A method of preparing maraviroc

Abstract

The application provides a novel preparation method of maraviroc, which forms a stable intermediate by protecting phenolic hydroxyl with n-pentyl, so that the condensation with (R)-(+)-tetrahydrofuran-2-formyl chloride has a high yield, and the by-products generated by removing the protecting group in the reaction process are reduced; the use of the controlled reagent 1-propyl phosphonic anhydride in the condensation of (R)-(+)-tetrahydrofuran-2-formic acid in the original process is eliminated. In the subsequent docking with the C fragment, by adjusting the polarity of the solvent, the product is easily precipitated, the conversion rate is improved, and the product is easy to separate and purify, so that the problem of low conversion rate of the protecting group reported in the literature is solved. The improved method has the advantages of simple reaction and operation, easy impurity removal, and a reaction yield increased by about 10% compared with the previous method, and is an industrialized amplification implementation feasible process.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of drug synthesis, and particularly relates to a preparation method of an anti-influenza drug baloxavir marboxil. BACKGROUND

[0002] Baloxavir marboxil, also known as baloxavir marboxil in Chinese, is an anti-influenza drug developed by Shionogi, a Japanese pharmaceutical company, and its trade name is Xofluza. Xofluza is an innovative Cap-dependent endonuclease inhibitor and is one of the few new drugs that can inhibit the proliferation of influenza viruses. It can inhibit the CAP structure of the 5' end of the host mRNA obtained by the influenza virus from the host cell, thereby inhibiting the transcription of the influenza virus mRNA. In February 2018, the drug was approved in Japan for the treatment of influenza A and B in adult and pediatric patients. In October 2018, it was approved by FDA for marketing, and is used for the treatment of acute influenza patients without complications for no more than 48 hours at the age of 12 and above.

[0003] Baloxavir marboxil is a prodrug that is hydrolyzed into active baloxavir in the body to exert anti-influenza virus activity.

[0004]

[0005] Baloxavir marboxil compound structure contains two parts of dibenzothiophene ring and oxazinopyridine triazine ring, which are first disclosed in patents WO2010147068 and WO2012039414. Patent WO2016175224 discloses a synthesis method of baloxavir marboxil. After the docking of the two parts of dibenzothiophene ring structure and oxazinopyridine triazine ring structure, the benzyl protecting group is removed, and then reacted with chloromethyl dimethyl carbonate to obtain baloxavir marboxil. This route is the simplest and most direct method to obtain baloxavir marboxil. However, since the oxazinopyridine triazine ring contains a chiral center, the hydroxyl protecting group on the oxazinopyridine triazine ring will produce a side reaction of benzyl protecting group removal under the reaction conditions of docking, and the product after docking will produce epimerization. The isomer has similar properties to the product, and it is extremely difficult to remove, greatly increasing the refining process, so the reaction yield of this step is still very low, only about 53%.

[0006]

[0007] Patent WO2017221869 discloses the following synthesis method: before the docking of the oxazinopyridine triazine ring and the dibenzothiophene ring, the replacement of the hydroxyl protecting agent on the oxazinopyridine triazine ring is carried out, and the benzyl group is replaced with n-hexyl group. The space steric hindrance and induction of different substituents are used to realize the conversion of crystallization-induced diastereomers to products. After the replacement of n-hexyl group, the selectivity of this method is improved, and the reported docking yield is 85%. However, in the patent method, when n-pentyl is used as a substituent in the reaction, the isomer ratio is still as high as 20%.

[0008]

[0009] The oxazinopyridine triazine ring fragment is a key intermediate in the synthesis of marbofloxacin, and its chemical name is (12AR)-3,4,12,12A-tetrahydro-7-(phenylmethoxy)-1H-[1,4]oxazino[3,4-C]pyrido[2,1-F][1,2,4]triazine-6,8-dione. This intermediate itself contains one chiral center. Patent WO2017221869 discloses the following synthesis route: when dimethoxy and Boc protecting group are removed, benzyl by-product is also removed. When compound 5 reacts with furan carboxylic acid, a by-product with simultaneous substitution on the hydroxyl group is produced, which is difficult to purify. In addition, the chemical reagent 1-propyl phosphoric acid anhydride used in the reaction of compound 5 and furan carboxylic acid is a controlled chemical reagent, which is expensive and not conducive to industrialization, increasing the production cost.

[0010]

[0011] With the marketing of marbofloxacin in various markets around the world and the increasingly widespread use of anti-influenza drugs, the demand for marbofloxacin is increasing. Therefore, there is an urgent need to develop an industrialized route with simple operation, fewer side reactions, high purity and low cost. SUMMARY

[0012] The purpose of the present application is to provide a new preparation method of marbofloxacin. The intermediate in the preparation method has stable properties, fewer by-products, simple operation, and the reagents used are simple and easy to obtain. It is a preparation method with industrial production prospect.

[0013] In one aspect of the present application, a preparation method of marbofloxacin (compound of formula V) is provided, which comprises the following synthesis route

[0014]

[0015] In another preferred embodiment, the synthesis route specifically comprises the following synthesis steps:

[0016] (1) Compound A is condensed with Compound B under the condition of an acid binding agent to obtain racemic Compound I, and further refined to obtain isomerically pure Compound I-1, wherein the acid binding agent is selected from one or more of triethylamine, diisopropylethylamine, pyridine;

[0017] (2) Compound I-1 is removed from the furan formyl group under the action of 1,8-diazabicyclo[5.4.0]-7-undecene to obtain Compound II, wherein the isomer purity of Compound II is not less than 99.2%;

[0018] (3) Compound II is condensed with Compound C in an organic solvent system under the action of 1-propyl phosphoric acid cyclic anhydride (T3P) to obtain Compound III;

[0019] (4) Compound III is removed from the protection group under the action of alkali metal halide and triethylamine to obtain Compound IV;

[0020] (5) Compound IV is suspended in dimethylacetamide solvent, reacts with chloroformic acid dimethyl carbonate under the action of potassium salt to obtain Compound V, i.e. marbofloxacin.

[0021] In another preferred example, Compound B in step (1) is prepared by the following method:

[0022]

[0023] Compound B-1 is reacted with a chlorinating agent selected from one or more of oxalyl chloride, sulfurous chloride, sulfuryl chloride, triphosgene, phosphorus trichloride, and phosphorus pentachloride; preferably one or both of oxalyl chloride and sulfurous chloride; more preferably oxalyl chloride.

[0024] In another preferred example, the molar ratio of Compound B-1 to oxalyl chloride is 1:0.5-1.5; preferably 1:0.6-1.0; more preferably 1:0.6-08.

[0025] In another preferred example, step (1) specifically comprises the following operations: in the reaction system of Compound A and triethylamine in an organic solvent, Compound B is added dropwise, and the reaction is carried out at room temperature for 2-3 hours, then extracted, concentrated, and then added with ethyl acetate, stirred at 60-65°C, then cooled to 0-5°C and stirred, filtered, and the filter cake is refined again with ethyl acetate to obtain Compound I-1, wherein the isomer purity of Compound I-1 is not less than 99.0%.

[0026] In another preferred example, the organic solvent system in step (3) is a mixed solvent of one or more of n-hexane, cyclohexane, n-heptane, and n-pentane and ethyl acetate; preferably a mixed solvent of ethyl acetate and n-hexane.

[0027] In another preferred embodiment, the alkali metal halide in step (4) is one or more of lithium chloride, lithium bromide, sodium bromide, sodium iodide, potassium chloride, potassium bromide; preferably lithium chloride, lithium bromide or a combination thereof, more preferably lithium bromide.

[0028] In another preferred embodiment, the potassium salt in step (5) is a mixture of potassium carbonate and potassium iodide.

[0029] In another preferred embodiment, the compound A is prepared by the following method:

[0030]

[0031] (a) reacting compound A-1 with dimethyl sulfate under basic conditions to obtain compound A-2;

[0032] (b) reacting compound A-2 with tert-butyl carbazate in a system containing pyridinium p-toluenesulfonate to obtain compound A-3;

[0033] (c) reacting compound A-3 and compound A-4 under the action of a condensing agent to obtain compound A-5, wherein the condensing agent is one or more of 1,8-diazabicyclo[5.4.0]-7-undecene, sodium methoxide, sodium ethoxide, sodium tert-butoxide; preferably 1,8-diazabicyclo[5.4.0]-7-undecene;

[0034] (d) adding an organic acid to the reaction system containing compound A-5 to obtain compound A, wherein the organic acid is one or more of methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, p-toluenesulfonic acid; preferably methanesulfonic acid.

[0035] The present application provides a preparation method of maraviroc key intermediate VII, and the advantages of the present application are:

[0036] (1) By protecting the phenolic hydroxyl group with n-pentyl to form a stable intermediate, the condensation of compound A with (R)-(+)-tetrahydrofuran-2-formyl chloride can be achieved with high yield, and the by-products generated by removal of the protecting group during the reaction process are reduced;

[0037] (2) The use of the original regulated reagent 1-propyl phosphonic anhydride is eliminated, and the reaction conditions are simple and easy to operate;

[0038] (3) By adjusting the polarity of the solvent, the intermediate product can be easily precipitated, thereby facilitating separation and purification;

[0039] (4) The overall reaction yield is increased by about 10%, thereby reducing the production cost.

[0040] It should be understood that, within the scope of the present application, the above technical features of the present application and the technical features specifically described hereinafter (e.g. in the examples) can be combined with each other to form new or preferred technical solutions. Due to the limited space, they will not be repeated one by one here. DETAILED DESCRIPTION

[0041] In the following examples, unless otherwise specified, the test methods described are generally carried out under conventional conditions or conditions recommended by the manufacturer, and the raw materials and reagents shown can be obtained by commercial purchase.

[0042] Example 1

[0043] Preparation of compound of formula A-2

[0044]

[0045] At room temperature, 800 ml of acetone was added to compound A-1 (91.75 g, 0.41 mol), potassium carbonate (36.51 g, 0.26 mol) was added, stirring, dropwise dimethyl sulfate (58.91 g, 0.47 mmol) was added, and the reaction was carried out at room temperature until the raw material completely disappeared. The pH was adjusted to 3-4 with hydrochloric acid, concentrated, removed the acetone, then extracted with ethyl acetate once, after separation, the aqueous phase was extracted with ethyl acetate, the organic phase was combined, concentrated to an oil, which was directly used in the next step.

[0046] Example 2

[0047] Preparation of compound of formula A-3

[0048]

[0049] At room temperature, 300 ml of N,N-dimethylacetamide was added to the A-2 concentrate prepared in Example 1, then pyridinium p-toluenesulfonate (265.42 g, 1.06 mol) was added, and the reaction system was heated to 60°C, then a solution of tert-butyl hydrazine carboxylate (69.80 g, 0.53 mmol) in N,N-dimethylacetamide (200 mL) was slowly added to the reaction mixture, after dropping, the stirring was continued for 1 hour, then the temperature was allowed to cool to room temperature. Water and ethyl acetate were added, extracted, after separation, the organic phase was concentrated. The concentrate was slurried with 100 mL of ethanol and 600 mL of water, stirred for 1 hour, suction filtered, and vacuum dried to obtain 124.2 g of compound A-3 with a purity of 95.4% and a yield of 86.3%.

[0050] Example 3

[0051] Preparation of compound of formula A-5

[0052]

[0053] To 40 ml THF, add compound A-3 (10.3 g, 0.07 mol) and 1,8-diazabicyclo[5.4.0]-7-undecene (8.9 g, 0.058 mol), add compound A-4 (18.93 g, 0.053 mol) to the solution, stir the solution. The reaction system is heated to 60 °C, and stirring is continued until the substrate is completely converted. The system is cooled to room temperature, water and acetic acid are added, and the pH is adjusted to 5-6. Then extract with ethyl acetate, combine the organic phases, and concentrate to obtain an oil. Add methyl tert-butyl ether to the oil, stir, and a solid is precipitated. Filter to obtain 22.0 g of yellowish to white solid compound A-5, purity 92.1%, molar yield 87.4%.

[0054] Example 4

[0055] Preparation of compound of formula A

[0056]

[0057] Add compound A-5 (19.19 g, 0.041 mol) to a mixture of 170 mL acetonitrile and 30 mL water, stir, then heat the reaction system to 60 °C, slowly add methanesulfonic acid (11.70 g, 0.12 mol), and continue stirring for 3-5 hours until the reaction is complete. Cool the system to room temperature, adjust the pH to 6-7 with 30% aqueous sodium hydroxide solution, concentrate the acetonitrile in the reaction system, stir the residue in water, collect the yellow precipitate obtained by filtration, and dry to obtain 10.2 g of yellow crystalline compound A, purity 94.1%, yield 85.7%.

[0058] Example 5

[0059] Preparation of compound of formula I-1

[0060]

[0061] Preparation of compound of formula B

[0062] Add (R)-(+)-tetrahydrofurfuric acid (compound B-1, 7.10 g, 0.06 mol) to 55 mL dichloromethane, control the internal temperature below 15 °C, and drop in oxalyl chloride (5.1 g, 0.04 mol). After the drop is complete, continue stirring for 0.5 h, then heat to room temperature and stir for 10 h, and concentrate at 40 °C to remove dichloromethane and oxalyl chloride to obtain compound V, which is ready for use.

[0063] Preparation of compound of formula I-1

[0064] In another reaction flask, compound A (9.4 g, 0.03 mol), 80 ml of N,N- dimethylformamide and triethylamine (8.0 g, 0.08 mol) were added, and the prepared compound B was added dropwise while controlling the internal temperature to be lower than 15°C. After the dropwise addition was completed, the reaction was stirred at room temperature for 2-3 hours, and the reaction was completed. 80 ml of dichloromethane was added, and water was added while stirring, and the mixture was separated, and the organic phase was concentrated. To the concentrate, 50 ml of ethyl acetate was added, and the mixture was stirred at 60-65°C for 0.5 hours, and further cooled to 0-5°C, and stirred for 0.5 hours, and filtered, and the filter cake was refined again with 30 ml of ethyl acetate, and filtered, and vacuum dried to obtain 5.8 g of compound VI-1 having a purity of 99.3% and a yield of 47.1%.

[0065] Example 6

[0066] Preparation of compound of formula II

[0067]

[0068] Compound VI-1 (14.56 g, 0.036 mol) was added to 120 ml of ethyl acetate, and after stirring and dissolving, 1,8-diazabicyclo[.4.0]-7-undecene (DBU) (5.3 g, 0.035 mol) was added, and the reaction mixture was heated to 30°C, and stirred for 1 hour, and further cooled to 0-5°C, and stirred for 0.5 hours, and filtered, and dried to obtain 10.76 g of white solid, which was compound II, having a purity of 99.1% and a yield of 97.3%.

[0069] Example 7

[0070] Preparation of compound of formula III

[0071]

[0072] Compound II (10.0 g, 30 mmol) and compound C (8.3 g, 31 mmol) were added to a mixture of 50 ml of ethyl acetate and 10 ml of n-hexane. 50(w / w)% 1-propyl phosphonic anhydride (19 g, 48 mmol) in ethyl acetate and methanesulfonic acid (6 g, 60 mmol) were added. The reaction mixture was heated to 65-70°C and stirred for 4 hours, and then the temperature was lowered to 55-60°C and stirring was continued until a large amount of solid was precipitated. After the temperature was lowered to room temperature, the mixture was filtered, and the filter cake was refluxed with a mixture of N-methylpyrrolidone and methanol for 1 hour, and then cooled in an ice water bath and filtered, and the filter cake was vacuum dried to obtain 16.7 g of compound of formula III, having a purity of 99.4% and a yield of 93.1%.

[0073] Example 8

[0074] Preparation of compound of formula IV

[0075]

[0076] Triethylamine (1.56 g, 15.4 mmol) was added to 10 ml of N-methyl pyrrolidone, compound III (10.0 g, 22.6 mmol) was added, stirred, then lithium bromide (8.02 g, 92.4 mmol) and acetic acid (0.93 g, 15.5 mmol) were added to the reaction system, the resulting mixture was heated to 100 °C and stirred for 4 hours, then cooled to 40 °C, acetonitrile and water were added to the reaction system and stirred. Then 80 ml of water was further added dropwise, and stirred at room temperature for 1.5 hours, then filtered, and the white precipitate was collected. Vacuum drying gave 8.15 g of compound IV, purity 99.2%, yield 93.3%.

[0077] Example 9

[0078] Preparation of compound V

[0079]

[0080] Compound IV (15 g, 31 mmol) was added to 60 ml of N,N-dimethylacetamide solution, then dimethylcarbonate chloroformate (5.8 g, 46.5 mmol), potassium carbonate (8.6 g, 62 mmol) and potassium iodide (5.1 g, 31 mmol) were added, the temperature was raised to 50 °C and stirred for 6 hours. After cooling to room temperature, the resulting filtrate was added dropwise with 10 ml of 1 mol / L aqueous hydrochloric acid solution under ice bath cooling, stirred for 1 hour, filtered, vacuum dried to give 16.7 g of compound V, which is maraviroc, purity 99.5%, yield 94.2%.

[0081] All the documents mentioned in the present application are incorporated herein by reference as if each document were individually incorporated. In addition, it is to be understood that various alterations and modifications can be made to the present application upon reading and understanding the above lecture of the present application, and these equivalent forms also fall within the scope of the appended claims of the present application.

Claims

1. A method for preparing mabaloxavir (compound of formula V), characterized in that: The following synthetic routes are included:

2. The method according to claim 1, characterized in that The synthetic route specifically comprises the following synthetic steps: (1) Compound A and Compound B are condensed in the presence of an acid-binding agent to obtain a racemic compound I, which is further purified to obtain an isomerically pure compound I-1, wherein the acid-binding agent is selected from one or more of triethylamine, diisopropylethylamine, and pyridine; (2) Compound I-1 is treated with 1,8-diazabicyclo[5.4.0]-7-undecene to remove the furanoyl group to obtain Compound II, wherein the isomer purity of Compound II is not less than 99.2%; (3) Compound II and Compound C are condensed in an organic solvent system under the action of 1-propylphosphoric acid cyclic anhydride to obtain Compound III; (4) Compound III is treated with an alkali metal halide and triethylamine to remove the protecting group to obtain compound IV; (5) Compound IV is suspended in dimethylacetamide solvent and reacted with dimethyl chloroformate carbonate in the presence of potassium salt to obtain compound V, namely mabaloxavir.

3. The method according to claims 1 and 2, characterized in that The compound B in step (1) is prepared by the following method: Compound B-1 reacts with a chlorinating agent to obtain compound B, wherein the chlorinating agent is selected from one or more of oxalyl chloride, thionyl chloride, sulfuryl chloride, triphosgene, phosphorus trichloride, and phosphorus pentachloride.

4. The method according to claim 2, characterized in that Step (1) specifically comprises the following operations: adding compound B dropwise to a reaction system of compound A and triethylamine in an organic solvent, reacting at room temperature for 2 to 3 hours, extracting, concentrating the organic phase, adding ethyl acetate, stirring at 60 to 65° C., then cooling to 0 to 5° C. and stirring, filtering, and refining the filter cake with ethyl acetate to obtain compound I-1, wherein the isomer purity of compound I-1 is not less than 99.0%.

5. The method according to claim 2, characterized in that: The organic solvent system in step (3) is a mixed solvent of one or more of n-hexane, cyclohexane, n-heptane, and n-pentane and ethyl acetate.

6. The method according to claim 2, characterized in that: The alkali metal halide in step (4) is one or more of lithium chloride, lithium bromide, sodium bromide, sodium iodide, potassium chloride and potassium bromide.

7. The method according to claim 2, characterized in that: The potassium salt in step (5) is a mixture of potassium carbonate and potassium iodide.

8. The method according to claim 1, characterized in that: The compound A is prepared by the following method: (a) Compound A-1 reacts with dimethyl sulfate under alkaline conditions to obtain compound A-2; (b) Compound A-2 reacts with tert-butyl carbazate in a system containing pyridinium p-toluenesulfonate to obtain compound A-3; (c) Compound A-3 and Compound A-4 react in the presence of a condensing agent to obtain Compound A-5, wherein the condensing agent is selected from one or more of 1,8-diazabicyclo[5.4.0]-7-undecene, sodium methoxide, sodium ethoxide, and sodium tert-butoxide; (d) adding an organic acid to a reaction system containing compound A-5 to react and obtain compound A, wherein the organic acid is selected from one or more of methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, and p-toluenesulfonic acid.

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