Preparation method and application of fluorobenzyl ribose intermediate

Abstract

The present invention discloses a preparation method and application of a fluorobenzyl ribose intermediate, and relates to the technical field of drug synthesis. The preparation method comprises the following steps: (1) reacting 2'-deoxy-2'-fluorouridine (compound 8), a benzylation agent, and an alkaline substance in an organic solvent to obtain compound 9; (2) reacting compound 9 with an acetylating agent and an acid in an organic solvent to obtain compound 10; (3) reacting compound 10 with an acid in methanol to obtain compound 1. Beneficial effects: The present invention simplifies and optimizes the technical route, uses inexpensive reaction raw materials to synthesize compound 1, is simple to operate, has a short reaction time, a high yield, and improves production efficiency.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method and application of a fluorobenzyl ribose intermediate. Background Art

[0002] Patent document No. US2021340169A1 discloses that compound (1) can be used to synthesize some anti-tumor compounds. The structural formula of compound (1) is According to the literature (10.1021 / ja0524043), compound (1) can be prepared from D-arabinose (2) according to the following route.

[0003]

[0004] However, the above route has many steps and low overall yield, resulting in a high cost for compound (1). Summary of the Invention

[0005] The technical problem to be solved by the present invention is how to solve the problem of complicated preparation steps and low yield of the existing compound 1.

[0006] The present invention solves the above technical problems through the following technical means:

[0007] The first aspect of the present invention provides a method for preparing a fluorobenzyl ribose intermediate, comprising the following steps:

[0008] (1) reacting 2'-deoxy-2'-fluorouridine (compound 8), a benzylation reagent, and a basic substance in an organic solvent to obtain compound 9;

[0009] (2) reacting compound 9 with an acetylating agent and an acid in an organic solvent to obtain compound 10;

[0010] (3) Compound 10 is reacted with acid in methanol to obtain compound 1

[0011] The technical route is as follows:

[0012]

[0013] Beneficial effects: The present invention simplifies and optimizes the technical route and synthesizes compound 1 using cheap reaction raw materials. The operation is simple, the reaction time is short, the yield is high, and the production efficiency is improved.

[0014] Preferably, in step (1), the molar ratio of 2'-deoxy-2'-fluorouridine, benzylating agent and alkaline substance is 1:2-6:5-10.

[0015] Preferably, in step (1), the molar ratio of 2'-deoxy-2'-fluorouridine, the benzylation reagent and the alkaline substance is 1:4:6.

[0016] Preferably, the benzylation agent in step (1) is selected from benzyl chloride or benzyl bromide.

[0017] Preferably, the organic solvent in step (1) is selected from a mixture of one or more of dichloromethane, tetrahydrofuran (THF), 2-methyltetrahydrofuran, N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).

[0018] Preferably, the alkaline substance in step (1) is selected from a mixture of one or more of sodium hydroxide, potassium hydroxide, tetrabutylammonium hydroxide, and sodium carbonate.

[0019] Preferably, in step (2), the volume ratio of the mass of compound 9 to the acetylating agent is 1 g / (3-15) mL.

[0020] Preferably, in step (2), the volume ratio of the mass of compound 9 to the acetylating agent is 1 g / 6 mL.

[0021] Preferably, the mass ratio of compound 9 to acid in step (2) is 1:0.05-2.

[0022] Preferably, the mass ratio of compound 9 to acid in step (2) is 1:0.1.

[0023] Preferably, the organic solvent in step (2) is selected from a mixture of one or more of acetic acid, dichloromethane, tetrahydrofuran (THF), 2-methyltetrahydrofuran, and methyl tert-butyl ether.

[0024] Preferably, the acetylating agent in step (2) is selected from a mixture of one or more of acetic acid and acetic anhydride.

[0025] Preferably, the acid in step (2) is selected from one of sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid.

[0026] Preferably, in step (3), the mass ratio of compound 10 to acid is 1:0.05-2.

[0027] Preferably, the mass ratio of compound 10 to acid in step (3) is 1:0.1.

[0028] Preferably, the acid in step (3) is selected from one of sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid.

[0029] The second aspect of the present invention provides a use of the fluorobenzyl ribose intermediate prepared by the above preparation method in drug synthesis.

[0030] The advantages of the present invention are:

[0031] 1. The present invention simplifies and optimizes the technical route and uses cheap reaction raw materials to synthesize compound 1, which has simple operation, short reaction time, high yield and improved production efficiency.

[0032] 2. The reagents required for the method of the present invention are relatively cheap and low in cost; the post-processing operation of the method of the present invention is simple.

[0033] 3. The method of the present invention has the advantages of short reaction time and easy industrial production. DETAILED DESCRIPTION

[0034] To make the objectives, technical solutions, and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts shall fall within the scope of protection of the present invention.

[0035] Example 1:

[0036] A method for preparing a fluorobenzyl ribose intermediate comprises the following steps:

[0037] (1) Compound 8 (1.0 g, 0.004 mol, 1.0 eq) was dissolved in DMF (5 mL), and the mixture was replaced with N2 three times. NaOH (powder, 0.96 g, 0.024 mol, 6 eq) and tetrabutylammonium iodide (0.15 g, 0.0004 mol, 0.1 eq) were added under ice bath, followed by BnCl (2.0 g, 0.016 mol, 4 eq). The mixture was stirred at room temperature for 20 hours. The reaction mixture was then partitioned between water and tert-methyl ether. The organic phase was separated and washed with 2 M hydrochloric acid and saturated sodium bicarbonate aqueous solution in sequence. The organic phase was concentrated in vacuo and the residue was purified by flash chromatography to give compound 9. Yield: 89%. HRMS: M+H + The molecular formula is C23H24FN2O5+, the calculated value is 427.1664, and the measured value is 427.1679.

[0038]

[0039] (2) Compound 9 (1.0 g) was dissolved in a mixed solvent of dichloromethane (1 mL), acetic acid (5 mL), and acetic anhydride (1 mL). Concentrated sulfuric acid (0.1 g) was added dropwise under ice-cooling, followed by stirring at room temperature for 1 h. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution, extracted with methyl tert-ether, and the organic phase was washed with a saturated aqueous sodium bicarbonate solution. The organic phase was then concentrated in vacuo and purified by flash chromatography to obtain compound 10. Yield: 47%. HRMS: (M-MeO) + The molecular formula is C19H20FO3+, the calculated value is 315.1391, and the measured value is 315.1399.

[0040]

[0041] (3) Compound 10 (1.0 g) was dissolved in methanol (5 mL), and concentrated sulfuric acid (0.1 g) was added dropwise in an ice bath. The mixture was then stirred at room temperature for 20 hours. Solid sodium carbonate was added to the reaction mixture to adjust the pH to about 7-8. The organic phase was concentrated in vacuo and purified by flash chromatography to obtain compound 1. Yield: 95%. HRMS: (M-MeO) + The molecular formula is C19H20FO3+, the calculated value is 315.1391, and the measured value is 315.1399.

[0042]

[0043] Application of compound 1 in the synthesis of drugs:

[0044] Referring to the method of patent document US2021340169A1, compound 1 (8.4 g, 24.2 mmol) was dissolved in a mixture of trifluoroacetic acid (90 mL) and water (10 mL). After stirring at 20-25 degrees Celsius for 16 hours, methyl tert-ether (50 mL) and water (50 mL) were added to the system. The organic phase was separated and washed with aqueous sodium bicarbonate until neutral. The organic phase was then concentrated in vacuo and purified by flash chromatography to obtain compound 11. The yield was 90%.

[0045]

[0046] Compound 11 (5.9 g, 17.8 mmol) was dissolved in a mixture of toluene (70 mL) and carbon tetrachloride (8 mL), cooled to -30 to -40 degrees Celsius, and a solution of tri(dimethylamino)phosphine (3.49 g, 21.41 mmol) in toluene (5 mL) was added dropwise with stirring. The mixture was stirred at 0 degrees Celsius for 3 hours, and then saturated brine was added to terminate the reaction. The organic phase was separated and concentrated to dryness, and the residue was dissolved in acetonitrile (100 mL). Compound 12 (3.2 g, 18.5 mmol) was added, followed by potassium hydroxide (3.1 g) and tri[2-(2-methoxyethoxy)ethyl]amine (0.6 g). The mixture was stirred at 20 to 25 degrees Celsius for 16 hours, and then tertiary methyl ether (50 mL) and water (50 mL) were added to the system. The organic phase was separated and washed with sodium bicarbonate aqueous solution until neutral. The organic phase was then concentrated in vacuo and purified by flash chromatography to obtain compound 13. Yield 61%.

[0047]

[0048] According to patent document US2021340169A1, compound 13 can be used to further synthesize nucleoside STING agonists.

[0049] Example 2:

[0050] A method for preparing a fluorobenzyl ribose intermediate comprises the following steps:

[0051] (1) Compound 8 (1.0 g, 0.004 mol, 1.0 eq) was dissolved in DMF (5 mL) and THF (2 mL), and the atmosphere was replaced with N2 three times. Potassium hydroxide (1.12 g, 0.02 mol, 5 eq) was added under ice-cooling, followed by BnBr (1.37 g, 0.008 mol, 2 eq). The mixture was stirred at room temperature for 16 hours. The reaction mixture was then partitioned between water and tert-methyl ether. The organic phase was separated and washed sequentially with 2M hydrochloric acid and saturated aqueous sodium bicarbonate solution. The organic phase was concentrated in vacuo and the residue was purified by flash chromatography to obtain compound 9. Yield: 85%.

[0052] (2) Compound 9 (1.0 g) was dissolved in a mixed solvent of THF (2 mL) and acetic acid (3 mL). Methanesulfonic acid (0.05 g) was added dropwise under ice-cooling, followed by stirring at room temperature for 1 h. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution and extracted with tert-methyl ether. The organic phase was washed with a saturated aqueous sodium bicarbonate solution, concentrated in vacuo, and purified by flash chromatography to obtain compound 10. Yield: 32%.

[0053] (3) Compound 10 (1.0 g) was dissolved in methanol (5 mL), and trifluoromethanesulfonic acid (0.05 g) was added dropwise in an ice bath. The mixture was then stirred at room temperature for 16 hours. Solid sodium carbonate was added to the reaction mixture to adjust the pH to about 7-8. The organic phase was concentrated in vacuo and purified by flash chromatography to obtain compound 1. The yield was 90%.

[0054] Example 3:

[0055] A method for preparing a fluorobenzyl ribose intermediate comprises the following steps:

[0056] (1) Compound 8 (1.0 g, 0.004 mol, 1.0 eq) was dissolved in DMSO (5 mL), and the atmosphere was replaced with N2 three times. Sodium carbonate (0.04 mol, 10 eq) was added under ice-bath, followed by BnCl (3 g, 0.024 mol, 6 eq). The mixture was stirred at room temperature for 24 hours. The reaction mixture was then partitioned between water and tert-methyl ether. The organic phase was separated and washed sequentially with 2 M hydrochloric acid and saturated aqueous sodium bicarbonate solution. The organic phase was concentrated in vacuo and the residue was purified by flash chromatography to obtain compound 9. Yield: 65%.

[0057] (2) Compound 9 (1.0 g) was dissolved in a mixed solvent of methyl tert-butyl ether (2 mL), acetic acid (10 mL), and acetic anhydride (5 mL). Trifluoromethanesulfonic acid (2 g) was added dropwise under ice-cooling, followed by stirring at room temperature for 1 h. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution and extracted with methyl tert-ether. The organic phase was washed with a saturated aqueous sodium bicarbonate solution, concentrated in vacuo, and purified by flash chromatography to obtain compound 10. Yield: 40%.

[0058] (3) Compound 10 (1.0 g) was dissolved in methanol (5 mL), and p-toluenesulfonic acid (2 g) was added dropwise in an ice bath. The mixture was then stirred at room temperature for 24 hours. Solid sodium carbonate was added to the reaction mixture to adjust the pH to approximately 7-8. The organic phase was concentrated in vacuo and purified by flash chromatography to obtain compound 1. The yield was 92%.

[0059] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. A method for preparing a fluorobenzyl ribose intermediate, characterized in that: The following steps are involved: (1) 2'-deoxy-2'-fluorouridine, a benzylating agent and an alkaline substance are reacted in an organic solvent to obtain compound 9; the structural formula of compound 9 is ; (2) Compound 9 is reacted with an acetylating agent and an acid in an organic solvent to obtain compound 10; the structural formula of compound 10 is ; (3) Compound 10 is reacted with an acid in methanol to obtain compound 1, the structural formula of which is .

2. The method for preparing a fluorobenzyl ribose intermediate according to claim 1, wherein: In the step (1), the mass ratio of 2'-deoxy-2'-fluorouridine, the benzylating agent and the alkaline substance is 1:2-6:5-10.

3. The method for preparing a fluorobenzyl ribose intermediate according to claim 1 or 2, characterized in that: The benzylation agent in step (1) is selected from benzyl chloride or benzyl bromide.

4. The method for preparing a fluorobenzyl ribose intermediate according to claim 3, wherein: The organic solvent in step (1) is selected from a mixture of one or more of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, and dimethyl sulfoxide; the alkaline substance in step (1) is selected from a mixture of one or more of sodium hydroxide, potassium hydroxide, tetrabutylammonium hydroxide, and sodium carbonate.

5. The method for preparing a fluorobenzyl ribose intermediate according to claim 4, wherein: The mass ratio of compound 9 to the volume of the acetylating agent in step (2) is 1 g / (3-15) mL; the mass ratio of compound 9 to the acid in step (2) is 1:0.05-2.

6. The method for preparing a fluorobenzyl ribose intermediate according to claim 1, wherein: The organic solvent in step (2) is selected from a mixture of one or more of acetic acid, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, and methyl tert-butyl ether.

7. The method for preparing a fluorobenzyl ribose intermediate according to claim 1, wherein: The acetylating agent in step (2) is selected from a mixture of one or more of acetic acid and acetic anhydride; and the acid in step (2) is selected from one of sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, and p-toluenesulfonic acid.

8. The method for preparing a fluorobenzyl ribose intermediate according to claim 1, wherein: In the step (3), the mass ratio of compound 10 to acid is 1:0.05-2.

9. The method for preparing a fluorobenzyl ribose intermediate according to claim 8, wherein: In step (3), the mass ratio of compound 10 to acid is 1:0.

1.

10. The method for preparing a fluorobenzyl ribose intermediate according to claim 1, wherein: The acid in step (3) is selected from one of sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid.

Images