Preparation method of lutrombopag intermediate

Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to a preparation method of a lutrombopag intermediate, which comprises the step of preparing an intermediate I p-toluenesulfonate by using a new salifying system.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a method for preparing a rutrombopag intermediate. The method includes using a novel salt-forming system to prepare intermediate I p-toluenesulfonate, which significantly reduces the content of chiral isomer impurity A and improves product purity. Background Technology

[0002] The chemical name of rutrombopag is (2E)-3-{2,6-dichloro-4-[(4-{3-[(1S)-1-(hexoxy)ethyl]-2-methoxyphenyl}-1,3-thiazo-2-yl)carbamoyl]phenyl}-2-methylprop-2-enoic acid, and it has the chemical structure shown in the following formula:

[0003]

[0004] Lutrombopag is an oral small molecule thrombopoietin (TPO) receptor agonist that interacts with the transmembrane region of the human TPO receptor expressed on megakaryocytes, thereby inducing the proliferation and differentiation of hematopoietic stem cell-derived progenitor cells and megakaryocyte maturation. It is indicated for adult patients with chronic liver disease and thrombocytopenia who have undergone surgery (including diagnostic procedures).

[0005] The preparation of leucovorin involves the preparation of a key intermediate, I, with the following structural formula:

[0006]

[0007] The original research company, Shionogi & Co., Ltd., applied for patent CN105992761A, which describes the following synthetic route A for intermediate I:

[0008]

[0009] This patented method uses 2,6-dibromoanisole as a raw material, reacting it with N-methoxy-N-methylacetamide in the presence of isopropyl magnesium chloride to obtain acetophenone. A chiral alcohol is then constructed through asymmetric reduction, followed by hexyl alkylation and the introduction of a chloroacetyl group with 2-chloro-N-methoxy-N-methylacetamide in the presence of isopropyl magnesium chloride. Finally, it is cyclized with thiourea to obtain the corresponding intermediate I. The reaction consists of five steps with an overall yield of 35-40%.

[0010] Synthetic route A requires column chromatography purification in the intermediate process, which makes industrial production difficult.

[0011] Hangzhou Lide Biotechnology Co., Ltd.'s patent application CN106565625A describes the following synthetic route B for intermediate I:

[0012]

[0013] Synthetic route B uses compound XI as a starting material. First, methylation yields compound X, followed by condensation with N,O-dimethylhydroxylamine to obtain compound IX. Then, reaction with a methyl Grignard reagent yields compound VIII. After asymmetric reduction and alkylation, compound VII is obtained. After hydroxyl protection, compound VI is obtained. After debromination with a Grignard reagent, compound V is condensed to obtain compound V. Finally, bromination is performed, followed by cyclization with thiourea to obtain intermediate I.

[0014] Synthetic route B avoids the use of column chromatography for intermediate post-processing, and the yield of the last two steps reaches over 80%, which is a significant improvement over the 25-30% yield of the last two steps in the original patent CN105992761A.

[0015] Although synthetic route B improves the yield of intermediate I, it produces a chiral isomer impurity A with the following structure in the asymmetric reduction process (i.e., the step of asymmetric reduction of compound VIII to obtain compound VII), and impurity A is not easily removed in its subsequent steps.

[0016]

[0017] Therefore, there is still an urgent need in this field to study new methods for preparing intermediate I, which can control the content of impurity A by controlling the generation or removal of impurity A and improve the purity of the product. Summary of the Invention

[0018] The first aspect of this invention provides a method for preparing intermediate I p-toluenesulfonate, the method comprising the following steps:

[0019] (i) Reacting compound V with pyridinium tribromide in an alcohol solvent to give intermediate IV.

[0020] (ii) Cyclic closure of intermediate IV obtained in step (i) with thiourea to obtain intermediate I.

[0021] (iii) Intermediate I is reacted with p-toluenesulfonic acid in an ester solvent to form a salt, yielding intermediate I p-toluenesulfonate.

[0022] The reaction formula is as follows:

[0023]

[0024] In an embodiment of the first aspect of the present invention, in step (i), the molar ratio of intermediate V to pyridinium tribromide is 1:0.9-1.5, preferably 1:1.0-1.2, and more preferably 1:1.0-1.05.

[0025] In an embodiment of the first aspect of the invention, in step (i), the alcohol solvent used to react intermediate V with pyridinium tribromide is selected from methanol, ethanol or isopropanol, preferably ethanol.

[0026] In an embodiment of the first aspect of the invention, the mass-to-volume ratio (g:mL) of intermediate V to alcohol solvent is 1:5-10, preferably 1:6-8, and more preferably 1:7-8. For example, when the alcohol solvent is ethanol, the mass-to-volume ratio (g:mL) of intermediate V to ethanol is 1:5-10, preferably 1:6-8, and more preferably 1:7-8.

[0027] In an embodiment of the first aspect of the present invention, the reaction temperature in step (i) is 5-30°C, preferably 10-20°C, more preferably 15-20°C; and the reaction time is 2-6 hours, preferably 3-4 hours.

[0028] In an embodiment of the first aspect of the present invention, the molar ratio of intermediate V to thiourea is 1:0.9-1.5, preferably 1:1.0-1.2, and more preferably 1:1.0-1.1.

[0029] In an embodiment of the first aspect of the invention, the reaction for preparing intermediate I in step (ii) is carried out in purified water.

[0030] In an embodiment of the first aspect of the present invention, the temperature of the stirring reaction for preparing intermediate I in step (ii) is 10-40°C, preferably 20-40°C, more preferably 20-30°C; and the reaction time is 2-6 hours, preferably 3-4 hours.

[0031] In an embodiment of the first aspect of the present invention, the preparation method further includes step (ii-1): concentrating the reaction solution obtained in step (ii) to remove ethanol, then adding ethyl acetate for extraction, and collecting the organic phase (i.e., the step of separating intermediate I).

[0032] In an embodiment of the first aspect of the invention, the ester solvent used in step (iii) to prepare intermediate I p-toluenesulfonate is selected from ethyl acetate, isopropyl acetate, methyl acetate, or mixtures thereof, preferably ethyl acetate.

[0033] In an embodiment of the first aspect of the present invention, in step (iii), the molar ratio of intermediate I to p-toluenesulfonic acid monohydrate is 1:0.9-1.2, preferably 1:0.9-1.1, and more preferably 1:0.9-1.0.

[0034] In an embodiment of the first aspect of the present invention, in step (iii), the reaction temperature for intermediate I to form a salt with p-toluenesulfonic acid is 40-60°C, more preferably 45-55°C; and the salt formation reaction time is 1.5-6 hours, preferably 1.5-2.5 hours.

[0035] In an embodiment of the first aspect of the present invention, the method further includes step (iii-1): cooling and crystallizing the intermediate I p-toluenesulfonate obtained in step (iii), adding an alkane solvent, continuing to stir and crystallize, filtering, and drying the solid to obtain intermediate I p-toluenesulfonate crystal form A. The alkane solvent is selected from n-heptane, n-hexane, cyclohexane, or combinations thereof; and the drying step is carried out under vacuum at 45-55°C.

[0036] In a preferred embodiment of the first aspect of the invention, in steps (iii) and (iii-1), the ethyl acetate solution of intermediate I reacts with p-toluenesulfonic acid monohydrate at 45-55°C to form a salt for 1-2 hours, then cools to 20-30°C and stirs to crystallize for 1-2 hours. After adding n-heptane, the temperature is lowered to 0-10°C and stirred to crystallize for 1-2 hours. The solid is then filtered, washed with n-heptane, and dried at 45-55°C for 3-4 hours to obtain intermediate I p-toluenesulfonate. In this embodiment, the obtained intermediate I p-toluenesulfonate is in crystal form A.

[0037] In a second aspect of the invention, an intermediate I p-toluenesulfonate is provided, which is prepared by the method described in the first aspect of the invention.

[0038] The intermediate I p-toluenesulfonate provided in the second aspect of the present invention exists in crystal form A, characterized by having characteristic peaks at 5.6°±0.2°, 11.1°±0.2°, and 22.2°±0.2° in the X-ray powder diffraction pattern expressed in 2θ angles using Cu-Kα radiation; more preferably, the intermediate I p-toluenesulfonate crystal form A of the present invention has the following characteristics: Figure 1 The X-RPD pattern shown.

[0039] The novel preparation method for intermediate I p-toluenesulfonate provided in the first aspect of this invention employs a novel salt-forming system, which can reduce the content of chiral isomer impurities, improve product quality, and lay a good quality foundation for the preparation of high-purity products. The intermediate p-toluenesulfonate and its crystal form A provided in the second aspect of this invention exhibit better (crystal form) stability and chemical stability. Under room temperature and normal storage conditions, it is not prone to crystal form transformation or decomposition, and significant improvements are achieved in solubility and bioavailability.

[0040] It should be noted that in this invention, intermediate V refers to (S)-1-(3-(1-(hexoxy)ethyl)-2-methoxyphenyl)ethyl ketone, intermediate I refers to (S)-4-(3-(1-(hexoxy)ethyl)-2-methoxyphenyl)thiazole-2-amine, and impurity A refers to (R)-4-(3-(1-(hexoxy)ethyl)-2-methoxyphenyl)thiazole-2-amine. Unless otherwise specified, the amounts of solvent and related reagents used are conventional amounts for the reaction and can be determined by those skilled in the art based on existing technology. The reagents used in this invention are all conventional reagents that can be purchased from the market, and the starting materials and reactants used can be prepared by existing technology or published literature. Attached Figure Description

[0041] Figure 1 This is the X-RPD pattern of intermediate I p-toluenesulfonate crystal form A obtained in Example 1.

[0042] Figure 2 This is the HPLC chromatogram of chiral isomer impurity A before crystallization of intermediate I obtained in Example 1.

[0043] Figure 3 This is the HPLC chromatogram of impurity A, the chiral isomer of intermediate I p-toluenesulfonate obtained in Example 1.

[0044] Figure 4 This is the HPLC chromatogram of related substances before crystallization of intermediate I obtained in Example 1.

[0045] Figure 5 This is the HPLC chromatogram of related substances of intermediate I p-toluenesulfonate obtained in Example 1.

[0046] Figure 6 This is the mass spectrum of intermediate I p-toluenesulfonate obtained in Example 1.

[0047] Figure 7 This is the 1H NMR spectrum of intermediate I p-toluenesulfonate obtained in Example 1.

[0048] Figure 8 This is the HPLC chromatogram of impurity A, the chiral isomer of intermediate I p-toluenesulfonate obtained in Example 3.

[0049] Figure 9 This is the HPLC chromatogram of related substances of intermediate I p-toluenesulfonate obtained in Example 3.

[0050] Figure 10 This is the HPLC chromatogram of impurity A, the chiral isomer of intermediate I p-toluenesulfonate obtained in Example 4.

[0051] Figure 11This is the HPLC chromatogram of related substances of intermediate I p-toluenesulfonate obtained in Example 4.

[0052] Figure 12 This is the HPLC chromatogram of impurity A, the chiral isomer of intermediate I p-toluenesulfonate obtained in Example 5.

[0053] Figure 13 This is the HPLC chromatogram of related substances of intermediate I p-toluenesulfonate obtained in Example 5.

[0054] Figure 14 This is the HPLC chromatogram of impurity A, the chiral isomer of intermediate I obtained in Comparative Example 1.

[0055] Figure 15 This is the HPLC chromatogram of related substances in intermediate I obtained from Comparative Example 1. Detailed Implementation

[0056] The following detailed description of specific embodiments further illustrates the above-mentioned content of the present invention, but should not be construed as limiting the scope of protection of the present invention in any way. All technical solutions implemented based on the above-mentioned content of the present invention fall within the scope of the present invention. The present invention provides a general and / or specific description of the materials and experimental methods used in the experiments. Those skilled in the art will understand that, unless otherwise specified, the operations performed in the present invention are conducted under conventional room temperature conditions, which have a well-known technical meaning in the art, generally referring to 20-35°C, preferably 20-30°C.

[0057] The content of isomer impurity A and other impurities (sometimes referred to as "related substances" in this context) in the product were determined by high-performance liquid chromatography (HPLC), but the specific detection methods differed. Specifically, the product purity determined by method 1 for isomer impurity A was based on the sum of target product intermediate I or its salt and impurity A; the product purity determined by method 2 for "other impurities (excluding impurity A)" was based on the sum of target product intermediate I or its salt and other impurities (excluding impurity A). In this context, the description of product purity generally refers to the purity determined by method 2.

[0058] The specific testing methods are shown in the table below:

[0059] Detection Method 1:

[0060] Table 1. Relevant parameters for high performance liquid chromatography.

[0061]

[0062] Gradient elution method:

[0063]

[0064] Note: One octadecylsilane-bonded silica gel column (Waters XBridge C18, 4.6 mm × 50 mm, 3.5 μm or equivalent performance) is connected in series before the column.

[0065] Solution preparation: Take an appropriate amount of this product, accurately weigh it, dissolve it in methanol and dilute it quantitatively to prepare a solution containing about 0.5 mg per 1 mL, inject it into liquid chromatography and determine it using the area normalization method.

[0066] Detection Method 2:

[0067] Table 2. Relevant parameters for high performance liquid chromatography.

[0068]

[0069] Gradient elution method:

[0070]

[0071] Note: Install a trapping column (Ghost Trap DS, 7.6mm × 30mm or equivalent trapping column) between the gradient mixer and the injector.

[0072] Solution preparation method: Accurately weigh an appropriate amount of this product, dissolve and dilute it with methanol to prepare a solution containing approximately 0.5 mg per mL. Inject into liquid chromatography and determine the concentration using the area normalization method.

[0073] X-ray powder diffraction (XRPD)

[0074] Solid samples were analyzed using a Malvern-Panaco D8 Advance A25 benchtop X-ray diffractometer. An appropriate amount of fine powder of the sample was placed in the groove of the sample holder and pressed into a flat and dense plane. The XRPD measurement parameters are shown in Table 3.

[0075] Table 3 XRPD Test Parameters

[0076] instrument D8 Advance A25 light source Cu target Light Blade Mode Low Scan coordinates Gonio Scanning angle 3-40°(2θ) Scanning method Single scan Scan step size 0.02° Time per step 40s Phototube voltage / current 40KV / 40mA Diverging slit 1 / 8°

[0077] 1H NMR spectrum

[0078] The proton NMR spectrum was measured using a 400MHz NMR spectrometer, and the test solvent was DMSO.

[0079] mass spectrometry

[0080] Mass spectrometry measurements were performed using a Q Exactive Plus liquid chromatography-mass spectrometry system. Test conditions: ESI-MS, electrospray ionization mass spectrometry.

[0081] Example 1: Preparation of (S)-4-(3-(1-(hexyloxy)ethyl)-2-methoxyphenyl)thiazole-2-amine p-toluenesulfonate (Intermediate I p-toluenesulfonate):

[0082] 26 g of intermediate V was added to 200 mL of anhydrous ethanol, cooled to 10-15 °C, and 31.4 g of pyridinium tribromide was added. The reaction was maintained at 10-15 °C for 3 hours to obtain the reaction solution of intermediate IV. The reaction was quenched with purified water, and 7.8 g of thiourea was added. The reaction was continued at 20-30 °C for 3 hours. 21 g of purified water was added, and the ethanol was distilled off under reduced pressure. 40 mL of ethyl acetate and 5 mL of 2 mol / L sodium hydroxide solution were added, and the mixture was stirred for 20 minutes. The organic phase was separated, concentrated, and the solid was dried at 40-50 °C for 3 hours. At that time, 0.5g of sample was taken for testing. The remaining sample was dissolved in 20mL of ethyl acetate, and then p-toluenesulfonic acid monohydrate was added. Salt formation was carried out at 45-55℃ for 2 hours. The temperature was then lowered to 20-30℃, and the mixture was stirred to crystallize for 2 hours. 25mL of n-heptane was added, and the temperature was lowered to 0-10℃. Crystallization was continued for 2 hours. The mixture was filtered, and the solid was washed with 10mL of n-heptane and dried under vacuum at 45-55℃ for 4 hours to obtain intermediate I p-toluenesulfonate, with a yield of 85.2%, a purity of 99.87%, and a chiral isomer impurity A content of 0.02%.

[0083] The HPLC chromatogram of intermediate I before crystallization is as follows: Figure 2 and 4 As shown. The X-RPD spectrum of the obtained intermediate I p-toluenesulfonate is shown below. Figure 1 As shown, the HPLC chromatogram is as follows: Figure 3 and 5 As shown; mass spectrum (see image). Figure 6 See NMR spectrum Figure 7 .

[0084] ESI(+): m / z 335.17899 [M+H] + ; 1 H-NMR(400MHz,DMSO)δ7.820-7.796(dd,1H,J=1.6Hz,7.6Hz),7.288-7.264(dd,1H ,J=2.0Hz,7.6Hz),7.185-7.148(t,1H,J=7.6Hz),7.056(s,1H),6.992(s,2H),4.79 5-4.779(d,1H,J=6.4Hz),3.616(s,3H),3.317-3.193(m,2H),1.501-1.459(m,2H), 1.361-1.345(d,3H,J=6.4Hz), 1.301-1.205(m,6H), 0.861-0.826(t,3H,J=6.8Hz).

[0085] Example 2: Preparation of (S)-4-(3-(1-(hexyloxy)ethyl)-2-methoxyphenyl)thiazole-2-amine p-toluenesulfonate (Intermediate I p-toluenesulfonate):

[0086] 260g of intermediate V was added to 2L of anhydrous ethanol, the temperature was lowered to 15-20℃, 314g of pyridinium tribromide was added, and the reaction was maintained at 15-20℃ for 3 hours to obtain the reaction solution of intermediate IV. The reaction was quenched with purified water, 78g of thiourea was added, and the reaction was continued at 20-30℃ for 3 hours. 210g of purified water was added, the ethanol was distilled off under reduced pressure, 500mL of ethyl acetate and 50mL of 2mol / L sodium hydroxide solution were added, the mixture was stirred for 20 minutes, the organic phase was separated, and the product was concentrated. Half the volume of ethyl acetate was added to p-toluenesulfonic acid monohydrate, and the mixture was allowed to form a salt at 55-60°C for 2 hours. The temperature was then lowered to 20-30°C, and the mixture was stirred to crystallize for 2 hours. 250 mL of n-heptane was added, and the temperature was lowered to 0-5°C. The mixture was kept at this temperature for another 2 hours to crystallize. The mixture was then filtered, and the solid was washed with 100 mL of n-heptane and dried under vacuum at 45-55°C for 4 hours to obtain intermediate I p-toluenesulfonate, with a yield of 84.5% and a purity of 99.85%, of which the chiral isomer impurity A content was 0.07%.

[0087] Example 3: Preparation of (S)-4-(3-(1-(hexyloxy)ethyl)-2-methoxyphenyl)thiazole-2-amine p-toluenesulfonate (Intermediate I p-toluenesulfonate):

[0088] 260g of intermediate V was added to 2L of methanol, the temperature was lowered to 15-20℃, 314g of pyridinium tribromide was added, and the reaction was maintained at 15-20℃ for 3 hours to obtain the reaction solution of intermediate IV. The reaction was quenched with purified water, 78g of thiourea was added, and the reaction was continued at 20-30℃ for 3 hours. 210g of purified water was added, and methanol was distilled off under reduced pressure. 500mL of ethyl acetate and 50mL of 2mol / L sodium hydroxide solution were added, and the mixture was stirred for 20 minutes. The organic phase was separated, concentrated, and discharged. Half the volume of ethyl acetate was added to p-toluenesulfonic acid monohydrate, and the mixture was allowed to form a salt at 55-60°C for 2 hours. The temperature was then lowered to 20-30°C, and the mixture was stirred to crystallize for 2 hours. 250 mL of n-heptane was added, and the temperature was lowered to 0-5°C. Crystallization was continued at this temperature for 2 hours. The mixture was filtered, and the solid was washed with 100 mL of n-heptane and dried under vacuum at 45-55°C for 4 hours to obtain intermediate I p-toluenesulfonate, with a yield of 82.5% and a purity of 99.60%, of which the chiral isomer impurity A content was 0.01%.

[0089] Example 4: Preparation of (S)-4-(3-(1-(hexyloxy)ethyl)-2-methoxyphenyl)thiazole-2-amine p-toluenesulfonate (Intermediate I p-toluenesulfonate):

[0090] 260g of intermediate V was added to 2L of ethanol, the temperature was lowered to 15-20℃, 314g of pyridinium tribromide was added, and the reaction was maintained at 15-20℃ for 3 hours to obtain the reaction solution of intermediate IV. The reaction was quenched with purified water, 78g of thiourea was added, and the reaction was continued at 20-30℃ for 3 hours. 210g of purified water was added, the ethanol was distilled off under reduced pressure, 500mL of isopropyl acetate and 50mL of 2mol / L sodium hydroxide solution were added, the mixture was stirred for 20 minutes, the organic phase was separated, and the product was concentrated. Half the volume of isopropyl acetate was added to p-toluenesulfonic acid monohydrate, and the mixture was allowed to form a salt at 55-60°C for 2 hours. The temperature was then lowered to 20-30°C, and the mixture was stirred to crystallize for 2 hours. 250 mL of n-heptane was added, and the temperature was lowered to 0-5°C. The mixture was kept at this temperature for another 2 hours to crystallize. The solid was filtered, washed with 100 mL of n-heptane, and dried under vacuum at 45-55°C for 4 hours to obtain intermediate I, p-toluenesulfonate, with a yield of 83.2%, a purity of 99.88%, and a chiral isomer impurity A content of 0.07%.

[0091] Example 5: Preparation of (S)-4-(3-(1-(hexyloxy)ethyl)-2-methoxyphenyl)thiazole-2-amine p-toluenesulfonate (Intermediate I p-toluenesulfonate):

[0092] 260g of intermediate V was added to 2L of ethanol, the temperature was lowered to 15-20℃, 314g of pyridinium tribromide was added, and the reaction was maintained at 15-20℃ for 3 hours to obtain the reaction solution of intermediate IV. The reaction was quenched with purified water, 78g of thiourea was added, and the reaction was continued at 20-30℃ for 3 hours. 210g of purified water was added, the ethanol was distilled off under reduced pressure, 500mL of methyl acetate and 50mL of 2mol / L sodium hydroxide solution were added, the mixture was stirred for 20 minutes, the organic phase was separated, and the solution was concentrated. Half the volume of methyl acetate was added, and p-toluenesulfonic acid monohydrate was added. Salt formation was carried out at 55-60℃ for 2 hours. The temperature was then lowered to 20-30℃, and the mixture was stirred to crystallize for 2 hours. 250 mL of n-heptane was added, and the temperature was lowered to 0-5℃. Crystallization was continued at this temperature for 2 hours. The mixture was filtered, and the solid was washed with 100 mL of n-heptane and dried under vacuum at 45-55℃ for 4 hours to obtain intermediate I p-toluenesulfonate, with a yield of 83.2%, a purity of 99.66%, and a chiral isomer impurity A content of 0.08%.

[0093] Comparative Example 1: Intermediate I was prepared according to the method in reference CN106565625A.

[0094] 320 g of intermediate V was added to 1.6 L of dichloromethane, and 215 g of N-bromosuccinimide was added in portions. The reaction was carried out at room temperature for 3 hours until the reaction was completed. After dilution with ethyl acetate, the product was washed with water and saturated sodium chloride solution. The ethyl acetate was concentrated to obtain crude compound IV, which was dissolved in 1.6 L of ethanol. Thiourea was added, and the mixture was refluxed until intermediate IV was completely converted. The ethanol was concentrated, and the organic phase was washed with water after dissolving in ethyl acetate. After concentration, the product was crystallized to obtain a white solid. The ethyl acetate was recrystallized to obtain intermediate I, with a yield of approximately 82.2%, a purity of 98.93%, and an impurity A content of 0.51%.

[0095] The HPLC chromatogram of the obtained intermediate I is as follows: Figure 14 and 15 As shown, the content of chiral isomer impurity A is 0.51%.

[0096] Table 4 shows the results of isomer impurity A in the product as determined by HPLC method 1.

[0097]

[0098] Table 5 shows the product purity and major impurities determined by HPLC method 2.

[0099]

[0100] Stability test

[0101] The sample of intermediate I p-toluenesulfonate obtained in Example 1 was placed at 35°C, and its chemical and crystal stability were investigated at 10, 20, 30, and 60 days. Specific stability testing methods can be found in Appendix XIXC of the 2010 edition of the Chinese Pharmacopoeia, Part II; purity was determined using HPLC, as described in Appendix VD of the 2010 edition of the Chinese Pharmacopoeia, Part II; and crystal form was determined using X-RPD. The experimental results show that crystal form A of intermediate I p-toluenesulfonate exhibits better crystal stability and chemical stability. Under room temperature and normal storage conditions, it is less prone to crystal transformation and decomposition, making it more suitable for product storage and transportation.

Claims

1. A method for preparing intermediate I p-toluenesulfonate, comprising the following steps: (i) Reacting compound V with pyridinium tribromide in an alcohol solvent to give intermediate IV. (ii) Cyclic closure of intermediate IV obtained in step (i) with thiourea to obtain intermediate I. (iii) Intermediate I is reacted with p-toluenesulfonic acid monohydrate in an ester solvent to form a salt, yielding intermediate I p-toluenesulfonate. The reaction formula is as follows:

2. The method according to claim 1, wherein the alcohol solvent in step (i) is selected from methanol, ethanol or isopropanol, preferably ethanol; and the ester solvent in step (iii) is selected from ethyl acetate, isopropyl acetate, methyl acetate or a mixture thereof, preferably ethyl acetate.

3. The method according to claim 1, wherein the reaction temperature in step (i) is 5-30°C, preferably 10-20°C, and most preferably 15-20°C; and the reaction time is 2-6 hours, preferably 3-4 hours; In step (iii), the temperature for the salt formation of intermediate I with p-toluenesulfonic acid is 40-60°C, preferably 45-55°C; the salt formation reaction time is 1.5-6 hours, preferably 1.5-2.5 hours.

4. The method according to any one of claims 1 to 3, wherein the method further comprises step (ii-1): concentrating the reaction solution obtained in step (ii) to remove ethanol, then adding ethyl acetate for extraction, and collecting the organic phase.

5. The method according to any one of claims 1 to 3, wherein the method further comprises step (iii-1): cooling and crystallizing intermediate I p-toluenesulfonate obtained in step (iii), adding an alkane solvent, continuing to stir and crystallize, filtering, and drying the solid to obtain intermediate I p-toluenesulfonate crystal form A.

6. The method according to claim 5, wherein the drying step is performed under vacuum at 45-55°C.

7. The method according to claim 5, wherein the alkane solvent is selected from n-heptane, n-hexane, cyclohexane, or combinations thereof.

8. An intermediate I p-toluenesulfonate, which is prepared by the method according to any one of claims 1 to 7.

9. The intermediate I p-toluenesulfonate according to claim 8, which exists in crystal form A, is characterized in that... Using Cu-Kα radiation, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 5.6°±0.2°, 11.1°±0.2°, and 22.2°±0.2°.

10. The intermediate I p-toluenesulfonate according to claim 9, wherein the crystal form A has the X-RPD pattern shown in FIG1.

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