The solvent is N, N-dibenzyl-Napos; -(6-chloro-6, 9-dihydro-1H-purine-2-yl) formamidine compound as well as preparation and application thereof

Abstract

The invention discloses a preparation method of high-purity N, N-dibenzyl-N '-(6-chloro-6, 9-dihydro-1H-purine-2-yl) formamidine (as shown in a formula 5) and a preparation method of the N, N-dibenzyl-N'-(6-chloro-6, 9-dihydro-1H-purine-2-yl) formamidine. According to the method, guanine (formula 3) is used as a raw material, and high-purity N, N-dibenzyl-N '-(6-chloro-6, 9-dihydro-1H-purine-2-yl) formamidine is prepared through amino activation and chlorination in sequence. The high-purity compound shown in the formula 5 can be used for preparing a medical intermediate, namely 2-amino-6-chloropurine (shown in the formula 1). The method has the advantages of high yield, high purity and less wastewater. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of chemical synthesis. Specifically, the present invention relates to N,N-dibenzyl-N'-(6-chloro-6,9-dihydro-1H-purine-2-yl)carboxamidine (Formula 5), ​​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] The prior art discloses a variety of methods for synthesizing 2-amino-6-chloropurine (Formula 1). However, these methods have many defects. For example, 1. POCl3 is used, and a large amount of phosphorus-containing wastewater is generated during post-treatment; 2. DMF is used, and a large amount of wastewater containing dimethylamine and DMF is generated during post-treatment; 3. The synthesized product 2-amino-6-chloropurine (1) contains a large amount of impurities 71, which affects the quality of the product.

[0005] Therefore, the present invention urgently needs a new method that can synthesize 2-amino-6-chloropurine (1) with high yield and high purity and with less difficult-to-treat wastewater. 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 23) to obtain a compound of formula 4 activated with dibenzyl amidine;

[0012] 2) subjecting the compound of formula 4 to a hydroxyl chlorination reaction with a Vilsmeier reagent (compound of formula 23) to obtain a compound of formula 5;

[0013] 3) hydrolyzing the compound of formula 5 to remove the dibenzyl 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 (3:23) of the compound of formula 3 (guanine) to the Vilsmeier reagent (compound of formula 23) is 1:2.00-1:3.0, for example 1:2.00, 1:2.05, 1:2.10, 1:2.15, 1:2.20, 1:2.50 or 1:3.0; preferably 1:2.10-1:2.20.

[0016] In a preferred embodiment, in step 1), the compound of formula 3 (guanine) reacts with Vilsmeier reagent (compound of formula 23) in solvent S at room temperature to obtain a compound of formula 4.

[0017] In a preferred embodiment, in step 2), the compound of formula 4 reacts with a Vilsmeier reagent (compound of formula 23) in a solvent S at a temperature T1 to undergo a hydroxyl chlorination reaction to obtain a compound of formula 5.

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

[0019] In a preferred embodiment, the reaction temperature T1 is 25-85°C; preferably 25-35°C.

[0020] In a specific embodiment, in step 2), the compound of formula 4 reacts with a Vilsmeier reagent (compound of formula 23) to obtain a compound of formula 5 and a compound 51,

[0021]

[0022] Preferably, the content of compound 51 is less than 4.0%.

[0023] In a preferred embodiment, in steps 3) and 4), the compound of formula 5 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,N-dibenzylformamide is prepared by reacting dibenzylamine with formic acid, and then reacting with triphosgene to prepare the compound of formula 23.

[0028]

[0029] In a second aspect, the present invention provides a method for preparing a high-purity N,N-dibenzyl-N'-(6-chloro-6,9-dihydro-1H-purin-2-yl)formamidine (Formula 5) 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 23) to obtain a dibenzyl amidine compound of formula 4;

[0033] 2) The compound of formula 4 is further reacted with Vilsmeier reagent (formula 23) to obtain the compound of formula 5.

[0034] In a preferred embodiment, the molar ratio E1 (3:23) of the compound of formula 3 (guanine) to the Vilsmeier reagent (compound of formula 23) is 1:2.00-1:3.0, for example 1:2.00, 1:2.05, 1:2.10, 1:2.15, 1:2.20, 1:2.50 or 1:3.0; preferably 1:2.10-1:2.20.

[0035] In a preferred embodiment, in step 1), the compound of formula 3 (guanine) reacts with Vilsmeier reagent (compound of formula 23) in solvent S at room temperature to obtain a compound of formula 4.

[0036] In a preferred embodiment, in step 2), the compound of formula 4 reacts with a Vilsmeier reagent (compound of formula 23) in a solvent S at a temperature T1 to undergo a hydroxyl chlorination reaction to obtain a compound of formula 5.

[0037] In a preferred embodiment, the solvent S is any one of dichloromethane, 1,2-dichloroethane, and acetonitrile; preferably dichloromethane and 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 4 reacts with Vilsmeier reagent (compound of formula 23) to obtain compound of formula 5 and compound 51.

[0040]

[0041] Preferably, the content of compound 51 is less than 4.0%.

[0042] In a preferred embodiment, N,N-dibenzylformamide is prepared by reacting dibenzylamine with formic acid, and then reacting with triphosgene to prepare the compound of formula 23.

[0043]

[0044] In a third aspect, the present invention provides a compound represented by formula 4,

[0045]

[0046] In a fourth aspect, the present invention provides a compound represented by Formula 5,

[0047]

[0048] In a fifth aspect, the present invention provides a compound represented by formula 51 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 the compound represented by Formula 4 or Formula 5 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 of formula 51 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 The formula 4 shows 1 H NMR spectrum;

[0060] Figure 6 The MS spectrum of Formula 5 is shown;

[0061] Figure 7 The formula 5 is shown 1 H NMR spectrum;

[0062] Figure 8 Showing a single crystal spectrum of Formula 5;

[0063] Fig. 9 The MS spectrum of impurity 51 is shown;

[0064] Fig.10 Impurity 51 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] During the research and development process, the inventors studied several main synthetic routes of 2-amino-6-chloropurine (Formula 1) reported in the 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] In addition, the method disclosed in CN 107312003 A1 improves the fourth method mentioned above by using triphosgene to replace phosphorus oxychloride (POCl3). Guanine reacts with Vilsmeier reagent (63, prepared by reaction of DMF and triphosgene), and dimethylamidine is introduced into the 2-position primary amine to activate compound 31, and then the hydroxyl group of 31 is chlorinated with Vilsmeier reagent (63) to obtain compound 32, and compound 32 is successively hydrolyzed to remove dimethylamino group and amide group hydrolysis to generate 2-amino-6-chloropurine (1), and the total yield is 78.3%.

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

[0084]

[0085] The inventors found that when the fourth method (EP0543095A2) 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 during 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 defects 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 produces less wastewater, is highly safe, and the raw materials are easily available and can be recycled. At the same time, the prepared 2-amino-6-chloropurine has high purity and high yield.

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

[0089] Aiming at the defects in the existing method for synthesizing 2-amino-6-chloropurine, the present invention provides a new method with high yield, high purity and less difficult-to-treat wastewater. The new method for synthesizing 2-amino-6-chloropurine of the present invention involves an intermediate with a completely new structure.

[0090] In a specific embodiment, the present invention provides a novel compound represented by formula 4,

[0091] and

[0092] The new compound is shown in Formula 5, and its structure is determined by single crystal as follows.

[0093]

[0094] The compounds shown in formula 4 and 5 can be synthesized by the method shown in the following reaction formula:

[0095]

[0096] The method comprises reacting a compound of formula 3 (guanine) with a Vilsmeier reagent (compound of formula 23) in a solvent S at room temperature to obtain a compound of formula 4. The compound of formula 4 is further reacted with a Vilsmeier reagent (compound of formula 23) in a solvent S at a temperature T1 to undergo a hydroxyl chlorination reaction to obtain a compound of formula 5 and a compound 51.

[0097] Based on the teachings of the present invention, those skilled in the art can determine various parameters in the above method. For example, the molar ratio E1 (3:23) of the compound 3 (guanine) to the Vilsmeier reagent (compound of formula 23) is 1:2.00, 1:2.05, 1:2.10, 1:2.15, 1:2.20, 1:2.50, 1:3.0, preferably 1:2.10 to 1:2.20; the solvent S is any one of dichloromethane, 1,2-dichloroethane, and acetonitrile, preferably dichloromethane and 1,2-dichloroethane; the reaction temperature T1 is 25-85°C, preferably 25-35°C. Under preferred conditions, the content of the compound 51 can be controlled to be less than 4.0%.

[0098] Based on the above method for preparing the compound of Formula 5, the present invention further provides a method for synthesizing 2-amino-6-chloropurine (1), the reaction formula of which is shown below:

[0099]

[0100] The method comprises the following steps:

[0101] 1) reacting a compound of formula 3 (guanine) with a Vilsmeier reagent (a compound of formula 23) to obtain a compound of formula 4 activated with dibenzyl amidine;

[0102] 2) further subjecting the compound of formula 4 to a hydroxyl chlorination reaction with a Vilsmeier reagent (compound of formula 23) to obtain a compound of formula 5;

[0103] 3) hydrolyzing the compound of formula 5 to remove the dibenzyl group to obtain the compound of formula 6;

[0104] 4) The compound of formula 6 is further hydrolyzed to obtain 2-amino-6-chloropurine (formula 1).

[0105] Considering that the reaction of the compound of formula 4 with the Vilsmeier reagent (compound of formula 23) will produce the compound of formula 5 and compound 51, the compound of formula 5 is hydrolyzed under the action of an acid, such as dilute hydrochloric acid, to produce 2-amino-6-chloropurine of formula 1 and impurity 71, as shown in the following reaction formula:

[0106]

[0107] Therefore, based on the use of the compound of formula 5 with an impurity 51 content of less than 4%, the compound of formula 1 can be purified in acetone water by acid and alkali to obtain compound 1 with an impurity 71 of less than 0.1%.

[0108] In the method of the present invention, the byproducts of the subsequent hydrolysis reaction of Formula 5 to generate 2-amino-6-chloropurine (Formula 1) are formic acid and water-insoluble dibenzylamine, which is different from the byproducts of the hydrolysis reaction of the intermediate in the prior art method, which are formic acid and water-soluble dimethylamine.

[0109]

[0110] The by-product dibenzylamine in the method of the present invention is insoluble in water, and can be separated and recovered by directly extracting and separating the liquid from the reaction solution during post-treatment, and then recycled, thereby effectively eliminating the problem of dimethylamine wastewater pollution in the prior art method.

[0111] The recovered by-product dibenzylamine can react with formic acid to generate N,N-dibenzylformamide, which can be used for the synthesis of the corresponding Vilsmeier reagent (23).

[0112]

[0113] The above N,N-dibenzylformamide reacts with triphosgene to generate the corresponding Vilsmeier reagent (23), which can be recycled and reused in the synthesis of compound 4 and compound 5 in the method of the present invention.

[0114]

[0115] Therefore, compared with the existing synthesis route, the first technical problem solved by the method of the present invention is to use recyclable N,N-dibenzylformamide to replace DMF, effectively eliminating the wastewater pollution caused by dimethylamine and DMF; and to use triphosgene to synthesize Vilsmeier reagent (23), effectively eliminating the difficult-to-treat phosphorus-containing wastewater.

[0116] In the present invention, by optimizing the reaction conditions, the compound 4 reacts with the Vilsmeier reagent 23 to generate the compound 5, and the amount of the disubstituted impurity 51 is small (<4%).

[0117]

[0118] Compound 5 with a small amount (<4%) of disubstituted impurity 51 is subsequently hydrolyzed to produce 2-amino-6-chloropurine (Formula 1) with a small amount (<0.1%) of disubstituted impurity 71.

[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 23) to obtain a compound of formula 4 activated with dibenzyl amidine;

[0124] 2) further subjecting the compound of formula 4 to a hydroxyl chlorination reaction with a Vilsmeier reagent (compound of formula 23) to obtain a compound of formula 5;

[0125] 3) hydrolyzing the compound of formula 5 to remove the dibenzyl 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, the Vilsmeier reagent (compound of formula 23) can be prepared by reacting dibenzylamine with formic acid to obtain N,N-dibenzylformamide, and then reacting it with triphosgene to obtain compound of formula 23.

[0128]

[0129] The method of the present invention involves intermediates and impurities with completely new structures, which are respectively: the compound shown in Formula 4, the compound shown in Formula 5, the compound shown in Formula 51, and the compound shown in Formula 71. Among them, the compound shown in Formula 4 or the compound shown in Formula 5 is an intermediate for synthesizing 2-amino-6-chloropurine. In a preferred embodiment, 2-amino-6-chloropurine can be used to synthesize purine antiviral drugs, including but not limited to famciclovir and penciclovir. The compound shown in Formula 51 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 4 can be prepared by reacting the compound represented by Formula 3 (guanine) with Vilsmeier reagent (compound represented by Formula 23) in a solvent S at room temperature. The reaction formula is shown below:

[0132]

[0133] The compound represented by Formula 5 can be prepared by reacting the compound represented by Formula 4 with Vilsmeier reagent (compound represented by Formula 23) in a solvent S at a temperature of T1 to undergo a hydroxyl chlorination reaction, thereby obtaining a compound represented by Formula 5 and a compound represented by Formula 51. 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 5. 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 25-85°C; preferably 25-35°C. In a specific embodiment, the content of the compound 51 is less than 4.0%.

[0136] The compound shown in Formula 1 can be prepared by subjecting the compound of Formula 5 in which the amount of impurity 51 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 dibenzylamine 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 CN 101139348 A)

[0146]

[0147] 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.

[0148] 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)

[0149] 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%)

[0150] Example 2 (Preparation of N,N-dibenzylformamide)

[0151] Add dibenzylamine (200.00g, 1013.788mmol, 1.00eq) and 300mL 1,2-dichloroethane to a 1L four-necked round-bottom flask, and stir to dissolve. Add formic acid (54.62g, 88%, 1044.223mmol, 1.03eq) and 100mL 1,2-dichloroethane in sequence, and heat to reflux for 5h. Evaporate the solvent 1,2-dichloroethane. Add 300ml cyclohexane and reflux to dissolve. Lower the reaction liquid temperature to room temperature, a large amount of solid precipitates in the reaction liquid, filter and dry to obtain 219.53g of N,N-dibenzylformamide with a purity of 96.1% and a yield of 99.71%.

[0152] Example 3 (Preparation of Formula 4 Reference Substance)

[0153] Triphosgene (8.399 g, 28.303 mmol, 0.855 eq) and 1,2-dichloroethane (15 mL) were added to a 50 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.

[0154] Add N,N-dibenzylformamide (16.771 g, 74.442 mmol, 2.250 eq) and 1,2-dichloroethane (15 mL) into a 100 mL three-necked round-bottom flask and stir until the N,N-dibenzylformamide solid is completely dissolved. Add the 1,2-dichloroethane solution of triphosgene dropwise to the 1,2-dichloroethane solution of N,N-dibenzylformamide to react. After the addition is completed, continue stirring for 30 minutes to obtain Vilsmeier reagent.

[0155] Compound 3 (5.001 g, 1.000 eq, 33.091 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 5 h. After the reaction was completed, triethylamine (21 mL) was added to the reaction bottle to quench, and the solvent was removed by vacuum distillation to obtain an orange-yellow syrupy liquid. 2.290 g of white solid formula 4 was separated by column chromatography (dichloromethane: methanol: triethylamine = 50: 1: 0.1), with a yield of 19.3% and a purity of 98.08%.

[0156] MS (ESI + ): C 20 H 18 N6O,m / z 359.16[M+H] + .

[0157] The compound of formula 4 1H NMR: (400MHz, DMSO-d6) δ8.97(s,1H),7.89(s,1H),7.36(ddt,J=30.0,23.4,6.9Hz,10H),4.64(s,2H),4.58(s,2H).

[0158] Example 4 (Preparation of Formula 5 Reference Substance)

[0159] Add dibenzylamine (118.70 g, 99%, 595.67 mmol, 3.00 eq) and 100 mL of 1,2-dichloroethane to a 1L four-necked round-bottom flask, stir to dissolve, then add formic acid (32.07 g, 88%, 613.11 mmol, 3.09 eq) and 260 mL of 1,2-dichloroethane. Heat the reaction solution to reflux for 2 h, and concentrate half of the solvent to obtain a 1,2-dichloroethane solution of N,N-dibenzylformamide.

[0160] In another 250 mL single-necked round-bottom flask, add triphosgene (89.25 g, 99%, 297.75 mmol, 1.50 eq) and 150 mL of 1,2-dichloroethane, and stir until dissolved to prepare a triphosgene 1,2-dichloroethane solution.

[0161] Under mechanical stirring, the 1,2-dichloroethane solution of triphosgene was added dropwise to the 1,2-dichloroethane solution of N,N-dibenzylformamide. After the addition was completed, stirring was continued for 20 minutes to obtain a Vilsmeier reagent solution.

[0162] Compound 3 (30.00 g, 198.50 mmol, 1.00 eq) and 10 mL of 1,2-dichloroethane solution were directly added to the 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 6 h. The reaction solution was poured into 2L 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 30 mL of 1,2-dichloroethane to obtain a solid crude compound 5. The crude compound 5 (wet weight 10.00 g) was taken and purified three times by hot beating with 25 mL of 1,2-dichloroethane. Filter, wash the filter cake with 25 mL of 1,2-dichloroethane, and dry to obtain 4.00 g of white solid formula 5.

[0163] MS (ESI + ): C 20 H 17 ClN6,m / z 377.13[M+H] + .

[0164] The compound of formula 5 1H NMR: (600MHz, DMSO-d6)δ13.33(s,1H),9.03(s,1H),8.38(s,1H),7.45–7.25(m,10H),4.67(s,2H),4.61(s,2H).

[0165] Example 5 (Preparation of Impurity 51 Reference Substance)

[0166] Triphosgene (5.62 g, 18.939 mmol, 0.95 eq) and 1,2-dichloroethane (10 mL) were added to a 25 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,N-dibenzylformamide (11.19 g, 49.669 mmol, 2.50 eq) and 10 mL of 1,2-dichloroethane to a 100 mL three-necked round-bottom flask, stir until the N,N-dibenzylformamide solid is completely dissolved, and then 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 Vilsmeier reagent.

[0168] Compound 3 (3.00 g, 19.850 mmol, 1.00 eq) and 1,2-dichloroethane (10 mL) were added to a reaction bottle containing Vilsmeier reagent, reacted at room temperature for 2 h, and then heated to 85 °C for 6 h. 4 mL of the reaction solution was taken, quenched with saturated NaHCO3 (4 mL), and separated by thin layer preparative chromatography (developing solvent: dichloromethane / methanol = 10:1, Rf value of the target color band was 0.65), and 0.064 g of light yellow solid 51 was prepared, with a yield of 0.4%.

[0169] MS (ESI) of compound 51 + ): C 40 H 33 C1N 12 ,m / z 712.27[M+H] + .

[0170] The compound of formula 51 1 H NMR: (400MHz, DMSO-d6)δ9.33(s,1H),9.27(s,1H),9.10(s,1H),8.47(s,1H),7.31(ddd,J=28.1,18.2,12.5Hz,20H),4.63(s,4H),4.52(s,4H).

[0171] Example 6 (Preparation of Impurity 71 Reference Substance)

[0172] Triphosgene (9.38 g, 99%, 0.950 eq, 31.293 mmol) and 30 mL of 1,2-dichloroethane were added to a 50 mL single-necked round-bottom flask and stirred until the triphosgene solid was completely dissolved to obtain a triphosgene 1,2-dichloroethane solution.

[0173] Add N,N-dibenzylformamide (18.66 g, 99%, 2.48 eq, 81.998 mmol) and 10 mL of 1,2-dichloroethane to a 100 mL three-necked round-bottom flask, stir until the N,N-dibenzylformamide solid is completely dissolved, and then dropwise add a solution of triphosgene in 1,2-dichloroethane. After the addition is complete, continue stirring for 30 minutes to obtain a Vilsmeier reagent solution.

[0174] Compound 3 (4.99 g, 1.00 eq, 33.018 mmol) and 10 mL of 1,2-dichloroethane were added to a reaction bottle containing Vilsmeier reagent. The mixture was stirred at room temperature for 2 h and then heated to reflux for 5 h.

[0175] After adding 10% NaOH solution to the reaction solution to adjust the pH to 1-2, the temperature was raised to 60°C and heated to react for 10 hours. After the reaction was completed, the reaction solution was transferred to a 250mL beaker and extracted with 10% NaOH aqueous solution (extracted 2 times, 50mL each time). The water layers recovered from the extraction were combined and washed with 1,2-dichloroethane (2 times, 20mL each time). 36% HCl solution was added to the aqueous phase after extraction to adjust the pH to neutral, filtered, and the filter cake was rinsed with 50mL of deionized water and dried to obtain 4.35g of crude compound 1 with an HPLC purity of 88.06% (the area% of impurity 71 was 9.21%).

[0176] In a 25 mL single-necked round-bottom flask, add 100 mg of crude compound 1, 10 μL of DMSO, and 15 mL of a mixed solution of methanol and acetonitrile (1:1), and stir at room temperature. After preparative liquid phase (prep-HPLC) separation, collect the eluate rich in 71, desolventize under reduced pressure to obtain a solid crude product of impurity 71, which is slurried with 3 mL of ethyl acetate and filtered, and dried to obtain 19 mg of a light yellow solid of impurity 71.

[0177] MS (ESI) of compound 71 + ): C 10 H7ClN 10 ,m / z 303.06[M+H] + .

[0178] Compound of formula 71 1 H NMR: (600MHz, DMSO-d6)δ8.73(s,1H),8.22(s,1H),7.31(s,2H),6.56(s,2H).

[0179] Example 7

[0180] Take seven single-necked round-bottom flasks.

[0181] Triphosgene (1.507 g, 99%, 5.028 mmol, 0.760 eq) was added to reaction bottle No. 1';

[0182] Triphosgene (1.545 g, 99%, 5.154 mmol, 0.779 eq) was added to reaction bottle No. 2';

[0183] Triphosgene (1.582 g, 99%, 5.278 mmol, 0.798 eq) was added to reaction bottle No. 3';

[0184] Triphosgene (1.620 g, 99%, 5.404 mmol, 0.817 eq) was added to reaction bottle No. 4';

[0185] Triphosgene (1.658 g, 99%, 5.531 mmol, 0.836 eq) was added to reaction bottle No. 5';

[0186] Triphosgene (1.884 g, 99%, 6.285 mmol, 0.950 eq) was added to reaction bottle No. 6';

[0187] Triphosgene (2.260 g, 99%, 7.540 mmol, 1.140 eq) was added to reaction bottle No. 7'.

[0188] Add 3 mL of 1,2-dichloroethane to bottles 1'-7' respectively, and stir until the solid is completely dissolved to prepare a 1,2-dichloroethane solution of triphosgene.

[0189] Take seven three-necked round-bottom flasks.

[0190] Add N,N-dibenzylformamide (3.012 g, 99%, 13.236 mmol, 2.00 eq) to reaction bottle No. 1;

[0191] Add N,N-dibenzylformamide (3.087 g, 99%, 13.565 mmol, 2.05 eq) to reaction bottle No. 2;

[0192] Add N,N-dibenzylformamide (3.163 g, 99%, 13.899 mmol, 2.10 eq) to reaction bottle No. 3;

[0193] Add N,N-dibenzylformamide (3.238 g, 99%, 14.229 mmol, 2.15 eq) to reaction bottle No. 4;

[0194] Add N,N-dibenzylformamide (3.313 g, 99%, 14.558 mmol, 2.20 eq) to reaction bottle No. 5;

[0195] Add N,N-dibenzylformamide (3.765 g, 99%, 16.545 mmol, 2.50 eq) to reaction bottle No. 6;

[0196] Triphosgene N,N-dibenzylformamide (4.518 g, 99%, 19.854 mmol, 3.00 eq) was added to reaction bottle No. 7.

[0197] Add 2 mL of 1,2-dichloroethane to bottles 1-7 respectively, stir until N,N-dibenzylformamide is completely dissolved, and then dropwise add triphosgene in 1,2-dichloroethane solution. Continue stirring for 30 minutes after the addition is completed to prepare the corresponding Vilsmeier reagent.

[0198] Compound 3 (1.000 g, 6.617 mmol, 1.00 eq) and 5 mL of 1,2-dichloroethane were directly added to bottles 1-7 containing Vilsmeier reagent, stirred at room temperature for 2 h, and then heated to 85 °C for reaction. The reaction solution was sampled at different time points and tested by HPLC. The area percentages (Area %) of compound 4, compound 5, and impurity 51 in the above 7 reactions were compared. For the convenience of comparison, the impurity peaks were deducted, as shown in the following table:

[0199]

[0200] Preferably, the molar ratio E1 of the raw material 3 and the Vilsmeier reagent 23 is 1:2.10eq or more, and the intermediate 4 can be basically reacted completely.

[0201] Example 8

[0202] Triphosgene (15.83 g, 99%, 52.811 mmol, 0.798 eq) and 50 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.

[0203] Add N,N-dibenzylformamide (31.62 g, 99%, 138.949 mmol, 2.10 eq) and 50 mL of 1,2-dichloroethane into a 250 mL round-bottom flask, stir until N,N-dibenzylformamide is completely dissolved, then drop freshly prepared triphosgene in 1,2-dichloroethane solution. Continue stirring for 30 minutes after the addition is complete to prepare Vilsmeier reagent.

[0204] Add compound 3 (10.00 g, 66.168 mmol, 1.00 eq) and 50 mL of 1,2-dichloroethane directly to the reaction bottle containing Vilsmeier reagent, and stir at room temperature for 2 h. Divide the reaction solution into 8 portions and transfer them to 50 mL reaction bottles respectively. Take 7 portions and place them at 85, 75, 65, 55, 45, 35, and 25 ° C for reaction. 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 4, compound 5 and impurity 51 in the above 7 reactions, as shown in the following table:

[0205]

[0206] The reaction temperature T1 is preferably 25 to 35° C., and the amount of impurity 51 is relatively small.

[0207] Example 9

[0208] Take nine single-necked round-bottom flasks, add triphosgene (1.582 g, 99%, 5.278 mmol, 0.798 eq) to flasks 1'-9' respectively, and add the following different solvents respectively:

[0209] Ethyl acetate (3 mL) was added to reaction flask No. 1';

[0210] Toluene (3 mL) was added to reaction flask No. 2';

[0211] Add dichloromethane (3 mL) to reaction flask No. 3';

[0212] Add acetone (3 mL) to reaction bottle No. 4';

[0213] Cyclohexane (3 mL) was added to reaction flask No. 5';

[0214] Add 1,2-dichloroethane (3 mL) to reaction flask No. 6';

[0215] Add acetonitrile (3 mL) to reaction bottle No. 7'

[0216] Add tetrahydrofuran (3 mL) to reaction flask No. 8'

[0217] Add 1,4-dioxane (3 mL) to reaction bottle No. 9'

[0218] Stir in bottles 1'-9' until the solids are dissolved (except cyclohexane and acetonitrile), and the triphosgene solution is prepared.

[0219] Take nine three-necked round-bottom flasks, add N,N-dibenzylformamide (3.163 g, 99%, 13.899 mmol, 2.10 eq) and the following different solvents respectively:

[0220] Ethyl acetate (2 mL) was added to reaction flask No. 1;

[0221] Toluene (2 mL) was added to reaction flask No. 2;

[0222] Add dichloromethane (2 mL) to reaction bottle No. 3;

[0223] Add acetone (2 mL) to reaction bottle No. 4;

[0224] Cyclohexane (2 mL) was added to reaction bottle No. 5;

[0225] Add 1,2-dichloroethane (2 mL) to reaction bottle No. 6;

[0226] Add acetonitrile (2 mL) to reaction bottle No. 7

[0227] Add tetrahydrofuran (2 mL) to reaction bottle No. 8

[0228] Add 1,4-dioxane (2 mL) to reaction bottle No. 9

[0229] Stir in bottles 1-9 until the solids are dissolved (except cyclohexane) to obtain N,N-dibenzylformamide solution.

[0230] 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.

[0231] Add compound 3 (1.000 g, 6.617 mmol, 1.00 eq) to flasks 1-9 containing Vilsmeier reagent, and add ethyl acetate (5 mL), toluene (5 mL), dichloromethane (5 mL), acetone (5 mL), cyclohexane (5 mL), 1,2-dichloroethane (5 mL), acetonitrile (5 mL), tetrahydrofuran (5 mL) and 1,4-dioxane (5 mL) to flasks 1-9, respectively. Stir and react at room temperature for 2 hours. Heat to 35 ° C and react for 30 hours. Take the reaction solution from flasks 1-9, perform HPLC detection, and calculate the area percentage (Area%, for comparison, subtract the miscellaneous peaks) of compound 4, compound 5 and impurity 51 in the above reaction, as shown in the following table:

[0232]

[0233] a The reaction solution showed solid agglomeration and the experiment was terminated. b The formation of intermediate 5 was not detected in the reaction.

[0234] In the acetonitrile solvent, half of the intermediate formula 4 is basically unreacted and other unknown impurities are generated. According to the minimum amount of the intermediate formula 4 remaining and the minimum amount of impurity 51, the preferred reaction solvent S is dichloromethane or 1,2-dichloroethane.

[0235] Example 10

[0236] Triphosgene (79.16 g, 99%, 0.798 eq, 264.091 mmol) and 150 mL of dichloromethane were added to a 250 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.

[0237] Add N,N-dibenzylformamide (158.13 g, 99%, 2.10 eq, 694.876 mmol) and 100 mL of dichloromethane to a 1L four-necked round-bottom flask, stir until the N,N-dibenzylformamide solid is completely dissolved, then dropwise add a dichloromethane solution of triphosgene. After the addition is complete, continue stirring for 30 minutes to obtain Vilsmeier reagent.

[0238] Compound 3 (50.00 g, 1.00 eq, 330.841 mmol) and 100 mL of dichloromethane were added to the reaction bottle of Vilsmeier reagent. After stirring at 25 °C for 2 h, the temperature was raised to 35 °C and the reaction was continued for 30 h (impurities in the reaction solution: the area% of 51 was 2.19%, excluding impurity peaks).

[0239] The reaction solution was poured into 1500 mL of saturated NaHCO3 solution, and the organic phase was extracted and recovered. The organic phase was stirred in an ice bath for 3.5 h, filtered, and the filter cake was dried to obtain 148.48 g of a light yellow solid crude product of compound 5, with a crude product yield of 119.1%. The filtrate 1 contained N,N-dibenzylformamide and dibenzylamine (recovered for later use).

[0240] In a 500 mL three-necked round-bottom flask, add 148.48 g crude compound 5 and 415 mL dichloromethane, slurry at 40°C for 1 h, filter with suction, and dry the filter cake to obtain 123.37 g of light yellow solid compound 5 with a yield of 83.1%. Filtrate 2 is combined with filtrate 1 (recovered for later use).

[0241] The total yield of the two-step reaction of preparing compound 5 from guanine (3) was 98.9% (119.1% x 83.1%).

[0242] Add 123.37 g of the light yellow solid of compound 5 and 2200 mL of 5% HCl solution to a 5L single-necked round-bottom flask, and stir at 40°C for 8 h. After the reaction is completed, cool in an ice-water bath, and add 40% NaOH solution to adjust the pH to 10. Wash with dichloromethane (3 times, 300 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 min. Filter with suction, and add 1000 mL of acetone to the filtrate. Add 20% HCl solution to the aqueous phase, adjust the pH to 3, and a large amount of white solid precipitates in the aqueous phase. Filter with suction, wash the filter cake with 500 ml of deionized water, 200 mL of acetone, and dry to obtain 52.6 g of white solid of compound 1, with a yield of 94.8% and an HPLC purity of 99.65% (the area% of impurity 71 is 0.05%).

[0243] Recover dibenzylamine: Combine the dichloromethane washings and filtrate 2 and filtrate 1 under reduced pressure to recover the solvent dichloromethane. Add 3500mL 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 126.94g of dibenzylamine as a brown oil with a dibenzylamine recovery rate of 92.6%.

[0244] MS (ESI) of the compound of formula 1 + ): C5H4ClN5, m / z 170.02[M+H] + .

[0245] The compound of formula 1 1 H NMR: (600MHz, DMSO-d6)δ12.89(s,1H),8.13(s,1H),6.79(s,2H).

[0246] HPLC method (3 preparation 5): Vanquish Core high performance liquid chromatograph (Thermo Fisher), chromatographic column: Thermo Fisher Hypersil GOLD TMC18 4.6×250mm 5μm; detector: DAD (detection wavelength: 210nm); column temperature: 30℃; flow rate: 1.0ml / min; mobile phase A: 10mM K2HPO4 aqueous solution, mobile phase B: acetonitrile solution; gradient elution: 0-20min, B: 40%→70%, 20-20.1min, B: 70%→40%, 20.1-30min, B: 40%; diluent: acetonitrile; injection volume: 1μl. Retention time: formula 4: 6.590min, formula 5: 6.330min, impurity 51: 20.167min.

[0247] HPLC method (5 Preparation 1): Vanquish Core high performance liquid chromatograph (Thermo Fisher), chromatographic column: Thermo Fisher Hypersil GOLD TM C18 4.6×250mm 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.

[0248] 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 23) to obtain a compound of formula 4 activated with dibenzyl amidine; 2) subjecting the compound of formula 4 to a hydroxyl chlorination reaction with a Vilsmeier reagent (compound of formula 23) to obtain a compound of formula 5; 3) hydrolyzing the compound of formula 5 to remove the dibenzyl 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 4 reacts with a Vilsmeier reagent (compound of formula 23) to obtain a compound of formula 5 and a compound 51, Preferably, the content of compound 51 is less than 4.0%.

3. A method for preparing a high-purity N,N-dibenzyl-N'-(6-chloro-6,9-dihydro-1H-purin-2-yl)formamidine (Formula 5) compound, 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 (formula 23) to obtain a dibenzyl amidine compound of formula 4; 2) The compound of formula 4 is further reacted with Vilsmeier reagent (formula 23) to obtain the compound of formula 5.

4. The method according to claim 3, characterized in that In step 2), the compound of formula 4 reacts with a Vilsmeier reagent (compound of formula 23) to obtain a compound of formula 5 and a compound 51. Preferably, the content of compound 51 is less than 4.0%.

5. The compound shown in formula 4, 6. The compound represented by formula 5, 7. The compound represented by formula 51 shown below 8. The compound represented by formula 71 shown below 9. Use of the compound represented by formula 4 or 5 for preparing 2-amino-6-chloropurine (1), an intermediate of purine antiviral drugs.

10. Use of the compound represented by formula 51 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.

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