A preparation method of 6-methylaminoguanine

Abstract

The present invention relates to the technical field of organic synthesis, and particularly relates to a preparation method of 6-methylaminoguanine. In the present invention, 6-chloroguanine, methylamine and water are mixed to carry out an aminolysis reaction to obtain 6-methylaminoguanine. The preparation method provided by the present invention uses methylamine as an aminolysis reagent and also as an acid-binding agent, and uses water as a solvent, reducing the N-alkylation by-products that may be generated by an alcohol solvent. There are few by-products, the product yield is high, and the purity is high; compared with using methylamine (gaseous state) as an aminolysis reagent, the requirements for the reaction device are low; the present invention uses water as a solvent, which is green and environmentally friendly, has low cost, is simple to operate, and is suitable for industrial production. Moreover, the post-treatment provided by the present invention only requires cooling the reaction system and then performing solid-liquid separation, and washing and drying the obtained solid product. The present invention directly crystallizes and precipitates in water, without recrystallization with an organic solvent. The post-treatment operation is simple, the cost is low, and it is green and environmentally friendly.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly relates to a method for preparing 6-methylaminoguanine. Background Art

[0002] Guanosine is a class of compounds with physiological activities. There are already many guanosine or nucleoside analog drugs under research or on the market. For example, the typical guanosine drug entecavir is developed by Bristol-Myers Squibb and is a clinical drug suitable for the treatment of chronic adult hepatitis B with active virus replication, continuous elevation of serum alanine aminotransferase (ALT), or active lesions shown by liver histology. Guanosine is generally synthesized from guanine base. Among them, ((S)-(((2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester hemisulfate, which is synthesized from 6-methylaminoguanine in guanine base, is a drug under research by Atea Pharmaceuticals and has good effects on the treatment of hepatitis C (HCV).

[0003]

[0004] The existing synthesis of 6-methylaminoguanine generally uses 6-chloroguanine as a raw material, with an alcohol such as ethanol or butanol as a solvent and an organic base such as triethylamine or potassium carbonate as an acid-binding agent. It reacts with monomethylamine to obtain a crude product, and the obtained crude product is then refined with an alcohol. The reaction formula is as follows:

[0005]

[0006] For example, Chinese Patent CN112961198A discloses a method for preparing 6-methylaminoguanine. Using tetrahydrofuran as a solvent, after reacting 6-chloroguanine with methylamine at 110°C, it is treated with diisopropylethylamine, filtered, concentrated, and then recrystallized with methanol to obtain the product. US Patent US20140303112A1 discloses a method for preparing 6-methylaminoguanine. Using butanol as a solvent and triethylamine as an acid-binding agent, after reacting 6-chloroguanine with methylamine at 90°C, the crude product of 6-methylaminoguanine is obtained by filtration. The crude product is then washed with water and butanol and crystallized with dimethylformamide or ethanol to obtain the product. However, the amineolysis reagent in the above preparation methods is methylamine gas, which requires high requirements for the reaction device. At the same time, the reaction uses organic solvents, which cannot avoid environmental pollution caused by organic solvents and has high costs. Summary of the Invention

[0007] In view of this, the object of the present invention is to provide a method for preparing 6-methylaminoguanine. The preparation method provided by the present invention uses methylamine as an aminolysis reagent and water as a solvent, which is green and environmentally friendly, has low cost, requires low requirements for the reaction device, and has high product yield and high purity.

[0008] In order to achieve the above object of the invention, the present invention provides the following technical solutions:

[0009] The present invention provides a method for preparing 6-methylaminoguanine, comprising the following steps: mixing 6-chloroguanine, methylamine and water, and carrying out an aminolysis reaction to obtain 6-methylaminoguanine.

[0010] Preferably, the mass ratio of 6-chloroguanine to methylamine is 1:0.4 - 0.44.

[0011] Preferably, the methylamine is used in the form of an aqueous methylamine solution, and the concentration of methylamine in the aqueous methylamine solution is 25 - 40 wt%.

[0012] Preferably, the mass ratio of 6-chloroguanine to water in the mixed solution is 1:2.

[0013] Preferably, the temperature of the aminolysis reaction is 45 - 55 °C, and the time is 14 - 17 h.

[0014] Preferably, the post-treatment is further included after the aminolysis reaction, and the post-treatment includes: cooling the aminolysis reaction system obtained by the aminolysis reaction and then performing solid-liquid separation, washing the obtained solid product with water and then drying.

[0015] Preferably, the temperature after cooling is 15 - 25 °C.

[0016] Preferably, the temperature of the drying is 100 - 110 °C.

[0017] The present invention provides a method for preparing 6-methylaminoguanine, comprising the following steps: mixing 6-chloroguanine, methylamine and water, and carrying out an aminolysis reaction to obtain 6-methylaminoguanine. The preparation method provided by the present invention uses methylamine as an aminolysis reagent and at the same time as an acid-binding agent, and uses water as a solvent, reducing the N-alkylation by-products that may be generated by the alcohol solvent, with fewer by-products, high product yield and high purity; compared with using methylamine (gaseous) as an aminolysis reagent, the requirements for the reaction device are low; the present invention uses water as a solvent, which is green and environmentally friendly, has low cost, simple operation, and is suitable for industrial production.

[0018] Furthermore, the post-treatment provided by the present invention only needs to cool the reaction system and then perform solid-liquid separation, wash the obtained solid product with water and then dry it. The present invention directly crystallizes out in water without recrystallization with an organic solvent. The post-treatment operation is simple, the cost is low, and it is green and environmentally friendly. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 1H NMR spectrum of 6-methylaminoguanine prepared in Example 1;

[0020] Figure 2 Mass spectrum of 6-methylaminoguanine prepared in Example 1;

[0021] Figure 3 Infrared spectrum of 6-methylaminoguanine prepared in Example 1. Detailed implementation mode

[0022] The present invention provides a method for preparing 6-methylaminoguanine, which comprises the following steps: mixing 6-chloroguanine, methylamine and water, and carrying out an aminolysis reaction to obtain 6-methylaminoguanine.

[0023] Unless otherwise specified, the materials and equipment used in the present invention are all commercially available products in the art.

[0024] In the present invention, the methylamine is preferably used in the form of an aqueous methylamine solution, and the concentration of methylamine in the aqueous methylamine solution is preferably 25-40 wt%, more preferably 25-35 wt%, and further preferably 25-30 wt%.

[0025] In the present invention, the mass ratio of 6-chloroguanine to methylamine (methylamine in the aqueous methylamine solution) is preferably 1:0.4-0.44, more preferably 1:0.4-0.43, further preferably 1:0.4-0.42, and even more preferably 1:0.4-0.41.

[0026] In the present invention, the mass ratio of 6-chloroguanine to water (excluding water in the aqueous methylamine solution) is preferably 1:1.2-2.0, more preferably 1:1.5-1.7, and further preferably 1:1.6.

[0027] In the present invention, the temperature of the aminolysis reaction is preferably 45-55 °C, more preferably 48-52 °C, and further preferably 50 °C; the time of the aminolysis reaction is preferably 14-17 h, more preferably 14.5-16.5 h, and further preferably 15-16 h; in the specific embodiments of the present invention, a large amount of white products are generated as the reaction proceeds, and it is preferably stopped when the remaining amount of the raw material 6-chloroguanine is <0.1% (area normalization method) by liquid phase detection.

[0028] In the present invention, the reaction formula of the aminolysis reaction is as follows:

[0029]

[0030] After completion of the aminolysis reaction, the present invention preferably further includes post-treatment, and the post-treatment preferably includes: cooling the aminolysis reaction system obtained from the aminolysis reaction and then performing solid-liquid separation, washing the obtained solid product with water and then drying it to obtain 6-methylaminoguanine.

[0031] In the present invention, the temperature after cooling is preferably 15-25°C, more preferably 20°C.

[0032] The present invention has no special limitation on the solid-liquid separation, and any solid-liquid separation method well-known to those skilled in the art can be used, such as filtration, suction filtration or centrifugal separation.

[0033] In the present invention, the water washing is preferably water spraying; the mass ratio of 6-chloroguanine to the water used for water washing is preferably 1:0.1-0.3, more preferably 1:0.2.

[0034] In the present invention, the drying temperature is preferably 100-110°C, more preferably 105°C. The present invention has no special limitation on the drying time, and it can be dried to a constant weight.

[0035] In order to further illustrate the present invention, the preparation method of 6-methylaminoguanine will be described in detail below with reference to examples, but they should not be construed as limiting the scope of protection of the present invention.

[0036] Example 1

[0037] 500 g of 6-chloroguanine, 800 g of water and 800 g of 25 wt% methylamine aqueous solution were successively added into a reaction flask. The flask was stoppered and heated to 50°C for reaction for 15 h. A large amount of white product was produced during the reaction. When the content of the raw material 6-chloroguanine detected by liquid phase was less than 0.1% (area normalization method), the temperature was lowered and the reaction was stopped. After cooling to 20°C, filtration was carried out. The obtained solid component was washed with 100 g of water and dried at 105°C to a constant weight to obtain 6-methylaminoguanine (478.2 g of white solid, HPLC purity: 99.76%. Yield: 98.8%).

[0038] Example 2

[0039] 6-Methylaminoguanine was prepared according to the method of Example 1, with "800 g of water" replaced by "1000 g of water", and other conditions remained unchanged. 6-Methylaminoguanine was obtained: 476.5 g, HPLC purity: 99.78%. Yield: 98.5%.

[0040] Example 3

[0041] 6-Methylaminoguanine was prepared according to the method of Example 1, replacing "800 g of 25 wt% aqueous methylamine solution" with "670 g of 30 wt% aqueous methylamine solution", with other conditions remaining unchanged, to obtain 6-methylaminoguanine: 478.5 g, HPLC purity: 99.72%. Yield: 98.9%.

[0042] Example 4

[0043] 6-Methylaminoguanine was prepared according to the method of Example 1, replacing "800 g of 25 wt% aqueous methylamine solution" with "500 g of 40 wt% aqueous methylamine solution", with other conditions remaining unchanged, to obtain 6-methylaminoguanine: 478.5 g, HPLC purity: 99.70%. Yield: 98.9%.

[0044] Example 5

[0045] 6-Methylaminoguanine was prepared according to the method of Example 1, replacing "800 g of 25 wt% aqueous methylamine solution" with "1000 g of 25 wt% aqueous methylamine solution", with other conditions remaining unchanged, to obtain 6-methylaminoguanine: 476.3 g, HPLC purity: 99.77%. Yield: 98.4%.

[0046] Example 6

[0047] 6-Methylaminoguanine was prepared according to the method of Example 1, with the reaction temperature at 55 °C and the reaction time at 14 h, with other conditions remaining unchanged, to obtain 6-methylaminoguanine: 474.8 g, HPLC purity: 99.62%. Yield: 98.1%.

[0048] Figure 1 1H-NMR spectrum of 6-methylaminoguanine, the 1H-NMR data are as follows: ( 1 1H-NMR)(DMSO-d6), 600 MHz): δ 2.90 (brs, 3H, CH3), 5.69 (s, 2H, NH2), 7.07 (brs, 1H, NH of NHCH3), 7.63 (s, 1H, CH), 12.07 (s, 1H, NH). (GC-MS): 165 (M+1, M = 164).

[0049] Figure 2 Mass spectrum of 6-methylaminoguanine, elemental analysis (C6H8N6, %)(found / calculated): C 43.81 / 43.90, H 4.95 / 4.91, N 51.16 / 51.19.

[0050] Figure 3 IR spectrum of 6-methylaminoguanine, the IR spectral data are as follows: (IR, KBr, cm -1 ): 3354 (δ N-H), 3210(δ N-H ), 1609(δ N＝CH ), 1477(δ C-H ), 1388(ν C-N ), 1347(ν C-N ), 1278(ν C-N ), 1160(ν C-N ), 1129(ν ＝C-H ), 935(ν ＝C-H ), 835(ν C-H ), 786(ν C-H ), 748(ν C-H ).

[0051] Although the above embodiments have described the present invention in detail, they are only a part of the embodiments of the present invention, rather than all embodiments. People can also obtain other embodiments according to the embodiments of the present invention without creative labor, and these embodiments all belong to the protection scope of the present invention.

Claims

1. A method for preparing 6-methylaminoguanine, characterized in that: The following steps are involved: Mix 6-chloroguanine, methylamine and water to carry out aminolysis reaction to obtain 6-methylaminoguanine; The methylamine is used in the form of a methylamine aqueous solution, wherein the concentration of methylamine in the methylamine aqueous solution is 25-40 wt %; The mass ratio of 6-chloroguanine to methylamine is 1:0.4-0.44; The mass ratio of 6-chloroguanine to water is 1:1.2-2; The temperature of the aminolysis reaction is 45-55° C. and the time is 14-17 hours.

2. The preparation method according to claim 1, characterized in that: The aminolysis reaction further includes post-treatment, which includes: cooling the aminolysis reaction system obtained by the aminolysis reaction, separating the solid from the liquid, and washing the obtained solid product with water and then drying it.

3. The preparation method according to claim 2, characterized in that: The temperature after cooling is 15-25°C.

4. The preparation method according to claim 2, characterized in that: The drying temperature is 100-110°C.

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