A method for synthesizing 9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-one and applications thereof

Abstract

The application provides a preparation method and application of a compound III, and belongs to the field of medicinal chemistry. The method uses compound I as a raw material, and compound III is prepared through acyl chloride and Friedel-Crafts acylation reaction in a one-pot two-step method, and a reaction formula is shown in the following formula: The synthesis method provided by the application solves many pain points of the existing synthesis method using polyphosphoric acid as a dehydrating agent, for example, the polyphosphoric acid has strong corrosion, is viscous and not easy to transfer, the reaction temperature is high, the substrate is easy to polymerize, product purification needs vacuum distillation, and there are many phosphorus-containing waste water, etc. The synthesis method has the advantages of simple operation, environmental friendliness, mild and safe reaction conditions, high reaction yield and the like, and is suitable for large-scale production.

Description

Technical Field

[0001] This invention relates to a method for the efficient synthesis of 9,10-dihydro-4H-benzo[4,5]cycloheptanetriene[1,2-B]thiophene-4-one and its application, belonging to the field of pharmaceutical chemistry. Background Technology

[0002] The compound 9,10-dihydro-4H-benzo[4,5]cycloheptatrien[1,2-B]thiophene-4-one of Formula III of this invention is a key pharmaceutical intermediate used in the synthesis of ketotifen fumarate, and its structure is shown below:

[0003]

[0004] In existing technologies, the synthetic method for the compound represented by Formula III uses the compound represented by Formula I, 2-[2-(2-thienyl)ethyl]benzoic acid, as a substrate and polyphosphoric acid as a dehydrating agent to carry out a Friedel-Crafts acylation reaction, as shown in the literature Helvetica Chimica Acta, 1966, 49(1):214-234., and Heterocyclic Communications, 2001, 7(5):449-454. The specific synthetic route is as follows:

[0005]

[0006] This method uses xylene as the reaction solvent and polyphosphoric acid as the dehydrating agent for Friedel-Crafts acylation, with reaction temperatures reaching as high as 120–130°C. Under these high-temperature conditions, intermolecular Friedel-Crafts acylation readily occurs, leading to the formation of polymers. The product requires purification by vacuum distillation, resulting in low yields. Furthermore, the use of viscous polyphosphoric acid makes material transfer difficult, complicating operations and generating large amounts of phosphorus-containing wastewater during post-processing.

[0007] In summary, existing synthetic methods have certain limitations. This invention aims to develop a more efficient and environmentally friendly method for synthesizing Formula III compounds. This invention successfully solves the problems of existing technologies, achieving efficient synthesis of the target product through a one-pot, two-step method. This method is simple to operate, requires no phosphorus-containing reagents, and is environmentally friendly; the reaction conditions are mild, the product yield and purity are high, and it does not require vacuum distillation purification, making it suitable for industrial production. Summary of the Invention

[0008] The first aspect of this invention provides an efficient method for synthesizing the compound 9,10-dihydro-4H-benzo[4,5]cycloheptatrien[1,2-B]thiophene-4-one of Formula III, which has the advantages of low cost, high yield, and being economical and environmentally friendly; it includes the following preparation steps:

[0009] Compound II-1 was synthesized by Friedel-Crafts acylation in an organic solvent under the catalysis of a protic acid to yield compound III; the synthetic route is shown below:

[0010]

[0011] As a further improvement of the present invention, the protic acid is selected from one or more of sulfonic acid protic acids, trifluoroacetic acid, acetic acid, concentrated sulfuric acid or hydrochloric acid, and the sulfonic acid protic acid is selected, for example, from one or more of p-toluenesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid or methanesulfonic acid.

[0012] As a further improvement of the present invention, the mass ratio of the protic acid to compound II-1 is (0.005-0.6):1; preferably (0.05-0.2):1.

[0013] As a further improvement of the present invention, the organic solvent is selected from one or more of dichloromethane, toluene, xylene, n-heptane, cyclohexane, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, N,N-dimethylformamide, acetonitrile, isopropyl ether, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, and sulfolane; preferably one or more of toluene, isopropyl ether, and cyclohexane, and particularly preferably toluene.

[0014] As a further improvement of the present invention, the volume of the organic solvent (mL) is 1 to 20 times the mass (g) of compound II-1; preferably 3 to 11 times; for example, 3 to 5 times, 5 to 7 times, 7 to 9 times, or 9 to 11 times.

[0015] As a further improvement of the present invention, the Friedel-Crafts acylation reaction temperature is 30–140°C; preferably 40–80°C, for example 40–45°C, 45–50°C, 50–55°C, 55–60°C, 60–65°C, 65–70°C, 70–75°C, or 75–80°C. Within the suitable and preferred reaction temperature range, the reaction rate is fast, there is no tar phenomenon, and the yield and purity are high, which is beneficial for industrial production.

[0016] As a further improvement of the present invention, the Friedel-Crafts acylation reaction time is 2 to 8 hours; for example, 2 to 3 hours, 3 to 5 hours, 5 to 7 hours, or 7 to 8 hours.

[0017] As a further improvement of the present invention, the post-processing of the Friedel-Crafts acylation reaction includes cooling, adjusting the pH to alkaline, separating the liquids, washing with water, and concentrating.

[0018] As a further improvement of the present invention, the cooling temperature is preferably 20-30°C, and the pH value is preferably 11-12.

[0019] As a further improvement of the present invention, the preparation of compound II-1 includes an acyl chloride reaction of compound I with an acyl chloride reagent, and the synthetic route is shown below:

[0020]

[0021] As a further improvement of the present invention, the acyl chloride reagent is selected from one or more of thionyl chloride, oxalyl chloride, phosphorus oxychloride, and phosphorus pentachloride; preferably one or more of thionyl chloride and oxalyl chloride, and particularly preferably thionyl chloride.

[0022] As a further improvement of the present invention, the molar ratio of the acyl chloride reagent to compound I is (1-2):1; for example, (1.00-1.05):1, (1.05-1.1):1, (1.1-1.15):1, (1.15-1.2):1, (1.2-1.25):1, (1.25-1.3):1, (1.3-1.35):1, (1.35-1.4):1, (1.4-1.45):1, (1.45-1.5):1, (1.5-1.55):1.

[0023] As a further improvement of the present invention, the acyl chloride reaction is carried out in an organic solvent, the solvent being selected from one or more of dichloromethane, toluene, xylene, n-heptane, cyclohexane, isopropyl ether, tetrahydrofuran, and 1,4-dioxane, preferably one or more of toluene, isopropyl ether, and cyclohexane, and particularly preferably toluene.

[0024] As a further improvement of the present invention, the volume (mL) of the organic solvent used in the acyl chlorination reaction is 1 to 12 times the mass (g) of compound I; for example, 2 to 4 times.

[0025] As a further improvement of the present invention, the reaction temperature of the acyl chloride reaction is 20-110°C; preferably 40-70°C, which results in a faster reaction and is beneficial for industrial production.

[0026] As a further improvement of the present invention, the compound II-1 obtained by the acyl chloride reaction can be selectively subjected to simple post-processing, such as concentration for the next step or direct Friedel-Crafts acylation reaction.

[0027] A second aspect of the present invention provides a compound II, the structure of which is shown below:

[0028]

[0029] X is selected from F, Cl, Br, and I.

[0030] A third aspect of the present invention provides a method for preparing ketotifen fumarate comprising the preparation of compound III of the first aspect and compound II of the second aspect.

[0031] The beneficial effects of adopting the technical solution described in this invention are mainly reflected in the following aspects:

[0032] 1) No polyphosphoric acid is required, industrial production is simple and does not generate a large amount of phosphorus-containing wastewater;

[0033] 2) By combining protic acid catalysts with reaction temperature, the occurrence of intermolecular Friedel-Crafts acylation side reactions can be cleverly avoided;

[0034] 3) The reaction is completely converted, and the product does not require vacuum distillation purification; only simple post-processing is needed to obtain a high-purity product with a purity of over 96%;

[0035] 4) Compared with existing technologies, the reaction yield is significantly improved, reaching up to 94.6%.

[0036] 5) Compound I hardly reacts directly with sulfonic acid protic acids (e.g., methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid). Attached Figure Description

[0037] Figure 1 This is the HPLC chromatogram of Example 2;

[0038] Figure 2 This is the HPLC chromatogram of Example 3;

[0039] Figure 3 This is the HPLC chromatogram of Example 4;

[0040] Figure 4 This is the HPLC chromatogram of Example 5;

[0041] Figure 5 This is the HPLC chromatogram of Example 6;

[0042] Figure 6 This is the HPLC chromatogram of Example 7;

[0043] Figure 7 This is the HPLC chromatogram of Example 8;

[0044] Figure 8 This is the HPLC chromatogram of Example 9;

[0045] Figure 9 This is the HPLC chromatogram of Example 10;

[0046] Figure 10 This is the HPLC chromatogram of Example 11;

[0047] Figure 11 This is the HPLC chromatogram of Example 12;

[0048] Figure 12 This is the HPLC chromatogram of Example 13;

[0049] Figure 13 This is the HPLC chromatogram of Example 14;

[0050] Figure 14 This is the HPLC chromatogram of Comparative Example 1;

[0051] Figure 15 This is the HPLC chromatogram of Comparative Example 2;

[0052] Figure 16 This is the HPLC chromatogram of Comparative Example 3. Detailed Implementation

[0053] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions.

[0054] Unless otherwise specified, all raw materials or reagents used in the examples are commercially available.

[0055] In the examples, room temperature refers to 20–30°C. Unless otherwise specified, the reagents are used directly without purification. All solvents were purchased from commercial suppliers, such as Sigma Aldrich, and are ready for use without treatment.

[0056]

[0057] Example 1

[0058] In the Friedel-Crafts acylation reaction, commonly used Lewis acid catalysts were preliminarily investigated, and the results are as follows:

[0059]

[0060] The above results indicate that the intramolecular Friedel-Crafts acylation reaction of compound II-1 readily produces a black, viscous oily substance using a Lewis acid catalyst. This is consistent with the intramolecular Friedel-Crafts acylation reaction of compound I using polyphosphoric acid, strongly suggesting that the black, viscous oily substance is a polymer produced by intermolecular Friedel-Crafts acylation. This is mainly because, as an active substrate, acyl chloride, under the catalysis of a strong Lewis acid, makes the 2-position of thiophene in compound II-1 more electron-rich than the 3-position, thus readily undergoing intermolecular Friedel-Crafts acylation. To reduce the catalytic activity of the Lewis acid, protic acids were attempted as catalysts; experimental results show that trifluoroacetic acid, as a catalyst, can effectively inhibit the intermolecular Friedel-Crafts acylation reaction.

[0061] Example 2

[0062] Compound I (20 g, 1.0 eq), cyclohexane (40 mL, 2.0 V), and thionyl chloride (10.76 g, 1.05 eq) were added to a 200 mL three-necked flask. The mixture was heated to 50–55 °C and reacted for 1 h. The reaction solution was concentrated to obtain compound II-1 (yield: 100%). Cyclohexane (100 mL, 5.0 V) and concentrated sulfuric acid (2 g, 10% wt) were added. The mixture was reacted at 50–55 °C for 5 h. The temperature was lowered to 20–30 °C, and the pH was adjusted to 11–12 with 30% sodium hydroxide solution. The mixture was separated, and the organic phase was washed twice with water. The organic phase was concentrated to obtain a pale yellow oily substance III (11.25 g, yield: 60.99%, purity: 98.37%). Figure 1 (As shown), the NMR data for compound III are as follows: 1 H-NMR (DMSO, 400MHz): 7.80 (d, J = 7.73Hz, 1H), 7.53 (m, J = 16.17Hz, 2H), 7.40 (dd, J = 19.68, 3H), 3.22 (m, J = 35.92, 4H).

[0063] Example 3

[0064] Compound I (20 g, 1.0 eq), cyclohexane (40 mL, 2.0 V), and thionyl chloride (10.76 g, 1.05 eq) were added to a 200 mL three-necked flask. The mixture was heated to 50–55 °C and reacted for 1 h. The reaction solution was concentrated to obtain compound II-1 (yield: 100%). Cyclohexane (100 mL, 5.0 V) and acetic acid (2 g, 10% wt) were added, and the mixture was reacted at 50–55 °C for 5 h. The temperature was then lowered to 20–30 °C, and the pH was adjusted to 11–12 with 30% sodium hydroxide solution. The mixture was separated, and the organic phase was washed twice with water. The organic phase was concentrated to obtain a pale yellow oily substance III (12.04 g, yield: 65.24%, purity: 97.20%). Figure 2 As shown), the NMR data of compound III are the same as in Example 2 above.

[0065] Example 4

[0066] Compound I (20 g, 1.0 eq), cyclohexane (40 mL, 2.0 V), and thionyl chloride (10.76 g, 1.05 eq) were added to a 200 mL three-necked flask. The mixture was heated to 50–55 °C and reacted for 1 h. The reaction solution was concentrated to obtain compound II-1 (yield: 100%). Cyclohexane (100 mL, 5.0 V) and trifluoroacetic acid (2 g, 10% wt) were added, and the mixture was reacted at 50–55 °C for 5 h. The temperature was then lowered to 20–30 °C, and the pH was adjusted to 11–12 with 30% sodium hydroxide solution. The mixture was separated, and the organic phase was washed twice with water. The organic phase was concentrated to obtain a pale yellow oily substance III (11.53 g, yield: 62.50%, purity: 97.91%). Figure 3 As shown), the NMR data of compound III are the same as in Example 2 above.

[0067] Example 5

[0068] Compound I (100 g, 1.0 eq), cyclohexane (200 mL, 2.0 V), and thionyl chloride (53.78 g, 1.05 eq) were added to a 1 L three-necked flask. The mixture was heated to 50–55 °C and reacted for 1 h. The reaction solution was concentrated to obtain compound II-1 (yield: 100%). Cyclohexane (500 mL, 5.0 V) and p-toluenesulfonic acid (10 g, 10% wt) were added. The mixture was reacted at 50–55 °C for 5 h. The temperature was lowered to 20–30 °C, and the pH was adjusted to 11–12 with 30% sodium hydroxide solution. The mixture was separated, and the organic phase was washed twice with water. The organic phase was concentrated to obtain a pale yellow oily substance III (85.37 g, yield: 92.55%, purity: 97.02%). Figure 4 As shown), the NMR data of compound III are the same as in Example 2 above.

[0069] Example 6

[0070] Compound I (50.00 g, 1.0 eq), cyclohexane (100 mL, 2.0 V), and thionyl chloride (26.89 g, 1.05 eq) were added to a 500 mL three-necked flask. The mixture was heated to 50–55 °C and reacted for 1 h. The reaction solution was concentrated to obtain compound II-1 (yield: 100%). Cyclohexane (250 mL, 5.0 V) and benzenesulfonic acid (5.00 g, 10% wt) were added, and the mixture was reacted at 50–55 °C for 5 h. The temperature was then lowered to 20–30 °C, and the pH was adjusted to 11–12 with 30% sodium hydroxide solution. The mixture was separated, and the organic phase was washed twice with water. The organic phase was concentrated to obtain a pale yellow oily substance III (42.51 g, yield: 92.17%, purity: 98.20%). Figure 5 As shown), the NMR data of compound III are the same as in Example 2 above.

[0071] Example 7

[0072] Compound I (200 g, 1.0 eq), cyclohexane (400 mL, 2.0 V), and thionyl chloride (106.76 g, 1.05 eq) were added to a 2 L reaction flask. The mixture was heated to 50–55 °C and maintained at this temperature for 1 h. The reaction solution was concentrated to obtain compound II-1 (yield 100%). Cyclohexane (1000 mL, 5.0 V) and methanesulfonic acid (20.00 g, 10% wt) were added. The mixture was reacted at 50–55 °C for 5 h. The temperature was then lowered to 20–30 °C, and the pH was adjusted to 11–12 with 30% sodium hydroxide solution. The mixture was separated, and the organic phase was washed twice with water. The organic phase was concentrated to obtain a pale yellow oily substance III (171.15 g, yield: 92.77%, purity: 99.27%). Figure 6 As shown), the NMR data of compound III are the same as in Example 2 above.

[0073] Example 8

[0074] Compound I (100 g, 1.0 eq), cyclohexane (200 mL, 2.0 V), and thionyl chloride (53.76 g, 1.05 eq) were added to a 1 L reaction flask. The mixture was heated to 50–55 °C and maintained at this temperature for 1 h. The reaction solution was concentrated to obtain compound II-1 (yield 100%). Cyclohexane (500 mL, 5.0 V) and trifluoromethanesulfonic acid (10.00 g, 10% wt) were added. The mixture was reacted at 50–55 °C for 5 h. The temperature was then lowered to 20–30 °C, and the pH was adjusted to 11–12 with 30% sodium hydroxide solution. The mixture was separated, and the organic phase was washed twice with water. The organic phase was concentrated to obtain a pale yellow oily substance III (86.67 g, yield: 93.96%, purity: 98.67%). Figure 7 As shown), the NMR data of compound III are the same as in Example 2 above.

[0075] Example 9

[0076] Compound I (100 g, 1.0 eq), isopropyl ether (200 mL, 2.0 V), and thionyl chloride (53.76 g, 1.05 eq) were added to a 1 L reaction flask. The mixture was heated to 50–55 °C and maintained at this temperature for 1 h. The reaction solution was concentrated to obtain compound II-1 (yield 100%). Isopropyl ether (500 mL, 5.0 V) and trifluoromethanesulfonic acid (10.00 g, 10% wt) were added. The mixture was reacted at 50–55 °C for 5 h. The temperature was then lowered to 20–30 °C, and the pH was adjusted to 11–12 with 30% sodium hydroxide solution. The mixture was separated, and the organic phase was washed twice with water. The organic phase was concentrated to obtain a pale yellow oily substance III (86.05 g, yield: 93.29%, purity: 98.41%). Figure 8 As shown), the NMR data of compound III are the same as in Example 2 above.

[0077] Example 10

[0078] Compound I (100 g, 1.0 eq), toluene (200 mL, 2.0 V), and thionyl chloride (53.76 g, 1.05 eq) were added to a 1 L reaction flask. The mixture was heated to 50–55 °C and maintained at this temperature for 1 h. The reaction solution was concentrated to obtain compound II-1 (yield 100%). Toluene (500 mL, 5.0 V) and trifluoromethanesulfonic acid (10.00 g, 10% wt) were added. The mixture was reacted at 50–55 °C for 5 h. The temperature was then lowered to 20–30 °C, and the pH was adjusted to 11–12 with 30% sodium hydroxide solution. The mixture was separated, and the organic phase was washed twice with water. The organic phase was concentrated to obtain a pale yellow oily substance III (87.02 g, yield: 94.34%, purity: 99.10%). Figure 9 As shown), the NMR data of compound III are the same as in Example 2 above.

[0079] Example 11

[0080] Compound I (100 g, 1.0 eq), toluene (200 mL, 2.0 V), and thionyl chloride (53.76 g, 1.05 eq) were added to a 1 L reaction flask. The mixture was heated to 50–55 °C and kept at that temperature for 1 h. The reaction solution was concentrated to obtain compound II-1 (yield 100%). Toluene (500 mL, 5.0 V) and trifluoromethanesulfonic acid (5.00 g, 5% wt) were added. The mixture was reacted at 50–55 °C for 5 h. The temperature was then lowered to 20–30 °C, and the pH was adjusted to 11–12 with 30% sodium hydroxide solution. The mixture was separated, and the organic phase was washed twice with water. The organic phase was concentrated to obtain a pale yellow oily substance III (86.70 g, yield: 93.99%, purity: 98.40%). The NMR data of compound III were the same as in Example 2 above.

[0081] Example 12

[0082] Compound I (100 g, 1.0 eq), toluene (200 mL, 2.0 V), and thionyl chloride (53.76 g, 1.05 eq) were added to a 1 L reaction flask. The mixture was heated to 50–55 °C and maintained at this temperature for 1 h. The reaction solution was concentrated to obtain compound II-1 (yield 100%). Toluene (500 mL, 5.0 V) and trifluoromethanesulfonic acid (15.00 g, 15% wt) were added. The mixture was reacted at 50–55 °C for 5 h. The temperature was then lowered to 20–30 °C, and the pH was adjusted to 11–12 with 30% sodium hydroxide solution. The mixture was separated, and the organic phase was washed twice with water. The organic phase was concentrated to obtain a pale yellow oily substance III (87.22 g, yield: 94.56%, purity: 98.25%). Figure 11 As shown), the NMR data of compound III are the same as in Example 2 above.

[0083] Example 13

[0084] Compound I (100 g, 1.0 eq), toluene (200 mL, 2.0 V), and thionyl chloride (53.76 g, 1.05 eq) were added to a 1 L reaction flask. The mixture was heated to 50–55 °C and maintained at this temperature for 1 h. The reaction solution was concentrated to obtain compound II-1 (yield 100%). Toluene (500 mL, 5.0 V) and trifluoromethanesulfonic acid (20.00 g, 20% wt) were added. The mixture was reacted at 50–55 °C for 5 h. The temperature was then lowered to 20–30 °C, and the pH was adjusted to 11–12 with 30% sodium hydroxide solution. The mixture was separated, and the organic phase was washed twice with water. The organic phase was concentrated to obtain a pale yellow oily substance III (86.82 g, yield: 94.12%, purity: 97.90%). Figure 12 As shown), the NMR data of compound III are the same as in Example 2 above.

[0085] Example 14

[0086] Compound I (100 g, 1.0 eq), toluene (200 mL, 2.0 V), and thionyl chloride (53.76 g, 1.05 eq) were added to a 1 L reaction flask. The mixture was heated to 50–55 °C and maintained at this temperature for 1 h. The reaction solution was concentrated to obtain compound II-1 (yield 100%). Toluene (500 mL, 5.0 V) and trifluoromethanesulfonic acid (10.00 g, 10% wt) were added. The mixture was reacted at 75–80 °C for 5 h. The temperature was then lowered to 20–30 °C, and the pH was adjusted to 11–12 with 30% sodium hydroxide solution. The mixture was separated, and the organic phase was washed twice with water. The organic phase was concentrated to obtain a pale yellow oily substance III (85.02 g, yield: 92.17%, purity: 96.27%). Figure 13 As shown), the NMR data of compound III are the same as in Example 2 above.

[0087] Comparative Example 1

[0088] Compound I (50.00 g, 1.0 eq), toluene (250 mL, 5.0 V), and p-toluenesulfonic acid (50.00 g, 1% wt) were added to a 500 mL three-necked flask equipped with a water separator. The mixture was heated to 120 °C and refluxed to separate the water. The reaction was carried out for 16 h, then cooled to 30-40 °C. RP-HPLC analysis revealed that 84.54% of the starting compound I remained, and 5.07% of the product compound III remained. Figure 14 As shown.

[0089] Comparative Example 2

[0090] Compound I (50.00 g, 1.0 eq), toluene (250 mL, 5.0 V), and methanesulfonic acid (50.00 g, 1% wt) were added to a 500 mL three-necked flask equipped with a water separator. The mixture was heated to 120 °C and refluxed to separate the water. The reaction was carried out for 16 h, then cooled to 30-40 °C. RP-HPLC analysis revealed that 95.97% of the starting compound I remained, and 0.23% of the product compound III was present. Figure 15 As shown.

[0091] Comparative Example 3

[0092] Compound I (50.00 g, 1.0 eq), toluene (250 mL, 5.0 V), and trifluoromethanesulfonic acid (50.00 g, 1% wt) were added to a 500 mL three-necked flask equipped with a water separator. The mixture was heated to 120 °C and refluxed to separate the water. The reaction was carried out for 16 h, then cooled to 30-40 °C. RP-HPLC analysis revealed that 98.82% of the starting compound I remained, and 1.18% of the product compound III was present. Figure 16 As shown.

Claims

1. A method for preparing compound III, comprising, in an organic solvent, compound II-1 undergoing a Friedel-Crafts acylation reaction catalyzed by a protic acid to prepare compound III, the synthetic route of which is shown below: ； The protic acid is selected from one or more of p-toluenesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid, or methanesulfonic acid; The Friedel-Crafts acylation reaction temperature is 40~80℃.

2. The preparation method according to claim 1, characterized in that, Friedel-Crafts acylation reactions satisfy one or more of the following conditions: 1) The mass ratio of the protic acid to compound II-1 is (0.005~0.6):1; 2) The organic solvent is selected from one or more of dichloromethane, toluene, xylene, n-heptane, cyclohexane, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, N,N-dimethylformamide, acetonitrile, isopropyl ether, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, and sulfolane. 3) The Friedel-Crafts acylation reaction time is 2~8 h.

3. The preparation method according to claim 2, characterized in that, The organic solvent is selected from one or more of toluene, isopropyl ether, and cyclohexane.

4. The preparation method according to claim 1, characterized in that, Friedel-Crafts acylation reactions satisfy one or more of the following conditions: 1) The mass ratio of the protic acid to compound II-1 is (0.05~0.2):1; 2) The volume of the organic solvent used, in mL, is 1 to 20 times the mass of compound II-1 used, in g.

5. The preparation method according to claim 4, characterized in that, The volume of the organic solvent, expressed in mL, is 3 to 11 times the mass of compound II-1, expressed in g.

6. The preparation method according to claim 1, characterized in that, The preparation of compound II-1 involves an acyl chloride reaction of compound I with an acyl chloride reagent, and the synthetic route is shown below: 。 7. The preparation method according to claim 6, characterized in that, Acyl chloride reactions satisfy one or more of the following conditions: 1) The acyl chloride reagent is selected from one or more of thionyl chloride, oxalyl chloride, phosphorus oxychloride, and phosphorus pentachloride; 2) The molar ratio of the acyl chloride reagent to compound I is (1~2):1; 3) The acyl chloride reaction is carried out in an organic solvent, which is selected from one or more of dichloromethane, toluene, xylene, n-heptane, cyclohexane, isopropyl ether, tetrahydrofuran, and 1,4-dioxane; 4) The reaction temperature of the acyl chloride reaction is 20~110℃.

8. The preparation method according to claim 7, characterized in that, The acyl chloride reagent is one or more of thionyl chloride and oxalyl chloride.

9. The preparation method according to claim 6, characterized in that, Acyl chloride reactions satisfy one or more of the following conditions: 1) The acyl chloride reaction is carried out in an organic solvent, wherein the organic solvent is selected from one or more of toluene, isopropyl ether, and cyclohexane; 2) The volume of the organic solvent used in the acyl chloride reaction, in mL, is 1 to 12 times the mass of compound I, in g. 3) The reaction temperature for acyl chloride reaction is 40~70℃.

10. The preparation method according to claim 9, characterized in that, The volume of the organic solvent used in the acyl chloride reaction, expressed in mL, is 2 to 4 times the mass of compound I, expressed in g.

11. A method for preparing ketotifen fumarate, comprising preparing ketotifen fumarate using the preparation method according to any one of claims 1 to 10.

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