A preparation method of baloxavir intermediate
By using a pressurized reaction method with palladium-containing catalyst in the synthesis of baroxavir intermediates, the problems of poor reaction safety and high equipment requirements in the prior art are solved, and a safer and easier industrialized synthesis process is achieved.
Patent Information
- Application Number
- CN201911181355.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2019-11-27
- Publication Date
- 2025-02-25
- Estimated Expiration
- 2039-11-27
AI Technical Summary
The existing baroxavir intermediate synthesis method has problems such as poor reaction safety and high equipment requirements, which limits its industrial applications.
Using the compound of formula (A) as the solvent and the alkali as the acid binding agent, under the action of a palladium-containing catalyst, the compound of formula (B) reacts with carbon monoxide and the compound of formula (A) under pressurization conditions, and obtains baro after post-treatment. Savir intermediate compound of formula E.
This method avoids the use of active organometallic reagents, with mild reaction conditions, safe and easy to operate, and improves the safety of the process and the feasibility of industrial amplification.
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Figure CN112851508B_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to a method for preparing a baloxavir intermediate. Background Art
[0002] Influenza, or influenza in full, is a disease caused by acute infection of the respiratory tract with highly contagious influenza viruses, with symptoms including fever, myalgia, mental depression, and upper respiratory tract symptoms. Antiviral drugs can be used to prevent and treat seasonal influenza, but they can only be used strictly as an adjunct to vaccination and cannot replace vaccination. Currently, drugs including M2 inhibitors (amantadine and rimantadine) and neuraminidase inhibitors (oseltamivir and zanamivir) are used for chemical prevention of influenza, with an efficacy of 70% to 90%.
[0003] Baloxavir marboxil is an innovative Cap-dependent endonuclease inhibitor developed by Shionogi Pharmaceuticals of Japan for the treatment of influenza A and influenza B. The advantage of this therapy is that it requires only a short number of doses and has a long duration of efficacy. Its chemical structure is as follows:
[0004]
[0005] Currently, there are few methods for synthesizing the compound. The literature Journal of Medicinal Chemistry, 2013, 56 (6): 2218-2234. and the literature Organic Process Research & Development, 2015, 19 (7): 721-734. disclose a method for preparing baloxavir intermediate 3,4-difluoro-2-methylbenzoic acid: the route uses compound 1 as a substrate, and bromination, Grignard reagent exchange, and carbon dioxide addition to prepare 3,4-difluoro-2-methylbenzoic acid. This route requires the use of a highly active Grignard reagent, and the reaction safety is poor, which limits its industrial application. The reaction route is as follows:
[0006]
[0007] In addition, the literature Journal of Heterocyclic Chemistry, 27(6), 1609–1616. reported a method for synthesizing baloxavir intermediate 3,4-difluoro-2-methylbenzoic acid: using compound 2 as a substrate to react with n-butyl lithium at -78°C, and then adding carbon dioxide. This method requires the use of highly active butyl lithium reagents and a low temperature environment of -78°C. The reaction safety is poor, the equipment requirements are high, and it is not conducive to industrial scale-up. The reaction route is as follows:
[0008]
[0009] In summary, the prior art of baloxavir intermediate synthesis has the following technical problems:
[0010] (1) Poor reaction safety;
[0011] (2) The reaction conditions are harsh and the equipment requirements are high, which is not conducive to industrial scale-up production.
[0012] Therefore, it is very necessary to develop a method for synthesizing baloxavir intermediates with high safety, mild reaction conditions and low equipment requirements. Summary of the invention
[0013] In one aspect, the present invention provides a method for preparing a baloxavir intermediate compound of formula E:
[0014]
[0015] The preparation method comprises the following steps: using a compound of formula (A) as a solvent and a base as an acid-binding agent, reacting a compound of formula (B) with carbon monoxide and a compound of formula (A) under pressure under the action of a palladium-containing catalyst, and performing post-treatment to obtain a compound of formula (E), wherein the general formula of R2 is CxHy or CxHyOH, x is an integer greater than 1, y is an integer greater than 1, and R1 is selected from chlorine, bromine, iodine, methanesulfonate, p-toluenesulfonate, and ethanesulfonate.
[0016] In some embodiments, the reaction temperature of the reaction is 65°C-105°C.
[0017] In some embodiments, the reaction temperature of the reaction is 75°C-95°C.
[0018] In some embodiments, the reaction temperature of the reaction is 85°C.
[0019] In some embodiments, the compound of formula A is selected from at least one of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, and benzyl alcohol.
[0020] In some embodiments, the added volume of the compound of formula A is 1-100 times the weight of the compound of formula B.
[0021] In some embodiments, the added volume of the compound of formula A is 2-50 times the weight of the compound of formula B.
[0022] In some embodiments, the added volume of the compound of formula A is 5-20 times the weight of the compound of formula B.
[0023] In some embodiments, the base is selected from at least one of triethylamine, pyridine, piperidine, morpholine, N,N-diisopropylethylamine, ethanolamine, ammonia water, diethylamine, N-methylmorpholine, tetrahydropyrrole, N-methyltetrahydropyrrole, N-methylpiperidine, lithium hydroxide, potassium hydroxide, cesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, calcium oxide, magnesium oxide, calcium hydroxide, and magnesium hydroxide.
[0024] In some embodiments, the molar ratio of the base to the compound of formula B is 0.1:1-10:1.
[0025] In some embodiments, the molar ratio of the base to the compound of formula B is 0.5:1-8:1.
[0026] In some embodiments, the molar ratio of the base to the compound of formula B is 1:1-5:1.
[0027] In some embodiments, the palladium-containing catalyst is selected from at least one of [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium, dichlorobistriphenylphosphine palladium, tetrakistriphenylphosphine palladium, palladium acetate, dichlorodibenzonitrile palladium, palladium carbon, and palladium hydroxide on carbon.
[0028] In some embodiments, the molar ratio of the palladium catalyst to the compound of formula B is 0.005:1-0.1:1.
[0029] In some embodiments, the molar ratio of the palladium catalyst to the compound of formula B is 0.01:1-0.05:1.
[0030] In some embodiments, the reaction pressure of the reaction is 0.5 MPa-5 MPa.
[0031] In some embodiments, the reaction pressure of the reaction is 1 MPa-4 MPa.
[0032] In some embodiments, the reaction pressure of the reaction is 2Mpa-3Mpa.
[0033] In some embodiments, the post-processing includes spin drying of the solvent, extraction, and purification.
[0034] On the other hand, the present invention also provides a method for preparing a baloxavir intermediate compound of formula D:
[0035]
[0036] The preparation method comprises the following steps: in the presence of a catalyst, in a mixed solvent containing water and an organic solvent miscible with water, a compound of formula E undergoes a hydrolysis reaction, and after post-treatment, a compound of formula D is obtained, wherein the general formula of R2 is CxHy or CxHyOH, x is an integer greater than 1, and y is an integer greater than 1.
[0037] In some embodiments, the catalyst is selected from at least one of hydroxides, alkaline carbonates, and alkaline oxides.
[0038] In some embodiments, the hydroxide is selected from at least one of sodium hydroxide or lithium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, and magnesium hydroxide.
[0039] In some embodiments, the molar ratio of the hydroxide to the compound of formula E is 0.5:1-6:1.
[0040] In some embodiments, the molar ratio of the hydroxide to the compound of formula E is 1:1-5:1.
[0041] In some embodiments, the molar ratio of the hydroxide to the compound of formula E is 1.5:1-3:1.
[0042] In some embodiments, the volume of water added is 0.5-40 times the weight of the compound of formula E.
[0043] In some embodiments, the volume of water added is 1-20 times the weight of the compound of formula E.
[0044] In some embodiments, the volume of water added is 2-10 times the weight of the compound of formula E.
[0045] In some embodiments, the volume of water added is 4-8 times the weight of the compound of formula E.
[0046] In some embodiments, the alkaline carbonate is selected from at least one of lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate.
[0047] In some embodiments, the basic oxide is selected from at least one of calcium oxide and magnesium oxide.
[0048] In some embodiments, the organic solvent is selected from at least one of methanol, tetrahydrofuran, ethanol, n-propanol, isopropanol, dioxane, N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide.
[0049] In some embodiments, the volume of the organic solvent added is 0.5-40 times the weight of the compound of formula E.
[0050] In some embodiments, the volume of the organic solvent added is 1-20 times the weight of the compound of formula E.
[0051] In some embodiments, the volume of the organic solvent added is 2-10 times the weight of the compound of formula E.
[0052] In some embodiments, the volume of the organic solvent added is 4-8 times the weight of the compound of formula E.
[0053] In some embodiments, the reaction temperature of the reaction is 0°C-50°C.
[0054] In some embodiments, the reaction temperature of the reaction is 10°C-40°C.
[0055] In some embodiments, the reaction temperature of the reaction is 20°C-30°C.
[0056] In some embodiments, the post-treatment includes decompressing and spinning the solvent, adding acid to adjust the pH to precipitate the product, cooling and stirring to crystallize, filtering, washing the filter cake with water, and drying the filter cake.
[0057] The beneficial technical effects of the present invention include:
[0058] (1) It avoids the use of active organometallic reagents (n-butyl lithium, Grignard reagent, etc.), and the reaction conditions are relatively mild, safe, and easy to operate.
[0059] (2) This route does not use highly active Grignard reagents, making the reaction safer. In addition, the first step uses a sulfuric acid-dibromohydantoin bromination system, which avoids the large amount of metal salts produced during post-treatment using Lewis acids. By improving the bromine source, the large amount of bromine vapor that may cause harm to humans during operation is avoided.
[0060] (3) The use of active reagents such as butyl lithium is avoided, which increases the safety of the process. At the same time, the extreme reaction conditions of -78°C are avoided, which greatly improves the feasibility of industrial scale-up.
[0061] Terminology Note:
[0062] "The added volume of the compound of formula (A) is 1-100 times the weight of the compound of formula B" means that 1 ml-100 ml of the compound of formula (A) is added for every gram of compound of formula B, and the definitions of other times of volume are similar. g means gram, mg means milligram, ℃ means degree Celsius, h means hour, mL means milliliter, min means minute, HPLC means high performance liquid chromatography, pH means pH, MPa means megapascal, CO means carbon monoxide, Pd(dppf)Cl2 means [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium, MeOH means methanol, TEA means triethylamine, DIPEA means N,N-diisopropylethylamine, H2O means water, THF means tetrahydrofuran, KOH means potassium hydroxide, and LiOH means lithium hydroxide.
[0063] In the description of the present invention, it should be understood that the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of the features. In the description of the present invention, the meaning of "plurality" is two or more, unless otherwise clearly and specifically defined.
[0064] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.
[0065] In the present invention, expressions such as "compound A" and "compound represented by formula A" refer to the same compound. DETAILED DESCRIPTION
[0066] Example 1 Preparation of Compound G
[0067]
[0068] At room temperature, add 10.00g of compound F, 0.70g of [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride, 100ml of methanol, and 9.77g of triethylamine to the autoclave, replace the air in the autoclave with carbon monoxide 3 times, pressurize to 1.0Mpa, stir and react at an internal temperature of 85°C until HPLC detects that there is no raw material. Cool the autoclave to room temperature, release carbon monoxide, spin dry to recover the solvent, add 50ml of water to the spin-dried product, extract the water layer with 20ml of toluene × 3 times, combine the organic layers, and purify the product by vacuum distillation to obtain 7.93g of compound G, with a yield of 88.2% and a purity of 97.1%. MS: [M+1] = 187.1, 1H NMR (400MHz, DMSO-d6): δ7.66 (m, 1H), 7.22 (m, 1H), 3.85 (s, 3H), 2.43 (s, 3H).
[0069] Example 2 Preparation of Compound G
[0070]
[0071] At room temperature, add 10.00g of compound F, 0.67g of tetrakistriphenylphosphine palladium, 100ml of methanol, 12.48g of DIPEA to the autoclave, replace the air in the autoclave with carbon monoxide 3 times, pressurize to 1.0Mpa, stir and react at an internal temperature of 85°C until there is no raw material detected by HPLC. Cool the autoclave to room temperature, release carbon monoxide, spin dry to recover the solvent, add 50ml of water to the spin-dried product, extract the water layer with 20ml of toluene × 3 times, combine the organic layers, and purify the product by vacuum distillation. 57.69g of product compound G is obtained, with a yield of 85.5% and a purity of 95.3%.
[0072] Example 3 Preparation of Compound G
[0073]
[0074] At room temperature, add 10.00g of compound F, 0.37g of dichlorodibenzonitrile palladium, 80ml of methanol, 9.77g of N-methylmorpholine to the autoclave, replace the air in the autoclave with carbon monoxide 3 times, pressurize to 1.0Mpa, stir and react at an internal temperature of 85°C until HPLC detects that there is no raw material. Cool the autoclave to room temperature, release carbon monoxide, spin dry to recover the solvent, add 50ml of water to the spin-dried product, extract the water layer with 20ml of toluene × 3 times, combine the organic layers, and purify the product by vacuum distillation. 5.91g of product compound G is obtained, with a yield of 65.7% and a purity of 92.2%.
[0075] Example 4 Preparation of Compound H
[0076]
[0077] At room temperature, add 10.00g of compound F, 1.12g of tetrakistriphenylphosphine palladium, 100ml of ethanol, 9.70g of N-methylpiperidine to the autoclave, replace the air in the autoclave with carbon monoxide 3 times, pressurize to 1.0Mpa, stir and react at an internal temperature of 85°C until HPLC detects that there is no raw material. Cool the autoclave to room temperature, release carbon monoxide, spin dry to recover the solvent, add 50ml of water to the spin-dried product, extract the water layer with 20ml of toluene × 3 times, combine the organic layers, and purify the product by vacuum distillation. 8.12g of product compound H is obtained, with a yield of 83.9% and a purity of 94.2%.
[0078] Example 5 Preparation of Compound of Formula D
[0079]
[0080] At room temperature, add 4.30g of sodium hydroxide, 30ml of water, and 30ml of methanol to the reaction flask. Stir at room temperature for 10min to dissolve. Add 10.00g of compound G to the reaction solution and stir at room temperature to react until HPLC detects that there is no raw material. Remove the methanol under reduced pressure and add 2mol / L HCl solution to the water under stirring to adjust the pH to 3. At this time, the reaction solution is turbid and the product precipitates. Stir and crystallize at 10℃ for 2h, filter with suction, wash the filter cake with 10ml of water × 2 times, and dry the filter cake to obtain 9.03g of compound D, with a yield of 97.7% and a purity of 98.5%. MS: [M-1] = 171.0, nuclear magnetic 1H NMR (400MHz, DMSO-d6): δ13.3 (s, 1H), 7.71 (m, 1H), 7.35 (m, 1H), 2.48 (s, 3H).
[0081] Example 6 Preparation of Compound D
[0082]
[0083] At room temperature, add 4.30g of sodium hydroxide, 30ml of water, and 30ml of THF to the reaction flask. Stir at room temperature for 10min to dissolve. Then add 10.00g of compound G to the reaction solution and stir at room temperature to react until HPLC detects that there is no raw material. Remove THF under reduced pressure and add 2mol / L HCl solution to the water under stirring to adjust pH=3. At this time, the reaction solution is turbid and the product precipitates. Stir at 10℃ for crystallization for 2h, filter with suction, wash the filter cake with 10ml of water×2 times, and dry the filter cake. 8.84g of compound D is obtained, with a yield of 95.6% and a purity of 98.2%.
[0084] Example 7 Preparation of Compound of Formula D
[0085]
[0086] Add 6.03g potassium hydroxide, 30ml water and 30ml ethanol to the reaction bottle at room temperature, stir and dissolve at room temperature for 10min, then add 10.00g compound of formula G to the reaction solution and stir and react at room temperature until HPLC detects that there is no raw material. Remove ethanol under reduced pressure, add 2mol / L HCl solution to the water under stirring to adjust pH=3, at which time the reaction solution is turbid and the product precipitates, stir and crystallize at 10℃ for 2h, filter with suction, wash the filter cake with 10ml water×2 times, and dry the filter cake. 8.88g of product compound of formula D is obtained, with a yield of 96.1% and a purity of 96.7%.
[0087] Example 8 Preparation of Compound of Formula D
[0088]
[0089] Add 2.60g of lithium hydroxide, 30ml of water, and 30ml of dioxane to the reaction flask at room temperature, stir and dissolve at room temperature for 10min, then add 10.00g of compound G to the reaction solution and stir at room temperature until HPLC detects that there is no raw material. Remove ethanol under reduced pressure, add 2mol / L HCl solution to the water under stirring to adjust pH=3, at which time the reaction solution becomes turbid and the product precipitates, stir and crystallize at 10℃ for 2h, filter with suction, wash the filter cake with 10ml*2 times, and dry the filter cake. 8.55g of compound D is obtained, with a yield of 92.5% and a purity of 97.4%.
[0090] The method of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein within the content, spirit and scope of the present invention to implement and apply the technology of the present invention. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters. It is particularly important to point out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.
Claims
1. A method for preparing a compound of formula (E), The following steps are involved: The compound of formula (A) is used as a solvent and a base is used as an acid-binding agent. In the presence of a palladium-containing catalyst, the compound of formula (B) reacts with carbon monoxide and the compound of formula (A) under pressure, and after post-treatment, a compound of formula (E) is obtained, wherein R1 is selected from bromine; the palladium-containing catalyst is selected from [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium or tetrakistriphenylphosphine palladium; and the compound of formula (A) is selected from at least one of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, and benzyl alcohol.
2. The method according to claim 1, characterized in that The reaction temperature of the reaction is 65°C-105°C.
3. The method according to claim 1, wherein the reaction temperature is 75°C-95°C. The method according to claim 1 , wherein the reaction temperature is 85° C.
5. The method according to claim 1, characterized in that The added volume of the compound of formula (A) is 1-100 times the weight of the compound of formula (B).
6. The method according to claim 1, characterized in that The added volume of the compound of formula (A) is 2-50 times the weight of the compound of formula (B).
7. The method according to claim 1, characterized in that The added volume of the compound of formula (A) is 5-20 times the weight of the compound of formula (B).
8. The method according to claim 1, characterized in that The base is selected from at least one of triethylamine, pyridine, piperidine, morpholine, N,N-diisopropylethylamine, ethanolamine, ammonia water, diethylamine, N-methylmorpholine, tetrahydropyrrole, N-methyltetrahydropyrrole, N-methylpiperidine, lithium hydroxide, potassium hydroxide, cesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, calcium oxide, magnesium oxide, calcium hydroxide, and magnesium hydroxide; the molar ratio of the base to the compound of formula (B) is 0.1:1-10:
1.
9. The method according to claim 8, characterized in that The molar ratio of the base to the compound of formula (B) is 0.5:1-8:
1.
10. The method according to claim 8, characterized in that The molar ratio of the base to the compound of formula (B) is 1:1-5:
1.
11. The method according to claim 1, characterized in that: The molar ratio of the palladium catalyst to the compound of formula (B) is 0.005:1-0.1:
1.
12. The method according to claim 1, characterized in that The molar ratio of the palladium catalyst to the compound of formula (B) is 0.01:1-0.05:
1.
13. A method for preparing a compound of formula (D), The following steps are involved: The compound of formula (E) is prepared according to the preparation method according to any one of claims 1 to 12, and then the compound of formula (E) is hydrolyzed in a mixed solvent containing water and an organic solvent miscible with water in the presence of a catalyst, and post-treated to obtain a compound of formula (D).
14. The method according to claim 13, characterized in that The catalyst is selected from at least one of hydroxides, alkaline carbonates and alkaline oxides.
15. The method according to claim 14, characterized in that The hydroxide is selected from at least one of sodium hydroxide or lithium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, and magnesium hydroxide; the alkaline carbonate is selected from at least one of lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; and the alkaline oxide is selected from at least one of calcium oxide and magnesium oxide.
16. The method according to claim 13, characterized in that The organic solvent is selected from at least one of methanol, tetrahydrofuran, ethanol, n-propanol, isopropanol, dioxane, N,N-dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide.
17. The method according to claim 13, characterized in that The reaction temperature of the reaction is 0°C-50°C.
18. The method according to claim 13, characterized in that The reaction temperature of the reaction is 10°C-40°C.
19. The method according to claim 13, characterized in that The reaction temperature of the reaction is 20°C-30°C.
Citation Information
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