INTERMEDIATE FOR SYNTHESIZING CAMPTOTHECIN DERIVATIVE, PREPARATION METHOD THEREFOR, AND USE THEREOF

Abstract

Provided are an intermediate for synthesizing a camptothecin derivative, a preparation method therefor, and the use thereof. An intermediate A can be obtained from 3-fluoro-4-methylaniline by means of acylation, bromination, and cross-coupling reactions. The intermediate A can be used for preparing an intermediate B to further prepare exatecan mesylate. The intermediate compound B can be obtained from the intermediate A by means of a rearrangement reaction, and exatecan mesylate can be obtained from the intermediate compound B by means of deprotection for acetamido and amino at the a site, a condensation reaction, and a hydrolysis reaction. The reaction starting materials have a low price, the reaction conditions of each step are moderate, the operation is simple, and the yield is high, such that the intermediate is suitable for industrial production.

Claims

1. A preparation method of an intermediate compound represented by formula B, characterized by comprising the step of: d, subjecting Compound A to a rearrangement reaction to obtain Compound B, ##STR00022##

2. The preparation method according to claim 1, characterized by subjecting Compound A to the rearrangement reaction in the presence of a catalyst, an oxidant, water and an organic solvent to obtain Compound B.

3. The preparation method according to claim 2, characterized in that the catalyst is one or more selected from copper powder, copper sulfate, cuprous chloride, cuprous bromide, cuprous iodide, silver nitrate, silver acetate, and silver fluoride; the oxidant is one or more selected from 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), potassium persulfate, and ceric ammonium nitrate; the organic solvent is one or more selected from acetonitrile, dichloromethane, toluene, tetrahydrofuran, and dimethyl sulfoxide.

4. A The preparation method according to claim 1, characterized in that Compound A is prepared by a method comprising the steps of: a, subjecting Compound 1 to an acylation reaction with an acylating agent in the presence of a catalyst to obtain Compound 2; b, subjecting Compound 2 to a bromination reaction with a brominating agent in the presence of a catalyst and an organic acid to obtain Compound 3; c, subjecting Compound 3 to a cross-coupling reaction with cyclobutanone in the presence of a base and an organic solvent to obtain Compound A; ##STR00023##

5. The preparation method according to claim 4, characterized in that in the step of a, the acylating agent is one or more selected from acetic anhydride, acetyl chloride, ketene, chloroacetate, and nitrile acetate; the catalyst is one or more selected from anhydrous aluminum chloride, anhydrous zinc chloride, polyphosphoric acid, and sulfuric acid.

6. The preparation method according to claim 4, characterized in that in the step of b, the brominating agent is one or more selected from liquid bromine, hydrogen bromide, phosphorus tribromide, aluminum tribromide and N-bromosuccinimide, the catalyst is one or more selected from magnesium bromide, zinc bromide, iodine, palladium acetate, sodium acetate, p-toluenesulfonic acid, copper trifluoromethanesulphonate and silver oxide; the organic acid is one or more selected from formic acid, acetic acid, propionic acid, butyric acid and trifluoroacetic acid.

7. The preparation method according to claim 4, characterized in that in the step of c, the base is one or more selected from potassium tert-butoxide, sodium hydrogen, n-butyllithium and sodium methoxide; the organic solvent is one or more selected from tetrahydrofuran, dioxane, and n-hexane.

8. The preparation method according to claim 7, characterized by further comprising the steps of: e, (i) reacting Compound B with an oximation agent in the presence of a base, (ii) performing a catalytic hydrogenolysis reaction in the presence of an acid, a catalyst and hydrogen under a normal pressure condition, (iii) protecting amino group with a protecting group to obtain Compound 4; wherein (ii) and (iii) may be performed in an exchanged order, or may be performed as a “one-pot process”; f, deprotecting an amino group in Compound 4 in the presence of an acid to obtain Compound 5; g, subjecting Compound 5 to a condensation reaction with Compound 6 to obtain Compound 7; h, subjecting Compound 7 to a hydrolysis reaction in the presence of an acid to obtain exatecan mesylate of formula 8; ##STR00024## ##STR00025##

9. The preparation method according to claim 8, characterized in that in the step of e (i), the oximation agent is a nitrite, which is one or more selected from amyl nitrite, n-butyl nitrite, and tert-butyl nitrite; the base is potassium tert-butoxide.

10. The preparation method according to claim 8, characterized in that in the step of g, Compound 5 is subjected to the condensation reaction with Compound 6 in the presence of pyridinium p-toluenesulfonate and toluene to obtain Compound 7.

11. The preparation method according to claim 8, characterized in that in the step of h, Compound 7 is subjected to the hydrolysis reaction in the presence of methanesulfonic acid and water to obtain exatecan mesylate of formula 8.

12. (canceled)

13. The preparation method according to claim 2, characterized in that a molar ratio of Compound A to the catalyst is 1:(0.1-0.5).

14. The preparation method according to claim 2, characterized in that a molar ratio of Compound A to the oxidant is 1:(2-5).

15. The preparation method according to claim 2, characterized in that a volume ratio of the organic solvent to water is 1:(0.9-2).

16. A preparation method of exatecan mesylate represented by formula 8, ##STR00026## characterized by preparing exatecan mesylate represented by formula 8 from a compound represented by formula A: ##STR00027##

17. The preparation method according to claim 16, characterized by comprising the step of: d, subjecting Compound A to a rearrangement reaction to obtain Compound B, ##STR00028##

18. The preparation method according to claim 8, characterized in that in the step of e (ii), the acid is hydrochloric acid; the catalyst is palladium carbon.

19. The preparation method according to claim 8, characterized in that in the step of e (iii), the protecting group is acetyl group.

20. The preparation method according to claim 19, characterized in that the condensation reaction is a reflux reaction.

21. A compound represented by formula A: ##STR00029##

Description

DESCRIPTION OF EXAMPLES

[0126] The technical solutions of the invention will be clearly and completely described below in combination with the specific examples, those skilled in the art will understand that the examples described below are a part of the examples of the invention, and not exhaustive. Such examples are intended to illustrate the invention and not to limit the scope of the invention. All other examples obtained by those skilled in the art based on the examples of the invention without creative efforts fall within the scope of protection of the invention. Conditions not specifically specified in the examples are conventional conditions or the conditions recommended by the manufacturers. Reagents or instruments used whose manufacturers are not indicated are commercially available conventional products.

[0127] Some reagents adopted in the specific example of the present invention can be as follows:

TABLE-US-00001 Reagent Raw material supplier 3-Fluoro-4-methylaniline J&K Scientific N-butyllithium Jiangsu Changjili New Energy Technology Co., Ltd Cyclobutanone Chengdu Apis Pharmaceutical Technology Co., Ltd potassium persulfate Wuhan Meng Qi Technology Co., Ltd. Acetic acid Jiangsu Bohan Industry Trade Co., Ltd.

Example 1

Synthesis of Compound A

[0128] ##STR00017##

[0129] The synthetic route of Compound A of this example is shown aforementioned, and the preparation method comprises the steps of:

[0130] a, acetic anhydride (300 mL) and sulfuric acid (1.5 mL) were added to a three-necked flask, and the temperature was cooled to 10° C. while stirring. Compound 1 (95 g) was added to the reaction flask in batches, after the addition, the mixture was stirred at 10° C. for 30 minutes. The reaction mixture was poured into ice water, then the solid was precipitated, filtered, washed with water three times, collected and dried to obtain the crude Compound 2 (117.8 g, 92.8%).

[0131] b, Compound 2 (115.5 g) and sodium acetate (68 g) were added to acetic acid (250 mL), and heated to 60° C., followed by adding dropwise a mixture of bromine (132.5 g) and acetic acid (100 mL), the reaction temperature was raised to 80° C. and the mixture was stirred for 2 hours. After the reaction, the reaction mixture was poured into ice water, and a yellow solid was produced. The solid was filtered and washed with water three times to obtain Compound 3 as a white solid (167 g, 98%).

[0132] c, Compound 3 (160 g) dissolved in tetrahydrofuran (1.5 L) was cooled to −78° C., and a solution of n-butyllithium in tetrahydrofuran (2.5 M, 0.624 L) was slowly dropped. After the mixture was stirred for one and a half hours, cyclobutanone (55 g) was slowly added dropwise, the reaction mixture was stirred at −78° C. for half an hour, and then the reaction temperature was restored to room temperature. Followed by stirring for a further half an hour, an aqueous ammonium chloride solution was added to quench the reaction. The solution was extracted with ethyl acetate (500 mL) three times. The organic layers were combined and washed once with saturated brine, dried with anhydrous sodium sulfate, filtered and spin-dried. The residue was recrystallized from two volumes of ethanol to obtain the pure Compound A (110.8 g, 72%).

Example 2

Synthesis of Compound A

[0133] The synthetic route of Compound A of this example is consistent with example 1, and the preparation method comprises the steps of:

[0134] a, acetyl chloride (45 mL) and anhydrous aluminum chloride (5 g) were added to a three-necked flask, and the temperature was cooled to 0° C. while stirring. Compound 1 (20 g) was added to the reaction flask in batches, and after the addition, the mixture was stirred at 0° C. for 45 minutes. The reaction mixture was poured into ice water, then the solid was precipitated, filtered, washed with water three times, collected and dried to obtain the crude Compound 2 (24 g, 90%).

[0135] b, Compound 2 (10 g) and iodine (15 g) were added to trifluoroacetic acid (15 mL), and heated to 55° C., followed by adding dropwise a mixture of liquid bromine (10.5 g) in trifluoroacetic acid (5 mL), the reaction temperature was raised to 85° C., and the mixture was stirred for 2 hours. After the reaction, the reaction mixture was poured into ice water, and a yellow solid was produced. The solid was filtered and washed with water three times to obtain Compound 3 as a white solid (14 g, 96%).

[0136] c, Compound 3 (30 g) dissolved in n-hexane (300 mL) was cooled to −78° C., and potassium tert-butoxide (27 g) was slowly added to the reaction solution, stirred for one and a half hours, cyclobutanone (17 g) was slowly dropped, the reaction mixture was stirred at −78° C. for one and a half hours, and then the reaction temperature was restored to room temperature. Followed by stirring for a further an hour, an aqueous ammonium chloride solution was added to quench the reaction. The solution was extracted with ethyl acetate (100 mL) three times. The organic layers were combined and washed once with saturated brine, dried with anhydrous sodium sulfate, filtered and spin-dried. The residue was recrystallized from two volumes of ethanol to obtain the pure Compound A (20.2 g, 70%).

Example 3

Synthesis of Compound A

[0137] The synthetic route of Compound A of this example is consistent with example 1, and the preparation method comprises the steps of:

[0138] a, acetic anhydride (9.2 L) and sulfuric acid (30 mL) were added to a three-necked flask, and the temperature was cooled to 5° C. while stirring. Compound 1 (2.5 kg) was added to the reaction flask in batches, and after the addition, the mixture was stirred at 5° C. for 60 minutes. The reaction mixture was poured into ice water, then the solid was precipitated, filtered, washed with water three times, collected and dried to obtain the crude Compound 2 (3.1 kg, 93%).

[0139] b, Compound 2 (1.5 kg) and sodium acetate (770 g) were added to acetic acid (3.6 L), and heated to 60° C., and then a mixture of liquid bromine (1.5 kg) and acetic acid (1.4 L) was added dropwise to the reaction mixture. The reaction temperature was raised to 90° C., and stirred for 3 hours. After the reaction, the reaction mixture was poured into ice water, and a yellow solid was produced. The solid was filtered and washed with water three times to obtain Compound 3 as a white solid (2.16 kg, 98%).

[0140] c, Compound 3 (2 kg) dissolved in tetrahydrofuran (15 L) was cooled to −78° C., and a solution of n-butyllithium in tetrahydrofuran (2.5 M, 7.8 L) was slowly dropped. After the mixture was stirred for one and a half hours, cyclobutanone (687 g) was slowly dropped, the reaction mixture was stirred at −78° C. for one and a half hours, and then the reaction temperature was restored to room temperature. Followed by stirring for a further one and a half hours, an aqueous ammonium chloride solution was added to quench the reaction. The solution was extracted with ethyl acetate (5 L) three times. The organic layers were combined and washed once with saturated brine, dried with anhydrous sodium sulfate, filtered and spin-dried. The residue was recrystallized from two volumes of ethanol to obtain the pure Compound A (1.45 kg, 75%).

Example 4

Synthesis of Compound A

[0141] The synthetic route of Compound A of this example is consistent with example 1, and the preparation method comprises the steps of:

[0142] a, acetic anhydride (30 mL) was added to a three-necked flask, and the temperature was cooled to 10° C. while stirring. Compound 1 (10 g) was added to the reaction flask in batches, after the addition, the mixture was stirred at 10° C. for 30 minutes. The reaction mixture was poured into ice water, then the solid was precipitated, filtered, washed with water three times, collected and dried to obtain the crude Compound 2 (6 g, 45%).

[0143] b, Compound 2 (10 g) was added to acetic acid (20 mL), and heated to 60° C., followed by adding dropwise the mixture of liquid bromine (11.5 g) and acetic acid (10 mL), the reaction temperature was raised to 80° C., and stirred for 2 hours. After the reaction, the reaction mixture was poured into ice water, and a yellow solid was produced. The solid was filtered and washed with water three times to obtain Compound 3 as a white solid (11.7 g, 80%).

[0144] c, Compound 3 (10 g) was dissolved in dioxane (100 mL), and cooled to −78° C., and sodium methoxide (5.5 g) was slowly added, after the mixture was stirred for one and a half hours, cyclobutanone (3.5 g) was slowly dropped, the reaction mixture was stirred at −78° C. for half an hour, and then the reaction temperature was restored to room temperature. Followed by stirring for a further half an hour, an aqueous ammonium chloride solution was added to quench the reaction. The solution was extracted with ethyl acetate (50 mL) three times. The organic layers were combined and washed once with saturated brine, dried with anhydrous sodium sulfate, filtered and spin-dried. The residue was recrystallized from two volumes of ethanol to obtain the pure Compound A (6.3 g, 65%).

[0145] The compounds obtained in each step were routinely separated and purified, and the pure product was characterized. The structural characterization data were as follows:

[0146] Compound 2: .sup.1H-NMR (CDCl.sub.3) δ: 7.68 (1H, s), 7.43 (1H, d, J=12 Hz), 7.07-7.14 (2H, m), 2.26 (3H, s), 2.20 (3H, s); ESI-MS: m/z C.sub.9H.sub.10FNO [M+H].sup.+ Calculated: 168.1; Found: 168.1;

[0147] Compound 3: .sup.1H-NMR (CDCl.sub.3) δ: 8.18 (1H, d, J=12 Hz), 7.59 (1H, s), 7.37 (1H, d, J=8 Hz), 2.27 (3H, s), 2.26 (3H, s); ESI-MS: m/z C.sub.9H.sub.9BrFNO [M+H].sup.+ Calculated: 246.0/248.0; Found: 246.0/248.0;

[0148] Compound A: .sup.1H-NMR (CD.sub.3OD) δ: 7.68 (1H, d, J=12 Hz), 7.29 (1H, d, J=8 Hz), 2.52-2.56 (2H, m), 2.35-2.43 (2H, m), 2.29 (3H, s), 2.17 (3H, s), 2.02-2.06 (1H, m), 1.65-1.7 (1H, m); ESI-MS: m/z C.sub.13H.sub.16FNO.sub.2 [M+H].sup.+ Calculated: 238.1; Found: 238.1.

Example 5

Synthesis of Compound B

[0149] ##STR00018##

[0150] The synthetic route of Compound B of this example is shown above, and the preparation method comprises the step of:

[0151] d, Compound A (50 g) was dissolved in acetonitrile (750 mL) and water (750 mL), followed by adding silver nitrate (7.1 g) and potassium persulfate (170 g), while stirring at 30° C. for 8 hours. After the reaction, the product was dissolved in ethyl acetate, filtered to remove inorganic salts. The filtrate was extracted three times with ethyl acetate. The organic layers were combined and washed once with saturated brine, dried with anhydrous sodium sulfate, filtered, spin dried and purified by column chromatography to obtain the pure key intermediate compound B of exatecan (33 g, 66%).

Example 6

Synthesis of Compound B

[0152] The synthetic route of Compound B of this example is consistent with example 5, and the preparation method comprises the step of:

[0153] d, Compound A (350 g) was dissolved in toluene (5.2 L) and water (6.2 L), followed by adding silver fluoride (46.8 g) and potassium persulfate (1.6 kg), while stirring at 25° C. for 10 hours. After the reaction, the product was dissolved in ethyl acetate, filtered to remove inorganic salts. The filtrate was extracted three times with ethyl acetate. The organic layers were combined and washed once with saturated brine, dried with anhydrous sodium sulfate, filtered, spin-dried and purified by column chromatography to obtain the pure key intermediate compound B of exatecan (222 g, 64%).

Example 7

Synthesis of Compound B

[0154] The synthetic route of Compound B of this example is consistent with example 5, and the preparation method comprises the step of:

[0155] d, Compound A (2.5 kg) was dissolved in dimethyl sulfoxide (25 L) and water (25 L), followed by adding silver nitrate (355 g) and potassium persulfate (8.5 kg), while stirring at 35° C. for 12 hours. After the reaction, the product was dissolved in ethyl acetate, filtered to remove inorganic salts. The filtrate was extracted three times with ethyl acetate. The organic layers were combined and washed once with saturated brine, dried with anhydrous sodium sulfate, filtered, spin-dried and purified by column chromatography to obtain the pure key intermediate compound B of exatecan (1.96 kg, 79%).

Example 8

Synthesis of Compound B

[0156] The synthetic route of Compound B of this example is consistent with example 5, and the preparation method comprises the step of:

[0157] d, Compound A (20 g) was dissolved in dichloromethane (300 mL) and water (300 mL), followed by adding silver nitrate (2.8 g) and potassium persulfate (68 g), while stirring at 30° C. for 8 hours. After the reaction, the product was dissolved in ethyl acetate, filtered to remove inorganic salts. The filtrate was extracted three times with ethyl acetate. The organic layers were combined and washed once with saturated brine, dried with anhydrous sodium sulfate, filtered, spin-dried and purified by column chromatography to obtain the pure key intermediate compound B of exatecan (4.6 g, 23%).

Example 9

Synthesis of Compound B

[0158] The synthetic route of Compound B of this example is consistent with example 5, and the preparation method comprises the step of:

[0159] d, Compound A (40 g) was dissolved in tetrahydrofuran (650 mL) and water (1 L), followed by adding silver acetate (8.4 g) and selectfluor (298 g), while stirring at 35° C. for 8 hours. After the reaction, the product was dissolved in ethyl acetate, filtered to remove inorganic salts. The filtrate was extracted three times with ethyl acetate. The organic layers were combined and washed once with saturated brine, dried with anhydrous sodium sulfate, filtered, spin-dried and purified by column chromatography to obtain the pure key intermediate compound B of exatecan (23.8 g, 60%).

Example 10

Synthesis of Compound B

[0160] The synthetic route of Compound B of this example is consistent with example 5, and the preparation method comprises the step of:

[0161] d, Compound A (35 g) was dissolved in dimethyl sulfoxide (520 mL) and water (520 mL), followed by adding silver fluoride (4.7 g) and potassium persulfate (160 g), while stirring at 30° C. for 10 hours. After the reaction, the product was dissolved in ethyl acetate, filtered to remove inorganic salts. The filtrate was extracted three times with ethyl acetate. The organic layers were combined and washed once with saturated brine, dried with anhydrous sodium sulfate, filtered, spin-dried and purified by column chromatography to obtain the pure key intermediate compound B of exatecan (24.3 g, 70%).

[0162] Compound B: .sup.1H-NMR (CDCl.sub.3) δ: 8.43 (1H, d, J=12 Hz), 2.88-2.91 (2H, m), 2.66-2.69 (2H, m), 2.24 (3H, s), 2.17 (3H, s), 2.09-2.12 (2H, m); ESI-MS: m/z C.sub.13H.sub.14FNO.sub.2 [M+H].sup.+ Calculated: 236.1; Found: 236.1.

Example 11

Synthesis of Compound 8 (Exatecan Mesylate)

[0163] ##STR00019## ##STR00020##

[0164] The synthetic route of Compound 8 of this example is shown above, and the preparation method comprises the steps of:

[0165] e, potassium tert-butoxide (34.6 g) was added to a mixture of tetrahydrofuran (650 mL) and tert-butanol (165 mL), dissolved at 5° C. while stirring to obtain the reaction mixture. Compound B (33.0 g) was dissolved in tetrahydrofuran (650 mL), and added dropwise to the reaction mixture, reacted for 10 min. Followed by adding dropwise n-butyl nitrite (23.2 g), the reaction was continued for an hour. The pH was adjusted to be acidic with 2N hydrochloric acid (360 mL), the mixture was extracted with ethyl acetate (1 L), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was slurried with methyl tert-butyl ether (200 mL), filtered and dried.

[0166] The aforementioned solid (27.5 g) was added to methanol (300 mL), followed by adding 2N hydrochloric acid (127 mL) and palladium carbon (3.3 g) at room temperature. The hydrogenation reaction was performed for 2 hours in a hydrogen stream under a normal pressure, and the reaction solution was directly used in the next step.

[0167] Acetic anhydride (33.0 g) was added to the aforementioned reaction solution, and the reaction was continued for an hour under the protection of hydrogen. After the reaction, the mixture was neutralized with sodium bicarbonate to pH>7, extracted with ethyl acetate (300 mL*2), washed with water, and washed with saturated brine, dried with anhydrous sodium sulfate, concentrated, and the crude product was slurried with a mixed solvent of methyl tert-butyl ether (100 mL) and ethyl acetate (50 mL), filtered and dried to obtain Compound 4 as a light yellow solid powder (25.6 g, 62%).

[0168] f, Compound 4 (15.5 g) was added to the solution of 2N hydrochloric acid (620 mL) and methanol (620 mL), and reacted at 60° C. for half an hour under argon protection. Then the mixture was cooled to 0˜10° C., neutralized to pH=3-4 with sodium carbonate (65.7 g) and water (1314 mL), then neutralized to pH=6˜7 with saturated aqueous sodium bicarbonate, filtered, washed with water (100 mL), and dried to obtain Compound 5 as a solid powder (12.4 g, 93%).

[0169] g, Compound 5 (10 g), Compound 6 (10 g) and pyridinium p-toluenesulfonate (6 g) were added to a three-necked flask, followed by adding toluene (500 mL), a reflux and water separation reaction is performed at 130˜140° C. for 48 hours. The reaction mixture was cooled, filtered, washed with methyl tert-butyl ether (100 mL), and the solid was collected and dried to obtain Compound 7 (18.4 g, 96.5%).

[0170] h, Compound 7 (30 g) was suspended in the water (600 mL), the methanesulfonic acid (300 mL) was slowly added, there was an exothermic phenomenon during the solid was dissolved. After nitrogen replacement, the reaction was heated to 112° C. for 7 hours. After the reaction, the reaction mixture was cooled to room temperature and filtered. The filter cake was washed with water (100 mL). The filtrate was diluted with ethanol (4 L), then the solid was precipitated, stirred, filtered, and drained at room temperature. A suspension of the crude product in ethanol/water=4:1(1 L) was heated under reflux for 2 hours. Then the mixture was cooled to room temperature and filtered. The solid was washed with small amount of ethanol, drained, and freeze dried to obtain exatecan mesylate (Compound 8, 16.7 g, 50%).

Example 12

Synthesis of Compound 7

[0171] ##STR00021##

[0172] The synthetic route of Compound 7 of this example is shown above, and the preparation method comprises the step of:

[0173] g, Compound 5 (5 g), Compound 6 (5 g) and pyridinium p-toluenesulfonate (3 g) were added to a three-necked flask. After the addition of toluene (200 mL), a reflux and water separation reaction is performed at 130˜140° C. for 72 hours. The reaction mixture was cooled, filtered, washed with methyl tert-butyl ether (50 mL), and the solid was collected and dried to obtain Compound 7 (6.4 g, 71%).

[0174] The compounds obtained in each step are routinely separated and purified, and the pure product is characterized. The structural characterization data are as follows:

[0175] Compound 4: .sup.1H-NMR (DMSO-d.sub.6) δ: 11.89 (s, 1H), 8.29 (d, J=13.0 Hz, 1H), 8.22 (d, J=7.8 Hz, 1H), 4.59-4.65 (m, 1H), 3.09-2.94 (m, 2H), 2.18-2.21 (m, 1H), 2.16 (s, 3H), 2.12 (s, 3H), 1.95-2.03 (m, 1H), 1.92 (s, 3H); ESI-MS: m/z C.sub.15H.sub.17FN.sub.2O.sub.3[M+H].sup.+ Calculated: 293.1; Found: 293.1;

[0176] Compound 5: .sup.1H-NMR (DMSO-d.sub.6) δ: 8.08 (d, J=7.9 Hz, 1H), 7.42 (s, 2H), 6.38 (d, J=12.5 Hz, 1H), 4.51-4.41 (m, 1H), 2.91-2.94 (m, 1H), 2.79-2.84 (m, 1H), 2.10-2.18 (m, 1H), 1.98 (s, 3H), 1.90 (s, 3H), 1.81-1.89 (m, 1H); ESI-MS: m/z C.sub.13H.sub.15FN.sub.2O.sub.2[M+H].sup.+ Calculated: 251.1; Found: 251.1;

[0177] Compound 7: .sup.1H-NMR (DMSO-d.sub.6) δ: 8.43-8.55 (m, 1H), 7.80 (d, J=10.9 Hz, 1H), 7.31 (d, J=3.8 Hz, 1H), 6.55 (s, 1H), 5.54-5.57 (m, 1H), 5.43 (s, 2H), 5.16-5.25 (m, 2H), 3.17 (s, 2H), 2.39 (s, 3H), 2.11-2.13 (m, 2H), 1.80-1.92 (m, 5H), 0.86-0.89 (m, 3H); ESI-MS: m/z C.sub.26H.sub.24FN.sub.3O.sub.5[M+H].sup.+ Calculated: 478.2; Found: 478.2;

[0178] Compound 8 (exatecan mesylate): .sup.1H-NMR (D.sub.2O) δ: 7.08 (d, J=10.3 Hz, 1H), 7.05 (s, 1H), 5.33-5.34 (m, 1H), 5.24-5.27 (m, 1H), 5.19-5.21 (m, 1H), 5.16-5.17 (m, 1H), 5.12 (s, 1H), 3.25 (d, J=13.4 Hz, 1H), 2.91-2.97 (m, 1H), 2.63-2.66 (m, 4H), 2.47-2.54 (m, 1H), 2.13 (s, 3H), 1.73-1.77 (m, 2H), 0.74 (t, J=7.3 Hz, 3H); ESI-MS: m/z C.sub.25H.sub.26FN.sub.3O.sub.7S [M+H].sup.+ Calculated: 532.2; Found: 532.2.

INDUSTRIAL APPLICABILITY

[0179] In the present invention, the reaction starting materials have a low price, the synthesis route of the intermediate is simple, the reaction conditions of each step are moderate, the post-processing is easy and the yield is high. Therefore the present invention is suitable for industrial production.

[0180] Finally, it should be noted that the aforementioned examples are merely illustrative of the technical solutions of the present invention, and are not intended to limit the same. Although the present invention has been described in detail with reference to the foregoing examples, it should be understood by those of ordinary skill in the art that modification may be made to the technical solutions described in the foregoing examples, or equivalent replacement may be made to some or all of the technical features; however, the modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of various examples of the present invention.