A method for preparing the main chain intermediate of isavuconazole

Abstract

The present application relates to the technical field of drug synthesis, and in particular to a method for preparing a main chain intermediate of isavuconazole; the method comprises: using a resolving agent to perform a resolving reaction on a racemate containing a first diastereomer and a second diastereomer to obtain a second diastereomer; using oxalyl chloride and ammonia water to perform an amidation reaction on the second diastereomer to obtain a first intermediate; performing a dehydration reaction on phosphorus oxychloride and the first intermediate to obtain a second intermediate; performing an alkali treatment on an alkaline substance and the second intermediate in an organic solvent and water to cause the second intermediate to undergo an α-position configuration flip to obtain an isavuconazole main chain intermediate M7. The method uses the racemate of two diastereomers of the isavuconazole intermediate M4 as a raw material, and successfully synthesizes the isavuconazole main chain intermediate M7 through steps such as resolving reaction, amidation reaction, dehydration reaction and alkali treatment, and the conversion rate of the alkali treatment is above 69%.

Description

Technical Field

[0001] The present application relates to the technical field of drug synthesis, and in particular to a method for preparing a main chain intermediate of isavuconazole. Background Art

[0002] Since the side chain of the molecular structure of isavuconazole has a high affinity with the fungal CYP51 protein, especially for fungi resistant to other triazole drugs, isavuconazole has a wide antifungal spectrum, so isavuconazole is a new ultra-broad-spectrum antifungal drug. In addition, after oral administration, the body can quickly absorb isavuconazole, especially the sulfate of isavuconazole can be rapidly hydrolyzed by plasma esterase and completely converted into the active metabolite isavuconazole, and the absolute bioavailability of isavuconazole is 98%. At present, isavuconazole has the fast-track approval qualification for the treatment of invasive fungal infections in patients with moderate to severe renal insufficiency, as well as the orphan drug qualification for the treatment of invasive aspergillosis and zygomycosis. As a first-line preventive drug for patients with invasive fungal infections, isavuconazole sulfate has been launched one after another. Compared with the characteristics of isavuconazole, isavuconazole sulfate has been widely used in clinical practice due to its broad antibacterial spectrum and high pharmacological activity. At present, the synthesis of isavuconazole sulfate requires the preparation of its main chain intermediate M7.

[0003] The current mainstream method for synthesizing the main chain intermediate M7 will produce a large number of diastereomers. The proportion of active ingredients in these diastereomers that can be used for the subsequent synthesis of isavuconazole is relatively low, which makes the cost of synthesizing isavuconazole relatively high. Therefore, it is necessary to develop a method for synthesizing the main chain intermediate M7 using diastereomers as raw materials, so as to expand the route of synthesizing isavuconazole from diastereomers and reduce the cost of synthesizing isavuconazole, so as to realize the resource utilization of drug raw materials.

[0004] The prior art method for synthesizing the main chain intermediate M7 includes: (1) using 1-(2,5-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone as a raw material, reacting with an organic zinc reagent, and then hydrolyzing to generate 3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazolyl)butyric acid, chiral separation to obtain a (2R,3R) configuration, and then activating amination to obtain M6, and then dehydrating to obtain isavuconazole intermediate M7. The specific reaction process is as follows: Figure 3 (2) Using LiHMDS as the raw material, acetone cyanohydrin is added under low temperature conditions to react. The specific reaction process is as follows: Figure 4 shown. Summary of the invention

[0005] The present application provides a method for preparing a main chain intermediate of isavuconazole to solve the following technical problem: how to reduce the cost of synthesizing isavuconazole.

[0006] In a first aspect, the present invention provides a method for preparing a main chain intermediate of isavuconazole, the method comprising:

[0007] Using a resolving agent to perform a resolving reaction on a racemate containing a first diastereomer and a second diastereomer to obtain a second diastereomer;

[0008] The second diastereomer is subjected to an amidation reaction using oxalyl chloride and aqueous ammonia to obtain a first intermediate;

[0009] Dehydrating phosphorus oxychloride and the first intermediate to obtain a second intermediate;

[0010] Treating the alkaline substance and the second intermediate with an alkali in an organic solvent and water to cause the second intermediate to flip its α-position configuration, thereby obtaining the isavuconazole main chain intermediate M7;

[0011] Wherein, the first diastereomer has a molecular structure as shown in Formula 1,

[0012] , Formula 1;

[0013] The second diastereomer has a molecular structure as shown in Formula 2,

[0014] Formula 2;

[0015] The first intermediate has a molecular structure as shown in Formula 3,

[0016] Formula 3;

[0017] The second intermediate has a molecular structure as shown in Formula 4,

[0018] Formula 4.

[0019] Optionally, the organic solvent comprises at least one of the following: methanol, ethanol, acetonitrile and tetrahydrofuran; and / or

[0020] The alkaline substance includes at least one of the following: sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.

[0021] Optionally, the resolving agent includes R-(+)-α-methylbenzylamine, and the solvent of the resolving agent includes ethyl acetate and isopropanol.

[0022] Optionally, the amount n1 of the alkaline substance and the amount n2 of the second intermediate satisfy the relationship: n1:n2=(0.5-5):1; and / or

[0023] The volume V1 of the organic solvent and the volume V2 of the water satisfy the relationship: V1:V2=1:(0.5-5).

[0024] Optionally, the amount n3 of the resolving agent and the amount n4 of the racemate satisfy the relationship: n3:n4=(1.00-1.10):1.

[0025] Optionally, the amount n5 of the oxalyl chloride and the amount n6 of the second diastereomer satisfy the relationship: n5:n6=(2-3):1.

[0026] Optionally, the amount n7 of the phosphorus oxychloride and the amount n8 of the first intermediate satisfy the relationship: n7:n8=(2-3):1.

[0027] Optionally, the temperature of the resolution reaction is ≥80°C, and the time of the resolution reaction is ≥1h.

[0028] Optionally, the temperature of the amidation reaction is 10° C. to 20° C., and the time of the amidation reaction is ≥1 h.

[0029] Optionally, the temperature of the dehydration reaction is 60°C to 70°C, and the time of the dehydration reaction is ≥12h.

[0030] The above technical solution provided by the embodiment of the present application has the following advantages compared with the prior art:

[0031] The present application provides a method for preparing a main chain intermediate of isavuconazole. The method uses a racemate of two diastereoisomers of 3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyric acid (isavuconazole intermediate M4) as a raw material, and splits the racemate into a single second diastereoisomer through a splitting reaction of a splitting agent. The second diastereoisomer is sequentially subjected to an amidation reaction to convert the carboxyl group of the second diastereoisomer into an amide group, and then a dehydration reaction is performed to convert the amide group into a cyano group. Finally, a base treatment is performed to promote the second diastereoisomer to be a second diastereoisomer. The second intermediate undergoes α-position configuration inversion after alkali treatment, thereby obtaining isavuconazole main chain intermediate M7; therefore, the method uses two diastereomers of isavuconazole intermediate M4 as raw materials, and obtains isavuconazole main chain intermediate M7 through a series of reactions such as resolution reaction, amidation reaction, dehydration reaction and alkali treatment; the method uses the racemic forms of two diastereomers of isavuconazole intermediate M4 as raw materials to synthesize isavuconazole main chain intermediate M7, expands the direct source of isavuconazole main chain intermediate M7, thereby improving the utilization rate of diastereomers produced by synthesizing isavuconazole, so as to reduce the cost of synthesizing isavuconazole. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments consistent with the present application and, together with the description, serve to explain the principles of the present application.

[0033] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, for ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative labor.

[0034] Figure 1 A schematic flow chart of a method for preparing a main chain intermediate of isavuconazole provided in an embodiment of the present application;

[0035] Figure 2 A schematic diagram of the principle of a method for preparing a main chain intermediate of isavuconazole provided in an embodiment of the present application;

[0036] Figure 3 This is a schematic diagram of the principle of synthesizing the main chain intermediate of isavuconazole in the prior art 1 disclosed in this application;

[0037] Figure 4 This is a schematic diagram of the principle of synthesizing isavuconazole according to the prior art 2 disclosed in this application;

[0038] Figure 5 The high performance liquid chromatogram provided in this application using the second intermediate as raw material;

[0039] Figure 6 This is a high performance liquid chromatogram of the main chain intermediate of isavuconazole provided in Example 1 of the present application;

[0040] Figure 7 This is a high performance liquid chromatogram of the main chain intermediate of isavuconazole provided in Example 2 of the present application;

[0041] Figure 8 This is a high performance liquid chromatogram of the main chain intermediate of isavuconazole provided in Example 3 of the present application;

[0042] Fig. 9 The hydrogen nuclear magnetic resonance spectrum of the second diastereomer M4-IM1 provided in Example 1 of the present application;

[0043] Fig.10 This is the hydrogen nuclear magnetic resonance spectrum of the first intermediate M6-IM1 provided in Example 1 of the present application;

[0044] Fig.11 This is the hydrogen nuclear magnetic resonance spectrum of the second intermediate M7-IM3 provided in Example 1 of the present application;

[0045] Fig.12 This is the hydrogen nuclear magnetic resonance spectrum of the isavuconazole main chain intermediate M7 provided in Example 1 of the present application. DETAILED DESCRIPTION

[0046] In order to make the purpose, technical solution and advantages of the embodiments of the present application clearer, the technical solution in the embodiments of the present application will be clearly and completely described below in conjunction with the drawings in the embodiments of the present application. Obviously, the described embodiments are part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of this application.

[0047] Various embodiments of the present application may be presented in the form of a range; it should be understood that the description in the form of a range is only for convenience and brevity and should not be understood as a rigid limitation on the scope of the present application; therefore, it should be considered that the range description has specifically disclosed all possible sub-ranges and single numerical values ​​within the range; for example, it should be considered that the range description from 1 to 6 has specifically disclosed sub-ranges, such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., as well as single numbers within the range, such as 1, 2, 3, 4, 5 and 6, which applies regardless of the range; in addition, whenever a numerical range is indicated in this document, it is meant to include any cited numbers (fractions or integers) within the indicated range.

[0048] In this document, the terms including "including" and "including" mean "including but not limited to". Relational terms such as "first" and "second" are used only to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. "And / or" describes the association relationship of associated objects, indicating that there can be three relationships. For example, A and / or B can mean: A exists alone, A and B exist at the same time, and B exists alone; where A and B can be singular or plural. "At least one" means one or more, "plurality" means two or more; "at least one", "at least one of the following" or similar expressions refer to any combination of these items, including any combination of single or plural items; for example, "at least one of a, b, or c", or "at least one of a, b, and c" can all mean: a, b, c, ab (i.e. a and b), ac, bc, or abc, where a, b, and c can be single or plural, respectively. "Parts" such as parts by weight and parts by mass indicate the proportional relationship between the components. In the proportional relationship involved in this article, the parameters that need to be described by proportion should be understood as the first term of the proportional formula in the order of description, and the proportional numbers should be understood as the second term of the proportional formula. For example, if the mass ratio of substance A, substance B and substance C is 1:2:3, then substance A, substance B and substance C should correspond to the proportional numbers in the proportional formula in the order of description, that is, the mass of substance A: the mass of substance B: the mass of substance C = 1:2:3.

[0049] Unless otherwise specified, various raw materials, reagents, instruments and equipment used in this article can be purchased from the market or prepared by existing methods.

[0050] It should be noted that the prior art (1) described in the background technology can first precipitate the reaction solution of ethyl 3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanoate (M3), collect the precipitate after centrifugation to obtain the racemate {(2R,3R) and (2S,3S)}, remove the diastereomers (2R,3S) and (2S,3R) remaining in the mother liquor, and then perform enzymatic separation of the racemate {(2R,3R) and (2S,3S)} of T001-M3 to obtain M3 (2R,3R); or precipitate ethyl 3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanoate (M3) to obtain M3 (2R,3R). ) The precipitation of ethyl butyrate (M3) reaction solution was stirred for 72h to remove diastereomers (2R, 3S) and (2S, 3R), and then the obtained T001-M3 racemate {(2R, 3R) and (2S, 3S)} was hydrolyzed to obtain T001-M4 racemate {(2R, 3R) and (2S, 3S)}, and then separated by a chiral resolving agent to obtain M4 (2R, 3R); The inventors found that: the above two methods can obtain M3 (2R, 3R) or M4 (2R, 3R) with higher chiral purity, but these methods do not treat diastereomers, so the proportion of active ingredients that can be used to synthesize isavuconazole is low, which will undoubtedly waste synthesis resources and increase synthesis costs.

[0051] The inventors found that the prior art (2) described in the background technology requires the reaction to be carried out under low temperature conditions, which is a relatively harsh reaction condition. In addition, the raw materials used are expensive, which is not conducive to large-scale industrial production. In addition, highly toxic substances such as acetone cyanohydrin are used in the synthesis process, which will introduce cyano groups into the entire reaction, increasing the safety risk of the reaction and being not conducive to safe industrial production.

[0052] Therefore, it is necessary to develop a method for synthesizing the main chain intermediate M7 using diastereoisomers as raw materials, so as to expand the route of synthesizing isavuconazole from diastereoisomers and reduce the cost of synthesizing isavuconazole, so as to realize the resource utilization of drug raw materials.

[0053] Figure 1 A schematic flow chart of a method for preparing a main chain intermediate of isavuconazole provided in an embodiment of the present application is exemplarily shown;

[0054] Figure 2 The schematic diagram of the principle of a method for preparing a main chain intermediate of isavuconazole provided in an embodiment of the present application is exemplarily shown;

[0055] like Figure 1 and Figure 2 As shown, the present embodiment provides a method for preparing a main chain intermediate of isavuconazole, the method comprising:

[0056] S1. using a resolving agent to perform a resolving reaction on a racemate containing a first diastereomer and a second diastereomer to obtain a second diastereomer;

[0057] S2. using oxalyl chloride and aqueous ammonia to carry out an amidation reaction on the second diastereomer to obtain a first intermediate;

[0058] S3. dehydrating phosphorus oxychloride and the first intermediate to obtain a second intermediate;

[0059] S4. treating the alkaline substance and the second intermediate with an alkali in an organic solvent and water to cause the second intermediate to flip its α-position configuration to obtain isavuconazole main chain intermediate M7;

[0060] Wherein, the first diastereomer has a molecular structure as shown in Formula 1,

[0061] ,

[0062] Formula 1;

[0063] The second diastereomer has a molecular structure as shown in Formula 2,

[0064] ,

[0065] Formula 2;

[0066] The first intermediate has a molecular structure as shown in Formula 3,

[0067] ,

[0068] Formula 3;

[0069] The second intermediate has a molecular structure as shown in Formula 4,

[0070] ,

[0071] Formula 4.

[0072] It should be noted that the isavuconazole main chain intermediate M7 has a molecular structure as shown in Formula 5,

[0073] ,

[0074] Formula 5.

[0075] It should be noted that the method for preparing the main chain intermediate of isavuconazole provided in the examples of the present application cleverly utilizes the racemates of two diastereoisomers of ethyl 3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanoate (i.e., isavuconazole intermediate M4) as starting materials. This choice not only enriches the source of raw materials, but also lays a solid foundation for the efficient implementation of subsequent steps. The specific principles are as follows:

[0076] First, the racemate is effectively resolved by a carefully designed resolving agent, converting it into a single second diastereomer. This step is key to ensuring the smooth progress of subsequent reactions because it eliminates the interference of non-target isomers, improves the specificity of the reaction and the purity of the product.

[0077] Next, the second diastereomer obtained by separation was subjected to an amidation reaction. By precisely controlling the reaction conditions and selecting appropriate reagents, the carboxyl functional group in the second diastereomer was cleverly converted into an amide functional group. This conversion not only provides the necessary reaction sites for the subsequent dehydration reaction, but also lays an important foundation for the structural construction of the final product.

[0078] Subsequently, the amide group was further converted to a cyano group through a dehydration reaction. This step not only enriched the structural diversity of the molecule, but also provided a key functional group for the synthesis of the isavuconazole backbone intermediate M7. The selectivity and efficiency of the dehydration reaction are crucial to the success of the entire synthetic route.

[0079] Finally, the alkaline treatment step caused the second intermediate to undergo an α-position configuration flip, thereby successfully obtaining the target product, isavuconazole main chain intermediate M7. This step not only achieved the final optimization of the product structure, but also improved the stability and biological activity of the product through configuration flipping.

[0080] In summary, this method successfully synthesized the isavuconazole main chain intermediate M7 by cleverly utilizing the racemic forms of the two diastereoisomers of the isavuconazole intermediate M4 as raw materials through a series of carefully designed reaction steps such as resolution reaction, amidation reaction, dehydration reaction and alkaline treatment. This method not only expands the direct source of the isavuconazole main chain intermediate M7, but also significantly reduces the cost of synthesizing isavuconazole by improving the utilization rate of diastereoisomers, providing strong technical support for the industrial production of isavuconazole.

[0081] In some optional embodiments, the organic solvent comprises at least one of: methanol, ethanol, acetonitrile and tetrahydrofuran; and / or

[0082] The alkaline substance comprises at least one of the following: sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate;

[0083] In these embodiments, the organic solvent may include at least one of methanol, ethanol, acetonitrile and tetrahydrofuran, and the alkaline substance may include at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate, which promotes the second intermediate to fully undergo α-position configuration inversion in the organic solvent and water, thereby obtaining the isavuconazole main chain intermediate M7.

[0084] In some optional embodiments, the resolving agent includes R-(+)-α-methylbenzylamine, and the solvent of the resolving agent includes ethyl acetate and isopropanol;

[0085] In these embodiments, the resolving agent includes R-(+)-α-methylbenzylamine, and the solvent of the resolving agent may include ethyl acetate and isopropanol. Compared with resolving agents such as S-(-)-α-methylbenzylamine, the resolving agent can effectively resolve the racemate into a second diastereomer with a specific structure, so that the resolution reaction is fully carried out.

[0086] In some optional embodiments, the amount n1 of the alkaline substance and the amount n2 of the second intermediate satisfy the relationship: n1:n2=(0.5-5):1; and / or

[0087] The volume V1 of the organic solvent and the volume V2 of the water satisfy the relationship: V1:V2=1:(0.5-5);

[0088] In these embodiments, the amount n1 of the alkaline substance and the amount n2 of the second intermediate can satisfy the relationship: n1:n2=(0.5-5):1, and the volume V1 of the organic solvent and the volume V2 of water can satisfy the relationship: V1:V2=1:(0.5-5), which promotes the second intermediate to fully undergo α-position configuration inversion in the organic solvent and water, thereby obtaining the isavuconazole main chain intermediate M7.

[0089] The amount n1 of the alkaline substance may be 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5 or 5.0.

[0090] The volume V1 of the organic solvent may be 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5 or 5.0.

[0091] In some optional embodiments, the amount n3 of the resolving agent and the amount n4 of the racemate satisfy the relationship: n3:n4=(1.00-1.10):1;

[0092] In these embodiments, the amount n3 of the resolving agent and the amount n4 of the racemate satisfy the relationship: n3:n4=(1.00-1.10):1, which promotes the resolution reaction to have enough resolving agent, and the second diastereomer of the racemate can be resolved by the resolving agent, thereby obtaining a sufficient amount of the second diastereomer.

[0093] The amount n3 of the resolving agent can be 1.00, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09 or 1.10.

[0094] In some optional embodiments, the amount n5 of the oxalyl chloride and the amount n6 of the second diastereomer satisfy the relationship: n5:n6=(2-3):1;

[0095] In these embodiments, the amount n5 of oxalyl chloride and the amount n6 of the second diastereomer can satisfy the relationship: n5:n6=(2-3):1, so that there is a sufficient amount of oxalyl chloride to promote the amidation reaction. The sufficient amount of oxalyl chloride can promote the conversion of the carboxyl group of the second diastereomer into an acyl chloride group, and then under the action of ammonia water, the sufficient amount of acyl chloride group is converted into an amide group, thereby obtaining a sufficient amount of the first intermediate.

[0096] The amount n5 of oxalyl chloride can be 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9 or 3.0.

[0097] In some optional embodiments, the amount n7 of the phosphorus oxychloride and the amount n8 of the first intermediate satisfy the relationship: n7:n8=(2-3):1;

[0098] In these embodiments, the amount n7 of phosphorus oxychloride and the amount n8 of the first intermediate can satisfy the relationship: n7:n8=(2-3):1, so that there is a sufficient amount of phosphorus oxychloride to promote the dehydration reaction. The sufficient amount of phosphorus oxychloride can promote the conversion of the amide group of the first intermediate into a cyano group, thereby obtaining a sufficient amount of the second intermediate.

[0099] The amount n7 of phosphorus oxychloride can be 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9 or 3.0.

[0100] In some optional embodiments, the temperature of the resolution reaction is ≥80°C, and the time of the resolution reaction is ≥1h;

[0101] In these embodiments, the temperature of the resolution reaction is ≥80°C, and the time of the resolution reaction is ≥1h, so that the resolution reaction has sufficient temperature and time, which can enable the resolving agent to effectively resolve the racemate to obtain a sufficient amount of the second diastereomer.

[0102] The temperature of the resolution reaction can be 80°C, 81°C, 82°C, 83°C, 84°C or 85°C.

[0103] The resolution reaction time can be 1.0 h, 1.5 h, 2.0 h, 2.5 h, 3.0 h, 3.5 h or 4.0 h.

[0104] In some optional embodiments, the temperature of the amidation reaction is 10°C to 20°C, and the time of the amidation reaction is ≥1h;

[0105] In these embodiments, the temperature of the amidation reaction can be 10°C to 20°C, and the time of the amidation reaction can be ≥1h, so that the amidation reaction has sufficient temperature and sufficient time. The amidation reaction with sufficient temperature and time can promote the conversion of the carboxyl group of the second diastereomer into amide, thereby obtaining a sufficient amount of the first intermediate.

[0106] The temperature of the amidation reaction can be 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C or 20°C.

[0107] The amidation reaction time can be 1.0 h, 1.5 h, 2.0 h, 2.5 h, 3.0 h, 3.5 h or 4.0 h.

[0108] It should be noted that the specific process of the amidation reaction is that oxalyl chloride first reacts with the second diastereomer to form an acyl chloride group on the structure of the second diastereomer, and then the acyl chloride group is converted into an amide group under the action of ammonia water.

[0109] In some optional embodiments, the temperature of the dehydration reaction is 60° C. to 70° C., and the time of the dehydration reaction is ≥ 12 h.

[0110] In these embodiments, the temperature of the dehydration reaction can be 60° C. to 70° C., and the time of the dehydration reaction can be ≥ 12 h, so that the dehydration reaction has sufficient temperature and time. The amidation reaction with sufficient temperature and time can prompt phosphorus oxychloride to effectively dehydrate the amide of the first intermediate to obtain a cyano group, thereby obtaining a sufficient amount of the second intermediate.

[0111] The temperature of the dehydration reaction can be 60°C, 61°C, 62°C, 63°C, 64°C, 65°C, 66°C, 67°C, 68°C, 69°C or 70°C.

[0112] The dehydration reaction time can be 12 h, 12.5 h, 13.0 h, 13.5 h, 14.0 h, 15.5 h or 16.0 h.

[0113] The present application is further described below in conjunction with specific examples. The experimental methods in the following examples where specific conditions are not specified are usually measured in accordance with national standards / industry standards; if there are no corresponding national standards / industry standards, they are measured in accordance with common international standards, conventional conditions or conditions recommended by the manufacturer.

[0114] Example 1: Multiple batches of raw materials were selected, and the proportions of their diastereoisomers are shown in Table 1.

[0115] Table 1 The proportion of diastereoisomers

[0116]

[0117] As can be seen from Table 1, in the actual synthesis of isavuconazole, the generated isavuconazole intermediate M4 and its enantiomers account for about 61% to 72% of the crude isavuconazole intermediate, of which M4 accounts for 30% to 36% of the crude isavuconazole intermediate; and the diastereoisomer M4-IM1 (the second diastereoisomer) accounts for 12% to 18% of the crude isavuconazole intermediate, accounting for about 1 / 3 to 1 / 2 of M4.

[0118] Based on the above analysis, a preparation method for the main chain intermediate M7 of isavuconazole was designed using the second diastereomer as the intermediate product.

[0119] like Figure 1 As shown, a method for preparing a main chain intermediate of isavuconazole comprises:

[0120] S1. Using a resolving agent to perform a resolving reaction on a racemate containing a first diastereomer and a second diastereomer to obtain a second diastereomer; the specific process is as follows:

[0121] 2200 mL of ethyl acetate and 100 mL of ethanol were added to the reaction flask, stirring was started, 200.00 g of M4 diastereomer (mixture of the first diastereomer and the second diastereomer) (amount of substance was 0.678 mol), 84.79 g of R(+)-α-methylbenzylamine (amount of substance was 0.699 mol) were added in sequence, and then the temperature was raised to 80°C for resolution reaction for 1 hour, and the temperature was naturally lowered to 20°C to 25°C for crystallization for 1 hour to obtain a crystal solution, and the crystal solution was filtered to obtain a white solid; then the white solid, 200 g of water and 25 g of sodium hydroxide were added to the reaction flask, stirred and dissolved to obtain a mixture; 4N dilute hydrochloric acid was dropped into the mixture to adjust the pH of the mixture to 2-3, and then suction filtered and dried to obtain 80.00 g of the second diastereomer M4-IM1 as a white solid, with a molar yield of 80.0%, HPLC>99%, and ee%>99%. The results of its H NMR spectrum are as follows Fig. 9 As shown, the result is:

[0122] 1 H NMR (400 MHz, DMSO-d6): δ 8.23(s, 1H), 7.65(s, 1H), 6.98-7.14(m,3H), 4.74-4.78(d, 1H), 4.58-4.61(d, 1H), 3.16-3.21(q, 1H), 1.24-1.26(d, 3H).

[0123] S2. The second diastereomer is subjected to amidation reaction using oxalyl chloride and ammonia water to obtain the first intermediate; the specific process is as follows:

[0124] 400 mL of tetrahydrofuran and 50.00 g of the second diastereomer M4-IM1 (the amount of substance is 0.168 mol) were added to the reaction flask in sequence, stirred and dissolved, then cooled to 10°C to 20°C, the temperature was controlled at 10°C to 20°C, and 53.37 g of oxalyl chloride (the amount of substance is 0.420 mol) was added dropwise at the same time to react for 1 hour to obtain a reaction solution; the reaction solution was added to 137.25 g of pre-cooled ammonia water (the amount of substance is 2.018 mol), the temperature was controlled at 20°C to 30°C and the reaction was continued for 1 hour to obtain a reaction solution; the reaction solution was filtered, and the filtrate was allowed to stand for liquid separation, and the organic phase was collected; the obtained organic phase was washed with 100 mL of 8% mass concentration sodium hydroxide aqueous solution and 100 mL of water in sequence, and then the washed organic phase was concentrated to obtain 40.00 g of a light yellow solid as the first intermediate M6-IM1, with a molar yield of 80%, and HPLC>95%. The results of its H NMR spectrum are as follows Fig.10 As shown, the result is:

[0125] 1 H NMR (400 MHz, DMSO-d6): δ 8.03(s, 1H), 7.72(s, 1H), 7.10(m, 1H),6.88-6.97(m,2H),5.83-5.89(d,2H),5.40(s,1H), 4.75-4.78(d, 1H), 4.55(d, 1H),3.22-3.27(q, 1H), 1.50-1.52(d, 3H).

[0126] S3. Dehydrating phosphorus oxychloride and the first intermediate to obtain a second intermediate; the specific process is:

[0127] 240 mL of tetrahydrofuran and 30.00 g of the first intermediate M6-IM1 (the amount of substance is 0.101 mol) were added to the reaction bottle in sequence for stirring and dissolving, and then the temperature was raised to 60°C to 62°C, and the temperature was controlled at 60°C to 70°C. At the same time, 38.82 g of phosphorus oxychloride (the amount of substance is 0.253 mol) was dripped in for dehydration reaction for 12 hours to obtain a reaction solution; the reaction solution was dripped into 100 mL of water, and then the pH was adjusted to 8 to 9, and the reaction solution was filtered to obtain 22.54 g of a white solid second intermediate M7-IM3, with a molar yield of 80% and a purity of >95%. The results of its nuclear magnetic resonance hydrogen spectrum are as follows Fig.11 As shown, the result is:

[0128] 1 H NMR (400 MHz, DMSO-d6): δ 8.28(s, 1H), 7.76(s, 1H), 7.11-7.24(m,3H), 6.66(s, 1H), 4.63-4.76(q, 2H), 3.68-3.73(q, 1H), 1.43-1.45(d, 3H).

[0129] S4. The alkaline substance and the second intermediate are treated with alkali in an organic solvent and water to cause the second intermediate to undergo an α-position configuration flip to obtain the isavuconazole main chain intermediate M7; the specific process is:

[0130] 80 mL of tetrahydrofuran, 80 mL of water, 20.00 g of the second intermediate M7-IM3 (the amount of substance is 0.067 mol), and 5.75 g of sodium hydroxide (the amount of substance is 0.143 mol) were added to the reaction flask in sequence, and then stirred at room temperature for 24 hours to complete the alkali treatment to obtain a reaction solution; the reaction solution was allowed to stand for liquid separation and the organic phase was concentrated to obtain a concentrated residue; then 20 mL of isopropanol was added to the concentrated residue, and the temperature was raised to 80°C and stirred for 1 hour, followed by cooling and suction filtration to obtain 17.0 g of a white solid containing an aqueous phase; the obtained white solid containing an aqueous phase was dried by blast drying at 50°C to obtain 15.0 g of a white solid, which is the main chain intermediate M7 of isavuconazole, with a purity of >99% and ee% >99%. The results of its hydrogen nuclear magnetic resonance spectrum are as follows: Fig.12 As shown, the result is:

[0131] 1 H NMR (400 MHz, DMSO-d6): δ 8.35(s, 1H), 7.74(s, 1H), 7.16-7.26(m,2H), 7.03-7.07(m, 1H), 6.72(s, 1H), 4.80-4.83(d, 1H), 4.67-4.71(d, 1H), 3.62-3.67(q, 1H), 1.04-1.06(d, 3H).

[0132] Example 2: Based on the content disclosed in Example 1, the following modifications are further made: the alkaline substance used in the alkali treatment is potassium hydroxide.

[0133] Example 3: Based on the content disclosed in Example 1, the following modifications are further made: the alkaline substance used in the alkali treatment is potassium carbonate.

[0134] Related experiments and effect data:

[0135] Using the second intermediate M7-IM3 (T001-M7-IM3-180401) of Example 1 as the raw material, the distribution of the products after alkali treatment of Example 1, Example 2 and Example 3 was statistically analyzed. The results are shown in Table 2. Figure 5 , Figure 6 , Figure 7 , Figure 8 shown.

[0136] Table 2 Distribution of products after alkali treatment in each example

[0137]

[0138] From Table 1 and Figures 5 to 8It can be seen that the embodiment of the present application provides a method for preparing the main chain intermediate of isavuconazole. The method cleverly uses the racemic forms of two diastereoisomers of the isavuconazole intermediate M4 as raw materials, and successfully synthesizes the isavuconazole main chain intermediate M7 through a series of carefully designed reaction steps such as resolution reaction, amidation reaction, dehydration reaction and alkali treatment, and the conversion rate of the second intermediate M7-IM3 in the alkali treatment step is above 69%.

[0139] In addition, the embodiments of the present application provide a method for preparing a main chain intermediate of isavuconazole, which not only expands the direct source of the main chain intermediate M7 of isavuconazole, but also significantly reduces the cost of synthesizing isavuconazole by improving the utilization rate of diastereoisomers, thereby providing strong technical support for the industrial production of isavuconazole.

[0140] In addition, the present application provides a method for preparing a main chain intermediate of isavuconazole. The yield of the second intermediate separated by the method is 80%. Combined with Table 1, 9.6% to 14.4% of the second intermediate in the isavuconazole intermediate can be used for backward derivatization and conversion into the second intermediate.

[0141] The above description is only a specific implementation of the present application, so that those skilled in the art can understand or implement the present application. It will be apparent to those skilled in the art that various modifications to these embodiments are possible, and the general principles defined in the present application can be implemented in other embodiments without departing from the spirit or scope of the present application. Therefore, the present application will not be limited to the embodiments shown in the present application, but will conform to the widest range consistent with the principles and novel features applied for by the present application.

Claims

1. A method for preparing a main chain intermediate of isavuconazole, the method comprising: Using a resolving agent to perform a resolving reaction on a racemate containing a first diastereomer and a second diastereomer to obtain a second diastereomer; The second diastereomer is subjected to an amidation reaction using oxalyl chloride and aqueous ammonia to obtain a first intermediate; Dehydrating phosphorus oxychloride and the first intermediate to obtain a second intermediate; treating the alkaline substance and the second intermediate with an alkali in an organic solvent and water to cause the second intermediate to flip its α-position configuration, thereby obtaining the isavuconazole main chain intermediate M7; Wherein, the first diastereomer has a molecular structure as shown in Formula 1, , formula 1; The second diastereomer has a molecular structure as shown in Formula 2, , formula 2; The first intermediate has a molecular structure as shown in Formula 3, , formula 3; The second intermediate has a molecular structure as shown in Formula 4, ， Formula 4; The resolving agent is R-(+)-α-methylbenzylamine, and the solvent of the resolving agent is ethyl acetate and isopropanol; The temperature of the resolution reaction is ≥80°C, and the time of the resolution reaction is ≥1h.

2. The method according to claim 1, wherein the organic solvent is selected from at least one of the following: methanol, ethanol, acetonitrile and tetrahydrofuran; and / or The alkaline substance is selected from at least one of the following: sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.

3. The method according to claim 1, wherein the amount n1 of the alkaline substance and the amount n2 of the second intermediate satisfy the relationship: n1:n2=(0.5-5):1; and / or The volume V1 of the organic solvent and the volume V2 of the water satisfy the relationship: V1:V2=1:(0.5-5).

4. The method according to claim 1, wherein the amount n3 of the resolving agent and the amount n4 of the racemate satisfy the relationship: n3:n4=(1.00-1.10):

1.

5. The method according to claim 1, wherein the amount n5 of the oxalyl chloride and the amount n6 of the second diastereomer satisfy the relationship: n5:n6=(2-3):

1. 6 . The method according to claim 1 , wherein the amount n7 of the phosphorus oxychloride and the amount n8 of the first intermediate satisfy the relationship: n7:n8=(2-3):

1.

7. The method according to claim 1, wherein the temperature of the amidation reaction is 10°C to 20°C, and the time of the amidation reaction is ≥ 1 h.

8. The method according to claim 1, wherein the temperature of the dehydration reaction is 60°C to 70°C, and the time of the dehydration reaction is ≥ 12 hours.

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