Process for the preparation of tedizolid intermediate and tedizolid phosphate

Abstract

The application provides a preparation method of a phosphoric acid detazolamide intermediate and phosphoric acid detazolamide, which has mild reaction conditions, avoids extremely low reaction temperature (below -70 DEG C), avoids the use of toxic tin reagents and extremely flammable butyl lithium, has low cost, can significantly improve yield and purity, and has the phosphoric acid detazolamide prepared by the method, the purity of which is not less than 99.6%, and the quality is stable after accelerated storage for 6 months.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and relates to a preparation method of Tedizolid phosphate and Tedizolid phosphate. BACKGROUND

[0002] Tedizolid phosphate, also known as Tedizolid phosphate, Tedizolid phosphate, Tedizolid phosphate, etc., is an oxazolidinone antibacterial prodrug. Its chemical name is [(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl]phenyl}-2-oxooxazolidin-5-yl]methyl hydrogen phosphate, and its structure is as follows:

[0003]

[0004] Tedizolid phosphate is a prodrug of Tedizolid, which significantly improves its solubility in water and increases its oral bioavailability. After oral or intravenous administration, it is converted into Tedizolid by phosphatase, and then exerts its efficacy by inhibiting bacterial protein synthesis. It is used for the treatment of acute bacterial skin and skin structure infections in adults caused by Staphylococcus aureus (including methicillin-resistant and methicillin-sensitive strains), various Streptococci and Enterococci, etc. Compared with Linezolid, it has a longer half-life. The phase III clinical trial of Tedizolid phosphate showed that its clinical effect was comparable to that of Linezolid, with an effective rate of 78% and 76%, respectively. The adverse reactions in the gastrointestinal tract and thrombocytopenia were less than those of Linezolid, and the incidence of drug resistance was lower.

[0005] The synthesis route of Tedizolid phosphate is disclosed in the prior art as follows:

[0006] CN 110938058 A discloses a preparation method of Tedizolid phosphate intermediate:

[0007]

[0008] In this preparation method, the synthesis of intermediate 21 needs to be carried out at-72℃, and butyl lithium, which is extremely flammable, is used. The preparation of compound 23 needs to be carried out at 145-150℃, which is very harsh for equipment requirements and is not suitable for industrial production. In the preparation of compound 24, a large amount of waste iron mud is generated, which needs a large amount of acid and water for treatment, which is not conducive to environmental protection and is not suitable for industrial production.

[0009] CN 1894242 A, CN 110804038 A and WO 2005058886 A1 disclose the following preparation method of Tedizolid phosphate 1:

[0010]

[0011] The first step of the synthesis method uses a toxic tin reagent, which is easy to remain in the phosphate drug of the raw material, and affects the safety of the drug, the second step of the condensation reaction is prepared with a yield of 26% of the key intermediate 14, and the third step of the reaction requires-78℃, the reaction time is long and the equipment requirement is extremely high, which is not conducive to industrial production.

[0012] Therefore, it is necessary to improve the prior art, find a synthesis process suitable for industrial production with mild reaction conditions, low production cost, high yield and purity, avoid using ultra-low temperature, avoid using toxic reagents, and avoid using highly flammable materials. SUMMARY

[0013] The present application is committed to researching the preparation process of phosphate tedizolid amine, and unexpectedly finds a preparation process of phosphate tedizolid amine suitable for industrial production with mild reaction conditions, avoiding extremely low reaction temperature (-70℃ or lower), avoiding the use of toxic tin reagents and highly flammable butyl lithium, low cost, and significantly improving the yield and purity of the preparation process route as shown below.

[0014]

[0015] The present application provides a preparation method of tedizolid amine intermediate 21, the structure of intermediate 21 is shown as follows, the intermediate 21 obtained by the preparation method has mild reaction conditions, avoids extremely low reaction temperature (-70℃ or lower), greatly reduces the production cost, and has a yield of not less than 91% and a purity of not less than 99.2%; preferably, the yield is not less than 92%, more preferably, the yield is not less than 94%.

[0016]

[0017] A preparation method of tedizolid amine intermediate 21, compound 13 reacts with boron acid triisopropyl (B(OiPr)3) under the action of magnesium and catalyst to prepare intermediate 21.

[0018]

[0019] The catalyst is iodine.

[0020] Further, the reaction includes reflux reaction, boronization reaction and refining reaction.

[0021] The reflux reaction is as follows: a reaction kettle is added with metal Mg, iodine, and a part of the tetrahydrofuran solution of compound 13, and heated to decolorization of the reaction system; the remaining tetrahydrofuran solution of compound 13 is added, and refluxed for reaction;

[0022] The boronation reaction is as follows: the reaction system is cooled to 0±5℃, and triisopropyl borate (B(OiPr)3) is added dropwise, and after the dropwise addition is completed, the temperature is controlled at 0±5℃ for reaction for 5-7h. An acid solution is added dropwise, and after stirring at 25±5℃ for 2-4h, water is added, and after standing, the liquid is separated, the water phase is extracted with ethyl acetate, the organic phases are combined, and concentrated to dryness under reduced pressure to obtain the crude product of intermediate 21.

[0023] The purification reaction is as follows: the crude product is added with ethyl acetate and n-heptane, and after stirring at 25±5℃ for 2-3h, it is filtered, the filter cake is washed with n-heptane, and then vacuum dried to obtain intermediate 21.

[0024] In the reflux reaction, the part of the tetrahydrofuran solution of compound 13 is 0.01-0.1 times the tetrahydrofuran solution of compound 13, preferably 0.03-0.1 times the tetrahydrofuran solution of compound 13.

[0025] In the reflux reaction, the reflux reaction time is 1-5h, preferably 1-4h, and more preferably 2-4h.

[0026] In the reflux reaction, the weight ratio of iodine to compound 13 is (0.001-0.005):1, preferably 0.0025:1.

[0027] In the reflux reaction, the molar ratio of metal Mg to compound 13 is (1.1-1.4):1, preferably (1.2-1.3):1, and more preferably 1.2:1.

[0028] In the boronation reaction, the molar ratio of triisopropyl borate to compound 13 is (1.2-1.4):1, preferably 1.2:1.

[0029] In the boronation reaction, the acid solution is hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, etc., preferably hydrochloric acid.

[0030] In the boronation reaction, the molar ratio of acid to compound 13 is (4-5):1, preferably 4.2:1.

[0031] In the purification reaction, the volume ratio of ethyl acetate to n-heptane is (0.5-1.5):20, preferably 1:20.

[0032] The application also provides a preparation method of the intermediate 18 of tedizolid, wherein the intermediate 18 has the following structural formula, the intermediate 18 obtained by the preparation method has mild reaction conditions, a yield of not less than 90%, and a purity of not less than 99.3%; preferably, the yield is not less than 92%.

[0033]

[0034] The preparation method of the intermediate 18 of tedizolid comprises the following steps: adding compound 3 and N,N-dimethylacetamide into a reaction kettle, adding lithium tert-butoxide under temperature control of 0±5℃, stirring for 1-3 hours, adding (R)-glycidyl butyrate (compound 7) under temperature control of 0±5℃, reacting for 5-8 hours under temperature control of 0±5℃, adding glacial acetic acid, water and ethyl acetate, standing and separating, washing and drying the organic solvent, and obtaining a crude product, and then slushing with isopropyl ether to obtain the intermediate 18.

[0035]

[0036] In the preparation method of the intermediate 18, the molar ratio of compound 7 to compound 3 is (1.2-1.5):1, and more preferably 1.5:1.

[0037] In the preparation method of the intermediate 18, the molar ratio of lithium tert-butoxide to compound 3 is selected from (3.0-4.0):1, and preferably 3.0:1.

[0038] In the preparation method of the intermediate 18, the volume weight ratio of isopropyl ether to compound 3 is (4-5):1.

[0039] The application also provides a preparation method of the intermediate 14 of tedizolid, wherein the intermediate 14 has the following structural formula, the intermediate 14 obtained by the preparation method has mild reaction conditions, a yield of not less than 85%, and a purity of not less than 99.2%; preferably, the yield is not less than 88%, and more preferably, the yield is not less than 89%.

[0040]

[0041] The preparation method of the intermediate 14 of tedizolid comprises the following steps: adding the intermediate 18, the intermediate 21, anhydrous potassium carbonate, Pd(dppf)Cl2, 2-methyltetrahydrofuran and water into a reaction kettle, stirring and refluxing for 4-8 hours, adding purified water, filtering, obtaining a crude product, and recrystallizing the crude product to obtain the intermediate 14.

[0042]

[0043] Pd(dppf)Cl2 is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium.

[0044] In the preparation method of the intermediate 14, the molar ratio of the intermediate 21 to the intermediate 18 is (1.0-1.2):1, preferably 1.05:1.

[0045] In the preparation method of the intermediate 14, the mass ratio of Pd(dppf)Cl2 to the intermediate 18 is (0.012-0.015):1, preferably 0.012:1.

[0046] In the preparation method of the intermediate 14, the molar ratio of the anhydrous potassium carbonate to the intermediate 18 is (3.0-3.5):1, preferably 3.0:1.

[0047] In the preparation method of the intermediate 14, the mass ratio of 2-methyltetrahydrofuran to water is (1-3):1, preferably 2:1.

[0048] In the preparation method of the intermediate 14, the recrystallization of the crude product comprises the following steps: adding N,N-dimethylformamide and 1,2-propanediamine into the crude product, optionally adding activated carbon, controlling the temperature at 90±5℃, stirring for 1-3h, and filtering; cooling the filtrate to 0±5℃, stirring for 1-3h, suction filtering, washing, and vacuum drying to obtain the intermediate 14.

[0049] Further, in the preparation method of the intermediate 14, the preparation of the intermediate 18 is optionally included.

[0050] Further, in the preparation method of the intermediate 14, the preparation of the intermediate 21 is optionally included.

[0051] The present application also provides a preparation method of the phosphoric acid brimonidine, comprising the following steps: adding the intermediate 14, tetrahydrofuran, and triethylamine into a reaction kettle, controlling the temperature at 5±5℃, adding a tetrahydrofuran solution of phosphorus oxychloride, stirring for 2-3h, adding water, stirring for 4-6h, suction filtering to obtain a crude product, and recrystallizing the crude product to obtain the phosphoric acid brimonidine.

[0052]

[0053] Further, in the preparation method of the phosphoric acid brimonidine, the preparation of the intermediate 14 is optionally included.

[0054] Preferably, in the preparation method of the phosphoric acid brimonidine, the preparation of the intermediate 14, the preparation of the intermediate 18, and the preparation of the intermediate 21 are included.

[0055]

[0056] The reagents and raw materials used in the present application are commercially available.

[0057] The present application also provides a pharmaceutical preparation containing phosphatidylserine, a pharmaceutical composition comprising phosphatidylserine prepared according to the method of the present application and a pharmaceutically acceptable carrier, optionally, the pharmaceutical composition can further comprise other therapeutic components.

[0058] When the pharmaceutical composition comprises phosphatidylserine prepared according to the method of the present application and a pharmaceutically acceptable carrier, it can be prepared into solid preparations, preferably oral tablets or injections, which can use corresponding excipients known to those skilled in the art and can be prepared using corresponding known pharmaceutical preparation techniques.

[0059] The intermediates 21, 18, 14 and phosphatidylserine prepared according to the present application all meet the requirements for pharmaceutical use, are stable in quality during storage and can ensure clinical efficacy and safety. BRIEF DESCRIPTION OF DRAWINGS

[0060] Figure 1 Liquid chromatogram of the intermediate 21 prepared in Example 1.

[0061] Figure 2 Liquid chromatogram of the intermediate 18 prepared in Example 3.

[0062] Figure 3 Liquid chromatogram of the intermediate 14 prepared in Example 5.

[0063] Figure 4 Liquid chromatogram of the phosphatidylserine prepared in Example 7.

[0064] The yield according to the present application is molar yield, the purity according to the present application is HPLC purity using area normalization method; the equivalent according to the present application is molar equivalent, which is expressed as equiv.

[0065] Detection method of the intermediate 21, 18, 14 and phosphatidylserine

[0066] Detection method of the intermediate 21: octadecylsilane bonded silica gel is used as the filler, 0.1% phosphoric acid aqueous solution is used as the mobile phase A, acetonitrile solution is used as the mobile phase B, gradient elution is performed according to the following table, the detection wavelength is 245 nm, the column temperature is 40℃, the flow rate is 0.8 ml per minute, and the injection volume is 10 μl.

[0067] Detection method of the intermediate 18: octadecylsilane bonded silica gel is used as the filler, 0.1% phosphoric acid aqueous solution is used as the mobile phase A, 0.1% phosphoric acid acetonitrile solution is used as the mobile phase B, gradient elution is performed according to the following table, the detection wavelength is 245 nm, the column temperature is 40℃, the flow rate is 0.8 ml per minute, and the injection volume is 10 μl.

[0068] The detection method of intermediate 14: octadecylsilane-bonded silica gel as the filler, ammonium acetate buffer solution as mobile phase A; tetrahydrofuran-acetonitrile as mobile phase B, gradient elution according to the following table; column temperature is 40℃; detection wavelength is 300nm; injection volume is 10μl.

[0069] The detection method of phosphazolamide: octadecylsilane-bonded silica gel as the filler, ammonium acetate buffer solution as mobile phase A; tetrahydrofuran-acetonitrile as mobile phase B, gradient elution according to the following table; column temperature is 40℃; detection wavelength is 300nm; injection volume is 10μl.

[0070] The present application is further illustrated by the following examples, but the examples do not limit the present application in any way. DETAILED DESCRIPTION

[0071] Preparation of intermediate 21 (reference to CN110938058A example 1 method)

[0072] Under nitrogen atmosphere, a 500mL three-necked reaction flask with an additional funnel and nitrogen inlet joint was added with compound 13 (20.0g, 0.083mol), THF (200mL) and triisopropyl borate (17.17g, 0.091mol, 1.1eq), the mixture was cooled to-72℃. In the additional funnel, n-butyllithium (15.3ml, 0.183mol, 2.2eq) was added in batches, and the temperature was controlled not to exceed-65℃ during the dropwise addition of about 2 hours. After the reaction was completed by HPLC, the reaction solution was quenched with 100ml 20%(w / w) ammonium chloride aqueous solution. When the temperature of the reaction solution rose to room temperature (two-phase separation), the THF layer was separated and concentrated to dryness under reduced pressure. After the crude product was pulsed with 30mL dichloromethane at room temperature, it was filtered, washed with a little dichloromethane and dried under vacuum to obtain intermediate 21, weight 12.91g, yield 75.6%; purity 98.24%.

[0073] Preparation of intermediate 21

[0074] Preparation of intermediate 21 (reference to CN110938058A example 1 method)

[0075] Into a 500 mL three-necked reaction flask with an additional funnel and nitrogen inlet adapter, compound 13 (20.0 g, 0.083 mol), THF (200 mL) were added, and the reaction was cooled to -55 °C. Isopropyl magnesium chloride (1 M, 125 ml) was added dropwise. After the addition was completed, the reaction was stirred for 30 minutes. Trimethyl borate (10.5 g, 0.1 mol, 1.2 equiv) was added to the reaction system, and the reaction was stirred for 4-5 hours. The reaction was quenched with saturated ammonium chloride solution at low temperature, and the reaction liquid was poured into 300 mL of 1 N dilute hydrochloric acid at room temperature and reacted for 1 hour. The organic phase was extracted with ethyl acetate three times, washed with saturated brine, and dried over anhydrous sodium sulfate. The obtained solid was washed with petroleum ether and recrystallized with water to obtain intermediate 21, weight 13.39 g, yield 78.4%, purity 96.32%.

[0076] Comparative Example 2-2: Trimethyl borate (10.5 g, 0.1 mol, 1.2 equiv) in Comparative Example 2-1 was replaced with triisopropyl borate (18.80 g, 0.1 mol, 1.2 equiv), and the rest was the same as Comparative Example 2-1. Intermediate 21 was obtained, weight 13.65 g, yield 79.9%, purity 96.51%.

[0077] Comparative Example 2-3: Only the reaction temperature was changed from -55 °C to 0 °C, and the rest was the same as Comparative Example 2-2. Intermediate 21 was obtained, weight 7.32 g, yield 42.9%.

[0078] Example 1: Preparation of intermediate 21

[0079] (1) Compound 13 (200.00 g, 833 mmol, 1.00 equiv) was dissolved in tetrahydrofuran to obtain 1000 mL of a tetrahydrofuran solution of compound 13.

[0080] (2) Reflux reaction: Under the protection of nitrogen, magnesium metal (24.30 g, 1.00 mol, 1.20 equiv), iodine 0.5 g, 30 ml of tetrahydrofuran solution of compound 13 (0.03 times the total amount) were added to the reaction kettle, heated to decolorization of the reaction system, then the remaining tetrahydrofuran solution of compound 13 was added, and the reflux reaction was continued for 3 h after the addition was completed;

[0081] (3) Boronation reaction: the reaction system was cooled to 0±5℃, and triisopropyl borate (188.02 g, 1.00 mol, 1.20 equiv.) was added dropwise. After the addition was completed, the temperature was controlled at 0±5℃ for 6 h. To the reaction system, 6M hydrochloric acid solution (600 mL, 3.00V / m) was added dropwise, and the temperature was controlled at 25±5℃ for 3 h. Then purified water was added to the reaction system, and after stirring, the mixture was allowed to stand and separate. The aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with purified water, and then concentrated under reduced pressure to dryness to obtain the crude product of intermediate 21;

[0082] (4) Purification reaction: the crude product was added with ethyl acetate (50 mL, 0.25V / m) and n-heptane (1000 mL, 5.00V / m), and the temperature was controlled at 25±5℃ for 3 h. After filtration, the filter cake was washed with n-heptane, and then dried under vacuum to obtain intermediate 21, with a weight of 160.87 g, a molar yield of 94.2%, and an HPLC purity of 99.23%.

[0083] Example 2: Influencing factors of the preparation process of intermediate 21

[0084] ① Influence of the molar equivalent of added magnesium metal: the amount of added magnesium metal was adjusted, and the other conditions were the same as in Example 1. The results are shown in Table 1.

[0085] Table 1: Results of the influence of the molar equivalent of added magnesium metal

[0086]

[0087] From Table 1, it can be seen that:

[0088] When the molar equivalent of added magnesium metal was 1.1-1.4, i.e., the molar ratio of magnesium metal to compound 13 was (1.1-1.4):1, the yield of the prepared intermediate 21 was not less than 91%, and the purity was not less than 99.2%. When the molar equivalent of added magnesium metal was 1.2-1.3, i.e., the molar ratio of magnesium metal to compound 13 was (1.2-1.3):1, the yield of the prepared intermediate 21 was not less than 92%. When the molar equivalent of added magnesium metal was 1.2, i.e., the molar ratio of magnesium metal to compound 13 was 1.2:1, the yield of the prepared intermediate 21 was not less than 94%.

[0089] When the molar equivalent of added magnesium metal was 1, i.e., the molar ratio of magnesium metal to compound 13 was 1:1, the yield of the prepared intermediate 21 was only 87.9%.

[0090] ② Influence of the addition ratio of tetrahydrofuran solution of compound 13

[0091] Step (2) was as follows, and the other steps were the same as in Example 1.

[0092] Example 2-5: Step (2): Under nitrogen protection, magnesium metal (24.30 g, 1.00 mol, 1.20 equiv), iodine 0.5 g, 100 mL of tetrahydrofuran solution of compound 13 (0.1 times the total amount) were added into the reaction kettle, heated to decolorization of the reaction system, then the remaining tetrahydrofuran solution of compound 13 was added, and the reflux was maintained, and after the addition was completed, the reflux reaction was continued for 3 h.

[0093] Result: yield 93.2%, purity 99.25%.

[0094] Example 2-6: Step (2): Under nitrogen protection, magnesium metal (24.30 g, 1.00 mol, 1.20 equiv), iodine 0.5 g, 300 mL of tetrahydrofuran solution of compound 13 (0.3 times the total amount) were added into the reaction kettle, heated to decolorization of the reaction system, then the remaining tetrahydrofuran solution of compound 13 was added, and the reflux was maintained, and after the addition was completed, the reflux reaction was continued for 3 h.

[0095] Result: yield 62.6%, purity 95.65%.

[0096] Example 2-7: Step (2): Under nitrogen protection, magnesium metal (24.30 g, 1.00 mol, 1.20 equiv), iodine 0.5 g, 400 mL of tetrahydrofuran solution of compound 13 (0.4 times the total amount) were added into the reaction kettle, heated to decolorization of the reaction system, then the remaining tetrahydrofuran solution of compound 13 was added, and the reflux was maintained, and after the addition was completed, the reflux reaction was continued for 3 h.

[0097] Result: During the reaction, the magnesium metal did not decrease, and it was speculated that the reaction did not proceed.

[0098] Therefore, it is preferred to first add 0.01-0.1 times the tetrahydrofuran solution of compound 13.

[0099] ③The effect of the molar equivalent of triisopropyl borate added: adjust the amount of triisopropyl borate added, and the rest of the conditions are the same as in Example 1, and the results are shown in Table 2.

[0100] Table 2: Effect of the molar equivalent of triisopropyl borate added

[0101]

[0102] From Table 2, we can know that:

[0103] When the added molar equivalent of triisopropyl borate is 1.2-1.3, i.e. the molar ratio of triisopropyl borate to compound 13 is (1.2-1.3):1, the intermediate 21 prepared has a yield of not less than 91% and a purity of not less than 99.2%; when the added molar equivalent of triisopropyl borate is 1.2, i.e. the molar ratio of triisopropyl borate to compound 13 is 1.2:1, the intermediate 21 prepared has a yield of not less than 94%.

[0104] When the added molar equivalent of triisopropyl borate is 1.1, i.e. the molar ratio of triisopropyl borate to compound 13 is 1.1:1, the intermediate 21 prepared has a yield of 90.3%.

[0105] (4) Effect of iodine: Step (2) is as follows, and the rest of the conditions are the same as in Example 1.

[0106] Example 2-10: Step (2): Under nitrogen protection, magnesium metal (24.30 g, 1.00 mol, 1.20 equiv.) and a solution of 0.03 times compound 13 (200.00 g, 833 mmol, 1.00 equiv.) in tetrahydrofuran (1000 mL, 5.00 V / m) were added to a reaction kettle, and after the addition was completed, the reaction was refluxed for 3 h.

[0107] Result: During the reaction, the magnesium metal did not decrease, suggesting that the reaction did not proceed.

[0108] (5) Effect of temperature:

[0109] Example 2-11: The boronation reaction temperature in step (3) of Example 1 was reduced from 0±5°C to -10±5°C, and the rest was the same as in Example 1.

[0110] Result: The molar yield of intermediate 21 was 51.7%, and the HPLC purity was 95.54%.

[0111] (6) Effect of solvent in the purification reaction:

[0112] Step (4) is as follows, and the rest of the conditions are the same as in Example 1.

[0113] Example 2-12: Step (4): N-heptane (1000 mL, 5.00 V / m) was added to the crude product, and after stirring at a temperature of 25±5°C for 3 h, suction filtration was performed, the filter cake was washed with n-heptane, and then vacuum drying was performed to obtain intermediate 21, which had a molar yield of 95.0% and an HPLC purity of 95.82%.

[0114] Example 2-13: Step (4): Methanol (1000 mL, 5.00 V / m) was added to the crude product, and after stirring at a temperature of 25±5°C for 3 h, suction filtration was performed, the filter cake was washed with methanol, and then vacuum drying was performed to obtain intermediate 21, which had a molar yield of 65.2% and an HPLC purity of 98.81%.

[0115] Example 3: Preparation of intermediate 18

[0116] Into a reaction kettle, compound 3 (200.00 g, 617 mmol, 1.00 equiv.) and N,N-dimethylacetamide (600 mL, 3.00 V / m) were added, and the temperature was reduced to 0±5°C under stirring. Lithium tert-butoxide (148.17 g, 1.85 mol, 3.00 equiv.) was added to the reaction system. After the addition was completed, the temperature was increased to 25±5°C, and the reaction was stirred at this temperature for 2 h. Then the reaction system was cooled to 0±5°C, and compound 7 (133.42 g, 925 mmol, 1.50 equiv.) was added dropwise at 0±5°C. After the dropwise addition was completed, the reaction was carried out at 0±5°C for 6.5 h. After the reaction was completed, glacial acetic acid, purified water, and ethyl acetate were added. After stirring, the mixture was allowed to stand and separate into two phases. The aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with purified water. After the water was removed under reduced pressure, the crude intermediate 18 was obtained.

[0117] Isopropyl ether (1000 mL, 5.00 V / m) was added to the crude product, and the mixture was stirred for 3 h. Filtration was performed, and vacuum drying was carried out for 4 h to obtain the phosphoric acid tetiglumazone intermediate 18, which had a weight of 165.56 g, a yield of 92.5%, and an HPLC purity of 99.46%.

[0118] Example 4: Process for preparing intermediate 18

[0119] 1. Effect of the molar equivalent of compound 7: The amount of compound 7 was adjusted, and the other conditions were the same as in Example 3. The results are shown in Table 3.

[0120] Table 3: Effect of the molar equivalent of compound 7

[0121]

[0122] From Table 3, it can be seen that:

[0123] When the molar equivalent of compound 7 was 1.2-1.5, i.e., the molar ratio of compound 7 to compound 3 was (1.2-1.5):1, the yield of the prepared intermediate 18 was not less than 91%, and the purity was not less than 99.3%. When the molar equivalent of compound 7 was 1.5, i.e., the molar ratio of compound 7 to compound 3 was 1.5:1, the yield of the prepared intermediate 18 was not less than 92%.

[0124] When the molar equivalent of compound 7 was less than 1.2, for example, 1.1, i.e., the molar ratio of compound 7 to compound 3 was 1.1:1, the yield of the prepared intermediate 18 was only 86.7%.

[0125] Effect of the molar equivalent of lithium tert-butoxide added: adjust the amount of lithium tert-butoxide added, and the rest of the conditions are the same as in Example 3, and the results are shown in Table 4.

[0126] Table 4: Effect of the molar equivalent of lithium tert-butoxide added

[0127]

[0128] From Table 4, it can be seen that:

[0129] When the molar equivalent of lithium tert-butoxide added is 3.0-4.0, i.e., the molar ratio of lithium tert-butoxide to compound 3 is (3.0-4.0): 1, the intermediate 18 prepared has a yield of not less than 90% and a purity of not less than 99.3%; when the molar equivalent of lithium tert-butoxide added is 3.0, i.e., the molar ratio of lithium tert-butoxide to compound 3 is 3.0: 1, the intermediate 18 prepared has a yield of not less than 92%.

[0130] When the molar equivalent of lithium tert-butoxide added is less than 3.0, for example, 1.5, 2.0, i.e., the molar ratio of lithium tert-butoxide to compound 3 is 1.5: 1, 2.0: 1, the intermediate 18 prepared has a yield of only 80.1%, 81.7%.

[0131] Effect of reaction temperature: adjust the reaction temperature, and the rest of the conditions are the same as in Example 3, and the results are shown in Table 5.

[0132] Table 5: Effect of reaction temperature

[0133]

[0134] From Table 5, it can be seen that when the reaction temperature is 0±5℃, the intermediate 18 prepared has a yield of not less than 90% and a purity of not less than 99.3%; when the reaction temperature is -10±5℃, the intermediate 18 prepared has a yield of only 79.4%; when the reaction temperature is 25±5℃, the intermediate 18 prepared has a yield of only 79.8%.

[0135] Effect of reaction solvent: use tetrahydrofuran instead of N,N-dimethylacetamide in Example 1, and the rest is the same as in Example 3, and the results are shown in Table 6.

[0136] Table 6: Effect of reaction solvent

[0137]

[0138] As can be seen from Table 6, when tetrahydrofuran is used as the reaction solvent, the yield is only 78.4% and the purity is only 88.92%; when N,N-dimethylformamide is used, the yield is 82.3% and the purity is 91.24%; when N,N-dimethylacetamide is used as the reaction solvent, the yield of the prepared intermediate 18 is not less than 92% and the purity is not less than 99.3%.

[0139] Therefore, compared with tetrahydrofuran and N,N-dimethylformamide as the reaction solvent, the yield and purity are significantly improved when N,N-dimethylacetamide is used as the reaction solvent.

[0140] 5. The influence of the beating solvent: adjust the amount of isopropyl ether added, and the rest of the conditions are the same as in Example 3.

[0141]

[0142] Therefore, the volume weight ratio of isopropyl ether to compound 3 is (4-5): 1.

[0143] Example 5: Preparation of intermediate 14

[0144] Into the reaction kettle, intermediate 18 prepared in Example 3 (150.00 g, 517 mmol, 1.00 equiv.), intermediate 21 prepared in Example 1 (127.19 g, 620 mmol, 1.20 equiv.), anhydrous potassium carbonate (214.40 g, 1.55 mol, 3.00 equiv.), Pd(dppf)Cl2(1.80 g, 2.46 mmol, 0.012 m / m), 2-methyltetrahydrofuran (750 mL, 5.00 V / m) and purified water (375 mL, 2.50 V / m) were added, and the reaction was stirred and refluxed for 5 h. After the reaction was completed, the reaction system was cooled to room temperature, then purified water was added to the reaction system, stirred for 1 h, and then suction filtered, and the filter cake was washed with purified water to obtain the crude product of intermediate 14.

[0145] Into the crude product, N,N-dimethylformamide (1500 mL, 10.0 V / m) and 1,2- propylenediamine (10.50 g, 0.07 m / m) were added, and the temperature was raised to 90±5°C, and stirred at this temperature for 2 h, then hot filtered, and the filtrate was stirred and cooled to 0±5°C, and stirred at this temperature for 2 h, then suction filtered, and the filter cake was washed with N,N-dimethylformamide and vacuum dried to obtain intermediate 14, with a weight of 172.54 g, a yield of 90.1%, and an HPLC purity of 99.53%.

[0146] Example 6: Exploration of the preparation process of intermediate 14

[0147] Effect of the molar equivalent of added anhydrous potassium carbonate: adjust the amount of added anhydrous potassium carbonate, and the rest of the conditions are the same as in Example 5, and the results are shown in Table 7.

[0148] Table 7: Effect of the molar equivalent of added anhydrous potassium carbonate

[0149]

[0150] From Table 7, we can see that:

[0151] When the molar equivalent of added anhydrous potassium carbonate is 3.0-3.5, i.e., the molar ratio of anhydrous potassium carbonate to intermediate 18 is (3.0-3.5):1, the yield of intermediate 14 prepared is not less than 89%, and the purity is not less than 99.4%; when the molar equivalent of added anhydrous potassium carbonate is 3.0, i.e., the molar ratio of anhydrous potassium carbonate to intermediate 18 is 3.0:1, the yield of intermediate 14 prepared is 89.6%.

[0152] When the molar equivalent of added anhydrous potassium carbonate is less than 3.0, for example, 1.5, i.e., the molar ratio of anhydrous potassium carbonate to intermediate 18 is 1.5:1, the yield of intermediate 14 prepared is only 78.3%.

[0153] Effect of the ratio of the amount of 2-methyltetrahydrofuran to water as the reaction solvent: adjust the ratio of the amount of 2-methyltetrahydrofuran to water, and the rest of the conditions are the same as in Example 5, and the results are shown in Table 8.

[0154] Table 8: Effect of the ratio of the amount of 2-methyltetrahydrofuran to water

[0155]

[0156] From Table 8, we can see that:

[0157] When the ratio of the amount of 2-methyltetrahydrofuran to water as the reaction solvent is (1-3):1, the yield of intermediate 14 prepared is not less than 85%, and the purity is not less than 99.4%; when the ratio of the amount of 2-methyltetrahydrofuran to water as the reaction solvent is 2:1, the yield of intermediate 14 prepared is not less than 89%.

[0158] Effect of the reaction solvent: use 1,4-dioxane instead of 2-methyltetrahydrofuran in Example 3, and the rest is the same as in Example 1, and the results are shown in Table 9.

[0159] Table 9: Effect of the reaction solvent

[0160]

[0161] From Table 9, it can be seen that when 1,4-dioxane is used as the reaction solvent, the yield is only 69.3%; when 2-methyltetrahydrofuran is used as the reaction solvent, the yield of the prepared intermediate 18 is not less than 89%.

[0162] Therefore, compared with 1,4-dioxane as the reaction solvent, the yield is significantly improved when 2-methyltetrahydrofuran is used as the reaction solvent.

[0163] (4) Effect of the added molar equivalent of Pd(dppf)Cl2: The amount of Pd(dppf)Cl2 added was adjusted, and the rest of the conditions were the same as in Example 5, and the results are shown in Table 10.

[0164] Table 10: Results table of the effect of the added molar equivalent of Pd(dppf)Cl2

[0165]

[0166] From Table 10, it can be seen that:

[0167] When the added molar equivalent of Pd(dppf)Cl2 is 0.012-0.015, i.e., the molar ratio of Pd(dppf)Cl2 to intermediate 18 is (0.012-0.015): 1, the yield of the prepared intermediate 14 is not less than 89%, and the purity is not less than 99.4%; when the added molar equivalent of Pd(dppf)Cl2 is 0.012, i.e., the molar ratio of Pd(dppf)Cl2 to intermediate 18 is 0.012: 1, the yield of the prepared intermediate 14 is 89.6%.

[0168] When the added molar equivalent of Pd(dppf)Cl2 is less than 0.012, for example, 0.010, i.e., the molar ratio of Pd(dppf)Cl2 to intermediate 18 is 0.010: 1, the yield of the prepared intermediate 14 is only 84.7%.

[0169] (5) Effect of the added molar equivalent of intermediate 21: The amount of intermediate 21 added was adjusted, and the rest of the conditions were the same as in Example 5, and the results are shown in Table 11.

[0170] Table 11: Results table of the effect of the added molar equivalent of intermediate 21

[0171]

[0172] From Table 11, it can be seen that:

[0173] When the added molar equivalent of intermediate 21 is 1.0-1.2, i.e. the molar ratio of intermediate 21 to intermediate 18 is (1.0-1.2):1, the intermediate 14 prepared has a yield of not less than 87% and a purity of not less than 99.4%; when the added molar equivalent of intermediate 21 is 1.05, i.e. the molar ratio of intermediate 21 to intermediate 18 is 1.05:1, the intermediate 14 prepared has a yield of 89.6%.

[0174] Example 7: Preparation of brimonidine phosphoric acid

[0175] The reaction kettle was charged with intermediate 14 prepared in Example 5 (160.00 g, 432 mmol, 1.00 equiv.) and tetrahydrofuran (2400 mL, 15.0 V / m), and after stirring to uniformity, triethylamine (131.15 g, 1.30 mol, 3.00 equiv.) was added to the reaction system, and a solution of phosphorus oxychloride (132.49 g, 864 mmol, 2.00 equiv) in tetrahydrofuran (800 mL, 5.00 V / m) was added at a temperature of 5±5°C, and the reaction was stirred at a temperature of 5±5°C for 2.5 h, and purified water was added to the reaction system, and after the addition was completed, the mixture was stirred at this temperature for 5 h, and then filtered under suction, and the filter cake was washed with purified water to obtain a crude brimonidine phosphoric acid product, and after recrystallization, brimonidine phosphoric acid 1 was obtained, having a weight of 172.57 g, a yield of 88.7%, and an HPLC purity of 99.91%.

[0176] Example 8: Stability test

[0177] An appropriate amount of intermediate 21 prepared in Example 1, intermediate 18 prepared in Example 3, intermediate 14 prepared in Example 5, and brimonidine phosphoric acid prepared in Example 7 were placed in a temperature of 40°C±2°C and a relative humidity of 75%±5% for 6 months, and their properties, related substances, and purity were determined, and the results are shown in Table 12.

[0178] Table 12: Stability test results

[0179]

[0180] As can be seen from Table 12, the intermediate 21 prepared in Example 1, the intermediate 18 prepared in Example 3, the intermediate 14 prepared in Example 5, and the brimonidine phosphoric acid prepared in Example 7 were stable in quality after being placed under accelerated conditions for 6 months.

Claims

1. A method for preparing an intermediate 21 of Tedizolid, wherein compound 13 is reacted with triisopropyl borate (B(OiPr)3) in the presence of magnesium and a catalyst to obtain the intermediate 21; and the catalyst is iodine. The reaction includes refluxing, boronation and purification. The refluxing is carried out by adding magnesium, iodine and a part of tetrahydrofuran solution of compound 13 into a reactor, heating the reaction system to decolorization, adding the rest of tetrahydrofuran solution of compound 13 and refluxing. The refluxing is carried out for 1-5 hours. The weight ratio of iodine to compound 13 is 0.001-0.

005. The molar ratio of magnesium to compound 13 is (1.2-1.3):

1. The part of tetrahydrofuran solution of compound 13 is 0.01-0.1 times of tetrahydrofuran solution of compound 13. The boronation is carried out by cooling the reaction system to 0±5℃, adding triisopropyl borate (B(OiPr)3) dropwise, controlling the temperature at 0±5℃ for 5-7 hours after the addition is completed, adding an acid solution, controlling the temperature at 25±5℃ for 2-4 hours, adding water, standing and separating, extracting the water phase with ethyl acetate, combining the organic phases, concentrating to dryness under reduced pressure to obtain the crude intermediate 21. The molar ratio of triisopropyl borate to compound 13 is (1.2-1.3):

1. The acid solution is hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid. The molar ratio of the acid to compound 13 is (4-5):

1. The purification is carried out by adding ethyl acetate and n-heptane to the crude product, controlling the temperature at 25±5℃ for 2-3 hours, filtering, washing the filter cake with n-heptane and vacuum drying to obtain compound 21. The volume ratio of ethyl acetate to n-heptane is (0.5-1.5):

20.

2. The production method according to claim 1, wherein The molar ratio of magnesium to compound 13 is 1.2:

1.

3. The production method according to claim 1, wherein The part of tetrahydrofuran solution of compound 13 is 0.03-0.1 times of tetrahydrofuran solution of compound 13.

4. The production method according to claim 1, wherein The molar ratio of triisopropyl borate to compound 13 is 1.2:

1.

5. The production method according to claim 1, wherein The acid solution is hydrochloric acid.

6. The production method according to claim 1, wherein The molar ratio of the acid to compound 13 is 4.2:

1.

7. The production method according to claim 1, wherein The volume ratio of ethyl acetate to n-heptane is 1:

20.

8. A method for preparing phosphoric acid Tedizolid, comprising the following steps: (1) preparing the intermediate 21 according to the method of claim 1; (2) reacting the intermediate 21 with the intermediate 18 to obtain the intermediate 14; comprising the following steps: adding the intermediate 18, the intermediate 21, anhydrous potassium carbonate, Pd(dppf)Cl2, 2-methyltetrahydrofuran and water into a reactor, stirring and refluxing for 4-8 hours, adding purified water, filtering to obtain a crude product, recrystallizing the crude product to obtain the intermediate 14; (3) reacting the intermediate 14 with phosphorus oxychloride to obtain phosphoric acid Tedizolid; comprising the following steps: The reaction kettle is added with intermediate 14, tetrahydrofuran, triethylamine, the temperature is controlled at 5±5 ℃, a phosphorus oxychloride tetrahydrofuran solution is added, stirring is carried out for 2-3 hours, water is added, stirring is carried out for 4-6 hours, and then filtration is carried out, to obtain a crude product, and the crude product is recrystallized to obtain brincidofovir;

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