Intermediates for the preparation of vibeglord and processes for their preparation

Abstract

This invention provides a salt of compound I as shown in formula (1), and also provides a method for preparing the salt of compound I and its use as an intermediate in the preparation of vilbergerone. Furthermore, this invention provides a method for preparing vilbergerone. The salt of compound I provided by this invention can be used as a key intermediate in the preparation of vilbergerone, yielding a target product with high yield and purity, and also simplifies the process. Therefore, the route for preparing vilbergerone using the salt of compound I as an intermediate has higher production efficiency and greater operability, making it more suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to a salt of compound I, its preparation method, and its use as an intermediate in the preparation of vilbegaron. This invention also relates to a method for preparing vilbegaron. Background Technology

[0002] Vibegron is a potent and highly selective β3-adrenergic receptor (β3-AR) agonist developed by Merck & Co., Ltd. It is used to treat urge incontinence, urgency, and frequency symptoms in patients with overactive bladder (OAB). Vibegron was approved for marketing in Japan by the Pharmaceuticals and Medical Devices Agency (PMDA) on September 21, 2018, and is marketed in Japan by Kyorin Pharmaceutical and Kissei under the brand name [Brand Name Missing]. Vibegron's chemical name is (6S)-N-[4-[[(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidine-2-yl]methyl]phenyl]-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxamide.

[0003] Compound I, as shown below, is a key intermediate in the preparation of Vibegron.

[0004]

[0005] The reaction formula for synthesizing compound I disclosed in patent document WO 2009124167A1 is as follows:

[0006]

[0007] The low yield of the target product in this route is not conducive to industrial production.

[0008] Patent document WO 2013062881A1 discloses the hemihydrate crystal form of vilbergerone intermediate I, which is used to prepare vilbergerone under acidic conditions via a condensation reaction.

[0009]

[0010] However, this preparation method is cumbersome to operate, the reaction system is complex, and the yield is low.

[0011] In conclusion, there is an urgent need to develop a new method for preparing vebergerone and its intermediates that is suitable for industrial production and can achieve higher yields and purity of the target product. Summary of the Invention

[0012] To overcome the shortcomings of the prior art, one object of the present invention is to provide a salt of compound I that can be used as an intermediate in the preparation of vibergron and can achieve very good yield and purity of the target product.

[0013] Another object of the present invention is to provide a method for preparing the salt of said compound I and its use.

[0014] Another object of the present invention is to provide a method for preparing vebergerone.

[0015] The first aspect of the present invention provides a salt of compound I as shown in formula (1), which is an inorganic acid salt or an organic acid salt of compound I.

[0016]

[0017] After extensive research, the inventors of this invention discovered that compound I can be readily prepared into a high-purity (including high effective content and high chiral purity) inorganic or organic acid salt. Using a salt of compound I instead of compound I as an intermediate in the preparation of vilbergerone significantly improves product yield, HPLC purity, and chiral purity. Furthermore, when using a salt of compound I to prepare vilbergerone, it is unnecessary to adjust the reaction system to acidity, thus simplifying the preparation process to some extent.

[0018] In the salt of compound I provided by this invention, the inorganic or organic acid salt of compound I can be formed by reacting compound I with an inorganic or organic acid commonly used in the art. In some preferred embodiments, the salt of compound I can be a salt formed by compound I with one or more of the following acids: HF, HCl, HBr, L-tartaric acid, D-tartaric acid, D-maleic acid, L-malic acid, D-malic acid, or D-mandelic acid.

[0019] Furthermore, the salt of compound I provided by the present invention can be compound I hydrochloride as shown in formula (2);

[0020]

[0021] Compared to other types of inorganic or organic acid salts, hydrochloride can achieve better reaction results in the preparation of vebergellon, with higher yields and purity. Moreover, the preparation cost of hydrochloride is also lower, making it more suitable for industrial production.

[0022] In some preferred embodiments, the compound I hydrochloride is crystal form A, and its X-ray powder diffraction pattern has characteristic peaks at the following diffraction angles 2θ: 7.28±0.2°, 8.68±0.2°, 10.41±0.2°, 11.67±0.2°, 12.47±0.2°, 14.49±0.2°, 15.82±0.2°, 16.39±0.2°, 17.41±0.2°, 18.00±0.2°, 18.76±0.2°, 22.80±0.2°, 23.32±0.2°, 24.54±0.2°, 25.51±0.2°, 29.00±0.2°, and 29.54±0.2°.

[0023] In some preferred embodiments, the X-ray powder diffraction pattern of crystal form A has characteristic peaks at the following diffraction angles 2θ: 7.28±0.2°, 8.68±0.2°, 10.41±0.2°, 11.67±0.2°, 12.47±0.2°, 14.49±0.2°, 15.82±0.2°, 16.39±0.2°, 17.41±0.2°, 18.00±0.2°, 18.76±0.2°, 19.25±0.2°, 20.44±0.2°, 20.79±0.2°, 21.73±0.2°, 22.80± 0.2°, 23.32±0.2°, 24.54±0.2°, 25.51±0.2°, 26.77±0.2°, 27.92±0.2°, 28.66±0.2°, 29.00±0.2°, 29.54±0.2°, 30.48±0.2°, 31.34±0.2°, 31.80±0.2°, 32.81±0.2°, 34.31±0.2°, 34.72±0.2°, 35.43±0.2°, 36.34±0.2°, 37.25±0.2°, 38.20±0.2°, 39.03±0.2°.

[0024] In some preferred embodiments, the X-ray powder diffraction pattern of crystal form A can be as follows: Figure 2 As shown.

[0025] A second aspect of the present invention provides a method for preparing a salt of compound I according to any one of the above technical solutions, comprising: in a first organic solvent, the compound I and the inorganic acid or organic acid are subjected to salt formation at 40 to 80°C, and then the temperature is lowered to -5 to 10°C for crystallization, thereby obtaining the inorganic acid salt or organic acid salt of the compound I.

[0026] In the method for preparing the salt of compound I provided by the present invention, the salt-forming temperature can be about 40°C, about 50°C, about 60°C, about 70°C, about 80°C, or any combination thereof. In some preferred embodiments, the salt-forming temperature can be further set to 50–60°C.

[0027] In the method for preparing the salt of compound I provided by the present invention, the crystallization temperature can be about -5°C, about 0°C, about 5°C, about 10°C, or any combination of these temperature ranges. In some preferred embodiments, the crystallization temperature can be further set to 0–5°C.

[0028] In the method for preparing the salt of compound I provided by the present invention, the first organic solvent can be a C1-C6 aliphatic saturated monohydric alcohol. In some preferred embodiments, the first organic solvent can be one or more of methanol, ethanol, and isopropanol.

[0029] In the method for preparing the salt of compound I provided by the present invention, the ratio of the first organic solvent to compound I can be 1 to 30:1 (volume-mass ratio, mL / g, i.e., 1 to 30 mL of the first organic solvent is used for every 1 g of compound I). In some preferred embodiments, the ratio of the first organic solvent to compound I can be 1 to 15:1, for example, 2 to 10:1.

[0030] In the method for preparing the salt of compound I provided by the present invention, the molar ratio of compound I to the inorganic or organic acid can be 1:1 to 5, for example, about 1:1, about 1:1.5, about 1:2, about 1:2.5, about 1:3, about 1:3.5, about 1:4, about 1:4.5, about 1:5, or any combination of molar ratios within a certain range. In some preferred embodiments, the molar ratio of compound I to the inorganic or organic acid can be 1:1.5 to 3.5.

[0031] Furthermore, the method for preparing the hydrochloride crystal form A of compound I provided by the present invention includes: adding HCl to a mixture of compound I and the first organic solvent at 0-20°C, raising the temperature to 40-80°C after the addition is complete to form a salt, and then cooling the temperature to -5-10°C to crystallize, thereby obtaining the crystal form A. In some preferred embodiments, the HCl can be a hydrochloric acid solution with a mass concentration of 10-36%, or it can be hydrogen chloride gas.

[0032] Furthermore, the method for preparing the hydrochloride crystal form A of compound I provided by the present invention includes: adding hydrochloric acid solution (e.g., with a mass concentration of 10-36%) dropwise to a mixture of compound I and the first organic solvent at 0-20°C (e.g., 5-10°C), raising the temperature to 40-80°C (e.g., 50-60°C) to form a salt (e.g., 0.5-3h), and then cooling the temperature to -5-10°C (e.g., 0-5°C) to crystallize, thereby obtaining the crystal form A.

[0033] A third aspect of the present invention provides the use of a salt of compound I as described in any of the above-described technical solutions, or a salt of compound I obtained by any of the above-described technical solutions as an intermediate in the preparation of vibergron.

[0034] The fourth aspect of the present invention provides a method for preparing vibergron, wherein, in the presence of a condensing agent, a salt of compound I as described in any one of the above technical solutions, or a salt of compound I obtained by the preparation method as described in any one of the above technical solutions, undergoes a condensation reaction with compound II as shown in formula (3) to obtain vibergron.

[0035]

[0036] In the preparation method of vebergerone provided by this invention, the salt of compound I can adopt crystal form A as described in any of the above technical solutions, and the reaction formula is as follows:

[0037]

[0038] In the preparation method of Vibergron provided by the present invention, the condensing agent can be one or more of the condensing agents commonly used in the art, such as EDCI (1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride), CDI (N,N'-carbonyldiimide), DCC (dicyclohexylcarbodiimide), T3P (1-n-propylphosphoric anhydride, PPACA), HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate), HBTU (benzotriazole-N,N,N,N-tetramethylurea hexafluorophosphate), and HOBT (1-hydroxybenzotriazole).

[0039] In the method for preparing veberbergron provided by this invention, the molar ratio of the salt of compound I to the condensing agent can be 1:1 to 3. In some preferred embodiments, the molar ratio of the salt of compound I to the condensing agent can be 1:1 to 1.5, for example, 1:1.1 to 1.2.

[0040] In the method for preparing veberbergron provided by this invention, the molar ratio of the salt of compound I to compound II can be 1:1 to 3. In some preferred embodiments, the molar ratio of the salt of compound I to compound II can be 1:1 to 2, for example, 1:1 to 1.5.

[0041] In the method for preparing veberbergron provided by this invention, the reaction temperature of the condensation reaction can be 0–15°C. In some preferred embodiments, the reaction temperature of the condensation reaction can be 0–5°C.

[0042] The method for preparing vebegenin provided by this invention may further include the following steps:

[0043] S1: In the presence of a condensing agent, the salt of compound I undergoes a condensation reaction with compound II in a first mixed solvent;

[0044] S2: After the condensation reaction is completed, the pH of the reaction system is adjusted to 10-14, and the crude wet product of Vibergron is obtained; and

[0045] S3: Recrystallize the crude wet Vibergron using a second mixed solvent to obtain Vibergron.

[0046] In the preparation method of Vibergron provided by the present invention, the first mixed solvent and the second mixed solvent can each be a mixture of water and a second organic solvent independently, that is, the first mixed solvent and the second mixed solvent can be the same or different.

[0047] In the method for preparing vebergellon provided by this invention, the second organic solvent can be a C1-C6 aliphatic saturated monohydric alcohol. In some preferred embodiments, the second organic solvent can be one or more of methanol, ethanol, and isopropanol.

[0048] In the method for preparing vebergellon provided by this invention, the volume ratio of the second organic solvent to the water can be 1:0.5 to 2. In some preferred embodiments, the volume ratio of the second organic solvent to the water can be 1:0.8 to 1.2, for example, 1:1.

[0049] In the method for preparing vebegenin provided by this invention, in step S2, an alkaline solution with a mass concentration of 5-30% can be used to adjust the pH value of the reaction system. In some preferred embodiments, the alkaline solution can be an aqueous solution of one or more of NaOH, LiOH, and KOH.

[0050] In the preparation method of vilbergerone provided by the present invention, the recrystallization process in step S3 may include: dissolving the crude wet vilbergerone in the second mixed solvent at 50-80°C (e.g., 60-65°C) and keeping it at that temperature (e.g., 0.5-2h), then cooling it to -5-10°C (e.g., 0-5°C) and keeping it at that temperature (e.g., 0.5-2h), separating the precipitated solid, and drying it to obtain the refined vilbergerone.

[0051] In the preparation method provided by the present invention, the desired material can be obtained through a separation step, such as separating crystals or solids. The separation equipment or method can be common in the art, including but not limited to natural sedimentation, (atmospheric pressure or vacuum) filtration, centrifugation and other common equipment.

[0052] The technical solution provided by this invention has the following advantages:

[0053] (1) The salt of compound I provided by the present invention can be used as a key intermediate for the preparation of vibergren. The target product obtained has high yield and good purity, and the process can be simplified. Therefore, the route of preparing vibergren by using the salt of compound I as an intermediate has higher production efficiency and stronger operability, and is therefore more suitable for industrial production.

[0054] (2) The preparation process of the salt of compound I provided by the present invention is simple, the conditions are mild and easy to control, the raw materials are cheap and readily available, the salt yield is high and the purity is good, and it will not increase the production cost of Vibergron. Therefore, it is of great significance for the expansion of Vibergron production and application. Attached Figure Description

[0055] Figure 1 The hydrochloride of compound I prepared in Example 1 1 HNMR spectrum;

[0056] Figure 2 The XRD pattern of compound I hydrochloride prepared in Example 1;

[0057] Figure 3 The DSC spectrum of compound I hydrochloride prepared in Example 1;

[0058] Figure 4 Vibergron prepared in Example 10 1 HNMR spectrum. Detailed Implementation

[0059] The technical solution of the present invention will be further described in detail below with reference to specific embodiments.

[0060] In the embodiments of the present invention, compound I was prepared according to patent document WO 2013062881A1, using isopropyl acetate and n-heptane crystallization instead of the steps of 2-propanol exchange concentration and the addition of water and i-11 hemihydrate seed crystals for crystallization in the patent document. Unless otherwise specified, all other raw materials or reagents used were commercially available products.

[0061] Unless otherwise specified, the detection equipment and conditions used in the embodiments and comparative examples of the present invention are common detection equipment and conditions in the art.

[0062] Unless otherwise specified, all percentages used in the embodiments and comparative examples of this invention are mass percentages.

[0063] Example 1: Preparation of Compound I Hydrochloride

[0064] 15 g of compound I (0.053 mol) and 60 mL of methanol were added sequentially to a reaction flask. 16.2 g of 36% HCl (0.16 mol) was added dropwise. During the addition of hydrochloric acid, the temperature of the reaction system was maintained at 5–10 °C. After the hydrochloric acid was completely added, the temperature was raised to 50–60 °C and maintained for 1 hour to fully form the salt. The solution was then cooled to 0–5 °C, crystallized, filtered, and dried to obtain 17.24 g of compound I hydrochloride. The yield was 91.4%, the HPLC purity was 99.1%, and the chiral purity was 99.2%.

[0065] The compound I hydrochloride obtained in this embodiment is crystal form A. 1 HNMR spectra as follows Figure 1 As shown, the XRD pattern is as follows Figure 2 As shown, the DSC spectrum is as follows Figure 3 As shown.

[0066] Example 2 Preparation of Compound I Hydrochloride

[0067] 15 g of compound I (0.053 mol) and 30 mL of ethanol were added sequentially to a reaction flask, followed by the dropwise addition of 16.2 g of 36% HCl (0.16 mol). During the dropwise addition of hydrochloric acid, the temperature of the reaction system was maintained at 0–5 °C. After the hydrochloric acid was completely added, the temperature was raised to 50–60 °C and maintained for 1 hour to fully form the salt. Then, the temperature was lowered to -5–0 °C for crystallization, filtered, and dried to obtain 17.59 g of compound I hydrochloride. The yield was 93.2%, the HPLC purity was 99.6%, and the chiral purity was 99.5%.

[0068] pass 1 A comparison of HNMR, XRD, and DSC spectra shows that the compound I hydrochloride prepared in this embodiment is crystal form A.

[0069] Example 3 Preparation of Compound I Hydrochloride

[0070] 15 g of compound I (0.053 mol) and 150 mL of isopropanol were added sequentially to a reaction flask, followed by the dropwise addition of 16.2 g of 36% HCl (0.16 mol). During the dropwise addition of hydrochloric acid, the temperature of the reaction system was maintained at 15–20 °C. After the hydrochloric acid was completely added, the temperature was raised to 40–50 °C and maintained for 1 hour to fully form the salt. Then, the temperature was lowered to 0–5 °C for crystallization, filtered, and dried to obtain 18.19 g of compound I hydrochloride. The yield was 96.1%, the HPLC purity was 99.5%, and the chiral purity was 99.6%.

[0071] pass 1 A comparison of HNMR, XRD, and DSC spectra shows that the compound I hydrochloride prepared in this embodiment is crystal form A.

[0072] Example 4: Preparation of L-tartrate of Compound I

[0073] 15 g of compound I (0.053 mol), 45 mL of methanol, and 16.5 g of L-tartaric acid (0.11 mol) were added sequentially to a reaction flask. After the addition was completed, the mixture was stirred and heated to 70–80 °C, and kept at this temperature for 1 hour to fully form a salt. Then, the mixture was cooled to 5–10 °C to crystallize, filtered, and dried to obtain 28.9 g of L-tartaric acid salt of compound I. The yield was 93.5%, the HPLC purity was 97.6%, and the chiral purity was 98.7%.

[0074] Example 5: Preparation of D-tartrate of Compound I

[0075] 15 g of compound I (0.053 mol), 45 mL of methanol, and 16.5 g of D-tartaric acid (0.11 mol) were added sequentially to a reaction flask. After the addition was completed, the mixture was stirred and heated to 70–80 °C, and kept at this temperature for 1 hour to fully form a salt. Then, the mixture was cooled to 5–10 °C to crystallize, filtered, and dried to obtain 29.5 g of D-tartaric acid salt of compound I. The yield was 95.7%, the HPLC purity was 98.4%, and the chiral purity was 98.2%.

[0076] Example 6 Preparation of D-maleate of compound I

[0077] 18 g of compound I (0.064 mol), 45 mL of methanol, and 11.8 g of D-maleic acid (0.102 mol) were added sequentially to a reaction flask. After the addition was completed, the mixture was stirred and heated to 50–60 °C, and kept at this temperature for 1 hour to fully form a salt. Then, the mixture was cooled to 0–5 °C to crystallize, filtered, and dried to obtain 31.6 g of D-maleic acid salt of compound I. The yield was 96.2%, the HPLC purity was 98.7%, and the chiral purity was 99.1%.

[0078] Example 7 Preparation of L-malate of Compound I

[0079] 14.1 g of compound I (0.05 mol), 45 mL of methanol, and 13.7 g of L-malic acid (0.102 mol) were added sequentially to a reaction flask. After the addition was completed, the mixture was stirred and heated to 60–70 °C, and kept at this temperature for 1 hour to fully form a salt. Then, the mixture was cooled to 0–5 °C to crystallize, filtered, and dried to obtain 25.8 g of L-malate of compound I. The yield was 94.1%, the HPLC purity was 98.4%, and the chiral purity was 99.6%.

[0080] Example 8: Preparation of D-malate of Compound I

[0081] 14.1 g of compound I (0.05 mol), 45 mL of methanol, and 13.7 g of D-malic acid (0.102 mol) were added sequentially to a reaction flask. After the addition was completed, the mixture was stirred and heated to 60–70 °C, and kept at this temperature for 1 hour to fully form a salt. Then, the mixture was cooled to 0–5 °C to crystallize, filtered, and dried to obtain 26.2 g of D-malate of compound I. The yield was 95.4%, the HPLC purity was 99.2%, and the chiral purity was 99.1%.

[0082] Example 9: Preparation of D-mandelate of Compound I

[0083] 16 g of compound I (0.05 mol), 45 mL of methanol, and 38.0 g of D-mandelic acid (0.25 mol) were added sequentially to a reaction flask. After the addition was completed, the mixture was stirred and heated to 50–60 °C, and kept at this temperature for 1 hour to fully form a salt. Then, the mixture was cooled to 0–5 °C to crystallize, filtered, and dried to obtain 31.4 g of D-mandelic acid salt of compound I. The yield was 94.5%, the HPLC purity was 97.9%, and the chiral purity was 98.3%.

[0084] Example 10: Preparation of Vibergron

[0085] 13.0 g of compound I hydrochloride (36.6 mmol), 8.14 g of compound II (40.26 mmol), 52 mL of isopropanol, and 52 mL of water were added sequentially to a reaction flask. The mixture was cooled to 0–5 °C, and 8.4 g of EDCI (43.92 mmol) was added in portions. The reaction was allowed to proceed for 2 hours. After the condensation reaction was complete, 10% KOH aqueous solution was added dropwise to adjust the pH to 12–14. The mixture was then filtered to obtain crude wet vibergren. The obtained crude wet vibergren, 52 mL of water, and 52 mL of isopropanol were added to a reaction flask. The mixture was stirred and heated to 60–65 °C and maintained at this temperature for 1 hour. The temperature was then lowered to 0–5 °C and maintained at this temperature for 1 hour. The mixture was filtered and dried to obtain 15.0 g of vibergren, with a yield of 92.6%, HPLC purity of 99.6%, and chiral purity of 99.9%. 1 HNMR spectra as follows Figure 4 As shown.

[0086] Example 11 Preparation of Vibergron

[0087] 13.0 g of compound I hydrochloride (36.6 mmol), 22.2 g of compound II (109.8 mmol), 52 mL of methanol, and 52 mL of water were added sequentially to a reaction flask. The mixture was cooled to 0–5 °C, and 32.6 g of T3P (102.4 mmol) was added in portions. The reaction was allowed to proceed for 2 hours. After the condensation reaction was complete, a 10% NaOH aqueous solution was added dropwise to adjust the pH to 12–14. The mixture was then filtered to obtain crude wet vibergren. The obtained crude wet vibergren, 52 mL of water, and 52 mL of methanol were added to a reaction flask. The mixture was stirred and heated to 60–65 °C and maintained at this temperature for 1 hour. The temperature was then lowered to 0–5 °C and maintained at this temperature for 1 hour. The mixture was filtered and dried to obtain 14.8 g of vibergren, with a yield of 91.4%, HPLC purity of 99.8%, and chiral purity of 99.9%.

[0088] Example 12 Preparation of Vibergron

[0089] 13 g of compound I hydrochloride (36.6 mmol), 8.14 g of compound II (40.26 mmol), 52 mL of ethanol, and 52 mL of water were added sequentially to a reaction flask. The mixture was cooled to 0–5 °C, and 14.6 g (38.43 mmol) of HATU was added in portions. The reaction was allowed to proceed for 2 hours. After the condensation reaction was complete, a 10% LiOH aqueous solution was added dropwise to adjust the pH to 12–14. The mixture was then filtered to obtain crude wet vibergron. The obtained crude wet vibergron, 52 mL of water, and 52 mL of ethanol were added to a reaction flask, stirred, and heated to 60–65 °C. The mixture was kept at this temperature for 1 hour, then cooled to 0–5 °C and kept at this temperature for 1 hour. The mixture was filtered and dried to obtain 14.9 g of vibergron. The yield was 91.8%, the HPLC purity was 99.5%, and the chiral purity was 99.9%.

[0090] Preparation of Vibergron in Examples 13-18

[0091] Except for replacing compound I hydrochloride with equimolar amounts of L-tartrate, D-tartrate, D-maleate, L-malate, D-malate, and D-mandelate of compound I, the preparation process was the same as in Example 10. The final yield, HPLC purity, and chiral purity of Vibergron are shown in Table 1.

[0092] Table 1. Yields and purity of the target product, vebeguron, in Examples 13-18.

[0093] Example raw material Yield (%) HPLC purity (%) Chiral purity (%) Example 13 L-Tartrate 82.9％ 99.4％ 99.4％ Example 14 D-Tartrate 84.7％ 99.3％ 99.1％ Example 15 D-maleate 80.4％ 99.2％ 99.2％ Example 16 L-malate 79.6％ 99.7％ 99.5％ Example 17 D-malate 81.2％ 99.3％ 99.3％ Example 18 D-Mandrine 76.3％ 99.6％ 99.6％

[0094] Comparative Example

[0095] Referring to patent document WO 2013062881A1, some of the preparation steps are as follows:

[0096]

[0097] 0.605 g of 5% platinum / alumina, 32 mL of THF, and 86 mL of THF solution containing 12.0 g of i-10 compound (10.95 g of hexamethyldiazane) were added sequentially to an autoclave. After hydrogenation at room temperature, the mixture was filtered. The filtrate was treated with 0.5 M hydrochloric acid, and the aqueous phase was separated. After treatment with IPAc and 5 N sodium hydroxide, the organic phase was separated. The organic phase was filtered through Solka Floc, concentrated, and concentrated by exchange with 2-propanol. Water and i-11 hemihydrate seed crystals were added, and the mixture was stirred at 41–43 °C for 1 h. After cooling, the mixture was filtered and dried to obtain 6.84 g of i-11 hemihydrate, with a yield of 72.6%.

[0098]

[0099] 10.0 g of i-11 hemihydrate, 7.87 g of i-12 compound, 40 mL of IPA, and 24 mL of water were added sequentially to a reaction flask. The pH was adjusted to 3.3–3.5 with 14.9 mL of 5N HCl. After adjustment, 7.47 g of EDC hydrochloride was added in portions. After the condensation reaction was completed, the pH was adjusted with 53.2 mL of 14% ammonia. The mixture was filtered and dried to obtain 14.3 g of crude wet product of compound (I) (Vibergron). The obtained crude wet product, 40 mL of water, and 40 mL of methanol were added to a reaction flask. The mixture was stirred and heated to 60–65 °C and kept at this temperature for 1 hour. Then, the temperature was lowered to 0–5 °C and kept at this temperature for 1 hour. The mixture was filtered and dried to obtain 11.16 g of Vibergron. Yield: 73.15%, HPLC purity: 99.18%, chiral purity: 99.5%.

[0100] Unless otherwise specified, the terms used in this invention have the meanings commonly understood by those skilled in the art.

[0101] The embodiments described in this invention are for illustrative purposes only and are not intended to limit the scope of protection of this invention. Those skilled in the art can make various other substitutions, changes and improvements within the scope of this invention. Therefore, this invention is not limited to the above embodiments, but is only defined by the claims.

Claims

1. A salt of compound I as shown in formula (1), characterized in that, The salt of compound I is an inorganic acid salt or an organic acid salt of compound I.

2. The salt of compound I according to claim 1, characterized in that, The salt of compound I is a salt formed by compound I with one or more of the following acids: HF, HCl, HBr, L-tartaric acid, D-tartaric acid, D-maleic acid, L-malic acid, D-malic acid, or D-mandelic acid.

3. The salt of compound I according to claim 1 or 2, characterized in that, The salt of compound I is the hydrochloride salt of compound I as shown in formula (2); Preferably, the compound I hydrochloride is crystal form A, and its X-ray powder diffraction pattern has characteristic peaks at the following diffraction angles 2θ: 7.28±0.2°, 8.68±0.2°, 10.41±0.2°, 11.67±0.2°, 12.47±0.2°, 14.49±0.2°, 15.82±0.2°, 16.39±0.2°, 17.41±0.2°, 18.00±0.2°, 18.76±0.2°, 22.80±0.2°, 23.32±0.2°, 24.54±0.2°, 25.51±0.2°, 29.00±0.2°, 29.54±0.2°; More preferably, the X-ray powder diffraction pattern of crystal form A has characteristic peaks at the following diffraction angles 2θ: 7.28±0.2°, 8.68±0.2°, 10.41±0.2°, 11.67±0.2°, 12.47±0.2°, 14.49±0.2°, 15.82±0.2°, 16.39±0.2°, 17.41±0.2°, 18.00±0.2°, 18.76±0.2°, 19.25±0.2°, 20.44±0.2°, 20.79±0.2°, 21.73±0.2°, and 22.80±0.2°. 23.32±0.2°, 24.54±0.2°, 25.51±0.2°, 26.77±0.2°, 27.92±0.2°, 28.66±0.2°, 29.00±0.2°, 29.54±0.2°, 30.48±0.2°, 31.34±0.2°, 31.80±0.2°, 32.81±0.2°, 34.31±0.2°, 34.72±0.2°, 35.43±0.2°, 36.34±0.2°, 37.25±0.2°, 38.20±0.2°, 39.03±0.2°; More preferably, the X-ray powder diffraction pattern of crystal form A is shown in Figure 2.

4. A method for preparing the salt of compound I according to any one of claims 1-3, characterized in that, The preparation method includes: in a first organic solvent, the compound I and the inorganic acid or organic acid are salted at 40-80°C, and then the temperature is lowered to -5-10°C for crystallization, thereby obtaining the inorganic acid salt or organic acid salt of the compound I; Preferably, the first organic solvent is a C1-C6 aliphatic saturated monohydric alcohol, preferably one or more of methanol, ethanol, and isopropanol; More preferably, the ratio of the first organic solvent to compound I is 1 to 30:1 (volume-to-mass ratio, mL / g), preferably 2 to 10:1; Preferably, the molar ratio of compound I to the inorganic or organic acid is 1:1 to 5.

5. The preparation method according to claim 4, characterized in that, The salt of compound I is crystal form A, and its preparation method includes: adding HCl to a mixture of compound I and the first organic solvent at 0-20°C, raising the temperature to 40-80°C after the addition is complete to form a salt, and then cooling the temperature to -5-10°C to crystallize, thereby obtaining crystal form A.

6. The preparation method according to claim 5, characterized in that, The HCl is a hydrochloric acid solution with a mass concentration of 10-36% or hydrogen chloride gas; Preferably, the salt formation time is 0.5 to 3 hours.

7. Use of a salt of compound I according to any one of claims 1-3, or a salt of compound I obtained by the preparation method according to any one of claims 4-6, as an intermediate in the preparation of vibergron.

8. A method for preparing veberbergron, characterized in that, In the presence of a condensing agent, the salt of compound I according to any one of claims 1-3, or the salt of compound I obtained by the preparation method according to any one of claims 4-6, undergoes a condensation reaction with compound II as shown in formula (3) to obtain vibergron. Preferably, the salt of compound I is crystal form A.

9. The preparation method according to claim 8, characterized in that, The condensing agent is one or more of EDCI, CDI, DCC, T3P, HATU, HBTU, and HOBT. Preferably, the molar ratio of the salt of compound I to the condensing agent is 1:1 to 3; and / or The molar ratio of the salt of compound I to compound II is 1:1 to 3; and / or The reaction temperature of the condensation reaction is 0–15°C.

10. The preparation method according to claim 8 or 9, characterized in that, The preparation method includes the following steps: S1: In the presence of a condensing agent, the salt of compound I undergoes a condensation reaction with compound II in a first mixed solvent; S2: After the condensation reaction is completed, the pH of the reaction system is adjusted to 10-14, and the crude wet product of Vibergron is obtained; and S3: Recrystallize the crude wet Vibergron using a second mixed solvent to obtain Vibergron; Preferably, the first mixed solvent and the second mixed solvent are each independently a mixture of water and a second organic solvent, wherein the second organic solvent is a C1-C6 aliphatic saturated monohydric alcohol, preferably one or more of methanol, ethanol, and isopropanol; more preferably, the volume ratio of the second organic solvent to the water is 1:0.5-2; and / or Preferably, in step S2, an alkaline solution with a mass concentration of 5-30% is used to adjust the pH value of the reaction system; more preferably, the alkaline solution is an aqueous solution of one or more of NaOH, LiOH, and KOH.

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