A method for resolving an intermediate of ozamod hydrochloride and a method for preparing ozamod hydrochloride.

Abstract

This application discloses a method for resolving an intermediate of ozamod hydrochloride, which includes the following steps: a pretreatment step: mixing a racemic mixture of 1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indene-4-carboxynitrile with an organic solvent and refluxing the mixture to obtain a reflux solution; a crystallization step: adding a resolving agent to the reflux solution to induce a salt formation reaction, stirring, and preliminarily crystallizing, wherein the resolving agent is selected from one of S-naphthol phosphate, tartaric acid, dibenzoyl tartaric acid, and di-p-methylbenzoyl tartaric acid; a posttreatment step: cooling, filtering, and drying to obtain (S)-1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indene-4-carboxynitrile salt; and a desalting step: converting the above acid salt into (S)-1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indene-4-carboxynitrile. The method for resolving the intermediate of ozamado hydrochloride of the present invention produces a chiral substance with extremely high chiral purity and ee value, and greatly improves the yield, making it suitable for large-scale industrial production.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical chemical synthesis technology, specifically relating to a method for resolving ozamod hydrochloride intermediates, and the application of this resolving method. Background Technology

[0002] Ozanimod hydrochloride (sometimes abbreviated as "YAZ"), with the molecular formula C0, has the following properties: 23 H 25 ClN4O3, molecular weight: 440.93, CAS number: 1306760-87-1, structural formula:

[0003]

[0004] Ozamod hydrochloride was originally developed by Receptos Inc., a US biopharmaceutical company, and marketed under the brand name Zeposia. It is used to treat ulcerative colitis and is a drug for the treatment of multiple sclerosis.

[0005] Patent CN102762100B reports a method for preparing ozamod hydrochloride. This patent describes a process using 4-bromo-indanone as a starting material, with zinc cyanide as a reagent, to obtain 4-cyano-1-indanone via cyanidation. This intermediate is then condensed with (R)-(+)-2-methyl-2-propylsulfinamide to generate an imine intermediate. The chirality of the sulfonamide is then used for inductive control, followed by hydrolysis of the sulfinyl group under strong acid conditions to obtain a chiral amino derivative. This derivative is then protected and subjected to nucleophilic substitution to obtain the next intermediate. A Schiff base intermediate is then obtained using sodium hydride, and finally, the final product is obtained through condensation and deprotection (route shown in Formula 1 below).

[0006]

[0007] The disadvantages of this route include: the overall reaction steps are relatively long, resulting in a long product production cycle; the zinc cyanide reagent used in the first step is highly toxic and poses a great threat to human health; the second step requires anhydrous and oxygen-free conditions, as well as ultra-low temperature reduction of chiral centers, which places high demands on process operation and equipment; the sixth step uses sodium hydride, which has poor reaction safety and is prone to explosion; finally, the product obtained by this method has low chiral purity and a low overall yield.

[0008] Ningbo Aino Medical Technology Co., Ltd.'s patent CN108727291A uses 4-cyano-1-indanone as a raw material and, in the presence of a catalyst, undergoes an asymmetric reduction reaction with aminoethanol to prepare (S)-1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indan-4-carboxynitrile. It was also reported that the condensation with aminoethanol and reduction by a reducing agent (boronide, lithium aluminum hydride, or hydrogen) yielded a racemic mixture of 1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indene-4-carboxynitrile, which was then subjected to a chiral acid to give the compound (S)-1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indene-4-carboxynitrile (wherein the chiral resolving agent, i.e., the chiral acid, was D-mandelic acid, D-tartaric acid, D-camphor sulfonic acid, D-lactic acid, D-malic acid, D-glutamic acid, or diacetone-L-gulonic acid; Example 2 specifically disclosed that the purity (related substances) of the compound of formula III obtained after resolution was 99%, and the yield was 35%). Subsequently, the amino and hydroxyl groups were protected with acetone fork to obtain (S)-1-(2,2-dimethyloxadiazol-3-yl)-2,3-dihydro-1H-indene-4-carboxynitrile; then, it underwent an amide oxime reaction with hydroxylamine hydrochloride to give compound (S)-1-(2,2-dimethyloxadiazol-3-yl)-N-hydroxy-1H-indene-4-mercaptooxime, and then compound (S)-1-(2,2-dimethyloxadiazol-3-yl)-N-hydroxy-1H-indene-4-mercaptooxime and compound 3-cyano-4-isopropoxybenzoic acid to give an intermediate. Finally, the final product was obtained by ring-opening and deprotection (route shown in Formula 2 below):

[0009]

[0010] The advantages of this route include: shortening the synthesis steps of Ozanimod (only 5-6 reaction steps), reducing the product production cycle; improving the overall yield and quality of the product; mild reaction conditions in the route, avoiding anhydrous and oxygen-free operation steps, reducing equipment and operation requirements; and an environmentally friendly and safe production process, suitable for industrial production. However, the disadvantage is that the chiral purity of the chiral resolution is generally lower.

[0011] Patent IN201741031729 reports a method using 4-cyano-1-indanone as a starting material, reducing it with sodium borohydride to obtain 4-cyano-1-indanol, then substituting it with thionyl chloride to obtain 1-chloro-2,3-dihydro-1H-indan-4-carboxynitrile. Then, 1-chloro-2,3-dihydro-1H-indan-4-carboxynitrile and ethanolamine undergo a substitution reaction to obtain a racemic 1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indan-4-carboxynitrile. Finally, 1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indan- The racemic 4-carboxynitrile was resolved by chiral acids to yield (S)-1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indene-4-carboxynitrile (the chiral acids mentioned include tartaric acid, dibenzoyl tartaric acid, di-p-methylbenzoyl tartaric acid, camphorsulfonic acid, glutamic acid, malic acid, mandelic acid, pyroglutamic acid, and valine); then (S)-1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indene-4-carboxynitrile underwent Boc protection, amidoxime reaction, condensation reaction, and deprotection to give the final product (route shown in Formula 3 below):

[0012]

[0013] The advantages of this route include: shortening the synthesis steps of Ozanimod (only 5-6 steps), reducing the product production cycle; improving the overall yield and quality of the product; mild reaction conditions, avoiding anhydrous and oxygen-free operation steps, reducing equipment and operational requirements; and an environmentally friendly and safe production process, suitable for industrial production. The disadvantages of this route include: when using thionyl chloride for substitution followed by chlorination and then for substitution with ethanolamine, it is difficult to control the reaction endpoint, resulting in the formation of disubstituted ethanolamine impurities, difficulty in controlling the purity of the intermediate, and low yield and chiral purity of the obtained chiral product (Example-2d discloses an HPLC chiral purity of "89.62%" for the target product), and this derivatization continues to the final product. Therefore, controlling the final product is quite challenging.

[0014] The aforementioned patents all mention the resolution of the racemic mixture of 1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indene-4-carboxynitrile by chiral acid, but these resolution methods are not effective. Summary of the Invention

[0015] In view of the problems existing in the prior art, the present invention provides a method for resolving ozamod hydrochloride intermediates and its application. This method uses a specific resolution technique for chiral resection, which not only has good safety and low resection cost, but also produces extremely high purity (ee value, optical purity) of the target chiral substance, while significantly increasing the yield, making it suitable for large-scale industrial production.

[0016] 1. This invention relates to a method for resolving an intermediate of ozamod hydrochloride, comprising the following steps in sequence:

[0017] Pretreatment step: The racemic mixture of 1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indene-4-carboxynitrile shown in chemical formula 1 below is mixed with an organic solvent and heated to reflux to obtain a reflux liquid;

[0018] Crystallization process: Add a resolving agent to the above reflux liquid to carry out a salt formation reaction, stir, and initially crystallize. The above resolving agent is selected from one of S-binaphthol phosphate, tartaric acid, dibenzoyl tartaric acid, and di-p-methylbenzoyl tartaric acid.

[0019] Post-processing steps: Cooling, filtration and drying to obtain (S)-1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indene-4-carboxynitrile salt as shown in the following chemical formula 2, wherein M represents the anion of an acid selected from S-binaphthol phosphate, tartaric acid, dibenzoyl tartaric acid and di-p-methylbenzoyl tartaric acid;

[0020] Salt desalting process: The above (S)-1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indene-4-carboxylate is converted into the following chemical...

[0021] Formula 3 shows (S)-1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indene-4-carboxynitrile.

[0022]

[0023] 2. According to the resolution method in 1 above, the resolving agent is S-binaphthol phosphate.

[0024] 3. According to the separation method of 1 or 2 above, wherein the organic solvent is selected from at least one of methanol, ethanol, isopropanol, acetonitrile, acetone, and tetrahydrofuran.

[0025] 4. According to the resolution methods 1 to 3 above, the liquid-to-solid ratio (ml / g) of the organic solvent to the racemic 1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indene-4-carboxynitrile is 3 to 100:1, further to 5 to 55:1, even further to 10 to 55:1, and still even further to 10 to 50:1.

[0026] 5. According to the resolution methods 1 to 3 above, wherein the molar equivalent ratio of the resolving agent to the racemic 1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indene-4-carboxynitrile is 0.10 to 1.00:1, further 0.3 to 0.75:1, and even further 0.3 to 0.5:1.

[0027] 6. According to the splitting method described in 1 to 3 above, in the above pretreatment process, the heat preservation time of the reflux is 10 min to 10 h, and further 0.5 h to 5 h.

[0028] 7. According to the separation methods 1 to 3 above, in the above crystallization process, after the initial crystallization, the system is stirred for 2 to 5 hours while being cooled to -30°C to 30°C for secondary crystallization.

[0029] 8. According to the splitting method in 7 above, the crystallization temperature of the secondary crystallization is -10℃ to -5℃.

[0030] 9. According to the splitting methods 1 to 3 above, in the above post-processing steps, the drying temperature is 30℃ to 80℃.

[0031] 10. A method for preparing ozamod hydrochloride, the method comprising resolving and desalting a racemic mixture of 1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indene-4-carboxynitrile as shown in Formula 1 below into (S)-1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indene-4-carboxynitrile as shown in Formula 3 below, wherein the resolving agent used for resolving is one of the resolving agents described in 1 to 9 above.

[0032]

[0033] Specifically:

[0034] The racemic structure of the 1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-inden-4-carboxynitrile involved in this invention is as follows:

[0035]

[0036] The racemic form of the above chemical formula (1) exists in two structures: the S configuration (chemical formula (3), (S)-1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indene-4-carboxynitrile, hereinafter referred to as "S configuration YAZ-1") and the R configuration (chemical formula (4), (R)-1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indene-4-carboxynitrile, hereinafter referred to as "R configuration YAZ-1"):

[0037]

[0038] The technical solution of the present invention is as follows: The present invention provides a method for resolving the intermediate of ozamod hydrochloride, wherein 1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indene-4-carboxynitrile (hereinafter referred to as "YAZ-1") is reacted with a resolving agent to form a salt, and then crystallized at a certain temperature to obtain the S-configuration YAZ-1 salt. Then, the S-configuration YAZ-1 salt is converted into the target chiral substance to be resolved, namely the S-configuration YAZ-1, through a reaction.

[0039] As a specific mixing method for the above-mentioned YAZ-1 and the above-mentioned resolving agent, it is preferable to pre-treat YAZ-1 before reacting it with the resolving agent to form a salt.

[0040] Preferably, the pretreatment step involves adding YAZ-1 to an organic solvent beforehand and then heating and refluxing.

[0041] The liquid-to-solid ratio (in ml / g) of the organic solvent to YAZ-1 is 3 to 100:1, more preferably 5 to 55:1, further preferably 10 to 55:1, and even more preferably 10 to 50:1. Specifically, it can be, for example, 3:1, 5:1, 10:1, 15:1, 20:1, 30:1, 40:1, 50:1, 55:1, 60:1, 80:1, 90:1, 100:1, etc., but is not limited thereto. When the liquid-to-solid ratio is too large, the yield of the obtained S-configuration YAZ-1 salt tends to decrease; when the liquid-to-solid ratio is too small, the content of the S-configuration obtained by resolution tends to be relatively small, while the content of the R-configuration increases.

[0042] Examples of organic solvents mentioned above include methanol, ethanol, isopropanol, acetonitrile, acetone, and tetrahydrofuran, but these are not limited to them. Methanol, ethanol, and isopropanol are preferred.

[0043] The temperature for the above-mentioned heating and reflux is usually 50 to 70°C, preferably 50 to 65°C, more preferably 60 to 65°C, but is not limited thereto.

[0044] As one specific implementation method of the above pretreatment process, one example is to stir 100 ml of methanol with 0.00 g of YAZ-11, then heat it to 50-70°C and reflux it for 0.5-5 hours until the system becomes clear and turns into an orange-yellow liquid, but it is not limited to this.

[0045] After the above pretreatment of YAZ-1, a resolving agent was added to the solution.

[0046] The resolving agent can be selected from one of S-binaphthol phosphate, tartaric acid, dibenzoyl tartaric acid, and di-p-methylbenzoyl tartaric acid, but is not limited to this. From the perspective of chiral purity, ee value and yield, S-binaphthol phosphate and tartaric acid are preferred, and S-binaphthol phosphate is even more preferred.

[0047] The molar equivalent ratio of the added resolving agent to YAZ-1 is typically 0.10 to 1.00:1, more preferably 0.3 to 0.75:1, and even more preferably 0.3 to 0.5:1. Specifically, for example, 0.10:1, 0.20:1, 0.30:1, 0.40:1, 0.50:1, 0.60:1, 0.70:1, 0.80:1, 0.90:1, 1.00:1, but it is not limited to these. If the molar equivalent ratio is too small, the salt formation will be insufficient and the yield will be low. If the molar equivalent ratio is too large, the chiral purity and ee value will be greatly reduced.

[0048] After adding a resolving agent such as S-binaphthol phosphate to the system, preliminary crystallization is performed beforehand, that is, a large amount of off-white solid gradually precipitates out of the system. It is preferable to keep the system at a constant temperature and stir it.

[0049] The holding time for the above-mentioned crystallization process is typically 10 min to 10 h, more preferably 10 min to 5 h, and even more preferably 0.5 h to 5 h, specifically for example: 10 min, 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, and 10 h. If the holding time is too short, complete salt formation will not be possible, resulting in a low yield.

[0050] After the above stirring, the system can be cooled and stirred again to induce secondary crystallization.

[0051] The crystallization temperature range for the aforementioned cooling is typically 30°C to -30°C, preferably -15°C to -5°C, more preferably -10°C to -5°C, but is not limited thereto.

[0052] The time for the secondary crystallization mentioned above is usually 30 min to 10 h, preferably 1 h to 10 h, more preferably 2 h to 5 h, and most preferably 2 h, but is not limited thereto.

[0053] As one specific implementation of the above crystallization process, it can be listed that after the aforementioned pretreatment step, the system is slowly cooled to -10 to -5℃ (crystallization temperature), stirred for 2 hours to crystallize, filtered, and the filter cake is collected, but it is not limited to this.

[0054] Following the crystallization process described above, a post-processing step is performed.

[0055] The post-processing step yields S-configuration YAZ-1 salt, which refers to the salt obtained by reacting S-configuration YAZ-1 with a resolving agent. When these resolving agents are acids, the salt formed is an acid salt formed by YAZ-1 and these acids. This salt is represented by the following chemical formula (2):

[0056] (Where M represents the anion of an acid selected from S-binaphthol phosphate, tartaric acid, dibenzoyl tartaric acid, and di-p-methylbenzoyl tartaric acid, but is not limited to these.)

[0057] As specific salts, for example, when the above-mentioned resolving agent uses S-naphthol phosphate, the resulting S-configuration YAZ-1 salt is "S-configuration YAZ-1S-naphthol phosphate"; when the above-mentioned resolving agent uses tartaric acid, the resulting S-configuration YAZ-1 salt is "S-configuration YAZ-1 tartrate"; and when the above-mentioned resolving agent uses dibenzoyl tartaric acid, the resulting S-configuration YAZ-1 salt is "S-configuration YAZ-1 dibenzoyl tartrate". As long as it can form a salt with S-configuration YAZ-1 acid, it is not limited to any of the forms listed in this invention.

[0058] As one specific implementation of this post-processing step, the filter cake can be washed and dried to obtain the final product.

[0059] As an example of the above-mentioned rinsing method, rinsing can be carried out using an organic solvent, such as methanol, ethanol, etc., but is not limited to this.

[0060] As an example of the above-mentioned drying method, blowing drying to constant weight at a drying temperature of 30 to 80°C is one example. The drying temperature is preferably 30 to 50°C, and more preferably 50°C.

[0061] After obtaining (S)-1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indene-4-carboxylate in the above post-processing steps, (S)-1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indene-4-carboxylate can be converted into the following chemical by the above desalting step.

[0062] Formula 3 shows (S)-1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indene-4-carboxynitrile:

[0063]

[0064] As for the specific conversion methods in the above-mentioned desalting process, as long as the salt can be converted into the target compound S configuration YAZ-1, it is not limited to any method. Specifically, for example, the obtained YAZ-1 salt is subjected to Boc protection with Boc anhydride to obtain YAZ-2; YAZ-2 and hydroxylamine hydrochloride undergo a methylamine oxime reaction to obtain YAZ-3; YAZ-3 and 3-cyano-4-isopropoxybenzoic acid undergo a condensation reaction to obtain YAZ-4; YAZ-4 and a methanol solution of hydrogen chloride undergo deBoc protection and salt formation reaction to obtain the YAZ product, but it is not limited to this method.

[0065] The main splitting route of the splitting method of the present invention is as follows:

[0066]

[0067] Furthermore, this invention also relates to a method for preparing ozamod hydrochloride, which includes the step of resolving YAZ-1 into S-configuration YAZ-1 and R-configuration YAZ-1, wherein the resolving agent used for resolution is the resolving agent used in this invention. The method of this invention has good safety, low resolution cost, and produces chiral substances with extremely high chiral purity and ee values, while significantly improving the yield, making it suitable for large-scale industrial production. Attached Figure Description

[0068] Figure 1 The high-performance liquid chromatogram of YAZ-1 salt from Example 1 is shown.

[0069] Figure 2 The high performance liquid chromatogram and related substance detection chromatogram of YAZ-1 salt in Example 1 are shown.

[0070] Figure 3 The liquid chromatography-mass spectrometry (LC-MS) plot of YAZ-1 in Example 1 is shown. Detailed Implementation

[0071] The technical solutions of the embodiments of this application will be clearly described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of this application. All other embodiments obtained by those skilled in the art based on the embodiments of this application are within the scope of protection of this application.

[0072] Example 1:

[0073] Preparation of YAZ-1 salt

[0074] 100 ml of methanol and 10.00 g of YAZ-1 were added to a 250 ml three-necked flask and stirred. The mixture was heated to reflux and maintained at this temperature for 5 hours. The system became clear, presenting as an orange-yellow liquid. 0.50 eq of S-naphthol phosphate was added to the mixture. During stirring, a large amount of off-white solid YAZ-1 salt precipitated from the system. The mixture was then kept at this temperature and stirred for 5 hours. The temperature was then slowly lowered to -5 °C, and crystallization was carried out with stirring for 2 hours. The mixture was filtered, and the filter cake was collected. The filter cake was washed with 30 ml of methanol and then dried in a forced-air oven at 40 °C to obtain 10.62 g of total off-white solid YAZ-1 salt.

[0075] The yield is calculated using the following method:

[0076] [Return]

[0077] The yield is calculated as follows:

[0078] Yield (%) = (m YAZ-1盐 ×MW YAZ-1 ) / (m YAZ-1 ×MW YAZ-1盐 )

[0079] in

[0080] “m YAZ-1盐 "Indicates the mass of YAZ-1 salt"

[0081] MW YAZ-1 "Indicates the molecular weight of YAZ-1"

[0082] “m YAZ-1 "Indicates the feed quality of YAZ-1"

[0083] MW YAZ-1盐 "Indicates the molecular weight of YAZ-1 salt"

[0084] Preparation of S-configuration YAZ-1

[0085] Add 150 ml of ethyl acetate and 10.00 g of YAZ-1 salt to a 250 ml three-necked flask and stir. Then add 100 ml of 2N sodium hydroxide aqueous solution and stir for 2 h. Stop stirring, separate the layers, and collect the upper organic phase. Concentrate the organic phase to dryness under vacuum of -0.10 MPa and at 40 °C to obtain S-configuration YAZ-1.

[0086] The chiral purity and ee value of the obtained S-configuration YAZ-1 were obtained by the following method:

[0087] [Chiral purity]

[0088] The chiral purity of S-configuration YAZ-1 was determined by high-performance liquid chromatography (HPLC).

[0089] Enantiomers: High-performance liquid chromatography (based on the General Rules, Part IV, of the Chinese Pharmacopoeia 2020 Edition)

[0090] Solvent: Methanol-anhydrous ethanol (10:90)

[0091] Test solution: Take an appropriate amount of this product, add solvent, sonicate to dissolve and dilute to prepare a solution containing about 2.0 mg per 1 ml, which is used as the test solution.

[0092] Control solution: Accurately measure an appropriate amount of the test solution and dilute it quantitatively with a solvent to prepare a solution containing approximately 10 μg per ml, which serves as the control solution.

[0093] System suitability solution: Accurately weigh appropriate amounts of R-configuration YAZ-1 and S-configuration YAZ-1, add solvent, sonicate to dissolve and dilute to prepare a mixed solution containing approximately 3 μg of R-configuration YAZ-1 and 2 μg of S-configuration YAZ-1 per 1 ml as the system suitability solution.

[0094] Chromatographic conditions: Use cellulose-3,5-dichlorophenylcarbamate-bonded silica gel as the packing material (recommended: DALCELCHIRPAK IC, 4.6×250mm, 5μm or equivalent column); use n-hexane-anhydrous ethanol-diethylamine (90:10:0.1) as mobile phase A and anhydrous ethanol as mobile phase B; perform gradient elution according to the table below; flow rate is 1.0 mL / min; column temperature is 30℃; detection wavelength is 215 nm; injection volume is 20 μL.

[0095]

[0096] System suitability requirements: In the chromatogram of a 20 μl solution for system suitability, the elution order of each component is S configuration YAZ-1 and R configuration YAZ-1, respectively.

[0097] [ee value]

[0098] The ee value is calculated as follows:

[0099] ee(%) = (S-configuration YAZ-1 – R-configuration YAZ-1) / (S-configuration YAZ-1 + R-configuration YAZ-1)) × 100%

[0100] Thus, the "chiral purity", "ee value" and "yield" of the S-configuration YAZ-1 obtained in Example 1 are shown in Table 1 below.

[0101] also, Figure 1 The high-performance liquid chromatography (HPLC) chromatogram of the YAZ-1 salt from Example 1 is shown. This chromatogram is a HPLC isomer detection chromatogram. Figure 1The peak table shows that the S-configuration product accounted for 98.693%, the R-configuration isomer accounted for 1.307%, that is, the chiral purity was 98.693%, and the ee value was 97.39%. Figure 2 The high-performance liquid chromatography (HPLC) chromatogram and related substance detection chromatogram of YAZ-1 salt in Example 1 are shown. Figure 2 The peak table shows that the principal components account for approximately 99.801%, while the largest unknown single impurities account for 0.052%. Figure 3 The LC-MS plot of “YAZ-1” in Example 1 is shown. Figure 3 This indicates that the molecular weight of YAZ-1 is 202.26, and the molecular ion peak M+1 is 203.

[0102] Furthermore, the detailed preparation process of the final product YAZ is as follows:

[0103] Preparation of YAZ-2

[0104] THF, water, and S-configuration YAZ-1 salt were added to a three-necked flask and stirred. The system gradually dissolved, forming an orange-yellow clear liquid. Sodium hydroxide aqueous solution and Boc anhydride were added, and the mixture was heated to 20–30 °C and stirred for 6–8.0 h. After the reaction was complete, ethyl acetate was added for extraction, and the upper organic phase was collected. Anhydrous sodium sulfate was added to the organic phase for drying, and then the mixture was filtered and concentrated at 30–35 °C to obtain an oily substance (S)-tert-butyl-[(4-cyano-2,3-dihydro-1H-inden-1-yl)-2-hydroxyethyl]carbamate (abbreviated as "YAZ-2").

[0105] Preparation of YAZ-3

[0106] Anhydrous ethanol, hydroxylamine hydrochloride, and triethylamine were added to a three-necked flask and stirred at 20–35 °C for 1.0 h. YAZ-2 was then added, and the temperature was raised to 80–85 °C. The system gradually dissolved and cleared, forming a yellow liquid, which was stirred for 3.0–4.0 h. The reaction solution was then concentrated to dryness to obtain a pale yellow solid. Dichloromethane and water were added to the pale yellow solid for liquid-liquid separation, and the organic phase was separated. The organic phase was washed with water, dried with anhydrous sodium sulfate, filtered, and collected. The organic phase was then concentrated to dryness to obtain a foamy white solid (S)-tert-butyl-[(4-cyano-2,3-dihydro-1H-inden-1-yl)-2-hydroxyethyl]carbamate (abbreviated as "YAZ-3").

[0107] Preparation of YAZ-4

[0108] Add DMF and 3-cyano-4-isopropoxybenzoic acid to a three-necked flask, then add EDCI.HCl and HOBt. Stir for 3.0-5.0 h until YAZ-SM-B is almost completely converted into the acid complex. Then add YAZ-3 and stir at 25-35℃ for 2.0 h until the acid complex is completely converted into the chain intermediate (transition state). Then raise the temperature to 110-120℃ and stir for 6.0-8.0 h until the chain intermediate (transition state) is almost completely converted. YAZ-4 was prepared, then cooled to room temperature, and ethyl acetate and a saturated sodium bicarbonate aqueous solution were added. The mixture was stirred for 10 min, then separated, and the upper organic phase was separated. The mixture was then dried with anhydrous sodium sulfate and concentrated to dryness at 40–50 °C to obtain an oily substance (S)-tert-butyl-[[[4-[5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazole]-3-yl]-2,3-dihydro-1H-indene-1-yl]-2-hydroxyethyl]carbamate (abbreviated as "YAZ-4").

[0109] Preparation of YAZ

[0110] Methanol and YAZ-4 were added to a three-necked flask. The system became clear. A methanol solution of hydrogen chloride was added and stirred at 50-60°C for 3.0 h. A white solid gradually precipitated during stirring. The mixture was cooled to room temperature, and a large amount of solid gradually precipitated. The mixture was then cooled to 0-10°C and stirred for 1.0 h. The mixture was filtered, and the filter cake was collected to obtain a white solid, which is the YAZ product.

[0111] Example 2:

[0112] 150 ml of methanol was added to a 250 ml three-necked flask. The temperature was maintained for 2 hours during the crystallization process. Other than this, the reaction conditions were the same as in Example 1. 9.25 g of a white solid YAZ-1 salt was obtained. The "chiral purity", "ee value" and "yield" of the S-configuration YAZ-1 obtained in Example 2 were measured using the same methods as described above. See Table 1 below.

[0113] Example 3:

[0114] 200 ml of methanol was added to a 250 ml three-necked flask. Other than this, the reaction conditions were the same as in Example 2, and 6.80 g of total off-white solid YAZ-1 salt was obtained. The "chiral purity", "ee value" and "yield" of the S configuration YAZ-1 obtained in Example 3 were measured by the same determination method as above. See Table 1 below.

[0115] Example 4:

[0116] 500 ml of methanol was added to a 250 ml three-necked flask. Other than this, the reaction conditions were the same as in Example 2, and 5.44 g of total white solid YAZ-1 salt was obtained. The "chiral purity", "ee value" and "yield" of the S configuration YAZ-1 obtained in Example 4 were measured by the same determination method as above. See Table 1 below.

[0117] Example 5:

[0118] The holding time in the crystallization process was 2 hours, and the cooling temperature for crystallization was -10°C. Other than that, the other reaction conditions were the same as in Example 1. 10.34 g of a white solid YAZ-1 salt was obtained. The "chiral purity", "ee value" and "yield" of the S-configuration YAZ-1 obtained in Example 5 were measured by the same method as above, as shown in Table 1 below.

[0119] Example 6:

[0120] The crystallization temperature in the crystallization process was -5℃. Other than that, the other reaction conditions were the same as in Example 5. 11.43 g of total off-white solid YAZ-1 salt was obtained. The "chiral purity", "ee value" and "yield" of the S-configuration YAZ-1 obtained in Example 6 were measured by the same determination method as above. See Table 1 below.

[0121] Example 7:

[0122] In the crystallization process, the molar equivalent ratio of the resolving agent to YAZ-1 was 0.3. Other than that, the reaction conditions were the same as in Example 6, and 5.44 g of total off-white solid YAZ-1 salt was obtained. The "chiral purity", "ee value" and "yield" of the S-configuration YAZ-1 obtained in Example 7 were measured by the same determination method as above, as shown in Table 1 below.

[0123] Example 8:

[0124] The holding time in the crystallization process was 1 hour. Other than that, the reaction conditions were the same as in Example 6. 10.89 g of a white solid YAZ-1 salt was obtained. The "chiral purity", "ee value" and "yield" of the S-configuration YAZ-1 obtained in Example 8 were measured by the same method as above. See Table 1 below.

[0125] Example 9:

[0126] The holding time in the crystallization process was 0.5 h. Other than that, the other reaction conditions were the same as in Example 6, and 10.89 g of white solid YAZ-1 salt was obtained. The "chiral purity", "ee value" and "yield" of the S-configuration YAZ-1 obtained in Example 9 were measured by the same determination method as above. See Table 1 below.

[0127] Comparative Example 1:

[0128] 50 ml of methanol was added to a 250 ml three-necked flask. Other than this, the reaction conditions were the same as in Example 6, and 13.07 g of total off-white solid YAZ-1 salt was obtained. The "chiral purity", "ee value" and "yield" of the S configuration YAZ-1 obtained in Comparative Example 1 were measured by the same determination method as above, as shown in Table 1 below.

[0129] Comparative Example 2:

[0130] 30 ml of methanol was added to a 250 ml three-necked flask. Other than this, the reaction conditions were the same as in Example 6, and 14.15 g of total off-white solid YAZ-1 salt was obtained. The "chiral purity", "ee value" and "yield" of the S configuration YAZ-1 obtained in Comparative Example 2 were measured by the same determination method as above, as shown in Table 1 below.

[0131] Comparative Example 3:

[0132] 20 ml of methanol was added to a 250 ml three-necked flask. Other than this, the reaction conditions were the same as in Example 6, and 16.33 g of total off-white solid YAZ-1 salt was obtained. The "chiral purity", "ee value" and "yield" of the S configuration YAZ-1 obtained in Comparative Example 3 were measured by the same determination method as above, as shown in Table 1 below.

[0133] Comparative Example 4:

[0134] 10 ml of methanol was added to a 250 ml three-necked flask. Other than this, the reaction conditions were the same as in Example 6, and 17.69 g of total off-white solid YAZ-1 salt was obtained. The "chiral purity", "ee value" and "yield" of the S configuration YAZ-1 obtained in Comparative Example 4 were measured by the same determination method as above, as shown in Table 1 below.

[0135] Comparative Example 5:

[0136] 550 ml of methanol was added to a 250 ml three-necked flask. Other than this, the reaction conditions were the same as in Example 6, and 2.18 g of total white solid YAZ-1 salt was obtained. The "chiral purity", "ee value" and "yield" of the S configuration YAZ-1 obtained in Comparative Example 5 were measured by the same determination method as above, as shown in Table 1 below.

[0137] Comparative Example 6:

[0138] In the crystallization process, the molar equivalent ratio of the resolving agent to YAZ-1 was 0.75. Other than that, the reaction conditions were the same as in Example 6, and 10.89 g of total off-white solid YAZ-1 salt was obtained. The "chiral purity", "ee value" and "yield" of the S-configuration YAZ-1 obtained in Comparative Example 6 were measured by the same determination method as above, as shown in Table 1 below.

[0139] Comparative Example 7:

[0140] In the crystallization process, the molar equivalent ratio of the resolving agent to YAZ-1 was 1.0. Other than that, the reaction conditions were the same as in Example 6, and 13.61 g of total off-white solid YAZ-1 salt was obtained. The "chiral purity", "ee value" and "yield" of the S-configuration YAZ-1 obtained in Comparative Example 7 were measured by the same determination method as above, as shown in Table 1 below.

[0141] Comparative Example 8:

[0142] In the crystallization process, the molar equivalent ratio of the resolving agent to YAZ-1 was 1.5. Other than that, the reaction conditions were the same as in Example 6, and 15.52 g of total off-white solid YAZ-1 salt was obtained. The "chiral purity", "ee value" and "yield" of the S-configuration YAZ-1 obtained in Comparative Example 8 were measured by the same determination method as above, as shown in Table 1 below.

[0143] Comparative Example 9:

[0144] In the crystallization process, the molar equivalent ratio of the resolving agent to YAZ-1 was 2.0. Other than that, the reaction conditions were the same as in Example 6, and 16.88 g of total off-white solid YAZ-1 salt was obtained. The "chiral purity", "ee value" and "yield" of the S-configuration YAZ-1 obtained in Comparative Example 9 were measured by the same determination method as above, as shown in Table 1 below.

[0145] Comparative Example 10:

[0146] In the crystallization process, D-acetylmaturelic acid was used as the resolving agent. Other than that, the reaction conditions were the same as in Example 6, and 8.98 g of total off-white solid YAZ-1 salt was obtained. The "chiral purity", "ee value" and "yield" of the S-configuration YAZ-1 obtained in Comparative Example 10 were measured by the same determination method as above, as shown in Table 1 below.

[0147] Comparative Example 11:

[0148] Camphor sulfonic acid was used as the resolving agent in the crystallization process. Other than that, the reaction conditions were the same as in Example 6, and 8.17 g of total off-white solid YAZ-1 salt was obtained. The "chiral purity", "ee value" and "yield" of the S-configuration YAZ-1 obtained in Comparative Example 11 were measured by the same determination method as above, as shown in Table 1 below.

[0149]

[0150]

[0151] Table 1

[0152] As can be seen from Table 1 above, the present invention has examined the liquid-solid ratio of solvent to YAZ-1, the type of resolving agent, and the ratio of resolving agent to YAZ-1 in the entire process. Among them, the "chiral purity" and "ee value" of the S-configuration YAZ-1 in Examples 1 to 7 are all above 90, which shows excellent resolving effect. At the same time, the "yield" of the S-configuration YAZ-1 in these examples is all above 20%, which is a high yield. As can be seen from the comparative examples, the solvent amounts in Comparative Examples 1 to 4 do not meet the scope of the present invention, and the "chiral purity" and "ee value" of the obtained S-configuration YAZ-1 are both low. Among them, although the "chiral purity" and "ee value" of the S-configuration YAZ-1 obtained in Comparative Example 5 are relatively high, the yield is only "8%", which is very low. The resolving agent equivalents in Comparative Examples 6 to 9 do not meet the scope of the present invention. Although the yield of the obtained S-configuration YAZ-1 is acceptable, the "chiral purity" and "ee value" of the obtained S-configuration YAZ-1 are both low. Comparative Examples 10 and 11 attempted to replace the "S-binaphthol phosphate" of the present invention with the resolving agents "D-acetylmaturelic acid" and "camphor sulfonic acid", but the "chiral purity" and "ee value" were both low, and the resolving effect was extremely unsatisfactory. Furthermore, although some of these comparative examples showed higher yield values, the chiral purity values ​​of these comparative examples were low, resulting in incomplete separation. The products obtained contained more R-configuration YAZ-1, which is the reason for the higher yield values.

[0153] The method for resolving the intermediate of ozamamod hydrochloride of the present invention yields chiral substances with extremely high chiral purity and ee value, and greatly improves the yield, making it suitable for large-scale industrial production.

[0154] The embodiments of this application have been described above with reference to the accompanying drawings. However, this application is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of this application without departing from the spirit and scope of the claims, and all of these forms are within the protection scope of this application.

Claims

1. A method for resolving an intermediate of ozamod hydrochloride, characterized in that, The process includes the following steps in sequence: Pretreatment step: The racemic mixture of 1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indene-4-carboxynitrile shown in the following chemical formula 1 is mixed with an organic solvent and heated to reflux to obtain a reflux liquid; Crystallization process: A resolving agent is added to the reflux liquid to carry out a salt formation reaction, and the mixture is stirred to induce preliminary crystallization. The resolving agent is S-binaphthol phosphate. Post-processing steps: Cooling, filtration and drying to obtain (S)-1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indene-4-carboxynitrile salt as shown in the following chemical formula 2, wherein M represents the acid radical ion in S-binaphthol phosphate; Salt desalting process: The above (S)-1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indene-4-carboxylate is converted into (S)-1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indene-4-carboxylate as shown in Formula 3 below. ， The liquid-to-solid ratio (ml / g) of the organic solvent to the racemic mixture of 1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indene-4-carboxynitrile is 10~50:

1. The molar equivalent ratio of the resolving agent to the racemic 1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indene-4-carboxynitrile is 0.3~0.5:

1.

2. The splitting method according to claim 1, wherein, The resolving agent is S-binaphthol phosphate.

3. The splitting method according to claim 1 or 2, wherein, The organic solvent is selected from at least one of methanol, ethanol, isopropanol, acetonitrile, acetone, and tetrahydrofuran.

4. The splitting method according to any one of claims 1 to 3, wherein, In the pretreatment process, the reflux holding time is 10 min to 10 h, and further 0.5 h to 5 h.

5. The splitting method according to any one of claims 1 to 3, wherein, In the crystallization process, after the initial crystallization, the system is stirred for 2 to 5 hours while being cooled to -30°C to 30°C for secondary crystallization.

6. The splitting method according to claim 5, wherein, The crystallization temperature for the secondary crystallization is -10℃ to -5℃.

7. The splitting method according to any one of claims 1 to 3, wherein, In the post-processing step, the drying temperature is 30℃~80℃.

8. A method for preparing ozamod hydrochloride, characterized in that, The preparation method includes resolving and desalting the racemic mixture of 1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indene-4-carboxynitrile as shown in Formula 1 below to obtain (S)-1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-indene-4-carboxynitrile as shown in Formula 3 below, wherein the resolving agent used for resolution is the resolving agent according to any one of claims 1 to 7.

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