Preparation Method and Application of a Fluorinated Ribose Intermediate

Abstract

The present invention discloses a preparation method and application of a fluorinated ribose intermediate, and particularly relates to the technical field of pharmaceutical synthesis. The preparation method comprises the following steps: (1) reacting 2'-deoxy-2'-fluorouridine with an acetylation reagent and a base in an organic solvent to obtain compound 6; (2) reacting compound 6 with an acetylation reagent and an acid in an organic solvent to obtain compound 7; (3) reacting compound 7 with an acid in methanol to obtain compound 8; reacting compound 8 with a base in a solvent to obtain compound 1. Beneficial effects: By simplifying and optimizing the technical route, the present invention synthesizes compound 1 by using inexpensive reaction raw materials, with simple operation, short reaction time, high yield, and improved production efficiency.

Description

Technical Field

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

[0002] Compound (1) can be used to synthesize A3 adenosine receptor substrates (10.1081 / NCN-120022687) or compounds with proliferation inhibitory activity (10.1080 / 15257779408013243). According to the literature (10.1080 / 15257779408013243), compound (1) can be prepared from D-arabinose according to the following route.

[0003]

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

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

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

[0007] A first aspect of the present invention provides a preparation method of a fluorinated ribose intermediate, comprising the following steps:

[0008] (1) React 2'-deoxy-2'-fluorouridine (compound 5) with an acetylation reagent and a base in an organic solvent to obtain compound 6;

[0009] (2) React compound 6 with an acetylation reagent and an acid in an organic solvent to obtain compound 7;

[0010] (3) React compound 7 with an acid in methanol to obtain compound 8;

[0011] (4) React compound 8 with a base in a solvent to obtain compound 1

[0012] The technical route is as follows:

[0013]

[0014] Advantageous Effects: By simplifying and optimizing the technical route, the present invention synthesizes compound 1 using inexpensive reaction raw materials, with simple operation, short reaction time, high yield, and improved production efficiency.

[0015] Preferably, in the step (1), the mass ratio of 2'-deoxy-2'-fluorouridine to the volume of the base is 1 g / (3 - 8) mL.

[0016] Preferably, in the step (1), the mass ratio of 2'-deoxy-2'-fluorouridine to the volume of the base is 1 g / 5 mL.

[0017] Preferably, in the step (1), the mass ratio of 2'-deoxy-2'-fluorouridine to the volume of the acetylation reagent is 1 g / (0.5 - 4) mL.

[0018] Preferably, in the step (1), the mass ratio of 2'-deoxy-2'-fluorouridine to the volume of the acetylation reagent is 1 g / 1 mL.

[0019] Preferably, the organic solvent in the step (1) is selected from one or more mixtures of dichloromethane, tetrahydrofuran (THF), 2-methyltetrahydrofuran, acetonitrile, and pyridine.

[0020] Preferably, the acetylation reagent in the step (1) is selected from one or more mixtures of acetic anhydride and acetyl chloride.

[0021] Preferably, the base in the step (1) is selected from one or more mixtures of triethylamine, diisopropylethylamine, pyridine, and 4-dimethylaminopyridine (DMAP).

[0022] Preferably, in the step (2), the mass ratio of compound 6 to the volume of the acetylation reagent is 1 g / (1 - 4) mL.

[0023] Preferably, in the step (2), the mass ratio of compound 6 to the volume of the acetylation reagent is 1 g / 2 mL.

[0024] Preferably, in the step (2), the mass ratio of compound 6 to the mass of the acid is 1:0.1 - 2.

[0025] Preferably, in the step (2), the mass ratio of compound 6 to the mass of the acid is 1:0.2.

[0026] Preferably, the organic solvents in the step (2) are all selected from one or more mixtures of acetic acid, dichloromethane, tetrahydrofuran (THF), 2-methyltetrahydrofuran, and methyl tert-butyl ether.

[0027] Preferably, the acetylation reagent in the step (2) is selected from one or more mixtures of acetic acid and acetic anhydride.

[0028] Preferably, the acid in the step (2) is selected from sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, and p-toluenesulfonic acid.

[0029] Preferably, in the step (3), the mass ratio of compound 7 to the acid is 1:0.05 - 0.5.

[0030] Preferably, in the step (3), the mass ratio of compound 7 to the acid is 1:0.1.

[0031] Preferably, the acid in the step (3) is selected from one of sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, and p-toluenesulfonic acid.

[0032] Preferably, in the step (4), the mass-to-volume ratio of compound 8 to the base is 1 g / (0.5 - 5) mL.

[0033] Preferably, in the step (4), the mass-to-volume ratio of compound 8 to the base is 1 g / 1 mL.

[0034] Preferably, the solvent in the step (4) is selected from one or a mixture of methanol, ethanol, isopropanol, water, tetrahydrofuran, 2-methyltetrahydrofuran, and methyl tert-butyl ether.

[0035] Preferably, the base in the step (4) is selected from one or a mixture of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, ammonia, aqueous ammonia, triethylamine, and diisopropylethylamine.

[0036] In a second aspect of the present invention, there is provided an application of a fluorinated ribose intermediate prepared by the above preparation method in drug synthesis.

[0037] The advantages of the present invention are as follows:

[0038] 1. By simplifying and optimizing the technical route, the present invention synthesizes compound 1 using inexpensive reaction raw materials, with simple operation, short reaction time, high yield, and improved production efficiency.

[0039] 2. The reagents required by the method of the present invention are relatively inexpensive, with low cost, and the post-treatment operation of the method of the present invention is simple.

[0040] 3. The method of the present invention has the advantages of short reaction time and easy industrial production. Specific Embodiments

[0041] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, 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. Apparently, the described embodiments are some, but not all, of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0042] Example 1:

[0043] A method for preparing a fluororibose intermediate comprises the following steps:

[0044] (1) Compound 5 (1.0 g, 1.0 eq) was dissolved in a mixed solution of THF (2 mL), acetic anhydride (1 mL) and pyridine (5 mL) at zero degrees Celsius, and then stirred at room temperature for 1 h. The reaction was completed by TLC. The reaction mixture was partitioned between water and isopropyl acetate. The organic phase was separated and washed with 2M aqueous hydrochloric acid solution and then with saturated sodium bicarbonate. The organic solvent was then concentrated and the residue was purified by flash chromatography to obtain compound 6. Yield: 95%. HRMS: M+H + The molecular formula is C13H16FN2O7+, the calculated value is 331.0936, and the measured value is 331.09345.

[0045]

[0046] (2) Compound 6 (0.5 g, 1.0 eq) was dissolved in a mixed solvent of acetic acid (3 mL) and acetic anhydride (1 mL). The temperature was controlled at 5-10 degrees Celsius. Concentrated sulfuric acid (0.1 g) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 3 h. After TLC detection, the reaction mixture was added to a saturated aqueous sodium bicarbonate solution and extracted with methyl tert-ether. The extract was concentrated in vacuo and purified by flash chromatography to obtain compound 7. Yield: 55%. HRMS: M+H + The molecular formula is C11H16FO7+, the calculated value is 279.0875, and the measured value is 279.0883.

[0047]

[0048] (3) Compound 7 (1.0 g, 1.0 eq) was dissolved in methanol (5 mL), the temperature was controlled at 0-5°C, concentrated sulfuric acid (0.1 g) was added dropwise, and the mixture was stirred at room temperature for 2 h. The reaction was completed by TLC. Solid sodium bicarbonate was added to the reaction mixture, and the reaction solution was concentrated in vacuo and purified by flash chromatography to obtain compound 8. The yield was 90%. HRMS: (M-MeO) + The molecular formula is C9H12FO5+, the calculated value is 219.0663, and the measured value is 219.0679.

[0049]

[0050] (4) Compound 8 (1.0 g, 1.0 eq) was dissolved in methanol (5 mL), and 7N ammonia methanol solution (1 mL) was added at room temperature. The mixture was stirred at room temperature for 2 h, concentrated to remove all volatile components, and the residue was purified by flash chromatography to obtain compound 1. The yield was 91%. HRMS: (M-MeO) +The molecular formula is C5H8FO3+, calculated value 135.0452, measured value 135.0461.

[0051]

[0052] Application of using Compound 1 to synthesize drugs:

[0053] According to the method in reference [DOI: 10.1080 / 15257779408013243], dissolve Compound 1 (175 mg) in pyridine (1 mL), add benzoyl chloride (0.49 mL) under ice bath, stir this mixture at room temperature for 16 hours, then quench with saturated sodium bicarbonate solution, extract with dichloromethane, separate the organic phase and concentrate it to dryness, and obtain Product 9 by column chromatography. HRMS: (M-MeO) + The molecular formula is C19H16FO5+, calculated value 343.0976, measured value 343.0981.

[0054]

[0055] According to the method in reference [DOI: 10.1080 / 15257779408013243], dissolve Compound 9 (4.5 g) in 90% aqueous trifluoroacetic acid solution (60 mL), stir at room temperature for 16 hours, then partition between dichloromethane (60 mL) and saturated sodium bicarbonate (600 mL), separate the organic phase and concentrate it to dryness, and obtain the crude product 10 by column chromatography. HRMS: (M-OH) + The molecular formula is C19H16FO5+, calculated value 343.0976, measured value 343.0985.

[0056]

[0057] According to the method in the reference [US2021340169], compound 10 (6.4 g, 17.8 mmol) was dissolved in a mixture of toluene (70 mL) and carbon tetrachloride (8 mL), cooled to -30 to -40 °C, and a solution of tris(dimethylamino)phosphine (3.49 g, 21.41 mmol) in toluene (5 mL) was added dropwise with stirring. The mixture was stirred at 0 °C for 3 hours, the reaction was terminated by adding saturated brine, 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 tris[2-(2-methoxyethoxy)ethyl]amine (0.6 g). After the mixture was stirred at 20 - 25 °C for 16 h, methyl tert-butyl ether (50 mL) and water (50 mL) were added to the system, the organic phase was separated, the organic phase was washed with an aqueous sodium bicarbonate solution until neutral, and then the organic phase was concentrated in vacuo and purified by flash chromatography to obtain compound 10. HRMS: (M+H) + The molecular formula is C24H18Cl2FN4O5+, the calculated value is 531.0633, and the measured value is 531.0641.

[0058]

[0059] According to the literature [DOI: 10.1080 / 15257779408013243], compound 11 can be further used for the synthesis of drugs with cell proliferation inhibitory activity.

[0060] Example 2:

[0061] A method for preparing a fluorinated ribose intermediate, comprising the following steps:

[0062] (1) Compound 5 (1.0 g, 1.0 eq) was dissolved in a mixed solution of dichloromethane (3 mL), acetyl chloride (0.5 mL) and triethylamine (3 mL) at zero degree, and then stirred at room temperature for 1 h. The reaction was detected by TLC to be completed. The reaction mixture was partitioned between water and isopropyl acetate, the organic phase was separated, washed with 2M aqueous hydrochloric acid solution, and then washed with saturated sodium bicarbonate. Subsequently, the organic solvent was concentrated, and the residue was purified by flash chromatography to obtain compound 6. The yield was 92%. HRMS: M+H + The molecular formula is C13H16FN2O7+, the calculated value is 331.0936, and the measured value is 331.09345.

[0063] (2) Dissolve compound 6 (0.5 g, 1.0 eq) in a mixed solvent of acetic acid (2 mL) and acetic anhydride (0.5 mL), control the temperature at 5 - 10 °C, add methanesulfonic acid (0.05 g) dropwise. After the addition is complete, stir at room temperature for 3 h. When TLC shows the reaction is complete, add the reaction mixture to saturated sodium bicarbonate aqueous solution and extract with methyl tert-butyl ether. Concentrate the extract under vacuum and purify by flash chromatography to obtain compound 7. Yield: 51%. HRMS: M + H + The molecular formula is C11H16FO7+, calculated value 279.0875, measured value 279.0883.

[0064] (3) Dissolve compound 7 (1.0 g, 1.0 eq) in methanol (5 mL), control the temperature at 0 - 5 °C, add trifluoromethanesulfonic acid (0.05 g) dropwise. After the addition is complete, stir at room temperature for 2 h. When TLC shows the reaction is complete, add solid sodium bicarbonate to the reaction mixture, then concentrate the reaction solution under vacuum and purify by flash chromatography to obtain compound 8. Yield: 92%. HRMS: (M - MeO) + The molecular formula is C9H12FO5+, calculated value 219.0663, measured value 219.0679.

[0065] (4) Dissolve compound 8 (1.0 g, 1.0 eq) in ethanol (5 mL), add sodium hydroxide solution (0.5 mL) at room temperature, then stir at room temperature for 2 h. Concentrate to remove all volatile components, and purify the residue by flash chromatography to obtain compound 1. Yield: 90%. HRMS: (M - MeO) + The molecular formula is C5H8FO3+, calculated value 135.0452, measured value 135.0461.

[0066] Example 3:

[0067] A method for preparing a fluorinated ribose intermediate, comprising the following steps:

[0068] (1) Dissolve compound 5 (1.0 g, 1.0 eq) in a mixed solution of acetonitrile (1 mL), 2 - methyltetrahydrofuran (2 mL), acetic anhydride (4 mL), diisopropylethylamine (4 mL), 4 - dimethylaminopyridine (mL) at zero degree. Then stir at room temperature for 1 h. When TLC shows the reaction is over, partition the reaction mixture between water and isopropyl acetate, separate the organic phase, wash with 2M hydrochloric acid aqueous solution, then wash with saturated sodium bicarbonate, and then concentrate the organic solvent. Purify the residue by flash chromatography to obtain compound 6. Yield: 96%. HRMS: M + H + The molecular formula is C13H16FN2O7+, calculated value 331.0936, measured value 331.09345.

[0069] (2) Dissolve compound 6 (0.5 g, 1.0 eq) in a mixed solvent of acetic acid (4 mL) and acetic anhydride (2 mL). Control the temperature at 5 - 10 °C, and add concentrated sulfuric acid (1 g) dropwise. After the addition, stir at room temperature for 3 h. When the reaction is completed as detected by TLC, add the reaction mixture to saturated sodium bicarbonate aqueous solution and extract with methyl tert-butyl ether. Concentrate the extract under vacuum and purify by flash chromatography to obtain compound 7. Yield: 60%. HRMS: M+H + The molecular formula is C11H16FO7+, calculated value: 279.0875, measured value: 279.0883.

[0070] (3) Dissolve compound 7 (1.0 g, 1.0 eq) in methanol (5 mL). Control the temperature at 0 - 5 °C, and add concentrated sulfuric acid (0.5 g) dropwise. After the addition, stir at room temperature for 2 h. When the reaction is completed as detected by TLC, add solid sodium bicarbonate to the reaction mixture, then concentrate the reaction solution under vacuum and purify by flash chromatography to obtain compound 8. Yield: 89%. HRMS: (M-MeO) + The molecular formula is C9H12FO5+, calculated value: 219.0663, measured value: 219.0679.

[0071] (4) Dissolve compound 8 (1.0 g, 1.0 eq) in methanol (5 mL). At room temperature, add potassium hydroxide (2 mL) and sodium ethoxide (3 mL), then stir at room temperature for 2 h. Concentrate to remove all volatile components, and purify the residue by flash chromatography to obtain compound 1. Yield: 91%. HRMS: (M-MeO) + The molecular formula is C5H8FO3+, calculated value: 135.0452, measured value: 135.0461.

[0072] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that: they can still modify the technical solutions recorded in the foregoing embodiments, or perform equivalent replacements for some of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a fluorinated ribose intermediate, characterized in that, It includes the following steps: (1) React 2'-deoxy-2'-fluorouridine with an acetylation reagent and a base in an organic solvent to obtain compound 6; (2) React compound 6 with an acetylation reagent and an acid in an organic solvent to obtain compound 7; (3) React compound 7 with an acid in methanol to obtain compound 8; (4) React compound 8 with a base in a solvent to obtain compound 1 ; The structural formula of the said compound 6 is ; The structural formula of the said compound 7 is ; The structural formula of the said compound 8 is .

2. The method for preparing a fluorinated ribose intermediate according to claim 1, wherein In step (1), the mass ratio of 2'-deoxy-2'-fluorouridine to the volume of the base is 1 g / (3 - 8) mL; the mass ratio of 2'-deoxy-2'-fluorouridine to the volume of the acetylation reagent is 1 g / (0.5 - 4) mL.

3. The method for preparing the fluorinated ribose intermediate according to claim 1 or 2, wherein In step (1), the organic solvent is selected from one or more mixtures of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, and pyridine; the acetylation reagent is selected from one or more mixtures of acetic anhydride and acetyl chloride.

4. The method for preparing a fluorinated ribose intermediate according to claim 3, characterized in that, In step (1), the base is selected from one or more mixtures of triethylamine, diisopropylethylamine, pyridine, and 4-dimethylaminopyridine.

5. The method for preparing the fluorinated ribose intermediate according to claim 4, wherein, In step (2), the mass ratio of compound 6 to the volume of the acetylation reagent is 1 g / (1 - 4) mL; the mass ratio of compound 6 to the mass of the acid is 1:0.1 - 2.

6. The method for preparing a fluorinated ribose intermediate according to claim 1, wherein, In step (2), the organic solvents are all selected from one or more mixtures of acetic acid, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, and methyl tert-butyl ether; the acetylation reagent is selected from one or more mixtures of acetic acid and acetic anhydride; the acid is selected from one of sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, and p-toluenesulfonic acid.

7. The method for preparing a fluorinated ribose intermediate according to claim 1, wherein In step (3), the acid is selected from one of sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, and p-toluenesulfonic acid; the mass ratio of compound 7 to the acid is 1:0.05 - 0.

5.

8. The method for preparing a fluorinated ribose intermediate according to claim 1, wherein In step (4), the solvent is selected from one or more mixtures of methanol, ethanol, isopropanol, water, tetrahydrofuran, 2-methyltetrahydrofuran, and methyl tert-butyl ether; the mass ratio of compound 8 to the volume of the base is 1 g / (0.5 - 5) mL.

9. The preparation method of the fluoro ribose intermediate according to claim 1, wherein, In step (4), the base is selected from one or more mixtures of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, ammonia, aqueous ammonia, triethylamine, and diisopropylethylamine.

10. The method for preparing a fluorinated ribose intermediate according to claim 8, characterized in that, In step (4), the mass ratio of compound 8 to the volume of the base is 1 g / 5 mL.

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