CN115724758A - Camptothecin derivative intermediate, synthetic method thereof and method for synthesizing camptothecin derivative by using intermediate - Google Patents

Abstract

The invention discloses a camptothecin derivative intermediate, a synthesis method thereof and a method for synthesizing a camptothecin derivative by using the intermediate. The preparation method has the advantages of cheap and easily-obtained raw materials, simple synthetic route of the intermediate, avoidance of oximation, catalytic hydrogenolysis and one-pot reaction of amino protection, great reduction of reaction steps, mild operation conditions, reduction of operation difficulty, low energy consumption and suitability for industrial scale-up production; the atom utilization rate is improved, and the method is more suitable for the industrial application of green chemistry; the yield of the synthesis of the derivatives of the ixitacon is improved, and the cost is further reduced.

Description

Camptothecin derivative intermediate and its synthesis method and use of intermediate to synthesize camptothecin Derivative method

technical field

The invention belongs to the technical field of pharmaceutical intermediates and organic synthesis, and in particular relates to an intermediate for synthesizing camptothecin derivatives, a preparation method thereof, and a synthesis method for synthesizing camptothecin derivatives using the intermediate.

Background technique

Antibody-drug conjugate (ADC) combines the high specificity of monoclonal antibody drugs with the high activity of small molecule cytotoxic drugs to improve the targeting of tumor drugs and reduce toxic side effects. The accurate recognition of the target of ADC drugs and the immunity of non-cancer cells have greatly improved the efficacy of the drug and reduced the side effects, which has attracted the attention of personnel in the field of pharmaceutical research and development. (Patent Documents 1 and 2 and Non-Patent Documents 1-3)

As one such antibody-drug conjugate, an antibody-drug conjugate comprising an antibody and exitecan (which is a topoisomerase I inhibitor) as its components is known (Patent Documents 3-5 and Non-Patent Documents 4 and 5). Since these antibody-drug conjugates exert particularly excellent antitumor effects and safety, they are currently under clinical investigation. The structure of Exatecan (Ixitecan) is as follows:

Patent EP0495432B1 discloses a kind of Exatecan (Ixitecan) compound and preparation method thereof, and the reaction process is as follows:

In the patent WO1996026181A1, another synthesis method of Ixitecan derivatives is disclosed:

The above-mentioned two technological routes all carry out repeated reaction continuously: in the route one, the carbonyl group is oxidized after the decarbonylation, and the amino group is protected after the deamination protection acetyl group, and the yield is only 5.6%. Ring-opening, oxidation, reduction and other processes, and potassium permanganate is used in the reaction process, which causes certain dangers to the production process. The two routes have long reaction steps, low atom utilization, complicated reaction operations, and are not suitable for industrial scale-up production.

The patent document WO2019044946A1 has carried out a series of optimizations on the synthesis of Ixitecan derivative intermediates and disclosed the following synthetic route 3:

In this process route, ixitecan is synthesized from 2-fluoro-1-methyl-4-nitrobenzene through 10 steps, and the total yield is about 5%.

Shanghai Haoyuan Company also disclosed another synthetic route 4 of the intermediate of Ixitecan derivatives in the patent CN111470998B:

The bromination reagent used in the bromination reaction of this synthetic route is liquid bromine, which is highly toxic and corrosive, and has certain dangers in the scale-up production, and the reaction process involves the use of Grignard reagents, which are easily Degradation, and it needs to be carried out in an ultra-low temperature environment, which requires high reaction equipment. The selectivity of the rearrangement reaction is low, the post-treatment is complicated, and it is not suitable for industrial scale-up production. Both synthetic route 3 and synthetic route 4 cannot avoid the "one-pot" reaction of oximation, catalytic hydrogenolysis and protection on amino groups, involving dangerous processes such as nitration and hydrogenation, and industrial production is relatively difficult.

It can be seen that, in order to meet the production demand of Ixitecan, it is urgent to develop a synthetic route of Ixitecan intermediate with high yield and suitable for industrial production.

Contents of the invention

In order to solve the problems existing in the prior art, the present invention provides a preparation method of Ixitecan mesylate, its intermediate and preparation method.

The present invention relates to a kind of preparation method of Ixitecan mesylate, it comprises the following steps:

(f) Compound A undergoes an intramolecular Friedel-Crafts acylation reaction under the action of an intramolecular cyclization reagent to obtain compound 6;

(g) performing selective deamination protection on compound 6 to obtain compound B;

(h) performing a condensation reaction between the compound B and compound 7 to obtain compound 8;

(i) compound 8 is hydrolyzed under the action of methanesulfonic acid to obtain ixinotecan, namely compound 9;

Wherein, in step (f), the cyclization reagent is selected from a Friedel-Crafts acylating reagent, such as a mixed reagent of a protic acid and an anhydride or a mixed reagent of a chlorinated reagent and a Lewis acid or polyphosphoric acid PPA;

Preferably, the protic acid is selected from trifluoroacetic acid, hydrochloric acid or sulfuric acid;

And/or, the acid anhydride is selected from trifluoroacetic anhydride or trifluoromethanesulfonic anhydride;

Preferably, the chlorination reagent is selected from thionyl chloride, sulfuryl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride or phosphorus pentachloride;

And/or, the Lewis acid is selected from aluminum trichloride, tin tetrachloride, and iron salts.

As an embodiment, in step (f), the amount of the cyclization reagent added is based on at least enabling the reaction to proceed, preferably the amount of the substance of the cyclization reagent and the compound A The ratio is 0.5-20:1, more preferably 1-5:1.

Furthermore, the reaction temperature in step (f) is preferably -40 to 150°C, more preferably 0 to 100°C, and even more preferably 0 to 80°C. Further, the reaction time of step (f) is preferably 0.5-24h, more preferably 2-12h.

Further, step (g) is preferably carried out using hydrochloric acid or a mixed solution of hydrochloric acid and alcohol, and can be more preferably carried out using 2N hydrochloric acid/ethanol.

Further, in step (g), the reaction temperature is preferably 40-100°C, more preferably 50-80°C; the reaction time is preferably 2-8h, more preferably 3-6h.

As an embodiment, in step (h), compound B and compound 7 undergo condensation reaction under the action of pyridinium p-toluenesulfonate, o-cresol and toluene to obtain compound 8.

Further, in step (h), preferably, the ratio of compound B to compound 7 is 1:0.9-1.5, more preferably 1:1.0-1.1.

Further, in step (h), preferably, the ratio of compound B to pyridinium p-toluenesulfonate is 1:0.01-0.30, more preferably 1:0.05-0.20.

Further, in step (h), preferably, the mass ratio of compound B to o-cresol is 1:0.5-4.0, more preferably 1:1.0-3.5.

Further, in step (h), the reaction temperature is preferably 80-130°C, more preferably 100-120°C.

Further, in step (h), the reaction time is preferably 18-72 hours, more preferably 24-36 hours. As an embodiment, in step (i), the reaction is carried out in a solvent, preferably, the solvent is selected from one or more of water, 2-methoxyethanol, ethylcyclohexane or toluene , preferably a mixed solution of water and toluene; the amount of the solvent added is 10-60 ml/g based on the mass of the compound 8.

Furthermore, in step (i), the reaction temperature is preferably 70-100°C, more preferably 80-90°C.

Furthermore, in step (i), the reaction time is preferably 4-12 hours, more preferably 6-8 hours.

The present invention also relates to a new intermediate compound A, which can be used to synthesize compound 6 or ixitecan or its mesylate,

The present invention also relates to providing a method for preparing an intermediate compound A, and the method for preparing the intermediate compound A specifically includes the following steps:

(e) carrying out catalytic hydrogenation reaction of compound 5 in the presence of a catalyst to obtain compound A,

Further, in step (e), the catalyst is selected from palladium catalyst, platinum catalyst, nickel catalyst, ruthenium catalyst or rhodium catalyst, more preferably palladium carbon catalyst, more preferably 5% palladium carbon catalyst.

Further, in step (e), the amount of the catalyst added is at least based on the progress of the reaction, preferably the mass ratio of the catalyst to the compound 5 is 0.02-0.4:1, more preferably 0.05- 0.15.

Further, in step (e), the reaction is performed in an organic solvent selected from the group consisting of acetonitrile, dichloromethane, chloroform, methanol, ethanol, ether, 1,2-dimethoxyethane, Tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethyl acetate, ethylcyclohexane, benzene, toluene, chlorobenzene, acetone, and water and their mixed solvents.

Further, in step (e), the amount of the organic solvent added is 10-60 ml/g based on the mass of the compound 5.

Further, in step (e), the reaction temperature is 40-70°C, preferably 50-70°C; the reaction time is 0.5-24h, preferably 6-12h.

The present invention also relates to providing an intermediate compound 5, which is used as an intermediate for the preparation of compound 6 or ixinotecan or its mesylate,

The present invention also relates to providing a preparation method of compound 5, comprising the following steps:

(d) Compound 4 and 2-acetylaminobut-3-enoic acid are subjected to a coupling reaction under the action of a coupling catalyst and an alkaline substance to obtain compound 5,

Wherein, R is selected from halogen, sulfonate group or diazo group, such as iodine, trifluoromethanesulfonyloxy group.

Further, in step (d), in step (d), the coupling catalyst is a complex formed by a palladium salt and a phosphine ligand;

And/or the palladium salt is selected from palladium chloride, palladium acetate, tetrakis(triphenylphosphine)palladium, palladium nitrate or triphenylphosphinepalladium dichloride, preferably palladium acetate;

And/or the phosphine ligand is selected from triphenylphosphine, tricyclohexylphosphine, tri(o-tolyl)phosphine, tri[3,5-bis(trifluoromethyl)phenyl]phosphine, triisopropylphosphine phosphine and dicyclohexyl-(2,6-diisopropylphenyl)phosphine, preferably tri(o-tolyl)phosphine.

Further, in step (d), the alkaline substance is selected from triethylamine, isopropylamine, pyridine, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium tert-butoxide, preferably triethylamine.

Further, in step (d), in step (d), the ratio of compound 4 to 2-acetylaminobut-3-enoic acid is 1:1.0-3.0, for example, 1:1.2-1.5;

And/or the amount of the coupling catalyst added is based on the amount of the phosphine ligand, and the ratio of the amount of compound 4 to the phosphine ligand is 1:0.05-0.75, for example, 1 : 0.15～0.30;

And/or the ratio of the compound 4 to the basic substance is 1:1.0-15.0, for example, 1:3.0-10.0.

Further, in step (d), the reaction is carried out in an organic solvent, and the organic solvent is selected from acetonitrile, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethyl Acetamide, toluene, water and mixed solvents thereof; the amount of the organic solvent added is 10-60ml/g based on the mass of compound 4.

Further, in step (d), the reaction temperature is 20-110°C, such as 50-80°C; the reaction time is 2-24h, preferably 8-16h.

The present invention also relates to providing a preparation method of compound 4, comprising the steps of:

(a) compound 1 is converted to obtain compound 2;

(b) compound 2 is catalytically hydrogenated under the action of a catalyst to obtain compound 3;

(c) Compound 3 and an acylating agent are subjected to an acylation reaction under the action of a catalyst to obtain compound 4;

R is selected from halogen, sulfonate or diazo, eg iodine, trifluoromethanesulfonyloxy.

Further, in step (a), preferably, the iodide is selected from iodine and N-iodosuccinimide, more preferably N-iodosuccinimide; the N-iodosuccinimide The amount of substituted succinimide is not limited as long as the reaction proceeds, and is preferably 1-1.5 equivalents. This step can preferably be performed in a mixed solvent of sulfuric acid and other solvents.

Further, in step (a), preferably, the reaction solvent is selected from the group consisting of dichloromethane, chloroform, 1,2-dimethoxyethane, hexane, pentane, heptane, cyclohexane, ethylcyclohexane alkanes, benzene, toluene, chlorobenzene and their mixed solvents.

Further, in step (a), the reaction temperature is preferably -10 to 30°C, more preferably 0 to 10°C.

Further, in step (a), the reaction time is preferably 0.5-4 hours, more preferably 1.5-2 hours.

Further, in step (b), preferably, the catalyst is selected from one or more of rhodium carbon catalyst, platinum carbon catalyst, platinum dioxide, titanium trichloride, nickel chloride, zinc powder, iron powder , more preferably a platinum-carbon catalyst; the amount of the catalyst is not limited, as long as the reaction proceeds, preferably, the mass ratio of the catalyst to compound 2 is 0.05 to 0.4:1, more preferably 0.05 to 0.1: 1.

Further, in step (b), preferably, the reaction solvent is selected from the group consisting of methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetic acid Ethyl ester, water and their mixed solvents; the added amount of the reaction solvent is 10-60ml/g based on the mass of the compound 1.

Further, in step (b), the reaction temperature is preferably 40-70°C, more preferably 50-70°C.

Furthermore, in step (b), the reaction time is preferably 0.5-8 hours, more preferably 2-4 hours.

Further, in step (c), preferably, the acylating agent is selected from one or more of acetic anhydride, acetyl chloride, ketene, chloroacetate and nitrile acetate, more preferably acetic anhydride ; The ratio of the amount of the acylating agent to the compound 2 is 0.5-1.5:1, more preferably 0.75-1:1.

Further, in step (c), preferably, the reaction is carried out under the action of a base, and the base is selected from triethylamine, isopropylamine, pyridine, sodium carbonate, potassium carbonate and potassium tert-butoxide, more preferably Triethylamine; the ratio of the amount of the base to the compound 2 is 0.5-1.5:1, more preferably 0.75-1.5:1.

Further, in step (c), preferably, the reaction solvent is selected from methanol, ethanol, tetrahydrofuran, dichloromethane, chloroform, acetone, toluene, ethyl acetate and water and mixed solvents thereof, more preferably ethyl acetate; The added amount of the reaction solvent is 10-60ml/g based on the mass of the compound 2.

Further, in step (c), the reaction temperature is preferably -10 to 40°C, more preferably 0 to 30°C.

Further, in step (c), the reaction time is preferably 2-24 hours, more preferably 3-12 hours.

The E and Z forms represented by the compounds 5 and 6 described in the present invention exist in the form of geometric isomers, and both are included in the represented compounds, so they are included in the scope of the present invention. The compound represented by compound 5 of the present invention may be a mixture of forms E and Z, and this mixture may be directly used in the next step.

Compared with prior art, the beneficial effect of the present invention is:

(1) The present invention provides a new intermediate 5 and A of ixitecan mesylate, which opens up the research field of important intermediates of ixitecan derivatives;

(2) The raw materials are cheap and easy to obtain, the synthetic route of the intermediate is simple, and the "one-pot" reaction of oximation, catalytic hydrogenolysis and protection on the amino group is avoided, the reaction steps are greatly reduced, the operating conditions are mild, and the difficulty of operation is reduced. Low energy consumption, suitable for industrial scale-up production;

(3) The utilization rate of atoms is improved, which is more in line with the industrial application of green chemistry; the yield of exitecan derivative synthesis is improved, and the cost is further reduced.

Detailed ways

The technical solution of the present invention will be clearly and completely described below in conjunction with specific embodiments, but those skilled in the art will understand that the embodiments described below are some examples of the present invention, rather than all embodiments, and are only for illustration invention, and should not be construed as limiting the scope of the invention. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without making creative efforts belong to the protection scope of the present invention. Those who do not indicate the specific conditions in the examples are carried out according to the conventional conditions or the conditions suggested by the manufacturer. The reagents or instruments used were not indicated by the manufacturer, and they were all conventional products that could be purchased from the market.

Example 1

Preparation of compound 4a

Concentrated sulfuric acid (90%, 50mL) was added to a three-necked flask, and compound 1 (10g, 64.5mmol) was added after cooling to about 1°C, and then N-iodosuccinimide (20.4g, 90.2mmol) was divided into six added to the reaction flask. The mixture was stirred at about 2°C for 2 hours. The resulting reaction solution was added to cold water (100 mL). After adding toluene (50 mL) for extraction and separation, the aqueous layer was removed. Then, the organic layer was washed with water (50 mL), 5.0 wt % sodium carbonate aqueous solution (50 mL), 5 wt % sodium sulfite aqueous solution (25 mL, 3 times). The organic layer was then concentrated under reduced pressure to obtain a crude product of compound 2 (200 g).

Compound 2 and ethyl acetate (15 mL) were added to the reaction kettle, followed by a suspension of 1% platinum on carbon catalyst (2.1 g) and ethyl acetate (90 mL), and the atmosphere was replaced with nitrogen and then with hydrogen. The reaction liquid was stirred at 65° C. for 3 hours in a hydrogen flow (0.2 MPa), and cooled to room temperature. The insoluble material was separated from the resulting suspension by filtration and washed with ethyl acetate (30 mL). Then, the filtrate was washed with 6.5wt% aqueous sodium bicarbonate (25mL) and 5wt% brine (25mL), and the obtained organic layer was concentrated under reduced pressure to obtain a solution of compound 3 in ethyl acetate (50mL ).

The ethyl acetate solution of compound 3 and triethylamine were added into a three-necked flask, cooled to about 0°C, acetic anhydride (3.4ml, 35.4mmol) was slowly added, and the mixture was stirred at room temperature for 4 hours. After the reaction was complete, saturated brine (50 ml) was added, and the aqueous layer was removed after separation. The organic layer was concentrated under reduced pressure. Acetonitrile (50 mL) and water (50 mL) were added to the concentrated residue, and the concentrated residue was stirred at 25°C. Precipitated crystals were collected by filtration, and washed with 50% aqueous acetonitrile (20 mL). The obtained crystals were dried at 40° C. under reduced pressure to obtain compound 4a as white crystals (6.4 g, yield 38%).

¹ H NMR (500MHz, CDCl ₃ )δ7.43(s,1H),7.38(d,J=7.8Hz,1H), 7.19(m,1H),2.27(d,J=7.8Hz,,3H), 2.15(s,3H).

Example 2

Preparation of Compound A

A solution of compound 4a (10.0 g, 34.1 mmol), 2-acetylaminobut-3-enoic acid (6.1 g, 42.6 mmol) and triethylamine (23.7 mL, 170.6 mmol) in acetonitrile (200 mL) was prepared under reduced pressure Degas and replace the atmosphere with nitrogen, then add tri(o-tolyl)phosphine (1.5g, 5.12mmol) and palladium(II) acetate (0.4g, 1.71mmol), and degas the mixture under reduced pressure, replace with nitrogen atmosphere, then heated to reflux for 8 hours, and cooled to room temperature. 2-Methyltetrahydrofuran (100 mL) and water (100 mL) were added to the reaction solution cooled to room temperature, 25 w/v% aqueous sodium hydroxide solution (6.5 mL, 40.2 mmol) was added, and the organic layer was removed. The aqueous layer was washed with 2-methyltetrahydrofuran (30 mL, twice), and the organic layer was removed. Concentrated hydrochloric acid (36%, 6.0 g, 60.1 mmol) and 2-methyltetrahydrofuran (30 mL, 2 times) were added to the aqueous layer. After separation, the aqueous layer was removed and the organic layer was washed with 10 wt% brine (60 mL). The organic layer was concentrated under reduced pressure to obtain a crude compound 5 (10.8 g) containing geometric isomers.

A suspension was obtained by adding tetrahydrofuran (100 mL), purified water (100 mL) and 5% palladium on carbon (2.1 g) to crude compound 5 (10.8 g) containing geometric isomers, and the atmosphere was replaced with nitrogen and then hydrogen . The mixture was stirred at 60° C. for 8 hours under hydrogen flow (0.5 MPa), and cooled to room temperature. The insoluble material was separated from the resulting suspension by filtration and washed with tetrahydrofuran (30 mL). The pH of the filtrate was adjusted to about 2 with 1N hydrochloric acid solution. The solvent was concentrated to dryness under reduced pressure, acetonitrile (40 mL) and water (80 mL) were added to the concentrated residue, and the concentrated residue was stirred at 25°C. Precipitated crystals were collected by filtration, and washed with 50% aqueous acetonitrile (10 mL). The obtained crystals were dried at 40° C. under reduced pressure to obtain Compound A as white crystals (9.2 g, yield 87%).

¹ H NMR (500MHz, DMSO-d6) δ12.64(s, 1H), 9.99(s, 1H), 8.29(d, J=7.8Hz, 1H), 7.41(dd, J=12.2, 2.1Hz, 1H ),7.07(d,J＝2.1Hz,1H), 4.21(m,1H),1.75-1.88(m,2H),2.59(m,2H),2.08(s,3H),2.02(s,3H) , 1.89(s,3H).

¹³ C NMR (126MHz, DMSO-d6) δ174.02, 169.93, 168.88, 161.73, 159.83, 142.40, 138.36, 117.15, 115.18, 104.20, 52.05, 32.07, 29.34, 24.45, 22.84, 10.07.

ESI-MS: m/z C ₁₅ H ₁₉ FN ₂ O ₄ [M+H]+calculated: 311.13; found 311.18;

Example 3

Preparation of Compound A

Compound 4a (10.0g, 34.1mmol), 2-acetylaminobut-3-enoic acid (6.1g, 42.6mmol) and sodium bicarbonate (8.6g, 102mmol) were added to a mixed solvent of toluene and water (150mL/50mL) , the reaction solution was degassed under reduced pressure and replaced the atmosphere with nitrogen, then added triphenylphosphine palladium dichloride (1.2 g, 1.7 mmol), and the mixture was degassed under reduced pressure, replaced the atmosphere with nitrogen, 100 ° C Heat to reflux for 24 hours. 2-Methyltetrahydrofuran (100 mL) and water (100 mL) were added to the reaction solution cooled to room temperature, 25 w/v% aqueous sodium hydroxide solution (6.5 mL, 40.2 mmol) was added, and the organic layer was removed. The aqueous layer was washed with 2-methyltetrahydrofuran (30 mL, twice), and the organic layer was removed. Concentrated hydrochloric acid (36%, 6.0 g, 60.1 mmol) and 2-methyltetrahydrofuran (30 mL, 2 times) were added to the aqueous layer. After separation, the aqueous layer was removed and the organic layer was washed with 10 wt% brine (60 mL). The organic layer was concentrated under reduced pressure to obtain a crude compound 5 (9.2 g).

A suspension was obtained by adding tetrahydrofuran (100 mL), purified water (100 mL) and 5% palladium on carbon (2.1 g) to crude compound 5 (9.0 g) containing geometric isomers, and the atmosphere was replaced with nitrogen and then hydrogen . The mixture was stirred at 40°C for 16 hours in a stream of hydrogen (0.4 MPa), and cooled to room temperature. The insoluble material was separated from the resulting suspension by filtration and washed with tetrahydrofuran (20 mL). The pH of the filtrate was adjusted to about 2 with 1N hydrochloric acid solution. The solvent was concentrated to dryness under reduced pressure, acetonitrile (40 mL) and water (80 mL) were added to the concentrated residue, and the concentrated residue was stirred at 25°C. Precipitated crystals were collected by filtration, and washed with 50% aqueous acetonitrile (10 mL). The obtained crystals were dried at 40° C. under reduced pressure to obtain Compound A as white crystals (8.5 g, yield 80%).

Comparative example 1

Compound 4a (0.84g, 3.4mmol), 2-butenoic acid-3-(acetylamino)-phenylmethyl ester (1.2g, 4.2mmol) and triethylamine (2.3mL, 17.1mmol) were dissolved in N,N - A solution of dimethylformamide (10 mL) was degassed under reduced pressure and the atmosphere was replaced with nitrogen, then tris(o-tolyl)phosphine (0.3 g, 0.48 mmol) and palladium(II) acetate (0.08 g, 0.16 mmol) were added ), and the mixture was degassed under reduced pressure, replaced the atmosphere with nitrogen, then heated to reflux for 8 hours, and cooled to room temperature.

The reaction solution was sampled for detection by LCMS, and no target compound was obtained from the reaction.

Comparative example 2

Compound 4b (0.84g, 3.4mmol), 2-amino-3-butanoic acid (0.7g, 4.2mmol) and triethylamine (2.3mL, 17.1mmol) were dissolved in N,N-dimethylformamide (10mL) The solution was degassed under reduced pressure and replaced the atmosphere with nitrogen, then added three (o-tolyl) phosphine (0.3g, 0.48mmol) and palladium (II) acetate (0.08g, 0.16mmol), and the mixture was decompressed Degassed, replaced the atmosphere with nitrogen, then heated to reflux for 8 hours, and cooled to room temperature.

The reaction solution was sampled for detection by LCMS, and no target compound was obtained from the reaction.

Comparative example 3

Compound 4a (1.0g, 3.4mmol), 2-amino-3-butanoic acid (0.7g, 4.2mmol) and triethylamine (2.3mL, 17.1mmol) were dissolved in N,N-dimethylformamide (10mL) The solution was degassed under reduced pressure and replaced the atmosphere with nitrogen, then added three (o-tolyl) phosphine (0.3g, 0.48mmol) and palladium (II) acetate (0.08g, 0.16mmol), and the mixture was decompressed Degassed, replaced the atmosphere with nitrogen, then heated to reflux for 8 hours, and cooled to room temperature.

The reaction solution was sampled for detection by LCMS, and no target compound was obtained from the reaction.

Example 4

Preparation of Compound 6

Put trifluoroacetic anhydride (25mL, 176.8mmol) into the reaction flask, cool to 0°C, add compound A (5.0g, 16.1mmol), then add concentrated sulfuric acid (2mL), continue stirring at 0°C for 1h, then Slowly rise to 35 ° C, continue to stir the reaction for 12h. The resulting reaction solution was added dropwise to a 50% aqueous acetonitrile solution (120 mL) that had been cooled to 5°C. After adjusting the pH to about 7 with 25 wt% aqueous sodium hydroxide solution, water (20 mL) was added. Then, the temperature of the reaction solution was returned to room temperature, and the precipitated crystals were collected by filtration and washed with water (60 mL) and 75% acetonitrile aqueous solution (60 mL). The obtained crystals were dried under reduced pressure to obtain Compound 6 as white crystals (4.2 g, yield 90%).

¹ H NMR (500MHz, CDCl ₃ )δ11.77(s,1H),8.41(d,1H),6.58(d,1H),4.63(dt,1H),2.95-3.06(m,2H),2.71- 2.76(m,1H),2.23(s,3H),2.14(d,3H),2.11(s,3H),1.79-1.88(m,1H).

ESI-MS: m/z C ₁₅ H ₁₈ FN ₂ O ₃ [M+H]+calculated: 293.1301; found: 293.1310;

Example 5

Preparation of Compound 6

Put 1,2-dichloroethane (50mL) into the reaction flask, cool to -40°C, add compound A (3.1g, 10mmol) and phosphorus pentachloride (2.1g, 10mmol), at -40°C Stirring was continued for 2 h, then slowly warmed to room temperature. AlCl ₃ (2.8 g, 21 mmol) was added to the reaction liquid, and the reaction was heated under reflux for 10 hours. The end of the reaction was monitored by TLC, and the reaction solution was slowly added to ice water (200mL), extracted with ethyl acetate, dried, filtered, and spin-dried, and the resulting solid was dried under reduced pressure to obtain compound 6 as white crystals (1.4g, yield 48%). The structural characterization data are the same as in Example 3.

Comparative example 4

Preparation of Compound 6a

Put polyphosphoric acid (2 mL) and compound A (100 mg) into the reaction flask, and react at 100° C. for 12 h. Then, the temperature of the reaction solution was brought back to room temperature, neutralized to pH=7 under ice-bath conditions, extracted with dichloromethane, and the organic phase was collected. The organic phase was dried over Na ₂ SO ₄ , filtered, and spin-dried to obtain white compound 6a (80 mg, yield 91%).

¹ H NMR (500MHz, DMSO-d6/CDCl ₃ ) δ10.01(s, 1H), 9.86(s, 1H), 8.27(s, 1H), 7.87(d, J=9.1Hz, 1H), 7.75( d,J=9.1Hz,1H),7.54(d,J=11.1Hz,1H),2.49(s,3H),2.26(s,3H),2.17(s,1H).

ESI-MS: m/z[M+H]+ calculated value: 275.12; measured value 275.18;

Example 6

Preparation of Compound B

A suspension of compound 6 (5.0 g, 17.1 mmol) in 2N hydrochloric acid/ethanol (50 mL) was stirred at 50°C for 6 hours. Water (45 mL) was added to the resulting reaction solution, and the mixture was cooled to 1°C. After triethylamine (14.5 mL, 103.9 mmol) was added dropwise at 1 °C, sodium sulfite (45 mg, 0.3 mmol) was added. After the mixture was stirred at 1°C for 2 hours, the precipitated crystals were collected by filtration and washed with cold 60% ethanol aqueous solution (50 mL) and water (15 mL). A suspension of the obtained crystals in acetone (30 mL) was stirred at 50° C. for 2 hours and then cooled to room temperature. Precipitated crystals were collected by filtration and washed with acetone (10 mL). The obtained crystals were dried at 40°C under reduced pressure to obtain Compound B (3.6 g, yield 85%).

¹ H NMR(500MHz,DMSO_d6)δ8.08(d,1H),7.41(s,2H),6.39(d,1H),4.48(dt,1H),2.93(d,1H),2.78-2.85(m ,1H),2.16(m,1H),2.14(s,3H),2.13(s,3H),1.81-1.98(m,1H).

ESI-MS: m/z C ₁₃ H ₁₆ FN ₂ O ₂ [M+H]+calculated: 251.1196; found: 251.1194;

Example 7

Preparation of Compound 8

Compound B (10g, 40.0mmol), compound 7 (10g, 38.0mmol), pyridinium p-toluenesulfonate (1.5g, 6.0mmol) and o-cresol (30ml, 264mmol) were added to a three-necked flask, and toluene ( 400 mL), reacted at 108°C for 32 hours and cooled. Precipitated crystals were collected by filtration, and washed with acetone (30 mL). The obtained crystals were dried at 40° C. under reduced pressure to obtain Compound 8 (15.4 g, yield 85%).

ESI-MS: m/z C ₂₆ H ₂₅ FN ₃ O ₅ [M+H]+calculated: 478.1778; found 478.1782;

Example 8

Preparation of Compound 9

Compound 8 (10g, 20.9mmol) was suspended in water (300ml) and toluene (300ml), methanesulfonic acid (150mL) was added slowly, the solid dissolved and exotherm occurred. Heated to 90°C for 8h, cooled to room temperature, separated and removed the organic phase. Filtrate the aqueous phase, dilute the filtrate with ethanol (4L), the solid precipitates, stir at room temperature for 20min, filter, drain, suspend the crude product in ethanol/water = 4:1, heat and reflux for 2h, cool to room temperature, filter, and use the solid After washing with a small amount of ethanol, it was sucked dry. After drying, Compound 9, i.e., Ixitecan mesylate (4.6 g, 45%) was obtained.

¹ H NMR(500MHz,DMSO_d6)δ8.47(s,3H),7.88(d,1H),7.34(s,1H),6.59(s,1H),5.72-5.40(m,4H),5.11(s ,1H),3.30(m,1H),3.10(t,1H),2.53(m,1H),2.42(s,3H),2.32(s,3H),2.19(m,1H),1.88(m, 2H), 0.88(t,3H).

_ESI -MS: m/z calcd for _C24H23FN3O4 [M+H]+: 436.1673 _{; found} 436.1678.

Claims (24)

1. a preparation method of compound 6, is characterized in that, comprises the following steps: (d) compound 4 undergoes a coupling reaction to obtain compound 5; (e) compound 5 obtains compound A through double bond reduction or hydrogenation reaction; (f) Compound A undergoes an intramolecular Friedel-Crafts acylation reaction under the action of an intramolecular cyclization reagent to obtain compound 6; Its reaction formula is as follows:

Wherein, R is selected from halogen, sulfonate group or diazo group, such as iodine, trifluoromethanesulfonyloxy group. 2. A preparation method of compound 6, characterized in that, comprising the following steps: (f) Compound A is subjected to an intramolecular Friedel-Crafts acylation reaction under the action of an intramolecular cyclization reagent to obtain compound 6,

3. the preparation method as claimed in claim 1 or 2, is characterized in that, in step (f), described cyclization reagent is selected from Friedel-Crafts acylating reagent, the mixed reagent of protonic acid and acid anhydride or chlorination reagent for example Mixed reagent with Lewis acid or polyphosphoric acid PPA; Preferably, the protic acid is selected from trifluoroacetic acid, hydrochloric acid or sulfuric acid; And/or, the acid anhydride is selected from trifluoroacetic anhydride or trifluoromethanesulfonic anhydride; Preferably, the chlorination reagent is selected from thionyl chloride, sulfuryl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride or phosphorus pentachloride; And/or, the Lewis acid is selected from aluminum trichloride, tin tetrachloride, and iron salts. 4. the preparation method as claimed in claim 1 or 2 is characterized in that, in step (f), the addition of described cyclization reagent is based on at least enabling the reaction to proceed, preferably, the The ratio of the amount of the cyclization reagent to the compound A is 0.5-20:1, more preferably 1-10:1, and more preferably 1-5:1. 5. The preparation method according to claim 1 or 2, characterized in that: in step (f), the reaction temperature is -40 to 150°C, such as 0 to 100°C; And/or the reaction time is 0.5-24 hours, such as 2-12 hours. 6. An intermediate compound A,

7. A preparation method of intermediate compound A, characterized in that, comprising the following steps: (e) carrying out catalytic hydrogenation reaction of compound 5 in the presence of a catalyst to obtain compound A,

8. the preparation method as claimed in claim 1 or 7, is characterized in that, in step (e), described catalyzer is selected from palladium catalyst, platinum catalyst, nickel catalyst, ruthenium catalyst or rhodium catalyst, is preferably palladium carbon catalyst , more preferably 5% palladium carbon catalyst. 9. the preparation method as claimed in claim 1 or 7 is characterized in that: in step (e), the add-on of described catalyzer is at least with reaction can carry out as a benchmark, preferably, described catalyzer and described The mass ratio of compound 5 is 0.02-0.4:1, more preferably 0.05-0.15. 10. the preparation method as claimed in claim 1 or 7 is characterized in that: in step (e), described reaction is carried out in organic solvent, and described organic solvent is selected from acetonitrile, methylene dichloride, chloroform, methyl alcohol , ethanol, ether, 1,2-dimethoxyethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethyl acetate, ethylcyclohexane, benzene, toluene, chlorobenzene, Acetone, water or any combination of several solvents. 11. The preparation method according to claim 1 or 7, characterized in that: in step (e), the reaction temperature is 25-100°C, such as 40-60°C; the reaction time is 0.5-24h, such as 6 ~12h. 12. A compound A as claimed in claim 6 is used as an intermediate in the preparation of compound 6 or ixinotecan or ixinotecan mesylate,

13. An intermediate compound 5,

14. A preparation method of compound 5, characterized in that, comprising the following steps: (d) Compound 4 and 2-acetylaminobut-3-enoic acid are subjected to a coupling reaction under the action of a coupling catalyst and an alkaline substance to obtain compound 5,

Wherein, R is selected from halogen, sulfonate group or diazo group, such as iodine, trifluoromethanesulfonyloxy group. 15. The preparation method according to claim 1 or 14, characterized in that: in step (d), the coupling catalyst is a complex formed by a palladium salt and a phosphine ligand; Preferably, the palladium salt is selected from palladium chloride, palladium acetate, tetrakis (triphenylphosphine) palladium, palladium nitrate or triphenylphosphine palladium dichloride, such as palladium acetate; And/or the phosphine ligand is selected from triphenylphosphine, tricyclohexylphosphine, tri(o-tolyl)phosphine, tri[3,5-bis(trifluoromethyl)phenyl]phosphine, triisopropyl phosphine and dicyclohexyl-(2,6-diisopropylphenyl)phosphine, such as tris(o-tolyl)phosphine. 16. the preparation method as claimed in claim 1 or 14 is characterized in that: in step (d), described alkaline substance is selected from triethylamine, isopropylamine, pyridine, sodium carbonate, sodium bicarbonate, potassium carbonate Or potassium tert-butoxide, such as triethylamine. 17. The preparation method according to claim 1 or 14, characterized in that: in step (d), the ratio of the amount of compound 4 to 2-acetylaminobut-3-enoic acid is 1:1.0 ~3.0, such as 1:1.2~1.5; And/or the amount of the coupling catalyst added is based on the amount of the phosphine ligand, and the ratio of the amount of compound 4 to the phosphine ligand is 1:0.05-0.75, for example, 1 : 0.15～0.30; And/or the ratio of the compound 4 to the basic substance is 1:1.0-15.0, for example, 1:3.0-10.0. 18. The preparation method according to claim 1 or 14, characterized in that: in step (d), the reaction is carried out in an organic solvent, and the organic solvent is selected from acetonitrile, tetrahydrofuran, 1,4-di Oxycycline, N,N-dimethylformamide, dimethylacetamide, toluene, water and their mixed solvents. 19. The preparation method according to claim 1 or 14, characterized in that: in step (d), the reaction temperature is 20-110°C, such as 50-80°C; the reaction time is 2-24h, preferably 8～16h. 20. A compound 5 as claimed in claim 13 is used as an intermediate in the preparation of compound A or ixinotecan or ixinotecan mesylate,

21. A preparation method of Ixitecan mesylate, characterized in that: comprising the following steps: (g) performing selective deamination protection on compound 6 to obtain compound B; (h) Condensation reaction of compound B and compound 7 to obtain compound 8; (i) Compound 8 is hydrolyzed under acidic conditions to obtain ixitecan mesylate, namely compound 9; Its reaction formula is as follows:

The compound 6 is prepared from the compound A according to the preparation method described in any one of claims 2-5. 22. The preparation method according to claim 21, characterized in that: said compound A is prepared from compound 5 according to the method according to any one of claims 7-11. 23. The preparation method according to claim 22, characterized in that: said compound 5 is prepared from compound 4 according to the method according to any one of claims 14-19. 24. The preparation method according to claim 1 or 23, characterized in that: the preparation method of the compound 4 comprises: (a) compound 1 is converted to obtain compound 2; (b) Catalytic hydrogenation reaction of compound 2 to obtain compound 3; (c) compound 3 undergoes an acylation reaction to obtain compound 4;

R is selected from halogen, sulfonate or diazo, eg iodine, trifluoromethanesulfonyloxy.