Preparation method of key intermediate of macloxvir

Abstract

The invention relates to a preparation method of a key intermediate of macarovir, and relates to the field of pharmaceutical chemicals, (R)-7-benzyloxy-3, 4, 12, 12A-tetrahydro-1H-[1, 4] azino [3, 4-C] pyrido [2, 1-F] [1, 2, 4] triazine-6, 8-diketone is used as a raw material, and the high-selectivity macarovir intermediate is obtained through a Grignard exchange reaction and a condensation reaction. According to the invention, 4-methyl-1-amyl is used for replacing benzyl in Grignard exchange, the chiral selectivity is improved in the condensation step, and the De value of the obtained key macavir intermediate is as high as 98.9%.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry, and specifically relates to a method for preparing a key intermediate of mabaloxavir. Background Art

[0002] Baloxavir marboxil (trade name: Xofluza) was jointly developed by Shionogi and Roche and was first approved in Japan in February 2018 and in the United States in October of the same year. To date, mabaloxavir has been approved in many countries and regions around the world. It is approved in Japan for the treatment of infections caused by influenza A or B viruses; in the United States, Singapore, Thailand, Hong Kong, China, and Taiwan, China, it is used to treat acute uncomplicated influenza patients aged 12 years and above whose symptoms have not appeared for more than 48 hours. The domestic synthesis of this drug is mainly the following routes:

[0003]

[0004] Mabaloxavir is produced by format exchange, condensation, hydrolysis, and esterification. However, in the condensation reaction, the existing patents all use n-hexyl to exchange with the benzyl of the starting material (see CN 109311911 B, CN 116751214 A). However, when the condensation reaction is carried out, a large number of non-corresponding isomers will be produced, which greatly reduces the yield of the next hydrolysis reaction and generates a large amount of waste materials. Summary of the invention

[0005] The invention provides an improved and effective method for preparing a key intermediate of mabaloxavir. The mabaloxavir intermediate prepared by the method has high selectivity, and the enantiomer selectivity is as high as 95%, thereby effectively improving the conversion rate and the yield.

[0006] The method for preparing a key intermediate of mabaloxavir of the present invention is carried out according to the following steps:

[0007] S1: using isopropyl magnesium chloride to react with 4-methyl-1-pentanol to prepare a 4-methyl-1-pentanol magnesium oxide solution, using (R)-7-benzyloxy-3,4,12,12A-tetrahydro-1H-[1,4]azino[3,4-C]pyrido[2,1-F][1,2,4]triazine-6,8-dione as a raw material to carry out a format exchange reaction with the 4-methyl-1-pentanol magnesium oxide solution, and forming a salt with p-toluenesulfonic acid to obtain (R)-7-(4-methyl-1-pentanoloxy)-3,4,12,12A-tetrahydro-1H-[1,4]oxazine[3,4-C]pyrido[2,1-F][1,2,4]triazine-6,8-dione p-toluenesulfonate as intermediate 1;

[0008] S2: (R)-7-(4-methyl-1-pentyloxy)-3,4,12,12A tetrahydro-1H-[1,4]oxazine[3,4-C]pyrido[2,1-F][1,2,4]triazine-6,8-dione p-toluenesulfonate was used as a raw material, and condensed with 7,8-difluoro-6,11-dihydro-dibenzo[B,E]thien-11-ol in an acidic system to obtain (R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thien-11-yl)-7-((4-methylpentyl)oxy)-3,4,12,12A tetrahydro-1H-[1,4]oxazine[3,4-C]pyrido[2,1-F][1,2,4]triazine-6,8-dione p-toluenesulfonate. 12a-tetrahydro-1H-[1,4]oxazine[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione is salified with methanesulfonic acid to obtain (R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophen-11-yl)-7-((4-methylpentyl)oxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazine[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione methanesulfonate as intermediate 2, that is, the key intermediate of mabaloxavir.

[0009] Furthermore, in the Grignard reaction, the ratio of (R)-7-benzyloxy-3,4,12,12A-tetrahydro-1H-[1,4]azino[3,4-C]pyrido[2,1-F][1,2,4]triazine-6,8-dione to isopropylmagnesium chloride is 1:0.3~1eq, and the ratio of (R)-7-benzyloxy-3,4,12,12A-tetrahydro-1H-[1,4]azino[3,4-C]pyrido[2,1-F][1,2,4]triazine-6,8-dione to 4-methyl-1-pentanol is 1:4~6eq.

[0010] Furthermore, the format exchange reaction temperature is 15-30° C., and the molar ratio of (R)-7-benzyloxy-3,4,12,12A-tetrahydro-1H-[1,4]azo[3,4-C]pyrido[2,1-F][1,2,4]triazine-6,8-dione to 4-methyl-1-pentanomagnesium oxide solution is 1:0.3-0.5eq.

[0011] Furthermore, the acidic system used in S2 is methanesulfonic acid or 1-propylphosphoric anhydride.

[0012] Furthermore, the (R)-7-(4-methyl-1-pentyloxy)-3,4,12,12A tetrahydro-1H-[1,4]oxazine[3,4-C]pyrido[2,1-F][1,2,4]triazine-6,8-dione is used in a ratio of 1:1.1-2eq to 7,8-difluoro-6,11-dihydro-dibenzo[B,E]thieno-11-ol, in a ratio of 1:1.1-2eq to methanesulfonic acid, and in a ratio of 1:1.1-2eq to 1-propylphosphoric anhydride.

[0013] Furthermore, the reaction temperature of the condensation reaction is 50-70°C.

[0014] The present invention finds that the chiral selectivity of the two-step condensation reaction using 4-methyl-1-pentyl to replace benzyl is as high as 99%, which significantly improves the yield.

[0015] The reaction route is as follows:

[0016]

[0017] The present invention has the following beneficial effects:

[0018] 1) The route of the present invention replaces the n-hexyl used in the format exchange step in the existing domestic synthesis route with 4-methyl-1-pentyl, thereby improving the chiral selectivity, with a selection ratio of more than 98%.

[0019] 2) The existing domestic synthesis process has low chiral selectivity of condensation, resulting in a large number of diastereoisomers. The diastereoisomers are derived into API and need to be purified and removed, resulting in reduced yield and increased production costs. The present invention improves the chiral selectivity of condensation and can effectively reduce production costs and cycles. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 is the HPLC spectrum of intermediate 1;

[0021] Figure 2 is the HPLC spectrum of intermediate 2;

[0022] Figure 3 This is the HPLC spectrum of the comparative experimental intermediate 1;

[0023] Figure 4 The HPLC spectrum of intermediate 2 in the comparative experiment. DETAILED DESCRIPTION

[0024] In order to make the objectives, technical solutions and advantages of the embodiments of the present invention more clearly understood, the spirit of the contents disclosed by the present invention will be described in detail below. After understanding the embodiments of the contents of the present invention, any technician in the relevant technical field can change and modify them according to the techniques taught by the contents of the present invention without departing from the spirit and scope of the contents of the present invention.

[0025] The exemplary embodiments of the present invention and the description thereof are used to explain the present invention but are not intended to limit the present invention.

[0026] Example

[0027] Example 1: Preparation of (R)-7-((4-methylpentyl)oxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazine[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione p-toluenesulfonate

[0028] 28 mL of 4-methyl-1-pentanol and 30 mL of THF were added to the reaction bottle, and the temperature of the mixture was adjusted to 20° C. A THF solution of isopropylmagnesium chloride (2 mol / L, 9.2 g) was added to the mixture to prepare a 4-methyl-1-pentanol magnesium oxide solution.

[0029] Add 25 mL of 4-methyl-1-pentanol and 14 g of (R)-7-benzyloxy-3,4,12,12A-tetrahydro-1H-[1,4]azino[3,4-C]pyrido[2,1-F][1,2,4]triazine-6,8-dione (SM1) to another reaction bottle, react at 20°C, and add the above-prepared 4-methyl-1-pentanol magnesium oxide solution. The mixture is stirred at 20°C for 3-4 hours. 46 mL of 8% citric acid aqueous solution is added dropwise. The mixture is extracted with THF, and the organic phase is washed with water. The organic layer is concentrated to dryness. A THF solution of p-toluenesulfonic acid (8 g of p-toluenesulfonic acid monohydrate is dissolved in 50 mL of THF) is added to the resulting concentrate. The mixture is concentrated under reduced pressure until no fraction is produced. 50 mL of THF is added to the concentrate and concentrated under reduced pressure until no fraction is produced. The mixture is heated to 50°C and 140 mL of methyl tert-butyl ether is added dropwise under temperature control. The resulting mixture was cooled to 10°C, stirred for 1.5 hours, and filtered. The filter cake was washed with 80 mL of methyl tert-butyl ether and dried to obtain 19 g of toluenesulfonate salt of intermediate 1 with a molar yield of 90%. The HPLC spectrum of intermediate 1 is shown in Figure 1 .

[0030] Example 2: Preparation of (R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophen-11-yl)-7-((4-methylpentyl)oxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazine[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione methanesulfonate

[0031] Add 15.5 g 7,8-difluoro-6,11-dihydro-dibenzo[B,E]thieno-11-ol (SM2), 90 mL ethyl acetate, and 19 g intermediate 1 to a reaction flask and stir at 25°C. Add 28 g 50 (w / w)% 1-propylphosphonic anhydride ethyl acetate solution dropwise, and then add 6 g methanesulfonic acid. Heat to 60°C and stir for 24 hours.

[0032] After cooling to 25°C, add 60 mL of THF and 38 mL of water, add 45 mL of 24% sodium hydroxide aqueous solution, extract and separate, retain the organic layer, and discard the water layer. Wash the organic layer with 60 mL of 7% sodium chloride aqueous solution. Add 5 g of methanesulfonic acid and 50 mL of ethyl acetate to the combined organic phase. Stir the mixture at 25°C for 2 hours and filter. Wash the filter cake with 80 mL of ethyl acetate and dry to obtain 19.9 g of mesylate of intermediate 2, with a molar yield of 95.6%. The HPLC spectrum of intermediate 2 is shown in Figure 2 .

[0033] Comparative Example 1: (R)-7-(Hexyloxy)-3,4,12,12A tetrahydro-1H-[1,4]oxazine[3,4-C]pyrido[2,1-F][1,2,4]triazine-6,8-dione p-toluenesulfonate

[0034] 25 g of n-hexanol and 26 mL of THF were added to the reaction bottle, and the temperature of the mixture was adjusted to 20° C. A THF solution of isopropylmagnesium chloride (2 mol / L, 10 g) was added to the mixture to prepare a magnesium hexaoxide solution.

[0035] Add 30 mL of n-hexanol and 13 g of (R)-7-benzyloxy-3,4,12,12A-tetrahydro-1H-[1,4]azino[3,4-C]pyrido[2,1-F][1,2,4]triazine-6,8-dione (SM1) to another reaction bottle, react at 20°C, and add the above-prepared magnesium oxide solution. The mixture is stirred at 20°C for 3-4 hours. 42 mL of 8% citric acid aqueous solution is added dropwise. The mixture is extracted with THF and the organic phase is washed with water. The organic layer is concentrated to dryness. A THF solution of p-toluenesulfonic acid (7.6 g of p-toluenesulfonic acid monohydrate is dissolved in 46 mL of THF) is added to the resulting concentrate. The mixture is concentrated under reduced pressure until no fraction is produced. 46 mL of THF is added to the concentrate and concentrated under reduced pressure until no fraction is produced. The mixture is heated to 50°C and 144 mL of methyl tert-butyl ether is added dropwise under temperature control. The resulting mixture is cooled to 10°C, stirred for 1.5 hours, and filtered. The filter cake was washed with 50 mL of methyl tert-butyl ether and dried to obtain 14 g of toluenesulfonate of intermediate 1 with a molar yield of 71.4%. Figure 3 .

[0036] Comparative Example 2: (R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophen-11-yl)-7-(hexyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazine[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione methanesulfonate

[0037] Add 11.4 g 7,8-difluoro-6,11-dihydro-dibenzo[B,E]thieno-11-ol (SM2), 80 mL ethyl acetate and 25 mL cyclohexane to the reaction flask. Add 14 g intermediate 1 from the previous step and stir at 25°C. Add 30 g 50 (w / w)% 1-propylphosphonic anhydride ethyl acetate solution dropwise, and then add 5 g methanesulfonic acid. Heat to 60°C and stir for 24 hours.

[0038] After cooling to 25°C, 50 mL of THF and 34 mL of water were added, 44 mL of 24% sodium hydroxide aqueous solution was added dropwise thereto, the liquid was extracted, the organic layer was retained, and the aqueous layer was discarded. The organic layer was washed with 86 mL of 7% sodium chloride aqueous solution. 4 g of methanesulfonic acid, 13 mL of cyclohexane and 50 mL of ethyl acetate were added to the combined organic phase. The mixture was stirred at 25°C for 2 hours and filtered. The filter cake was washed with 70 mL of ethyl acetate and dried to obtain 15.4 g of the mesylate salt of intermediate 2. The molar yield was 81.9%. The HPLC spectrum of intermediate 2 in the comparative experiment is shown in Figure 4 .

[0039] It can be seen from the data of Examples 1 and 2 and Comparative Examples 1 and 2 that the De value of the mabaloxavir intermediate 2 obtained in the comparative example is 87.8%, and the De value of the mabaloxavir intermediate 2 obtained in the example is as high as 98.9%.

Claims

1. A method for preparing a key intermediate of mabaloxavir, characterized in that It is carried out according to the following steps: S1: using isopropyl magnesium chloride to react with 4-methyl-1-pentanol to prepare a 4-methyl-1-pentanol magnesium oxide solution, using (R)-7-benzyloxy-3,4,12,12A-tetrahydro-1H-[1,4]azino[3,4-C]pyrido[2,1-F][1,2,4]triazine-6,8-dione as a raw material to undergo a format exchange reaction with the 4-methyl-1-pentanol magnesium oxide solution, and forming a salt with p-toluenesulfonic acid to obtain (R)-7-(4-methyl-1-pentanoloxy)-3,4,12,12A-tetrahydro-1H-[1,4]oxazine[3,4-C]pyrido[2,1-F][1,2,4]triazine-6,8-dione p-toluenesulfonate as intermediate 1; S2: (R)-7-(4-methyl-1-pentyloxy)-3,4,12,12A tetrahydro-1H-[1,4]oxazine[3,4-C]pyrido[2,1-F][1,2,4]triazine-6,8-dione p-toluenesulfonate was used as a raw material, and condensed with 7,8-difluoro-6,11-dihydro-dibenzo[B,E]thien-11-ol in an acidic system to obtain (R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thien-11-yl)-7-((4-methylpentyl)oxy)-3,4,12,12A tetrahydro-1H-[1,4]oxazine[3,4-C]pyrido[2,1-F][1,2,4]triazine-6,8-dione p-toluenesulfonate. 12a-tetrahydro-1H-[1,4]oxazine[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione is salified with methanesulfonic acid to obtain (R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophen-11-yl)-7-((4-methylpentyl)oxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazine[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione methanesulfonate as intermediate 2, that is, the key intermediate of mabaloxavir.

2. The method for preparing a key intermediate of mabaloxavir according to claim 1, characterized in that In the described Grignard reaction, the ratio of (R)-7-benzyloxy-3,4,12,12A-tetrahydro-1H-[1,4]azino[3,4-C]pyrido[2,1-F][1,2,4]triazine-6,8-dione to isopropylmagnesium chloride is 1:0.3-1eq, and the ratio of (R)-7-benzyloxy-3,4,12,12A-tetrahydro-1H-[1,4]azino[3,4-C]pyrido[2,1-F][1,2,4]triazine-6,8-dione to 4-methyl-1-pentanol is 1:4-6eq.

3. A method for preparing a key intermediate of mabaloxavir according to claim 1 or 2, characterized in that The format exchange reaction temperature is 15-30° C., and the molar ratio of (R)-7-benzyloxy-3,4,12,12A-tetrahydro-1H-[1,4]azo[3,4-C]pyrido[2,1-F][1,2,4]triazine-6,8-dione to 4-methyl-1-pentanomagnesium oxide solution is 1:0.3-0.5eq.

4. The method for preparing a key intermediate of mabaloxavir according to claim 1, characterized in that The acidic system used in S2 is methanesulfonic acid or 1-propylphosphoric anhydride.

5. The method for preparing a key intermediate of mabaloxavir according to claim 1, characterized in that The (R)-7-(4-methyl-1-pentyloxy)-3,4,12,12A tetrahydro-1H-[1,4]oxazine[3,4-C]pyrido[2,1-F][1,2,4]triazine-6,8-dione is used in a ratio of 1:1.1-2eq to 7,8-difluoro-6,11-dihydro-dibenzo[B,E]thieno-11-ol, a ratio of 1:1.1-2eq to methanesulfonic acid, and a ratio of 1 to 2eq to 1-propylphosphoric anhydride.

6. The method for preparing a key intermediate of mabaloxavir according to claim 1, characterized in that The reaction temperature of the condensation reaction is 50-70°C.

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