CN115724758B

CN115724758B - Camptothecin derivative intermediate, synthesis method thereof and method for synthesizing camptothecin derivative by using intermediate

Info

Publication number: CN115724758B
Application number: CN202110972653.6A
Authority: CN
Inventors: 郑骏浩; 俞哲健; 周靖
Original assignee: Hangzhou Zhongmei Huadong Pharmaceutical Co Ltd
Current assignee: Hangzhou Zhongmei Huadong Pharmaceutical Co Ltd
Priority date: 2021-08-24
Filing date: 2021-08-24
Publication date: 2024-12-27
Anticipated expiration: 2041-08-24
Also published as: CN115724758A; WO2023025138A1

Abstract

本发明公开了一种喜树碱衍生物中间体及其合成方法和利用中间体合成喜树碱衍生物的方法。所述的制备方法原料便宜易得，中间体的合成路线简单，避免了肟化、催化氢解和氨基上保护的“一锅法”反应，大大减少了反应步骤，操作条件温和，降低了操作难度，能耗低，适合工业化放大生产；提高原子利用率，更符合绿色化学的工业化应用；提高了伊喜替康衍生物合成的收率，进一步降低成本。The invention discloses a camptothecin derivative intermediate and a synthesis method thereof, and a method for synthesizing camptothecin derivatives using the intermediate. The preparation method has cheap and readily available raw materials, a simple synthesis route of the intermediate, avoids the "one-pot" reaction of oximation, catalytic hydrogenolysis and amino group protection, greatly reduces the reaction steps, has mild operating conditions, reduces the difficulty of operation, has low energy consumption, is suitable for industrialized scale-up production, improves atomic utilization, is more in line with the industrial application of green chemistry, improves the yield of isotecan derivative synthesis, and further reduces costs.

Description

Camptothecin derivative intermediate, synthesis method thereof and method for synthesizing camptothecin derivative by using intermediate

Technical Field

The invention belongs to the technical fields of medical intermediates and organic synthesis, and particularly relates to an intermediate for synthesizing a camptothecin derivative, a preparation method thereof and a synthesis method for synthesizing the camptothecin derivative by using the intermediate.

Background

The antibody-drug conjugate (ADC) combines the high specificity of monoclonal antibody drugs with the high activity of small molecule cytotoxic drugs, so as to improve the targeting of tumor drugs and reduce the toxic and side effects. The accurate identification of the ADC drug to the target spot and the noninjugated cell are not affected, so that the drug effect is greatly improved, the toxic and side effects are reduced, and the ADC drug is concerned by the personnel in the field of medicine research and development. (patent documents 1 and 2 and non-patent documents 1 to 3)

As one such antibody-drug conjugate, an antibody-drug conjugate comprising an antibody and irinotecan, which is a topoisomerase I inhibitor, as its components is known (patent documents 3 to 5 and non-patent documents 4 and 5). These antibody-drug conjugates are currently under clinical investigation because they exert particularly excellent antitumor effects and safety. Exatecan (irinotecan) has the structure shown below:

patent EP0495432B1 discloses a Exatecan (irinotecan) compound and a preparation method thereof, wherein the reaction process is as follows:

Another synthetic method of the derivatives of irinotecan is also disclosed in patent WO1996026181 A1:

The two process routes are all repeated, wherein in the first route, carbonyl is oxidized after decarbonylation, amino is protected after acetyl is protected by deamination, the yield is only 5.6%, the route is repeated for closing rings, opening rings, oxidizing, reducing and the like, and the reaction process adopts potassium permanganate, so that a certain danger is caused to the production process. The two routes have long reaction steps, low atom utilization rate, complex reaction operation and inapplicability to industrialized amplified production.

Patent document WO2019044946A1 carried out a series of optimizations for the synthesis of the intermediate of the irinotecan derivative and disclosed the following synthetic route three:

the process route is to prepare the irinotecan by synthesizing 2-fluoro-1-methyl-4-nitrobenzene, which takes 10 steps altogether, and the total yield is about 5%.

Another synthetic route for the intermediate of the derivative of ixitecan is also disclosed by Shanghai Haoyuan in patent CN111470998B, four:

The bromination reagent used in bromination reaction in the synthetic route is liquid bromine, belongs to highly toxic substances and corrosive substances, has certain danger in amplified production, and the reaction process involves the use of Grignard reagent which is easy to degrade when meeting air, and needs to be carried out in an ultralow-temperature environment, thus having higher requirements on reaction equipment. The rearrangement reaction has low selectivity and complex post-treatment, and is not suitable for industrial scale-up production. The 'one-pot method' reaction of oximation, catalytic hydrogenolysis and protection on amino groups cannot be avoided in the third and fourth synthetic routes, the dangerous processes such as nitration and hydrogenation are involved, and the industrial production difficulty is high.

Thus, in order to meet the production requirements of irinotecan, it is highly desirable to develop a synthetic route for an intermediate of irinotecan which is high in yield and suitable for industrial production.

Disclosure of Invention

In order to solve the problems in the prior art, the invention provides a preparation method of the Ixitidine Kang Jia sulfonate, an intermediate thereof and a preparation method.

The invention relates to a preparation method of Yi xi Tei Kang Jia sulfonate, which comprises the following steps:

(f) Under the action of an intramolecular cyclization reagent, performing intramolecular friedel-crafts acylation reaction on the compound A to obtain a compound 6;

(g) Carrying out selective deamination protection on the compound 6 to obtain a compound B;

(h) Carrying out condensation reaction on the compound B and the compound 7 to obtain a compound 8;

(i) Hydrolyzing the compound 8 under the action of methanesulfonic acid to obtain the irinotecan, namely a compound 9;

Wherein in step (f) the cyclizing reagent is selected from friedel-crafts acylation reagents, such as a mixture of protic acids and anhydrides or a mixture of a chloro reagent and a lewis acid or polyphosphoric acid PPA;

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

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

Preferably, the chlorinating agent 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 ferric salt.

In one embodiment, in the step (f), the amount of the cyclizing reagent added is at least such that the reaction can proceed, preferably the ratio of the amount of the cyclizing reagent to the amount of the substance of the compound a is 0.5 to 20:1, more preferably 1 to 5:1.

Further, the reaction temperature in the step (f) is preferably-40 to 150 ℃, more preferably 0 to 100 ℃, and still more preferably 0 to 80 ℃. Further, the reaction time in the step (f) is preferably 0.5 to 24 hours, more preferably 2 to 12 hours.

Further, in step (g), it is preferably performed using hydrochloric acid or a mixed solution of hydrochloric acid and alcohol, and may be more preferably performed using 2N hydrochloric acid/ethanol.

In step (g), the reaction temperature is preferably 40-100 ℃, more preferably 50-80 ℃, and the reaction time is preferably 2-8 hours, more preferably 3-6 hours.

In one embodiment, in step (h), compound B is condensed with compound 7 under the action of pyridinium p-toluenesulfonate, o-cresol and toluene to give compound 8.

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

In the step (h), the ratio of the amount of the compound B to the amount of the substance of the pyridine p-toluenesulfonate is preferably 1:0.01 to 0.30, more preferably 1:0.05 to 0.20.

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

Further, in the step (h), the reaction temperature is preferably 80 to 130 ℃, more preferably 100 to 120 ℃.

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

Further, in the step (i), the reaction temperature is preferably 70 to 100 ℃, more preferably 80 to 90 ℃.

In step (i), the reaction time is preferably 4 to 12 hours, more preferably 6 to 8 hours.

The invention also relates to a novel intermediate compound A which can be used as a synthetic compound 6 or as irinotecan or its mesylate,

The invention also relates to a preparation method of the intermediate compound A, which specifically comprises the following steps:

(e) The compound 5 is subjected to catalytic hydrogenation reaction in the presence of a catalyst to obtain a 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, and still more preferably 5% palladium carbon catalyst.

In step (e), the catalyst is preferably added in an amount of 0.02 to 0.4:1, more preferably 0.05 to 0.15, based on the reaction performance.

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

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

In the step (e), the reaction temperature is 40-70 ℃, preferably 50-70 ℃, and the reaction time is 0.5-24 hours, preferably 6-12 hours.

The invention also relates to the provision of an intermediate compound 5 for use as an intermediate in the preparation of compound 6 or irinotecan or a mesylate thereof,

The invention also relates to a preparation method of the compound 5, which comprises the following steps:

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

Wherein R is selected from halogen, sulfonate or diazo groups, such as iodine, trifluoromethanesulfonyl.

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

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

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

Further, in the step (d), the basic substance is selected from the group consisting of triethylamine, isopropylamine, pyridine, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium t-butoxide, preferably triethylamine.

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

And/or the coupling catalyst is added in an amount calculated by the amount of the phosphine ligand substance, wherein the ratio of the amount of the compound 4 to the amount of the phosphine ligand substance is 1:0.05-0.75, such as 1:0.15-0.30;

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

In the step (d), the reaction is carried out in an organic solvent, wherein the organic solvent is selected from acetonitrile, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, dimethylacetamide, toluene, water and a mixed solvent thereof, and the addition amount of the organic solvent is 10-60 ml/g based on the mass of the compound 4.

Further, in the step (d), the reaction temperature is 20-110 ℃, for example 50-80 ℃, and the reaction time is 2-24 hours, preferably 8-16 hours.

The invention also relates to a preparation method of the compound 4, which comprises the following steps:

(a) Converting the compound 1 to obtain a compound 2;

(b) The compound 2 is subjected to catalytic hydrogenation reaction under the action of a catalyst to obtain a compound 3;

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

r is selected from halogen, sulfonate or diazo groups, such as iodine, trifluoromethanesulfonyl.

Further, in the step (a), it is preferable that the iodinating agent is selected from iodine and N-iodosuccinimide, more preferably N-iodosuccinimide, and the amount of the N-iodosuccinimide is not limited as long as the reaction proceeds, preferably 1 to 1.5 equivalents. This step may preferably be performed in a mixed solvent of sulfuric acid and other solvents.

Further, in step (a), it is preferable that the reaction solvent is selected from the group consisting of methylene chloride, chloroform, 1, 2-dimethoxyethane, hexane, pentane, heptane, cyclohexane, ethylcyclohexane, benzene, toluene, chlorobenzene and a mixed solvent thereof.

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

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

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

In the step (b), preferably, the reaction solvent is selected from methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 2-dimethoxyethane, 1, 4-dioxane, ethyl acetate, water and a mixed solvent thereof, wherein the addition amount of the reaction solvent is 10-60 ml/g based on the mass of the compound 1.

Further, in the step (b), the reaction temperature is preferably 40 to 70 ℃, more preferably 50 to 70 ℃.

In step (b), the reaction time is preferably 0.5 to 8 hours, more preferably 2 to 4 hours.

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

Further, in the step (c), it is preferable that the reaction is carried out under the action of a base selected from triethylamine, isopropylamine, pyridine, sodium carbonate, potassium carbonate and potassium t-butoxide, more preferably triethylamine, and the ratio of the amount of the base to the amount of the substance of the compound 2 is 0.5 to

1.5:1, More preferably 0.75 to 1.5:1.

In the step (c), the reaction solvent is preferably selected from the group consisting of methanol, ethanol, tetrahydrofuran, dichloromethane, chloroform, acetone, toluene, ethyl acetate, water and a mixture thereof, more preferably ethyl acetate, and the amount of the reaction solvent added is 10-60 ml/g based on the mass of the compound 2.

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

In step (c), the reaction time is preferably 2 to 24 hours, more preferably 3 to 12 hours.

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

Compared with the prior art, the invention has the beneficial effects that:

(1) The invention provides a new Ixitidine Kang Jia sulfonate intermediate 5 and A, which opens up the research field of important intermediate of Ixitecan derivatives;

(2) The raw materials are cheap and easy to obtain, the synthesis route of the intermediate is simple, the one-pot reaction of oximation, catalytic hydrogenolysis and amino protection is avoided, the reaction steps are greatly reduced, the operation condition is mild, the operation difficulty is reduced, the energy consumption is low, and the method is suitable for industrial scale-up production;

(3) The atomic utilization rate is improved, and the method is more suitable for the industrialized application of green chemistry;

the yield of the synthesis of the irinotecan derivative is improved, and the cost is further reduced.

Detailed Description

The technical solution of the present invention will be clearly and completely described in conjunction with the specific embodiments, but it will be understood by those skilled in the art that the examples described below are some, but not all, examples of the present invention, and are only for illustrating the present invention and should not be construed as limiting the scope of the present invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.

Example 1

Preparation of Compound 4a

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

To the reaction vessel were added compound 2 and ethyl acetate (15 mL), followed by a suspension of 1% platinum carbon catalyst (2.1 g) and ethyl acetate (90 mL), the atmosphere was replaced with nitrogen, and then with hydrogen. The reaction solution was stirred in a hydrogen stream (0.2 MPa) at 65 ℃ for 3 hours and cooled to room temperature. 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 (25 mL) and 5wt% brine (25 mL), and the resulting organic layer was concentrated under reduced pressure to give a solution of compound 3 in ethyl acetate (50 mL).

An ethyl acetate solution of compound 3 and triethylamine were added to a three-necked flask, cooled to about 0 ℃, acetic anhydride (3.4 ml,35.4 mmol) was slowly added, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, saturated brine (50 ml) was added thereto, 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 ℃. The precipitated crystals were collected by filtration and washed with 50% aqueous acetonitrile (20 mL). The obtained crystals were dried under reduced pressure at 40 ℃ to give compound 4a as white crystals (6.4 g, yield 38%).

¹H NMR(500MHz,CDCl₃)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-acetamido-but-3-enoic acid (6.1 g,42.6 mmol) and triethylamine (23.7 mL,170.6 mmol) in acetonitrile (200 mL) was degassed under reduced pressure and the atmosphere replaced with nitrogen, then tris (o-tolyl) phosphine (1.5 g,5.12 mmol) and palladium (II) acetate (0.4 g,1.71 mmol) were added, and the mixture was degassed under reduced pressure, the atmosphere replaced with nitrogen, then heated to reflux for 8 hours, and cooled to room temperature. To the reaction solution cooled to room temperature, 2-methyltetrahydrofuran (100 mL) and water (100 mL) were added 25w/v% aqueous sodium hydroxide (6.5 mL,40.2 mmol) and the organic layer was removed. The aqueous layer was washed with 2-methyltetrahydrofuran (30 mL,2 times) and the organic layer was removed. Concentrated hydrochloric acid (36%, 6.0g,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 10wt% brine (60 mL). The organic layer was concentrated under reduced pressure to give crude compound 5 containing geometric isomer (10.8 g).

A suspension was obtained by adding tetrahydrofuran (100 mL), purified water (100 mL) and 5% palladium on charcoal (2.1 g) to a crude product of compound 5 (10.8 g) containing geometric isomers, replacing the atmosphere with nitrogen and then with hydrogen. The mixture was stirred in a stream of hydrogen (0.5 MPa) at 60 ℃ for 8 hours and cooled to room temperature. Insoluble material was separated from the resulting suspension by filtration and washed with tetrahydrofuran (30 mL). The filtrate was adjusted to a pH of 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 ℃. The precipitated crystals were collected by filtration and washed with 50% aqueous acetonitrile (10 mL). The obtained crystals were dried under reduced pressure at 40 ℃ to give compound a as white crystals (9.2 g, yield 87%).

¹H 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).

¹³C 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 calculated as M/z C ₁₅H₁₉FN₂O₄ [ M+H ] + 311.13, found 311.18;

Example 3

Preparation of Compound A

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

A suspension was obtained by adding tetrahydrofuran (100 mL), purified water (100 mL) and 5% palladium on charcoal (2.1 g) to a crude product of compound 5 (9.0 g) containing geometric isomer, replacing the atmosphere with nitrogen and then with hydrogen. The mixture was stirred in a stream of hydrogen (0.4 MPa) at 40 ℃ for 16 hours and cooled to room temperature. Insoluble material was separated from the resulting suspension by filtration and washed with tetrahydrofuran (20 mL). The filtrate was adjusted to a pH of 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 ℃. The precipitated crystals were collected by filtration and washed with 50% aqueous acetonitrile (10 mL). The obtained crystals were dried under reduced pressure at 40 ℃ to give compound a as white crystals (8.5 g, yield 80%).

Comparative example 1

A solution of compound 4a (0.84 g,3.4 mmol), 2-butenoic acid-3- (acetamido) -phenylmethyl ester (1.2 g,4.2 mmol) and triethylamine (2.3 mL,17.1 mmol) in N, N-dimethylformamide (10 mL) was degassed under reduced pressure and the atmosphere 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, the atmosphere replaced with nitrogen, then heated to reflux for 8 hours and cooled to room temperature.

The reaction was sampled and LCMS was detected and the reaction did not give the target compound.

Comparative example 2

A solution of compound 4b (0.84 g,3.4 mmol), 2-amino-3-butanoic acid (0.7 g,4.2 mmol) and triethylamine (2.3 mL,17.1 mmol) in N, N-dimethylformamide (10 mL) was degassed under reduced pressure and the atmosphere 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, the atmosphere replaced with nitrogen, then heated to reflux for 8 hours, and cooled to room temperature.

Comparative example 3

A solution of compound 4a (1.0 g,3.4 mmol), 2-amino-3-butanoic acid (0.7 g,4.2 mmol) and triethylamine (2.3 mL,17.1 mmol) in N, N-dimethylformamide (10 mL) was degassed under reduced pressure and the atmosphere 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, the atmosphere replaced with nitrogen, then heated under reflux for 8 hours, and cooled to room temperature.

Example 4

Preparation of Compound 6

Trifluoroacetic anhydride (25 mL,176.8 mmol) was put into a reaction flask, cooled to 0 ℃, compound a (5.0 g,16.1 mmol) was added, concentrated sulfuric acid (2 mL) was further added, stirring was continued for 1h at 0 ℃, then slowly rising to 35 ℃, and stirring was continued for 12h. The resulting reaction solution was added dropwise to a 50% acetonitrile in water (120 mL) which had been cooled to 5 ℃. After adjusting the pH to about 7 with 25wt% aqueous sodium hydroxide, water (20 mL) was added. Then, the reaction solution was allowed to warm 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 give compound 6 as white crystals (4.2 g, yield 90%).

¹H NMR(500MHz,CDCl₃)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 calculated as M/z C ₁₅H₁₈FN₂O₃ [ M+H ] + 293.1301, found 293.1310;

Example 5

Preparation of Compound 6

1, 2-Dichloroethane (50 mL) was charged to the reaction flask, cooled to-40℃and compound A (3.1 g,10 mmol) and phosphorus pentachloride (2.1 g,10 mmol) were added, stirring was continued for 2h at-40℃and then slowly warmed to room temperature. AlCl ₃ (2.8 g,21 mmol) was added to the reaction mixture, and the mixture was heated under reflux for 10 hours. TLC monitored the end of the reaction, the reaction was slowly added to ice water (200 mL), extracted with ethyl acetate, dried, filtered, and spin-dried, and the resulting solid was dried under reduced pressure to give compound 6 as white crystals (1.4 g, yield 48%). The structural characterization data are the same as in example 3.

Comparative example 4

Preparation of Compound 6a

Polyphosphoric acid (2 mL) and compound A (100 mg) were charged into a reaction flask and reacted at 100℃for 12 hours. Then, the reaction solution was allowed to warm 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 ₂SO₄, filtered and dried by spin to give white compound 6a (80 mg, 91% yield).

¹H NMR(500MHz,DMSO-d6/CDCl₃)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,3H).

ESI-MS calculated M/z [ M+H ] + 275.12, found 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℃for 6 hours. Water (45 mL) was added to the resulting reaction solution, and the mixture was cooled to 1 ℃. After dropwise addition of triethylamine (14.5 mL,103.9 mmol) at 1℃sodium sulfite (45 mg,0.3 mmol) was added. After stirring the mixture at 1 ℃ for 2 hours, the precipitated crystals were collected by filtration and washed with cold 60% aqueous ethanol (50 mL) and water (15 mL). The resulting suspension of crystals in acetone (30 mL) was stirred at 50 ℃ for 2 hours and then cooled to room temperature. The precipitated crystals were collected by filtration and washed with acetone (10 mL). The resulting crystals were dried under reduced pressure at 40℃to give compound B (3.6 g, yield 85%).

¹H 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 calculated as M/z C ₁₃H₁₆FN₂O₂ [ M+H ] + 251.1196, found 251.1194;

Example 7

Preparation of Compound 8

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

ESI-MS calculated as M/z C ₂₆H₂₅FN₃O₅ [ M+H ] + 478.1778, found 478.1782;

Example 8

Preparation of Compound 9

Compound 8 (10 g,20.9 mmol) was suspended in water (300 mL) and toluene (300 mL) and methanesulfonic acid (150 mL) was slowly added, and the solid dissolved and exothermed. Heated to 90 ℃ for reaction for 8h, cooled to room temperature, separated and the organic phase removed. The aqueous phase was filtered, the filtrate was diluted with ethanol (4L) and the solid precipitated, stirred at room temperature for 20min, filtered and drained, the crude product was suspended in ethanol/water=4:1, heated to reflux for 2h, cooled to room temperature, filtered, the solid was washed with a small amount of ethanol and drained, and dried to give compound 9, i.e. the irinotecan Kang Jia sulfonate (4.6 g, 45%).

¹H 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 calculated as M/z C ₂₄H₂₃FN₃O₄ [ M+H ] + 436.1673 found 436.1678.

Claims

1. A method for preparing compound 6, characterized in that it comprises the following steps:

(d) Compound 4 is subjected to coupling reaction to obtain compound 5;

(e) Compound 5 is reduced by double bond to obtain compound A;

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

The reaction formula is as follows:

wherein R is selected from iodine;

In step (f), the cyclization reagent is selected from a mixed reagent of a protonic acid and an acid anhydride or a mixed reagent of a chlorination reagent and a Lewis acid;

The protonic acid is selected from trifluoroacetic acid, hydrochloric acid or sulfuric acid;

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

The chlorinating agent is selected from thionyl chloride, sulfuryl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride or phosphorus pentachloride.

The Lewis acid is selected from aluminum trichloride, tin tetrachloride and iron salt.

2. A method for preparing compound 6, characterized in that it comprises the following steps:

(f) subjecting compound A to an intramolecular Friedel-Crafts acylation reaction under the action of an intramolecular cyclization agent to obtain compound 6,

The chlorinating agent is selected from thionyl chloride, sulfuryl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride or phosphorus pentachloride;

3. The preparation method according to claim 1 or 2, characterized in that, in step (f), the amount of the cyclization reagent added is based on at least allowing the reaction to proceed.

4. The preparation method according to claim 1 or 2, characterized in that in step (f), the molar ratio of the cyclization reagent to the compound A is 0.5 to 20:1.

5. The preparation method according to claim 1 or 2, characterized in that in step (f), the molar ratio of the cyclization reagent to the compound A is 1 to 10:1.

6. The preparation method according to claim 1 or 2, characterized in that in step (f), the molar ratio of the cyclization reagent to the compound A is 1 to 5:1.

7. The preparation method according to claim 1 or 2, characterized in that: in step (f), the reaction temperature is -40 to 150°C;

And/or the reaction time is 0.5 to 24 hours.

8. The preparation method according to claim 1 or 2, characterized in that: in step (f), the reaction temperature is 0 to 100°C; and/or the reaction time is 2 to 12 hours.

9. An intermediate compound A,

10. A method for preparing an intermediate compound A, characterized in that it comprises the following steps:

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

11. The preparation method according to claim 1 or 10, characterized in that in step (e), the catalyst is selected from a palladium catalyst, a platinum catalyst, a nickel catalyst, a ruthenium catalyst or a rhodium catalyst.

12. The preparation method according to claim 1 or 10, wherein in step (e), the catalyst is selected from a palladium-carbon catalyst.

13. The preparation method according to claim 1 or 10, characterized in that, in step (e), the catalyst is selected from 5% palladium-carbon catalyst.

14. The preparation method according to claim 1 or 10, characterized in that: in step (e), the amount of the catalyst added is at least based on the reaction being able to proceed.

15. The preparation method according to claim 1 or 10, characterized in that: in step (e), the mass ratio of the catalyst to the compound 5 is 0.02-0.4:1.

16. The preparation method according to claim 1 or 10, characterized in that: in step (e), the mass ratio of the catalyst to the compound 5 is 0.05-0.15:1.

17. The preparation method according to claim 1 or 10, characterized in that: in step (e), the reaction is carried out in an organic solvent, and the organic solvent is selected from acetonitrile, dichloromethane, chloroform, methanol, ethanol, ether, 1,2-dimethoxyethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethyl acetate, ethylcyclohexane, benzene, toluene, chlorobenzene, acetone, water or a mixed solvent of any of them.

18. The preparation method according to claim 1 or 10, characterized in that: in step (e), the reaction temperature is 25-100°C and the reaction time is 0.5-24h.

19. The preparation method according to claim 1 or 10, characterized in that: in step (e), the reaction temperature is 40-60°C and the reaction time is 6-12h.

20. Compound A as claimed in claim 9 is used as an intermediate in the preparation of compound 6 or isotecan or isotecan mesylate,

21. An intermediate compound 5,

22. A method for preparing compound 5, characterized in that it comprises the following steps:

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

Wherein, R is selected from iodine.

23. The preparation method according to claim 1 or 22, characterized in that: in step (d), the coupling catalyst is a complex formed by a palladium salt and a phosphine ligand.

24. The preparation method according to claim 1 or 22, characterized in that: in step (d), the palladium salt is selected from palladium chloride, palladium acetate, tetrakis(triphenylphosphine)palladium, palladium nitrate or triphenylphosphine palladium dichloride;

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

25. The preparation method according to claim 1 or 22, characterized in that: in step (d), the alkaline substance is selected from triethylamine, isopropylamine, pyridine, sodium carbonate, sodium bicarbonate, potassium carbonate or potassium tert-butoxide.

26. The preparation method according to claim 1 or 22, characterized in that: in step (d), the molar ratio of the compound 4 to 2-acetylaminobut-3-enoic acid is 1:1.0-3.0;

and/or the amount of the coupling catalyst added is calculated based on the amount of the phosphine ligand, and the ratio of the amount of the compound 4 to the amount of the phosphine ligand is 1:0.05-0.75;

And/or the molar ratio of the compound 4 to the alkaline substance is 1:1.0-15.0.

27. The preparation method according to claim 1 or 22, characterized in that: in step (d), the molar ratio of the compound 4 to 2-acetylaminobut-3-enoic acid is 1:1.2-1.5;

and/or the amount of the coupling catalyst added is calculated based on the amount of the phosphine ligand, and the ratio of the amount of the compound 4 to the amount of the phosphine ligand is 1:0.15-0.30;

And/or the molar ratio of the compound 4 to the alkaline substance is 1:3.0-10.0.

28. The preparation method according to claim 1 or 22, 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-dioxane, N,N-dimethylformamide, dimethylacetamide, toluene, water and a mixed solvent thereof.

29. The preparation method according to claim 1 or 22, characterized in that: in step (d), the reaction temperature is 20-110°C and the reaction time is 2-24h.

30. The preparation method according to claim 1 or 22, characterized in that: in step (d), the reaction temperature is 50-80°C and the reaction time is 8-16 hours.

31. A method of using the compound 5 as claimed in claim 21 as an intermediate in the preparation of compound A or isotecan or isotecan mesylate,

32. A method for preparing isotecan mesylate, characterized in that it comprises the following steps:

(g) selectively deaminating compound 6 to obtain compound B;

(h) subjecting compound B to a condensation reaction with compound 7 to obtain compound 8;

(i) Compound 8 is hydrolyzed under acidic conditions to obtain isotecan mesylate, i.e., Compound 9;

The reaction formula is as follows:

The compound 6 is prepared from compound A according to the preparation method described in any one of claims 2 to 8.

33. The preparation method as claimed in claim 32, characterized in that: the compound A is prepared from compound 5 according to the method as claimed in any one of claims 10 to 18.

34. The preparation method as claimed in claim 32 is characterized in that the compound 5 is prepared from compound 4 according to the method as claimed in any one of claims 23 to 31.

35. The preparation method according to claim 1 or 32, characterized in that: the preparation method of compound 4 comprises:

(a) Compound 1 is converted into Compound 2;

(b) catalytic hydrogenation of compound 2 to obtain compound 3;

(c) Compound 3 is subjected to acylation reaction to obtain compound 4;

R is selected from iodine.