Synthetic method of ipragliflozin intermediate

Abstract

The invention discloses a synthesis method of an ipragliflozin intermediate, and belongs to the technical field of medicine synthesis. According to the invention, a commercial raw material thiophene-2-formic acid is used as a starting material, and a target molecule is synthesized through three steps of condensation, alkylation coupling and reduction; the invention relates to a method for preparing 2-(5-bromo-2-fluorobenzyl) benzo [b] thiophene, which comprises the following steps: firstly preparing corresponding activated amide of benzothiophene-2-formic acid, then coupling with 4-bromofluorobenzene to obtain benzo [B] thiophene-2-(5-bromo-2-fluorophenyl) ketone, and then reducing to obtain 2-(5-bromo-2-fluorobenzyl) benzo [b] thiophene. Compared with the prior art, the method has the advantages of simple process, convenience and safety in operation, high product yield, easiness in impurity control and high yield, and is suitable for industrial production. The method is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to a method for synthesizing an intermediate of iodine, belonging to the field of pharmaceutical synthesis technology. Background Technology

[0002] Ipragliflozin L-Proline Tablets (brand name: Suglat) have a recommended daily dose of 50 mg, which can be increased to 100 mg daily for patients with poor response. Developed through a research collaboration between Astellas Pharmaceuticals, Kotobuki Pharmaceuticals, and Merck Sharp & Dohme (MSD), ivgliflozin L-Proline Tablets were launched in Japan in January 2014. As the first SGLT2 inhibitor to be marketed in Japan, ivgliflozin L-Proline Tablets offer advantages such as good hypoglycemic efficacy, fewer adverse reactions (e.g., weight gain, hypoglycemia), and compatibility with other hypoglycemic agents. Ipragliflozin lowers blood glucose levels by inhibiting SGLT2 protein activity, reducing urinary glucose excretion. It also helps patients lose weight, which is particularly important for obese or overweight diabetic patients. The chemical name for L-proline ioglitazone is: a compound of L-proline and (1S)-1,5-dehydrated-1-{3-[(1-benzothiophene-2-yl)methyl]-4-fluorophenyl}-D-glucol. The structural formula is as follows:

[0003]

[0004] The original patent CN101568537A discloses a method for synthesizing ioggliflozin proline, and its synthetic route is shown below:

[0005]

[0006] Among them, compound V (2-(5-bromo-2-fluorobenzyl)benzo[b]thiophene) is an important intermediate of iodine, and its synthesis methods are mainly as follows:

[0007] The literature Bioorganic Med. Chem. 2012, 20(10), 3263–3279 reports a concise synthetic scheme. In the first step, benzothiophene and 5-bromo-2-fluorobenzaldehyde are coupled at low temperature to obtain diaryl benzyl alcohol. The benzyl alcohol reacts directly with triethylsilane in the presence of Lewis acid to generate 2-(5-bromo-2-fluorobenzyl)benzo[b]thiophene. The two-step yield is 64%.

[0008]

[0009] US20070161787 reports another synthetic scheme. Similarly, benzothiophene and 5-bromo-2-fluorobenzaldehyde are coupled at low temperature to give diaryl benzyl alcohol, which is then chlorinated and reduced with NaBH4 to give 2-(5-bromo-2-fluorobenzyl)benzo[b]thiophene.

[0010]

[0011] However, all the above methods use benzothiophene and 5-bromo-2-fluorobenzaldehyde as starting materials. Commercially available benzothiophene has a high unit price, and due to its small molecular weight, it consumes a large amount of butyllithium in the subsequent reaction with 5-bromo-2-fluorobenzaldehyde under the action of butyllithium, resulting in low coupling reaction efficiency. In addition, the other starting material, 5-bromo-2-fluorobenzaldehyde, is in liquid form, and the separation and purification process is stressful, leading to its high unit price, which is not conducive to industrial production. Summary of the Invention

[0012] The purpose of this invention is to address the aforementioned technical problems in the synthesis of the ioglitazone intermediate 2-(5-bromo-2-fluorobenzyl)benzo[b]thiophene in existing technologies. This invention provides a method for synthesizing the ioglitazone intermediate. This method uses commercially available thiophene-2-carboxylic acid as a starting material and synthesizes the target molecule through three steps: condensation, alkylation coupling, and reduction. This improves reaction efficiency; the synthetic route is simple, easy to operate, and requires minimal equipment, enabling large-scale production. This provides an excellent method for synthesizing this core intermediate.

[0013] To achieve the above objectives, the present invention provides a method for synthesizing the ioglitazone intermediate 2-(5-bromo-2-fluorobenzyl)benzo[b]thiophene, comprising the following steps:

[0014] Step 1. Dissolve benzothiophene-2-carboxylic acid in a solvent, add a catalytic amount of N,N'-dimethylformamide (DMF), and then add an acylation reagent to carry out the reaction. After the reaction is completed, concentrate to obtain the intermediate benzothiophene-2-carboxyl chloride. Add solvent and base to react with an activated amine to obtain a solid compound of formula III. The reaction equation is shown in formula A. Alternatively, dissolve benzothiophene-2-carboxylic acid in a solvent, add N,N'-carbonyldiimidazole to carry out the reaction to obtain compound III: amide 4-(1-benzo[B]thiophene-2-carbonyl)imidazole. The reaction equation is shown in formula B.

[0015]

[0016] Step 2. Add p-bromofluorobenzene to the reaction vessel, add an organic solvent, and under low temperature conditions below 0°C, add a strongly basic lithium reagent dropwise to carry out the reaction. Under the action of the strongly basic lithium reagent, p-bromofluorobenzene undergoes a directional metallization reaction at the ortho position of the fluorine atom, forming an ortho-Li salt compound. Then, add a solution of compound III dropwise to obtain the coupled compound of formula IV. The reaction equation is shown below:

[0017]

[0018] Step 3. Dissolve the coupling compound IV in a solvent, add a Lewis acid to form a complex, then add a silicon-based reducing agent to reduce the carbonyl group to a methylene group; after the reaction is complete, quench the reaction, separate the contents, wash, concentrate the organic matter, recrystallize to obtain the solid compound V. The reaction equation is shown below:

[0019]

[0020] In step 1: the acylation reagent is at least one of oxaloyl chloride and thionyl chloride; the activated amine is at least one of N-methoxy-N-methylamine, morpholine and imidazole; and the organic base is an amine compound.

[0021] The strong alkaline lithium reagent in step 2 is at least one of lithium diisopropylaminolithium (LDA) and lithium tetramethylpiperidine (LiTMP);

[0022] The silicon-based reducing agent in step 3 is a silane compound and / or a siloxane compound.

[0023] Further, the solvent in step 1 is at least one of dichloromethane, ethyl acetate, isopropyl acetate, and toluene;

[0024] And / or, the solvent in step 2 is at least one of tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl ether, 1,4-dioxane and toluene;

[0025] And / or, the solvent in step 3 is at least one of dichloromethane, trichloromethane, chlorobenzene, fluorobenzene, and toluene.

[0026] Furthermore, the solvent in step 1 is dichloromethane.

[0027] Furthermore, the solvent in step 2 is tetrahydrofuran.

[0028] Furthermore, the solvent in step 3 is dichloromethane and / or toluene.

[0029] Further, the organic base in step 1 is at least one of triethylamine, diisopropylethylamine, morpholine, pyridine, and 2,6-dimethylpyridine;

[0030] And / or, the silicon-based reducing agent in step 3 is 1,1,3,3-tetramethyldisiloxane and / or triethylsilane;

[0031] And / or, the Lewis acid in step 3 is at least one of aluminum trichloride, boron trifluoride ether solution, methanesulfonic acid, trifluoromethanesulfonic acid, and titanium tetrachloride.

[0032] Furthermore, the organic base in step 1 is triethylamine and / or morpholine.

[0033] Furthermore, the Lewis acid in step 3 is aluminum trichloride and / or boron trifluoride diethyl ether solution.

[0034] Further, in step 1: the molar ratio of the acylation reagent to benzothiophene-2-carboxylic acid is 1.0–3.0:1, the molar ratio of the activated amine to benzothiophene-2-carboxylic acid is 1.1–3.0:1, the molar ratio of N,N'-dimethylformamide to benzothiophene-2-carboxylic acid is 0.02–0.1:1; the molar ratio of the organic base to benzothiophene-2-carboxylic acid is 1.1–5.0:1; and the reaction temperature is between -10 and 50°C, preferably between 15 and 40°C.

[0035] Furthermore, in step 1, the molar ratio of benzothiophene-2-carboxylic acid to N,N'-carbonyldiimidazole is 1.1 to 3.0:1.

[0036] Further, in step 2: the molar ratio of p-bromofluorobenzene to the strong basic lithium reagent is 1:1 to 3; the molar ratio of compound III to p-bromofluorobenzene is 1:1 to 3; and the reaction temperature is -100 to 0°C, preferably -80°C to -30°C.

[0037] Furthermore, in step 3, the molar ratio of compound V to Lewis acid is 1:0.1 to 3, with 1:0.5 to 2 being more preferred.

[0038] Furthermore, in step 3, the molar ratio of compound V to silicon-based reducing agent is 1:1 to 3, more preferably 1:1 to 2; and the reaction temperature is 10 to 30°C.

[0039] Compared with the prior art, the present invention has the following beneficial effects:

[0040] This invention uses thiophene-2-carboxylic acid as the starting material and synthesizes the target molecule in three steps: condensation, alkylation coupling, and reduction, thereby improving the reaction efficiency. Compared with the prior art, the raw materials are inexpensive and readily available, the reaction steps are short, the reaction conditions are mild, the operation is simple, the overall yield is high, the production cost is reduced, and it is suitable for industrial production. Detailed Implementation

[0041] To make the present invention more apparent and understandable, preferred embodiments are described in detail below.

[0042] Unless otherwise specified, the raw materials and reagents used in the following examples are all commercially available products.

[0043] Example 1

[0044] Preparation of N-methoxy-N-methylbenzo[B]thiophene-2-carboxamide (thionyl chloride as acylation reagent):

[0045] In a 1000 mL three-necked glass flask equipped with a dropping funnel, thermometer, and tail gas absorption device, add 89 g of benzothiophene-2-carboxylic acid (0.5 mol), 710 g of dichloromethane, and 1 g of DMF, and cool the system to 10-15 °C. Dissolve 71.3 g of thionyl chloride (0.6 mol) in 133 g of dichloromethane, then transfer this solution to a constant pressure dropping funnel and slowly add it dropwise to the benzothiophene-2-carboxylic acid solution. After the addition is complete, heat the system to 20-30 °C and react until the reaction is complete, monitored by TLC. The solvent was removed under reduced pressure to obtain a yellow solid. This solid was then dissolved in 710 g of dichloromethane. The mixture was cooled to 5-10 °C, and N-methoxy-N-methylamine hydrochloride (63.4 g, 0.65 mol) was added. Triethylamine (151.5 g, 1.5 mol) was then added dropwise. After the addition was complete, the system was heated to 20-30 °C and reacted until the reactant was completely converted by TLC. 300 mL of water was added, the mixture was separated, concentrated, and a pale yellow solid was obtained. After purification by methanol crystallization, 93.9 g of pale yellow solid N-methoxy-N-methylbenzo[B]thiophene-2-carboxamide was obtained, with a purity of 98.4% and a yield of 85%. The NMR and mass spectrometry characterization data are as follows: 1 H NMR (400MHz, CDCl3): δ8.28-8.17(m, 1H), 7.84-7.89(m, 2H), 7.37-7.46(m, 2H), 3.82(s, 3H), 3.42(s, 3H); 13 C NMR (100MHz, CDCl3): δ162.53, 142.61, 138.08, 133.34, 131.28, 126.54, 125.34, 124.67, 122.31, 61.91, 33.24; ESI-MS: 237[M+H + ].

[0046] Example 2

[0047] Preparation of N-methoxy-N-methylbenzo[B]thiophene-2-carboxamide (oxalyl chloride as acylation reagent):

[0048] In a 1000 mL three-necked glass flask equipped with a dropping funnel, thermometer, and tail gas absorption device, add 89 g of benzothiophene-2-carboxylic acid (0.5 mol), 710 g of dichloromethane, and 1 g of DMF, and cool the system to 10-15 °C. Dissolve 127 g of oxalyl chloride (1 mol) in 133 g of dichloromethane, and then transfer this solution to a constant pressure dropping funnel. Slowly add this solution dropwise to the benzothiophene-2-carboxylic acid solution. After the addition is complete, heat the system to 20-30 °C and react until the reaction is complete, monitored by TLC. The solvent was removed under reduced pressure to obtain a yellow solid. This solid was then dissolved in 710 g of dichloromethane. The mixture was cooled to 5-10 °C, and N-methoxy-N-methylamine hydrochloride (63.4 g, 0.65 mol) was added. Triethylamine (151.5 g, 1.5 mol) was then added dropwise. After the addition was complete, the system was heated to 20-30 °C and reacted until the reactants were confirmed to be converted by TLC. 300 mL of water was added, the mixture was separated, concentrated, and a pale yellow solid was obtained. After purification by methanol crystallization, 99.5 g of pale yellow N-methoxy-N-methylbenzo[B]thiophene-2-carboxamide was obtained, with a purity of 98.9% and a yield of 90%. Characterization data were the same as in Example 1.

[0049] Example 3

[0050] Preparation of 4-(1-benzo[B]thiophene-2-carbonyl)morpholine (oxalyl chloride as acylation reagent):

[0051] In a 250 mL three-necked glass flask equipped with a dropping funnel, thermometer, and nitrogen protection, benzothiophene-2-carboxylic acid (17.8 g, 0.1 mol), 142 g dichloromethane, and 200 mg DMF were added, and the system was cooled to 10-15 °C. Oxaloyl chloride (25.4 g, 0.2 mol) was dissolved in 27 g dichloromethane, and this solution was transferred to a constant-pressure dropping funnel and slowly added dropwise to the benzothiophene-2-carboxylic acid solution. After the addition was complete, the system was heated to 20-30 °C and reacted until the reactants were completely converted, as monitored by TLC. The solvent was removed under reduced pressure to obtain a yellow solid. This solid was then dissolved in 142 g dichloromethane, cooled to 5-10 °C, and morpholine (26.1 g, 0.3 mol) was added dropwise. After the addition was complete, the system was heated to 20-30 °C and reacted for 2 h. Add 60 mL of water, separate the layers, concentrate, and obtain a pale yellow solid. After purification by crystallization with isopropanol, 19.2 g of 4-(1-benzo[B]thiophene-2-carbonyl)morpholine, with a purity of 99.4% and a yield of 78%, was obtained. NMR and mass spectrometry characterization data are as follows: 1 H NMR (400MHz, CDCl3): δ7.75-7.82(m, 2H), 7.45(s, 1H), 7.40-7.29(m, 2H), 3.90-3.53(m, 8H);13 C NMR (100MHz, CDCl3): δ163.77, 140.13, 138.59, 136.28, 125.91, 125.39, 124.88, 124.67, 122.39, 66.80; ESI-MS: 248[M+H + ].

[0052] Example 4

[0053] Preparation of benzo[B]thiophene-2-(5-bromo-2-fluorophenyl) methyl ketone from N-methoxy-N-methylbenzo[B]thiophene-2-carboxamide:

[0054] In a 500 mL three-necked glass flask equipped with a dropping funnel, thermometer, and nitrogen protection, p-bromofluorobenzene (35 g, 0.2 mol) and 250 mL tetrahydrofuran were added, and the system was cooled to -78 °C. Lithium diisopropylamino (LDA, 100 mL, 0.2 mol) was slowly added dropwise to the p-bromofluorobenzene solution. After the addition was complete, the system was incubated at -50 °C to -78 °C for 2 h. Subsequently, N-methoxy-N-methylbenzo[B]thiophene-2-carboxamide (23.6 g, 0.1 mol) dissolved in 100 mL tetrahydrofuran was slowly added dropwise to the reaction system, and the reaction was carried out at -70 °C to -78 °C until the starting material conversion was complete, as monitored by TLC. The reaction system was slowly heated to -30°C, and 2N HCl was added until the pH reached 5-7. The solvent tetrahydrofuran was removed under reduced pressure to obtain a yellow solid. The solid was dried to obtain a crude product. The crude product was purified by methanol crystallization to obtain 27.8 g of a pale yellow solid, benzo[B]thiophene-2-(5-bromo-2-fluorophenyl) ketone, with a purity of 98.2% and a yield of 83%. NMR and mass spectrometry characterization data are as follows:

[0055] 1 H NMR (400MHz, CDCl3): δ7.86-7.75 (m, 2H), 7.72-7.60 (m, 2H), 7.54-7.57 (m, 1H), 7.31-7.43 (m, 2H), 7.04 (t, J=8.9Hz, 1H); 13 C NMR (100MHz, CDCl3): δ184.86, 158.69 (d, J=253.2Hz), 143.33, 142.77, 138.91, 135.83 (d, J=8.3Hz), 133.33 (d, J=2.8Hz), 132.83 (d, J=2.8Hz), 128.54 (d, J=17.0Hz), 128.13, 126.45, 125.28, 123.07, 118.56, 116.94 (d, J=3.6Hz); ESI-MS: 335[M+H + ].

[0056] Example 5

[0057] Preparation of benzo[B]thiophene-2-(5-bromo-2-fluorophenyl) methyl ketone from N-methoxy-N-methylbenzo[B]thiophene-2-carboxamide (LiTMP as base):

[0058] In a 500 mL three-necked glass flask equipped with a dropping funnel, thermometer, and nitrogen protection, p-bromofluorobenzene (35 g, 0.2 mol) and 250 mL tetrahydrofuran were added, and the system was cooled to -78 °C. Lithium tetramethylpiperidine (LiTMP, 29.4 g, 0.2 mol) was slowly added dropwise to the p-bromofluorobenzene solution. After the addition was complete, the system was incubated at -70 °C to -78 °C for 2 h. Subsequently, N-methoxy-N-methylbenzo[B]thiophene-2-carboxamide (23.6 g, 0.1 mol) dissolved in 100 mL tetrahydrofuran was slowly added dropwise to the reaction system, and the reaction was carried out at -50 °C to -78 °C until the starting material conversion was complete as monitored by TLC. The reaction system was slowly raised to -30 °C, and 2N HCl was added until the pH of the system was adjusted to 5–7. The solvent THF was removed under reduced pressure to obtain a yellow solid. The solid was dried to obtain a crude product. The crude product was purified by methanol crystallization to obtain 25.4 g of a pale yellow solid, benzo[B]thiophene-2-(5-bromo-2-fluorophenyl)methyl ketone, with a purity of 96.2% and a yield of 76%. Characterization data were the same as in Example 4.

[0059] Example 6

[0060] Preparation of benzo[B]thiophene-2-(5-bromo-2-fluorophenyl) methyl ketone from 4-(1-benzo[B]thiophene-2-carbonyl)morpholine:

[0061] In a 500 mL three-necked glass flask equipped with a dropping funnel, thermometer, and nitrogen protection, 17.5 g (0.1 mol) of p-bromofluorobenzene and 150 mL of tetrahydrofuran were added, and the system was cooled to -78 °C. LDA (50 mL, 0.1 mol) was slowly added dropwise to the p-bromofluorobenzene solution. After the addition was complete, the system was incubated at -70 °C to -78 °C for 2 h. Subsequently, 12.3 g (50 mmol) of 4-(1-benzo[B]thiophene-2-carbonyl)morpholine was dissolved in 50 mL of tetrahydrofuran and slowly added dropwise to the reaction system. The reaction was carried out at -50 °C to -78 °C until the starting material was completely converted, as monitored by TLC. The reaction system was slowly raised to -30 °C, and 2N HCl was added until the pH of the system was adjusted to 5–7. The solvent THF was removed under reduced pressure to obtain a yellow solid. The solid was dried to obtain a crude product. The crude product was purified by methanol crystallization to obtain 11.4 g of a pale yellow solid, benzo[B]thiophene-2-(5-bromo-2-fluorophenyl)methyl ketone, with a purity of 95.8% and a yield of 68%. Characterization data were the same as in Example 4.

[0062] Example 7

[0063] Preparation of benzo[B]thiophene-2-(5-bromo-2-fluorophenyl) methyl ketone from 4-(1-benzo[B]thiophene-2-carbonyl)imidazolium:

[0064] In a 250 mL three-necked glass flask equipped with a dropping funnel, thermometer, and nitrogen protection, add benzothiophene-2-carboxylic acid (17.8 g, 0.1 mol), 90 mL of tetrahydrofuran, and N,N'-carbonyldiimidazole (19.4 g, 0.12 mol) in portions. After the addition is complete, react at room temperature for 3 h. Once TLC shows that the starting material has been completely converted, set aside for later use.

[0065] In another 500 mL three-necked glass flask equipped with a dropping funnel, thermometer, and nitrogen protection, 35 g (0.2 mol) of p-bromofluorobenzene and 250 mL of tetrahydrofuran were added, and the system was cooled to -78 °C. 100 mL (0.2 mol) of LDA was slowly added dropwise to the p-bromofluorobenzene solution. After the addition was complete, the system was kept at -70 °C to -78 °C for 2 h. Subsequently, the 4-(1-benzo[B]thiophene-2-carbonyl)imidazolium THF solution prepared above was slowly added dropwise to the reaction system, and the reaction was continued at -70 °C to -78 °C until the starting material conversion was complete, as monitored by TLC. The reaction system was slowly raised to -30 °C, and 2N HCl was added until the pH of the system was adjusted to 5-7. The solvent tetrahydrofuran was removed under reduced pressure to obtain a yellow solid. The solid was dried to obtain a crude product. The crude product was purified by methanol crystallization to obtain 21.8 g of a pale yellow solid, benzo[B]thiophene-2-(5-bromo-2-fluorophenyl)methyl ketone, with a purity of 97.3% and a two-step yield of 65%. Characterization data were the same as in Example 4.

[0066] Example 8

[0067] Preparation of 2-(5-bromo-2-fluorobenzyl)benzo[b]thiophene from benzo[b]thiophene-2-(5-bromo-2-fluorophenyl)methyl ketone:

[0068] In a 500 mL three-necked glass flask equipped with a dropping funnel, thermometer, and nitrogen protection, benzo[B]thiophene-2-(5-bromo-2-fluorophenyl) ketone (33.4 g, 0.1 mol) and 330 mL of DCM were added. After the solid was completely dissolved, aluminum trichloride (13.3 g, 0.1 mol) was added at 20-25 °C, and the mixture was cooled to 15-20 °C and stirred for 0.5 h. 1,1,3,3-tetramethyldisiloxane (26.8 g, 0.2 mol) dissolved in 20 mL of DCM was added dropwise. After the addition was complete, the reaction was carried out at 20-25 °C until the reactants were completely converted by TLC. The reaction was quenched with 50 mL of 1N HCl, and the mixture was separated. The dichloromethane layer was washed with 10% sodium chloride, separated again, and concentrated to obtain a pale yellow crude solid. The crude solid was purified by methanol crystallization to obtain 25.9 g of a white solid with a purity of 99.4% and a yield of 81%. The NMR and mass spectrometry characterization data are as follows:1 H NMR (400MHz, CDCl3): δ7.74 (d, J=7.8Hz, 1H), 7.67 (d, J=7.8Hz, 1H), 7.42-7.36 (m, 1H), 7.36-7.29 (m, 2H), 7.29-7.25 (m, 1H), 7.03 (s, 1H), 6.96 (t, J=9.0Hz, 1H), 4.20 (s, 2H); 13 C NMR (100MHz, CDCl3): δ159.82 (d, J=247.0Hz), 142.21 (s), 139.87 (d, J=17.6Hz), 1 33.53 (d, J=4.0Hz), 131.55, 131.49, 128.93 (d, J=17.4Hz), 124.33, 123.98, 123.1 122.31, 122.22, 117.28 (d, J=23.9Hz), 116.71 (d, J=3.5Hz), 29.66 (d, J=3.2Hz); ESI-MS: 321[M+H + ].

[0069] Example 9

[0070] Preparation of 2-(5-bromo-2-fluorobenzyl)benzo[b]thiophene from benzo[b]thiophene-2-(5-bromo-2-fluorophenyl)methyl ketone:

[0071] In a 500 mL three-necked glass flask equipped with a dropping funnel, thermometer, and nitrogen protection, benzo[B]thiophene-2-(5-bromo-2-fluorophenyl) ketone (33.4 g, 0.1 mol) and 330 mL of toluene were added. After the solid was completely dissolved, aluminum trichloride (13.3 g, 0.1 mol) was added at 20-25 °C, and the mixture was cooled to 15-20 °C and stirred for 0.5 h. 1,1,3,3-tetramethyldisiloxane (26.8 g, 0.2 mol) dissolved in 20 mL of chlorobenzene was added dropwise. After the addition was complete, the reaction was carried out at 20-25 °C until the reactants were completely converted by TLC. The reaction was quenched with 50 mL of 1N HCl, and the mixture was separated. The toluene layer was washed with 10% sodium chloride, separated again, and concentrated to obtain a pale yellow crude solid. The crude solid was purified by methanol crystallization to obtain 23.9 g of a white solid with a purity of 97.9% and a yield of 75%. The characterization data are the same as in Example 8.

[0072] Example 10

[0073] Preparation of 2-(5-bromo-2-fluorobenzyl)benzo[b]thiophene from benzo[b]thiophene-2-(5-bromo-2-fluorophenyl)methyl ketone:

[0074] In a 500 mL three-necked glass flask equipped with a dropping funnel, thermometer, and nitrogen protection, benzo[B]thiophene-2-(5-bromo-2-fluorophenyl) ketone (33.4 g, 0.1 mol) and 330 mL of chlorobenzene were added. After the solid was completely dissolved, aluminum trichloride (13.3 g, 0.1 mol) was added at 20-25 °C, and the mixture was cooled to 15-20 °C and stirred for 0.5 h. 1,1,3,3-tetramethyldisiloxane (26.8 g, 0.2 mol) dissolved in 20 mL of toluene was added dropwise. After the addition was complete, the reaction was carried out at 20-25 °C until the reactants were completely converted as monitored by TLC. The reaction was quenched with 50 mL of 1N HCl, and the mixture was separated. The chlorobenzene layer was washed with 10% sodium chloride, separated again, and concentrated to obtain a pale yellow crude solid. The crude solid was purified by methanol crystallization to obtain 21.4 g of a white solid with a purity of 98.8% and a yield of 67%. The characterization data are the same as in Example 8.

[0075] Example 11

[0076] Preparation of 2-(5-bromo-2-fluorobenzyl)benzo[b]thiophene from benzo[b]thiophene-2-(5-bromo-2-fluorophenyl)methyl ketone:

[0077] In a 500 mL three-necked glass flask equipped with a dropping funnel, thermometer, and nitrogen protection, benzo[B]thiophene-2-(5-bromo-2-fluorophenyl) ketone (33.4 g, 0.1 mol) and 330 mL of DCM were added. After the solid was completely dissolved, aluminum trichloride (13.3 g, 0.1 mol) was added at 20-25 °C, and the mixture was cooled to 15-20 °C and stirred for 0.5 h. A dichloromethane solution dissolved in 20 mL of triethylsilane (23.2 g, 0.2 mol) was added dropwise. After the addition was complete, the reaction was carried out at 20-25 °C until the reactants were completely converted by TLC. The reaction was quenched with 50 mL of 1 N HCl, and the mixture was separated. The dichloromethane layer was washed with 10% sodium chloride, separated, and concentrated to obtain a pale yellow crude solid. The crude solid was purified by methanol crystallization to obtain 17.2 g of a white solid with a purity of 98.1% and a yield of 54%. Characterization data were the same as in Example 8.

[0078] Example 12

[0079] Preparation of 2-(5-bromo-2-fluorobenzyl)benzo[b]thiophene from benzo[b]thiophene-2-(5-bromo-2-fluorophenyl)methyl ketone:

[0080] In a 500 mL three-necked glass flask equipped with a dropping funnel, thermometer, and nitrogen protection, benzo[B]thiophene-2-(5-bromo-2-fluorophenyl) ketone (33.4 g, 0.1 mol) and 330 mL of DCM were added. After the solid was completely dissolved, boron trifluoride diethyl ether solution (14.2 g, 0.1 mol) was added at 20-25 °C, and the mixture was cooled to 15-20 °C and stirred for 0.5 h. Triethylsilane (23.2 g, 0.2 mol) dissolved in 20 mL of DCM was added dropwise. After the addition was complete, the reaction was carried out at 20-25 °C until the reactants were completely converted by TLC. The reaction was quenched with 50 mL of 1 N HCl, and the mixture was separated. The dichloromethane layer was washed with 10% sodium chloride, separated, and concentrated to obtain a pale yellow crude solid. The crude solid was purified by methanol crystallization to obtain 13.8 g of a white solid with a purity of 96.5% and a yield of 41%. Characterization data were the same as in Example 8.

[0081] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any form or substance. It should be noted that those skilled in the art can make several improvements and additions without departing from the present invention, and these improvements and additions should also be considered within the scope of protection of the present invention.

Claims

1. A process for the synthesis of an intermediate of ipragliflozin, 2-(5-bromo-2- fluorobenzyl)benzo[b]thiophene, characterized in that, The method comprises the following steps: Step 1. Dissolve benzothiophene-2-carboxylic acid in a solvent, add a catalytic amount of N,N'-dimethylformamide (DMF), then drop acylating reagent for reaction, after the reaction is completed, concentrate to obtain intermediate benzothiophene-2-carbonyl chloride, then add a solvent and a base to react with an activated amine to obtain a solid compound of formula III, as shown in formula A; or dissolve benzothiophene-2-carboxylic acid in a solvent, add N,N'-carbonyldiimidazole for reaction to obtain compound III: amide 4-(1-benzo[B]thiophene-2-carbonyl)imidazole, as shown in formula B: Step 2. Add p-bromofluorobenzene to a reaction container, add a solvent, and drop a strong basic lithium reagent for reaction under low-temperature conditions below 0°C, wherein the ortho position of the fluorine atom of p-bromofluorobenzene is subjected to directional metallization under the action of the strong basic lithium reagent to form an ortho Li salt compound, then drop a solution of compound III for reaction to obtain coupling compound IV, as shown in the following reaction equation: Step 3. Dissolve coupling compound IV in a solvent, add a Lewis acid to form a complex, then add a silicon-based reducing agent for reaction to reduce the carbonyl group to a methylene group; after the reaction is completed, quench the reaction, separate the liquid, wash, concentrate the organic matter, and recrystallize to obtain a solid compound of formula V, as shown in the following reaction equation: In step 1, the acylating reagent is at least one of oxalyl chloride and thionyl chloride; the activated amine is at least one of N-methoxy-N-methylamine, morpholine and imidazole; and the organic base is an amine compound. The strong basic lithium reagent in step 2 is at least one of lithium diisopropylamide (LDA) and lithium tetramethylpiperidide (LiTMP). The silicon-based reducing agent in step 3 is a silane compound and / or a siloxane compound.

2. The method of synthesis of claim 1, wherein, The solvent in step 1 is at least one of dichloromethane, ethyl acetate, isopropyl acetate and toluene; And / or, the solvent in step 2 is at least one of tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl ether, 1,4-dioxane and toluene; And / or, the solvent in step 3 is at least one of dichloromethane, chloroform, chlorobenzene, fluorobenzene and toluene.

3. The method of synthesis of claim 1, wherein, The organic base in step 1 is at least one of triethylamine, diisopropyl ethylamine, morpholine, pyridine and 2,6-lutidine; And / or, the silicon-based reducing agent in step 3 is 1,1,3,3-tetramethyldisiloxane and / or triethylsilane; And / or, the Lewis acid in step 3 is at least one of aluminum trichloride, boron trifluoride ether solution, methane sulfonic acid, trifluoromethanesulfonic acid and titanium tetrachloride.

4. The method of synthesis of claim 1, wherein, In the step 1 : the molar ratio of the acylating reagent to benzothiophene-2-carboxylic acid is 1.0-3.0:1, the molar ratio of the activated amine to benzothiophene-2-carboxylic acid is 1.1-3.0:1, the molar ratio of N,N'-dimethylformamide to benzothiophene-2-carboxylic acid is 0.02-0.1:1; the molar ratio of the organic base to benzothiophene-2-carboxylic acid is 1.1-5.0:1; the temperature of the reaction is between -10-50°C, and 15-40°C is more preferred.

5. The method of synthesis of claim 1, wherein, In the step 1 : the molar ratio of benzothiophene-2-carboxylic acid to N,N'- carbonyldiimidazole is 1.1-3.0:

1.

6. The method of synthesis of claim 1, wherein, In the step 2: the molar ratio of the p-bromofluorobenzene to the strong basic lithium reagent is 1:1-3; the molar ratio of the compound of formula III to p- bromofluorobenzene is 1:1-3; the temperature of the reaction is -100-0°C, and -80°C- -30°C is more preferred.

7. The method of synthesis of claim 1, wherein, In the step 3: the molar ratio of the compound of formula V to Lewis acid is 1:0.1-3, and 1:0.5-2 is more preferred.

8. The method of synthesis of claim 1, wherein, In the step 3: the molar ratio of the compound of formula V to silicon-based reducing agent is 1:1-3, and 1:1-2 is more preferred; the temperature of the reaction is 10-30°C.

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