Method for synthesizing 4-chloropyrrolopyrimidine compound or derivative thereof

Abstract

Disclosed in the present invention is a method for synthesizing a 4-chloropyrrolopyrimidine compound or a derivative thereof, comprising the following steps: reacting an alkylene oxide compound with a cyanoacetate compound by taking an alkaline substance as a catalyst to generate intermediate 1, and further carrying out ring closure to obtain intermediate 2; by taking an alkaline substance as a catalyst, reacting a formamidine acetate compound with intermediates 1 and 2 by using a one-pot method to obtain a 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol compound; further by using the one-pot method, using an oxidizing agent to oxidize the 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol compound into an aldehyde compound, and then further carrying out ring closure to obtain a 4-hydroxypyrrolopyrimidine compound; and adding an organic alkali for a chlorination reaction between the 4-hydroxypyrrolopyrimidine compound and phosphorus oxychloride to obtain the 4-chloropyrrolopyrimidine compound. In the present invention, the 4-chloropyrrolopyrimidine compound is synthesized by using a novel synthesis strategy, and the synthesis has a simple operation, cost effective raw materials, and a relatively high yield and is suitable for large-scale production in factories.

Description

A method for synthesizing 4-chloropyrrolopyrimidine compounds or their derivatives Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry technology, and in particular to a method for synthesizing 4-chloropyrrolopyrimidine compounds or derivatives thereof. The method includes a method for synthesizing intermediates 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol compounds or derivatives thereof, and a method for synthesizing 4-hydroxypyrrolopyrimidine compounds or derivatives thereof. Background Art

[0002] 4-Chloropyrrolopyrimidine is an important intermediate for many drugs such as tofacitinib, ruxolitinib, and baricitinib, and is widely used in the pharmaceutical field. Currently disclosed synthesis processes for 4-chloropyrrolopyrimidine compounds include:

[0003] Method 1: 4-chloropyrrolopyrimidine (US2010190981) is prepared using 4,6-dihydroxypyrimidine as a raw material, as shown in Formula 1. This synthesis process is long, the starting materials are expensive, the raw material utilization rate is low, and the overall yield is low.

[0004] Method 2: 4-chloropyrrolopyrimidine (PCT2010014930) was prepared using ethyl cyanoacetate as a starting material, as shown in Formula 2. This synthetic route is lengthy, and the mercapto-methylenediamine used is highly irritating. Furthermore, the hydrogenation reduction reaction is hazardous and expensive, making it unsuitable for large-scale production.

[0005] Method 3: Using ethyl cyanoacetate, 2-bromomethyl-1,3-dioxolane, and formamidine acetate as raw materials, 4-chloropyrrolopyrimidine (CN105622616A) is obtained through a three-step reaction process consisting of α-alkylation, ring closure, and chlorination, as shown in Formula 3. This route is prone to the formation of bimolecular impurities, and the α-alkylation yield is relatively low. In addition, the main raw material, 2-bromomethyl-1,3-dioxolane, is expensive, resulting in high costs.

[0006] Since the existing preparation methods of 4-chloropyrrolopyrimidine all have certain defects, the development of new synthesis methods and process improvements for 4-chloropyrrolopyrimidine is of great significance and application value.

[0007] Summary of the Invention

[0008] To overcome the problems existing in the prior art, the present invention, through extensive and in-depth research, provides a synthesis process for 4-chloropyrrolopyrimidine compounds or their derivatives. The preparation of the intermediate 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol compound is a newly developed process synthesis route. This synthesis method significantly improves overall yield, reduces production costs, increases raw material utilization, and avoids some hazardous reactions, facilitating large-scale industrial application.

[0009] The synthetic route of the 4-chloropyrrolopyrimidine compound or its derivatives in the present invention is as follows:

[0010] The synthesis steps include: using an alkaline substance as a catalyst to "extract hydrogen" from a cyanoacetic acid ester compound, so that the alkylene oxide compound as a raw material is ring-opened and reacts with the cyanoacetic acid ester to obtain intermediate 1, and then ring-closing to obtain intermediate 2; using an alkaline substance as a catalyst to react methylimidazolium acetate compounds with intermediates 1 and 2 to obtain intermediate 3 (6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol compound) in a one-pot process; using an oxidant to oxidize intermediate 3 to an aldehyde in a one-pot process, and further ring-closing to obtain intermediate 4; adding an organic base as an acid-binding agent to cause intermediate 4 to undergo a chlorination reaction with phosphorus oxychloride to obtain a 4-chloropyrrolopyrimidine compound.

[0011] To achieve the above object, the present invention adopts the following technical solutions:

[0012] The first aspect of the present invention is to provide a 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol compound or a derivative thereof, wherein the structural formula of the compound is shown in Formula III:

[0013] wherein R2 is selected from the group consisting of hydrogen (H), methyl (Me), and ethyl (Et);

[0014] R3 is selected from the group consisting of hydrogen (H), methyl (Me), amino (NH2), and hydroxyl (OH).

[0015] Furthermore, the above compounds also include intermediates for preparing 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol compounds or their derivatives, and products prepared from 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol compounds or their derivatives. The intermediates include compounds of formula I and formula II, and their specific structures are shown below:

[0016] wherein R1 is selected from the group consisting of methyl (Me), ethyl (Et), methylsulfonyl (Ms), p-toluenesulfonyl (Ts), and propyl (Pr);

[0017] R2 is selected from the group consisting of hydrogen (H), methyl (Me), and ethyl (Et).

[0018] The second aspect of the present invention is a method for preparing a 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol compound or a derivative thereof, which comprises:

[0019] Step S1, using a basic substance as a catalyst, reacting an alkylene oxide compound with a cyanoacetate compound to obtain a compound of formula I, and then performing a ring-closure reaction on the compound of formula I to obtain a compound of formula II;

[0020] Step S2, using a basic substance as a catalyst, reacting the methylimidazole acetate compound with the compound of formula I and the compound of formula II in a one-pot reaction to obtain a compound of formula III, wherein the compound of formula III is a 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol compound;

[0021] The structural formulas of the alkylene oxide compound, cyanoacetate compound, compound of formula I, compound of formula II, methylimidazolium acetate compound, and compound of formula III are shown below in order:

[0022] R1 is selected from the group consisting of methyl (Me), ethyl (Et), methylsulfonyl (Ms), p-toluenesulfonyl (Ts), and propyl (Pr);

[0023] R2 is selected from the group consisting of hydrogen (H), methyl (Me), and ethyl (Et);

[0024] R3 is selected from the group consisting of hydrogen (H), methyl (Me), amino (NH2), and hydroxyl (OH).

[0025] Furthermore, in a specific embodiment, preferably R1 is ethyl (Et), R2 is hydrogen (H), and R3 is hydrogen (H).

[0026] Furthermore, the reaction mechanism of the above reaction is as follows:

[0027] Furthermore, the molar ratio of the cyanoacetate compound, the alkylene oxide compound, the formamidine acetate compound, and the alkaline substance (calculated as their solution, for example, the alkaline substance is sodium ethoxide, which is added in the form of a sodium ethoxide solution) is 1:1-1.87: 1-2.14: 1-9.2. Specifically, the molar ratio of the alkaline substance in step S1 to the alkaline substance in step S2 is 1:1-3, for example, 1:1-1.5, 1:2.2-3.0, etc. More preferably, the molar ratio of the cyanoacetate compound, the alkylene oxide compound, the formamidine acetate compound, the alkaline substance in step S1, and the alkaline substance in step S2 is 1:1-1.26:1-1.25:1-1.05:1-2.67, and more preferably the molar ratio is 1:1.26:1.25:1.05:2.67.

[0028] Furthermore, the reaction temperature of step S1 and step S2 is 45-80°C, and the total reaction time is 16-26 hours; preferably, the total reaction time is 20-26 hours, 18-22 hours, 16-20 hours, 16-19 hours, etc. Specifically, the reaction temperature of step S1 is 30-50°C, and the reaction time is 2-12 hours; the reaction temperature of step S2 is 60-80°C, and the reaction time is 12-16 hours. In a specific embodiment, an alkaline substance is added to a cyanoacetic acid ester compound and stirred at room temperature for 1-1.5 hours, an alkylene oxide compound is added under ice bath conditions, the temperature is raised to 45°C and the reaction is kept warm for 1 hour, the formamidine acetate compound and the alkaline substance are added, the temperature is raised to 60°C, the reaction is kept warm for 30 minutes, the temperature is raised to 80°C, and the reaction is kept warm for 12 hours.

[0029] Furthermore, the alkylene oxide compound is added in the form of a mixed solution, which is dissolved in one or more of n-heptane and tetrahydrofuran to form the mixed solution.

[0030] Furthermore, the alkaline substance is selected from one or more of sodium ethoxide, sodium methoxide, potassium tert-butoxide, sodium hydride, n-butyl lithium, sodium hydroxide, and potassium hydroxide; preferably, the alkaline substance is sodium ethoxide.

[0031] Furthermore, the reactions of step S1 and step S2 are carried out in a first solvent, wherein the first solvent is selected from one or more of sodium ethoxide solution, tetrahydrofuran, and sodium methoxide solution. The sodium ethoxide solution is an ethanol solution of sodium ethoxide, and the sodium methoxide solution is a methanol solution of sodium methoxide. Preferably, the first solvent is a sodium ethoxide solution or a sodium methoxide solution, and the sodium ethoxide or sodium methoxide contained therein can be used as the alkaline substance. The purity of the sodium ethoxide solution or the sodium methoxide solution is 15-30%, preferably 20%.

[0032] Furthermore, in a specific embodiment, it is preferred that the alkylene oxide compound is propylene oxide, the cyanoacetate compound is ethyl cyanoacetate, and the formamidine acetate compound is formamidine acetate.

[0033] Furthermore, after the reaction in step S2 is completed, subsequent treatment steps are performed for purification. In a specific embodiment, the steps are as follows: after the reaction is completed, the pH is adjusted to 2-3, ethanol is concentrated under reduced pressure, water is added to dissolve, and the aqueous phase is extracted with EA, the pH is adjusted to 6-7, and the mixture is stirred in an ice bath for 2-3 hours to precipitate the solid and filter it. The above steps can be replaced by conventional treatment steps in the art.

[0034] The third aspect of the present invention is to provide a method for preparing a pyrrolopyrimidine compound or a derivative thereof, which uses a 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol compound or a derivative thereof as a raw material and obtains the pyrrolopyrimidine compound or a derivative thereof through further reaction;

[0035] Wherein, the 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol compound is any compound of formula III described in the first aspect of the present invention, or is prepared by any preparation method described in the second aspect of the present invention (i.e., using the above steps S1 and S2);

[0036] The pyrrolopyrimidine compound is selected from 4-hydroxypyrrolopyrimidine compounds or derivatives thereof, 4-chloropyrrolopyrimidine compounds or derivatives thereof;

[0037] The structural formula of the 4-hydroxypyrrolopyrimidine compound is:

[0038] The structural formula of the 4-chloropyrrolopyrimidine compound is:

[0039] Furthermore, when preparing 4-hydroxypyrrolopyrimidine compounds or derivatives thereof, the preparation method includes:

[0040] Step S3: using an oxidizing agent to oxidize the 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol compound or its derivative into an aldehyde through a one-pot reaction, and further performing a ring-closure reaction to obtain a 4-hydroxypyrrolopyrimidine compound or its derivative.

[0041] Furthermore, the reaction mechanism of the above reaction is as follows:

[0042] Furthermore, the molar ratio of the 6-amino-5-(2-hydroxyethyl)pyrimidine-4-ol compound or its derivative to the oxidant is 1:1-3; preferably the molar ratio is 1:1-1.5 or 1:1.5-3, and more preferably the molar ratio is 1:1.5.

[0043] Furthermore, the oxidant is selected from one or more of pyridinium chlorochromate (PCC), Dess-Martin oxidant, Jones reagent, pyridine sulfur trioxid, hydrogen peroxide (H2O2), manganese dioxide (MnO2), sodium tungstate (NaWO4), tetramethylpiperidinium oxide (Tempo), diacetoxyiodobenzene (IBD), and sodium hypochlorite (NaClO). Preferably, the oxidant is PCC oxidant, Dess-Martin oxidant, or H2O2.

[0044] Furthermore, the reaction in step S3 is carried out in a second solvent, and the second solvent is selected from one or more of dichloromethane, water, acetone, and 1,4-dioxane; preferably, the second solvent is dichloromethane or 1,4-dioxane.

[0045] Furthermore, the reaction temperature of step S3 is 20-30°C, and the reaction time is 0.5-3 hours. Preferably, the reaction time is 0.5-1 hour, 1-2 hours, 1-3 hours, etc. In a specific embodiment, 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol is preferably mixed with PCC oxidant and dichloromethane and reacted at room temperature for 1-2 hours.

[0046] Furthermore, after the reaction in step S3 is completed, subsequent treatment steps are performed for purification. In a specific embodiment, the subsequent treatment steps are: adjusting the pH to 2-3, stirring at room temperature for 1 hour, and filtering the precipitated solid. The above steps can be replaced by conventional treatment steps in the art.

[0047] Furthermore, the above preparation method further comprises step S4, wherein the 4-hydroxypyrrolopyrimidine compound or its derivative is further reacted to prepare a 4-chloropyrrolopyrimidine compound or its derivative.

[0048] Furthermore, step S4 specifically includes: adding an organic base as an acid-binding agent to chlorinate the 4-hydroxypyrrolopyrimidine compound or its derivative with phosphorus oxychloride to obtain a 4-chloropyrrolopyrimidine compound or its derivative. It is understood that this step can be replaced by other conventional methods in the art, for example, chlorinating 4-hydroxypyrrolopyrimidine with bis(trichloromethyl) carbonate under the catalysis of an organic base to obtain 4-chloropyrrolopyrimidine.

[0049] Furthermore, the molar ratio of the organic base, phosphorus oxychloride and 4-hydroxypyrrolopyrimidine compound or its derivative is 1-2:1-2.5:1; the preferred molar ratio is 1-2:1-2.5:1, 1-1.2:1-1.5:1, 1.2-2.5:1.5-2.7:1, etc.; the more preferred molar ratio is 1.2:1.5:1.

[0050] Furthermore, the organic base is at least one of N,N-diisopropylethylamine (DIPEA) and triethylamine, and preferably the organic base is DIPEA.

[0051] Furthermore, the reaction in step S4 is carried out in a third solvent, and the third solvent is toluene.

[0052] Furthermore, the reaction temperature of step S4 is 50-60°C, and the reaction time is 6-10 hours. Preferably, the reaction time is 6-7 hours, 7-8 hours, 8-10 hours, etc. In a specific embodiment, 4-hydroxypyrrolopyrimidine is preferably added toluene and DIPEA, and then phosphorus oxychloride is added, heated to 60°C, and stirred for 6-7 hours.

[0053] Further, after the reaction in step S4 is completed, a subsequent treatment step is used for purification. In a specific embodiment, the reaction solution is slowly added dropwise to ice water under ice-water bath conditions, the pH is slowly adjusted to 5-6, and the filtered solid is washed with water and dried; water is added to the dried solid and stirred, filtered, ethyl acetate is added to the filter cake, and heated to 60-70°C, and stirred until basically dissolved, activated carbon is added and continued to heat, and then the organic phase is filtered and concentrated under reduced pressure. The concentrated solution is heated to 60-70°C, stirred for 1 hour, and then naturally cooled to room temperature, cooled to 0-5°C with an ice-water bath for crystallization, filtered, washed with ethyl acetate, and dried to obtain an off-white solid. The above can be replaced with conventional treatment steps in the art.

[0054] Compared with the prior art, the present invention adopts the above technical solution to achieve the following beneficial effects:

[0055] The present invention adopts a brand-new synthetic concept to prepare 4-chloropyrrolopyrimidine compounds or their derivatives. It discloses for the first time the reaction steps of using an alkylene oxide compound to open the ring and react with a cyanoacetic acid ester compound to generate intermediates 1 and 2, preparing intermediate 3 in a one-pot method, and oxidizing intermediate 3 to an aldehyde and further ring-closing to generate intermediate 4. The above method involves the synthesis of new compounds during the synthesis process, and has simple operation, cheap raw materials, high yield, and is suitable for large-scale production in factories. DETAILED DESCRIPTION

[0056] The following examples clearly and completely describe the technical solutions in the embodiments of the present invention. It should be understood that the described embodiments are only some of the embodiments of the present invention, and are not exhaustive. All other embodiments obtained by persons of ordinary skill in the art based on the embodiments of the present invention without inventive effort are intended to fall within the scope of protection of the present invention. Experimental methods in the following examples, where specific conditions are not specified, are generally measured in accordance with national standards. Experimental materials in the following examples, where no source is indicated, are commercially available. The equipment used in each step of the following examples is conventional. Where applicable, national standards are not available, procedures are performed in accordance with generally accepted international standards, conventional conditions, or the conditions recommended by the manufacturer. Unless otherwise specified, all parts are by weight, and all percentages are by mass. Unless otherwise defined or indicated, all technical and scientific terms used in this invention have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein may be applied to the methods of the present invention. It should be noted that, where not in conflict, the features of the embodiments and examples of the present invention may be combined. The present invention is further described below with reference to specific examples, but is not intended to be limiting of the invention.

[0057] Example 1-6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol compound or its derivatives synthesis method 1

[0058] This embodiment provides a preferred method for synthesizing 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol compounds, comprising the steps of: adding 67.77 g (185.68 mmol / 20% purity) of sodium ethoxide solution to a four-necked flask, slowly adding dropwise 20.0 g (176.82 mmol) of ethyl cyanoacetate in an ice bath, stirring at room temperature for 1 to 1.5 hours, then slowly adding dropwise 39.99 g (224.05 mmol, 5 mol / L) of propylene oxide solution in an ice bath, heating to 45° C. and incubating for 1 hour to obtain intermediates 1 and 2; and adding 23.04 g (221.03 mmol) of methylimidazole acetate and 162.16 g (472.16 mmol / 20% purity) of sodium ethoxide solution to the reaction flask, heating to 60° C. and incubating for 30 minutes, then heating to 80° C. and incubating for 12 hours. After the reaction, the pH was adjusted to 2-3 with HCl, the ethanol was concentrated under reduced pressure, dissolved in water, and extracted three times with EA to obtain the aqueous phase. The pH was adjusted to 6-7 with aqueous ammonia, and the mixture was stirred in an ice bath for 2-3 hours. The precipitated solid was filtered to obtain 18.46 g (theoretical yield: 27.43 g) of the product, 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol, with a yield of 67.32%. 1H NMR (400MHz, DMSO-d6) δ11.69(s,1H),7.73(s,1H),6.25(s,2H),4.08(s,1H),3.44-3.41(m,2H),2.48-2.45(m,2H).

[0059] Example 2-6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol compound or its derivatives synthesis method 2

[0060] This embodiment is a preferred method for synthesizing 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol compounds, which includes the following steps: adding 53.79 g (185.68 mmol / 20% purity) of a methanol solution of sodium methoxide to a four-necked flask, slowly adding dropwise 20.0 g (176.82 mmol) of ethyl cyanoacetate in an ice bath, stirring at room temperature for 1 to 1.5 hours, then slowly adding dropwise 39.99 g (224.05 mmol, 5 mol / L) of a propylene oxide solution in an ice bath, heating the mixture to 45° C. and incubating the mixture for 1 hour to obtain intermediates 1 and 2; adding 23.04 g (221.03 mmol) of methylimidazole acetate and 128.73 g (472.16 mmol / 20% purity) of a methanol solution of sodium methoxide to the reaction flask, heating the mixture to 60° C. and incubating the mixture for 30 minutes, then heating the mixture to 80° C. and incubating the mixture for 12 hours. After the reaction, the pH was adjusted to 2-3 with HCl, the ethanol was concentrated under reduced pressure, dissolved in water, and extracted three times with EA to obtain the aqueous phase. The pH was adjusted to 6-7 with aqueous ammonia, and the mixture was stirred in an ice bath for 2-3 hours. The precipitated solid was filtered to obtain 16.34 g (theoretical yield: 27.43 g) of the product, 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol, in a yield of 59.59%. 1 H NMR (400MHz, DMSO-d6) δ11.69(s,1H),7.73(s,1H),6.25(s,2H),4.08(s,1H),3.44-3.41(m,2H),2.48-2.45(m,2H).

[0061] Example 3-Synthesis of 4-hydroxypyrrolopyrimidine compounds or their derivatives 1

[0062] This embodiment is a preferred method for synthesizing 4-hydroxypyrrolopyrimidine compounds, which includes the following steps:

[0063] Prepare 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol using the steps described in Example 1 or Example 2;

[0064] 2.0 g (12.89 mmol) of 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol, 4.17 g (19.34 mmol) of PCC oxidant, and 14.0 g of dichloromethane were added to a reaction flask under nitrogen atmosphere and allowed to react at room temperature for 1-2 hours. HCl was added to adjust the pH to 2-3 and the mixture was stirred at room temperature for 1 hour. The precipitated solid was filtered to obtain 0.74 g of the product, 4-hydroxypyrrolopyrimidine (theoretical product: 1.74 g), in a yield of 42.36%. 1 H NMR (400MHz, DMSO-d6) δ7.82(s,1H),7.04(dd,1H),6.45(dd,1H).

[0065] Example 4-Synthesis of 4-Hydroxypyrrolopyrimidine compounds or their derivatives 2

[0066] This embodiment is a preferred method for synthesizing 4-hydroxypyrrolopyrimidine compounds, which includes the following steps:

[0067] Prepare 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol using the steps described in Example 1 or Example 2;

[0068] 2.0 g (12.89 mmol) of 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol, 8.20 g (19.34 mmol) of Dess-Martin oxidant, and 14.0 g of dichloromethane were added to a reaction flask under nitrogen atmosphere and allowed to react at room temperature for 1-2 hours. HCl was added to adjust the pH to 2-3 and the mixture was stirred at room temperature for 1 hour. The precipitated solid was filtered to obtain 0.68 g (theoretical product: 1.74 g) of 4-hydroxypyrrolopyrimidine, a yield of 39.08%. 1 H NMR (400MHz, DMSO-d6) δ7.82(s,1H),7.04(dd,1H),6.45(dd,1H).

[0069] Example 5-4-Hydroxypyrrolopyrimidine compound or its derivatives synthesis method 3

[0070] This embodiment is a preferred method for synthesizing 4-hydroxypyrrolopyrimidine compounds, which includes the following steps:

[0071] Prepare 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol using the steps described in Example 1 or Example 2;

[0072] 2.0 g (12.89 mmol) of 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol, 2.45 g (19.34 mmol) of H₂O₂ (30% aqueous solution), and 14.0 g of 1,4-dioxane were added to a reaction flask under nitrogen atmosphere and allowed to react at room temperature for 1-2 hours. HCl was added to adjust the pH to 2-3 and the mixture was stirred at room temperature for 1 hour. The precipitated solid was filtered to obtain 0.49 g (theoretical product: 1.74 g) of 4-hydroxypyrrolopyrimidine, a yield of 28.16%. 1 H NMR (400MHz, DMSO-d6) δ7.82(s,1H),7.04(dd,1H),6.45(dd,1H).

[0073] Example 6-4-Chloropyrrolopyrimidine compound and its derivatives synthesis method 1

[0074] This embodiment is a preferred synthetic method for preparing 4-chloropyrrolopyrimidine compounds, comprising the steps of:

[0075] Prepare 4-hydroxypyrrolopyrimidine using the steps described in Example 3, Example 4, or Example 5;

[0076] To 10.0 g (74.01 mmol) of 4-hydroxypyrrolopyrimidine solid, 42.0 g of toluene and 11.48 g (88.81 mmol) of DIPEA were added, and 17.02 g (111.01 mmol) of phosphorus oxychloride was slowly added dropwise in a water bath. The oil bath was slowly heated to 60°C and stirred for 6-7 h. The reaction solution was slowly added dropwise to 100 mL of ice water in an ice-water bath, and then 10% NaOH aqueous solution was slowly added. The pH was slowly adjusted to 5-6. A large amount of brown solid precipitated, which was filtered, washed with water (24 mL*2), and dried. To the dried solid, 30 mL of water was added, stirred, and filtered. 263.0 g of ethyl acetate was added to the filter cake and heated to 60-70 ° C. While stirring until basically dissolved, 1.2 g of activated carbon was added and continued to heat for 1 h. The organic phase was filtered and concentrated under reduced pressure to 3 V. The concentrate was heated to 60-70 ° C. and stirred for 1 h, then naturally cooled to room temperature. It was cooled to 0-5 ° C in an ice water bath for crystallization, filtered, washed with ethyl acetate (0-5 ° C, 10.0 g * 1) and dried to obtain 8.70 g of an off-white solid (theoretical yield 11.37 g) with a yield of 76.50%. 1 H NMR (400MHz, DMSO-d6) δ8.55(s,1H),7.65-7.66(d,1H),6.56-6.57(d,1H).

[0077] Example 7-Synthesis of 4-chloropyrrolopyrimidine compounds and their derivatives 2

[0078] This embodiment is a preferred synthetic method for preparing 4-chloropyrrolopyrimidine compounds, comprising the steps of:

[0079] Prepare 4-hydroxypyrrolopyrimidine using the steps described in Example 3, Example 4, or Example 5;

[0080] To 10.0 g (74.01 mmol) of 4-hydroxypyrrolopyrimidine solid, 42.0 g of toluene and 8.99 g (88.81 mmol) of triethylamine were added, and 17.02 g (111.01 mmol) of phosphorus oxychloride was slowly added dropwise in a water bath. The oil bath was slowly heated to 60°C and stirred for 6-7 h. The reaction solution was slowly added dropwise to 100 mL of ice water in an ice-water bath, and then a 10% aqueous NaOH solution was slowly added. The pH was slowly adjusted to 5-6. A large amount of brown solid precipitated, which was filtered, washed with water (24 mL*2), and dried. To the dried solid, 30 mL of water was added, stirred, and filtered. 263.0 g of ethyl acetate was added to the filter cake and heated to 60-70 ° C. While stirring until basically dissolved, 1.2 g of activated carbon was added and continued to heat for 1 h. The organic phase was filtered and concentrated to 3 V under reduced pressure. The concentrate was heated to 60-70 ° C. and stirred for 1 h, then naturally cooled to room temperature. It was cooled to 0-5 ° C in an ice water bath for crystallization, filtered, washed with ethyl acetate (0-5 ° C, 10.0 g * 1), and dried to obtain 7.96 g of an off-white solid (theoretical yield 11.37 g) with a yield of 70.08%. 1 H NMR (400MHz, DMSO-d6) δ8.55(s,1H),7.65-7.66(d,1H),6.56-6.57(d,1H).

[0081] Example 8 - Alternative Example

[0082] This embodiment is an alternative embodiment for synthesizing 4-chloropyrrolopyrimidine compounds and their derivatives, which includes:

[0083] Step 1) Under the premise that other process conditions and steps are the same as in Example 1, different amounts of cyanoacetic acid ester compounds, alkylene oxide compounds, formamidine acetate compounds and alkaline substances (specifically sodium ethoxide solution), different reaction temperatures, and different reaction times are used to synthesize 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol compounds or their derivatives. The reaction conditions and yields are shown in the following table:

[0084] Step 2) Step 1) was used to prepare 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol compounds or derivatives thereof. Under the same conditions as in Example 3, other process conditions and steps were used, and different amounts of 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol compounds or derivatives thereof, oxidants (specifically PCC oxidants), different reaction temperatures, and different reaction times were used to synthesize 4-hydroxypyrrolopyrimidine compounds or derivatives thereof. The reaction conditions and yields are shown in the following table:

[0085] Step 3) 4-hydroxypyrrolopyrimidine compounds or derivatives thereof were prepared using step 2). Under the same conditions as in Example 6, other process conditions and steps were used, and different amounts of 4-hydroxypyrrolopyrimidine compounds or derivatives thereof, POCl3, and DIPEA were used. Different reaction temperatures and different reaction times were used to synthesize 4-chloropyrrolopyrimidine compounds or derivatives thereof. The yields are shown in the following table:

[0086] As can be seen from the above examples, the synthesis method of 4-chloropyrrolopyrimidine of the present invention is simple to operate, easy to purify, has a high yield, and uses cheap raw materials, which greatly improves the yield of 4-chloropyrrolopyrimidine and greatly reduces the cost.

[0087] While the specific embodiments of the present invention have been described in detail above, these are intended to be exemplary only, and the present invention is not limited thereto. For those skilled in the art, any equivalent modifications and substitutions to the present invention are also within the scope of the present invention. Therefore, any equivalent changes and modifications made without departing from the spirit and scope of the present invention are intended to be encompassed within the scope of the present invention.

Claims

1. A 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol compound or a derivative thereof, characterized in that: The structural formula of the compound is shown in Formula III: wherein R2 is selected from the group consisting of hydrogen, methyl, and ethyl; R3 is selected from the group consisting of hydrogen, methyl, amino, and hydroxy.

2. A method for preparing a 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol compound or a derivative thereof, characterized in that: The preparation method comprises: Step S1: Using a basic substance as a catalyst, an alkylene oxide compound and a cyanoacetate compound are reacted to obtain a compound of formula I, wherein the structural formula of the compound of formula I is: The compound of formula I is subjected to a ring-closure reaction to obtain a compound of formula II, and the structural formula of the compound of formula II is: Step S2: Using a basic substance as a catalyst, reacting the methylimidazole acetate compound with the compound of formula I and the compound of formula II in a one-pot reaction to obtain a compound of formula III, wherein the compound of formula III is a 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol compound, and the structure of the compound of formula III is: Wherein, the structural formula of the alkylene oxide compound is: The structural formula of the cyanoacetate compound is: The structural formula of the methylimidazole acetate compound is: R1 is selected from the group consisting of methyl, ethyl, methylsulfonyl, p-toluenesulfonyl, and propyl; R2 is selected from the group consisting of hydrogen, methyl, and ethyl; R3 is selected from the group consisting of hydrogen, methyl, amino, and hydroxy.

3. The preparation method according to claim 2, characterized in that The molar ratio of the cyanoacetate compound, the alkylene oxide compound, the formamidine acetate compound, and the alkaline substance is 1:1-1.87:1-2.14:1-9.2; And / or, the reaction temperature of step S1 and step S2 is 45-80° C., and the total reaction time is 16-26 h.

4. The preparation method according to claim 2, characterized in that The alkylene oxide compound is added in the form of a mixed solution, which is dissolved in one or more of n-heptane and tetrahydrofuran to form the mixed solution; And / or, the alkaline substance is one or more selected from sodium ethoxide, sodium methoxide, potassium tert-butoxide, sodium hydride, n-butyl lithium, sodium hydroxide, and potassium hydroxide; And / or, the reaction of step S1 and step S2 is carried out in a first solvent, and the first solvent is selected from one or more of sodium ethoxide solution, tetrahydrofuran, and sodium methoxide solution.

5. A method for preparing a pyrrolopyrimidine compound or a derivative thereof, characterized in that: Using 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol compounds or derivatives thereof as raw materials, and further reacting to obtain pyrrolopyrimidine compounds or derivatives thereof; Wherein, the 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol compound is the compound of formula III according to claim 1, or is prepared by the preparation method according to any one of claims 2 to 4; The pyrrolopyrimidine compound is selected from 4-hydroxypyrrolopyrimidine compounds or derivatives thereof, 4-chloropyrrolopyrimidine compounds or derivatives thereof; The structural formula of the 4-hydroxypyrrolopyrimidine compound is: The structural formula of the 4-chloropyrrolopyrimidine compound is:

6. The preparation method according to claim 5, characterized in that When preparing 4-hydroxypyrrolopyrimidine compounds or derivatives thereof, the preparation method includes: Step S3: using an oxidizing agent to oxidize the 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol compound or its derivative into an aldehyde through a one-pot reaction, and further performing a ring-closure reaction to obtain a 4-hydroxypyrrolopyrimidine compound or its derivative.

7. The preparation method according to claim 6, characterized in that The molar ratio of the 6-amino-5-(2-hydroxyethyl)pyrimidine-4-ol compound or its derivative to the oxidant is 1:1-3; and / or, the oxidant is selected from one or more of pyridinium chlorochromate, Dess-Martin periodinane, Jones reagent, pyridinium sulfur trioxide, hydrogen peroxide, manganese dioxide, sodium tungstate, tetramethylpiperidinium oxide, diacetoxyiodobenzene, and sodium hypochlorite; And / or, the reaction in step S3 is carried out in a second solvent, wherein the second solvent is selected from one or more of dichloromethane, water, acetone, and 1,4-dioxane; And / or, the reaction temperature of step S3 is 20-30° C., and the reaction time is 0.5-3 h.

8. The preparation method according to any one of claims 6 to 7, characterized in that The method further comprises step S4, wherein the 4-hydroxypyrrolopyrimidine compound or its derivative is further reacted to prepare a 4-chloropyrrolopyrimidine compound or its derivative.

9. The preparation method according to claim 8, characterized in that The step S4 specifically includes: adding an organic base as an acid-binding agent to carry out a chlorination reaction between the 4-hydroxypyrrolopyrimidine compound or its derivative and phosphorus oxychloride to obtain the 4-chloropyrrolopyrimidine compound or its derivative.

10. The preparation method according to claim 9, characterized in that The molar ratio of the organic base, phosphorus oxychloride and 4-hydroxypyrrolopyrimidine compound or its derivative is 1-2.5:1-2.0:1; And / or, the organic base is at least one of N,N-diisopropylethylamine and triethylamine; And / or, the reaction in step S4 is carried out in a third solvent, wherein the third solvent is toluene; And / or, the reaction temperature of step S4 is 50-60° C., and the reaction time is 6-10 h.

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