Preparation method of macloxvir impurity

Abstract

The invention relates to a preparation method of a macloxvir impurity, and belongs to the technical field of medicine synthesis, in the presence of alkali, a compound with a structure as shown in a formula II and a # imgabs0 compound are placed in a reaction solvent to react at a reaction temperature, and a compound with a structure as shown in a formula III is obtained, the compound with the structure as shown in the formula I and the compound with the structure as shown in the formula II and the compound with the structure as shown in the formula III are as follows: # imgabs1 # R is selected from unsubstituted alkyl, halogenated alkyl or aryl, and X is selected from Cl, Br or F. The method is simple in process, high in preparation purity and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical synthesis and relates to a method for preparing mabaloxavir impurities. Background Art

[0002] Mabaloxavir is a small molecule prodrug that hydrolyzes in vivo to its active ingredient, baloxavir. Its mechanism of action differs from existing antiviral therapies in that it selectively inhibits cap-dependent endonucleases, preventing polymerase function and influenza virus mRNA replication. Compared to existing anti-influenza drugs that target neuraminidase, baloxavir targets an earlier stage in the viral replication cycle. This is the first new anti-influenza drug with a novel mechanism of action approved by the FDA in nearly 20 years.

[0003] During the preparation of the mabaloxavir API, the active ingredient baloxavir undergoes an affinity substitution reaction with a halomethyl carbonate, resulting in a side reaction to form a compound having the structure shown in Formula III. Currently, there are no reports on the synthesis and preparation of this impurity, making it difficult to provide inexpensive, readily available, high-quality impurity reference materials for mabaloxavir quality control research. This impurity significantly impacts the quality of mabaloxavir. If the level of this impurity in the crude mabaloxavir product is too high, the final product, mabaloxavir, must undergo multiple refinements to reduce the impurity level. This compound is highly likely to be produced during the preparation of mabaloxavir and is a key process impurity. Its reaction mechanism is as follows:

[0004]

[0005] Combined with the reaction mechanism, this impurity is inevitable in the process of synthesizing mabaloxavir. Therefore, in order to ensure the full and accurate study of this type of impurity, we developed a preparation method for this type of compound.

[0006] The original patent (CN 201680037827.7 / CN 107709321A) discloses a compound of mabaloxavir, but there is no report on the preparation method of this type of compound. Therefore, we tried the following preparation methods:

[0007] Method 1:

[0008]

[0009] The method comprises the following steps: preparing a compound of structure shown in formula II and halogenated methyl carbonate in the presence of an organic base, triethylamine, to prepare a compound of structure shown in formula III. In this method, the alkalinity of triethylamine is relatively weak, and the reaction conversion rate is not high.

[0010] Method 2:

[0011]

[0012] The method comprises the following steps: preparing a compound of structure represented by formula II and a halogenated methyl carbonate under the action of an inorganic base, sodium hydroxide, to prepare a compound of structure represented by formula III; wherein the inorganic base, sodium hydroxide, has a relatively strong alkalinity, and as the reaction proceeds, the compound of structure represented by formula III is gradually converted into a compound of structure represented by formula II.

[0013] Therefore, providing a preparation method of the compound of formula III with mild reaction, high reaction conversion rate and high safety is of great significance for improving the drug quality control of mabaloxavir. Summary of the Invention

[0014] The object of the present invention is to solve the problem that the prior art lacks a method for preparing key process impurities of mabaloxavir. To address this problem, the present invention provides a method for preparing key process impurities of mabaloxavir with simple process, high preparation purity, and suitability for industrial production.

[0015] The present invention adopts the following technical solutions to achieve its purpose:

[0016] The present invention provides a method for preparing a compound of formula III, which comprises the following steps: reacting a compound of formula II with The compound of formula III is obtained by reacting with the intermediate and competing with the enolization-alkylation reaction under alkaline conditions. The reaction route is:

[0017]

[0018] Wherein, the structural compound represented by formula II and the structural compound represented by formula III are:

[0019]

[0020] R is selected from unsubstituted alkyl, halogenated alkyl or aryl, and X is selected from Cl, Br or F.

[0021] Preferably, R is methyl, X is Cl, and the structure is shown in Formula III:

[0022]

[0023] Preferably, the structural compound shown in formula II and The molar ratio of the compounds is 1:(1.00-4.00).

[0024] Preferably, the base used in the reaction is selected from one or more of triethylamine, diisopropylethylamine, pyridine, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, dipotassium hydrogen phosphate, potassium phosphate, and cesium carbonate, and the molar ratio of the structural compound represented by Formula II to the base is 1:(0.50-3.00).

[0025] Preferably, the reaction solvent is an aprotic solvent selected from one or more of dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, 1,4-dioxane, acetonitrile, chloroform, and 1,2-dichloroethane.

[0026] Preferably, in the preparation method, the volume ratio of the compound represented by formula II to the reaction solvent is 1:(1-10).

[0027] Preferably, the reaction temperature is not limited, but the reaction can be usually carried out at -20°C to 100°C, preferably at 0 to 80°C.

[0028] Preferably, the reaction time is not limited, but the reaction can usually be carried out for 0.5 h to 24 h, preferably 1 to 16 h.

[0029] The inventor found that the difficulty lies in the reaction process. Control the amount of compound used and the type of reaction base used. If the alkalinity of the reaction base is too strong, the formed product will degrade, thereby reducing the reaction yield. If the amount of the compound used is too small, the reaction will be incomplete, resulting in a low product yield. For details, see Examples 2 and 3.

[0030] The beneficial effects of the present invention are:

[0031] The present invention fills the gap in the technology for preparing impurities in the key process of mabaloxavir, can provide a low-cost, high-quality impurity reference substance for quality research of mabaloxavir, and is of great significance to the safe use of mabaloxavir. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 It is the mass spectrum of the structural compound shown in formula III.

[0033] Figure 2 1H-NMR spectrum of the compound represented by formula III.

[0034] Figure 3 The HPLC spectrum of the structural compound shown in formula III.

[0035] Figure 4 The HPLC spectrum shows the location of the compound represented by the structure of Formula III in mabaloxavir. DETAILED DESCRIPTION

[0036] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts should fall within the scope of protection of the present invention.

[0037] Example 1

[0038] Preparation of the structural compound shown in formula III

[0039] At room temperature, 5.00 g (10.34 mmol, 1.00 equivalent) of the compound represented by formula II and 3.14 g (31.02 mmol, 3.00 equivalent) of triethylamine were mixed in 20 ml of dichloromethane and stirred to dissolve. Then, 5.15 g (5.76 mmol, 4.00 equivalent) of dimethyl chloromethyl carbonate was added. After stirring and reacting at room temperature for 14 hours, 20 ml of water was added to the reaction solution for washing and extraction. After standing and separating the liquids, the upper aqueous phase was retained and concentrated to dryness under reduced pressure to obtain a white solid powder of the compound represented by formula III (2.73 g, yield 46.03%, purity 96.14%).

[0040] Example 2

[0041] Comparison of reaction base types prepared from the structural compound shown in Formula III

[0042] Specific embodiments As shown in Example 1, we tried to use the same equivalent of different types of reaction bases (listed in Table 1 below) to prepare the structural compound represented by Formula III. The corresponding reaction yields and product purities are shown in Table 1 below:

[0043] Table 1 Effect of different reaction bases on the preparation of the structural compound shown in formula III

[0044] Reaction base Product yield Product purity Triethylamine 46.03％ 96.14％ N,N-Diisopropylethylamine 51.56％ 97.83％ potassium carbonate 89.23％ 99.17％ Sodium hydroxide 57.89％ 94.07％ Sodium bicarbonate 70.41％ 95.33％ Sodium methoxide 7.99％ 80.32％ Pyridine 77.14％ 95.33％ sodium carbonate 78.65％ 96.32％ potassium bicarbonate 66.89％ 96.80％ Potassium dihydrogen phosphate 62.34％ 97.44％ potassium phosphate 82.91％ 98.23％ Cesium carbonate 87.25％ 98.12％

[0045] Example 3

[0046] Comparison of the amount of dimethyl chloroformate prepared from the structural compound shown in formula III

[0047] Specific embodiments As shown in Example 1, potassium carbonate was used as the base, and different equivalents (relative to 1 molar equivalent of the compound of the structure shown in Formula II, as listed in Table 2 below) of dimethyl chloromethyl carbonate were tried to prepare the compound of the structure shown in Formula III. The corresponding reaction yields and product purities are shown in Table 2 below:

[0048] Table 2 Effect of different equivalents of dimethyl chloromethyl carbonate on the preparation of the structural compound shown in formula III

[0049] Molar equivalent Product yield Product purity 1.00 12.45％ 91.21％ 2.00 60.82％ 95.97％ 3.00 72.36％ 96.88％ 4.00 89.78％ 99.17％

[0050] Example 4

[0051] Comparison of different halogenated reagents for the preparation of the structural compound shown in Formula III

[0052] (1) At room temperature, 5.00 g (10.34 mmol, 1.00 equivalent) of the compound of formula II and 1.43 g (10.34 mmol, 1.00 equivalent) of potassium carbonate were mixed in 20 ml of dichloromethane and stirred to dissolve. Subsequently, 6.99 g (41.37 mmol, 4.00 equivalent) of bromomethyl dimethyl carbonate was added. After stirring and reacting at room temperature for 14 hours, 20 ml of water was added to the reaction solution for washing and extraction. After standing and separating the liquids, the upper aqueous phase was retained and concentrated to dryness under reduced pressure to obtain a white solid powder of the compound of formula III (2.54 g, yield 42.9%, purity 94.3%).

[0053] (2) At room temperature, 5.00 g (10.34 mmol, 1.00 equivalent) of the compound of formula II and 1.43 g (10.34 mmol, 1.00 equivalent) of potassium carbonate were mixed in 20 ml of dichloromethane and stirred to dissolve. Then, 4.47 g (41.37 mmol, 4.00 equivalent) of dimethyl fluoromethyl carbonate was added. After stirring and reacting at room temperature for 14 hours, 20 ml of water was added to the reaction solution for washing and extraction. After standing and separating the liquids, the upper aqueous phase was retained and concentrated to dryness under reduced pressure to obtain a white solid powder of the compound of formula III (2.28 g, yield 38.6%, purity 91.7%).

[0054] Example 5

[0055] Preparation of the structural compound shown in formula III

[0056] At room temperature, 22.42 g (46.37 mmol, 1.00 equivalent) of the compound represented by formula II and 6.41 g (46.37 mmol, 1.00 equivalent) of potassium carbonate were mixed in 20 ml of dichloromethane and stirred to dissolve. Then, 5.15 g (185.48 mmol, 4.00 equivalent) of dimethyl chloromethyl carbonate was added. After stirring and reacting at room temperature for 16 hours, 20 ml of water was added to the reaction solution for washing and extraction. After standing and separating the liquids, the upper aqueous phase was retained and concentrated to dryness under reduced pressure to obtain a white solid powder having the structure represented by formula III (23.69 g, yield 89.23%, purity 99.17%). + =573.5. 1H-NMR(400MHz,DMSO)δ:7.51–7.31(m,2H),7.05–7.20(m,3H),6.84–6.90(d,1H), 6.77–6.84(d,1H),6.56–6.58(d,1H),5.76–5.81(d,4H),5.36–5.40(dd,1H),4.44 –4.48(dd,1H),4.37-4.40(d,1H),4.07–4.13(d,1H),3.89–3.92(dd,1H),3.76(s, 2H),3.58–3.41(dd,1H),3.35–3.41(m,1H),3.18–3.25(m,1H),2.73–2.82(m,1H).

[0057] A method for detecting a compound of the structure represented by formula III of mabaloxavir, characterized by comprising:

[0058] (1) Dilution: Solution A (0.1% trifluoroacetic acid solution containing 0.5 mmol / L disodium ethylenediaminetetraacetic acid)-acetonitrile (3:1);

[0059] (2) Test solution: Take the product, dissolve it in diluent and dilute it to a solution containing approximately 0.4 mg of mabaloxavir per 1 ml;

[0060] (3) Chromatographic conditions: Octadecylsilane bonded silica gel was used as the filler; solution A was used as mobile phase A, acetonitrile was used as mobile phase B, the column temperature was 35°C, and gradient elution was performed as shown in the table below; the flow rate was 0.6 ml / min; the column temperature was 35°C; the detection wavelength was 259 nm; and the injection volume was 5 μl.

[0061] Time / minute Mobile phase A / % Mobile phase B / % 0 70 30 5 70 30 45 10 90 55 10 90 55.1 70 30 70 70 30

[0062] (4) Determination method: Accurately measure the test solution, inject it into the liquid chromatograph, and record the chromatogram.

[0063] Finally, it should be noted that the above-described embodiments are only specific implementation methods of the present invention, which are used to illustrate the technical solutions of the present invention rather than to limit them. The protection scope of the present invention is not limited thereto. Although the present invention has been described in detail with reference to the above-mentioned embodiments, ordinary technicians in this field should understand that any technician familiar with this technical field can still modify the technical solutions recorded in the above-mentioned embodiments within the technical scope disclosed by the present invention, or make equivalent replacements for some of the technical features therein; and these modifications, changes or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention, and should all be covered by the protection scope of the present invention.

Claims

1. A method for preparing a compound having a structure represented by formula III, characterized in that: In the presence of a base, the structural compound shown in formula II is The compound is placed in a reaction solvent and reacted at a reaction temperature to obtain a compound of formula III, wherein the compound of formula II and the compound of formula III are as follows: R is selected from unsubstituted alkyl, halogenated alkyl or aryl, and X is selected from Cl, Br or F.

2. The method for preparing a compound of formula III according to claim 1, wherein: The R is methyl, and X is Cl.

3. The method for preparing a compound of formula III according to claim 1, wherein: The structural compound shown in formula II and formula The molar ratio of the compounds is 1:(1.00-4.00).

4. The method for preparing a compound of formula III according to claim 1, wherein: The molar ratio of the compound represented by formula II to the base is 1:(0.50-3.00).

5. The method for preparing a compound of formula III according to claim 1 or 4, characterized in that: The base is selected from one or more of triethylamine, diisopropylethylamine, pyridine, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, dipotassium hydrogen phosphate, potassium phosphate, and cesium carbonate.

6. The method for preparing a compound of formula III according to claim 1, wherein: The volume ratio of the compound represented by formula II to the reaction solvent is 1:(1-10).

7. The method for preparing a compound of formula III according to claim 1 or 6, characterized in that: The reaction solvent is selected from one or more of dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, 1,4-dioxane, acetonitrile, chloroform, and 1,2-dichloroethane.

8. The method for preparing a compound of formula III according to claim 1, wherein: The reaction temperature is 0-80°C.

9. The method for preparing a compound of formula III according to claim 1, wherein: The reaction time of the reaction is 1-10h.

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