Prepn process of brivudine

Abstract

The present invention relates to medicine technology, and is especially preparation process of brivudine. The preparation process includes the following steps: reaction between the 2'-deoxy uracil material and paraformaldehyde to obtain 5-methylol-2'-deoxy uracil; oxidizing 5-methylol-2'-deoxy uracil with manganese dioxide to prepare 5-formyl-2'-deoxy uracil; condensation of 5-formyl-2'-deoxy uracil and malonic acid to prepare (E)-5-(2-carboxyl vinyl)-2'-deoxy uracil; and reaction of (E)-5-(2-carboxyl vinyl)-2'-deoxy uracil and N-bromo succimide under the action of potassium acetate to obtain the ultimate product. The present invention has greatly lowered cost, simple operation, high yield, environment friendship and easy use in industrial production.

Description

technical field

[0001] The invention relates to a preparation method in the technical field of medicine, in particular to a preparation method of bromfuridine. technical background

[0002] Bromofuridine: (E)-5-(2-bromovinyl)-2'-deoxyuracil, referred to as BVDU, is a pyrimidine nucleoside derivative. The compound is currently the most active anti-varicella-herpes virus (VZV) drug, and its potency is 1000 times that of acyclovir. Bromfuridine is mainly used for congenital immunodeficiency caused by herpes zoster, varicella virus skin disease and type I simple virus; or immunosuppression in patients with secondary immunodeficiency (such as after organ transplantation); or cytostatic Skin and mucous membrane infections that occur during drug therapy. It has been confirmed that oral administration of BVDU (125mg / time, 3 times / day, for 5 consecutive days) is effective in treating severe herpes zoster in cancer patients. As a replacement product of antiviral drugs, bromfuridine...

Examples

Embodiment 1

[0028] (1) Preparation of 5-hydroxymethyl-2'-deoxyuracil (I)

[0029] 2'-deoxyuracil (5.25g, 23.1mmol) and paraformaldehyde (3.11g, 103.5mmol) were dissolved in 0.5 M triethylamine aqueous solution (80ml), heated up to 60°C, reacted for four days, and added Paraformaldehyde (4.49g, 149.5mmol; 3.21g, 105.8mmol) was added once, triethylamine (1ml) and water (10ml) were added once in the middle, and finally concentrated and recrystallized in methanol to obtain 4.11g of white solid, namely: 5-Hydroxymethyl-2'-deoxyuracil (I), yield 70%.

[0030] Its characteristic parameters are: 1 H NMR (400MHz, DMSO-d6) δ: 11.34(s, 1H, N-H), 7.71(s, 1H, 6-H), 6.17(t, J=6.8Hz, 1H, 1'-H), 5.26( s, 1H, 3'-OH), 4.97 (s, 2H, 5'-OH and CH 2 O-H), 4.20(q, J=3.2Hz, 1H, 4'-H), 4.10(s, 2H, 5-H), 3.75(q, J=3.2Hz, 1H, 3'-H), 3.57- 3.47(m, 2H, 5'-H), 2.09-1.99(m, 2H, 2'-H)).

[0031] (2) Preparation of 5-formyl-2'-deoxyuracil (II) from compound (I)

[0032] (1) (0.70g, 2.7mmol) and newly prepared manga...

Embodiment 2

[0041] (1) Preparation of 5-hydroxymethyl-2'-deoxyuracil (I)

[0042] 2'-Deoxyuracil (15.25g, 69.3mmol) and paraformaldehyde (9.96g, 311.9mmol) were dissolved in 0.5M triethylamine aqueous solution (240ml), heated to 60°C, reacted for four days, then every other day Add paraformaldehyde (14.38g, 450.5mmol; 10.18g, 318.8mmol) once, add triethylamine (3ml) and water (30ml) once in the middle, and finally concentrate and recrystallize with methanol to obtain 10.01g of 5-hydroxymethyl Base-2'-deoxyuracil (I), the yield was 56%.

[0043] (2) Preparation of 5-formyl-2'-deoxyuracil (II) from compound (I)

[0044] (I) (1.01g, 3.9mmol) and manganese dioxide (7.78g, 89.5mmol) in 20ml DMF (N, N-dimethylformamide), after reacting at 10 ℃ for 4 days, filter with diatomaceous earth , the resulting filtrate was concentrated and recrystallized in methanol to obtain 0.60 g of 5-formyl-2'-deoxyuracil (II), with a yield of 61%.

[0045] (3) Preparation of (E)-5-(2-carboxyvinyl)-2'-deoxyuracil...

Embodiment 3

[0050] (1) Preparation of 5-hydroxymethyl-2'-deoxyuracil (I)

[0051] The synthesis method refers to (1) in Example 1.

[0052] (2) Preparation of 5-formyl-2'-deoxyuracil (II) from compound (I)

[0053] (I) (0.20g, 0.8mmol) and manganese dioxide (1.54g, 8mmol) (10eq.) in 5ml DMF (N,N-dimethylformamide), after reacting at 10°C for 9 hours, use silicon Manganese dioxide was removed by algal earth suction filtration, concentrated, and passed through a column with ethyl acetate to obtain 0.08 g of 5-formyl-2'-deoxyuracil (II), with a yield of 42%.

[0054] (3) Preparation of (E)-5-(2-carboxyvinyl)-2'-deoxyuracil (III) from compound (II)

[0055] The synthesis method refers to (3) in Example 1.

[0056] (4) Preparation of (E)-5-(2-bromovinyl)-2'-deoxyuracil (IV) from compound

[0057] The synthesis method refers to (4) in Example 1.

technical field

[0001] The invention relates to a preparation method in the technical field of medicine, in particular to a preparation method of bromfuridine. technical background

[0002] Bromofuridine: (E)-5-(2-bromovinyl)-2'-deoxyuracil, referred to as BVDU, is a pyrimidine nucleoside derivative. The compound is currently the most active anti-varicella-herpes virus (VZV) drug, and its potency is 1000 times that of acyclovir. Bromfuridine is mainly used for congenital immunodeficiency caused by herpes zoster, varicella virus skin disease and type I simple virus; or immunosuppression in patients with secondary immunodeficiency (such as after organ transplantation); or cytostatic Skin and mucous membrane infections that occur during drug therapy. It has been confirmed that oral administration of BVDU (125mg / time, 3 times / day, for 5 consecutive days) is effective in treating severe herpes zoster in cancer patients. As a replacement product of antiviral drugs, bromfuridine...

Examples

Embodiment 1

[0028] (1) Preparation of 5-hydroxymethyl-2'-deoxyuracil (I)

[0029] 2'-deoxyuracil (5.25g, 23.1mmol) and paraformaldehyde (3.11g, 103.5mmol) were dissolved in 0.5 M triethylamine aqueous solution (80ml), heated up to 60°C, reacted for four days, and added Paraformaldehyde (4.49g, 149.5mmol; 3.21g, 105.8mmol) was added once, triethylamine (1ml) and water (10ml) were added once in the middle, and finally concentrated and recrystallized in methanol to obtain 4.11g of white solid, namely: 5-Hydroxymethyl-2'-deoxyuracil (I), yield 70%.

[0030] Its characteristic parameters are: 1 H NMR (400MHz, DMSO-d6) δ: 11.34(s, 1H, N-H), 7.71(s, 1H, 6-H), 6.17(t, J=6.8Hz, 1H, 1'-H), 5.26( s, 1H, 3'-OH), 4.97 (s, 2H, 5'-OH and CH 2 O-H), 4.20(q, J=3.2Hz, 1H, 4'-H), 4.10(s, 2H, 5-H), 3.75(q, J=3.2Hz, 1H, 3'-H), 3.57- 3.47(m, 2H, 5'-H), 2.09-1.99(m, 2H, 2'-H)).

[0031] (2) Preparation of 5-formyl-2'-deoxyuracil (II) from compound (I)

[0032] (1) (0.70g, 2.7mmol) and newly prepared manga...

Embodiment 2

[0041] (1) Preparation of 5-hydroxymethyl-2'-deoxyuracil (I)

[0042] 2'-Deoxyuracil (15.25g, 69.3mmol) and paraformaldehyde (9.96g, 311.9mmol) were dissolved in 0.5M triethylamine aqueous solution (240ml), heated to 60°C, reacted for four days, then every other day Add paraformaldehyde (14.38g, 450.5mmol; 10.18g, 318.8mmol) once, add triethylamine (3ml) and water (30ml) once in the middle, and finally concentrate and recrystallize with methanol to obtain 10.01g of 5-hydroxymethyl Base-2'-deoxyuracil (I), the yield was 56%.

[0043] (2) Preparation of 5-formyl-2'-deoxyuracil (II) from compound (I)

[0044] (I) (1.01g, 3.9mmol) and manganese dioxide (7.78g, 89.5mmol) in 20ml DMF (N, N-dimethylformamide), after reacting at 10 ℃ for 4 days, filter with diatomaceous earth , the resulting filtrate was concentrated and recrystallized in methanol to obtain 0.60 g of 5-formyl-2'-deoxyuracil (II), with a yield of 61%.

[0045] (3) Preparation of (E)-5-(2-carboxyvinyl)-2'-deoxyuracil...

Embodiment 3

[0050] (1) Preparation of 5-hydroxymethyl-2'-deoxyuracil (I)

[0051] The synthesis method refers to (1) in Example 1.

[0052] (2) Preparation of 5-formyl-2'-deoxyuracil (II) from compound (I)

[0053] (I) (0.20g, 0.8mmol) and manganese dioxide (1.54g, 8mmol) (10eq.) in 5ml DMF (N,N-dimethylformamide), after reacting at 10°C for 9 hours, use silicon Manganese dioxide was removed by algal earth suction filtration, concentrated, and passed through a column with ethyl acetate to obtain 0.08 g of 5-formyl-2'-deoxyuracil (II), with a yield of 42%.

[0054] (3) Preparation of (E)-5-(2-carboxyvinyl)-2'-deoxyuracil (III) from compound (II)

[0055] The synthesis method refers to (3) in Example 1.

[0056] (4) Preparation of (E)-5-(2-bromovinyl)-2'-deoxyuracil (IV) from compound

[0057] The synthesis method refers to (4) in Example 1.

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