N-methyl-N-benzyl-N '-(6-chloro-6, 9-dihydro-1H-purine-2-yl) formamidine compound and preparation and application thereof

Abstract

The present invention discloses a process for the preparation of high purity N-methyl-N-benzyl-N '-(6-chloro-6, 9-dihydro-1H-purin-2-yl) formamidine (Formula 85). According to the method, guanine (shown in a formula 3) is used as a raw material, and high-purity N-methyl-N-benzyl-N '-(6-chloro-6, 9-dihydro-1H-purine-2-yl) formamidine (shown in a formula 85) is prepared through amino activation and chlorination in sequence. The high-purity compound of the formula 85 can be used for preparing a medical intermediate, namely 2-amino-6-chloropurine (formula 1). The method disclosed by the invention is high in yield, high in purity and less in wastewater. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of chemical synthesis. Specifically, the present invention relates to N-methyl-N-benzyl-N'-(6-chloro-6,9-dihydro-1H-purine-2-yl)carboxamidine (Formula 85), a preparation method of the compound, a novel structural intermediate for synthesizing the compound, and the use of the compound in preparing 2-amino-6-chloropurine (Formula 1). Background Art

[0002] 2-Amino-6-chloropurine (Formula 1) is an important intermediate for synthesizing purine antiviral drugs famciclovir and penciclovir.

[0003]

[0004] Although various methods for synthesizing 2-amino-6-chloropurine (Formula 1) are disclosed in the prior art, these prior art methods have various defects. These defects mainly lie in the use of POCl3 in the preparation process, resulting in the generation of a large amount of phosphorus-containing wastewater during post-treatment; the use of DMF in the preparation process, resulting in the generation of a large amount of wastewater containing dimethylamine and DMF during post-treatment; and the final synthesized product 2-amino-6-chloropurine (1) contains a large amount of impurities 71, thereby affecting the product quality.

[0005] Therefore, there is an urgent need in the art for a new method for synthesizing 2-amino-6-chloropurine (1), which should not only prepare 2-amino-6-chloropurine in high yield and high purity, but also produce as little difficult-to-treat wastewater as possible. Summary of the invention

[0006] The object of the present invention is to provide a method for synthesizing 2-amino-6-chloropurine, which has high yield and purity of synthesizing 2-amino-6-chloropurine and less difficult-to-treat wastewater.

[0007] The present invention also aims to provide a novel intermediate used in the synthesis of 2-amino-6-chloropurine and a preparation method thereof.

[0008] In a first aspect, the present invention provides a method for preparing 2-amino-6-chloropurine (1), wherein the reaction formula of the method is as follows:

[0009]

[0010] The method comprises the following steps:

[0011] 1) reacting a compound of formula 3 (guanine) with a Vilsmeier reagent (a compound of formula 24) to obtain a compound of formula 84 activated with N-methyl-N-benzylamidine;

[0012] 2) further reacting the compound of formula 84 with a Vilsmeier reagent (compound of formula 24) to undergo a hydroxyl chlorination reaction to obtain a compound of formula 85;

[0013] 3) hydrolyzing the compound of formula 85 to remove the N-methyl-N-benzyl group to obtain the compound of formula 6;

[0014] 4) The compound of formula 6 is further hydrolyzed to obtain 2-amino-6-chloropurine (formula 1).

[0015] In a preferred embodiment, the molar ratio E1 (3:24) of the compound of formula 3 (guanine) to the Vilsmeier reagent (compound of formula 24) is 1:3.00-1:5.00, for example 1:3.00, 1:3.25, 1:3.50, 1:3.75, 1:4.00 and 1:5.00; preferably the molar ratio E1 is 4.00eq-5.00eq.

[0016] In a preferred embodiment, in step 1), the compound of formula 3 (guanine) reacts with Vilsmeier reagent (compound of formula 24) in solvent S at room temperature to obtain a compound of formula 84.

[0017] In a preferred embodiment, in step 2), the compound of formula 84 reacts with a Vilsmeier reagent (compound of formula 24) in a solvent S at a temperature T1 to undergo a hydroxyl chlorination reaction to obtain a compound of formula 85.

[0018] In a preferred embodiment, the solvent S is any one of dichloromethane, 1,2-dichloroethane, and acetonitrile; preferably dichloromethane or 1,2-dichloroethane.

[0019] In a preferred embodiment, the reaction temperature T1 is 20-85°C; preferably 20-40°C.

[0020] In a specific embodiment, in step 2), the compound of formula 84 reacts with Vilsmeier reagent (compound of formula 24) to obtain a compound of formula 85 and a compound 851,

[0021]

[0022] Preferably, the content of compound 851 is less than 4.0%.

[0023] In a preferred embodiment, in steps 3) and 4), the compound of formula 85 is hydrolyzed under the action of dilute hydrochloric acid to obtain 2-amino-6-chloropurine of formula 1.

[0024] In a preferred embodiment, the method further comprises step 5), purifying the compound of formula 1 to obtain compound 1 with impurity 71 < 0.1%

[0025]

[0026] In a preferred embodiment, the compound of formula 1 is purified by acid or base in acetone water.

[0027] In a preferred embodiment, N-methylbenzylamine is reacted with formic acid to generate N-methyl-N-benzylformamide, and then N-methyl-N-benzylformamide is reacted with triphosgene to generate the corresponding Vilsmeier reagent (24), as shown in the following reaction formula:

[0028]

[0029] In a second aspect, the present invention provides a method for preparing a high-purity N-methyl-N-benzyl-N'-(6-chloro-6,9-dihydro-1H-purin-2-yl)formamidine (Formula 85) compound, the reaction formula of the method is shown below:

[0030]

[0031] The method comprises the following steps:

[0032] 1) reacting a compound of formula 3 (guanine) with a Vilsmeier reagent (formula 24) to obtain a compound of formula 84 of N-methyl-N-benzyl amidine;

[0033] 2) The compound of formula 84 is further reacted with Vilsmeier reagent (formula 24) to obtain the impurity compound of formula 85.

[0034] In a preferred embodiment, the molar ratio E1 (3:24) of the compound of formula 3 (guanine) to the Vilsmeier reagent (compound of formula 24) is 1:3.00-1:5.00, for example 1:3.00, 1:3.25, 1:3.50, 1:3.75, 1:4.00 and 1:5.00; preferably the molar ratio E1 is 4.00eq-5.00eq.

[0035] In a preferred embodiment, in step 1), the compound of formula 3 (guanine) reacts with Vilsmeier reagent (compound of formula 24) in solvent S at room temperature to obtain a compound of formula 84.

[0036] In a preferred embodiment, in step 2), the compound of formula 84 reacts with a Vilsmeier reagent (compound of formula 24) in a solvent S at a temperature T1 to undergo a hydroxyl chlorination reaction to obtain a compound of formula 85.

[0037] In a preferred embodiment, the solvent S is any one of dichloromethane, 1,2-dichloroethane, and acetonitrile; preferably dichloromethane or 1,2-dichloroethane.

[0038] In a preferred embodiment, the reaction temperature T1 is 25-85°C; preferably 25-35°C.

[0039] In a specific embodiment, in step 2), the compound of formula 84 reacts with Vilsmeier reagent (compound of formula 24) to obtain a compound of formula 85 and a compound 851

[0040]

[0041] Preferably, the content of compound 851 is less than 4.0%.

[0042] In a preferred embodiment, N-methylbenzylamine is reacted with formic acid to generate N-methyl-N-benzylformamide, and then N-methyl-N-benzylformamide is reacted with triphosgene to generate the corresponding Vilsmeier reagent (24), as shown in the following reaction formula:

[0043]

[0044] In a third aspect, the present invention provides a compound represented by formula 84,

[0045]

[0046] In a fourth aspect, the present invention provides a compound of formula 85,

[0047]

[0048] In a fifth aspect, the present invention provides a compound represented by formula 851 as shown below

[0049]

[0050] In a sixth aspect, the present invention provides a compound represented by formula 71 as shown below

[0051]

[0052] In a seventh aspect, the present invention provides the use of a compound represented by Formula 84 or Formula 85 for preparing 2-amino-6-chloropurine (1), an intermediate of purine antiviral drugs.

[0053] In an eighth aspect, the present invention provides the use of the compound represented by formula 851 or 71 as a standard for quality inspection or quality control in the preparation process of 2-amino-6-chloropurine (1), an intermediate of purine antiviral drugs.

[0054] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0055] Figure 1 The MS spectrum of Formula 1 is shown;

[0056] Figure 2 It shows that the 1 H NMR spectrum;

[0057] Figure 3 It shows that the 13 C NMR spectrum;

[0058] Figure 4 The MS spectrum of formula 4 is shown;

[0059] Figure 5 Shows the formula 84 1 H NMR spectrum;

[0060] Figure 6 The single crystal pattern of formula 84 is shown;

[0061] Figure 7 The MS spectrum of formula 85 is shown;

[0062] Figure 8 Shows the formula 85 1 H NMR spectrum;

[0063] Fig. 9 The MS spectrum of impurity 851 is shown;

[0064] Fig.10 Impurity 851 is shown 1 H NMR spectrum;

[0065] Fig.11 The MS spectrum of impurity 71 is shown;

[0066] Fig.12 Impurity 71 is shown 1 H NMR spectrum. DETAILED DESCRIPTION

[0067] After extensive and in-depth research, the inventor unexpectedly found that the synthesis methods of 2-amino-6-chloropurine (Formula 1) reported in the existing literature have defects. Specifically, there are several synthesis routes of 2-amino-6-chloropurine (Formula 1) reported in the existing literature:

[0068] The first method (EP 0203685 A2): Using guanine (3) as the starting material, a chlorination reaction of the hydroxyl group was carried out in the presence of a chlorination reagent, phosphorus oxychloride (POCl3) and a phase transfer catalyst, tetraethylammonium chloride (TEACl), to obtain 2-amino-6-chloropurine (1) with a yield of 42%.

[0069]

[0070] The method uses a large amount of phase transfer catalyst tetraethylammonium chloride (TEACl is 1.00 to 1.50 times that of guanine, mol / mol), resulting in a lot of solid waste and high cost. At the same time, 6 equivalents of chlorination reagent phosphorus oxychloride (POCl3) are used in the reaction, which will produce a large amount of difficult-to-treat phosphoric acid-containing wastewater during post-treatment.

[0071] The second method (WO 9315075 A1): using guanine as the starting material, acetyl protecting groups were introduced on the 2-amino group and the 7-nitrogen atom of guanine to obtain compound 21. Compound 21 was subjected to hydroxyl chlorination reaction to obtain compound 22, and then the acetyl protecting group was removed by hydrolysis to obtain 2-amino-6-chloropurine (1). The total yield was 74.6%.

[0072]

[0073] This method has a higher yield than the first method, but still requires the use of a phase transfer catalyst, which is costly. In addition, phosphorus oxychloride (POCl3) is used in the reaction, which will produce a large amount of phosphorus-containing wastewater during post-treatment.

[0074] The third method (CN 108892669 A1): The 2-amino group of guanine was oxidized to a nitro group using hydrogen peroxide to obtain compound 41. The hydroxyl group of 41 was chlorinated under the action of SOCl2 to obtain compound 42. The nitro group of compound 42 was reduced to an amino group using hydrazine hydrate to obtain 2-amino-6-chloropurine (1). The total yield was 81.6%.

[0075]

[0076] This method uses explosive chemicals such as hydrogen peroxide and hydrazine hydrate, which poses a major safety hazard.

[0077] The fourth method (EP 0543095 A2): Guanine is reacted with Vilsmeier reagent (62, prepared by the reaction of DMF and POCl3), dimethylamidine is introduced into the 2-position primary amine for activation to obtain compound 31, and then the hydroxyl group is chlorinated with Vilsmeier reagent (62) to obtain compound 32, compound 32 is hydrolyzed to remove the dimethylamino group to obtain formamide compound 6, and the formamide group of compound 6 is hydrolyzed under alkaline conditions to obtain 2-amino-6-chloropurine (1), with a total yield of 70%.

[0078]

[0079] In this method, DMF and POCl3 are used to react to prepare Vilsmeier reagent (62), and a large amount of difficult-to-treat wastewater containing phosphoric acid and DMF is generated during post-treatment.

[0080]

[0081] Compound 32 generates byproducts of formic acid and dimethylamine during the subsequent hydrolysis reaction to generate 2-amino-6-chloropurine (1). The byproduct dimethylamine is easily soluble in water, and has a strong and unpleasant ammonia odor at high concentrations and a fish oil odor at extremely low concentrations. Wastewater containing dimethylamine is difficult to treat.

[0082] Finally, CN 107312003 A1 improved the fourth method by replacing phosphorus oxychloride (POCl3) with triphosgene. Guanine reacted with Vilsmeier reagent (63, prepared by reaction of DMF and triphosgene), introduced dimethylamidine to the 2-position primary amine to activate compound 31, and then chlorinated the hydroxyl group of 31 with Vilsmeier reagent (63) to obtain compound 32. Compound 32 was hydrolyzed to remove dimethylamino group and amide group hydrolysis to generate 2-amino-6-chloropurine (1), with a total yield of 78.3%.

[0083] This method also introduces a dimethylamidine activating group, and post-treatment will produce a large amount of dimethylamine wastewater.

[0084]

[0085] The inventors found that when the fourth method (EP 0543095A2) was repeated, the reaction of compound 31 with Vilsmeier reagent (prepared by POCl3 or triphosgene and DMF) produced about 10% of impurity 72 in addition to the main product 32. Impurity 72 was converted into impurity 71 along with the removal of dimethylamine group and hydrolysis reaction of 32, and impurity 71 affected the quality of product 1.

[0086]

[0087] In order to overcome the various defects existing in the prior art, the inventors have unexpectedly discovered a new synthetic route involving a new intermediate after extensive and in-depth research. The synthesis of 2-amino-6-chloropurine by this route effectively eliminates various wastewaters, and the raw materials are easily available and can be recycled. In addition, the 2-amino-6-chloropurine prepared by the method of the present invention has high purity and high yield.

[0088] The method and novel intermediate of the present invention

[0089] In the present invention, a method for synthesizing 2-amino-6-chloropurine is provided. The method has the advantages of high yield, high purity, less difficult-to-treat wastewater, etc. In addition, the novel method for synthesizing 2-amino-6-chloropurine provided by the present invention also involves an intermediate with a completely new structure.

[0090] To this end, the present invention provides a new compound shown in formula 84, and its structure is determined by single crystal as follows:

[0091] Formula 84 and the single crystal structure formula of Formula 84;

[0092] and a new compound represented by formula 85,

[0093]

[0094] In the present invention, the compounds represented by formula 84 and 85 can be prepared by the method represented by the following reaction formula:

[0095]

[0096] The method comprises reacting a compound of formula 3 (guanine) with a Vilsmeier reagent (compound of formula 24) in a solvent S at room temperature to obtain a compound of formula 84. The compound of formula 84 is further reacted with a Vilsmeier reagent (compound of formula 24) in a solvent S at a temperature T1 to undergo a hydroxyl chlorination reaction to obtain a compound of formula 85 and a compound 851.

[0097] Based on the teachings of the present invention, those skilled in the art can further optimize various process parameters of the above method. In a preferred embodiment, the molar ratio E1 (3:24) of the compound 3 to the Vilsmeier reagent (compound of formula 24) to prepare the intermediate of formula 85 is 1:3.00, 1:3.25, 1:3.50, 1:3.75, 1:4.00 and 1:5.00, preferably the molar ratio E1 is 4.00eq-5.00eq; the reaction temperature T1 can be controlled at 20-85°C, preferably 20-40°C; the solvent S is any one of dichloromethane, 1,2-dichloroethane, and acetonitrile, preferably dichloromethane or 1,2-dichloroethane.

[0098] On the basis of optimizing the process conditions, the content of impurity compound 851 can be controlled to be less than 4.0%.

[0099] Based on the compounds shown in Formulae 84 and 85, the present invention provides a novel method for synthesizing 2-amino-6-chloropurine (1), the reaction formula of which is shown below:

[0100]

[0101] The method comprises the following steps:

[0102] 1) reacting a compound of formula 3 (guanine) with a Vilsmeier reagent (a compound of formula 24) to obtain a compound of formula 84 activated with N-methyl-N-benzylamidine;

[0103] 2) further reacting the compound of formula 84 with a Vilsmeier reagent (compound of formula 24) to undergo a hydroxyl chlorination reaction to obtain a compound of formula 85;

[0104] 3) hydrolyzing the compound of formula 85 to remove N-methylbenzylamine to obtain the compound of formula 6;

[0105] 4) The compound of formula 6 is further hydrolyzed to obtain 2-amino-6-chloropurine (formula 1).

[0106] In the method for synthesizing 2-amino-6-chloropurine (Formula 1) of the present invention, the compound of Formula 84 undergoes a hydroxyl chlorination reaction with a Vilsmeier reagent (compound of Formula 24) to obtain a compound of Formula 85 and an impurity compound of Formula 851, and the compound of Formula 85 is hydrolyzed, for example, under the action of an acid (such as dilute hydrochloric acid) to obtain 2-amino-6-chloropurine and an impurity 71. The reaction formula of the process is shown below:

[0107]

[0108] Therefore, reducing the content of the impurity compound of formula 851 is beneficial to improving the purity of 2-amino-6-chloropurine. In a specific embodiment, the compound of formula 85 with a content of impurity 851 less than 4% is used to prepare 2-amino-6-chloropurine shown in formula 1. The compound of formula 1 can be purified by acid and alkali in acetone water to obtain compound 1 with impurity 71 less than 0.1%.

[0109] In the method of the present invention, the byproducts of 2-amino-6-chloropurine (Formula 1) generated by Formula 85 during the subsequent hydrolysis reaction are formic acid and water-insoluble N-methylbenzylamine, which is different from the byproducts of the hydrolysis reaction of the intermediate in the prior art method, which are formic acid and water-insoluble N-methylbenzylamine.

[0110]

[0111] The byproduct, N-methylbenzylamine, is insoluble in water and can be directly extracted from the reaction solution during post-treatment to separate and recover the product and recycle it, thereby effectively eliminating the problem of dimethylamine wastewater pollution in the prior art method. The recovered byproduct N-methylbenzylamine can react with formic acid to generate N-methyl-N-benzylformamide, which can be used for the synthesis of the corresponding Vilsmeier reagent (24).

[0112]

[0113] The above N-methyl-N-benzylformamide reacts with triphosgene to generate the corresponding Vilsmeier reagent (24), which can be recycled and reused in the synthesis of compound 84 and compound 85 in the method of the present invention.

[0114]

[0115] Therefore, compared with the existing synthesis route, the first technical problem solved by the present invention is to use recyclable N-methyl-N-benzylformamide to replace DMF, thereby effectively eliminating the wastewater pollution caused by dimethylamine and DMF; and to use triphosgene to synthesize Vilsmeier reagent (24), effectively eliminating the difficult-to-treat phosphorus-containing wastewater.

[0116] In the method of the present invention, by optimizing the reaction conditions, the amount of the disubstituted impurity 851 in the compound 85 generated by the reaction of compound 84 with Vilsmeier reagent 24 is significantly reduced, for example, <4%.

[0117]

[0118] Compound 85 with a small amount (<4%) of disubstituted impurity 851 will generate 2-amino-6-chloropurine (Formula 1) with a small amount (<0.1%) of disubstituted impurity 71 through subsequent hydrolysis reaction.

[0119]

[0120] In a specific embodiment, the preparation method of 2-amino-6-chloropurine (Formula 1) of the present invention is as follows:

[0121]

[0122] The method comprises the following steps:

[0123] 1) reacting a compound of formula 3 (guanine) with a Vilsmeier reagent (a compound of formula 24) to obtain a compound of formula 84 activated with N-methyl-N-benzylamidine;

[0124] 2) further reacting the compound of formula 84 with a Vilsmeier reagent (compound of formula 24) to undergo a hydroxyl chlorination reaction to obtain a compound of formula 85;

[0125] 3) hydrolyzing the compound of formula 85 to remove the N-methyl-N-benzyl group to obtain the compound of formula 6;

[0126] 4) The compound of formula 6 is further hydrolyzed to obtain 2-amino-6-chloropurine (formula 1).

[0127] Among them, Vilsmeier reagent (compound of formula 24) can be prepared by reacting N-methylbenzylamine with formic acid to obtain N-methyl-N-benzylformamide, and then reacting with triphosgene to obtain compound of formula 24.

[0128]

[0129] In the method of the present invention, a completely new structure of intermediates and impurities is provided, which are respectively: a compound shown in Formula 84, a compound shown in Formula 85, a compound shown in Formula 851, and a compound shown in Formula 71. Among them, the compound shown in Formula 84 or 85 is an intermediate for synthesizing 2-amino-6-chloropurine, and 2-amino-6-chloropurine is an important intermediate for synthesizing purine antiviral drugs. In a preferred embodiment, the purine antiviral drugs include but are not limited to famciclovir and penciclovir. The compound shown in Formula 851 or the compound shown in Formula 71 can be used as a standard for quality detection or quality control in the preparation process of purine antiviral drugs or intermediate 2-amino-6-chloropurine (1).

[0130]

[0131] The compound represented by Formula 84 can be prepared by reacting the compound represented by Formula 3 (guanine) with Vilsmeier reagent (compound represented by Formula 24) in a solvent S at room temperature. The reaction formula is shown below:

[0132]

[0133] The compound represented by Formula 85 can be prepared by reacting the compound represented by Formula 84 with Vilsmeier reagent (compound represented by Formula 24) in a solvent S at a temperature of T1 to undergo hydroxyl chlorination reaction, thereby obtaining the compound represented by Formula 85 and the compound represented by Formula 851. The reaction formula is shown below:

[0134]

[0135] The inventors further optimized the process parameters in the reaction process of synthesizing the compound shown in formula 85. In a specific embodiment, the solvent S is any one of dichloromethane, 1,2-dichloroethane, and acetonitrile; preferably dichloromethane and 1,2-dichloroethane. In a specific embodiment, the reaction temperature T1 is 20-85°C, preferably 20-40°C, and more preferably 40°C. In a specific embodiment, the content of the compound 851 is <4.0%.

[0136] The compound shown in Formula 1 can be prepared by subjecting the compound of Formula 85 in which the amount of impurity 851 is less than 4% to acid hydrolysis reaction, thereby obtaining 2-amino-6-chloropurine shown in Formula 1 and impurity 71. The reaction formula is as follows:

[0137]

[0138] In a specific embodiment, the amount of 71 in compound 1 obtained by the method through acid-base purification in acetone-water is less than 0.1%.

[0139] The main advantages of the present invention include:

[0140] 1. The method for preparing 2-amino-6-chloropurine of the present invention produces less wastewater, and effectively eliminates wastewater containing dimethylamine, wastewater containing DMF, and wastewater containing phosphorus;

[0141] 2. The raw material N-methylbenzylamine in the method for preparing 2-amino-6-chloropurine of the present invention is easily available and can be recycled in the method;

[0142] 3. The product purity of the method for preparing 2-amino-6-chloropurine of the present invention is high.

[0143] 4. The method for preparing 2-amino-6-chloropurine of the present invention has high yield.

[0144] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods for which specific conditions are not specified in the following examples are usually performed under normal conditions or under conditions recommended by the manufacturer. Unless otherwise indicated, percentages and parts are weight percentages and weight parts, and eq represents the equivalent to the reaction substrate.

[0145] Example 1 (reference patent CN 101139348 A)

[0146]

[0147]

[0148] Preparation of Vilsmeier reagent: DMF (40 mL, 518.777 mmol, 3.92 eq) was added to a 100 mL three-necked round-bottom flask with magnetic stirring, and POCl3 (35 mL, 382.345 mmol, 2.89 eq) was added dropwise in an ice bath to obtain Vilsmeier reagent 62.

[0149] Add compound 3 (20.00 g, 132.336 mmol, 1.00 eq) and 200 mL of 1,2-dichloroethane to a 500 mL three-necked round-bottom flask. Add Vilsmeier reagent 62 dropwise to the 1,2-dichloroethane solution of compound 3 under magnetic stirring. Adjust the oil bath to 35°C and heat the reaction for 30 hours. (Reaction solution: area% of compound 32 is 92.38%, area% of impurity 72 is 7.62%, excluding other impurity peaks)

[0150] After the reaction is completed, wait for the reaction liquid to cool to room temperature, pour the reaction liquid into 300 mL of ice water, and extract and recover the aqueous phase solution. Add 10% NaOH solution to the recovered aqueous phase to adjust the pH value to 3.0, and react at 80°C for 5 hours. After the reaction is completed, wait for the reaction liquid to cool to room temperature and filter. Transfer the wet filter cake to a 500 mL beaker, add 150 mL of 10% NaOH solution, and stir magnetically. After reacting at room temperature for 3 hours, add 10% HCl solution to adjust the pH value to neutral. Filter by suction, wash the filter cake with deionized water, and dry to obtain 18.46 g of 2-amino-6-chloropurine solid crude product, with a yield of 82.5% and a purity of 98.82% (the area% of impurity 71 is 0.89%)

[0151] Example 2 (Preparation of N-methyl-N-benzylformamide)

[0152] Add methylbenzylamine (200.05g, 97%, 1601.324mmol, 1.00eq) and 300mL cyclohexane to a 1L four-necked round-bottom flask and stir to dissolve. Add formic acid (86.27g, 88%, 1649.307mmol, 1.03eq) and 100mL cyclohexane. Heat the reaction solution to reflux for 9h. After the reaction is completed, wait for the reaction solution temperature to drop to room temperature, separate the reaction solution, recover the non-cyclohexane layer, and evaporate the solvent to prepare 235.10g of N-methyl-N-benzylformamide with a purity of 99.43% and a yield of 98.4%.

[0153] Example 3 (Preparation of Formula 84 Reference Substance)

[0154] Triphosgene (8.87 g, 99%, 0.45 eq, 29.592 mmol) and 1,2-dichloroethane (30 mL) were added to a 100 mL single-necked round-bottom flask and stirred at room temperature until the triphosgene was completely dissolved to prepare a triphosgene-1,2-dichloroethane solution.

[0155] Add N-methyl-N-benzylformamide (12.37 g, 99%, 1.24 eq, 82.084 mmol) and 1,2-dichloroethane (20 mL) into a 250 mL three-necked round-bottom flask and stir evenly. Add the 1,2-dichloroethane solution of triphosgene dropwise to the 1,2-dichloroethane solution of N-methyl-N-benzylformamide to react. After the addition is completed, continue stirring for 30 minutes to obtain Vilsmeier reagent.

[0156] Compound 3 (10.00 g, 1.00 eq, 66.168 mmol) and 1,2-dichloroethane (20 mL) were directly added to the reaction bottle of the newly prepared Vilsmeier reagent and stirred at room temperature for 8 h. After the reaction was completed, the reaction solution was poured into 300 mL of saturated NaHCO3 solution. The filter cake was filtered and washed with 50 mL of 1,2-dichloroethane in batches and dried to obtain a white compound solid crude product formula 8420.72 g, with a yield of 110.9% and a purity of 93.24%. 2.005 g was purified by column chromatography (dichloromethane: methanol = 15:1) to obtain a white solid formula 84 0.920 g, with a yield of 45.9% and a purity of 98.90%.

[0157] MS (ESI) of compound 84 + ): C 14 H 14 N6O,m / z 283.13[M+H] + .

[0158] Compound of formula 84 1 H NMR: (600MHz, DMSO-d6) δ12.59(s,1H),11.39(d,J=65.1Hz,1H),8.81(t,J=75.2Hz,1H),7 .91(d,J=138.1Hz,1H),7.56-7.17(m,5H),4.70(d,J=41.1Hz,2H),3.00(d,J=87.4Hz,3H).

[0159] Example 4 (Preparation of Formula 85 Reference Substance)

[0160] Triphosgene (28.63 g, 99%, 1.44 eq, 95.514 mmol) and 1,2-dichloroethane (50 mL) were added to a 100 mL single-necked round-bottom flask and stirred at room temperature until the triphosgene was completely dissolved to prepare a triphosgene 1,2-dichloroethane solution.

[0161] Add N-methyl-N-benzylformamide (39.93 g, 99%, 4.00 eq, 264.964 mmol) and 1,2-dichloroethane (40 mL) into a 250 mL three-necked round-bottom flask and stir evenly. Add the 1,2-dichloroethane solution of triphosgene dropwise to the 1,2-dichloroethane solution of N-methyl-N-benzylformamide to react. After the addition is completed, continue stirring for 30 min to obtain Vilsmeier reagent.

[0162] Compound 3 (10.00 g, 1.00 eq, 66.168 mmol) and 10 mL of 1,2-dichloroethane solution were directly added to a reaction bottle containing Vilsmeier reagent solution. After reacting at room temperature for 2 h, the temperature was raised to 85 °C and the reaction was continued for 2 h. The reaction solution was poured into 300 mL of saturated NaHCO3 solution and the organic phase was recovered. Under ice-water bath conditions, the organic phase was magnetically stirred for 1 h, then filtered, and the filter cake was washed with 50 mL of 1,2-dichloroethane to obtain a solid crude product of compound 85. 2.001 g of crude compound 85 was taken and purified by column chromatography (dichloromethane: methanol = 50:1 → 30:1) to obtain 0.417 g of white solid formula 85.

[0163] MS (ESI + ): C 14 H 13 ClN6,m / z 301.10[M+H] + .

[0164] The compound of formula 85 1 H NMR: (600MHz, DMSO-d6) δ13.23(s,1H),8.81(d,J=59.7Hz,1H),8.33(s,1H),7.47-7.20(m,5H),4.72(d,J=58.1Hz,2H),3.01(d,J=86.6Hz,3H).

[0165] Example 5 (Preparation of impurity 851 reference substance)

[0166] Triphosgene (14.37 g, 99%, 47.941 mmol, 1.45 eq) and 1,2-dichloroethane (25 mL) were added to a 50 mL single-necked round-bottom flask and stirred until the triphosgene solid was completely dissolved to prepare a triphosgene 1,2-dichloroethane solution.

[0167] Add N-methyl-N-benzylformamide (17.98 g, 99%, 119.310 mmol, 3.61 eq) and 10 mL of 1,2-dichloroethane to a 100 mL three-necked round-bottom flask, stir evenly with a magnetic stirrer, and drop a solution of triphosgene in 1,2-dichloroethane into the reaction flask. After the addition is complete, continue stirring for 30 minutes to obtain the Vilsmeier reagent.

[0168] Compound 3 (5.00 g, 33.084 mmol, 1.00 eq) and 1,2-dichloroethane (5 mL) were added to a reaction bottle containing Vilsmeier reagent, and the mixture was reacted at room temperature for 2 h, and then the temperature was raised to 85°C for 1.5 h. 7.01 g of the reaction solution was taken, quenched with saturated triethylamine (5 mL), and then column chromatography (dichloromethane / methanol = 25:1) was performed to obtain a mixture of compound 85 and impurity 851. The mixture was subjected to prep-HPLC to obtain 23 mg of a light yellow impurity 851 solid.

[0169] MS (ESI) of compound 851 + ): C 28 H 25 C1N 12 ,m / z 565.21[M+H] + .

[0170] Compound of formula 851 1 H NMR: (600MHz, DMSO-d6)δ13.26(s,1H),9.48–8.12(m,4H),7.33(ddtd,J=24.3,14.7,6.8,3.5Hz,10H),5.26–4.08(m,4H),3.16–2.67(m,6H).

[0171] Example 6

[0172] Six single-necked round-bottom flasks were used to prepare triphosgene in 1,2-dichloroethane solutions.

[0173] Triphosgene (2.142 g, 99%, 7.146 mmol, 1.08 eq) was added to reaction bottle No. 1';

[0174] Triphosgene (2.321 g, 99%, 7.743 mmol, 1.17 eq) was added to reaction bottle No. 2';

[0175] Triphosgene (2.499 g, 99%, 8.337 mmol, 1.26 eq) was added to reaction bottle No. 3';

[0176] Triphosgene (2.678 g, 99%, 8.934 mmol, 1.35 eq) was added to reaction bottle No. 4';

[0177] Triphosgene (2.856 g, 99%, 9.528 mmol, 1.44 eq) was added to reaction bottle No. 5';

[0178] Triphosgene (3.570 g, 99%, 11.910 mmol, 1.80 eq) was added to reaction bottle No. 6'.

[0179] 5 mL of 1,2-dichloroethane was added respectively and stirred magnetically until the solid was completely dissolved to prepare a 1,2-dichloroethane solution of triphosgene.

[0180] Take another six three-necked round-bottom flasks.

[0181] N-methyl-N-benzylformamide (2.991 g, 99%, 19.847 mmol, 3.00 eq) was added to reaction bottle No. 1; N-methyl-N-benzylformamide (3.241 g, 99%, 21.506 mmol, 3.25 eq) was added to reaction bottle No. 2;

[0182] Add N-methyl-N-benzylformamide (3.490 g, 99%, 23.159 mmol, 3.50 eq) to reaction bottle No. 3;

[0183] Add N-methyl-N-benzylformamide (3.739 g, 99%, 24.811 mmol, 3.75 eq) to reaction bottle No. 4;

[0184] Add N-methyl-N-benzylformamide (3.989 g, 99%, 26.470 mmol, 4.00 eq) to reaction bottle No. 5;

[0185] N-methyl-N-benzylformamide (4.986 g, 99%, 33.086 mmol, 5.00 eq) was added to reaction bottle No. 6.

[0186] 5 mL of 1,2-dichloroethane was added respectively. A solution of triphosgene in 1,2-dichloroethane was added dropwise to a three-necked round-bottom flask. The addition took 30 minutes in total. After the addition was completed, stirring was continued for 30 minutes to prepare the Vilsmeier reagent.

[0187] Compound 3 (1.000 g, 6.617 mmol, 1.00 eq) and 10 mL of 1,2-dichloroethane were directly added to three-necked round-bottom flask 1-6 and mechanically stirred. The reaction was carried out at 85°C. The area percentages (Area%, for the sake of comparison, the main impurity peaks were deducted) of compound 84, compound 85 and impurity 851 in the above 6 reactions were compared, as shown in the following table:

[0188]

[0189] Preferably, the molar ratio E1 of 3 to Vilsmeier reagent 24 is 1:4.00eq or more, and the intermediate 84 can be substantially reacted completely.

[0190] Example 7

[0191] Triphosgene (28.56 g, 99%, 95.281 mmol, 1.44 eq) and 30 mL of 1,2-dichloroethane were added to a 100 mL single-necked round-bottom flask and stirred until the triphosgene solid was completely dissolved to prepare a triphosgene 1,2-dichloroethane solution.

[0192] Add N-methyl-N-benzylformamide (39.89 g, 99%, 264.698 mmol, 4.00 eq) and 20 mL of 1,2-dichloroethane into a 250 mL round-bottom flask, stir evenly, and dropwise add the freshly prepared triphosgene in 1,2-dichloroethane solution. Continue stirring for 30 minutes after the addition is complete to prepare the Vilsmeier reagent.

[0193] Add compound 3 (10.00 g, 66.168 mmol, 1.00 eq) and 150 mL of 1,2-dichloroethane directly to the reaction bottle containing Vilsmeier reagent and stir mechanically. Divide the reaction solution into 5 equal portions and transfer them to 50 mL reaction bottles respectively. Take 4 portions and react them at 85, 60, 40, and 20 ° C respectively. Sample the reaction solution at different time points and perform HPLC detection. Compare the area percentages (Area%, for ease of comparison, deduct the main impurity peaks) of compound 84, compound 85, and impurity 851 in the above 7 reactions, as shown in the following table:

[0194]

[0195] The preferred reaction temperature T1 is 20 to 40° C., and the amount of impurity 851 is relatively small.

[0196] Example 8

[0197] Take nine single-necked round-bottom flasks, add triphosgene (2.856 g, 99%, 9.528 mmol, 1.44 eq) to flasks 1'-9' respectively, and add the following different solvents respectively:

[0198] Ethyl acetate (3 mL) was added to reaction flask No. 1';

[0199] Toluene (3 mL) was added to reaction flask No. 2';

[0200] Add dichloromethane (3 mL) to reaction flask No. 3';

[0201] Add acetone (3 mL) to reaction bottle No. 4';

[0202] Cyclohexane (3 mL) was added to reaction flask No. 5';

[0203] Add 1,2-dichloroethane (3 mL) to reaction flask No. 6';

[0204] Add acetonitrile (3 mL) to reaction bottle No. 7';

[0205] Tetrahydrofuran (3 mL) was added to reaction bottle No. 8';

[0206] 1,4-Dioxane (3 mL) was added to reaction bottle No. 9'.

[0207] Stir in bottles 1'-9' until the solids are dissolved (except cyclohexane and acetonitrile), and the triphosgene solution is prepared.

[0208] Take another nine three-necked round-bottom flasks, add N-methyl-N-benzylformamide (3.989 g, 99%, 26.470 mmol, 4.00 eq) and the following different solvents respectively:

[0209] Ethyl acetate (2 mL) was added to reaction flask No. 1;

[0210] Toluene (2 mL) was added to reaction flask No. 2;

[0211] Add dichloromethane (2 mL) to reaction bottle No. 3;

[0212] Add acetone (2 mL) to reaction bottle No. 4;

[0213] Cyclohexane (2 mL) was added to reaction bottle No. 5;

[0214] Add 1,2-dichloroethane (2 mL) to reaction bottle No. 6;

[0215] Add acetonitrile (2 mL) to reaction bottle No. 7;

[0216] Tetrahydrofuran (2 mL) was added to reaction bottle No. 8;

[0217] Add 1,4-dioxane (2 mL) into reaction bottle No. 9.

[0218] Stir in bottles 1-9 until the solid is dissolved (except cyclohexane) to obtain N-methyl-N-benzylformamide solution.

[0219] Add triphosgene solution of corresponding solvent (bottles 1'-9') dropwise to bottles 1-9 respectively. Continue stirring for 30 minutes after the addition is completed to obtain Vilsmeier reagent.

[0220] Add compound 3 (1.000 g, 6.617 mmol, 1.00 eq) to flasks 1-9 containing Vilsmeier reagent, and add ethyl acetate (15 mL), toluene (15 mL), dichloromethane (15 mL), acetone (15 mL), cyclohexane (15 mL), 1,2-dichloroethane (15 mL), acetonitrile (15 mL), tetrahydrofuran (15 mL) and 1,4-dioxane (15 mL) to flasks 1-9, respectively. Stir mechanically and place in an oil bath at an external temperature of 40°C for 24 hours. Take the reaction solution from flasks 1-9, perform HPLC detection, and calculate the area percentage (Area%, for comparison, subtract the miscellaneous peaks), as shown in the following table:

[0221]

[0222] a The reaction solution showed solid agglomeration and the experiment was terminated. b The formation of intermediate 85 was not detected in the reaction.

[0223] In the acetonitrile solvent, half of the intermediate formula 84 is basically unreacted and other unknown impurities are generated. According to the minimum amount of the intermediate formula 84 remaining and the minimum amount of the impurity 851, the preferred reaction solvent S is dichloromethane or 1,2-dichloroethane.

[0224] Example 9

[0225] Triphosgene (148.75 g, 99%, 1.50 eq, 496.254 mmol) and 300 mL of dichloromethane were added to a 500 mL single-necked round-bottom flask, and the mixture was stirred and dissolved until the solid triphosgene was completely dissolved to obtain a dichloromethane solution of triphosgene.

[0226] Add N-methyl-N-benzylformamide (204.42 g, 99%, 4.10 eq, 1356.470 mmol) and 200 mL of dichloromethane into a 2L four-necked round-bottom flask, stir mechanically and then dropwise add a dichloromethane solution of triphosgene. After the addition is complete, continue stirring for 30 minutes to obtain Vilsmeier reagent.

[0227] Compound 3 (50.00 g, 1.00 eq, 330.841 mmol) and 250 mL of dichloromethane were added to the reaction bottle of Vilsmeier reagent. After stirring at room temperature for 2 h, the temperature was raised to 40 °C and the reaction was continued for 44 h (impurities in the reaction solution: the area% of 851 was 3.72%, excluding impurity peaks).

[0228] The reaction solution was poured into 2L saturated NaHCO3 solution, and the organic phase was extracted and recovered. The organic phase was stirred in an ice bath for 1h, filtered, and the filter cake was dried to obtain 100.17g of a light yellow solid crude product of compound 85, with a crude product yield of 100.7%. The filtrate 1 contained N-methyl-N-benzylformamide and N-methylbenzylamine (recovered for later use).

[0229] In a 500 mL three-necked round-bottom flask, add 100.17 g of crude compound 85 and 500 mL of dichloromethane, slurry at 40°C for 1 h, filter with suction, and dry the filter cake to obtain 97.71 g of light yellow solid compound 85 with a yield of 97.5%. Filtrate 2 is combined with filtrate 1 (recovered for later use).

[0230] The total yield of the two-step reaction of preparing compound 85 from guanine (3) was 98.2% (100.7% x 97.5%).

[0231] Add 97.71 g of the light yellow solid of compound 85 and 2.5 L of 5% HCl solution to a 5L beaker, and stir at 70°C for 34 hours. After the reaction is completed, cool in an ice-water bath, and add 40% NaOH solution dropwise to adjust the pH to 10. Wash with dichloromethane (3 times, 400 mL each time), and recover the aqueous phase. Combine the dichloromethane washings with filtrate 2 and filtrate 1. Add 10.0 g of activated carbon to the aqueous phase and stir for 30 minutes. Filter with suction, add 400 mL of acetone to the filtrate, add 36% HCl solution dropwise until the pH value is neutral, filter with suction, wash the filter cake with 800 mL of deionized water, and dry to obtain 45.10 g of white solid of compound 1 with a yield of 81.9% and an HPLC purity of 99.20% (the area% of impurity 71 is 0.02%).

[0232] The total yield of the reaction of preparing 2-amino-6-chloropurine (1) from compound 85 was 81.9%.

[0233] The total yield of the reaction of preparing 2-amino-6-chloropurine (1) from guanine (3) was 80.4% (98.2% x 81.9%).

[0234] Recover N-methylbenzylamine: Combine the dichloromethane washings and filtrate 2 and filtrate 1 under reduced pressure to recover the solvent dichloromethane. Add 1000mL of water and 87.5mL of concentrated hydrochloric acid to the residual liquid and reflux for 6 hours. Wash the reaction solution twice with 300ml of dichloromethane. Add 500mL of dichloromethane and drop 40% sodium hydroxide solution to adjust the pH to 10. Separate the liquids and extract the water layer twice with 100ml of dichloromethane. Combine the dichloromethane layers, dry with magnesium sulfate, filter, and evaporate the solvent to obtain 137.98g of N-methylbenzylamine as a brown oil with a recovery rate of 83.9% for N-methylbenzylamine.

[0235] MS (ESI) of the compound of formula 1+ ): C5H4ClN5, m / z 170.02[M+H] + .

[0236] The compound of formula 1 1 H NMR: (600MHz, DMSO-d6) δ12.89(s,1H),8.13(s,1H),6.79(s,2H).

[0237] HPLC method (3 Preparation 85): Vanquish Core high performance liquid chromatograph (Thermo Fisher), chromatographic column: Thermo Syncronis C18 4.6×250mm 5μm; detector: DAD (detection wavelength: 210nm); column temperature: 30℃; flow rate: 1.0ml / min; mobile phase A: 10mM KH2PO4 aqueous solution, mobile phase B: acetonitrile solution; gradient elution: 0-5.0min, B: 5%, 5.0-25.0min, B: 5%→50%, 25.0-35.0min, B: 50%→75%, 35.0-40.0min, B: 75%, 40.0-40.1min, B: 75%→5%, 40.1-50.0min, B: 5%; diluent: acetonitrile; injection volume: 1μl. Retention time: Formula 84: 20.463 min, Formula 85: 23.177 min, Impurity 851: 31.417 min. HPLC method (85 Preparation 1): Vanquish Core high performance liquid chromatograph (Thermo Fisher), chromatographic column: Thermo Fisher Hypersil GOLD TM C184.6×250mm 5μm; detector: DAD (detection wavelength: 210nm); column temperature: 30℃; flow rate: 1.0ml / min; mobile phase A: 0.04% H3PO4 aqueous solution, mobile phase B: 0.04% H3PO4 acetonitrile solution; gradient elution: 0-5min, B: 5%, 5-25min, B: 5%→85%, 25-35min, B: 85%, 35-35.1min, B: 85%→5%, 35.1-40min, B: 5%; diluent: acetonitrile; injection volume: 1μl. Retention time: formula 1: 10.893min, formula 71: 14.007min.

[0238] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for preparing 2-amino-6-chloropurine (1), wherein the reaction formula of the method is as follows: The method comprises the following steps: 1) reacting a compound of formula 3 (guanine) with a Vilsmeier reagent (a compound of formula 24) to obtain a compound of formula 84 activated with N-methyl-N-benzylamidine; 2) further reacting the compound of formula 84 with a Vilsmeier reagent (compound of formula 24) to undergo a hydroxyl chlorination reaction to obtain a compound of formula 85; 3) hydrolyzing the compound of formula 85 to remove the N-methyl-N-benzyl group to obtain the compound of formula 6; 4) The compound of formula 6 is further hydrolyzed to obtain 2-amino-6-chloropurine (formula 1).

2. The method according to claim 1, characterized in that In step 2), the compound of formula 84 reacts with a Vilsmeier reagent (compound of formula 24) to obtain a compound of formula 85 and a compound 851. Preferably, the content of compound 851 is less than 4.0%.

3. A method for preparing a high-purity N-methyl-N-benzyl-N'-(6-chloro-6,9-dihydro-1H-purin-2-yl)formamidine (Formula 85) compound, the reaction formula of the method is shown below: The method comprises the following steps: 1) reacting a compound of formula 3 (guanine) with a Vilsmeier reagent (formula 24) to obtain a compound of formula 84 of N-methyl-N-benzyl amidine; 2) The compound of formula 84 is further reacted with Vilsmeier reagent (formula 24) to obtain the impurity compound of formula 85.

4. The method according to claim 3, characterized in that In step 2), the compound of formula 84 reacts with a Vilsmeier reagent (compound of formula 24) to obtain a compound of formula 85 and a compound 851 Preferably, the content of compound 851 is less than 4.0%.

5. The compound represented by formula 84, 6. The compound represented by formula 85, 7. The compound represented by formula 851 shown below 8. The compound represented by formula 71 shown below 9. Use of the compound represented by formula 84 or 85 for preparing 2-amino-6-chloropurine (1), an intermediate of purine antiviral drugs.

10. Use of the compound represented by formula 851 or 71 as a standard substance for quality inspection or quality control in the preparation process of 2-amino-6-chloropurine (1), an intermediate of purine antiviral drugs.

Images