CN116082361B - Method for preparing Marbalo Sha Wei intermediate and Marbalo Sha Wei - Google Patents
Method for preparing Marbalo Sha Wei intermediate and Marbalo Sha Wei Download PDFInfo
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Abstract
The present invention provides a process for the preparation of an intermediate of marbalo Sha Wei and marbalo Sha Wei. In the method, the lithium chloride or the zinc chloride with the catalytic amount of 0.1-0.3 eq is added into the reaction system, so that the conversion rate of the reaction can be obviously improved, and the dosage (about equivalent) of the n-hexanol can be obviously reduced. After the reaction is finished, the crude product of the compound IN1 is obtained through simple post-treatment, the purity is more than 97%, the yield reaches 95%, and the next reaction can be directly carried out. In addition, 1-3% mol of phase transfer catalyst such as 1-hexyl pyridine tetrafluoroborate is added in the step 2, so that the reaction efficiency can be remarkably improved, meanwhile, the reaction can be carried out at 20-30 ℃, the reaction can be completed after 30 hours, and the ratio of target products to diastereoisomers reaches 30-33: 1. in the post-treatment, after salt formation crystallization by using methanesulfonic acid, the yield can reach 90 percent, and the chiral purity is more than 99 percent.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a method for preparing an intermediate of marballo Sha Wei and a method for preparing marballo Sha Wei.
Background
Marbalo Sha Wei (Baloxavir marboxil) is a type A or type B influenza therapeutic drug commonly developed by Japanese salt field and Swiss Rogowski pharmaceutical company.
The molecular formula of the Mabalo Sha Wei is C 27 H 23 F 2 N 3 O 7 S, the chemical structure is as follows:
approval was obtained in japan for 2 months in 2018. Currently, mabalo Sha Wei has been approved in various countries and regions worldwide for the treatment of influenza a or b virus-caused infections.
In japanese patent application (CN 109311911A) by salt wild pharmaceutical company, the following synthetic route is disclosed:
in step 1 (step 1) of the synthetic route, the yield of the step 1 reaction reached 87%, but the n-hexanol added in step 1 was in a large excess. After the end of the reaction in step 1, a large excess of n-hexanol must be removed by salification crystallization, otherwise the excess of n-hexanol would affect the reaction in step 2 (step 2) and would result in a large yield loss during salification and crystallization with p-toluene sulfonic acid.
IN addition, IN step 2 of the process, the solubility of the intermediates IN1 and SM2 IN the reaction system is poor, the heterogeneous reaction leads to a slower reaction speed, and the reaction can be completed only by heating the reaction system to 60 ℃ for 24 hours. The temperature is increased, and simultaneously, the steric configuration selectivity of the compound 2 and the compound 3 IN butt joint is reduced, so that the ratio of the product (IN 2) IN the step 2 to diastereoisomers thereof is 10-15: 1, the diastereomer ratio in the total reaction product is relatively high. There is a large space for optimization of the routes disclosed in the prior art.
Disclosure of Invention
In view of the problems of the prior art, the present invention provides a method for preparing an intermediate of marbalo Sha Wei and a raw material drug (API) of marbalo Sha Wei.
IN one aspect the present invention provides a process for the preparation of an intermediate compound of formula IN1 of marbaluo Sha Wei, comprising the steps of:
(1-1) adding 0.9-1.1eq of n-hexanol calculated by SM1 into an organic solvent 1, adding a Grignard reagent under the protection of nitrogen, then adding lithium chloride or zinc chloride, stirring at 20-60 ℃ for 0.5-5 hours, adding SM1 for reaction until the reaction is completed, and performing post-treatment to obtain IN1;
preferably, the grignard reagent is selected from at least one of isopropyl magnesium chloride, ethyl magnesium chloride and methyl magnesium chloride; more preferably, the Grignard reagent is added in an amount of 0.3 to 0.8 eq based on SM1
Preferably, in the step (1-1), the addition amount of lithium chloride or zinc chloride is 0.1 to 0.3eq in terms of SM 1. Preferably, after adding lithium chloride or zinc chloride, stirring is performed at a temperature of 20 to 30 ℃ (e.g., 25 ℃) for 2 hours.
Another aspect of the present invention provides a process for preparing an intermediate compound IN2 of the formula marbalo Sha Wei, comprising the steps of:
(2-2) dissolving the IN1 obtained IN the step (2-1) IN an organic solvent 2, adding SM2 and a phase transfer catalyst, adding propyl phosphoric anhydride (T3P) under the protection of nitrogen, stirring for reaction, then adding methanesulfonic acid for reaction at the temperature of 0-40 ℃ until the reaction is completed, and carrying out post-treatment to obtain IN2;
wherein the phase transfer catalyst is selected from at least one of polyethylene glycol dimethyl ether (NHD-250), 18-crown ether-6 or 1-hexyl pyridine tetrafluoroborate.
Preferably, in step (2-1), the organic solvent 1 is selected from at least one of tetrahydrofuran, ethyl acetate, methyl tertiary butyl ether.
Preferably, in step (2-1), the grignard reagent is selected from at least one of isopropyl magnesium chloride, ethyl magnesium chloride and methyl magnesium chloride; more preferably, the added amount of the grignard reagent is 0.3 to 0.8 eq based on SM 1.
Preferably, in the step (2-1), the addition amount of lithium chloride or zinc chloride is 0.1 to 0.3eq based on SM 1. Within this equivalent range, not only the conversion of the raw material SM1 is ensured, but also the waste of the material and the trouble of post-treatment are avoided.
Preferably, IN the step (2-1), the addition amount of the phase transfer catalyst is 1% -3% by mass of the compound IN1; more preferably, the phase transfer catalyst is 1-hexylpyridine tetrafluoroborate.
Preferably, IN the step (2-2), the amount of the added propylphosphoric anhydride is 1.2 to 1.8eq and the amount of the added methanesulfonic acid is 1.0 to 3.0eq based on the compound IN 1.
Preferably, in the step (2-2), the reaction temperature is 20 to 30 ℃. The reaction is carried out at room temperature, the operation is simple and easy, and the energy is saved.
Yet another aspect of the present invention provides a process for preparing marballo Sha Wei, comprising the following route:
the method comprises the following steps:
(3-1) adding 0.9-1.1eq of n-hexanol calculated by SM1 into an organic solvent 1, adding a Grignard reagent under the protection of nitrogen, then adding lithium chloride or zinc chloride, stirring at 20-60 ℃ for 0.5-5 hours, adding SM1 for reaction until the reaction is completed, and performing post-treatment to obtain IN1;
(3-2) dissolving the IN1 obtained IN the step (3-1) IN an organic solvent 2, adding SM2 and a phase transfer catalyst, adding propyl phosphoric anhydride under the protection of nitrogen, stirring for reaction, then adding methanesulfonic acid for reaction at the temperature of 0-40 ℃ until the reaction is completed, and obtaining IN2 through post-treatment;
wherein the phase transfer catalyst is selected from at least one of polyethylene glycol dimethyl ether (NHD-250), 18-crown ether-6 or 1-hexyl pyridine tetrafluoroborate;
(3-3) adding IN2 into the organic solvent 3, then adding a deprotection agent, reacting at 75-80 ℃ under the protection of nitrogen until the reaction is completed, and performing post-treatment to obtain a compound IN3;
(3-4) adding IN3, potassium iodide and potassium carbonate into an organic solvent 4, dropwise adding chloromethyl dimethyl carbonate IN batches at the temperature of 45-50 ℃ under the protection of nitrogen, reacting at the temperature of 45-50 ℃, and detecting after the reaction is finished; after post-treatment and purification, the compound API is obtained.
Preferably, in step (3-1), the organic solvent 2 is selected from at least one of tetrahydrofuran, ethyl acetate, methyl tertiary butyl ether. Preferably, in step (3-1), the grignard reagent is selected from at least one of isopropyl magnesium chloride, ethyl magnesium chloride and methyl magnesium chloride; more preferably, the added amount of the grignard reagent is 0.3 to 0.8 eq based on SM 1.
Preferably, in the step (3-1), the addition amount of lithium chloride or zinc chloride is 0.1-0.3 eq calculated by SM 1; more preferably, after adding lithium chloride or zinc chloride, stirring is performed at a temperature of 20-30 ℃ for 2 hours.
Preferably, IN the step (3-2), the addition amount of the phase transfer catalyst is 1% -3% by mass of the compound IN1; more preferably, the phase transfer catalyst is 1-hexylpyridine tetrafluoroborate.
Preferably, IN the step (3-2), the amount of the propylphosphoric anhydride added is 1.2 to 1.8eq and the amount of the methanesulfonic acid added is 1.0 to 3.0eq based on the molar amount of the compound IN 1.
Preferably, in the step (3-2), the reaction temperature is 20 to 30 ℃.
Preferably, in step (3-3), the deprotection agent is selected from lithium bromide and lithium chloride, more preferably lithium bromide.
In step (3-3), the organic solvent 3 is at least one selected from the group consisting of N-methylpyrrolidone (NMP), dimethylacetamide (DMAc), dimethylsulfoxide (DMSO), N-Dimethylformamide (DMF), preferably DMAc.
In step (3-3), the solution used for the post-treatment is selected from at least one of acetonitrile, acetone, isopropanol, preferably isopropanol.
IN the step (3-4), the amount of dimethyl chloroformate added is 1.5 to 2.5eq, preferably 2.0eq, based on the compound IN 3.
In the step (3-4), the organic solvent 4 is at least one selected from dimethylacetamide (DMAc), N-methylpyrrolidone (NMP), tetrahydrofuran (THF), preferably DMAc.
IN the step (3-4), the amount of potassium iodide added is 0.5 to 1.0eq, preferably 1.0eq, based on the compound IN 3.
IN the step (3-4), the amount of potassium carbonate added is 2.0 to 2.5eq, preferably 2.0. 2.0eq, based on the compound IN 3.
The beneficial effects of the invention are that
In the method of the invention, the conversion rate of the reaction can be remarkably improved by adding lithium chloride or zinc chloride (preferably zinc chloride) with a catalytic amount of 0.1-0.3 eq (preferably 0.3 eq) into the reaction system. The use of low equivalent (0.9-1.1 eq) of n-hexanol is combined, so that simpler subsequent operation and higher purity and yield are realized. IN the step of synthesizing the compound IN1, after the reaction is finished, n-hexanol is not required to be removed by adding p-toluenesulfonic acid to form salt crystals, and the crude product of the compound IN1 is obtained by simple post-treatment, the purity is more than 97 percent, the yield reaches 95 percent, and the next reaction can be directly carried out.
The inventors of the present invention have further found that the reaction efficiency can be significantly improved by adding 1 to 3% mol of a phase transfer catalyst such as polyethylene glycol dimethyl ether (NHD-250), 18-crown-6 or 1-hexylpyridine tetrafluoroborate (preferably 1-hexylpyridine tetrafluoroborate) IN the step of synthesizing IN 2. Meanwhile, the temperature can be reduced to 20-30 ℃ for reaction, and the raw materials can be completely reacted after 30 hours of reaction. The configuration selectivity of the product is higher through HPLC detection, and the proportion of the target product to the diastereoisomer reaches 30-33: 1, in the post-treatment process, after salt formation crystallization by using methanesulfonic acid, the yield can reach 90%, and the chiral purity is more than 99%.
Drawings
FIG. 1 is a pilot HPLC profile of Compound IN1 at the end of step 1;
FIG. 2 is a chemical purity HPLC profile of Compound IN2 obtained IN example 2;
FIG. 3 is a chiral HPLC plot of compound IN2 obtained IN example 3;
FIG. 4 is a chiral HPLC plot of compound IN3 obtained IN example 3;
FIG. 5 is a chemical purity HPLC profile of the compound API obtained in example 3;
FIG. 6 is a chiral HPLC plot of the compound API obtained in example 3.
Detailed Description
The invention is further illustrated by the following specific examples.
Example 1
Synthesis of Compound IN1
The synthetic route for compound IN1 is as follows:
table 1 shows the material data of this example.
TABLE 1
The procedure for the synthesis of compound IN 1:
and adding THF and n-hexanol into a 1L three-port bottle, cooling the ice bath to 0-5 ℃, adding isopropyl magnesium chloride under the protection of nitrogen for about 30min, adding anhydrous zinc chloride after the adding of the isopropyl magnesium chloride is completed, heating to room temperature for reaction for 2h, then adding SM1 in batches, preserving heat for reaction for 2h, sampling and detecting, and prompting the completion of the reaction.
Post-treatment: and adding acetic acid into the reaction liquid to quench the reaction, then washing with saturated ammonium chloride for 1 time, washing with water for 1 time, washing with saturated sodium chloride for 1 time, and concentrating the organic phase at 40-70 ℃ under reduced pressure to obtain 93.3g of crude product, and directly carrying out the next reaction. The results of the product HPLC detection are shown in FIG. 1. As can be seen from FIG. 1, the purity of the crude product without purification reaches 97.48%, and the yield reaches 95%.
Example 2
Synthesis of Compound IN2
The synthetic route for compound IN2 is as follows:
table 2 shows the material data of this example.
TABLE 2
The operation process comprises the following steps:
methyl tert-butyl (MTBE), IN1, SM2 and 1-hexyl pyridine tetrafluoroborate are added into a 1L three-port bottle, T3P is added under the protection of nitrogen, stirring is carried out for 0.5h, then methanesulfonic acid is added, the temperature is controlled to be 20 ℃ for reaction for 30h, sampling detection is carried out, and the completion of the reaction is indicated.
Post-treatment: THF was added to the reaction system, washed once with saturated sodium bicarbonate, separated, the aqueous phase was extracted once with THF, the organic phases were combined, washed once with saturated sodium chloride, the organic phases were concentrated to dryness under reduced pressure to give crude product, 715ml EA was added to the crude product, stirred to complete dissolution, and methanesulfonic acid was added dropwise: 27g, stirring and crystallizing for 1h at room temperature, and performing suction filtration and drying to obtain the product IN2 (173 g), wherein the chemical purity is 96.2%, and the chiral purity is 97.2%. The chemical purity HPLC profile of the product IN2 is shown IN FIG. 2, and the chiral purity HPLC profile is shown IN FIG. 3.
In this example, the effect of reaction temperature on the diastereomer ratio was further studied. The results data for temperature, reaction completion time and diastereomer ratio are presented in table 3.
TABLE 3 Table 3
As can be seen from the example, the addition of 1-3% mol of a phase transfer catalyst such as polyethylene glycol dimethyl ether (NHD-250), 18-crown ether-6 or 1-hexylpyridine tetrafluoroborate (preferably 1-hexylpyridine tetrafluoroborate) can significantly improve the reaction efficiency. The reaction can be completed after the temperature is reduced to room temperature of 20 ℃ for 30 hours, and the configuration selectivity of the product is higher through HPLC detection, and the ratio of the target product to diastereoisomers reaches 30-33: 1, after the post-treatment is salified and crystallized by methanesulfonic acid, the yield reaches 90 percent, and the chiral purity is more than 99 percent.
Example 3
Synthesis of Compound Marbalano Sha Wei
The synthetic route for the compound marbaluo Sha Wei is as follows:
the operations of step 1 (step 1) and step 2 (step 2) are the same as those of the above embodiments 1 and 2.
Table 4 shows the material data of step 3 (step 3).
TABLE 4 Table 4
The operation process comprises the following steps:
and adding DMAc, IN2 and lithium bromide into a 3L three-port bottle, heating to 75-80 ℃ under the protection of nitrogen, reacting for 12 hours, sampling and detecting, and prompting the completion of the reaction.
Post-treatment: isopropanol is added into the reaction liquid, the temperature is reduced to room temperature, water is slowly added dropwise for crystallization, the mixture is dripped for Bi Jiaoban hours, suction filtration and blast drying are carried out at 50 ℃ to obtain the product IN3 (119 g), the yield is 95%, and the purity is 98.4%. The HPLC detection pattern of the product IN3 is shown IN FIG. 4.
Table 5 shows the material data of step 4.
TABLE 5
The operation process comprises the following steps: adding DMAc, IN3, potassium iodide and potassium carbonate into a 2L three-port bottle, and dropwise adding chloromethyl dimethyl carbonate under the protection of nitrogen at the temperature of 45-50 ℃:46g, for about 30min, for 16h, followed by dropwise addition of chloromethyl dimethyl carbonate: 15.3g, the time is about 15min, the reaction is kept for 5h, sampling detection is carried out, and the completion of the reaction is prompted.
Post-treatment: adding water into the reaction system, stirring for 1h, and performing suction filtration to obtain a crude product; the crude product is dissolved by DCM, then washed by water, separated, the organic phase is decompressed and concentrated to obtain the crude product of the API, isopropanol is added for pulping for 2 hours, the target product of the API (126 g) is obtained by suction filtration and drying, the yield is 90 percent, the chemical purity is 99.83 percent, and the chiral purity is 99.98 percent. Chemical purity HPLC profile of compound API is shown in figure 5, chiral purity HPLC profile is shown in figure 6.
The invention provides a novel method for preparing the Mabalo Sha Wei, which can realize simpler operation, and simultaneously remarkably improves the proportion of a target final product and diastereoisomers, the yield and the chiral purity.
Claims (10)
1. A process for preparing a marbalo Sha Wei intermediate comprising the steps of:
(1-1) adding 0.9-1.1eq of n-hexanol calculated by SM1 into an organic solvent 1, adding a Grignard reagent under the protection of nitrogen, then adding lithium chloride or zinc chloride, stirring at 20-60 ℃ for 0.5-5 hours, adding SM1 for reaction until the reaction is completed, and performing post-treatment to obtain IN1;
wherein the organic solvent 1 is at least one selected from tetrahydrofuran, ethyl acetate and methyl tertiary butyl ether.
2. The method according to claim 1, wherein the grignard reagent is at least one selected from isopropyl magnesium chloride, ethyl magnesium chloride and methyl magnesium chloride, and the added amount of the grignard reagent is 0.3-0.8 eq based on SM 1.
3. The method according to claim 1, wherein the amount of lithium chloride or zinc chloride added is 0.1 to 0.3eq based on SM 1.
4. A process for preparing a marbalo Sha Wei intermediate comprising the steps of:
wherein the organic solvent 1 is at least one selected from tetrahydrofuran, ethyl acetate and methyl tertiary butyl ether;
(2-2) dissolving the IN1 obtained IN the step (2-1) IN an organic solvent 2, adding SM2 and a phase transfer catalyst, adding propyl phosphoric anhydride under the protection of nitrogen, stirring for reaction, then adding methanesulfonic acid for reaction at the temperature of 0-40 ℃ until the reaction is completed, and carrying out post-treatment to obtain IN2;
wherein the organic solvent 2 is selected from at least one of tetrahydrofuran, ethyl acetate and methyl tertiary butyl ether, and the phase transfer catalyst is selected from at least one of polyethylene glycol dimethyl ether, 18-crown ether-6 or 1-hexyl pyridine tetrafluoroborate.
5. The method according to claim 4, wherein in the step (2-1), the grignard reagent is at least one selected from isopropyl magnesium chloride, ethyl magnesium chloride and methyl magnesium chloride, and the added amount of the grignard reagent is 0.3 to 0.8 eq based on SM 1.
6. The method according to claim 4, wherein in the step (2-1), the addition amount of lithium chloride or zinc chloride is 0.1 to 0.3eq in terms of SM 1.
7. The method according to claim 4, wherein IN the step (2-2), the phase transfer catalyst is 1-hexylpyridine tetrafluoroborate, and the addition amount of the phase transfer catalyst is 1% -3% by mass of the compound IN 1.
8. A process for preparing marbalo Sha Wei, the process comprising the following routes:
the method comprises the following steps:
(3-1) adding 0.9-1.1eq of n-hexanol calculated by SM1 into an organic solvent 1, adding a Grignard reagent under the protection of nitrogen, then adding lithium chloride or zinc chloride, stirring at 20-60 ℃ for 0.5-5 hours, adding SM1 for reaction until the reaction is completed, and performing post-treatment to obtain IN1;
wherein the organic solvent 1 is at least one selected from tetrahydrofuran, ethyl acetate and methyl tertiary butyl ether;
(3-2) dissolving the IN1 obtained IN the step (3-1) IN an organic solvent 2, adding SM2 and a phase transfer catalyst, adding propyl phosphoric anhydride under the protection of nitrogen, stirring for reaction, then adding methanesulfonic acid for reaction at the temperature of 0-40 ℃ until the reaction is completed, and obtaining IN2 through post-treatment;
wherein the organic solvent 2 is selected from at least one of tetrahydrofuran, ethyl acetate and methyl tertiary butyl ether, and the phase transfer catalyst is selected from at least one of polyethylene glycol dimethyl ether (NHD-250), 18-crown ether-6 or 1-hexyl pyridine tetrafluoroborate;
(3-3) adding IN2 into the organic solvent 3, then adding a deprotection agent, reacting at 75-80 ℃ under the protection of nitrogen until the reaction is completed, and performing post-treatment to obtain a compound IN3;
wherein the organic solvent 3 is at least one selected from N-methylpyrrolidone, dimethylacetamide, dimethyl sulfoxide and N, N-dimethylformamide;
(3-4) adding IN3, potassium iodide and potassium carbonate into an organic solvent 4, dropwise adding chloromethyl dimethyl carbonate IN batches at the temperature of 45-50 ℃ under the protection of nitrogen, reacting at the temperature of 45-50 ℃, and detecting after the reaction is finished; after post-treatment and purification, a compound API is obtained;
wherein the organic solvent 4 is at least one selected from dimethylacetamide, N-methylpyrrolidone and tetrahydrofuran.
9. The method according to claim 8, wherein in the step (3-1), the grignard reagent is at least one selected from isopropyl magnesium chloride, ethyl magnesium chloride and methyl magnesium chloride, and the amount of the grignard reagent added is 0.3 to 0.8 eq in terms of SM1, and the amount of the lithium chloride or zinc chloride added is 0.1 to 0.3eq in terms of SM 1.
10. The method according to claim 8, wherein IN the step (3-2), the phase transfer catalyst is 1-hexylpyridine tetrafluoroborate, and the addition amount of the phase transfer catalyst is 1% -3% by mass of the compound IN 1.
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