Preparation method of macloxvir intermediate
During the synthesis of mabaloxavir, compound R-IV with chiral alcohol structure was prepared, and sulfonylation and coupling reaction was carried out under alkaline conditions to direct the formation of compound S-II, achieving the high chiral purity of mabaloxavir intermediate, solving the uncertainty of chiral purity and synthesis route in the existing methods.
Patent Information
- Application Number
- CN202411862291.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-17
- Publication Date
- 2025-03-28
AI Technical Summary
In the existing mabaloxavir preparation methods, there is a lack of an effective method that can direct the generation of optically active mabaloxavir intermediates, resulting in uncertainty in chiral purity and synthetic route.
Compound IV with chiral alcohol structure was prepared, and sulfonylation and coupling reaction was carried out under basic conditions to direct the formation of compound S-II, and then compound I was prepared. This method uses chiral catalysts and specific alkaline reagents to ensure the formation of chiral centers of the reaction.
The high chiral purity of the mabaloxavir intermediate was achieved (up to 99.70%), and an unreported synthetic route was provided, solving the uncertainty of chiral purity and synthetic routes in the original method.
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of pharmaceutical intermediate synthesis, and particularly relates to a method for preparing a mabaloxavir intermediate. Background Art
[0002] The statements herein merely provide background information related to the present invention and do not necessarily constitute prior art.
[0003] Baloxavir marboxil is a drug developed jointly by Shionogi of Japan and Roche of Switzerland for the treatment of influenza A or B. On February 23, 2018, mabaloxavir tablets were first launched in Japan and were approved for marketing by the U.S. FDA in October of the same year.
[0004] Mabaloxavir structure:
[0005]
[0006] The patent (CN 109311911 B) of the original manufacturer, Shionogi Pharmaceutical Co., Ltd. of Japan, discloses a method for preparing Mabaloxavir. The original process uses n-propyl phosphoric anhydride as a condensation agent, and compound III and optically inactive 7,8-difluoro-6,11-dihydro-dibenzo[B,E]thieno-11-ol undergo a coupling reaction to generate compound S-II, which can be directly crystallized in the reaction solution. The synthesis route is as follows:
[0007] Summary of the invention
[0008] The purpose of the present invention is to provide a method for preparing a mabaloxavir intermediate, and the method has not been reported so far. The present invention first prepares a compound R-IV having a chiral alcohol structure, and then the compound R-IV is sulfonylated, the sulfonyl group is removed under alkaline conditions, and a coupling reaction occurs with the compound III to generate the compound S-II in a directional manner.
[0009] In order to achieve the above object, the present invention is implemented through the following technical solutions:
[0010] The present invention provides a method for preparing a mabaloxavir intermediate, comprising the following steps:
[0011] Its synthetic route is:
[0012]
[0013] Add (S)-2-methyl-CBS-oxazaborolidine to a mixed solution of compound V and a reducing agent to react to obtain R-IV;
[0014] Under ice bath conditions, add 1-1.2 molar equivalents of alkaline reagent to the mixed solution of compound R-Ⅳ and sulfonylating agent, and react at 20-30°C for 2-3h; then add 1-1.5 molar equivalents of alkaline reagent, and add compound III, and react at 50-60°C for 6-10h, cool the reaction solution for crystallization, and the obtained white solid and methanesulfonic acid form a salt to obtain compound S-Ⅱ;
[0015] The mixed solution of compound S-Ⅱ and lithium chloride is reacted at 60-70°C for 10-20h to obtain compound Ⅰ.
[0016] The compound IV in the original research route is not optically active, and the present invention specifically prepares the optically active compound R-IV;
[0017] The chiral alcohol is first sulfonylated and then coupled with an amino compound to produce a product having a specific chirality; the compound S-II prepared by this method has a chiral center corresponding to the original research route.
[0018] Compound R-IV generates a sulfonylation transition state, and the sulfonyl group is removed under alkaline conditions to generate a carbon cation center, and then the amine group of compound III is coupled with it.
[0019] In the above reaction, the chiral catalyst ((S)-2-methyl-CBS-oxazaborolidine) and the reducing agent borane will have a specific reaction to achieve the effect of chiral reduction; other catalysts such as L-prolinol and diphenylprolinol have been verified and do not react with borane.
[0020] The molar equivalent of the alkaline reagent added for the first time is substantially equal to that of the sulfonylating reagent, and its function is to provide an alkaline environment. The hydroxyl group of compound R-IV reacts with the sulfonylating reagent to generate a sulfonyl-protected transition state compound, and hydrogen chloride is generated at the same time. The hydrogen chloride can form a salt and neutralize with the alkaline reagent.
[0021] After the sulfonyl-protected transition state compound is generated, an alkaline reagent is further added, and the sulfonyloxy group is removed under alkaline conditions to form a carbon cation, which then reacts and couples with the amine group of the added compound III.
[0022] Compound S-II is reacted with lithium chloride to prepare compound I, wherein 9.0 molar equivalents of lithium chloride can be complexed with oxygen atoms to remove the n-butyl protecting group.
[0023] During the preparation of the mabaloxavir intermediate, a small amount of isomeric impurities are generated. The structural formula of the isomeric impurities is as follows:
[0024]
[0025] In some embodiments, the solvent of the mixed solution of compound V and the reducing agent is selected from at least one of tetrahydrofuran, ethyl acetate or dichloromethane.
[0026] Preferably, the solvent is tetrahydrofuran.
[0027] In some embodiments, the reducing agent is borane dimethyl sulfide or borane tetrahydrofuran.
[0028] Preferably, the reducing agent is borane tetrahydrofuran. Compared with borane dimethyl sulfide, borane tetrahydrofuran has less irritating odor; comparing Example 1 with Example 2, the yield of compound R-IV prepared using borane tetrahydrofuran is higher.
[0029] Preferably, the amount of the reducing agent added is 1.0 to 1.2 equivalents based on the molar equivalent of compound V.
[0030] In some embodiments, the amount of (S)-2-methyl-CBS-oxazaborolidine added is 0.05 to 0.3 equivalents based on the molar equivalent of compound V.
[0031] Preferably, the addition temperature of (S)-2-methyl-CBS-oxazaborolidine is -5 to 5°C.
[0032] Preferably, (S)-2-methyl-CBS-oxazaborolidine is added dropwise, and after the addition is complete, the reaction is carried out for 1 to 2 hours to obtain R-IV.
[0033] After the chiral catalyst is added, it first reacts with borane to form a complex, and the complex further chirally reduces the ketone to an alcohol. The reaction process is highly exothermic and needs to be kept at a low temperature.
[0034] In some embodiments, the solvent of the mixed solution of compound R-IV and the sulfonylating agent is selected from at least one of ethyl acetate, tetrahydrofuran, N,N-dimethylacetamide or methyl tert-butyl ether.
[0035] Preferably, the solvent is ethyl acetate.
[0036] In some embodiments, the sulfonylating agent is selected from at least one of methylsulfonyl chloride, ethylsulfonyl chloride, propylsulfonyl chloride, cyclopropylsulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, and 4-chlorobenzenesulfonyl chloride.
[0037] Preferably, the sulfonylating agent is p-toluenesulfonyl chloride. It has been found through experiments that p-toluenesulfonyl chloride reacts with chiral alcohols, and the chiral alcohols can react completely, while when other sulfonyl reagents are used, the chiral alcohols are difficult to react completely, so when p-toluenesulfonyl chloride is used, the yield is higher, as can be seen from the yields of the white solids in Examples 1 and 2.
[0038] Preferably, the amount of the sulfonylating agent added is 1.0 to 1.2 equivalents based on the molar equivalent of compound IV.
[0039] In some embodiments, the alkaline agent is selected from at least one of triethylamine, diisopropylethylamine, DBU, sodium bicarbonate, sodium carbonate, potassium carbonate, and cesium carbonate.
[0040] Preferably, the alkaline agent is diisopropylethylamine. When diisopropylethylamine is used as the alkaline agent, the temperature rise of the reaction is significantly moderate, and the reaction is relatively slow.
[0041] Preferably, the amount of the alkaline agent added is 2.0 to 2.6 equivalents based on the molar equivalent of compound IV.
[0042] In some embodiments, the solvent of the mixed solution of compound S-II and lithium chloride is selected from at least one of N,N-dimethylacetamide, N,N-dimethylacetamide, N-dimethylpyrrolidone, and dimethyl sulfoxide.
[0043] Preferably, the solvent is N-dimethylpyrrolidone.
[0044] Preferably, based on the molar equivalent of compound S-II, the amount of lithium chloride added is 6.0 eq to 10.0 eq, preferably 9 eq.
[0045] The beneficial effects achieved by one or more embodiments of the present invention are as follows:
[0046] The present invention first prepares a compound R-IV with a chiral alcohol structure, the compound R-IV is sulfonylated, and then coupled with a compound III under alkaline conditions to generate an optically active compound S-II, and the compound I is further prepared from the compound S-II; the present invention couples two parent nucleus structures of mabaloxavir by a new method, constructs a carbon-nitrogen bond chiral center, and directionally prepares a mabaloxavir intermediate, and the synthetic route embodied by the method has not been reported before; the highest chiral purity of the prepared compound I is 99.70%.
[0047] In addition, the present invention also includes a method for preparing isomers of a mabaloxavir intermediate, and develops a liquid phase detection method for the impurity. BRIEF DESCRIPTION OF THE DRAWINGS
[0048] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.
[0049] Figure 1 is the chiral purity HPLC spectrum of compound R-IV in Example 1, wherein the isomeric impurity of compound R-IV has an absorption peak at a retention time of 20.356 min, Figure 8 The retention time of compound S-IV in Example 4 corresponds to the same;
[0050] Figure 2 is the chiral purity HPLC spectrum of compound S-Ⅱ in Example 1, wherein the isomeric impurity of compound S-Ⅱ has an absorption peak at a retention time of 10.929 min, Fig. 9 The retention time of compound R-Ⅱ is consistent;
[0051] Figure 3 This is the chiral purity HPLC spectrum of compound I in Example 1, and no corresponding isomeric impurities were detected;
[0052] Figure 4 is the chiral purity HPLC spectrum of compound R-IV in Example 2;
[0053] Figure 5 is the chiral purity HPLC spectrum of compound S-II in Example 2;
[0054] Figure 6 is the chiral purity HPLC spectrum of compound I in Example 2, wherein the isomeric impurity of compound I has an absorption peak at a retention time of 29.729 min, and Fig.10 The retention time of the isomeric impurities of compound Ⅰ is consistent;
[0055] Figure 7 is the chiral purity HPLC spectrum of compound Ⅰ in Example 3;
[0056] Figure 8 is the chiral purity HPLC spectrum of compound S-IV in Example 4;
[0057] Fig. 9 is the chiral purity HPLC spectrum of compound R-II in Example 4;
[0058] Fig.10 This is the chiral purity HPLC spectrum of the isomeric impurities of Compound Ⅰ in Example 4. DETAILED DESCRIPTION
[0059] It should be noted that the following detailed descriptions are illustrative and intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used in the present invention have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.
[0060] The present invention will be further described below in conjunction with the embodiments.
[0061] Example 1: Preparation of Compound I
[0062] The synthetic route of compound I is as follows:
[0063]
[0064] S1. Measure 100 ml (10V) of dichloromethane and add it to the reaction bottle, then add 23 ml of borane tetrahydrofuran (2N, 1.2 eq) and compound V (10 g, 1.0 eq), and start stirring; after the system is clarified, place the reaction bottle in an ice bath, cool to 0°C, and start adding 2.2 ml of (S)-2-methyl-CBS-oxazaborolidine (1N, 0.1 eq). After the addition is complete, control the temperature at 0-5°C to react for 1 hour, take samples for testing, and it indicates that compound V has reacted completely.
[0065] Post-treatment: control the temperature at 0-5°C, add 20ml (2V) methanol to quench the reaction, then add 50ml (5V) 1N hydrochloric acid, stir for 30 minutes, let stand, separate the phases, collect the organic phase, wash once with saturated sodium bicarbonate solution and once with saturated brine, respectively, and concentrate the organic phase under reduced pressure at 45-60°C to obtain a crude compound R-IV; measure 50ml (5V) of methanol and add it to the reaction bottle where the crude compound R-IV is located, heat to 50°C and stir for 30 minutes, then slowly cool to 10-15°C, crystallize and stir for 1 hour, filter, and dry to obtain compound R-IV (8.3g), with a yield of 83.2%, and the chiral purity of compound R-IV is 97.88%.
[0066] The chiral purity spectrum of compound R-Ⅳ is shown in the attached Figure 1 .
[0067] S2. 50 ml (7V) of tetrahydrofuran was added to the reaction bottle, stirring was started, compound R-Ⅳ (6.1 g, 1.0 eq) and p-toluenesulfonyl chloride (4.6 g, 1.05 eq) prepared in step S1 were added, the reaction bottle was placed in a 5-10°C water bath, diisopropylethylamine (2.45 g, 1.1 eq) was slowly added dropwise to the reaction bottle, after addition, the temperature was raised to 20°C, reacted for 3 hours, and sampled for testing to confirm that compound R-Ⅳ was basically reacted; diisopropylethylamine (3.34 g, 1.3 eq) was added to the reaction bottle, and then compound III (7.36 g, 1.0 eq) was added, the temperature was raised to 50°C, and reacted for 8 hours. Sampled again for testing to confirm that compound III was reacted completely, and the temperature was lowered to 20°C.
[0068] Post-treatment: Following the above steps, after stirring at 20°C for 1 hour, a solid-liquid mixture was obtained. The filter cake was collected by filtration and rinsed with ethyl acetate. The filter cake was collected and dried to obtain a white solid (10.12 g) with a yield of 78.7%.
[0069] Salt formation: add 24 ml (3V) of tetrahydrofuran to the reaction bottle, and then add the above-mentioned white solid (8 g, 1.0 eq); prepare an ethyl acetate solution of methanesulfonic acid: weigh methanesulfonic acid (1.40 g, 1.1 eq) and ethyl acetate (40 ml, 5V) and add them to a conical flask, and stir evenly; add the ethyl acetate solution of methanesulfonic acid dropwise to the reaction bottle, react at room temperature for 3 hours after the addition, filter, collect the filter cake, rinse with ethyl acetate, collect the filter cake, and dry to obtain the salt-formed compound S-Ⅱ (8.7 g), the salt formation yield is 93.1%, and the chiral purity of compound S-Ⅱ is 94.67%.
[0070] Chiral purity test method for mabaloxavir intermediates and their isomeric impurities:
[0071] 1. Chromatographic conditions:
[0072] Chromatographic column: CHIRALPAK AD, amylose-tris (3,5-diphenylcarbamate) as filler (4.6 mm × 250 mm, 10 μm or chromatographic column with equivalent performance);
[0073] Mobile phase A: n-hexane; Mobile phase B: ethanol (0.3% TFA, v / v);
[0074] Detection wavelength: 210nm; flow rate: 0.8ml / min;
[0075] Injection volume: 5 μl; elution ratio: n-hexane: ethanol = 70:30, v / v;
[0076] Running time: 40 minutes.
[0077] 2. Solution preparation:
[0078] Solvent: ethanol-n-hexane (4:1).
[0079] Test solution: Take about 2 mg of the product, weigh accurately, place in a 25 ml brown volumetric flask, add solvent to dissolve and dilute to the scale, and shake well.
[0080] The chiral purity spectrum of compound S-Ⅱ is shown in the attached Figure 2 .
[0081] S3. Take N-dimethylpyrrolidone (35 ml, 5V) and add it into the reaction bottle. Then add compound S-Ⅱ (7 g, 1.0 eq) prepared in step S2 and lithium chloride (4.15 g, 9 eq). Heat to 60°C and react for 24 hours. Sample testing indicated that the reaction of compound S-Ⅱ was complete. Then cool to 25°C.
[0082] Post-treatment: control the temperature at 10-20°C, add 35 ml of purified water (5V) to the reaction solution, then stir for 30 minutes, filter, rinse the filter cake with purified water, collect the filter cake, and dry to constant weight to obtain a crude compound I; add the crude compound I to the reaction bottle again, add a mixed solution of dichloromethane (50 ml, 7V) and isopropyl ether (50 ml, 7V), heat to 45°C, stir for 1 hour, then cool to 10-15°C, crystallize and stir for 30 minutes, filter, collect the filter cake, and dry to constant weight to obtain compound I (4.29 g), with a yield of 82.1%, and the chiral purity of compound I is 99.70%.
[0083] The chiral purity spectrum of compound Ⅰ is shown in the attached Figure 3 .
[0084] Example 2: Preparation of Compound I
[0085] The synthetic route of compound I is the same as that of Example 1, and the specific steps are as follows:
[0086] S1. Measure 120 ml (8V) of tetrahydrofuran and add it to the reaction bottle, then add 60 ml of borane dimethyl sulfide (1N, 1.05 eq) and compound V (15 g, 1.0 eq), and start stirring; after the system is clarified, place the reaction bottle in an ice bath, cool to -5°C, and start adding 11.5 ml of (S)-2-methyl-CBS-oxazaborolidine (1N, 0.2 eq) dropwise. After the addition is complete, control the temperature at 0-5°C to react for 1 hour, take samples for testing, and it indicates that compound V has reacted completely.
[0087] Post-treatment: control the temperature at 0-5°C, add 30ml (2V) methanol to quench the reaction, then add 75ml (5V) 1N hydrochloric acid, stir for 30 minutes, let stand, separate the phases, collect the organic phase, wash once with saturated sodium bicarbonate solution and once with saturated brine, respectively, and concentrate the organic phase under reduced pressure at 45-60°C to obtain a crude compound R-IV; measure 75ml (5V) of methanol and add it to the reaction bottle where the crude compound R-IV is located, heat to 50°C and stir for 30 minutes, then slowly cool to 10-15°C, crystallize and stir for 1 hour, filter, and dry to obtain compound R-IV (11.2g), with a yield of 73.9%, and the chiral purity of compound R-IV is 97.81%.
[0088] The chiral purity spectrum of compound R-Ⅳ is shown in the attached Figure 4 .
[0089] S2. Measure 120ml (12V) of ethyl acetate and add it to the reaction bottle, start stirring, add compound IV (10g, 1.0eq) and ethylsulfonyl chloride (5.9g, 1.2eq) prepared in step S1, place the reaction bottle in a 5-10°C water bath, slowly drop triethylamine (4.6g, 1.2eq) into the reaction bottle, after adding, heat to 20°C, react for 3 hours, take samples for testing, and confirm that compound R-IV is basically reacted; then add triethylamine (5.0g, 1.3eq) to the reaction bottle, then add compound III (12.2g, 1.0eq), heat to 50°C, and react for 8 hours. Take samples for testing again, and after confirming that compound III is reacted completely, start cooling to 20°C.
[0090] Post-treatment: Following the above steps, after stirring at 20°C for 1 hour, a solid-liquid mixture was obtained. The filter cake was collected by filtration and rinsed with ethyl acetate. The filter cake was collected and dried to obtain a white solid (16.4 g) with a yield of 76.2%.
[0091] Salt formation: add 30 ml (2V) of tetrahydrofuran to the reaction bottle, and then add the above-mentioned white solid (15 g, 1.0 eq); prepare an ethyl acetate solution of methanesulfonic acid: weigh methanesulfonic acid (2.6 g, 1.0 eq) and ethyl acetate (75 ml, 5V) and add them to a conical flask, and stir evenly; add the ethyl acetate solution of methanesulfonic acid dropwise to the reaction bottle, react at room temperature for 3 hours after the addition, filter, collect the filter cake, rinse with ethyl acetate, collect the filter cake, and dry to obtain the salt-formed compound S-Ⅱ (16.8 g), the salt formation yield is 95.8%, and the chiral purity of compound S-Ⅱ is 95.29%.
[0092] The chiral purity spectrum of compound S-Ⅱ is shown in the attached Figure 5 .
[0093] S3. Take N,N-dimethylacetamide (110ml, 11V) and add it into the reaction bottle. Then add compound S-Ⅱ (10g, 1.0eq) prepared in step S2 and lithium chloride (4.5g, 7eq). Heat to 65℃ and react for 24 hours. Sample testing showed that compound S-Ⅱ reacted completely and then cool to 15℃.
[0094] Post-treatment: control the temperature at 10-20°C, add 80 ml of purified water (8V) to the reaction solution, then stir for 30 minutes, filter, rinse the filter cake with purified water, collect the filter cake, and dry to constant weight to obtain a crude compound I; add the crude compound I to the reaction bottle again, add a mixed solution of dichloromethane (70 ml, 7V) and isopropyl ether (70 ml, 7V), heat to 45°C, stir for 1 hour, then cool to 10-15°C, crystallize and stir for 30 minutes, filter, collect the filter cake, and dry to constant weight to obtain compound I (4.89 g), with a yield of 68.2%, and the chiral purity of compound I is 98.71%.
[0095] The chiral purity spectrum of compound Ⅰ is shown in the attached Figure 6 .
[0096] Example 3: Preparation of Compound I
[0097] The synthetic route of compound I is the same as that of Example 1, and the specific steps are as follows:
[0098] S1. 40 ml (8V) of tetrahydrofuran was added to the reaction bottle, and then 21 ml of borane dimethyl sulfide (1N, 1.1 eq) and compound V (5 g, 1.0 eq) were added, and stirring was started; after the system was clarified, the reaction bottle was placed in an ice bath, cooled to 0°C, and 1.9 ml of (S)-2-methyl-CBS-oxazaborolidine (1N, 0.1 eq) was added dropwise. After the addition was complete, the temperature was controlled at 0-5°C for reaction for 1 hour, and sampling was performed, indicating that compound V had reacted completely.
[0099] Post-treatment: control the temperature at 0-5°C, add 10ml (2V) methanol to quench the reaction, then add 25ml (5V) 1N hydrochloric acid, stir for 30 minutes, let stand, separate the phases, collect the organic phase, wash once with saturated sodium bicarbonate solution and once with saturated brine, respectively, and concentrate the organic phase under reduced pressure at 45-60°C to obtain a crude compound R-IV; measure 25ml (5V) of methanol and add it to the reaction bottle where the crude compound R-IV is located, heat to 50°C and stir for 30 minutes, then slowly cool to 10-15°C, crystallize and stir for 1 hour, filter, and dry to obtain compound R-IV (3.29g), with a yield of 65.3%.
[0100] S2. Take 30ml (10V) of ethyl acetate and add it to the reaction bottle, start stirring, add compound R-Ⅳ (3g, 1.0eq) and methylsulfonyl chloride (1.45g, 1.1eq) prepared in step S1, place the reaction bottle in a 5-10℃ water bath, slowly drop diisopropylethylamine (1.76g, 1.2eq) to the reaction bottle, after adding, heat to 30℃, react for 2 hours, take samples for testing, confirm that compound R-Ⅳ is basically reacted completely; then add diisopropylethylamine (2.1g, 1.4eq) to the reaction bottle, then add compound III (3.65g, 1.0eq), heat to 60℃, react for 10 hours. Take samples for testing again, confirm that compound III is reacted completely, then start cooling to 20℃.
[0101] Post-treatment: Following the above steps, after stirring at 20°C for 1 hour, a solid-liquid mixture was obtained. The filter cake was collected by filtration and rinsed with ethyl acetate. The filter cake was collected and dried to obtain a white solid (4.56 g) with a yield of 70.8%.
[0102] Salt formation: add 12 ml (3V) of tetrahydrofuran to the reaction bottle, and then add the above-mentioned white solid (4 g, 1.0 eq); prepare the ethyl acetate solution of methanesulfonic acid: weigh methanesulfonic acid (0.74 g, 1.1 eq) and ethyl acetate (20 ml, 5V) and add them to a conical flask, and stir evenly; add the ethyl acetate solution of methanesulfonic acid dropwise to the reaction bottle, react at room temperature for 5 hours after the addition, filter, collect the filter cake, rinse with ethyl acetate, collect the filter cake, and dry to obtain the salt-formed compound S-Ⅱ (4.13 g), with a salt formation yield of 88.6%.
[0103] S3. Take N-dimethylpyrrolidone (20ml, 5V) and add it into the reaction bottle. Then add compound S-Ⅱ (4g, 1.0eq) prepared in step S2 and lithium chloride (2.3g, 9eq). Heat to 60℃ and react for 24 hours. Sample testing showed that the reaction of compound S-Ⅱ was complete. Then cool to 25℃.
[0104] Post-treatment: control the temperature at 10-20°C, add 20 ml of purified water (5V) to the reaction solution, then stir for 30 minutes, filter, rinse the filter cake with purified water, collect the filter cake, and dry to constant weight to obtain a crude compound I; add the crude compound I to the reaction bottle again, add a mixed solution of dichloromethane (40 ml, 10V) and isopropyl ether (40 ml, 10V), heat to 45°C, stir for 1 hour, then cool to 10-15°C, crystallize and stir for 30 minutes, filter, collect the filter cake, and dry to constant weight to obtain compound I (1.91 g), with a yield of 65.6%, and the chiral purity of compound I is 99.21%.
[0105] The chiral purity spectrum of compound Ⅰ is shown in the attached Figure 7 .
[0106] Example 4: Preparation of isomers of compound I
[0107] The isomer synthesis route of compound Ⅰ is as follows:
[0108]
[0109]
[0110] S1. 50 ml (10V) of dichloromethane was added to the reaction bottle, and then 10.5 ml of borane dimethyl sulfide (1N, 1.1 eq) and compound V (5 g, 1.0 eq) were added, and stirring was started; after the system was clarified, the reaction bottle was placed in an ice bath, cooled to 0°C, and 2.0 ml of (S)-2-methyl-CBS-oxazaborolidine (1N, 0.2 eq) was started to be added. After the addition was completed, the temperature was controlled at 0-5°C for reaction for 1 hour, and sampling was performed, indicating that compound V had reacted completely.
[0111] Post-treatment: control the temperature at 0-5°C, add 10ml (2V) methanol to quench the reaction, then add 25ml (5V) 1N hydrochloric acid, stir for 30 minutes, let stand, separate the phases, collect the organic phase, wash once with saturated sodium bicarbonate solution and once with saturated brine, respectively, and concentrate the organic phase under reduced pressure at 45-60°C to obtain a crude compound S-IV; measure 25ml (5V) of methanol and add it to the reaction bottle where the crude compound S-IV is located, heat to 50°C and stir for 30 minutes, then slowly cool to 10-15°C, crystallize and stir for 1 hour, filter, and dry to obtain compound S-IV (3.87g), with a yield of 77.4% and a chiral purity of 100%.
[0112] The chiral purity spectrum of compound S-Ⅳ is shown in the attached Figure 8 .
[0113] S2. Measure 21ml (7V) of tetrahydrofuran and add it to the reaction bottle, start stirring, add compound IV (3g, 1.0eq) and p-toluenesulfonyl chloride (2.4g, 1.1eq) prepared in step S1, place the reaction bottle in a 5-10°C water bath, slowly drop diisopropylethylamine (1.8g, 1.2eq) into the reaction bottle, after adding, heat to 20°C, react for 3 hours, take samples for testing, and confirm that compound R-IV is basically reacted; then add diisopropylethylamine (1.8g, 1.2eq) to the reaction bottle, then add compound III (3.64g, 1.0eq), heat to 70°C, and react for 6 hours. Take samples for testing again, and after confirming that compound III is reacted completely, start cooling to 15°C.
[0114] Post-treatment: Following the above steps, after stirring at 20°C for 1 hour, a solid-liquid mixture was obtained. The filter cake was collected by filtration and rinsed with ethyl acetate. The filter cake was collected and dried to obtain a white solid (4.98 g) with a yield of 77.3%.
[0115] Salt formation: add 9 ml (3V) of tetrahydrofuran to the reaction bottle, then add the above white solid (4 g, 1.0 eq), and start stirring; prepare ethyl acetate solution of methanesulfonic acid: weigh methanesulfonic acid (0.68 g, 1.0 eq) and ethyl acetate (20 ml, 5V) and add them to a conical flask, and stir evenly; add the ethyl acetate solution of methanesulfonic acid dropwise to the reaction bottle, react at room temperature for 2 hours after adding, filter, collect the filter cake, rinse with ethyl acetate, collect the filter cake, and dry to obtain the salt-formed compound R-Ⅱ (4.09 g), with a salt formation yield of 87.5% and a chiral purity of 93.15%.
[0116] S3. Take N-dimethylpyrrolidone (15 ml, 5V) and add it into the reaction bottle. Then add compound R-Ⅱ (3 g, 1.0 eq) prepared in step S2 and lithium chloride (1.92, 10 eq). Heat to 70°C and react for 24 hours. Sample testing indicated that the reaction of compound S-Ⅱ was complete. Then cool to 25°C.
[0117] The chiral purity spectrum of compound R-Ⅳ is shown in the attached Fig. 9 .
[0118] Post-treatment: control the temperature at 10-20°C, add 15 ml of purified water (5V) to the reaction solution, then stir for 30 minutes, filter, rinse the filter cake with purified water, collect the filter cake, and dry to constant weight to obtain the crude isomer of compound I; add the crude isomer of compound I to the reaction bottle again, add a mixed solution of dichloromethane (21 ml, 7V) and isopropyl ether (21 ml, 7V), heat to 45°C, stir for 1 hour, then cool to 10-15°C, crystallize and stir for 30 minutes, filter, collect the filter cake, and dry to constant weight to obtain compound I (1.59 g), with a yield of 72.6% and a chiral purity of 100%.
[0119] The chiral purity spectrum of the isomers of compound Ⅰ is shown in the attached Fig.10 .
[0120] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.
Claims
1. A method for preparing a mabaloxavir intermediate, characterized in that: The steps include: Its synthetic route is: Add (S)-2-methyl-CBS-oxazaborolidine to a mixed solution of compound V and a reducing agent to react to obtain R-IV; Under ice bath conditions, add 1-1.2 molar equivalents of alkaline reagent to the mixed solution of compound R-Ⅳ and sulfonylating agent, and react at 20-30°C for 2-3h; then add 1-1.5 molar equivalents of alkaline reagent, and add compound III, and react at 50-60°C for 6-10h, cool the reaction solution for crystallization, and the obtained white solid and methanesulfonic acid form a salt to obtain compound S-Ⅱ; The mixed solution of compound S-Ⅱ and lithium chloride is reacted at 60-70°C for 10-20h to obtain compound Ⅰ.
2. The method for preparing the mabaloxavir intermediate according to claim 1, characterized in that: The solvent of the mixed solution of compound V and the reducing agent is selected from at least one of tetrahydrofuran, ethyl acetate or dichloromethane; Preferably, the solvent is tetrahydrofuran.
3. The method for preparing the mabaloxavir intermediate according to claim 1, characterized in that: The reducing agent is borane dimethyl sulfide or borane tetrahydrofuran; Preferably, the reducing agent is borane tetrahydrofuran; Preferably, the amount of the reducing agent added is 1.0 to 1.2 equivalents based on the molar equivalent of compound V.
4. The method for preparing the mabaloxavir intermediate according to claim 1, characterized in that: The amount of (S)-2-methyl-CBS-oxazaborolidine added is 0.05 to 0.3 equivalents based on the molar equivalent of compound V; Preferably, the addition temperature of (S)-2-methyl-CBS-oxazaborolidine is -5 to 5°C; Preferably, (S)-2-methyl-CBS-oxazaborolidine is added dropwise, and after the addition is complete, the reaction is carried out for 1 to 2 hours to obtain R-IV.
5. The method for preparing the mabaloxavir intermediate according to claim 1, characterized in that: The solvent of the mixed solution of compound R-IV and the sulfonylating agent is selected from at least one of ethyl acetate, tetrahydrofuran, N,N-dimethylacetamide or methyl tert-butyl ether; Preferably, the solvent is ethyl acetate.
6. The method for preparing the mabaloxavir intermediate according to claim 1, characterized in that: The sulfonylating agent is selected from at least one of methylsulfonyl chloride, ethylsulfonyl chloride, propylsulfonyl chloride, cyclopropylsulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride and 4-chlorobenzenesulfonyl chloride; Preferably, the sulfonylating agent is p-toluenesulfonyl chloride; Preferably, the amount of the sulfonylating agent added is 1.0 to 1.2 equivalents based on the molar equivalent of compound IV.
7. The method for preparing the mabaloxavir intermediate according to claim 1, characterized in that: The alkaline reagent is selected from at least one of triethylamine, diisopropylethylamine, DBU, sodium bicarbonate, sodium carbonate, potassium carbonate, and cesium carbonate; Preferably, the alkaline agent is diisopropylethylamine; Preferably, the amount of the alkaline agent added is 2.0 to 2.6 equivalents based on the molar equivalent of compound IV.
8. The method for preparing the mabaloxavir intermediate according to claim 1, characterized in that: The solvent of the mixed solution of compound S-II and lithium chloride is selected from at least one of N,N-dimethylacetamide, N,N-dimethylacetamide, N-dimethylpyrrolidone and dimethyl sulfoxide.
9. The method for preparing the mabaloxavir intermediate according to claim 8, characterized in that: The solvent is N-dimethylpyrrolidone.
10. The method for preparing the mabaloxavir intermediate according to claim 1, characterized in that: Based on the molar equivalent of compound S-Ⅱ, the amount of lithium chloride added is 6.0eq to 10.0eq, preferably 9eq.
Citation Information
Patent Citations
Methods for preparing substituted polycyclic pyridinone derivatives and their crystals
CN109311911B