Synthesis Method of Anti-Tumor Compounds and Their Intermediates

Abstract

The present invention relates to the pharmaceutical technical field, specifically to a method for synthesizing antitumor compounds and their intermediates. The synthesis method of the present invention improves operability and simplifies the process, and the synthesized target compound can be obtained with higher purity without the need for complicated recrystallization processes, reducing the generation of waste products and making it more suitable for large-scale industrial production. The intermediates provided by the present invention can be used to prepare antitumor compounds, effectively reducing by-products during the reaction and increasing the total reaction yield, which is at least 1-fold higher than conventional synthesis methods.

Description

Technical Field

[0001] The present invention relates to the technical field of medicine, and specifically to a method for synthesizing an antitumor compound and an intermediate thereof.

Background Art

[0002] The growth and metastasis of tumors depend not only on the overexpression of mitotic kinases (such as Aurora kinase), but also on the generation of a large number of new blood vessels. Among them, the VEGF / VEGFR (vascular endothelial growth factor / vascular endothelial growth factor receptor) pathway plays an important role in the generation of tumor new blood vessels.

[0003] Patent WO2018108079A1 discloses a series of compounds that can inhibit, regulate and / or control the activities of one or more protein kinases such as Aurora kinase and VEGFR kinase, and reverse the tumor microenvironment and exert tumor immune effects and antitumor effects by inhibiting the growth and metastasis of tumors. The synthesis method of compound 29 is described in this patent. Further research shows that the synthesis process needs to be further optimized to obtain a synthesis method that is simpler, more efficient, higher in purity, lower in cost, and suitable for large-scale industrial production.

[0004]

Chemical Formula

Summary of the Invention

[0005] In a first aspect, the present invention provides the following technical solutions 1 to 15. 1. A method for synthesizing an antitumor compound of formula 7, comprising:

[0006]

Chemical Formula

[0007] (a) In an organic solvent, the compound of formula 1 is subjected to an aromatic nucleophilic substitution reaction with the compound of formula 2M under the action of a base to obtain the compound of formula IM. The compound of formula IM is then continuously subjected to an aromatic nucleophilic substitution reaction with the compound of formula 3, either isolated or without isolation. For example, the compound of formula 3 is continuously subjected to an aromatic nucleophilic substitution reaction under basic conditions to obtain the compound of formula 4M.

[0008] (b) In an organic solvent, the compound of formula 4M is subjected to a reduction reaction under the action of a catalyst to obtain the compound of formula 5M.

[0009] (c) In an organic solvent, the compound of formula 5M is subjected to ring closure under the action of an acid to obtain the compound of formula 6M.

[0010] (d) In an organic solvent, the amino group protecting group is removed from the compound of formula 6M to obtain the antitumor compound of formula 7. The reaction formula is as follows.

[0011]

Chemical formula

[0012] Among them, X1 and X2 are each selected from halogens, P1 is an amino group protecting group, preferably, P1 is selected from Boc, Cbz, Tos, Fmoc, PMB, MOM, EOM, tBu, Bn, Ac, SEM, Trt or THP, for example Boc, Cbz, Tos, Fmoc, PMB, Trt or THP. P1 is connected to any N atom in the ring where it is located, preferably, P1 is connected to the N atom at the ortho position of the methyl in the ring where it is located. A method for synthesizing an antitumor compound of formula 7, characterized by this.

[0013] 2. A method for synthesizing an antitumor compound of formula 7, comprising:

[0014]

Chemical formula

[0015] (d) In an organic solvent, removing the amino group protecting group from the compound of Formula 6M to obtain an antitumor compound of Formula 7, The reaction formula is as follows:

[0016]

Chemical formula

[0017] Among them, P1 is an amino group protecting group, preferably, P1 is selected from Boc, Cbz, Tos, Fmoc, PMB, MOM, EOM, tBu, Bn, Ac, SEM, Trt or THP, for example Boc, Cbz, Tos, Fmoc, PMB, Trt or THP, P1 is connected to any N atom in the ring where it is located, preferably, P1 is connected to the N atom at the ortho position of the methyl in the ring where it is located. A method for synthesizing an antitumor compound of Formula 7, characterized by this.

[0018] 3. A method for synthesizing an intermediate compound of Formula 6M or the method according to any one of the above technical solutions,

Chemical formula

[0019] (c) In an organic solvent, cyclizing the compound of Formula 5M under the action of an acid to obtain a compound of Formula 6M, The reaction formula is as follows:

[0020]

Chemical formula

[0021] Among them, P1 is an amino group protecting group. Preferably, P1 is selected from Boc, Cbz, Tos, Fmoc, PMB, MOM, EOM, tBu, Bn, Ac, SEM, Trt or THP, for example Boc, Cbz, Tos, Fmoc, PMB, Trt or THP. P1 is connected to any N atom in the ring where it is located. Preferably, P1 is connected to the N atom at the ortho position of the methyl group in the ring where it is located. A method characterized by this.

[0022] 4. A method for synthesizing the intermediate compound of formula 5M or the method according to any one of the above technical solutions,

[0023]

Chemical formula

[0024] (b) In an organic solvent, including the step of subjecting the compound of formula 4M to a reduction reaction under the action of a catalyst to obtain the compound of formula 5M, The reaction formula is as follows,

[0025]

Chemical formula

[0026] Among them, P1 is an amino group protecting group. Preferably, P1 is selected from Boc, Cbz, Tos, Fmoc, PMB, MOM, EOM, tBu, Bn, Ac, SEM, Trt or THP, for example Boc, Cbz, Tos, Fmoc, PMB, Trt or THP. P1 is connected to any N atom in the ring where it is located. Preferably, P1 is connected to the N atom at the ortho position of the methyl group in the ring where it is located. A method characterized by this.

[0027] 5. A method for synthesizing the intermediate compound of formula 4M or the method according to any one of the above technical solutions,

[0028]

Chemical formula

[0029] (a) In an organic solvent, the compound of formula 1 is subjected to an aromatic nucleophilic substitution reaction with the compound of formula 2M under the action of a base to obtain the compound of formula IM. The compound of formula IM undergoes a subsequent aromatic nucleophilic substitution reaction with the compound of formula 3, either isolated or without isolation. For example, it includes the step of further performing an aromatic nucleophilic substitution reaction with the compound of formula 3 under basic conditions to obtain the compound of formula 4M. The reaction formula is as follows:

[0030]

Chemical formula

[0031] Among them, X1 and X2 are each selected from halogens, P1 is an amino group protecting group. Preferably, P1 is selected from Boc, Cbz, Tos, Fmoc, PMB, MOM, EOM, tBu, Bn, Ac, SEM, Trt or THP. For example, it is Boc, Cbz, Tos, Fmoc, PMB, Trt or THP. P1 is connected to any N atom in the ring where it is located. Preferably, P1 is connected to the N atom at the ortho position of the methyl in the ring where it is located. This is a characteristic method.

[0032] 6. In step (a), the organic solvent is selected from one or more of 2-methyltetrahydrofuran, acetonitrile, tetrahydrofuran and toluene, and the base is selected from one or more of sodium hydride, sodium hydroxide, cesium carbonate, triethylenediamine, sodium tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide and sodium hexamethyldisilazide.

[0033] Optionally in step (a), The reaction pressure is 0 to 10 MPa (gauge pressure), for example, normal pressure. The reaction time is 1 to 96 hours, for example, 17 hours. The reaction temperature may be the reflux temperature.

[0034] In particular, when the compound of Formula 1 is subjected to an aromatic nucleophilic substitution reaction with the compound of Formula 2M in the presence of a base, the reaction time is 3 to 18 hours, for example, the reaction time is 3 to 8 hours, the reaction temperature is 40 to 70 °C, for example, the reaction temperature is 40 to 60 °C,

[0035] In particular, when the compound of Formula 3 is subsequently subjected to an aromatic nucleophilic substitution reaction, the reaction time is 8 to 16 hours, for example, 13 to 16 hours, and the reaction temperature may be the reflux temperature,

[0036] The ratio is solvent: compound of Formula 1: compound of Formula 2M: compound of Formula 3: base = 0.5 to 60 L: 0.1 to 11 mol: 1 mol: 0.3 to 30 mol: 0.2 to 25 mol, for example, 5.8 L: 1.1 mol: 1 mol: 3 mol: 2.5 mol,

[0037] In particular, magnesium sulfate is added when the compound of Formula 1 is subjected to an aromatic nucleophilic substitution reaction with the compound of Formula 2M in the presence of a base, and acetic acid is added when the compound of Formula 3 is subsequently subjected to an aromatic nucleophilic substitution reaction,

[0038] The ratio is solvent: compound of Formula 1: compound of Formula 2M: compound of Formula 3: base: magnesium sulfate: acetic acid = 0.5 to 60 L: 0.1 to 11 mol: 1 mol: 0.3 to 30 mol: 0.2 to 25 mol: 0.2 to 20 mol: 0.1 to 15 mol, for example, 5.8 L: 1.1 mol: 1 mol: 3 mol: 2.5 mol: 1.6 mol: 1.5 mol, which is characterized by any one of the above technical solutions.

[0039] 7. In step (b), the organic solvent is selected from one or more of methanol, ethanol, isopropyl alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, acetic acid and acetonitrile, and the catalyst is selected from iron powder, platinum oxide, Pt / C, Pd(OH)2 / C, Rh / C or Pd / C.

[0040] Optionally, in step (b), when the catalyst is iron powder, the reaction time is 1 to 96 hours, for example 15 to 24 hours, the reaction pressure is 0 to 10 MPa (gauge pressure), for example normal pressure, and the reaction temperature is the reflux temperature.

[0041] The ratio is organic solvent: compound of formula 4M: catalyst = 1 to 130 L: 1 mol: 1 to 150 mol, for example 13 L: 1 mol: 10 to 18 mol, for example 13 L: 1 mol: 14 to 18 mol, for example 13 L: 1 mol: 15 mol.

[0042] In particular, when the catalyst is iron powder, in step (b), 0.05 to 5 mol, for example 0.5 mol of ammonium chloride is further added, and the solvent is a mixed solvent of ethanol and tetrahydrofuran. For example, the volume ratio of ethanol to tetrahydrofuran is (6 to 10):10.

[0043] In particular, in step (b), when the catalyst is platinum oxide, Pt / C, Pd(OH)2 / C, Rh / C or Pd / C, the reaction is carried out at 30 to 80 °C for 20 to 80 hours under a hydrogen atmosphere. For example, the reaction is carried out at 60 to 80 °C for 20 to 72 hours under a hydrogen atmosphere, the reaction pressure is 0 to 10 MPa (gauge pressure), for example 0.5 to 2 MPa, and the ratio is solvent: compound of formula 4M: catalyst = 1 to 50 mL: 1 g: 0.03 to 0.2 g, for example 22 mL: 1 g: 0.1 g.

[0044] Optionally, in step (b), a small amount of water is further added to step (b). For example, the volume ratio of water to tetrahydrofuran is (0.2 to 2):10. The method according to any one of the preceding technical solutions, characterized in that.

[0045] 8. In step (c), the acid is selected from one or more of trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, and hydrochloric acid, and the organic solvent is selected from at least one of dichloromethane, methanol, ethanol, and isopropyl alcohol.

[0046] Optionally in step (c), the reaction time is 1 to 96 hours, for example 1.5 to 3 hours, the reaction pressure is 0 to 10 MPa (gauge pressure), for example normal pressure, the reaction temperature is the reflux temperature, and the ratio is solvent: compound of formula 5M: acid = 0.5 to 70 L: 1 mol: 0.220 mol, for example 6.6 L: 1 mol: 2 mol. The method according to any one of the preceding technical solutions, characterized in that.

[0047] 9. Step (c) specifically comprises refluxing the compound of formula 5M in isopropyl alcohol under the action of trifluoroacetic acid for 1 to 3 hours. The method according to any one of the preceding technical solutions, characterized in that.

[0048] 10. In step (d), the organic solvent is selected from one or more of toluene, dichloromethane, acetonitrile, tetrahydrofuran, methanol, ethanol, and isopropyl alcohol.

[0049] In step (d), an acid is further added, and the acid is selected from at least one of formic acid, acetic acid, hydrochloric acid, methanesulfonic acid, and trifluoroacetic acid.

[0050] In step (d), an alcohol or phenol other than the solvent is further added, the alcohol is selected from methanol and / or ethanol, and the phenol is selected from phenol and / or p-methoxyphenol.

[0051] Optionally, in step (d), the reaction time is 1 to 96 hours, for example 17 hours, the reaction pressure is 0 to 10 MPa (gauge pressure), for example atmospheric pressure, the reaction temperature is the reflux temperature, and the ratio is solvent: compound of formula 6M: acid: alcohol or phenol = 10 to 800 L: 1 mol: 0.1 to 10 mol: 0.2 to 20 mol, for example 84 L: 1 mol: 1 mol: 2 mol, and the method according to any one of the above technical solutions is characterized by this.

[0052] 11. Further comprising the step of synthesizing the compound of formula 2M, that is,

[0053] (i) In a solvent such as concentrated sulfuric acid, acetic anhydride, acetic acid, etc., reacting the compound of formula 2-1 (for example, 1 mol equivalent) with nitric acid (for example, 1 to 2 mol equivalents) in a nitration reaction (reaction time is 0.5 to 2 hours, reaction temperature is 10 to 20 ° C) to obtain the compound of formula 2-2;

[0054] (ii) In an organic solvent such as one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, and acetonitrile, reacting the compound of formula 2-2 (for example, 1 mol equivalent) with an amino group protecting reagent (for example, 1 to 1.5 mol equivalents) in an amino group protecting reaction (reaction time is 1 to 48 hours, reaction temperature is 60 to 100 ° C) to obtain the compound of formula (2-3)M;

[0055] (iii) In an organic solvent such as one or more of ethanol, tetrahydrofuran, and acetonitrile, removing phthaloyl from the compound of formula (2-3)M (for example, 1 mol equivalent) (for example, reaction time is 1 to 3 hours, reaction temperature is the reflux temperature) to obtain the compound of formula 2M, and further comprising The reaction formula is as follows:

[0056]

Chemical formula

[0057] Among them, the amino group protecting reagent is Boc2O, CbzCl, TosCl, FmocCl, PMBBr, MOMCl, EOMCl, tert-butanol, isobutene, BnCl, acetic anhydride, SEMCl, TrtCl or DHP, for example, Boc2O, CbzCl, TosCl, FmocCl, PMBBr, TrtCl or DHP; P1 is selected from Boc, Cbz, Tos, Fmoc, PMB, MOM, EOM, tBu, Bn, Ac, SEM, Trt or THP, for example, Boc, Cbz, Tos, Fmoc, PMB, Trt or THP; P1 is connected to any N atom in the ring where it is located, and preferably, P1 is connected to the N atom at the ortho position of the methyl group in the ring where it is located. The method according to any one of the preceding technical solutions, characterized in that.

[0058] 12. When the amino group protecting reagent is TrtCl, as the reaction conditions for step (ii), under the action of a base, the reaction is carried out at 60-100 °C for 1-48 hours.

[0059] When the amino group protecting reagent is DHP, as the reaction conditions for step (ii), under the action of p-toluenesulfonic acid or pyridine p-toluenesulfonate, the reflux reaction is carried out at 60-100 °C for 3-48 hours. The method according to technical solution 11, characterized in that.

[0060] 13. Further comprising the step of synthesizing the compound of formula 1, that is,

[0061] For example, in an organic solvent such as THF, the compound of formula 1-1 (for example, 1-2 mol equivalents) is subjected to a coupling reaction with the compound of formula 1-2 (for example, 1-2 mol equivalents) (reaction time is 2-4 hours, reaction temperature is -70-60 °C) to obtain the compound of formula 1. Further comprising the step of The reaction formula is as follows:

[0062]

Chemical formula

[0063] Among them, X1, X2, and X3 are each selected from halogens, and preferably, X1, X2, and X3 are each selected from chlorine. The method according to any one of the preceding technical solutions, characterized in that.

[0064] 14. An intermediate for preparing the antitumor compound of formula 7, having the following structural formula:

[0065]

Chemical formula

[0066] Among them, X1 and X2 are each selected from halogens.

[0067] P1 is selected from Trt or THP, and P1 is connected to any N atom in the ring where it is located. Preferably, P1 is connected to the N atom at the ortho position of the methyl group in the ring where it is located. The intermediate is characterized in that.

[0068] 15. An intermediate for preparing the antitumor compound of formula 7, having the following structural formula:

[0069]

Chemical formula

[0070] Among them, P1 is selected from Trt or THP, and P1 is connected to any N atom in the ring where it is located. Preferably, P1 is connected to the N atom at the ortho position of the methyl group in the ring where it is located.

[0071] The formula 6M is a complex containing one molecule of trifluoroacetic acid and one molecule of isopropyl alcohol. The intermediate is characterized in that.

[0072] In the second aspect, the object of the present invention is to provide a method for synthesizing the antitumor compound of formula 7 including the following steps, that is,

[0073]

Chemical formula

[0074] (a) In an organic solvent, the compound of Formula 1 is subjected to an aromatic nucleophilic substitution reaction with the compound of Formula 2 under the action of a base, and then a subsequent aromatic nucleophilic substitution reaction is carried out with the compound of Formula 3. For example, a subsequent aromatic nucleophilic substitution reaction is carried out with the compound of Formula 3 under basic conditions to obtain the compound of Formula 4, and

[0075] (b) In an organic solvent, the compound of Formula 4 is subjected to a reduction reaction under the action of a catalyst to obtain the compound of Formula 5, and

[0076] (c) In an organic solvent, the compound of Formula 5 is subjected to ring closure under the action of an acid to obtain the compound of Formula 6, and

[0077] (d) In an organic solvent, the amino group protecting group is removed from the compound of Formula 6 to obtain the antitumor compound of Formula 7, and includes The reaction formula is as follows,

[0078]

Chemical formula

[0079] Among them, X1 and X2 are each selected from halogens, and P1 is an amino group protecting group. Preferably, P1 is selected from Boc, Cbz, Tos, Fmoc, PMB, MOM, EOM, tBu, Bn, Ac, SEM, Trt or THP, for example, Boc, Cbz, Tos, Fmoc, PMB, Trt or THP.

[0080] In one of the embodiments, in step (a), the organic solvent is selected from one or more of 2-methyltetrahydrofuran, acetonitrile, tetrahydrofuran, and toluene, and the base is selected from one or more of sodium hydride, sodium hydroxide, cesium carbonate, triethylenediamine, sodium tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide, and sodium hexamethyldisilazide.

[0081] In one of the embodiments, in step (b), the organic solvent is selected from one or more of methanol, ethanol, isopropyl alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, and acetonitrile, and the catalyst is selected from iron powder, platinum oxide, Pt / C, or Pd / C.

[0082] In one of the embodiments, in step (c), the acid is selected from one or more of trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, and hydrochloric acid, and the organic solvent is selected from at least one of dichloromethane, methanol, ethanol, and isopropyl alcohol.

[0083] In one of the embodiments, step (c) is specifically as follows, that is, the compound of formula 5 is refluxed in isopropyl alcohol under the action of trifluoroacetic acid for 1 to 3 hours, for example, 1.5 to 3 hours.

[0084] In one of the embodiments, in step (d), the organic solvent is selected from one or more of toluene, dichloromethane, acetonitrile, tetrahydrofuran, methanol, ethanol, and isopropyl alcohol.

[0085] In step (d), a catalyst is further added, and the catalyst is selected from at least one of formic acid, acetic acid, hydrochloric acid, methanesulfonic acid, and trifluoroacetic acid.

[0086] In step (d), alcohol or phenol is further added, the alcohol is selected from methanol and / or ethanol, and the phenol is selected from phenol and / or p-methoxyphenol.

[0087] In one of the embodiments, it further includes the step of synthesizing the compound of Formula 2, that is,

[0088] (i) In a solvent, reacting the compound of Formula 2-1 with nitric acid in a nitration reaction to obtain the compound of Formula 2-2;

[0089] (ii) In an organic solvent, reacting the compound of Formula 2-2 with an amino group protecting reagent in an amino group protection reaction to obtain the compound of Formula 2-3;

[0090] (iii) In an organic solvent, further removing phthaloyl from the compound of Formula 2-3 to obtain the compound of Formula 2. The reaction formula is as follows:

[0091]

Chemical formula

[0092] Among them, the amino group protecting reagent is Boc2O, CbzCl, TosCl, FmocCl, PMBBr, MOMCl, EOMCl, tert-butanol, isobutene, BnCl, acetic anhydride, SEMCl, TrtCl or DHP, for example, Boc2O, CbzCl, TosCl, FmocCl, PMBBr, TrtCl or DHP, and P1 is selected from Boc, Cbz, Tos, Fmoc, PMB, MOM, EOM, tBu, Bn, Ac, SEM, Trt or THP, for example, Boc, Cbz, Tos, Fmoc, PMB, Trt or THP.

[0093] In one of the embodiments, when the amino group protecting reagent is TrtCl, as the reaction conditions for step (ii), under the action of a base, the reaction is carried out at 60 to 100 °C for 1 to 48 hours,

[0094] when the amino group protecting reagent is DHP, as the reaction conditions for step (ii), under the action of p-toluenesulfonic acid or pyridine p-toluenesulfonate, the reflux reaction is carried out at 60 to 100 °C for 3 to 48 hours.

[0095] In one of the embodiments, it further includes the step of synthesizing the compound of formula 1, that is,

[0096] it further includes the step of subjecting the compound of formula 1-1 to a coupling reaction with the compound of formula 1-2 in an organic solvent to obtain the compound of formula 1, The reaction formula is as follows,

[0097]

Chemical formula

[0098] Among them, X1, X2 and X3 are each selected from halogens, and preferably, X1, X2 and X3 are each selected from chlorine.

[0099] In a third aspect, the present invention further provides an intermediate for preparing an antitumor compound of formula 7 having the following structural formula,

[0100]

Chemical formula

[0101] Among them, X1 and X2 are each selected from halogens,

[0102] P1 is selected from Trt or THP,

[0103] P2 is selected from Trt or THP, and P3 is absent, or P3 is selected from Trt or THP, and P2 is absent, PG1 is acetyl or PG1-NH-

[0104]

Chemical formula

[0105] and

[0106]

Chemical formula

[0107] represents a single bond or a double bond that may exist.

[0108] In a fourth aspect, the present invention provides an intermediate for preparing an antitumor compound of formula 7 having the following structural formula,

[0109]

Chemical formula

[0110] wherein P1 is selected from Trt or THP,

[0111] Formula 6 is a complex containing one molecule of trifluoroacetic acid and one molecule of isopropyl alcohol.

[0112] Compared with the prior art, the present invention has the following beneficial effects.

[0113] (1) Different from the conventional synthesis process of first deprotecting and then synthesizing the tricyclic ring, the present invention adopts a method of first synthesizing the tricyclic ring and then deprotecting. Using the intermediate (compound of formula 2) as a raw material, through aromatic nucleophilic substitution reaction and reduction reaction, to obtain the compound of formula 5, the process of the compound of formula 5 first synthesizing the tricyclic ring and then deprotecting can be realized. Therefore, the deficiencies in the conventional process, namely, 1 the problem of wastewater due to the need to use a large amount of trifluoroacetic acid when deprotecting first, 2 the problem that the operation and post-treatment are complicated due to using stannous chloride to reduce the ring when synthesizing the tricyclic ring later, 3 the problem that the whole process is complicated and needs to be realized through a column, etc. can be avoided.

[0114] (2) The synthesis method of the present invention improves the operability, simplifies the process, and the synthesized compound of formula 7 can obtain higher purity without a complicated recrystallization process, reduces the generation of "three wastes" (wastewater, exhaust gas and solid waste), and is more suitable for large-scale industrial production.

[0115] (3) The intermediate provided by the present invention is used for preparing anti-tumor compounds, effectively reduces the by-products during the reaction, improves the total yield of the reaction, and is at least doubled compared with the synthesis method of compound 29 in the patent WO2018108079A1.

Embodiments for Carrying out the Invention

[0116] Hereinafter, the above content of the present invention will be further described in more detail by specific embodiments, but it should not be understood that the scope of the above subject matter of the present invention is limited to the following examples. Any technology realized based on the above content of the present invention belongs to the scope of the present invention.

[0117] The abbreviations used in this specification have the meanings generally understood in the art and are as follows.

[0118] "Halogen" refers to fluorine, chlorine, bromine, iodine, etc. "Boc2O" refers to di-tert-butyl dicarbonate. 「Boc」 refers to tert-butoxycarbonyl. 「CbzCl」 refers to benzyl chloroformate. 「Cbz」 refers to benzyloxycarbonyl. 「TosCl」 refers to p-toluenesulfonyl chloride. 「Tos」 refers to p-toluenesulfonyl. 「FmocCl」 refers to 9-fluorenylmethyl chloroformate. 「Fmoc」 refers to 9-fluorenylmethoxycarbonyl. 「PMBBr」 refers to p-methoxybenzyl bromide. 「PMB」 refers to p-methoxybenzyl. 「MOMCl」 refers to chloromethyl methyl ether. 「MOM」 refers to methoxymethyl. 「EOMCl」 refers to chloroethyl ethyl ether. 「EOM」 refers to ethoxymethyl. 「tBu」 refers to tert-butyl. 「BnCl」 refers to benzyl chloride. 「Bn」 refers to benzyl. 「Ac」 refers to acetyl. 「SEMCl」 refers to 2-(trimethylsilyl)ethoxymethyl chloride. 「SEM」 refers to 2-(trimethylsilyl)ethoxymethyl. 「TrtCl」 refers to triphenylchloromethane. 「Trt」 refers to triphenylmethyl. 「DHP」 refers to 3,4-dihydro-2H-pyran. 「THP」 refers to 2-tetrahydropyranyl. 「THF」 refers to tetrahydrofuran. 「2-MeTHF」 refers to 2-methyltetrahydrofuran. 「MTBE」 refers to methyl tert-butyl ether. 「ACN」 refers to acetonitrile. "TEA" refers to triethylamine. "TFA" refers to trifluoroacetic acid. "IPA" refers to isopropyl alcohol. "TEMPO" refers to 2,2,6,6-tetramethylpiperidine-1-oxide. "DCM" refers to dichloromethane. "TLC" refers to thin-layer chromatography. "HNMR" refers to proton nuclear magnetic resonance spectroscopy. "DMSO" refers to dimethyl sulfoxide. "HPLC" refers to high-performance liquid chromatography. "PE" refers to petroleum ether. "EA" refers to ethyl acetate. "LC-MS" refers to liquid chromatography / mass spectrometry.

[0119] In the present invention, the catalyst includes substances that can change the reaction rate in the ordinary sense, and also includes substances that have an oxidation-reduction action or an acid-base action during the reaction.

[0120] In the present invention, unless otherwise specified, the reaction is carried out at normal pressure.

[0121] In the present invention, the reaction temperature is the highest temperature reached during the reaction. The whole process of the reaction or a part of the process of the reaction is carried out at the said highest temperature.

[0122] In the present invention, when referring to "ratio", for example, when it is stated that solvent: compound of formula 1: compound of formula 2M: compound of formula 3: base = 5.8 L: 1.1 mol: 1 mol: 3 mol: 2.5 mol, this expression refers to the ratio relationship of the supply amounts of each material during the reaction. That is, when 1 mol of the compound of formula 2M is supplied, correspondingly, the supply amounts of the solvent, the compound of formula 1, the compound of formula 3, and the base are 5.8 L, 1.1 mol, 3 mol, and 2.5 mol respectively. When the supply amount of the compound of formula 2M increases or decreases, the supply amounts of the other materials also increase or decrease proportionally. The supply amount of each material is the total amount of the supply amount of that material during the reaction. For example, if a certain material is supplied all at once, the supply amount is the amount supplied all at once. If the material is supplied in several portions, the supply amount is the total of the supply amounts in several portions. The supply of each material indicated by the ratio may be carried out simultaneously or separately.

[0123] In the present invention, the chemical structural formula represents the form of the free base or free acid of the compound represented by the formula, the form of hydrate, solvate, acidic salt, basic salt, and combinations thereof. For example, the following formula A includes the form of the free base of formula A and each complex of formula A such as a complex containing 1 molecule of trifluoroacetic acid and 1 molecule of isopropyl alcohol (as shown by the following formula B, for example).

[0124]

Chemical formula

[0125] The present invention provides a method for synthesizing an antitumor compound of formula 7, which includes the following steps, that is,

[0126]

Chemical formula

[0127] (a) In an organic solvent, the compound of formula 1 is subjected to an aromatic nucleophilic substitution reaction with the compound of formula 2M under the action of a base to obtain the compound of formula IM, and the compound of formula IM is continuously subjected to an aromatic nucleophilic substitution reaction with the compound of formula 3, with or without isolation, for example, continuously subjected to an aromatic nucleophilic substitution reaction with the compound of formula 3 under basic conditions to obtain the compound of formula 4M;

[0128] (b) In an organic solvent, the compound of formula 4M is subjected to a reduction reaction under the action of a catalyst to obtain the compound of formula 5M;

[0129] (c) In an organic solvent, the compound of formula 5M is subjected to ring closure under the action of an acid to obtain the compound of formula 6M;

[0130] (d) In an organic solvent, the amino group protecting group is removed from the compound of formula 6M to obtain the antitumor compound of formula 7, The reaction formula is as follows,

[0131]

Chemical formula

[0132] Among them, X1 and X2 are each selected from halogens. P1 is an amino group protecting group, preferably, P1 is selected from Boc, Cbz, Tos, Fmoc, PMB, MOM, EOM, tBu, Bn, Ac, SEM, Trt or THP, for example, Boc, Cbz, Tos, Fmoc, PMB, Trt or THP, and P1 is connected to any N atom in the ring where it is located, preferably, P1 is connected to the N atom at the ortho position of the methyl in the ring where it is located.

[0133] In some embodiments, the compound of formula 2M includes the compound of formula 2 and the compound of formula 2m as follows, that is,

[0134]

Chemical formula

[0135] and preferably, the compound of Formula 2M is the compound of Formula 2.

[0136] The compound of Formula IM includes the compound of Formula I and the compound of Formula Im below, that is,

[0137]

Chemical formula

[0138] and preferably, the compound of Formula IM is the compound of Formula I.

[0139] The compound of Formula 4M includes the compound of Formula 4 and the compound of Formula 4m below, that is,

[0140]

Chemical formula

[0141] and preferably, the compound of Formula 4M is the compound of Formula 4.

[0142] The compound of Formula 5M includes the compound of Formula 5 and the compound of Formula 5m below, that is,

[0143]

Chemical formula

[0144] and preferably, the compound of Formula 5M is the compound of Formula 5.

[0145] The compound of Formula 6M includes the compound of Formula 6 and the compound of Formula 6m below, that is,

[0146]

Chemical formula

[0147] and preferably, the compound of Formula 6M is the compound of Formula 6.

[0148] Preferably, P1 is selected from Trt or THP.

[0149] In some embodiments, the method for synthesizing the compound of formula 4 is step (a), that is, in an organic solvent, the compound of formula 1 is subjected to an aromatic nucleophilic substitution reaction with the compound of formula 2 under the action of a base to obtain the compound of formula I, and the compound of formula IM is not isolated and is subsequently subjected to an aromatic nucleophilic substitution reaction with the compound of formula 3. For example, the compound of formula 3 is subsequently subjected to an aromatic nucleophilic substitution reaction under basic conditions to obtain the compound of formula 4.

[0150] In the present invention, when synthesizing the compound of formula 4, there is no need to directly react with the compound of formula 3 and separate the product I after reacting the compound of formula 1 with the compound of formula 2, which simplifies the process and improves the yield.

[0151] In some embodiments, in step (a), the organic solvent is selected from one or more of 2-methyltetrahydrofuran, acetonitrile, tetrahydrofuran, and toluene.

[0152] Preferably, the organic solvent is selected from 2-methyltetrahydrofuran or acetonitrile.

[0153] In some embodiments, in step (a), the base is selected from one or more of sodium hydride, sodium hydroxide, cesium carbonate, triethylenediamine, sodium tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide, and sodium hexamethyldisilazide.

[0154] In some embodiments, as the basic condition shown in step (a), without adding a base, morpholine may be used as the base. For example, basic reagents such as one or more of sodium hydride, sodium hydroxide, cesium carbonate, triethylenediamine, sodium tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide, and sodium hexamethyldisilazide may be added. In some embodiments, in step (a), the base is sodium hydride and the solvent is 2-methyltetrahydrofuran.

[0155] In some embodiments, as the conditions for subjecting the compound of formula 1 to an aromatic nucleophilic substitution reaction with the compound of formula 2 in step (a), the reaction is carried out at 40 to 70 °C for 3 to 18 hours. For example, the reaction is carried out at 40 to 60 °C for 3 to 8 hours.

[0156] In some embodiments, as the conditions for subsequently carrying out an aromatic nucleophilic substitution reaction with the compound of formula 3 in step (a), the reflux reaction is carried out for 8 to 16 hours. For example, the reflux reaction is carried out for 8 to 12 hours, or, for example, the reflux reaction is carried out for 13 to 16 hours.

[0157] In some embodiments, in step (a), the molar ratio of the compound of formula 1, the compound of formula 2, and the compound of formula 3 is (1 to 1.2):1:3.

[0158] In some embodiments, in step (a), magnesium sulfate, molecular sieve, or activated carbon may be added as a catalyst.

[0159] In particular, magnesium sulfate is added as a catalyst, and the addition amount of magnesium sulfate is 0.2 to 3 mol equivalents of the compound of formula 2. For example, the addition amount of magnesium sulfate is 2 to 3 mol equivalents of the compound of formula 2, or, for example, the addition amount of magnesium sulfate is 1 to 3 mol equivalents of the compound of formula 2.

[0160] Furthermore, after the reaction in step (a) is completed, the compound of formula 4 is purified, and the purification operation may be carried out by adopting the conventional methods in the art.

[0161] The present invention further provides another method for synthesizing the compound of formula 4 including the following steps.

[0162] In an organic solvent, the compound of formula 1 is subjected to an aromatic nucleophilic substitution reaction with the compound of formula 2 under the action of a base to obtain the compound of formula I.

[0163] In an organic solvent, the compound of formula I is subjected to an aromatic nucleophilic substitution reaction with the compound of formula 3 under the action of a base to obtain the compound of formula 4. The reaction formula is as follows,

[0164]

Chemical formula

[0165] Among them, X1 and X2 are each selected from halogens, P1 is an amino group protecting group, preferably, P1 is selected from Boc, Cbz, Tos, Fmoc, PMB, MOM, EOM, tBu, Bn, Ac, SEM, Trt or THP, for example, Boc, Cbz, Tos, Fmoc, PMB, Trt or THP.

[0166] In this method, the organic solvent is selected from one or more of 2-methyltetrahydrofuran, acetonitrile, tetrahydrofuran and toluene. The base is selected from one or more of sodium hydride, sodium hydroxide, cesium carbonate, triethylenediamine, sodium tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide and sodium hexamethyldisilazide.

[0167] In some embodiments, the synthesis steps and reaction conditions of the compound of formula 4m are the same as those described in the synthesis method of the compound of formula 4 above, with the difference being that the compound of formula 2 is replaced by the compound of formula 2m and the compound of formula I is replaced by the compound of formula Im.

[0168] In some embodiments, the synthesis method of the compound of formula 5 is step (b), that is, in an organic solvent, the compound of formula 4 is subjected to a reduction reaction under the action of a catalyst to obtain the compound of formula 5.

[0169] In some embodiments, in step (b), the organic solvent is selected from one or more of methanol, ethanol, isopropyl alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, acetic acid, and acetonitrile.

[0170] In some embodiments, in step (b), the catalyst is selected from iron powder, platinum oxide, Pt / C, Pd(OH)2 / C, Rh / C, or Pd / C.

[0171] In some embodiments, the mass fraction of Pt / C and Rh / C is 5%. The mass fraction of Pd / C is 5% and 10%. The mass fraction of Pd(OH)2 / C is 10% and 20%.

[0172] When the catalyst is iron powder, the addition amount of iron powder is 10 - 18 mol equivalents of the compound of formula 4. For example, the addition amount of iron powder is 14 - 18 mol equivalents of the compound of formula 4.

[0173] In particular, in step (b), ammonium chloride is further added, and the addition amount of ammonium chloride is 0.4 - 0.6 mol equivalents of the compound of formula 4. The solvent is a mixed solvent of ethanol and tetrahydrofuran. For example, the volume ratio of ethanol to tetrahydrofuran is (6 - 10):10. In particular, in step (b), a small amount of water is further added. The volume ratio of water to tetrahydrofuran is (0.2 - 0.5):10. Furthermore, as the conditions for carrying out the reduction reaction, the reflux reaction is carried out for 15 - 24 hours.

[0174] When the catalyst is platinum oxide, as the conditions for carrying out the reduction reaction, it reacts at 35 to 80 °C for 20 to 70 hours in a hydrogen atmosphere (for example, 0.5 to 0.8 MPa). For example, as the conditions for carrying out the reduction reaction, it reacts at 35 to 50 °C for 40 to 50 hours in a hydrogen atmosphere.

[0175] Furthermore, after the reaction in step (b) is completed, the compound of formula 5 is purified, and the purification operation may be carried out by adopting a conventional method in the art.

[0176] In some embodiments, the synthesis steps and reaction conditions of the compound of formula 5m are as shown in the synthesis method of the compound of formula 5 above, and the difference is that the compound of formula 4 is replaced by the compound of formula 4m.

[0177] In some embodiments, the synthesis method of the compound of formula 6 is step (c), that is, in an organic solvent, the compound of formula 5 is cyclized by the action of an acid to obtain the compound of formula 6.

[0178] In some embodiments, in step (c), the acid is selected from one or more of trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, and hydrochloric acid. The organic solvent is selected from at least one of dichloromethane, methanol, ethanol, and isopropyl alcohol.

[0179] In particular, the acid is selected from trifluoroacetic acid, and the organic solvent is isopropyl alcohol.

[0180] In some embodiments, in step (c), the molar ratio of the compound of formula 5 to the acid is 1:(1.5 to 2).

[0181] In some embodiments, step (c) is specifically as follows, that is, the compound of formula 5 is refluxed in isopropyl alcohol under the action of trifluoroacetic acid for 1 to 3 hours. For example, the reaction time is 1.5 to 3 hours.

[0182] Furthermore, after the reaction in step (c) is completed, the compound of formula 6 is purified, that is, the reaction solution is suction filtered, the filter cake is rinsed with isopropyl alcohol, dried, and the purified compound of formula 6 is obtained.

[0183] In some embodiments, the synthesis steps and reaction conditions of the compound of formula 6m are the same as those described in the synthesis method of the compound of formula 6 above, the difference being that the compound of formula 5 is replaced by the compound of formula 5m.

[0184] In some embodiments, the synthesis method of the compound of formula 7 is step (d), that is, in an organic solvent, the amino group protecting group is removed from the compound of formula 6 to obtain the antitumor compound of formula 7.

[0185] In some embodiments, in step (d), the organic solvent is selected from one or more of toluene, dichloromethane, acetonitrile, tetrahydrofuran, methanol, ethanol, and isopropyl alcohol. In particular, the organic solvent is toluene.

[0186] In some embodiments, in step (d), a catalyst may be added. The catalyst is selected from at least one of formic acid, acetic acid, hydrochloric acid, methanesulfonic acid, and trifluoroacetic acid. In particular, the catalyst is selected from trifluoroacetic acid.

[0187] Furthermore, in step (d), alcohol or phenol is further added. The alcohol is selected from methanol and / or ethanol, and the phenol is selected from phenol and / or p-methoxyphenol. Furthermore, for example, the addition amount of alcohol or phenol is 1 to 2 molar equivalents of the compound of formula 6.

[0188] Furthermore, after the reaction in step (d) is completed, the compound of formula 7 is purified, and the purification operation may be performed by adopting a conventional method in the art.

[0189] In some embodiments, the synthetic step and reaction conditions for replacing the compound of Formula 6 with the compound of Formula 6m to synthesize the compound of Formula 7 are as described in the synthesis method of the compound of Formula 7 above.

[0190] In some embodiments, the compound of Formula 7 can be further synthesized directly in one step from the compound of Formula 5M. As the reaction conditions, in an organic solvent, the compound of Formula 5M is reacted under the action of an acid to obtain the compound of Formula 7. For example, under the action of trifluoroacetic acid, a reflux reaction is carried out for 20 to 40 hours. The organic solvent is selected from one or more of toluene, dichloromethane, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, methanol, ethanol, and isopropyl alcohol.

[0191] In some embodiments, the synthesis method of the antitumor compound of Formula 7 further includes the step of synthesizing the compound of Formula 2M, that is,

[0192] (i) In a solvent, reacting the compound of Formula 2-1 with nitric acid in a nitration reaction to obtain the compound of Formula 2-2;

[0193] (ii) In an organic solvent, reacting the compound of Formula 2-2 with an amino group protecting reagent in an amino group protection reaction to obtain the compound of Formula (2-3)M;

[0194] (iii) Removing phthaloyl from the compound of Formula (2-3)M in an organic solvent to obtain the compound of Formula 2M, including The reaction formula is as follows,

[0195]

Chemical Formula

[0196] Among them, the amino group protecting reagent is Boc2O, CbzCl, TosCl, FmocCl, PMBBr, MOMCl, EOMCl, tert-butanol, isobutene, BnCl, acetic anhydride, SEMCl, TrtCl or DHP, for example, Boc2O, CbzCl, TosCl, FmocCl, PMBBr, TrtCl or DHP; P1 is selected from Boc, Cbz, Tos, Fmoc, PMB, MOM, EOM, tBu, Bn, Ac, SEM, Trt or THP, for example Boc, Cbz, Tos, Fmoc, PMB, Trt or THP; P1 is connected to any N atom in the ring where it is located, preferably, P1 is connected to the N atom at the ortho position of the methyl group in the ring where it is located. Preferably, the amino group protecting reagent is TrtCl or DHP, and P1 is selected from Trt or THP.

[0197] In some embodiments, the compound of formula (2-3) M includes the compound of formula 2-3 below and the compound of formula (2-3) m, that is,

[0198]

Chemical formula

[0199] is as follows. In some embodiments, the solvent in step (i) is, for example, concentrated sulfuric acid, acetic anhydride, acetic acid.

[0200] In some embodiments, the conditions for carrying out the nitration reaction in step (i) are to react in concentrated sulfuric acid at 10-20 °C for 0.5-2 hours.

[0201] Furthermore, the mass-volume ratio of the compound of formula 2-1 to concentrated sulfuric acid is 100 g:(150-250) mL.

[0202] Furthermore, after the nitration reaction is completed, the obtained compound of formula 2-2 is easy to filter and has good solubility in solvents such as tetrahydrofuran, dichloromethane, and acetonitrile, so the selection of the reaction solvent becomes richer.

[0203] In some embodiments, in step (ii), reaction conditions are set according to the nature of the amino group protecting reagent. In particular, when the amino group protecting reagent is TrtCl, as the reaction conditions for step (ii), under the action of a base, the reaction is carried out at 60-100 °C for 1-48 hours. When the amino group protecting reagent is DHP, as the reaction conditions for step (ii), under the action of p-toluenesulfonic acid or pyridine p-toluenesulfonate, the reflux reaction is carried out at 60-100 °C for 3-48 hours.

[0204] In some embodiments, the organic solvent for the reaction in step (ii) is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, and acetonitrile.

[0205] In particular, when the amino group protecting reagent is TrtCl, as the reaction conditions for step (ii), under the catalytic action of triethylamine, the reflux reaction is carried out in acetonitrile for 1-3 hours.

[0206] In some embodiments, as the reaction conditions for removing phthaloyl in step (iii), under the action of hydrazine hydrate, the reflux reaction is carried out in an organic solvent for 1-3 hours, and the organic solvent is selected from one or more of ethanol, tetrahydrofuran, and acetonitrile.

[0207] In some embodiments, the method for synthesizing the anti-tumor compound of formula 7 further includes the synthesis steps of the compound of formula 1, that is,

[0208] a step of carrying out a coupling reaction between the compound of formula 1-1 and the compound of formula 1-2 in an organic solvent to obtain the compound of formula 1, The reaction formula is as follows,

[0209]

Chemical formula

[0210] Among them, X1, X2 and X3 are each selected from halogens. Preferably, X1, X2 and X3 are each selected from chlorine.

[0211] Furthermore, as the conditions for coupling the compound of Formula 1-1 and the compound of Formula 1-2, the reaction is carried out at -70 to -60 °C under the action of iron acetylacetonate.

[0212] The present invention further provides an intermediate for preparing an antitumor compound of Formula 7 having the following structural formula,

[0213]

Chemical formula

[0214] Preferably, the intermediate has the following structure,

[0215]

Chemical formula

[0216] Among them, X1 and X2 are each selected from halogens, P1 is selected from Trt or THP, P1 is connected to any N atom in the ring where it is located, and preferably, P1 is connected to the N atom at the ortho position of the methyl in the ring where it is located.

[0217] The present invention further provides an intermediate for preparing an antitumor compound of Formula 7, which is characterized by having the following structural formula,

[0218]

Chemical formula

[0219] Preferably, it has the following structure,

[0220]

Chemical formula

[0221] Among them, P1 is selected from Trt or THP, The formula 6M is a complex containing one molecule of trifluoroacetic acid and one molecule of isopropyl alcohol.

[0222] Hereinafter, the present invention will be further described by way of examples, but the scope of the claims of the present invention is not limited by these examples.

[0223] The raw materials used in the examples of the present invention are all commercially available products and have chemically pure purity.

[0224] Example 1 Synthesis of the compound of formula 1'

[0225]

Chemical formula

[0226] Prepare a THF solution of (2-chlorophenyl)magnesium chloride: (2-chlorophenyl)magnesium chloride (27.34 mol) was prepared in a THF solution (50.44 L, 0.542 M), and the solution was kept warm under oxygen interruption at -5 to 5 °C for use.

[0227] Prepare a THF solution of 4,6-dichloronicotinoyl chloride: To 4,6-dichloronicotinoyl chloride (3.85 kg, 18.32 mol), add THF (25.0 L) and iron acetylacetonate (193.16 g, 0.55 mol, 0.03 eq) to prepare a solution (28.0 L, 0.651 M) for use.

[0228] Prepare dilute hydrochloric acid: Add 2.8 L of concentrated hydrochloric acid and 5.6 L of water to a 100 L reaction kettle, control the temperature at 5 to 15 °C, and prepare it for quenching.

[0229] The reaction temperature of the microreactor was set at -70 to -60 °C, and a THF solution of (2-chlorophenyl)magnesium chloride was reacted with a THF solution of 4,6-dichloronicotinoyl chloride in the microreactor to obtain a reaction solution of (2-chlorophenyl)(4,6-dichloropyridin-3-yl)ketone. The reaction solution was introduced into dilute hydrochloric acid prepared to carry out quenching. Liquid separation was performed to obtain a yellow transparent organic phase, which was concentrated. MTBE (17.5 L) was added to the concentrated residue and liquid separation was carried out. After the obtained organic phase was concentrated to remove the solvent, 2 L of n-heptane was added to obtain a yellowish-brown crude product. 3.3 L of ethanol and 9.9 L of n-heptane were added to the crude product, heated to 60 °C, dissolved until it became clear, then cooled to 5 - 10 °C, filtered, and the filter cake was dried to obtain 2.78 kg of a pale yellow powder, and the yield was 53.3%.

[0230] 1 HNMR (400 MHz, DMSO-d6) δ (ppm): 8.61 - 8.57 (m, 1H), 8.02 (s, 1H), 7.70 - 7.62 (m, 3H), 7.55 - 7.51 (m, 1H).

[0231] Synthesis of the compound of Formula 1'' Step 1: Synthesis of (6-bromopyridin-3-yl)(2-chlorophenyl)methanol

[0232]

Chemical formula

[0233] Add anhydrous tetrahydrofuran (500 mL) and 2,5-dibromopyridine (100.0 g, 0.42 mol, 1.0 eq) to a 2 L four-necked flask, cool the mixture to 2 °C in an ice-water bath with stirring, and add isopropylmagnesium chloride (210.5 mL, 2.0 M, 0.42 mol, 1.0 eq) dropwise while controlling the temperature below 10 °C. The addition was completed after about 0.5 h. Stir at room temperature (20 °C) for 1 h, then cool to 10 °C in an ice-water bath again, and add dropwise a tetrahydrofuran solution (200 mL) of 2-chlorobenzaldehyde (62.3 g, 0.443 mol, 1.05 eq). The addition was completed after about 0.5 h. Stir at 10 °C for 2 h, and TLC indicated the completion of the reaction. Add saturated aqueous ammonium chloride solution (300 mL) to the reaction system, stir for 10 min, then separate the layers, and concentrate the organic phase to obtain a yellow oil. Extract the aqueous phase with ethyl acetate (1.0 L × 2), combine with the yellow oil obtained above, wash with water (500 mL), wash with saturated brine (500 mL), dry over anhydrous Na2SO4, and concentrate to obtain a brown oil (140 g of crude product).

[0234] Step 2: Synthesis of (6-bromopyridin-3-yl)(2-chlorophenyl)ketone

[0235]

Chemical Structure

[0236] (6-Bromopyridin-3-yl)(2-chlorophenyl)methanol (140 g of crude product) was dissolved in DCM (1.3 L), and TEMPO (1.51 g, 9.4 mmol) and NaBr (1.92 g, 18.8 mmol) were added. The temperature was lowered to 3 °C in an ice-water bath, and an aqueous NaClO solution (1.34 mol / L, 600 L, 0.71 mol) neutralized with NaHCO3 (45.0 g) was added dropwise, and the temperature was kept below 20 °C during the addition. After the addition was complete, the mixture was stirred for 10 minutes, and TLC indicated the completion of the reaction. The layers were separated, the aqueous phase was extracted with DCM (1.0 L), the organic phases were combined, washed with water (1.0 L), washed with saturated brine (1.0 L), dried over anhydrous Na2SO4, concentrated to obtain a brown oil, and the crude product was slurried in (150 mL of methyl tert-butyl ether / 500 mL of petroleum ether) to obtain a yellow solid (50.3 g, yield 39.7% in two steps).

[0237] Step 3: Synthesis of (6-bromo-4-iodo-pyridin-3-yl)(2-chlorophenyl)methanone

[0238]

Chemical formula

[0239] Under the protection of nitrogen gas, a lithium tetramethylpiperidine / magnesium chloride solution (281 mL, 1.5 mol / L, 0.43 mol, 2.5 eq) was added to a 2 L four-necked flask, and the temperature was lowered to -65 °C in a dry ice / ethanol bath. A solution of (6-bromopyridin-3-yl)(2-chlorophenyl)ketone (50.0 g, 0.17 mol, 1.0 eq) in tetrahydrofuran (50 mL) was added dropwise, and the addition was completed after about 0.5 h. Then, the temperature was raised to -45 °C and stirred for 1 h, then lowered to -65 °C again, and a solution of I2 (129.3 g, 0.51 mol, 3.0 eq) in tetrahydrofuran (400 mL) was added dropwise, and the addition was completed after about 1 h. After stirring for 20 min, TLC indicated the completion of the reaction. A saturated aqueous ammonium chloride solution (500 mL) and a saturated aqueous NaHSO3 solution (500 mL) were added to the reaction system, stirred for 15 min, filtered, and the insoluble matter was washed with ethyl acetate (500 mL×2). The filtrates were combined, separated, the aqueous phase was extracted with ethyl acetate (1.0 L×2), all the organic phases were combined, washed with water (800 mL), washed with saturated brine (800 mL), dried over anhydrous Na2SO4, concentrated to obtain a yellow solid, slurried with methyl tert-butyl ether (500 mL) / petroleum ether (500 mL), and dried to obtain a yellow solid (30 g, yield 41.8%).

[0240] Example 2 Synthesis of Compound 2' Step 1: Synthesis of the compound of formula 2-2

[0241]

Chemical formula

[0242] Add concentrated sulfuric acid (7.5 L) to a four-necked flask, stir uniformly, lower the temperature of the reaction system to 20 °C or below in an ice-water bath, add the compound of formula 2-1 (3590 g, 15.80 mol, 1.0 eq) in several portions, control the temperature of the reaction system at 10-20 °C, and slowly add concentrated nitric acid (1896.4 g, 18.96 mol, 1.2 eq) with a mass fraction of 63% to the reaction system dropwise. After the dropwise addition is completed, remove the ice-water bath and react at 10-20 °C for 1 hour. The completion of the conversion of the raw materials was detected by TLC (DCM:MeOH = 20:1). Slowly pour the reaction solution into 36 kg of ice water, perform suction filtration completely, add the filter cake to a 50 L wide-mouth bucket, add 36 L of water, stir for half an hour, perform suction filtration, and wash the filter cake with water (6 L). Dry the filter cake to a constant weight (about 72 hours) to obtain the compound of formula 2-2 as an off-white solid (4160 g, yield 96.7%, HPLC purity 95.5%).

[0243] 1 HNMR (400 MHz, DMSO-d6) δ (ppm): 14.23 (br, 1H), 8.08 - 7.97 (m, 4H), 2.64 (s, 3H).

[0244] Step 2: Synthesis of the compound of formula 2-3'

[0245]

Chemical formula

[0246] Add ACN (38 L) to the reaction kettle, and while stirring, add the compound of Formula 2-2 (4140 g, 15.21 mol, 1.0 eq), TEA (1847 g, 18.25 mol, 1.2 eq), stir uniformly, and add triphenylchloromethane (4664 g, 16.73 mol, 1.1 eq). Heat up the reaction system to reflux (82 °C) over 2 hours and react completely. Cool down to 25 °C, perform suction filtration, and wash the filter cake twice with ACN (4 L * 2 times). After filtration and drying, slurry the filter cake in 30 L of water for 2 hours, perform suction filtration, wash the filter cake twice with water (4 L * 2 times), filter and dry, and then dry the filter cake in a forced-air drying oven at 50 °C for 24 hours to obtain the compound of Formula 2-3' as a white solid (6920 g, HPLC purity 99.7%, yield 88.4%).

[0247] 1 HNMR (400 MHz, CDCl3) δ (ppm): 7.97 - 7.92 (m, 2H), 7.82 - 7.78 (m, 2H), 7.41 - 7.33 (m, 9H), 7.22 - 7.19 (m, 6H), 2.08 (s, 3H).

[0248] Step 3: Synthesis of the compound of Formula 2'

[0249]

Chemical Structure

[0250] Divide 55 L of THF evenly into four 20-L four-necked flasks. While stirring, add the compound of Formula 2-3' (6900 g, 13.41 mol, 1.0 eq) and 85% by mass of N2H4·H2O (1580 g, 26.82 mol, 2.0 eq) to each flask respectively. Heat up the mixture until refluxing, and let it react completely after 3 hours. Allow the temperature to drop naturally, and perform suction filtration. Wash the filter cake twice with THF (2 L * 2 times). Concentrate the filtrate under reduced pressure in a 50°C water bath to remove 24 L of THF. Transfer the remaining filtrate to a 50-L reaction kettle, heat it up until refluxing, and slowly add 95% ethanol (36 L). A yellow-green solid slowly precipitates, and stir for 2 hours. Let the temperature drop to room temperature, perform crystallization, and stir overnight. Perform suction filtration, wash the filter cake once with 2 L of 95% ethanol, and dry the filter cake to obtain a yellow-green powdery solid (4480 g, HPLC is 100.0%, yield is 86.9%) which is the compound of Formula 2'.

[0251] 1 HNMR (400MHz, CDCl3) δ(ppm): 7.38 - 7.36 (m, 9H), 7.25 - 7.22 (m, 6H), 5.43 (s, 2H), 2.46 (s, 3H).

[0252] Synthesis of Compound 2'' Step 1: Synthesis of 2-(5-methyl-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)isoindoline-1,3-dione

[0253]

Chemical Structure

[0254] Add anhydrous acetonitrile (270 mol), p-toluenesulfonic acid (1.72 g, 0.01 mol, 0.1 eq), and pyridine (0.79 g, 0.01 mol, 0.1 eq) to the reaction flask, heat the temperature to 50 °C and stir for 2 hours. Add the compound of formula 2-2 (27.2 g, 0.1 mol, 1.0 eq), heat the temperature until refluxing, and after 1 hour, add DHP (16.8 g, 0.2 mol, 2.0 eq) dropwise. After refluxing for about 20 hours, concentrate the reaction solution, add ethyl acetate (90 mL) to the residue and slurry for 1 hour, filter, and dry the filter cake to obtain 28.6 g of the compound of formula 2-3'', with a yield of 80.3%.

[0255] 1 HNMR (400MHz, DMSO-d6) δ(ppm): 8.08-7.98(m, 4H), 5.76-5.71 (m, 1H), 4.01-3.75(m, 2H), 2.76 (s, 3H), 2.30-2.16 (m, 1H), 1.98-1.94(m, 2H), 1.72-1.67 (m, 1H), 1.57-1.56 (m, 2H).

[0256] Step 2: Synthesis of 5-methyl-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine

[0257]

Chemical formula

[0258] To the reaction flask, add the compound of Formula 2-3'' (569.4 g, 1.6 mol, 1.0 eq) and THF (5.7 L), heat up to reflux, add hydrazine hydrate (85%) (141.1 g, 2.4 mol, 1.5 eq) dropwise, and complete the dropping after about half an hour. Continue the reflux reaction for about 8 hours, indicate that the reaction is complete by TLC (PE:EA = 2:1), cool down to 20 - 25 °C, perform suction filtration, and concentrate the filtrate to obtain 303 g of crude product. Add 3 L of 95% ethanol to the crude product, heat up to reflux, cool down to room temperature, filter, and obtain the compound of Formula 2'' as a yellow-green solid. The yield was 62.5%.

[0259] 1 HNMR (400MHz, DMSO-d6) δ(ppm): 6.15 (s, 2H), 5.42 - 5.38 (m, 1H), 3.91 - 3.87 (m, 1H), 3.69 - 3.65 (m, 1H), 2.58 (s, 3H), 2.17 - 1.98 (m, 1H), 1.98 - 1.93 (m, 1H), 1.81 - 1.76 (m, 1H), 1.66 - 1.52 (m, 3H).

[0260] Example 3 Synthesis of the compound of Formula 4' [(2-chlorophenyl)(4-((5-methyl-4-nitro-1-trityl-1H-pyrazol-3-yl)amino)-6-morpholinopyridin-3-yl)ketone]

[0261] Step 1: Synthesis of (6-chloro-4-((5-methyl-4-nitro-1-trityl-1H-pyrazol-3-yl)amino)pyridin-3-yl)(2-chlorophenyl)ketone

[0262]

Chemical Structure

[0263] NaH (10.0 g) was added to 2-MeTHF (600 mL). After the temperature was raised to 50 °C, the compound of formula 2' (38.4 g, 0.1 mol) was added. After stirring for 1 hour, the compound of formula 1' (28.5 g, 0.1 mol) was added. The reaction was allowed to proceed completely for 6 - 8 hours. After the temperature was lowered to 20 - 25 °C, acetic acid (9 g) was added dropwise, water (200 mL) was added, and the mixture was stirred until it was separated into layers. After the organic phase was concentrated to about 100 mL, ethanol (300 mL) was added, and the mixture was refluxed for 4 - 6 hours. Then, heating was stopped, and the mixture was cooled to 20 - 25 °C and filtered, and then dried to obtain 41.4 g of a yellow solid, the compound of formula I', with a yield of 65.4%, which was directly used in the next step.

[0264] Step 2: Synthesis of (2-chlorophenyl)(4-((5-methyl-4-nitro-1-trityl-1H-pyrazol-3-yl)amino)-6-morpholinopyridin-3-yl)ketone

[0265]

Chemical formula

[0266] The compound of formula I' (41.4 g), morpholine (17.1 g), and 2-MeTHF (400 mL) were added to a reaction flask. The mixture was heated to 80 °C and reacted for 12 - 16 hours. After the reaction solution was concentrated to about 200 mL, ethanol (300 mL) was added while refluxing, and the mixture was refluxed for 1 hour. Then, it was cooled to 20 - 25 °C, filtered, and dried to obtain 41 g of a yellow solid, the compound of formula 4', with a yield of 91.7%.

[0267] Example 4 Step 1: Synthesis of the compound of formula 4'' (2-chlorophenyl)(4-((5-methyl-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)-6-morpholinopyridin-3-yl)methanone

[0268]

Chemical formula

[0269] Sodium hydride (87.36 g, 2.18 mol) with a mass fraction of 60% was added to a 10 L three-necked flask, and 2-MeTHF (4.3 L) was added to make the reaction system milky turbid. The reaction system was stirred at 45 - 50 °C for 1 hour. The compound of formula 2'' (197.4 g, 0.87 mol) was added in several portions. After the reaction system changed from yellow to brown and was stirred for 1 hour, the compound of formula 1' (231.5 g, 0.81 mol) was added, and the reaction was carried out at 45 - 50 °C for 2.5 hours. The completion of the reaction was centrally controlled by HPLC. The temperature was lowered to 12 °C, and acetic acid (78.61 g, 1.31 mol) was added in several portions. The internal temperature rose to 18 °C, and then morpholine (228.3 g, 2.62 mol) was added again. The reaction was carried out at 90 °C for 15 hours. The completion of the reaction was centrally controlled by HPLC. The temperature was lowered to 20 - 25 °C, 2 L of water was added, and liquid separation was carried out. The organic phase was concentrated, 1 L of ethyl acetate was added and slurried for 2 - 4 hours, then filtered, and the filter cake was dried by blowing air to obtain 218 g of the compound of formula 4'' as a yellow solid, with a yield of 51.2%.

[0270] Step 2: Synthesis of the compound of formula 7, 4-(5-(2-chlorophenyl)-3-methyl-2,10-dihydropyrazolo[4,3-b]pyrido[4,3-e][1,4]diazocin-8-yl)morpholine

[0271]

Chemical formula

[0272] 4'' (1 g, 1.90 mmol) was dissolved in 60 mL of acetic acid, 6 mL of water and 300 mg of Pd / C were added, and the reaction was carried out with hydrogen for 24 hours. After filtration, the mother liquor was concentrated, 50 mL of water was added, a large amount of yellow solid precipitated, and after filtration and drying, 720 mg of the compound of formula 6'' was obtained, with a yield of 80%.

[0273] 6'' (1 g, 2.09 mmol) was dissolved in methanol, p-toluenesulfonic acid (0.43 g, 2.50 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The temperature was raised to 55 °C, p-toluenesulfonic acid (0.28 g, 1.6 mmol) was added, and the reaction was carried out for 3 hours. The mixture was concentrated, and the product 7, a yellow solid, was obtained by column chromatography. Molecular formula: C 20 H 19 ClN6O Molecular weight: 394.86 LC-MS (Pos, m / z) = 395.22 [M+H] +

[0274] Example 5 Synthesis of the compound of formula 7 Step 1: Synthesis of the compound of formula 4' (2-chlorophenyl)(4-((5-methyl-4-nitro-1-trityl-1H-pyrazol-3-yl)amino)-6-morpholinopyridin-3-yl)ketone

[0275]

Chemical formula

[0276] Add 2-MeTHF (15 L) to the reaction flask, and while stirring, add magnesium sulfate (500 g, 4.15 mol) and sodium hydride with a mass fraction of 60% (260 g, 6.50 mol). Stir at 50 °C for 2 hours, add the compound of formula 2' (1000 g, 2.60 mol) in several portions. After the reaction system turns yellowish-brown and is stirred for 1 hour, the reaction system turns brown, and then add the compound of formula 1' (820 g, 2.86 mol). React at 46 - 60 °C for 3.5 hours, and centrally control the completion of the reaction of the compound of formula 1' by HPLC. Add acetic acid (234 g, 3.90 mol) in several portions. The reaction system becomes a brown suspension, add morpholine (680 g, 7.80 mol), and carry out a reflux reaction for 15 hours. Centrally control the end of the reaction by HPLC, and cool the reaction system to 15 - 25 °C. Add 7.5 L of water, separate the layers, dry the organic phase with anhydrous magnesium sulfate, filter, concentrate the filtrate until about 1 - 2 L of solvent remains, add 5 L of toluene and 15 L of ethanol, slurry at 78 °C for 2 hours, cool to room temperature, filter, and dry to obtain 1250 g of a yellow solid, with a yield of 70.3%.

[0277] 1 HNMR (400MHz, DMSO-d6) δ(ppm): 12.55 (s, 1H), 7.89 (s, 1H), 7.60 - 7.52 (m, 2H), 7.50 - 7.49 (m, 2H), 7.42 - 7.33 (m, 9H), 7.29 - 7.27 (m, 6H), 7.21 (s, 1H), 3.60 - 3.50(m, 4H), 3.70 (s, 4H), 2.07 (s, 3H).

[0278] Step 2: Synthesis of the compound of formula 5' (4 - ((4 - amino - 5 - methyl - 1 - trityl - 1H - pyrazol - 3 - yl)amino) - 6 - morpholinopyridin - 3 - yl)(2 - chlorophenyl)ketone

[0279]

Chemical formula

[0280] (Example 1) Water (300 mL), ethanol (95%, 7.5 L), ammonium chloride (30.30 g, 0.57 mol), and iron powder (950 g, 17 mol) were added to a 20 L reaction flask, stirred at 55 - 60 °C for 1.5 hours, THF (7.5 L) and the compound of formula 4' (775 g, 1.13 mol) were added, and the reflux reaction was carried out for 5 hours. Iron powder (320 g, 5.66 mol) was added, and the reflux reaction was carried out for 15 hours. The completion of the reaction was centrally controlled by HPLC. The reaction solution was hot-filtered through diatomaceous earth (1.5 kg), the filter cake was washed with THF (3 L), the filtrate was concentrated until about 5 L of solvent remained, 5 L of ethanol was added, slurried at 65 °C for 3 hours, cooled to room temperature, filtered, the filter cake was washed with 4 L of ethanol, and dried to obtain 590 g of a yellow solid with a yield of 79.6%.

[0281] 1 HNMR (300MHz, CDCl3) δ(ppm): 11.42 (s, 1H), 8.04 (s, 1H), 7.47 - 7.23 (m, 19H), 7.11 (s, 1H), 3.67 - 3.63 (m, 4H), 3.27 - 3.24 (m, 4H), 1.59 (s, 3H).

[0282] (Example 2) The compound of formula 4' (6.8 g, 10.0 mmol) and THF (150 mL) were added to an autoclave, platinum oxide (700 mg) was added, hydrogen at 0.5 - 0.8 MPa was introduced, and the reaction was carried out at 40 °C for 46 hours. It was detected by HPLC that the reaction was completely carried out. The reaction solution was filtered, the filtrate was concentrated until about 50 mL remained, 100 mL of n - heptane was added dropwise while refluxing, cooled to room temperature, filtered, and dried to obtain 5.5 g of a yellow solid with a yield of 84.6%.

[0283] Step 3: Synthesis of the compound of formula 6', 4-(5-(2 - chlorophenyl)-3 - methyl - 2 - trityl - 2,10 - dihydropyrazolo[4,3 - b]pyrido[4,3 - e][1,4]diazepin - 8 - yl)morpholine isopropanolate trifluoroacetate

[0284]

Chem.

[0285] 20 L of isopropyl alcohol was added to a 50 L reaction kettle, the compound of formula 5' (1980 g, 3.03 mol) and TFA (690 g, 6.05 mol) were added, the temperature was raised until refluxing, after reacting for 2 hours, the completion of the reaction was centrally controlled by HPLC, the temperature was lowered to 20°C, suction filtration was carried out, and the filter cake was washed with isopropyl alcohol until the filtrate became clear, and then dried to obtain 2300 g of a yellow solid, and the yield was 93.8%.

[0286] 1 HNMR (400 MHz, DMSO-d6) δ (ppm): 9.24 (s, 1H), 7.51 - 7.48 (m, 1H), 7.43 - 7.35 (m, 9H), 7.32 - 7.29 (m, 3H), 7.17 - 7.15 (m, 6H), 6.79 (s, 1H), 6.17 (s, 1H), 3.81 - 3.74 (m, 1H), 3.66 - 3.64 (m, 4H), 3.36 - 3.33 (m, 4H), 1.36 (s, 3H), 1.48 - 1.32 (d, 6H, J = 6.12 Hz).

[0287] Step 4: Synthesis of the compound of formula 7, 4-(5-(2-chlorophenyl)-3-methyl-2,10-dihydropyrazolo[4,3-b]pyrido[4,3-e][1,4]diazepin-8-yl)morpholine

[0288]

Chem.

[0289] The compound of formula 6' (58.0 g, 71.5 mmol), methanol (4.6 g, 143.7 mmol) were added to toluene (600 mL), trifluoroacetic acid (8.2 g, 71.9 mmol) was added, and the mixture was heated for 17 hours until reflux reaction occurred, then cooled to 50 °C, filtered by suction. The filter cake was slurried with toluene (400 mL) at 50 °C for 1 hour, then filtered by suction and dried by blowing air at 100 °C to obtain 32 g of a yellow solid. The obtained solid was dissolved in methanol (300 mL) and water (100 mL), ammonia (diluted 1-fold) was adjusted to pH = 7 - 8, a large amount of yellow solid precipitated, stirred at 50 °C for 1 hour, filtered by suction, and the filter cake was dried to obtain 24 g of a yellow solid, with a purity of 99.7% and a yield of 85.4%.

[0290] 1 H-NMR (DMSO-d6, 400MHz) 11.57 (s, 1H), 8.29 (s, 1H), 7.32 - 7.47 (m, 4H), 6.89 (s, 1H), 5.95 (s, 1H), 3.61 (m, 4H), 3.31 (m, 4H), 1.97 (s, 3H).

[0291] Example 6 Step 1: Synthesis of the compound of formula 7 4-(5-(2-chlorophenyl)-3-methyl-2,10-dihydropyrazolo[4,3-b]pyrido[4,3-e][1,4]diazepin-8-yl)morpholine

[0292]

Chemical formula

[0293] The compound of formula 5' (1 g, 1.53 mmol) was dissolved in DCM (10 mL), and TFA (350 mg, 3.06 mmol) was added. The mixture was stirred for 2.5 hours, and a yellow solid precipitated from the reaction system. It was heated until refluxing, and the reaction system gradually changed from a yellow turbidity to an orange clarity. It was stirred overnight for a total reaction time of 24 hours, and the reaction system became a dark brown clarity. EA (100 mL) and a saturated aqueous sodium bicarbonate solution were added, and after liquid separation, the organic phase was concentrated, slurried with 20 mL of EA, and filtered to obtain the compound of formula 7.

[0294] Example 7: The steps of this example were similar to Step 1 of Example 5, with 2-MeTHF replaced by toluene, and the compound of formula 4' was prepared.

[0295] Example 8: The steps of this example were similar to Step 1 of Example 5, with 2-MeTHF replaced by acetonitrile, and the compound of formula 4' was prepared.

[0296] Example 9: The steps of this example were similar to Step 1 of Example 5, with 2-MeTHF replaced by tetrahydrofuran, and the compound of formula 4' was prepared.

[0297] Example 10:

[0298]

Chemical formula

[0299] The compound of formula I' (1.3 g, 2 mmol), morpholine (5 mL, 57 mmol), and potassium carbonate (2.0 g, 14.5 mmol) were added to DCM (10 mL). After heating to 40 °C and reacting for 2 hours, the completion of the reaction was detected by HPLC. Heating was stopped, and after filtration, EtOH (10 mL) was added to the filtrate. After heating to reflux for 2 hours, heating was stopped, and it was naturally cooled to 20 - 25 °C. After filtration, the filter cake was dried to obtain 1.2 g.

[0300] Example 11:

[0301]

Chemical formula

[0302] Add 2-MeTHF (10 L) to the reaction flask, add 60% sodium hydride (300 g, 7.50 mol) while stirring, heat up to 50 °C, add the compound of formula 2' (1153.2 g, 3 mol) in several portions, stir for 1 hour, and then add a solution of the compound of formula 1' (940.3 g, 3.3 mol) in 2-MeTHF (2 L). React at 50 °C for 6 hours, and detect the completion of the reaction of the compound of formula 1' by TLC spotting plate. Cool down to 20 °C, slowly add acetic acid (270 g, 4.5 mol), stir for 10 minutes, then add morpholine (784.8 g, 9 mol), carry out a reflux reaction for 15 hours, centrally control the end of the reaction by HPLC, stop heating, and cool the reaction system to 15 - 25 °C. Wash with water (10 L × 2), dry the organic phase with anhydrous Na2SO4, perform suction filtration, and wash the filter cake with 2-MeTHF (2 L). Add 200 g of activated carbon to the filtrate, reflux for 1 hour, filter while it is hot, wash the filter cake with 2-MeTHF (1 L), distill 6 L of the solvent at normal pressure from the filtrate, add EtOH (8 L) again, reflux for 1 hour, stop heating, naturally cool down to 20 - 25 °C, filter, wash the filter cake with EtOH (1 L), transfer the obtained wet product to DCM (15 L), heat up to reflux, add activated carbon (300 g), stir for 0.5 hour, filter while it is hot, wash the filter cake with DCM (1 L), distill 2 L of the solvent at normal pressure from the filtrate, add EtOH (12 L), stir by reflux for 4 hours, stop heating, naturally cool down to 20 - 25 °C, perform suction filtration, and dry to obtain 1234.5 g of a yellow solid with a yield of 60.1%.

[0303] Example 12 The steps of this example were similar to step 2 (Example 2) of Example 5, replacing platinum oxide with Pt / C, preparing after the reaction to obtain the compound of formula 5', and the yield reached over 80%.

[0304] Example 13 The steps of this example were similar to step 2 (Example 2) of Example 5, replacing platinum oxide with Pd / C, preparing after the reaction to obtain the compound of formula 5'.

[0305] Example 14 The steps of this example were similar to step 2 (Example 2) of Example 5, replacing platinum oxide with Pd(OH)2 / C, preparing after the reaction to obtain the compound of formula 5'.

[0306] Example 15 The steps of this example were similar to step 2 (Example 2) of Example 5, replacing platinum oxide with Rh / C, preparing after the reaction to obtain the compound of formula 5'.

[0307] Example 16 The steps of this example were similar to step 2 of Example 5, replacing THF (Example 2) with a mixture of THF and isopropyl alcohol, preparing after the reaction to obtain the compound of formula 5'.

[0308] Example 17 The steps of this example were similar to step 3 of Example 5, replacing trifluoroacetic acid (TFA) with p-toluenesulfonic acid, preparing after the reaction to obtain the compound of formula 6’.

[0309] Example 18 The steps of this example were similar to step 3 of Example 5, replacing trifluoroacetic acid (TFA) with methanesulfonic acid, preparing after the reaction to obtain the compound of formula 6’.

[0310] Example 19 The steps of this example were similar to step 4 of Example 5, replacing methanol with ethanol, preparing after the reaction to obtain the compound of formula 7, and the yield reached over 80%.

[0311] Example 20 The compound of formula 6' (385 g, 0.47 mol), TFA (138 g, 1.21 mol), and EtOH (55.66 g, 1.21 mol) were added to DCM (4 L), heated until refluxing, and after 1.5 hours, the heating was stopped and cooled to 20 - 25 °C. An aqueous solution of NaOH (66 g) in water (2 L) was added, a solid precipitated, and after stirring for 1 hour, suction filtration was performed. The filter cake was dissolved in 12 L of EtOH + 2 L of water, 15 g of activated carbon was added, and after stirring for 0.5 hour, suction filtration was performed. The filtrate was stirred and concentrated to 1.5 L, reflux was continued for 1 hour, cooled to 20 - 25 °C, suction filtered, and dried to obtain 114 g of a yellow solid with a yield of 61.0%.

[0312] The above are only preferred embodiments of the present invention and do not limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the claims of the present invention.

Claims

1. A method for synthesizing an antitumor compound of Formula 7, comprising: 【Chemical Formula 1】 (a) In an organic solvent, subjecting a compound of Formula 1 to an aromatic nucleophilic substitution reaction with a compound of Formula 2M in the presence of a base to obtain a compound of Formula IM, and then, with or without isolation, subjecting the compound of Formula IM to a subsequent aromatic nucleophilic substitution reaction with a compound of Formula 3 to obtain a compound of Formula 4M; (b) In an organic solvent, subjecting the compound of Formula 4M to a reduction reaction in the presence of a catalyst to obtain a compound of Formula 5M; (c) In an organic solvent, subjecting the compound of Formula 5M to ring closure in the presence of an acid to obtain a compound of Formula 6M; (d) In an organic solvent, removing the amino group protecting group from the compound of Formula 6M to obtain the antitumor compound of Formula 7, The reaction scheme is as follows: 【Chemical Formula 2】 wherein X 1 and X 2 are each chlorine, P 1 is an amino group protecting group, and P1 is connected to any N atom in the ring where it is located. A method for synthesizing an antitumor compound of Formula 7, characterized by the above.

2. The method according to Claim 1, wherein in step (a), a subsequent aromatic nucleophilic substitution reaction is carried out with the compound of Formula 3 under basic conditions to obtain a compound of Formula 4M.

3. The method according to Claim 1, wherein P1 is selected from Boc, Cbz, Tos, Fmoc, PMB, MOM, EOM, tBu, Bn, Ac, SEM, Trt, and THP.

4. The method according to Claim 1, wherein P1 is selected from Boc, Cbz, Tos, Fmoc, PMB, Trt, and THP.

5. The method according to Claim 1, wherein P1 is connected to the N atom at the ortho position of the methyl in the ring where it is located.

6. In step (a), the organic solvent is selected from one or more of 2-methyltetrahydrofuran, acetonitrile, tetrahydrofuran, and toluene, and the base is selected from one or more of sodium hydride, sodium hydroxide, cesium carbonate, triethylenediamine, sodium tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide, and sodium hexamethyldisilazide. In step (a), the reaction pressure is 0 to 10 MPa in gauge pressure, the reaction time is 1 to 96 hours, and the reaction temperature is the reflux temperature. During the aromatic nucleophilic substitution reaction of the compound of formula 1 with the compound of formula 2M under the action of a base, the reaction time is 3 to 18 hours, and the reaction temperature is 40 to 70 °C. During the subsequent aromatic nucleophilic substitution reaction with the compound of formula 3, the reaction time is 8 to 16 hours, and the reaction temperature is the reflux temperature. The ratio is solvent: compound of formula 1: compound of formula 2M: compound of formula 3: base = 0.5 to 60 L: 0.1 to 11 mol: 1 mol: 0.3 to 30 mol: 0.2 to 25 mol. The method according to any one of claims 1 to 5, characterized in that.

7. During the aromatic nucleophilic substitution reaction of the compound of formula 1 with the compound of formula 2M under the action of a base, magnesium sulfate is added, and during the subsequent aromatic nucleophilic substitution reaction with the compound of formula 3, acetic acid is added. The ratio is solvent: compound of formula 1: compound of formula 2M: compound of formula 3: base: magnesium sulfate: acetic acid = 0.5 to 60 L: 0.1 to 11 mol: 1 mol: 0.3 to 30 mol: 0.2 to 25 mol: 0.2 to 20 mol: 0.1 to 15 mol. The method according to claim 6, characterized in that. **Claim 8**: As the basic condition described in step (a), morpholine can be used as the base without adding other bases, or other bases selected from one or more of sodium hydride, sodium hydroxide, cesium carbonate, triethylenediamine, sodium tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide, and sodium hexamethyldisilazide can be added. The method according to claim 2, characterized by the above. **Claim 9** In step (b), the organic solvent is selected from one or more of methanol, ethanol, isopropyl alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, acetic acid, and acetonitrile. The catalyst is selected from iron powder, platinum oxide, Pt / C, Pd(OH) 2 / C, Rh / C or Pd / C, In step (b), when the catalyst is iron powder, the reaction time is 1 to 96 hours, the reaction pressure is 0 to 10 MPa in gauge pressure, and the reaction temperature is the reflux temperature. The ratio is organic solvent: compound of formula 4M: catalyst = 1 to 130 L: 1 mol: 1 to 150 mol. The method according to any one of claims 1 to 8, characterized by the above. **Claim 10**: In step (b), when the catalyst is iron powder, 0.05 to 5 mol equivalents of ammonium chloride are further added, the solvent is a mixed solvent of ethanol and tetrahydrofuran, and the volume ratio of ethanol to tetrahydrofuran is (6 to 10):

10. The method according to claim 9, characterized by the above. **Claim 11**: In step (b), when the catalyst is platinum oxide, Pt / C, Pd(OH)2 / C, Rh / C or Pd / C, the reaction is carried out at 30 to 80 °C for 20 to 80 hours under a hydrogen atmosphere, the reaction pressure is 0 to 10 MPa in gauge pressure, and the ratio is solvent: compound of formula 4M: catalyst = 1 to 50 mL: 1 g: 0.03 to 0.2 g. The method according to claim 9, characterized by the above. **Claim 12**: In step (b), the organic solvent is tetrahydrofuran, and water is further added, with the volume ratio of water to tetrahydrofuran being (0.2 - 2):

10. The method according to claim 3, characterized in that. **Claim 13** In step (c), the acid is selected from one or more of trifluoroacetic acid, methanesulfonic acid, p - toluenesulfonic acid, formic acid, acetic acid, and hydrochloric acid, and the organic solvent is selected from at least one of dichloromethane, methanol, ethanol, and isopropyl alcohol. In step (c), the reaction time is 1 - 96 hours, the reaction pressure is 0 - 10 MPa in gauge pressure, the reaction temperature is the reflux temperature, and the ratio is solvent:compound of formula 5M:acid = 0.5 - 70 L:1 mol:0.220 mol. The method according to any one of claims 1 - 12, characterized in that. **Claim 14** Step (c) is characterized in that the compound of formula 5M is refluxed in isopropyl alcohol under the action of trifluoroacetic acid for 1 - 3 hours. The method according to any one of claims 1 - 13, characterized in that. **Claim 15** In step (d), the organic solvent is selected from one or more of toluene, dichloromethane, acetonitrile, tetrahydrofuran, methanol, ethanol, and isopropyl alcohol. In step (d), an acid is further added, and the acid is selected from at least one of formic acid, acetic acid, hydrochloric acid, methanesulfonic acid, and trifluoroacetic acid. In step (d), an alcohol or phenol other than the solvent is further added. The alcohol is selected from methanol and / or ethanol, and the phenol is selected from phenol and / or p - methoxyphenol. In step (d), the reaction time is 1 to 96 hours, the reaction pressure is 0 to 10 MPa in gauge pressure, the reaction temperature is the reflux temperature, and the ratio is solvent: compound of formula 6M: acid: alcohol or phenol = 10 to 800 L: 1 mol: 0.1 to 10 mol: 0.2 to 20 mol, the method according to any one of claims 1 to 14, characterized in that.

16. Further comprising the step of synthesizing a compound of formula 2M, that is, (i) In a solvent selected from concentrated sulfuric acid, acetic anhydride, and acetic acid, reacting a compound of formula 2-1 with nitric acid at a reaction time of 0.5 to 2 hours and a reaction temperature of 10 to 20 °C to obtain a compound of formula 2-2; (ii) In an organic solvent selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, and acetonitrile, reacting the compound of formula 2-2 with an amino group protecting reagent at a reaction time of 1 to 48 hours and a reaction temperature of 60 to 100 °C to obtain a compound of formula (2-3)M; (iii) Further comprising the step of removing phthaloyl from the compound of formula (2-3)M in an organic solvent selected from one or more of ethanol, tetrahydrofuran, and acetonitrile to obtain a compound of formula 2M, The reaction formula is as follows: 【Chemical formula 3】 , Among them, the amino group protecting reagent is Boc 2 O, CbzCl, TosCl, FmocCl, PMBBr, MOMCl, EOMCl, tert-butanol, isobutene, BnCl, acetic anhydride, SEMCl, TrtCl, or DHP, P 1 is selected from Boc, Cbz, Tos, Fmoc, PMB, MOM, EOM, tBu, Bn, Ac, SEM, Trt, or THP, and P 1 is connected to any N atom in the ring where it is located, the method according to any one of claims 1 to 15, characterized in that. **Claim 17**: The method according to claim 16, wherein P1 is connected to the N atom at the ortho position of the methyl group in the ring where it is located. **Claim 18**: When the amino group protecting reagent is TrtCl, as the reaction conditions for step (ii), under the action of a base, the reaction is carried out at 60 - 100 °C for 1 - 48 hours. When the amino group protecting reagent is DHP, as the reaction conditions for step (ii), under the action of p - toluenesulfonic acid or pyridine p - toluenesulfonate, the reflux reaction is carried out at 60 - 100 °C for 3 - 48 hours. The method according to claim 16, characterized in that. **Claim 19**: Further comprising the step of synthesizing the compound of formula 1, that is, In an organic solvent, at a reaction time of 2 - 4 hours and a reaction temperature of - 70 - 60 °C, coupling the compound of formula 1 - 1 with the compound of formula 1 - 2 to obtain the compound of formula 1. Further comprising the step of The reaction formula is as follows: **Chemical Formula 4**: , Among them, X3 is selected from halogens, and X1 and X2 are each chlorine. The method according to any one of claims 1 - 18, characterized in that. **Claim 20**: The method according to claim 19, characterized in that X3 is chlorine. **Claim 21**: An intermediate for preparing the antitumor compound of formula 7, having the following structural formula: **Chemical Formula 5**: , Among them, X 1 and X 2 are each chlorine, P 1 is selected from Trt or THP, and P 1 is connected to any N atom in the ring where it is located. An intermediate, characterized in that. The intermediate according to claim 21, wherein P1 is connected to the N atom at the ortho position of the methyl group in the ring where it is located. Claim 23 An intermediate for preparing an antitumor compound of formula 7, having the following structural formula: 【Chemical Formula 6】 Among them, P 1 is selected from Trt or THP, and P 1 is connected to any N atom in the ring where it is located, The formula 6M is a complex containing one molecule of trifluoroacetic acid and one molecule of isopropyl alcohol. The intermediate is characterized by this. The intermediate according to claim 23, wherein P1 is connected to the N atom at the ortho position of the methyl group in the ring where it is located.

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