CN119977967A

CN119977967A - N-methyl-N-benzyl-N′-(6-chloro-6,9-dihydro-1H-purin-2-yl)formamidine compound and its preparation and application

Info

Publication number: CN119977967A
Application number: CN202510376081.3A
Authority: CN
Inventors: 吴泰志; 留岳斌; 杨小龙; 陈小爱; 陆建吾; 史银菲; 袁顺; 徐衍晟
Original assignee: China Pharmaceutical Industry Research Institute Co ltd; Shanghai Pharmaceutical Industry Research Institute Co ltd; Huanggang Luban Pharmaceutical Co ltd
Current assignee: China Pharmaceutical Industry Research Institute Co ltd; Shanghai Pharmaceutical Industry Research Institute Co ltd; Huanggang Luban Pharmaceutical Co ltd
Priority date: 2025-03-27
Filing date: 2025-03-27
Publication date: 2025-05-13

Abstract

本发明披露了制备高纯度N‑甲基‑N‑苄基‑N'‑(6‑氯‑6,9‑二氢‑1H‑嘌呤‑2‑基)甲脒(式85)的方法。所述方法以鸟嘌呤(式3)为原料，依次经过氨基活化、氯代反应制得高纯度的N‑甲基‑N‑苄基‑N'‑(6‑氯‑6,9‑二氢‑1H‑嘌呤‑2‑基)甲脒(式85)。高纯度式85化合物可用于制备医药中间体，2‑氨基‑6‑氯嘌呤(式1)。本发明方法的收率高、纯度高、废水少。 The present invention discloses a method for preparing high-purity N-methyl-N-benzyl-N'-(6-chloro-6,9-dihydro-1H-purine-2-yl)formamidine (Formula 85). The method uses guanine (Formula 3) as a raw material, and successively obtains high-purity N-methyl-N-benzyl-N'-(6-chloro-6,9-dihydro-1H-purine-2-yl)formamidine (Formula 85) through amino activation and chlorination reaction. The high-purity Formula 85 compound can be used to prepare a pharmaceutical intermediate, 2-amino-6-chloropurine (Formula 1). The method of the present invention has high yield, high purity and less wastewater.

Description

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

Technical Field

The invention belongs to the field of chemical synthesis. In particular, the invention relates to N-methyl-N-benzyl-N' - (6-chloro-6, 9-dihydro-1H-purin-2-yl) formamidine (formula 85), a preparation method of the compound, a brand new structural intermediate for synthesizing the compound and application of the compound in preparing 2-amino-6-chloropurine (formula 1).

Background

2-Amino-6-chloropurine (formula 1) is an important intermediate for synthesizing purine antiviral drugs Famciclovir and Penciclovir.

Although various methods for synthesizing 2-amino-6-chloropurine (formula 1) are disclosed in the prior art, these prior art methods have various drawbacks. These drawbacks are mainly that POCl ₃ is used in the preparation process, which results in a large amount of phosphorus-containing wastewater during post-treatment, that DMF is used in the preparation process, which results in a large amount of dimethylamine and DMF-containing wastewater during post-treatment, and that the final synthesized product 2-amino-6-chloropurine (1) contains more impurities 71, which affect the product quality.

Thus, there is an urgent need in the art for a new method for synthesizing 2-amino-6-chloropurine (1) which not only produces 2-amino-6-chloropurine in high yield and purity, but also produces as little waste water as possible which is difficult to treat.

Disclosure of Invention

The invention aims to provide a method for synthesizing 2-amino-6-chloropurine, which has high yield, high purity and less wastewater difficult to treat.

The invention also aims to provide a novel intermediate with a structure used in synthesizing 2-amino-6-chloropurine and a preparation method thereof.

In a first aspect, the present invention provides a process for the preparation of 2-amino-6-chloropurine (1), said process having the following reaction scheme:

the method comprises the following steps:

1) Reacting the compound of formula 3 (guanine) with a Vilsmeier reagent (compound of formula 24) to give an N-methyl-N-benzamidine activated compound of formula 84;

2) Continuing to perform hydroxychloroation reaction on the compound of the formula 84 and a Vilsmeier reagent (the compound of the formula 24) to obtain a compound of the formula 85;

3) Hydrolyzing the compound of formula 85 to remove N-methyl-N-benzyl to obtain a compound of formula 6;

4) The compound of formula 6 is further hydrolyzed to give 2-amino-6-chloropurine (formula 1).

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 from 1:3.00 to 1:5.00, for example from 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 from 4.00eq to 5.00eq.

In a preferred embodiment, in step 1), the compound of formula 3 (guanine) is reacted with a Vilsmeier reagent (compound of formula 24) in solvent S at room temperature to give the compound of formula 84.

In a preferred embodiment, in step 2), the compound of formula 84 is hydroxychlororeacted with a Vilsmeier reagent (compound of formula 24) at a temperature T1 and solvent S to give a compound of formula 85.

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

In a preferred embodiment, the reaction temperature T1 is in the range from 20 to 85℃and preferably in the range from 20 to 40 ℃.

In a specific embodiment, in step 2), the compound of formula 84 is reacted with a Vilsmeier reagent (compound of formula 24) to provide a compound of formula 85 and a compound 851,

Preferably, the content of said compound 851 is <4.0%.

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

In a preferred embodiment, the process further comprises step 5), purifying the compound of formula 1 to obtain compound 1 having an impurity 71<0.1%

In a preferred embodiment, the compound of formula 1 is acid-base purified in acetone water.

In a preferred embodiment, N-methyl-N-benzylformamide is formed by reacting N-methylbenzylamine with formic acid, followed by reacting N-methyl-N-benzylformamide with triphosgene to form the corresponding Vilsmeier reagent (24) of the formula:

In a second aspect, the present invention provides a process for preparing a high purity N-methyl-N-benzyl-N' - (6-chloro-6, 9-dihydro-1H-purin-2-yl) formamidine compound (formula 85) as follows:

the method comprises the following steps:

1) Reacting a compound of formula 3 (guanine) with a Vilsmeier reagent (formula 24) to produce a compound of formula 84;

2) The compound of formula 84 continues to react with Vilsmeier reagent (formula 24) to produce the impurity compound of formula 85.

In a preferred embodiment, the reaction temperature T1 is from 25 to 85℃and preferably from 25 to 35 ℃.

In a specific embodiment, in step 2), the compound of formula 84 is reacted with a Vilsmeier reagent (compound of formula 24) to provide the compound of formula 85 and compound 851

Preferably, the content of said compound 851 is <4.0%.

in a third aspect, the invention provides a compound of formula 84,

In a fourth aspect, the invention provides a compound of formula 85,

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

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

In a seventh aspect, the present invention provides use of a compound of formula 84 or formula 85 for preparing 2-amino-6-chloropurine (1), an intermediate of a purine antiviral drug.

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

It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.

Drawings

FIG. 1 shows an MS spectrum of formula 1;

FIG. 2 shows ¹ H NMR of formula 1;

FIG. 3 shows ¹³ C NMR of formula 1;

FIG. 4 shows an MS spectrum of formula 4;

FIG. 5 shows a ¹ H NMR chart of formula 84;

FIG. 6 shows a single crystal plot of formula 84;

FIG. 7 shows an MS spectrum of formula 85;

FIG. 8 shows a ¹ H NMR chart of formula 85;

FIG. 9 shows an MS spectrum of impurity 851;

FIG. 10 shows ¹ H NMR of impurity 851;

FIG. 11 shows an MS spectrum of impurity 71;

FIG. 12 shows ¹ H NMR of impurity 71.

Detailed Description

The inventors have conducted extensive and intensive studies and have unexpectedly found that the methods for synthesizing 2-amino-6-chloropurine (formula 1) reported in the prior art documents are each deficient. Specifically, the following synthetic routes exist for 2-amino-6-chloropurine (formula 1) reported in the prior literature:

The first (EP 0203685 A2) is to perform the chlorination reaction of hydroxyl groups with guanine (3) as a starting material under the conditions of a chlorinating reagent phosphorus oxychloride (POCl ₃) and a phase transfer catalyst tetraethylammonium chloride (TEACl) to obtain 2-amino-6-chloropurine (1) in a yield of 42%.

In the method, a large amount of tetraethylammonium chloride (TEACl is 1.00-1.50 times of guanine in mol/mol) serving as a phase transfer catalyst is used, so that a large amount of solid wastes are caused, and the cost is high. Meanwhile, 6 equivalents of the chlorinating reagent phosphorus oxychloride (POCl ₃) is used in the reaction, and a large amount of refractory phosphoric acid-containing wastewater is generated during post-treatment.

And the second (WO 9315075 A1) is to take guanine as a starting material, introduce acetyl protecting groups on amino groups at the 2-position and nitrogen atoms at the 7-position of guanine to obtain a compound 21, perform hydroxychloroation on the compound 21 to obtain a compound 22, and remove the acetyl protecting groups through hydrolysis to obtain 2-amino-6-chloropurine (1), wherein the total yield is 74.6%.

The method has higher yield than the first method, but still needs to use a phase transfer catalyst for catalysis, and has higher cost. And phosphorus oxychloride (POCl ₃) is used in the reaction, and a large amount of phosphorus-containing wastewater is generated during the post-treatment.

And a third (CN 108892669 A1) wherein the hydroxy group of the compound 41,41 obtained by oxidizing the amino group at the 2-position of guanine to a nitro group with hydrogen peroxide was subjected to chlorination under the action of SOCl ₂ to obtain the compound 42, and the nitro group of the compound 42 was reduced to the amino group by hydrazine hydrate to obtain 2-amino-6-chloropurine (1), with a total yield of 81.6%.

The method uses the easy-to-explosion chemicals of hydrogen peroxide and hydrazine hydrate, and has great potential safety hazard.

Fourth (EP 0543095 A2) is that guanine reacts with Vilsmeier reagent (62, prepared by DMF reacting with POCl ₃), dimethyl amidine is introduced on primary amine at 2-position to activate to obtain compound 31, then hydroxy is chlorinated by Vilsmeier reagent (62) to obtain compound 32, dimethylamino is removed by hydrolysis of compound 32 to obtain formamide compound 6, and carboxamide group of compound 6 is hydrolyzed under alkaline condition to obtain 2-amino-6-chloropurine (1), total yield is 70%.

In the method, DMF and POCl ₃ are used for reaction to prepare Vilsmeier reagent (62), and a large amount of refractory wastewater containing phosphoric acid and DMF is generated during post-treatment.

In the course of the subsequent hydrolysis reaction of compound 32 to 2-amino-6-chloropurine (1), formic acid and dimethylamine are produced as by-products. The byproduct dimethylamine is easily dissolved in water, and has strong unpleasant ammonia odor when the dimethylamine is in high concentration, fish oil odor when the concentration is extremely low, and the wastewater containing dimethylamine is difficult to treat.

Finally, CN 107312003 A1 modified the fourth method described above, replacing phosphorus oxychloride (POCl ₃) with triphosgene. Guanine reacts with Vilsmeier reagent (63, DMF reacts with triphosgene to prepare), dimethyl amidine is introduced on primary amine at 2-position to activate to obtain compound 31, then hydroxyl of 31 is chlorinated by Vilsmeier reagent (63) to obtain compound 32, compound 32 is hydrolyzed to remove dimethylamino and amido, 2-amino-6-chloropurine (1) is generated, and the total yield is 78.3%.

The method also introduces a dimethyl amidine activating group, and a large amount of dimethylamine wastewater is generated after the post-treatment.

The inventors have found that when repeating the fourth process (EP 0543095 A2) the reaction of compound 31 with Vilsmeier reagent (POCl ₃ or triphosgene prepared with DMF) all produced about 10% of impurity 72, except for the main product 32. Impurity 72 is converted into impurity 71 by the dimethylaminoremoval reaction and hydrolysis reaction of 32, and impurity 71 affects the quality of product 1.

The present inventors have conducted extensive and intensive studies to overcome various drawbacks of the prior art, and have unexpectedly found a novel synthetic route involving novel intermediates. By adopting the route to synthesize the 2-amino-6-chloropurine, various waste water and raw materials are effectively eliminated, and the raw materials are easy to obtain and can be recycled. In addition, the 2-amino-6-chloropurine prepared by the method has high purity and high yield.

The process and novel intermediates of the invention

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 wastewater difficult to treat and the like. In addition, the novel method for synthesizing 2-amino-6-chloropurine provided by the invention also relates to an intermediate with a brand new structure.

To this end, the present invention provides a novel compound represented by formula 84, and its structure is determined as follows by single crystals

Single crystal structural formulae of formulae 84 and 84;

the novel compounds represented by formula 85,

In the present invention, the compounds represented by formulas 84 and 85 can be prepared by a method represented by the following reaction formula:

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 provide a compound of formula 84. The compound of formula 84 is continuously subjected to hydroxychloroation reaction with a Vilsmeier reagent (compound of formula 24) at a temperature T1 and a solvent S to obtain a compound of formula 85 and a compound 851.

Based on the teachings of the present invention, one of ordinary skill in the art can further optimize the various process parameters of the above-described methods. In a preferred embodiment, the molar ratio E1 (3:24) of the 3 compound to the Vilsmeier reagent (compound of formula 24) to 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 to 5.00eq, the reaction temperature T1 can be controlled between 20 and 85 ℃, preferably between 20 and 40 ℃, and the solvent S is any of dichloromethane, 1, 2-dichloroethane, acetonitrile, preferably dichloromethane or 1, 2-dichloroethane.

The content of the impurity compound 851 may be controlled to be <4.0% on the basis of optimizing the process conditions.

Based on the compounds of formulae 84 and 85, the present invention provides a novel process for the synthesis of 2-amino-6-chloropurine (1), the reaction scheme of which is as follows:

the method comprises the following steps:

3) Hydrolyzing the compound of formula 85 to remove N-methylbenzylamine to obtain a compound of formula 6;

In the method for synthesizing 2-amino-6-chloropurine (formula 1) of the present invention, the hydroxy chlorination reaction of the compound of formula 84 with Vilsmeier reagent (formula 24) gives the compound of formula 85 and the impurity compound of formula 851, and the hydrolysis of the compound of formula 85, for example, under the action of an acid (such as dilute hydrochloric acid) gives 2-amino-6-chloropurine and impurity 71, the reaction formula of the process is as follows:

Therefore, lowering the content of the impurity formula 851 compound is advantageous for improving the purity of 2-amino-6-chloropurine. In a specific embodiment, 2-amino-6-chloropurine of formula 1 is prepared using a compound of formula 85 having a content of impurity 851 < 4%. And the compound of formula 1 can be purified by acid and alkali in acetone water to obtain compound 1 with impurity 71< 0.1%.

In the process of the present invention, the by-products of formula 85 which form 2-amino-6-chloropurine (formula 1) upon subsequent hydrolysis are formic acid and water insoluble N-methylbenzylamine, unlike the by-products of the hydrolysis of the intermediates of the prior art processes which form formic acid and water insoluble N-methylbenzylamine.

The by-product, N-methylbenzylamine, is insoluble in water, and can be directly extracted from the reaction liquid for separation and recovery during post-treatment, and recycled, so that the problem of dimethylamine wastewater pollution in the prior art method is effectively solved. The recovered by-product N-methylbenzylamine can be reacted with formic acid to form N-methyl-N-benzylformamide, which can be used for the synthesis of the corresponding Vilsmeier reagent (24).

The N-methyl-N-benzyl formamide reacts with triphosgene to generate a corresponding Vilsmeier reagent (24), which can be recycled for the synthesis of the compounds 84 and 85 in the method of the invention.

Therefore, compared with the existing synthetic route, the invention solves the first technical problem that the recyclable N-methyl-N-benzyl formamide is used for replacing DMF, thereby effectively eliminating the pollution of dimethylamine and DMF wastewater, and the Vilsmeier reagent (24) is synthesized by triphosgene, thereby effectively eliminating the refractory phosphorus-containing wastewater.

In the process of the present invention, the amount of disubstituted impurity 851 in compound 85 produced by the reaction of compound 84 with Vilsmeier reagent 24 is significantly reduced, e.g., <4%, by optimization of the reaction conditions.

Compound 85 having a small amount (< 4%) of disubstituted impurity 851 undergoes subsequent hydrolysis to produce 2-amino-6-chloropurine (formula 1) having a small amount (< 0.1%) of disubstituted impurity 71.

In a specific embodiment, the method for preparing 2-amino-6-chloropurine (formula 1) of the present invention is as follows:

the method comprises the following steps:

Wherein the Vilsmeier reagent (compound of formula 24) can be prepared by reacting N-methylbenzylamine with formic acid to prepare N-methyl-N-benzylformamide, and then with triphosgene.

In the method of the present invention, intermediates and impurities having a novel structure are provided, which are a compound represented by formula 84, a compound represented by formula 85, a compound represented by formula 851, and a compound represented by formula 71, respectively. Wherein, the compound shown in the formula 84 or 85 is an intermediate for synthesizing 2-amino-6-chloropurine, and the 2-amino-6-chloropurine is an important intermediate for synthesizing purine antiviral drugs. In a preferred embodiment, the purine antiviral drug includes, but is not limited to, famciclovir (Famciclovir), penciclovir (Penciclovir). The compound shown in the formula 851 or the compound shown in the formula 71 can be used as a standard substance for quality detection or quality control in the preparation process of purine antiviral drugs or intermediates 2-amino-6-chloropurine (1).

The compound represented by formula 84 can be produced by reacting a compound of formula 3 (guanine) with a Vilsmeier reagent (compound of formula 24) in a solvent S at room temperature. The reaction formula is as follows:

Compounds of formula 85 and 851 may be prepared by reacting a compound of formula 84 with a Vilsmeier reagent (compound of formula 24) at a temperature T1 and a solvent S to undergo hydroxychloroation. The reaction formula is as follows:

The present inventors have further optimized the process parameters in the reaction scheme for synthesizing the compound of 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 ℃, preferably 20-40 ℃, more preferably 40 ℃. In a specific embodiment, the content of the compound 851 is <4.0%.

The compound represented by formula 1 can be produced by acid hydrolysis of a compound of formula 85 with an amount of impurity 851 <4%, thereby producing 2-amino-6-chloropurine represented by formula 1 and impurity 71. The reaction formula is as follows:

in a specific embodiment, the method yields an amount of 71 <0.1% in compound 1 via purification with an acid base in acetone-water.

The main advantages of the invention include:

1. The method for preparing 2-amino-6-chloropurine has less waste water, and effectively eliminates dimethylamine-containing waste water, DMF-containing waste water and phosphorus-containing waste water;

2. The raw material N-methylbenzylamine of the method for preparing 2-amino-6-chloropurine is easy to obtain and can be recycled in the method;

3. the method for preparing 2-amino-6-chloropurine has high product purity.

4. The method for preparing 2-amino-6-chloropurine has high yield.

The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise indicated, percentages and parts are weight percentages and parts, eq represents equivalents to the reaction substrate.

Example 1 (refer to patent CN 101139348A)

Vilsmeier reagent preparation Vilsmeier reagent 62 was prepared by adding DMF (40 mL,518.777mmol,3.92 eq) to a 100mL three-necked round bottom flask, magnetically stirring, and dropwise adding POCl ₃ (35 mL,382.345mmol,2.89 eq) under ice-bath conditions.

In a 500mL three-necked round bottom flask was charged compound 3 (20.00 g,132.336mmol,1.00 eq) and 200mL 1, 2-dichloroethane. Vilsmeier reagent 62 was added dropwise to a solution of compound 3 in 1, 2-dichloroethane under magnetic stirring. The oil bath was adjusted to 35 ℃ and the reaction was heated for 30h. (reaction solution: 92.38% of area of Compound 32, 7.62% of area of impurity 72, other peaks were subtracted)

After the reaction was completed, the reaction solution was cooled to room temperature, poured into 300mL of ice water, and the aqueous solution was recovered by extraction. 10% NaOH solution is added into the recovered water phase to adjust the pH value to 3.0,80 ℃ for reaction for 5 hours. After the reaction is finished, the reaction liquid is cooled to room temperature and is filtered by suction. The filter cake wet was transferred to a 500mL beaker, 150mL 10% NaOH solution was added and magnetically stirred. After 3h at room temperature, the pH was adjusted to neutral by addition of 10% HCl solution. Suction filtering, immersing and washing the filter cake with deionized water, drying to obtain 18.46g 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%)

Example 2 (preparation of N-methyl-N-benzylformamide)

In a 1L four-necked round bottom flask was added methylbenzylamine (200.05 g,97%,1601.324mmol,1.00 eq) and 300mL cyclohexane, and dissolved with stirring. Formic acid (86.27 g,88%,1649.307mmol,1.03 eq) and 100mL cyclohexane were added. The reaction mixture was warmed to reflux for 9h. After the reaction, the temperature of the reaction solution is reduced to room temperature, the reaction solution is layered, a non-cyclohexane layer is recovered, and the solvent is distilled off, so that 235.10g of N-methyl-N-benzylformamide with the purity of 99.43% and the yield of 98.4% are prepared.

Example 3 (preparation of control of formula 84)

Triphosgene (8.87 g,99%,0.45eq, 29.292 mmol) and 1, 2-dichloroethane (30 mL) were added to a100 mL single-necked round bottom flask and stirred at room temperature until triphosgene was completely dissolved to prepare a1, 2-dichloroethane solution of triphosgene.

N-methyl-N-benzylformamide (12.37 g,99%,1.24eq,82.084 mmol) and 1, 2-dichloroethane (20 mL) were added to a 250mL three-necked round bottom flask and mechanically stirred well. The 1, 2-dichloroethane solution of triphosgene was added dropwise to the 1, 2-dichloroethane solution of N-methyl-N-benzylformamide for reaction. And after the dripping is finished, stirring for 30min continuously to obtain the Vilsmeier reagent.

Compound 3 (10.00 g,1.00eq,66.168 mmol) and 1, 2-dichloroethane (20 mL) were added directly to the reaction flask of freshly prepared Vilsmeier reagent and stirred at room temperature for 8h. After the reaction was completed, the reaction solution was poured into 300mL of saturated NaHCO ₃ solution. Suction filtration, washing the filter cake with 50ml of 1, 2-dichloroethane in batches, and drying to obtain the white compound solid crude product of formula 84.72 g, with a yield of 110.9% and a purity of 93.24%. 2.005g was purified by column chromatography (dichloromethane: methanol=15:1) to give 84.920 g as a white solid with a yield of 45.9% and a purity of 98.90%.

MS (ESI ⁺)：C₁₄H₁₄N₆O,m/z 283.13[M+H]⁺) of the compound of formula 84.

Of a compound of formula 84 ¹H 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).

Example 4 (preparation of control of formula 85)

Triphosgene (28.63 g,99%,1.44eq,95.514 mmol) and 1, 2-dichloroethane (50 mL) were added to a 100mL single-necked round bottom flask and stirred at room temperature until triphosgene was completely dissolved to prepare a1, 2-dichloroethane solution of triphosgene.

N-methyl-N-benzylformamide (39.93 g,99%,4.00eq,264.964 mmol) and 1, 2-dichloroethane (40 mL) were added to a 250mL three-necked round bottom flask and mechanically stirred well. The 1, 2-dichloroethane solution of triphosgene was added dropwise to the 1, 2-dichloroethane solution of N-methyl-N-benzylformamide for reaction. After the completion of the dropwise addition, stirring was continued for 30 minutes to obtain a Vilsmeier reagent.

A solution of compound 3 (10.00 g,1.00eq,66.168 mmol) and 10mL of 1, 2-dichloroethane were directly fed into a reaction flask containing Vilsmeier reagent solution and after 2h reaction at room temperature, the reaction was continued at 85℃for 2h. The reaction solution was poured into 300mL of saturated NaHCO ₃ solution, and the organic phase was recovered. Under the ice water bath condition, the organic phase is magnetically stirred for 1h, and then is filtered by suction, and the filter cake is washed by 50ml of 1, 2-dichloroethane, thus obtaining a solid crude product of the compound 85. 2.001g of crude compound 85 was taken and purified by column chromatography (dichloromethane: methanol=50:1→30:1) to give 0.417g of white solid 85.

MS (ESI ⁺)：C₁₄H₁₃ClN₆,m/z 301.10[M+H]⁺) of the compound of formula 85.

Of a compound of formula 85 ¹H 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).

Example 5 (preparation of impurity 851 control)

Triphosgene (14.37 g,99%,47.941mmol,1.45 eq) and 1, 2-dichloroethane (25 mL) were added to a 50mL single-necked round bottom flask and stirred until the triphosgene solid was completely dissolved to give a1, 2-dichloroethane solution of triphosgene.

Into a 100mL three-necked round bottom flask was charged N-methyl-N-benzylformamide (17.98 g,99%,119.310mmol,3.61 eq) and 10mL of 1, 2-dichloroethane, and the mixture was stirred magnetically and a solution of triphosgene in 1, 2-dichloroethane was added dropwise to the reaction flask. And after the dripping is finished, stirring for 30min continuously to obtain the Vilsmeier reagent.

To a Vilsmeier reagent-containing reaction flask were added compound 3 (5.00 g,33.084mmol,1.00 eq) and 1, 2-dichloroethane (5 mL), reacted at room temperature for 2h, and then warmed to 85℃for 1.5h. 7.01g of the reaction solution was quenched with saturated triethylamine (5 mL), and then subjected to column chromatography (dichloromethane/methanol=25:1) to obtain a mixture of compound 85 and impurity 851, and the mixture was subjected to prep-HPLC to obtain 23mg of pale yellow impurity 851 as a solid.

MS (ESI ⁺)：C₂₈H₂₅ClN₁₂,m/z 565.21[M+H]⁺) of a compound of formula 851.

Of compounds of formula 851 ¹H 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).

Example 6

Six single-necked round bottom flasks were taken to prepare triphosgene in 1, 2-dichloroethane.

Triphosgene (2.142 g,99%,7.146mmol,1.08 eq) was added to reaction flask 1';

Triphosgene (2.321 g,99%,7.743mmol,1.17 eq) was added to the reaction flask number 2';

Triphosgene (2.499 g,99%,8.337mmol,1.26 eq) was added to the 3' flask;

Triphosgene (2.678 g,99%,8.934mmol,1.35 eq) was added to the reaction flask No. 4';

triphosgene (2.856 g,99%,9.528mmol,1.44 eq) was added to the 5' flask;

triphosgene (3.570 g,99%,11.910mmol,1.80 eq) was added to the 6' flask.

5ML of 1, 2-dichloroethane is added respectively, and the solution is magnetically stirred until the solid is completely dissolved, thus obtaining the 1, 2-dichloroethane solution of triphosgene.

Six additional three-necked round bottom flasks were taken.

N-methyl-N-benzylformamide (2.991 g,99%,19.847mmol,3.00 eq) was added to a reaction flask No. 1, and N-methyl-N-benzylformamide (3.241 g,99%,21.506mmol,3.25 eq) was added to a reaction flask No. 2;

N-methyl-N-benzylformamide (3.490 g,99%,23.159mmol,3.50 eq) was added to a reaction flask number 3;

N-methyl-N-benzylformamide (3.739 g,99%, 24.81mmol, 3.75 eq) was added to a reaction flask No. 4;

N-methyl-N-benzylformamide (3.989 g,99%,26.470mmol,4.00 eq) was added to a reaction flask No. 5;

N-methyl-N-benzylformamide (4.986 g,99%,33.086mmol,5.00 eq) was added to a reaction flask No. 6.

5ML of 1, 2-dichloroethane was added separately. Into a three-necked round bottom flask was added dropwise a solution of triphosgene in 1, 2-dichloroethane. The total time of the dropwise addition is 30min. And (5) continuously stirring for 30min after the dripping is finished, thus preparing the Vilsmeier reagent.

To a three-necked round bottom flask 1-6 was added compound 3 (1.000 g, 6.611 mmol,1.00 eq) and 10mL of 1, 2-dichloroethane with mechanical stirring. 85 ℃. The Area percentages (Area) of compound 84, compound 85 and impurity 851 in the above 6 reactions were compared, and the major impurity peaks were subtracted for ease of comparison, as shown in the following table:

preferably, the molar ratio E1 of 3 to Vilsmeier reagent 24 is greater than 1:4.00eq, and the reaction of intermediate 84 is substantially complete.

Example 7

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

N-methyl-N-benzylformamide (39.89 g,99%,264.698mmol,4.00 eq) and 20mL of 1, 2-dichloroethane are added to a 250mL round bottom flask, mechanically stirred well and a fresh solution of triphosgene in 1, 2-dichloroethane is added dropwise. And (5) continuously stirring for 30min after the dripping is finished, thus preparing the Vilsmeier reagent.

To a reaction flask containing Vilsmeier reagent was directly added compound 3 (10.00 g,66.168mmol,1.00 eq) and 1, 2-dichloroethane 150mL, mechanically stirred. The reaction solution was divided into 5 parts and transferred to 50mL reaction bottles, respectively. 4 parts of the mixture are taken and respectively placed in 85 ℃, 60 ℃, 40 ℃ and 20 ℃ for reaction. The reaction solution was sampled at different time points and subjected to HPLC detection. Comparing the Area percentages (Area) of compound 84, compound 85 and impurity 851 in the 7 reactions described above, the major impurity peaks were subtracted for ease of comparison, as shown in the following table:

the reaction temperature T1 is preferably 20 to 40 ℃, and the amount of impurities 851 is small.

Example 8

Nine single-necked round bottom flasks, 1'-9' were each charged with triphosgene (2.856 g,99%,9.528mmol,1.44 eq) and the following different solvents were each charged:

Ethyl acetate (3 mL) was added to a reaction flask 1';

toluene (3 mL) was added to a reaction flask No. 2';

dichloromethane (3 mL) was added to the reaction flask 3';

Acetone (3 mL) was added to the reaction flask No. 4';

cyclohexane (3 mL) was added to the reaction flask 5';

1, 2-dichloroethane (3 mL) was added to a reaction flask No. 6';

Acetonitrile (3 mL) was added to a reaction flask No. 7';

Tetrahydrofuran (3 mL) was added to the reaction flask number 8';

1, 4-Dioxa-hexacyclic ring (3 mL) was added to the reaction flask 9'.

Stirring the mixture in a No. 1'-9' bottle until solid solution is clear (except cyclohexane and acetonitrile), and preparing triphosgene solution.

Nine additional three-necked round bottom flasks were charged with N-methyl-N-benzylformamide (3.989 g,99%,26.470mmol,4.00 eq), respectively, with the following different solvents:

Ethyl acetate (2 mL) was added to a reaction flask No. 1;

toluene (2 mL) was added to a reaction flask No. 2;

Dichloromethane (2 mL) was added to reaction flask No. 3;

acetone (2 mL) was added to a reaction flask No. 4;

cyclohexane (2 mL) was added to reaction flask number 5;

1, 2-dichloroethane (2 mL) was added to a reaction flask No. 6;

acetonitrile (2 mL) was added to a reaction flask No. 7;

tetrahydrofuran (2 mL) was added to a reaction flask number 8;

1, 4-Dioxa-hexacyclic ring (2 mL) was added to reaction flask 9.

Stirring the mixture in a No. 1-9 bottle until the solid is dissolved (except cyclohexane) to obtain the N-methyl-N-benzyl formamide solution.

The triphosgene solutions of the corresponding solvents (1 '-9' bottles) were added dropwise to the 1-9 bottles, respectively. And (5) continuously stirring for 30min after the dripping is finished, thus obtaining the Vilsmeier reagent.

To each of flasks No. 1-9 containing Vilsmeier reagent was added Compound 3 (1.000 g, 6.611 mmol,1.00 eq), and each of flasks No. 1-9 was charged ethyl acetate (15 mL), toluene (15 mL), methylene chloride (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). Mechanically stirring, and reacting for 24h at the external temperature of 40 ℃ in an oil bath. The reaction solutions were collected from flasks 1 to 9, and subjected to HPLC detection to calculate the Area percentages (Area%, for comparison, and peak deduction) of the compound 84, the compound 85, and the impurity 851 in the above reaction, as shown in the following table:

^a The reaction solution showed solid caking and the experiment was terminated. ^b The reaction did not detect the formation of intermediate 85.

Substantially half of intermediate 84 in acetonitrile solvent is unreacted and other unknown impurities are formed. The amount of impurities 851 is minimized, and the preferred reaction solvent S is methylene chloride, 1, 2-dichloroethane, depending on the minimal residual amount of intermediate 84.

Example 9

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

Into a 2L four-necked round bottom flask was charged N-methyl-N-benzylformamide (204.42 g,99%,4.10eq,1356.470 mmol) and 200mL of dichloromethane, and after mechanical stirring was complete, a solution of triphosgene in dichloromethane was added dropwise. After the completion of the dropwise addition, stirring was continued for 30 minutes to obtain a Vilsmeier reagent.

To a Vilsmeier reagent reaction flask were added compound 3 (50.00 g,1.00eq,330.841 mmol) and 250mL of methylene chloride, and after stirring at room temperature for 2 hours, the reaction was continued at 40℃for 44 hours (impurity: 851 area% in the reaction solution: 3.72%, and peak was subtracted).

The reaction solution was poured into 2L of saturated NaHCO ₃ solution, and the organic phase was recovered by extraction. After stirring the organic phase Yu Bing in a bath for 1h, suction filtration and filter cake drying are carried out, so as to obtain 100.17g of light yellow compound 85 solid crude product, and the crude product yield is 100.7%. The filtrate 1 contained N-methyl-N-benzylformamide and N-methylbenzylamine (recovered for use).

To a 500mL three-necked round bottom flask was added 100.17g of crude compound 85, 500mL of dichloromethane, and after beating at 40℃for 1h, suction filtration was performed, and the filter cake was dried to obtain 97.71g of pale yellow solid compound 85, with a yield of 97.5%. Filtrate 2 was combined with filtrate 1 (recovered for later use).

The overall yield of the two-step reaction to prepare compound 85 from guanine (3) was 98.2% (100.7% ×97.5%).

97.71G of pale yellow solid of compound 85, 2.5L of 5% HCl solution, and stirring at 70℃were added to the 5L beaker and reacted for 34 hours. After the reaction was completed, the mixture was cooled by adding an ice-water bath, and a 40% NaOH solution was added dropwise to adjust ph=10. The aqueous phase was recovered by washing with dichloromethane (3 times each with 400 mL). Dichloromethane wash and filtrate 2 were combined with filtrate 1. 10.0g of active carbon is added into the water phase and stirred for 30min. Filtering, adding 400mL of acetone into the filtrate, dropwise adding 36% HCl solution until the pH value is neutral, filtering, washing a filter cake with 800mL of deionized water, and drying to obtain 45.10g of a white solid of the compound 1, wherein the yield is 81.9% and the HPLC purity is 99.20% (the area% of the impurity 71 is 0.02%)

The total yield of the reaction for producing 2-amino-6-chloropurine (1) from compound 85 was 81.9%.

The total yield of the reaction for producing 2-amino-6-chloropurine (1) from guanine (3) was 80.4% (98.2%. Times.81.9%).

N-methylbenzylamine was recovered by combining the dichloromethane washes with filtrate 2 and filtrate 1 and recovering the solvent dichloromethane under reduced pressure. The residue was added with 1000mL of water and 87.5mL of concentrated hydrochloric acid, and the mixture was refluxed for 6 hours. The reaction solution was washed twice with 300ml of methylene chloride. Dichloromethane 500mL was added and a 40% sodium hydroxide solution was added dropwise to adjust the pH to 10. The mixture was separated, and the aqueous layer was extracted 2 times with 100ml of dichloromethane. The dichloromethane layers were combined, dried over magnesium sulfate, filtered and the solvent was distilled off to give 137.98g of N-methylbenzylamine as a brown oil, which was recovered at 83.9%.

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

¹H NMR：(600MHz,DMSO-d₆) Δ12.89 (s, 1H), 8.13 (s, 1H), 6.79 (s, 2H) of the compound of formula 1.

HPLC method (preparation 85) Vanquish Core high performance liquid chromatograph (Thermo Fisher), chromatographic column Thermo Syncronis C18.6X250 mM 5 μm, detector DAD (detection wavelength: 210 nm), column temperature: 30 ℃ C., flow rate: 1.0ml/min, mobile phase A:10mM KH ₂PO₄ 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％; dilution: acetonitrile, sample introduction amount: 1 μl. Retention time was 84:20.463min, 85:23.177min, impurity 851:31.417min. HPLC method (85 preparation 1) Thermo flash Core high performance liquid chromatograph (Thermo Fisher), chromatographic column, thermo FISHER HYPERSIL GOLD ^TM C18.6X105 mm 5 μm, detector DAD (detection wavelength: 210 nm), column temperature: 30 ℃, flow rate: 1.0ml/min, mobile phase A:0.04% H ₃PO₄ aqueous solution, mobile phase B:0.04% H ₃PO₄ acetonitrile solution, gradient elution: 0-5min, B:5%,5-25min, B: 5%. Fwdarw.85%, 25-35min, B:85%,35-35.1min, B: 85%. Fwdarw.5%, 35.1-40min, B:5%, diluent: acetonitrile, sample injection amount: 1 μl. Retention time was 1:10.893min, 71:14.0070min.

All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims

1. A process for the preparation of 2-amino-6-chloropurine (1), said process having the reaction formula:

the method comprises the following steps:

2. The method of claim 1, wherein in step 2), the compound of formula 84 is reacted with a Vilsmeier reagent (compound of formula 24) to provide a compound of formula 85 and a compound 851,

Preferably, the content of said compound 851 is <4.0%.

3. A process for preparing a high purity N-methyl-N-benzyl-N' - (6-chloro-6, 9-dihydro-1H-purin-2-yl) formamidine compound of formula 85, said process having the reaction formula:

the method comprises the following steps:

4. A process according to claim 3, wherein in step 2) the compound of formula 84 is reacted with a Vilsmeier reagent (compound of formula 24) to give a compound of formula 85 and a compound 851

Preferably, the content of said compound 851 is <4.0%.

5. The compound represented by the formula 84,

6. The compound represented by the formula 85,

7. Compounds of formula 851 shown below

8. The compound represented by formula 71 shown below

9. The application of the compound shown in the formula 84 or the formula 85 is used for preparing an intermediate 2-amino-6-chloropurine (1) of the purine antiviral drug.

10. The application of the compound shown in the formula 851 or 71 is used as a standard substance for quality detection or quality control in the preparation process of a purine antiviral drug intermediate 2-amino-6-chloropurine (1).