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

Abstract

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

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical intermediates and organic synthesis, and particularly relates to an intermediate for synthesizing camptothecin derivatives and a preparation method thereof, and a synthesis method of synthesizing camptothecin derivatives using the intermediate. Background Art

[0002] Antibody-drug conjugates (ADCs) combine 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. ADC drugs have accurate recognition of targets and are not affected by non-cancerous cells, which greatly improves drug efficacy and reduces toxic side effects, and has attracted much attention in the field of pharmaceutical research and development. (Patent Documents 1 and 2 and Non-Patent Documents 1-3)

[0003] As one such antibody-drug conjugate, an antibody-drug conjugate containing an antibody and exatecan (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 research. The structure of Exatecan is shown below:

[0004]

[0005] Patent EP0495432B1 discloses an Exatecan compound and a preparation method thereof, and the reaction process is as follows:

[0006]

[0007] Patent WO1996026181A1 also discloses another method for synthesizing isotecan derivatives:

[0008]

[0009] The above two process routes are repeated reactions: Route 1 undergoes decarbonylation followed by oxidation of the carbonyl group, deamination to protect the acetyl group followed by amino protection, and the yield is only 5.6%; Route 2 repeats ring closure, 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 atomic utilization, and complex reaction operations, and are not suitable for industrial scale-up production.

[0010] Patent document WO2019044946A1 has made a series of optimizations on the synthesis of isotecan derivative intermediates and disclosed the following synthesis route three:

[0011]

[0012] The process route involves 10 steps in total to prepare isotecan from 2-fluoro-1-methyl-4-nitrobenzene, with a total yield of about 5%.

[0013] Shanghai Haoyuan Company also disclosed another synthesis route 4 of isotecan derivative intermediates in patent CN111470998B:

[0014]

[0015] The bromination reagent used in the bromination reaction of this synthetic route is liquid bromine, which is a highly toxic and corrosive substance. It is dangerous in scale-up production. The reaction process also involves the use of Grignard reagents, which are easily degraded when exposed to air. It needs to be carried out in an ultra-low temperature environment, which places high demands on the reaction equipment. The rearrangement reaction has low selectivity and complex post-processing, and is not suitable for industrial scale-up production. Both synthetic routes three and four cannot avoid the "one-pot" reaction of oximation, catalytic hydrogenolysis and amino protection, involving dangerous processes such as nitration and hydrogenation, and are difficult to produce industrially.

[0016] It can be seen that in order to meet the production demand of isotecan, it is urgent to develop a synthesis route of isotecan intermediates with high yield and suitable for industrial production. Summary of the invention

[0017] In order to solve the problems existing in the prior art, the present invention provides a preparation method of isotecan mesylate, an intermediate thereof and a preparation method thereof.

[0018] The present invention relates to a method for preparing isotecan mesylate, which comprises the following steps:

[0019] (f) Compound A undergoes an intramolecular Friedel-Crafts acylation reaction under the action of an intramolecular cyclization reagent to obtain compound 6;

[0020] (g) selectively deaminating compound 6 to obtain compound B;

[0021] (h) subjecting the compound B to a condensation reaction with the compound 7 to obtain the compound 8;

[0022] (i) Compound 8 is hydrolyzed under the action of methanesulfonic acid to obtain isotecan, i.e., compound 9;

[0023]

[0024] Wherein, in step (f), the cyclization reagent is selected from a Friedel-Crafts acylating reagent, such as a mixed reagent of a protonic acid and an acid anhydride or a mixed reagent of a chlorination reagent and a Lewis acid or polyphosphoric acid PPA;

[0025] Preferably, the protonic acid is selected from trifluoroacetic acid, hydrochloric acid or sulfuric acid;

[0026] And / or, the acid anhydride is selected from trifluoroacetic anhydride or trifluoromethanesulfonic anhydride;

[0027] Preferably, the chlorination agent is selected from thionyl chloride, sulfuryl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride or phosphorus pentachloride;

[0028] And / or, the Lewis acid is selected from aluminum trichloride, tin tetrachloride, and iron salts.

[0029] As an embodiment, in step (f), the amount of the cyclization reagent added is at least sufficient to enable the reaction to proceed, preferably, the molar ratio of the cyclization reagent to the compound A is 0.5 to 20:1, more preferably 1 to 5:1.

[0030] Furthermore, the reaction temperature of step (f) is preferably -40 to 150° C., more preferably 0 to 100° C., and even more preferably 0 to 80° C. Furthermore, the reaction time of step (f) is preferably 0.5 to 24 h, and more preferably 2 to 12 h.

[0031] Furthermore, in step (g), hydrochloric acid or a mixed solution of hydrochloric acid and alcohol is preferably used, and 2N hydrochloric acid / ethanol may be more preferably used.

[0032] Furthermore, in step (g), the reaction temperature is preferably 40 to 100° C., more preferably 50 to 80° C.; the reaction time is preferably 2 to 8 h, more preferably 3 to 6 h.

[0033] As an embodiment, in step (h), compound B and compound 7 are subjected to a condensation reaction under the action of pyridinium p-toluenesulfonate, o-cresol and toluene to obtain compound 8.

[0034] Furthermore, in step (h), preferably, the molar ratio of compound B to compound 7 is 1:0.9-1.5, more preferably 1:1.0-1.1.

[0035] Furthermore, in step (h), preferably, the molar ratio of the compound B to the pyridinium p-toluenesulfonate is 1:0.01-0.30, more preferably 1:0.05-0.20.

[0036] Furthermore, 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.

[0037] Furthermore, in step (h), the reaction temperature is preferably 80-130°C, more preferably 100-120°C.

[0038] Further, in step (h), the reaction time is preferably 18 to 72 hours, more preferably 24 to 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 to 60 ml / g based on the mass of the compound 8.

[0039] Furthermore, in step (i), the reaction temperature is preferably 70 to 100°C, more preferably 80 to 90°C.

[0040] Furthermore, in step (i), the reaction time is preferably 4 to 12 hours, more preferably 6 to 8 hours.

[0041] The present invention also relates to a new intermediate compound A, which can be used to synthesize compound 6 or isotecan or its mesylate.

[0042]

[0043] The present invention also provides a method for preparing an intermediate compound A, and the method for preparing the intermediate compound A specifically comprises the following steps:

[0044] (e) subjecting compound 5 to a catalytic hydrogenation reaction in the presence of a catalyst to obtain compound A,

[0045]

[0046] Furthermore, in step (e), the catalyst is selected from a palladium catalyst, a platinum catalyst, a nickel catalyst, a ruthenium catalyst or a rhodium catalyst, more preferably a palladium-carbon catalyst, more preferably a 5% palladium-carbon catalyst.

[0047] Furthermore, in step (e), the amount of the catalyst added is at least based on the reaction being able to proceed, and preferably the mass ratio of the catalyst to the compound 5 is 0.02 to 0.4:1, more preferably 0.05 to 0.15.

[0048] Further, 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, and water and a mixed solvent thereof.

[0049] Furthermore, in step (e), the amount of the organic solvent added is 10 to 60 ml / g based on the mass of the compound 5.

[0050] Furthermore, in step (e), the reaction temperature is 40 to 70° C., preferably 50 to 70° C.; the reaction time is 0.5 to 24 h, preferably 6 to 12 h.

[0051] The present invention also provides an intermediate compound 5, which is used as an intermediate in the preparation of compound 6 or isotecan or its mesylate.

[0052]

[0053] The present invention also provides a method for preparing compound 5, comprising the following steps:

[0054] (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.

[0055]

[0056] Wherein, R is selected from halogen, sulfonate or diazo, such as iodine or trifluoromethanesulfonyloxy.

[0057] Further, in step (d), in step (d), the coupling catalyst is a complex formed by a palladium salt and a phosphine ligand;

[0058] and / or the palladium salt is selected from palladium chloride, palladium acetate, tetrakis(triphenylphosphine)palladium, palladium nitrate or triphenylphosphine palladium dichloride, preferably palladium acetate;

[0059] 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, preferably tri(o-tolyl)phosphine.

[0060] Furthermore, in step (d), the alkaline substance is selected from triethylamine, isopropylamine, pyridine, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium tert-butoxide, preferably triethylamine.

[0061] Further, in step (d), in step (d), the molar ratio of the compound 4 to 2-acetylaminobut-3-enoic acid is 1:1.0-3.0, for example, 1:1.2-1.5;

[0062] 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, for example, 1:0.15-0.30;

[0063] And / or the molar ratio of the compound 4 to the alkaline substance is 1:1.0-15.0, for example, 1:3.0-10.0.

[0064] 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, dimethylacetamide, toluene, water and a mixed solvent thereof; the amount of the organic solvent added is 10 to 60 ml / g based on the mass of compound 4.

[0065] Furthermore, in step (d), the reaction temperature is 20 to 110° C., such as 50 to 80° C.; the reaction time is 2 to 24 h, preferably 8 to 16 h.

[0066] The present invention also provides a method for preparing compound 4, comprising the following steps:

[0067] (a) Compound 1 is converted into Compound 2;

[0068] (b) Compound 2 is subjected to a catalytic hydrogenation reaction in the presence of a catalyst to obtain Compound 3;

[0069] (c) Compound 3 is reacted with an acylating agent in the presence of a catalyst to undergo an acylation reaction to obtain compound 4;

[0070]

[0071] R is selected from halogen, sulfonate or diazo, such as iodine, trifluoromethanesulfonyloxy.

[0072] Further, in step (a), preferably, the iodination agent is selected from iodine and N-iodosuccinimide, more preferably N-iodosuccinimide; the amount of N-iodosuccinimide is not limited as long as the reaction proceeds, preferably 1-1.5 equivalents. This step can be preferably carried out in a mixed solvent of sulfuric acid and other solvents.

[0073] Furthermore, in step (a), preferably, the reaction solvent is selected from the group consisting of dichloromethane, chloroform, 1,2-dimethoxyethane, hexane, pentane, heptane, cyclohexane, ethylcyclohexane, benzene, toluene, chlorobenzene and mixed solvents thereof.

[0074] Furthermore, in step (a), the reaction temperature is preferably -10 to 30°C, more preferably 0 to 10°C.

[0075] Furthermore, in step (a), the reaction time is preferably 0.5 to 4 h, more preferably 1.5 to 2 h.

[0076] Further, in step (b), preferably, the catalyst is selected from one or more of a rhodium carbon catalyst, a platinum carbon catalyst, platinum dioxide, titanium trichloride, nickel chloride, zinc powder, and iron powder, and is more preferably a platinum carbon catalyst; the amount of the catalyst is not limited as long as the reaction proceeds, and preferably, the mass ratio of the catalyst to compound 2 is 0.05 to 0.4:1, and more preferably 0.05 to 0.1:1.

[0077] 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, ethyl acetate, water and mixed solvents thereof; the amount of the reaction solvent added is 10 to 60 ml / g based on the mass of the compound 1.

[0078] Furthermore, in step (b), the reaction temperature is preferably 40 to 70°C, more preferably 50 to 70°C.

[0079] Furthermore, in step (b), the reaction time is preferably 0.5 to 8 h, more preferably 2 to 4 h.

[0080] Further, in 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; the molar ratio of the acylating agent to compound 2 is 0.5 to 1.5:1, more preferably 0.75 to 1:1.

[0081] Further, in step (c), preferably, the reaction is carried out in the presence of a base, the base being selected from triethylamine, isopropylamine, pyridine, sodium carbonate, potassium carbonate and potassium tert-butoxide, more preferably triethylamine; the molar ratio of the base to compound 2 is 0.5 to

[0082] 1.5:1, more preferably 0.75-1.5:1.

[0083] Further, in step (c), preferably, the reaction solvent is selected from the group consisting of methanol, ethanol, tetrahydrofuran, dichloromethane, chloroform, acetone, toluene, ethyl acetate and water and a mixed solvent thereof, more preferably ethyl acetate; the amount of the reaction solvent added is 10 to 60 ml / g based on the mass of the compound 2.

[0084] Furthermore, in step (c), the reaction temperature is preferably -10 to 40°C, more preferably 0 to 30°C.

[0085] Furthermore, in step (c), the reaction time is preferably 2 to 24 hours, more preferably 3 to 12 hours.

[0086] The E and Z forms represented by compounds 5 and 6 of the present invention exist as geometric isomers, and both are included in the compounds represented, and are therefore included in the scope of the present invention. The compound represented by compound 5 of the present invention can be a mixture of E and Z forms, and the mixture can be directly used in the next step.

[0087] Compared with the prior art, the present invention has the following beneficial effects:

[0088] (1) The present invention provides a new isotecan mesylate intermediate 5 and A, which opens up the research field of important intermediates of isotecan derivatives;

[0089] (2) The raw materials are cheap and readily available, and the synthetic route of the intermediates is simple, avoiding the "one-pot" reaction of oximation, catalytic hydrogenolysis and amino group protection, greatly reducing the number of reaction steps, and the operating conditions are mild, which reduces the difficulty of operation, has low energy consumption, and is suitable for industrial scale-up production;

[0090] (3) Improve atomic utilization, which is more in line with the industrial application of green chemistry;

[0091] The yield of the synthesis of isotecan derivatives is improved and the cost is further reduced. DETAILED DESCRIPTION

[0092] The technical scheme of the present invention will be clearly and completely described below in conjunction with specific embodiments, but it will be appreciated by those skilled in the art that the following described embodiments are examples of a part of the present invention, rather than all embodiments, and are only used to illustrate the present invention, and should not be considered as limiting the scope of the present invention. Based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work, all belong to the scope of protection of the present invention. If specific conditions are not indicated in the embodiments, they are carried out according to normal conditions or conditions recommended by the manufacturer. If the manufacturer is not indicated in the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0093] Example 1

[0094] Preparation of compound 4a

[0095]

[0096] Concentrated sulfuric acid (90%, 50 mL) was added to a three-necked flask, and compound 1 (10 g, 64.5 mmol) was added after cooling to about 1°C, and then N-iodosuccinimide (20.4 g, 90.2 mmol) was added to the reaction flask in six portions. The mixture was stirred at about 2°C for 2 hours. The obtained reaction solution was added to cold water (100 mL). After adding toluene (50 mL) for extraction and separation, the water layer was removed. Then, the organic layer was washed with water (50 mL), 5.0 wt% sodium carbonate aqueous solution (50 mL), and 5 wt% sodium sulfite aqueous solution (25 mL, 3 times). The organic layer was then concentrated under reduced pressure to obtain a crude product (200 g) of compound 2.

[0097] Compound 2 and ethyl acetate (15mL) were added to the reactor, followed by a suspension of 1% platinum carbon catalyst (2.1g) and ethyl acetate (90mL), the atmosphere was replaced with nitrogen, and then replaced with hydrogen. The reaction solution was stirred at 65 ° C for 3 hours in a hydrogen stream (0.2MPa), and cooled to room temperature. Insoluble matter was separated from the resulting suspension by filtration and washed with ethyl acetate (30mL). Then, the filtrate was washed with 6.5wt% sodium bicarbonate aqueous solution (25mL) and 5wt% brine (25mL), and the obtained organic layer was concentrated under reduced pressure to obtain a solution (50mL) of compound 3 in ethyl acetate.

[0098] The ethyl acetate solution of compound 3 and triethylamine were added to 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 (50ml) was added, and the water layer was removed after separation. The organic layer was concentrated under reduced pressure. Acetonitrile (50mL) and water (50mL) were added to the concentrated residue, and the concentrated residue was stirred at 25°C. The precipitated crystals were collected by filtration and washed with 50% acetonitrile aqueous solution (20mL). The obtained crystals were dried under reduced pressure at 40°C to obtain compound 4a as white crystals (6.4g, yield 38%).

[0099] 1 H NMR (500 MHz, 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).

[0100] Example 2

[0101] Preparation of Compound A

[0102]

[0103] 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 degassed under reduced pressure and the atmosphere was replaced with nitrogen, then tri(o-tolyl)phosphine (1.5 g, 5.12 mmol) and palladium acetate (II) (0.4 g, 1.71 mmol) were added, and the mixture was degassed under reduced pressure, the atmosphere was replaced with nitrogen, 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% sodium hydroxide aqueous 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, 2 times) to remove the organic layer. 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 product (10.8 g) of compound 5 containing geometric isomers.

[0104] By adding tetrahydrofuran (100mL), purified water (100mL) and 5% palladium on carbon (2.1g) to the crude compound 5 (10.8g) containing geometric isomers to obtain a suspension, the atmosphere is replaced with nitrogen, and then replaced with hydrogen. The mixture is stirred at 60°C for 8 hours in a hydrogen stream (0.5MPa) and cooled to room temperature. The insoluble matter is separated from the obtained suspension by filtration and washed with tetrahydrofuran (30mL). The filtrate is adjusted to pH about 2 with 1N hydrochloric acid solution. The solvent is concentrated to dryness under reduced pressure, acetonitrile (40mL) and water (80mL) are added to the concentrated residue, and the concentrated residue is stirred at 25°C. The precipitated crystals are collected by filtration and washed with 50% acetonitrile aqueous solution (10mL). The obtained crystals are dried under reduced pressure at 40°C to obtain compound A as white crystals (9.2g, yield 87%).

[0105] 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).

[0106] 13C NMR(126MHz,DMSO-d6)δ174.02,169.93,168.88,161.73,159.83,142.40,1 38.36,117.15,115.18,104.20,52.05,32.07,29.34,24.45,22.84,10.07.

[0107] ESI-MS: m / z C 15 H 19 FN 2 O 4 [M+H]+ calculated: 311.13; found: 311.18;

[0108] Example 3

[0109] Preparation of Compound A

[0110]

[0111] Compound 4a (10.0 g, 34.1 mmol), 2-acetylaminobut-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 mixture was heated to reflux at 100°C for 24 hours. 2-Methyltetrahydrofuran (100 mL) and water (100 mL) were added to the reaction solution cooled to room temperature, 25 w / v% sodium hydroxide aqueous 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, 2 times) 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).

[0112] By adding tetrahydrofuran (100mL), purified water (100mL) and 5% palladium on carbon (2.1g) to the crude compound 5 (9.0g) containing geometric isomers to obtain a suspension, the atmosphere is replaced with nitrogen, and then replaced with hydrogen. The mixture is stirred at 40°C for 16 hours in a hydrogen stream (0.4MPa) and cooled to room temperature. The insoluble matter is separated from the obtained suspension by filtration and washed with tetrahydrofuran (20mL). The filtrate is adjusted to pH about 2 with 1N hydrochloric acid solution. The solvent is concentrated to dryness under reduced pressure, acetonitrile (40mL) and water (80mL) are added to the concentrated residue, and the concentrated residue is stirred at 25°C. The precipitated crystals are collected by filtration and washed with 50% acetonitrile aqueous solution (10mL). The obtained crystals are dried under reduced pressure at 40°C to obtain compound A as white crystals (8.5g, yield 80%).

[0113] Comparative Example 1

[0114]

[0115] A solution of compound 4a (0.84 g, 3.4 mmol), 2-butenoic acid-3-(acetylamino)-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 was replaced with nitrogen, and then tri(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 was replaced with nitrogen, and then heated to reflux for 8 hours and cooled to room temperature.

[0116] The reaction solution was sampled and tested by LCMS, and no target compound was obtained in the reaction.

[0117] Comparative Example 2

[0118]

[0119] A solution of compound 4b (0.84 g, 3.4 mmol), 2-amino-3-butyric 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 was replaced with nitrogen, and then tri(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 was replaced with nitrogen, then heated to reflux for 8 hours, and cooled to room temperature.

[0120] The reaction solution was sampled and tested by LCMS, and no target compound was obtained in the reaction.

[0121] Comparative Example 3

[0122]

[0123] A solution of compound 4a (1.0 g, 3.4 mmol), 2-amino-3-butyric 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 was replaced with nitrogen, and then tri(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 was replaced with nitrogen, and then heated to reflux for 8 hours and cooled to room temperature.

[0124] The reaction solution was sampled and tested by LCMS, and no target compound was obtained in the reaction.

[0125] Example 4

[0126] Preparation of compound 6

[0127]

[0128] Trifluoroacetic anhydride (25mL, 176.8mmol) was put into a reaction flask, cooled to 0°C, compound A (5.0g, 16.1mmol) was added, and concentrated sulfuric acid (2mL) was added. Stirring was continued at 0°C for 1h, then slowly raised to 35°C, and stirring was continued for 12h. The obtained reaction solution was added dropwise to a 50% acetonitrile aqueous solution (120mL) cooled to 5°C. After the pH was adjusted to about 7 with a 25wt% sodium hydroxide aqueous solution, water (20mL) was added. Then, the reaction solution temperature was returned to room temperature, the precipitated crystals were collected by filtration, and washed with water (60mL) and 75% acetonitrile aqueous solution (60mL). The obtained crystals were dried under reduced pressure to obtain compound 6 as white crystals (4.2g, yield 90%).

[0129] 1 H NMR (500 MHz, 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).

[0130] ESI-MS: m / z C 15 H 18 FN 2 O 3[M+H]+ calculated: 293.1301; found: 293.1310;

[0131] Example 5

[0132] Preparation of compound 6

[0133]

[0134] 1,2-Dichloroethane (50 mL) was added to the reaction flask, cooled to -40°C, compound A (3.1 g, 10 mmol) and phosphorus pentachloride (2.1 g, 10 mmol) were added, and stirring was continued at -40°C for 2 h, and then the temperature was slowly raised to room temperature. AlCl 3 (2.8 g, 21 mmol), heated to reflux for 10 hours. After the reaction was completed by TLC monitoring, the reaction solution was slowly added to ice water (200 mL), extracted with ethyl acetate, dried, filtered, and spin-dried. The obtained solid was dried under reduced pressure to obtain compound 6 as white crystals (1.4 g, yield 48%). The structural characterization data are the same as those in Example 3.

[0135] Comparative Example 4

[0136] Preparation of compound 6a

[0137]

[0138] Polyphosphoric acid (2 mL) and compound A (100 mg) were added to a reaction flask and reacted at 100°C for 12 h. Then, the reaction solution was returned to room temperature and neutralized to pH = 7 under ice bath conditions. The organic phase was extracted with dichloromethane and collected. 2 SO 4 Dry, filter and spin dry to obtain white compound 6a (80 mg, yield 91%).

[0139] 1 H NMR (500 MHz, 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,3H).

[0140] ESI-MS: m / z[M+H]+ calculated: 275.12; found: 275.18;

[0141] Example 6

[0142] Preparation of compound B

[0143]

[0144] 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. The precipitated crystals were collected by filtration and washed with acetone (10 mL). The resulting crystals were dried under reduced pressure at 40 ° C to obtain compound B (3.6 g, yield 85%).

[0145] 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).

[0146] ESI-MS: m / z C 13 H 16 FN 2 O 2 [M+H]+ calculated: 251.1196; found: 251.1194;

[0147] Example 7

[0148] Preparation of compound 8

[0149]

[0150] Compound B (10 g, 40.0 mmol), compound 7 (10 g, 38.0 mmol), p-toluenesulfonic acid pyridinium salt (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, and the mixture was reacted at 108 ° C for 32 hours and cooled. The precipitated crystals were collected by filtration and washed with acetone (30 mL). The obtained crystals were dried under reduced pressure at 40 ° C to obtain compound 8 (15.4 g, yield 85%).

[0151] ESI-MS: m / z C26 H 25 FN 3 O 5 [M+H]+ calculated value: 478.1778; found value 478.1782;

[0152] Example 8

[0153] Preparation of compound 9

[0154]

[0155] 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. The solid dissolved and exothermic phenomenon occurred. The mixture was heated to 90 °C for 8 h, cooled to room temperature, separated and the organic phase was removed. The aqueous phase was filtered, the filtrate was diluted with ethanol (4 L), the solid precipitated, stirred at room temperature for 20 min, filtered, and dried. The crude product was suspended in ethanol / water = 4:1, heated to reflux for 2 h, cooled to room temperature, filtered, the solid was washed with a small amount of ethanol and dried, and compound 9, i.e., isotecan mesylate (4.6 g, 45%), was obtained after drying.

[0156] 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).

[0157] ESI-MS: m / z C 24 H 23 FN 3 O 4 [M+H]+ calculated: 436.1673; found: 436.1678.

Claims

1. A method for preparing compound 6, characterized in that: The following steps are involved: (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: The following steps are involved: (f) subjecting compound A to an intramolecular Friedel-Crafts acylation reaction under the action of an intramolecular cyclization agent to obtain compound 6, 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.

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 enough to allow 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: The following steps are involved: (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, characterized in that: In step (e), the catalyst is selected from 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 any mixed solvent thereof.

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 0.5-24 h.

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 6-12 hours.

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: The following steps are involved: (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 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 2-24 h.

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: The steps include: (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 according to claim 32, characterized in that: The compound A is prepared from compound 5 according to the method described in any one of claims 10 to 18.

34. The preparation method according to claim 32 is characterized in that: The compound 5 is prepared from compound 4 according to the method described 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.

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