (5.0 g) and acetone (6.7 mL) in a 100 mL round bottom flask A, basic Al2O3 (11.5 g) and toluene (30 mL) were added. The reaction was stirred at 20-30 °C for 24 h. After completion of the reaction, the mixture was filtered. The cake was rinsed with toluene (20 mL) and the filtrate was transferred to a 250 mL round bottom flask B, where N,N-dimethylformamide dimethyl sulfate adduct (DMF-DMS) (15.4 g), acetic anhydride (0.92 g) were added. The mixture was cooled to 0-10 °C, and then triethylamine (7.5 mL) was added dropwise. The reaction was stirred at 20-30 °C for 15 h. Water (40 mL) was added. The mixture was stirred for an additional 5 h. The layers were separated. The aqueous phase was extracted with DCM (3 x 30 mL). The combined organic phase was concentrated. The crude material was purified by column chromatography (EtOAc:n-heptane=1:10) to give compound V (3.0 g, 32%) as a pale yellow solid.

[0073] Compound V 1 H NMR: 1 H NMR(400MHz,DMSO-d6)δ7.96(d,J=12.8Hz,1H),7.55(d,J=12.8Hz,1H),3.31(d,J=2.2H) z,1H),3.25(s,3H),3.13(m,1H),2.97(s,3H),2.24(s,3H),1.01(dd,J=6.8,3.6Hz,7H).

[0074] Compound V MS: [M+H] + =207.1.

[0075] Example 5: [ka]

[0076] A mixture of compound V (60 mg), methanol (1.8 mL), and ammonium acetate (0.22 g) in a 10 mL round-bottom flask was stirred at 20-30 °C for 5 days. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (EtOAc: n-heptane = 1:6) to obtain compound III (23 mg, 50% yield) as an oily liquid.

[0077] Compound III 1 H NMR: 1 H NMR (400MHz, DMSO-d6) δ8.63(d,J=5.1Hz,1H),7.35(dd,J=5.0,0.8Hz,1H),3.41(m,1H),2.50(s,J=0.6Hz,3H),1.27(d,J=6.8Hz,6H).

[0078] MS for compound III: [M+H] + =161.1.

[0079] The present application includes, but is not limited to, the above embodiments. Any equivalent replacement or partial improvement made under the principle of the spirit of the present application shall be deemed to be within the protection scope of the present application.

Claims

1. A method for preparing a compound of formula I from a compound of formula II, comprising converting an amide group from said compound of formula II to an amino group by a Hofmann rearrangement reaction to produce said compound of formula I: 【Chemistry 1】 A method comprising:

2. The method of claim 1, wherein the Hofmann rearrangement reaction conditions include a mixture of NaOBr and water.

3. 3. The method of claim 2, wherein the NaOBr is in the form of an aqueous solution of NaOBr.

4. The NaOBr is a mixture of NaOH and water. ２ to obtain said aqueous solution of NaOBr; ２ the mass ratio of NaOH to water in the NaOH and water mixture is 0.3:1; the mass ratio of the compound of formula II to Br ２ the mass ratio of the compound of formula II to NaOBr is (0.8-1.2):1 The method of claim 2.

5. The mixture of NaOBr and water is obtained by adding NaOBr to a mixture of the compound of formula II and water; the addition is dropwise; the addition is performed at a temperature of -10°C to 10°C; in the mixture of the compound of formula II and water, the mass ratio of the compound of formula II to the water is 0.5:

1. The method of claim 2.

6. 3. The method of claim 2, wherein in the mixed system, the mass ratio of the total amount of water to the compound of formula II is 7:

1.

7. The method of claim 1, wherein the Hoffmann rearrangement reaction is carried out at a temperature of 10 to 100° C.

8. The method further includes a work-up process, which includes adding an organic solvent to the reaction mixture for extraction after the Hoffmann rearrangement reaction is completed to result in a reaction mixture, and washing, concentrating, separating and purifying the organic phase; the organic solvent is ethyl acetate; the washing is performed using saturated brine as a washing solvent; and the separation and purification are performed by silica gel column chromatography. The method of claim 1.

9. Hydrolyzing a compound of formula III with an acid to obtain said compound of formula II: 【Chemistry 2】 The method of claim 1 further comprising:

10. 10. The method of claim 9, wherein the acid is sulfuric acid, the mass ratio of the acid to the compound of formula III is 2.25:1, and the hydrolysis is carried out at 105°C.

11. After the hydrolysis, the method further comprises the steps of: adding water to the hydrolysis reaction mixture obtained by the hydrolysis to adjust the pH to 10-11; filtering and drying to obtain the compound of formula II; adjusting the pH by adding 50% aqueous sodium hydroxide solution; and directly using the compound of formula II in the Hoffmann rearrangement reaction.

10. The method of claim 9.

12. carrying out a Kumada coupling reaction between the compound of formula IV and an isopropyl Grignard reagent in the presence of N-methylpyrrolidone and an iron catalyst in an organic solvent to obtain the compound of formula III; 【Chemistry 3】 10. The method of claim 9, comprising:

13. the organic solvent is an ether solvent; the mass-to-volume ratio of the compound of formula IV to the organic solvent is 0.03-0.04 g / mL; the volume to mass ratio of the N-methylpyrrolidone to the compound of formula IV is 9.5:1; the iron catalyst is iron triacetylacetonate; the isopropyl Grignard reagent is an isopropylmagnesium chloride solution in an ether solvent; the volume to mass ratio of the isopropyl Grignard reagent to the compound of formula IV is (2.6-4.4):1; and the Kumada coupling reaction is carried out at 0-10° C. The method of claim 12.

14. After the completion of the Kumada coupling reaction, the method further comprises sequentially adding an aqueous citric acid solution, a saturated aqueous sodium bicarbonate solution, and an organic solvent to the Kumada coupling reaction mixture obtained from the Kumada coupling reaction to obtain an organic phase; extracting, concentrating, separating, and purifying the organic phase to obtain the compound of formula III; the organic solvent for extraction is an ester solvent; and the separation and purification are carried out by silica gel column chromatography.

10. The method of claim 9.

15. The compound of formula V is subjected to a cyclization reaction to obtain the compound of formula III: 【Chemistry 4】 The method of claim 9 further comprising:

16. 16. The method of claim 15, wherein the cyclization reaction comprises reacting the compound of formula V with an ammonia source, followed by an intramolecular substitution reaction to form the compound of formula III.

17. 17. The method of claim 16, wherein the ammonia source is selected from the group consisting of ammonia gas, ammonium acetate, and ammonium chloride.

18. Compound of Formula VI: 【Chemistry 5】 16. The method of claim 15, further comprising subjecting to a condensation reaction to obtain the compound of formula V.

19. 19. The method of claim 18, wherein the condensation reaction is carried out in the presence of N,N-dimethylformamide dimethyl acetal (DMF-DMA) or N,N-dimethylformamide dimethyl sulfate adduct (DMF-DMS) as a reactant.

20. The compound of formula VII is subjected to the above-mentioned condensation reaction with acetone to obtain the compound of formula VI: 【Chemistry 6】 20. The method of claim 19, further comprising:

21. Step (1): A compound of formula VII is subjected to a condensation reaction with acetone in the presence of basic alumina in an organic solvent to obtain a compound of formula VI; Step (2): In an organic solvent, in the presence of acetic anhydride and triethylamine, the compound of formula VI is subjected to a condensation reaction with N,N-dimethylformamide dimethyl sulfate condensate to obtain the compound of formula V: 【Chemistry 7】 The method of claim 15 further comprising:

22. The organic solvent in step (1) is an aromatic solvent; and / or, in step (1), the mass-to-volume ratio of the compound of formula VII to the organic solvent is 0.10-0.20 g / mL; and / or in step (1), the mass ratio of the basic alumina to the compound of formula VII is (2-4):1; And / or, in step (1), the temperature of the condensation reaction is 0 to 50° C.; and / or step (1) also includes a work-up process, which includes filtering when the condensation reaction is completed, washing the filtered cake with the organic solvent, and combining the resulting filtrates for direct use in step (2); And / or, in step (2), the organic solvent is an aromatic solvent; and / or, in step (2), the mass ratio of the N,N-dimethylformamide dimethyl sulfate condensate to the compound of formula VII is (2-4):1; and / or in step (2), the mass ratio of the acetic anhydride to the compound of formula VII is (0.1-0.4):1; and / or in step (2), the mass-to-volume ratio of the triethylamine to the compound of formula VII is 1-2 mL / g; And / or, in step (2), the temperature of the condensation reaction is 0 to 50° C.; and / or step (2) is a step of sequentially adding acetic anhydride and triethylamine to the compound of formula VI obtained in step (1) to condense it with N,N-dimethylformamide dimethyl sulfate in the mixture of substances, and carrying out the condensation reaction; the temperature for adding acetic anhydride is 0-10°C; the temperature for adding triethylamine is 20-30°C; And / or, step (2) also includes a work-up process, which includes adding water when the condensation reaction is completed, stirring, separating the layers, extracting the aqueous phase with an organic solvent, combining and concentrating the organic phases, separating and purifying to obtain the compound of formula V; the organic solvent for extraction can be dichloromethane; the separation and purification can be silica gel column chromatography.

20. The method of claim 17.

23. Formula II: 【Chemistry 8】 、 Formula V: 【Chemistry 9】 or Formula VI: 【Chemistry 10】 ,or Those salts A compound having the formula: A compound of formula V, wherein the double bond attached to the dimethylamino group is in the form of Z, E, or a mixture of Z and E.

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