Preparation method of dotenorad key intermediate

Abstract

The invention discloses a preparation method of a dotenorad key intermediate, and belongs to the technical field of compound synthesis. In the preparation method of the dotenorad key intermediate, provided by the invention, 2-aminothiophenol and formaldehyde are used as raw materials to carry out cyclization reaction to prepare a compound as shown in a formula 1, and then the compound as shown in the formula 1 and 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3 According to the method, 3-(3, 5-dichloro-4-methoxybenzoyl chloride)-2, 3-dihydro-1, 3-benzothiazole is used as a raw material, an amidation reaction is carried out on 3, 5-dichloro-4-methoxybenzoyl chloride in an aqueous solution of an organic solvent, and the key intermediate 3-(3, 5-dichloro-4-methoxybenzoyl)-2, 3-dihydro-1, 3-benzothiazole of dotenorad can be effectively prepared; the obtained dotenorad key intermediate is relatively high in yield and purity; moreover, benzothiazoline which is widely used in the prior art does not need to be used in the preparation method, an activating agent or a solubilizer does not need to be used, the operation method is simple, reaction conditions are mild, and the method is suitable for actual industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of compound synthesis, and in particular relates to a method for preparing a key intermediate of polytinorel. Background Art

[0002] Dotinorel, chemical name: (3,5-dichloro-4-hydroxyphenyl)(1,1-dioxo-1,2-dihydro-3H-1λ 6 -1,3-benzothiazol-3-yl) ketone, the structural formula of which is shown in Formula I. The chemical name of the key intermediate of Dotinol is: 3-(3,5-dichloro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole, the structural formula of which is shown in Formula II;

[0003]

[0004] Dotinorel was developed by Fuji Pharmaceuticals Co., Ltd. in Japan and was approved in China in December 2024 for the treatment of hyperuricemia and gout. Dotinorel is a novel gout treatment that selectively inhibits the urate transporter (URAT1), which is involved in uric acid reabsorption in the kidneys, thereby inhibiting uric acid reabsorption and lowering blood uric acid levels. As a selective URAT1 inhibitor, dotinorel effectively inhibits URAT1 in the proximal renal tubules without affecting the function of the uric acid excretion factors ABCG2 and OAT1 / 3, making it more efficient in lowering blood uric acid than non-selective URAT1 inhibitors.

[0005] Currently, many patents have disclosed the synthesis method of polytinol. The original patent CN102639518 uses 2-aminothiophenol as a raw material, undergoes a condensation reaction with formaldehyde to obtain benzothiazoline, which is then subjected to an amidation reaction with 3,5-dichloro-4-methoxybenzoyl chloride, and then undergoes an oxidation reaction and a demethylation reaction to prepare polytinol. The reaction route is as follows: Figure 1 Patent CN111662247 uses benzothiazoline and 3,5-dichloro-4-hydroxybenzoic acid as raw materials to prepare polytinol through oxidation reaction and condensation reaction. The reaction route is as follows Figure 2 shown.

[0006] As can be seen from the above synthetic route, benzothiazoline is an important raw material for the synthesis of dostinex. According to the synthetic method of benzothiazoline reported in the original patent CN102639518, it is found that there are many by-products in the reaction process, and benzothiazoline with high purity cannot be obtained, which is not conducive to the subsequent reaction, and thus the key intermediate of dostinex (compound of formula II) cannot be prepared. To solve the above problems, in patent CN119462557, 2-aminobenzenethiol is first alkalized to form sodium 2-aminobenzenethiolate, and then cyclized with formaldehyde to prepare benzothiazoline, and finally condensed with 3,5-dichloro-4-methoxybenzoyl chloride to obtain the key intermediate of dostinex. The above solution not only increases the reaction steps, but also requires sodium hydride in the process. Sodium hydride is a strong reducing agent, which can react violently with water and oxygen to produce hydrogen, with extremely high danger and is not suitable for industrial production. Similarly, in order to avoid excessive side reactions and improve the conversion yield and product quality of the product, patent CN119504641 adds a solubilizer and an activator to the synthetic process of benzothiazoline, and strictly controls the dosage of paraformaldehyde at 1.0-|1.2 equivalents, and the reaction temperature is controlled at 20-60 °C. The above process increases the material cost and has high requirements for process conditions, and is not an ideal industrial production process. SUMMARY OF THE INVENTION

[0007] An object of the present invention is to overcome the deficiencies of the above-mentioned prior art and provide a preparation method of a key intermediate of dostinex with simple operation, low equipment requirements, mild reaction conditions, high yield and high purity of the prepared product.

[0008] To achieve the above object, the present invention provides a preparation method of a key intermediate of dostinex, the preparation method comprising the following steps:

[0009] (1) Taking 2-aminobenzenethiol and formaldehyde for cyclization reaction to obtain the compound shown in formula 1;

[0010] (2) Adding the compound shown in formula 1, 3,5-dichloro-4-methoxybenzoyl chloride and an acid-binding agent into an aqueous solution of an organic solvent for amidation reaction to obtain the key intermediate of dostinex, 3-(3,5-dichloro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole;

[0011] In the step (2), the acid-binding agent includes at least one of carbonate and phosphate;

[0012]

[0013] In the preparation method of the key intermediate of dostinex provided by the present invention, the compound shown in Formula 1 is prepared by a cyclization reaction using 2-aminothiophenol and formaldehyde as raw materials. Subsequently, the compound shown in Formula 1 and 3,5-dichloro-4-methoxybenzoyl chloride are subjected to an amidation reaction in an aqueous solution of an organic solvent under a specific kind of acid-binding agent, and the key intermediate of dostinex, 3-(3,5-dichloro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole, can be effectively prepared; the yield and purity of the obtained key intermediate of dostinex are relatively high; moreover, in the preparation method, benzothiazoline widely used in the prior art does not need to be used, and an activator or a solubilizer does not need to be used. The operation method is simple, the reaction conditions are mild, and it is suitable for actual industrial production.

[0014] As a preferred embodiment of the preparation method of the present invention, in the step (1), the molar ratio of 2-aminothiophenol to formaldehyde is 1:(1.5 - 5).

[0015] Exemplarily, in the step (1), the molar ratio of 2-aminothiophenol to formaldehyde can be any point value or any two-point range value between 1:(1.5 - 5), such as 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, etc.

[0016] Preferably, in the step (1), the molar ratio of 2-aminothiophenol to formaldehyde is 1:(2.5 - 3.5).

[0017] More preferably, in the step (1), the molar ratio of 2-aminothiophenol to formaldehyde is 1:3.

[0018] The present invention has found through research that when the molar ratio of 2-aminothiophenol to formaldehyde in the step (1) is within the above range, the compound shown in Formula 1 can be effectively synthesized, thereby improving the purity and yield of the obtained key intermediate of dostinex.

[0019] As a preferred embodiment of the preparation method of the present invention, in the step (1), the temperature of the cyclization reaction is 60 - 100°C, and the time is 8 - 16 h.

[0020] Exemplarily, in the step (1), the temperature of the cyclization reaction can be any point value or any two-point range value between 60 - 100°C, such as 60°C, 70°C, 80°C, 90°C, 100°C, etc. The time of the cyclization reaction can be any point value or any two-point range value between 8 - 16 h, such as 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, etc.

[0021] Preferably, in the step (1), the temperature of the cyclization reaction is 60 - 70°C, and the time is 10 - 14 h.

[0022] The present invention has found that when the temperature and time of the cyclization reaction are further selected within the above ranges, not only can the compound of Formula 1 be efficiently prepared, but the yield and purity of the key intermediate of polytinorel prepared subsequently are also better.

[0023] As a preferred embodiment of the preparation method of the present invention, in step (1), formaldehyde can be added in the form of formaldehyde aqueous solution, paraformaldehyde, or paraformaldehyde aqueous solution.

[0024] As a preferred embodiment of the preparation method of the present invention, in step (1), the organic solvent in the cyclization reaction includes at least one of tetrahydrofuran, toluene, acetonitrile, methanol, and ethanol.

[0025] Preferably, in step (1), the organic solvent in the cyclization reaction comprises at least one of tetrahydrofuran and toluene.

[0026] As a preferred embodiment of the preparation method of the present invention, in the cyclization reaction, the mass volume ratio of 2-aminothiophenol to the organic solvent added in the cyclization reaction is 1 g: (5-15) mL.

[0027] As a preferred embodiment of the preparation method of the present invention, a post-treatment process is further included after the cyclization reaction is completed.

[0028] Preferably, the post-treatment process includes: concentrating under reduced pressure to remove the organic solvent after the cyclization reaction is completed.

[0029] As a preferred embodiment of the preparation method of the present invention, in step (2), the molar ratio of the compound represented by formula 1 to the acid binding agent is 1:(2-6).

[0030] Illustratively, in step (2), the molar ratio of the compound represented by Formula 1 to the acid-binding agent can be any point value or any two point range values between 1:(2-6), for example, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, etc.

[0031] Preferably, in step (2), the molar ratio of the compound represented by formula 1 to the acid binding agent is 1:(2.5-3.5).

[0032] More preferably, in step (2), the molar ratio of the compound represented by formula 1 to the acid binding agent is 1:3.

[0033] The present invention has found that by further selecting the molar ratio of the compound represented by Formula 1 to the acid-binding agent within the above range, the key intermediate of polytinol with better yield and purity can be obtained.

[0034] As a preferred embodiment of the preparation method of the present invention, in the step (2), the temperature of the amidation reaction is 50-100°C, and the time is 4-14h.

[0035] Exemplarily, in the step (2), the temperature of the amidation can be any point value or any two-point range value between 50-100°C, such as 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, etc. The time of the amidation can be any point value or any two-point range value between 4-14h, such as 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 13h, 14h, etc.

[0036] Preferably, in the step (2), the temperature of the amidation reaction is 60-80°C, and the time is 8-12h.

[0037] The present invention has found that when the temperature and time of the amidation reaction are further selected within the above ranges, it is beneficial to improve the reaction yield and the purity of the product.

[0038] As a preferred embodiment of the preparation method of the present invention, in the step (2), the acid-binding agent includes at least one of sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, and potassium phosphate.

[0039] Preferably, in the step (2), the acid-binding agent includes at least one of sodium carbonate and potassium carbonate.

[0040] The present invention has found that by selecting the above types of acid-binding agents, it is possible to preferably synthesize the key body of dutasteride with high purity, and the yield of the obtained product is relatively high.

[0041] As a preferred embodiment of the preparation method of the present invention, in the step (2), the organic solvent includes at least one of toluene, xylene, tetrahydrofuran, acetonitrile, and acetone.

[0042] Preferably, in the step (2), the organic solvent includes at least one of toluene and xylene.

[0043] As a preferred embodiment of the preparation method of the present invention, in the aqueous solution of the organic solvent in the step (2), the volume ratio of the organic solvent to water is 1:(0.5-4).

[0044] Exemplarily, in the step (2), in the aqueous solution of the organic solvent, the volume ratio of the organic solvent to water can be any point value or any two-point range value between 1:(0.5-4), such as 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, etc.

[0045] Preferably, in the step (2), in the aqueous solution of the organic solvent, the volume ratio of the organic solvent to water is 1:(0.8 - 1.5).

[0046] More preferably, in the step (2), in the aqueous solution of the organic solvent, the volume ratio of the organic solvent to water is 1:1.

[0047] The present invention has found that in the amidation reaction, by selecting the aqueous solution of the organic solvent within the above volume ratio range and in the presence of a specific acid-binding agent, a key intermediate of domatinostat with better yield and purity can be obtained.

[0048] As a preferred embodiment of the preparation method of the present invention, in the step (2), the molar ratio of the compound shown in Formula 1 to 3,5-dichloro-4-methoxybenzoyl chloride is 1:(1.5 - 2).

[0049] Preferably, in the step (2), the molar ratio of the compound shown in Formula 1 to 3,5-dichloro-4-methoxybenzoyl chloride is 1:1.8.

[0050] As a preferred embodiment of the preparation method of the present invention, in the step (2), the mass-to-volume ratio of the compound shown in Formula 1 to the aqueous solution of the organic solvent is 1 g:(14 - 20) mL.

[0051] As a preferred embodiment of the preparation method of the present invention, in the step (2), after the amidation reaction, a post-treatment step is further included.

[0052] Preferably, the post-treatment includes: after the amidation reaction is completed, standing for layering, collecting the organic phase, then concentrating under reduced pressure to remove the organic solvent, then adding ethanol and stirring at 50 - 80 °C for 2 - 6 h, then cooling to 20 - 30 °C and continuing to stir for 2 - 6 h, then filtering, collecting the filter residue and drying.

[0053] Preferably, the mass-to-volume ratio of ethanol to 3,5-dichloro-4-methoxybenzoyl chloride is 1 g:(5 - 15) mL.

[0054] As a preferred embodiment of the preparation method of the present invention, the preparation method of 3,5-dichloro-4-methoxybenzoyl chloride is: adding 3,5-dichloro-4-methoxybenzoic acid and an acylating agent into an organic solvent for an acylation reaction to obtain 3,5-dichloro-4-methoxybenzoyl chloride.

[0055] The present invention has found that the raw material 3,5-dichloro-4-methoxybenzoyl chloride can be further prepared by the method provided by the present invention, which can better reduce the cost.

[0056] As a preferred embodiment of the preparation method of the present invention, the acylating agent includes any one of thionyl chloride and oxalyl chloride.

[0057] As a preferred embodiment of the preparation method of the present invention, the organic solvent includes at least one of dichloromethane, toluene, and tetrahydrofuran.

[0058] Preferably, the organic solvent includes at least one of dichloromethane and toluene.

[0059] As a preferred embodiment of the preparation method of the present invention, the addition of a catalyst is also included in the acylation reaction.

[0060] Preferably, the catalyst includes N,N-dimethylformamide.

[0061] Preferably, based on the mole of 3,5-dichloro-4-methoxybenzoic acid, the mole percentage of N,N-dimethylformamide is 1.5-4%; more preferably, the mole percentage of N,N-dimethylformamide is 2.5-3%.

[0062] As a preferred embodiment of the preparation method of the present invention, the molar ratio of 3,5-dichloro-4-methoxybenzoic acid to the acylating agent is 1:(1.2-1.8).

[0063] As a preferred embodiment of the preparation method of the present invention, the mass-volume ratio of 3,5-dichloro-4-methoxybenzoic acid to the organic solvent is 1 g:(3-7) mL.

[0064] As a preferred embodiment of the preparation method of the present invention, the temperature of the acylation reaction is 30-70 °C, and the time is 1-5 h.

[0065] Preferably, the temperature of the acylation reaction is 30-5o °C, and the time is 2-4 h.

[0066] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0067] In the preparation method of the key intermediate of dolutegravir provided by the present invention, by carrying out a cyclization reaction with 2-aminothiophenol and formaldehyde as raw materials to prepare the compound shown in Formula 1, and then carrying out an amidation reaction of the compound shown in Formula 1 and 3,5-dichloro-4-methoxybenzoyl chloride in an aqueous solution of an organic solvent under a specific type of acid-binding agent, the key intermediate of dolutegravir, 3-(3,5-dichloro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole, can be effectively prepared; the yield and purity of the obtained key intermediate of dolutegravir are relatively high; and, in the preparation method, it is not necessary to use benzothiazoline widely used in the prior art, and it is not necessary to use an activator or a solubilizer. The operation method is simple, the reaction conditions are mild, and it is suitable for actual industrial production. Description of the Drawings

[0068] Figure 1 It is the synthetic route diagram of dostinel in the original research patent CN102639518;

[0069] Figure 2 It is the synthetic route diagram of dostinel in patent CN111662247;

[0070] Figure 3 It is the synthetic route diagram of the key intermediate of dostinel in Example 1;

[0071] Figure 4 It is the nuclear magnetic resonance spectrum of the compound shown in Formula 1 prepared in Example 1;

[0072] Figure 5 It is the nuclear magnetic resonance spectrum of the key intermediate of dostinel prepared in Example 1. Detailed implementation manners

[0073] To better illustrate the purpose, technical solutions and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments.

[0074] The reagents, methods and equipment used in the present invention are all conventional reagents, methods and equipment in the art unless otherwise specified.

[0075] Example 1

[0076] The embodiment of the present invention provides a preparation method of a key intermediate of dostinel, and the synthetic route diagram of the preparation is as Figure 3 shown, and the preparation method includes the following steps:

[0077] (1) Synthesis of the compound shown in Formula 1 (Compound 1)

[0078] At room temperature (25 °C), 2-aminothiophenol (SM1, 60.00 g, 0.48 mol), paraformaldehyde (43.15 g, 1.44 mol) and 600 mL of tetrahydrofuran were added to the reaction flask, and then the temperature was raised to 70 °C and stirred for cyclization reaction for 12 h. After the reaction was completed, the organic solvent was removed by reduced pressure concentration to obtain 65.20 g of Compound 1, with a yield of 95.0% and a purity of 98.8%, which was directly used for the next step of the reaction;

[0079] The hydrogen spectrum of the compound shown in Formula 1 is as Figure 4 described, 1 H NMR(CDCl3, 400 MHz) δ: 7.17 - 7.11(m, 2H), 7.04 - 7.00(m, 2H), 6.82 - 6.78(m, 2H), 6.68 - 6.67(m, 2H), 4.87(s, 4H), 4.59(s, 2H).

[0080] (2) Synthesis of 3,5-dichloro-4-methoxybenzoyl chloride (Compound 2)

[0081] At room temperature (25 °C), add 3,5-dichloro-4-methoxybenzoic acid (SM2, 120.00 g, 0.54 mol), 1.06 g of N,N-dimethylformamide, and 600 mL of dichloromethane to a reaction flask. Dropwise add thionyl chloride (96.25 g, 0.81 mol), then raise the temperature to 40 °C and stir for the substitution reaction for 3 h. After the reaction is completed, concentrate under reduced pressure to remove the organic solvent to obtain 128.06 g of Compound 2, with a yield of 98.5% and a purity of 99.2%, which is directly used for the next reaction.

[0082] (3) Synthesis of the key intermediate of dostinex

[0083] At room temperature (25 °C), add Compound 1 (57.20 g, 0.2 mol), Compound 2 (87.27 g, 0.36 mol), sodium carbonate (63.51 g, 0.6 mol), 500 mL of toluene, and 500 mL of water to a reaction flask. Raise the temperature to 70 °C and stir for the amidation reaction for 10 h. After the reaction is completed, let it stand to separate the organic phase, concentrate under reduced pressure to remove the organic solvent, then add 870 mL of ethanol and stir at 65 °C for 4 h, then cool to 25 °C and continue to stir for 4 h. Subsequently, filter, collect the filter residue and dry it to obtain 110.96 g of the key intermediate of dostinex, with a yield of 89.5% and a purity of 99.5%;

[0084] The NMR spectrum of the obtained key intermediate of dostinex is as Figure 5 shown 1 H NMR (CDCl3, 500 MHz) δ: 7.51 (s, 2H), 7.28 - 7.02 (m, 4H), 5.28 (s, 2H), 3.97 (s, 3H).

[0085] Example 2

[0086] The present invention provides a method for preparing the key intermediate of dostinex. The difference between the preparation method and that of Example 1 lies in step (1). Step (1) of this example is as follows:

[0087] At room temperature (25 °C), add 2-aminothiophenol (SM1, 60.00 g, 0.48 mol), aqueous paraformaldehyde solution (116.62 g, the mass percentage of paraformaldehyde in the aqueous paraformaldehyde solution is 37%, that is, the molar amount of paraformaldehyde is 1.44 mol), and 600 mL of tetrahydrofuran to a reaction flask. Subsequently, raise the temperature to 60 °C and stir for the cyclization reaction for 15 h. After the reaction is completed, concentrate under reduced pressure to remove the organic solvent to obtain 63.48 g of Compound 1, with a yield of 92.5% and a purity of 97.5%, which is directly used for the next reaction.

[0088] Example 3

[0089] The present embodiment provides a method for preparing a key intermediate of polytinorel. The difference between the preparation method and Example 1 lies in step (3). Step (3) of this embodiment is:

[0090] Compound 1 (57.20 g, 0.2 mol), compound 2 (87.27 g, 0.36 mol), sodium carbonate (82.81 g, 0.78 mol), 500 mL of toluene and 500 mL of water were added to the reaction flask at room temperature (25 ° C). The temperature was raised to 60 ° C and stirred for amidation reaction for 10 hours. After the reaction was completed, the organic phase was allowed to stand and separated. The organic solvent was removed by concentration under reduced pressure, and then purified by ethanol to obtain 106.00 g of the key intermediate of polytinol with a yield of 85.5% and a purity of 99.1%.

[0091] Example 4

[0092] The present embodiment provides a method for preparing a key intermediate of polytinorel. The difference between the preparation method and Example 1 lies in step (3). Step (3) of this embodiment is:

[0093] Compound 1 (57.20 g, 0.2 mol), compound 2 (87.27 g, 0.36 mol), sodium carbonate (63.51 g, 0.6 mol), 500 mL of tetrahydrofuran and 500 mL of water were added to the reaction flask at room temperature (25 ° C). The temperature was raised to 60 ° C and stirred for amidation reaction for 12 h. After the reaction was completed, the organic phase was allowed to stand and separated. The organic solvent was removed by concentration under reduced pressure, and then purified by ethanol to obtain 101.04 g of the key intermediate of polytinol with a yield of 81.5% and a purity of 98.6%.

[0094] Examples 5-13 and Comparative Examples 1-4

[0095] The present invention provides a key intermediate of polytinol. The difference between the preparation method of the key intermediate of polytinol and Example 1 is the differences listed in Table 1, including the molar ratio M1 of 2-aminothiophenol and formaldehyde in step (1), the molar ratio M2 of the compound represented by Formula 1 and the acid binding agent, the type of the acid binding agent, the type and volume ratio of the aqueous solution of the organic solvent in step (3), the temperature and time of the cyclization reaction in step (1), and the temperature and time of the amidation reaction in step (3) are as shown in Table 1.

[0096] Table 1

[0097]

[0098] Comparative Example 5

[0099] The comparative example of the present invention provides a preparation method of a multi - tenore critical intermediate. The difference between the preparation method and that of Example 1 lies in step (3). The step (3) of this example is as follows:

[0100] At room temperature (25 °C), add compound 1 (57.20 g, 0.2 mol), triethylamine (60.63 g, 1.67 mol) and 500 mL of dichloromethane into a reaction flask. Dropwise add a dichloromethane solution (400 mL) of compound 2 (87.27 g, 0.36 mol). Heat up to 70 °C and stir for the amidation reaction for 12 h. The reaction solution was detected by HPLC, and the target multi - tenore critical intermediate product was not detected.

[0101] Comparative Example 6

[0102] The comparative example of the present invention provides a preparation method of a multi - tenore critical intermediate. The difference between the preparation method and that of Example 1 lies in step (3). The step (3) of this example is as follows:

[0103] At room temperature (25 °C), add compound 1 (57.20 g, 0.2 mol), triethylamine (60.63 g, 1.67 mol) and 500 mL of toluene into a reaction flask. Dropwise add a toluene solution (400 mL) of compound 2 (87.27 g, 0.36 mol). Heat up to 70 °C and stir for the amidation reaction for 12 h. The reaction solution was detected by HPLC, and the target multi - tenore critical intermediate product was not detected.

[0104] Effect Example

[0105] The effect example of the present invention records the yields and purities of the multi - tenore critical intermediates prepared in Examples 1 - 13 and Comparative Examples 1 - 6. The data obtained are recorded in Table 2;

[0106] Among them, the calculation method of the yield is as follows:

[0107] Calculation formula for the yield of the key intermediate: (weight of the key intermediate ÷ 340.22) / (amount of compound 2 fed ÷ 239.48) × 100%;

[0108] Among them, the " / " at the yield in Table 2 indicates that the key intermediate cannot be separated, so there is no yield data; the " / " at the purity indicates that the corresponding key intermediate cannot be prepared;

[0109] Table 2

[0110]

[0111]

[0112] As can be seen from Table 2, when the preparation method provided by the present invention is adopted, the yield and purity of the key intermediate of dolutegravir are relatively high; specifically, the yield of the key intermediate of dolutegravir obtained is above 79.5%, and the purity is above 98.5%.

[0113] As can be seen from Example 1 and Comparative Example 1, when the molar ratio of formaldehyde to 2-aminothiophenol in the cyclization reaction of step (1) is only 1:1, the purity of the key intermediate of dolutegravir obtained decreases significantly, only 45%; as can be seen from Example 1 and Comparative Example 2, when the acid-binding agent in step (3) is not a carbonate or phosphate, the corresponding key intermediate of dolutegravir cannot be prepared; as can be seen from Example 1 and Comparative Example 3, when no acid-binding agent is added in step (3), the key intermediate of dolutegravir cannot be prepared; as can be seen from Example 1 and Comparative Example 4, when the solvent in step (3) is only an organic solvent without water, the purity of the key intermediate of dolutegravir obtained decreases significantly, only 23%.

[0114] Finally, it should be noted that the above embodiments are used to illustrate the technical solutions of the present invention rather than to limit the protection scope of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A method for preparing a key intermediate of polytinoride, characterized in that: The preparation method comprises the following steps: (1) 2-aminothiophenol and formaldehyde are subjected to a cyclization reaction to obtain the compound shown in Formula 1; (2) The compound shown in Formula 1, 3,5-dichloro-4-methoxybenzoyl chloride and an acid-binding agent are added to an aqueous solution of an organic solvent for an amidation reaction to obtain the key intermediate of dorniciclib, 3-(3,5-dichloro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole; In the step (2), the acid-binding agent comprises at least one of carbonates and phosphates; 2. The preparation method according to claim 1, wherein, In the step (1), the molar ratio of 2-aminothiophenol to formaldehyde is 1:(1.5-5).

3. The preparation method according to claim 1, wherein In the step (1), the temperature of the cyclization reaction is 60-100 °C, and the time is 8-16 h.

4. The preparation method according to claim 1, characterized in that, In the step (2), the molar ratio of the compound shown in Formula 1 to the acid-binding agent is 1:(2-6).

5. The preparation method according to claim 1, wherein In the step (2), the temperature of the amidation reaction is 50-100 °C, and the time is 4-14 h.

6. The preparation method according to claim 1, characterized in that, In the step (2), the acid-binding agent comprises at least one of sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, and potassium phosphate; And / or, in the step (2), the organic solvent comprises at least one of toluene, xylene, tetrahydrofuran, acetonitrile, and acetone.

7. The preparation method according to claim 1, characterized in that, In the aqueous solution of the organic solvent in the step (2), the volume ratio of the organic solvent to water is 1:(0.5-4).

8. The preparation method according to claim 1, wherein, The preparation method of the 3,5-dichloro-4-methoxybenzoyl chloride is as follows: 3,5-dichloro-4-methoxybenzoic acid and an acylating agent are added to an organic solvent for an acylation reaction to obtain 3,5-dichloro-4-methoxybenzoyl chloride.

9. The preparation method according to claim 8, wherein, The acylating agent comprises any one of thionyl chloride and oxalyl chloride; And / or, the organic solvent comprises at least one of dichloromethane, toluene, and tetrahydrofuran.

10. The preparation method according to claim 8, wherein, The temperature of the acylation reaction is 30-70 °C, and the time is 1-5 h.

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