Method for synthesizing 4-chloropyrrolopyrimidine analog compounds or their derivatives.

Abstract

This invention discloses a method for synthesizing 4-chloropyrrolopyrimidine analog compounds or derivatives thereof, comprising the following steps: Using an alkaline substance as a catalyst, an alkylene oxide compound and a cyanoacetate compound are reacted to produce intermediate 1, and further cyclized to obtain intermediate 2. Using an alkaline substance as a catalyst, a formamidine acetate compound is reacted with intermediates 1 and 2 to obtain a 6-amino-5-(2-hoseethyl)pyrimidine-4-ol compound using a one-pot method. Continuing the one-pot method, an oxidizing agent is used to oxidize the 6-amino-5-(2-hoseethyl)pyrimidine-4-ol compound to an aldehyde compound, and further cyclized to obtain a 4-chloropyrrolopyrimidine analog compound. An organic alkali is added, and the 4-chloropyrrolopyrimidine analog compound is chlorinated with phosphorus oxychloride to obtain a 4-chloropyrrolopyrimidine analog compound. This invention synthesizes 4-chloropyrrolopyrimidine analog compounds using a novel synthesis method, which is easy to operate, requires few raw materials, and yields high yields, making it suitable for large-scale production in factories.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and particularly to a method for synthesizing 4-chloropyrrolopyrimidine analog compounds or their derivatives. The method includes methods for synthesizing compounds of 6-amino-5-(2-hydroxyethyl)pyrimidine-4-ols and their derivatives, as well as compounds of 4-hydroxypyrrolopyrimidines and their derivatives.

Background Art

[0002] 4-Chloropyrrolopyrimidine analogs are widely used in the pharmaceutical field as important intermediates for many drugs such as tofacitinib, rucotinib, and baricitinib. The currently disclosed synthetic processes for 4-chloropyrrolopyrimidine analog compounds include the following methods.

[0003] Method 1: Synthesizing 4-chloropyrrolopyrimidine analogs using 4,6-dihydroxypyrimidine as a raw material (US2010190981). It is shown as in the following formula 1. This synthetic method has problems such as a long step, a high price of the starting material, low utilization efficiency of the raw material, and a low total yield.

Chemical Formula

[0004] Method 2: Synthesizing 4-chloropyrrolopyrimidine analogs using ethyl cyanate as a raw material (PCT2010014930). It is shown as in the following formula 2. This synthetic method has a long synthetic route, a strong irritation of the used sulfhydryl-methacrylic acid, and at the same time, the addition reaction has a certain risk, a high cost, and is disadvantageous for large-scale production.

Chemical Formula

[0005] Method 3: Using starting materials such as ethyl cyanate, 2-bromomethyl-1,3-dioxypane, and methylacetylhydrodiamine, a 4-chloropyrrolopyrimidine analog (CN105622616A) is obtained through three sequential reactions: α-alkylation, cyclization, and chlorination. This is shown in Equation 3 below. This synthetic route has the problem of easily generating two molecules of impurities and having a relatively low yield of α-alkylation. In addition, the main starting material, 2-bromomethyl-1,3-dioxypane, is expensive, resulting in a high cost. [ka] Existing methods for producing 4-chloropyrrolopyrimidine analogs all have certain drawbacks, so developing new synthesis methods and improving synthesis processes has significant importance and potential applications. [Overview of the project]

[0006] To overcome the limitations of prior art, the present invention provides a newly developed process synthesis route for preparing intermediate 6-amino-5-(2-hoseethyl)pyrimidine-4-ol compounds, through extensive and in-depth research, and offers a synthesis method for 4-chloropyrrolopyrimidine analog compounds or their derivatives. By adopting the above synthesis method, the total yield is significantly improved, production costs are reduced, raw material utilization is increased, several hazardous reactions are avoided, and it is advantageous for large-scale industrial applications.

[0007] The synthetic route for the 4-chloropyrrolopyrimidine analog compound or its derivatives in this invention is shown below: [ka] The synthesis process is as follows: Using an alkaline substance as a catalyst, the cyanate ester compounds are dehydrated to open the ring of the starting epoxy alkane and react with the cyanoacetic acid ester to obtain intermediate 1, and intermediate 2 to close the ring. Using an alkaline substance as a catalyst, the methyl acetate compound is reacted with intermediates 1 and 2 to obtain intermediate 3 (6-amino-5-(2-hydroxyethyl)pyrimidine-4-ol compound) using a one-pot reaction. Using a one-pot reaction, intermediate 3 is oxidized to an aldehyde with an oxidizing agent and then cyclized to obtain intermediate 4. An organic base is added as an acid binder, and intermediate 4 is reacted with phosphorus oxychloride to obtain 4-chloropyrrolopyrimidine.

[0008] To achieve the above objectives, the present invention employs the following technical solutions. A first aspect of the present invention is to provide a 6-amino-5-(2-hydroxyethyl)pyrimidine-4-ol compound or a derivative thereof. The structural formula of this compound is shown in formula III, [ka] Here, R2 is selected from the group of hydrogen (H), methyl (Me), and ethyl (Et). R3 is selected from the groups hydrogen (H), methyl (Me), amino (NH2), and ol (OH).

[0009] Furthermore, the above compounds include intermediates used in the preparation of 6-amino-5-(2-hydroxyethyl)pyrimidine-4-ol compounds or their derivatives, and products prepared from 6-amino-5-(2-hydroxyethyl)pyrimidine-4-ol compounds or their derivatives, the above intermediates include compounds of formula I and compounds of formula II. [ka] Here, R1 is selected from the group consisting of methyl (Me), ethyl (Et), methylsulfonyl (Ms), p-toluenesulfonyl (Ts), and propyl (Pr). R2 is selected from the groups of hydrogen (H), methyl (Me), and ethyl (Et).

[0010] The second aspect of the present invention is to protect a method for producing a 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol compound or a derivative thereof, which comprises reacting an alkylene oxide compound with a cyanoacetate compound using an alkaline substance as a catalyst to obtain a compound of formula I, and subjecting the compound of formula I to a ring-closure reaction to obtain a compound of formula II in step S1; using an alkaline substance as a catalyst and reacting a formamidine acetate compound with the compound of formula I and the compound of formula II in one pot to obtain the compound of formula III, the 6-amino-5-(2-hydroxyethyl)pyrimidin-4-ol compound in step S2, wherein the structural formulas of the above-mentioned alkylene oxide compound, cyanoacetate compound, compound of formula I, compound of formula II, formamidine acetate compound, and compound of formula III are shown sequentially as follows:

Chemical formula

[0013] Furthermore, the molar ratio of the above-mentioned cyanoacetate compound, alkylene oxide compound, formamidine acetate compound, and alkaline substance (calculated based on the solution amount, for example, when sodium ethoxide is used as the alkaline substance, it is added in the form of a sodium ethoxide solution) is 1:1 to 1.87:1 to 2.14:1 to 9.2. Specifically, the molar ratio of the alkaline substance in Step S1 to the alkaline substance in Step S2 is 1:1 to 3, for example, 1:1 to 1.5, 1:2.2 to 3.0, etc. Furthermore, it is more preferable that the molar ratio of the cyanoacetate compound, alkylene oxide compound, formamidine acetate compound, the alkaline substance in Step S1, and the alkaline substance in Step S2 is 1:1 to 1.26:1 to 1.25:1 to 1.05:1 to 2.67, and more preferably, the molar ratio is 1:1.26:1.25:1.05:2.67.

[0014] Furthermore, the reaction temperatures of Step S1 and Step S2 are 45 to 80°C, and the total reaction time is 16 to 26 hours. Preferably, the total reaction time is 20 to 26 hours, 18 to 22 hours, 16 to 20 hours, 16 to 19 hours. Specifically, the reaction temperature of Step S1 is 30 to 50°C, and the reaction time is 2 to 12 hours, and the reaction temperature of Step S2 is 60 to 80°C, and the reaction time is 12 to 16 hours. In a specific embodiment, the alkaline substance is added to the cyanoformamidine compound and stirred at room temperature for 1 to 1.5 hours, the alkylene oxide compound is added under ice bath conditions, heated to 45°C, and reacted for 1 hour. Then, the formamidine acetate compound and the alkaline substance are added, heated to 60°C, and reacted for 30 minutes, and then heated to 80°C and reacted for 12 hours.

[0015] Furthermore, the above-mentioned alkylene oxide compound is added as a mixed solution dissolved in one or more of n-heptane and tetrahydrofuran.

[0016] Furthermore, the alkaline substance is selected from one or more of the following: sodium ethoxide, sodium methoxide, potassium tert-butoxide, sodium hydride, n-butyllithium, sodium hydroxide, and potassium hydroxide, and preferably the alkaline substance is sodium ethoxide.

[0017] Furthermore, the reactions in steps S1 and S2 are carried out in a first solvent, the first solvent being selected from one or more of the following: 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 sodium methoxide solution is 15-30%, preferably 20%.

[0018] Furthermore, in certain embodiments, it is preferable that the alkylene oxide compound is propylene oxide, the cyanoacetate compound is ethyl cyanoacetate, and the formamidine acetate compound is formamidine acetate.

[0019] Furthermore, after the reaction in step S2 is complete, the product is purified using subsequent processing steps. In a particular embodiment, after the reaction is complete, the pH is adjusted to 2-3, the ethanol is concentrated under reduced pressure, water is added to dissolve it, the aqueous phase is extracted with EA, the pH is adjusted to 6-7, the mixture is stirred in an ice bath for 2-3 hours, and the precipitated solid is filtered off. The above can be replaced with conventional processing steps in the art.

[0020] A third aspect of the present invention is to provide a method for producing pyrrolopyrimidine compounds or derivatives thereof, which are obtained by further reactions using 6-amino-5-(2-hydroxyethyl)pyrimidine-4-ol compounds or derivatives thereof as raw materials. Here, the above 6-amino-5-(2-hydroxyethyl)pyrimidine-4-ol compound is a compound of formula III described in any one of the first aspects of the present invention, or is produced by the production method described in any one of the second aspects of the present invention (i.e., steps S1 and S2 above), The above pyrrolopyrimidine compounds are selected from 4-hydroxypyrrolopyrimidine compounds or their derivatives, 4-chloropyrrolopyrimidine compounds or their derivatives, The structural formula of the above 4-hydroxypyrrolopyrimidine compound is, [ka] And, The structural formula of the above 4-chloropyrrolopyrimidine compound is, [ka] That is the case.

[0021] Furthermore, when preparing 4-hydroxypyrrolopyrimidine compounds or their derivatives, the preparation method is as follows: The process includes step S3, in which a 6-amino-5-(2-hydroxyethyl)pyrimidine-4-ol compound or its derivative is oxidized to an aldehyde by a one-pot reaction using an oxidizing agent, and then a ring-closing reaction is carried out to obtain a 4-hydroxypyrrolopyrimidine compound or its derivative.

[0022] Furthermore, the reaction mechanism described above is as follows: [ka] Furthermore, the molar ratio of the above-mentioned 6-amino-5-(2-hydroxyethyl)pyrimidine-4-ol compound or its derivatives to the oxidizing agent is 1:1 to 3, with a preferred molar ratio of 1:1 to 1.5 or 1:1.5 to 3, and a more preferred molar ratio of 1:1.5.

[0023] Furthermore, the oxidizing agent is selected from one or more of the following: pyridinium chlorochromate (PCC), Dess-Martin oxidizing agent, Jones reagent, pyridine sulfur trioxid, hydrogen peroxide (H2O2), manganese dioxide (MnO2), sodium tungstate (NaWO4), tetramethylpiperidine oxide (Tempo), diacetoxyiodobenzene (IBD), and sodium hypochlorite (NaClO). Preferably, the oxidizing agent is PCC oxidizing agent, Dess-Martin oxidizing agent, or H2O2.

[0024] Furthermore, the reaction in step S3 is carried out in a second solvent, the second solvent being selected from one or more of dichloromethane, water, acetone, and 1,4-dioxane, preferably the second solvent being dichloromethane or 1,4-dioxane.

[0025] Furthermore, the reaction temperature in step S3 is 20-30°C, and the reaction time is 0.5-3 hours. Preferred reaction times are 0.5-1 hour, 1-2 hours, 1-3 hours, etc. In certain embodiments, it is preferable to mix 6-amino-5-(2-hydroxyethyl)pyrimidine-4-ol, the PCC oxidizing agent, and dichloromethane and react them at room temperature for 1-2 hours.

[0026] Furthermore, after the reaction in step S3 is complete, the product is purified using a subsequent processing step, which in a particular embodiment involves adjusting the pH to 2-3, stirring at room temperature for 1 hour, and filtering the precipitated solid. The above can be replaced with conventional processing steps in the art.

[0027] Furthermore, the above manufacturing method also includes step S4, which involves further reacting a 4-hydroxypyrrolopyrimidine compound or its derivatives to produce a 4-chloropyrrolopyrimidine compound or its derivatives.

[0028] Furthermore, step S4 described above specifically includes a process of adding an organic base as an acid binder and chlorinating the 4-hydroxypyrrolopyrimidine compound or its derivative with phosphorus oxychloride to obtain a 4-chloropyrrolopyrimidine compound or its derivative. It is understood that this process can be replaced by conventional methods in the art. For example, 4-hydroxypyrrolopyrimidine can be prepared by the chlorination reaction of 4-hydroxypyrrolopyrimidine with bis(trichloromethyl)carbonate under organic base catalysis.

[0029] Furthermore, the molar ratio of the above-mentioned organic base, phosphorus oxychloride, and 4-hydroxypyrrolopyrimidine compound or its derivatives is 1-2:1-2.5:1, preferred molar ratios are 1-2:1-2.5:1, 1-1.2:1-1.5:1, 1.2-2.5:1.5-2.7:1, and a more preferred molar ratio is 1.2:1.5:1.

[0030] Furthermore, the above organic base is at least one of N,N-diisopropylethylamine (DIPEA) and triethylamine, with DIPEA being the preferred organic base.

[0031] Furthermore, the reaction in step S4 is carried out in a third solvent, which is toluene.

[0032] Furthermore, the reaction temperature in step S4 is 50-60°C, and the reaction time is 6-10 hours. Preferred reaction times are 6-7 hours, 7-8 hours, 8-10 hours, etc. In certain embodiments, it is preferable to add toluene and DIPEA to 4-hydroxypyrrolopyrimidine, then add phosphorus oxychloride, heat to 60°C, and stir for 6-7 hours.

[0033] Furthermore, after the reaction in step S4 is complete, the solution is purified using subsequent processing steps. In certain embodiments, the reaction solution is slowly added dropwise to ice water under ice water bath conditions to slowly adjust the pH to 5-6. The filtered solid is washed with water and dried. Water is added to the dried solid, stirred, and filtered. Ethyl acetate is added to the filter cake and heated to 60-70°C with stirring until completely dissolved. After adding activated carbon and continuing to heat, the organic phases are sequentially filtered and concentrated under reduced pressure. The concentrate is heated to 60-70°C and stirred for 1 hour, then allowed to cool naturally to room temperature. It is cooled to 0-5°C using an ice water bath to crystallize, extracted, washed with acetoethyl ester, and dried to obtain a white solid. The above can be replaced with conventional processing steps in the art.

[0034] Compared to existing technologies, the present invention employs the above-mentioned technical solutions and has the following advantageous effects.

[0035] This invention employs a novel synthetic idea for preparing 4-chloropyrrolopyrimidine compounds or derivatives, and discloses for the first time a reaction process in which an alkylene oxide compound undergoes ring-opening and reacts with a cyanoacetate compound to prepare intermediates 1 and 2, intermediate 3 is prepared in a one-pot reaction, intermediate 3 is oxidized to an aldehyde, and then ring-closed to prepare intermediate 4. The above method involves the synthesis of a new compound during the synthetic process, is easy to operate, uses inexpensive raw materials, and yields relatively high results, making it suitable for large-scale production in factories. [Modes for carrying out the invention]

[0036] The following describes, in combination with embodiments of the present invention, the technical solutions in embodiments of the present invention clearly and completely. Obviously, the embodiments described below are only some embodiments of the present invention, not all embodiments. All other embodiments obtained by those skilled in the art without creative work based on embodiments of the present invention are included within the scope of protection of the present invention. Experimental methods that do not specify conditions in the following examples are usually measured according to national standards. In the following embodiments, all experimental materials that do not specify a source are raw materials available on the market. All apparatus used in each step in the following embodiments are common apparatus. If there is no suitable national standard, general international standards, general conditions, or conditions recommended by the manufacturer shall be followed. Unless otherwise specified, all quantities are in weight units, and all percentages are in mass percentages. Unless otherwise defined or specified, all technical and scientific terms used in the present invention shall be identical in meaning to those skilled in the art. Furthermore, embodiments and features in embodiments of the present invention can be combined with each other, as long as they do not contradict each other. The following describes the present invention in combination with specific embodiments, but without limitation to the present invention.

[0037] Example 1: Method for synthesizing 6-amino-5-(2-hydroxyethyl)pyrimidine-4-ol compounds or their derivatives. This example represents a preferred method for synthesizing the 6-amino-5-(2-hydroxyethyl)pyrimidine-4-ol compound and includes the following steps: 67.77 g (185.68 mmol / 20% purity) of sodium ethoxide solution is added to a four-necked flask, 20.0 g (176.82 mmol) of ethyl cyanoethyl is slowly added dropwise in an ice bath, and the mixture is stirred at room temperature for 1 to 1.5 hours. Then, 39.99 g (224.05 mmol, 5 mol / L) of propylene oxide solution is slowly added dropwise in an ice bath, and the mixture is heated to 45°C for 1 hour to obtain intermediate 1 and intermediate 2. 23.04 g (221.03 mmol) of formamidine acetate and 162.16 g of sodium ethoxide solution (472.16 mmol / 20% purity) were added to the reaction bottle, the temperature was raised to 60°C, the reaction was maintained for 30 minutes, the temperature was raised to 80°C, and the reaction was maintained for 12 hours. After the reaction, the pH was adjusted to 2-3 with HCl, 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, the mixture was stirred in an ice bath for 2-3 hours to precipitate the solid, and the mixture was filtered to obtain 18.46 g of the product 6-amino-5-(2-hydroxyethyl)pyrimidine-4-ol (theoretical yield 27.43 g). The yield was 67.32%. 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).

[0038] Example 2: Method for synthesizing 6-amino-5-(2-hydroxyethyl)pyrimidine-4-ol compounds or their derivatives 2 This example represents a preferred method for synthesizing the 6-amino-5-(2-hydroxyethyl)pyrimidine-4-ol compound and comprises the following steps: 53.79 g (185.68 mmol / 20% purity) of sodium methoxide methanol solution was added to a four-necked flask, and 20.0 g (176.82 mmol) of ethyl cyanoethyl was slowly added under an ice bath. The mixture was stirred at room temperature for 1 to 1.5 hours, and then 39.99 g of propylene oxide solution (224.05 mmol, 5 mol / L) was slowly added under an ice bath. The temperature was raised to 45°C and maintained for 1 hour to obtain intermediates 1 and 2. 23.04 g of formamidine acetate (221.03 mmol) and 128.73 g of sodium methoxide methanol solution (472.16 mmol / 20% purity) were added to a reaction bottle, heated to 60°C, maintained for 30 minutes, then heated to 80°C, and maintained for 12 hours. After the reaction, the pH was adjusted to 2-3 with HCl, 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, the mixture was stirred in an ice bath for 2-3 hours to precipitate the solid, and the mixture was filtered to obtain 16.34 g of the product 6-amino-5-(2-hydroxyethyl)pyrimidine-4-ol (theoretical yield 27.43 g). The yield was 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).

[0039] Example 3: Method for synthesizing 4-hydroxypyrrolopyrimidine compounds or their derivatives 1 This example represents a preferred method for synthesizing 4-hydroxypyrrolopyrimidine compounds and includes the following steps.

[0040] 6-amino-5-(2-hydroxyethyl)pyrimidine-4-ol was prepared using the steps described in Example 1 or Example 2. 2.0 g (12.89 mmol) of 6-amino-5-(2-hydroxyethyl)pyrimidine-4-ol, 4.17 g (19.34 mmol) of PCC oxidizing agent, and 14.0 g of dichloromethane were added to a reaction bottle under nitrogen protection and reacted 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 (1.74 g theoretical product). The yield was 42.36%. ¹H NMR (400 MHz, DMSO-d6) δ 7.82 (s, ¹H), 7.04 (dd, ¹H), 6.45 (dd, ¹H).

[0041] Example 4: Method 2 for the synthesis of 4-hydroxypyrrolopyrimidine compounds or their derivatives This example represents a preferred method for synthesizing 4-hydroxypyrrolopyrimidine compounds and includes the following steps.

[0042] 6-amino-5-(2-hydroxyethyl)pyrimidine-4-ol was prepared using the steps described in Example 1 or Example 2.

[0043] 2.0 g of 6-amino-5-(2-hydroxyethyl)pyrimidine-4-ol (12.89 mmol), 8.20 g of Dess-Martin oxidizing agent (19.34 mmol), and 14.0 g of dichloromethane were added to a reaction bottle and reacted at room temperature for 1-2 hours under nitrogen protection. 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 of the product 4-hydroxypyrrolopyrimidine (1.74 g of theoretical product). The yield was 39.08%. 1 H NMR (400MHz, DMSO-d6) δ7.82 (s, 1H), 7.04 (dd, 1H), 6.45 (dd, 1H).

[0044] Example 5: Method 3 for the synthesis of 4-hydroxypyrrolopyrimidine compounds or their derivatives This example represents a preferred method for synthesizing 4-hydroxypyrrolopyrimidine compounds and includes the following steps.

[0045] 6-amino-5-(2-hydroxyethyl)pyrimidine-4-ol was prepared using the steps described in Example 1 or Example 2.

[0046] 2.0 g of 6-amino-5-(2-hydroxyethyl)pyrimidine-4-ol (12.89 mmol), 2.45 g (19.34 mmol) of H2O2 (30% aqueous solution), and 14.0 g of 1,4-dioxane were added to a reaction bottle and reacted at room temperature for 1-2 hours under nitrogen protection. 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 of the product 4-hydroxypyrrolopyrimidine (1.74 g of theoretical product). The yield was 28.16%. 1 H NMR (400MHz, DMSO-d6) δ7.82 (s, 1H), 7.04 (dd, 1H), 6.45 (dd, 1H).

[0047] Example 6: Method for synthesizing 4-chloropyrrolopyrimidine compounds and their derivatives 1 This example represents a preferred synthetic method for preparing 4-chloropyrrolopyrimidine compounds and includes the following steps.

[0048] 4-hydroxypyrrolopyrimidine was prepared using the steps described in Example 3, Example 4, or Example 5.

[0049] Add 10.0 g (74.01 mmol) of 4-hydroxypyrrolopyrimidine solid to 42.0 g of toluene and 11.48 g (88.81 mmol) of DIPEA, and slowly add 17.02 g (111.01 mmol) of phosphorus oxychloride under water bath conditions. While slowly heating the reaction solution to 60°C in an oil bath, slowly add the reaction solution dropwise to 100 mL of ice water in an ice bath, then slowly add 10% NaOH aqueous solution to slowly adjust the pH to 5-6, precipitate a large amount of brown solid, filter by suction, wash with water (24 mL x 2), and dry. The mixture was dried, 30 mL of water was added, stirred, filtered, 263.0 g of ethyl acetate was added to the filter cake, heated to 60-70°C, stirred until completely dissolved, then 1.2 g of activated carbon was added, and heating continued for 1 hour. The organic phase was filtered, concentrated to 3V under reduced pressure, the concentrated solution was heated to 60-70°C, stirred for 1 hour, then cooled to room temperature, cooled to 0-5°C in an ice bath to crystallize, filtered by suction, washed with ethyl acetate (0-5°C, 10.0 g x 1), and dried to obtain 8.70 g of off-white solid (theoretical yield: 11.37 g). The yield was 76.50%. 1 H NMR (400MHz, DMSO-d6) δ8.55(s,1H), 7.65-7.66(d,1H), 6.56-6.57(d,1H).

[0050] Example 7: Method 2 for the synthesis of 4-chloropyrrolopyrimidine compounds and their derivatives This example represents a preferred synthetic method for preparing 4-chloropyrrolopyrimidine compounds and includes the following steps.

[0051] 4-hydroxypyrrolopyrimidine was prepared using the steps described in Example 3, Example 4, or Example 5.

[0052] 42.0 g of toluene and 8.99 g (88.81 mmol) of triethylamine were added to 10.0 g (74.01 mmol) of 4-hydroxypyrrolopyrimidine solid. Under water bath conditions, 17.02 g (111.01 mmol) of phosphorus oxychloride was slowly added, and the mixture was slowly heated to 60°C in an oil bath while stirring for 6-7 hours. The reaction mixture was slowly added dropwise to 100 mL of ice water in an ice bath, and then 10% NaOH aqueous solution was slowly added to adjust the pH to 5-6. A large amount of brown solid precipitated, which was filtered by suction, washed with water (24 mL x 2), and dried. 30 mL of water was added to the dried solid, stirred, and filtered. 263.0 g of ethyl acetate was added to the filter cake, heated to 60-70°C, stirred until completely dissolved, then 1.2 g of activated carbon was added, and heating continued for 1 hour. The organic phase was filtered and concentrated to 3V under reduced pressure. The concentrated solution was heated to 60-70°C, stirred for 1 hour, and then cooled to room temperature. It was cooled to 0-5°C in an ice bath to crystallize, filtered by suction, washed with ethyl acetate (0-5°C, 10.0 g x 1), and dried to obtain 7.96 g of off-white solid (theoretical yield: 11.37 g). The yield was 76.50%. 1 H NMR (400MHz, DMSO-d6) δ8.55(s,1H), 7.65-7.66(d,1H), 6.56-6.57(d,1H).

[0053] Example 8: Alternative Example This example is an alternative example for synthesizing 4-chloropyrrolopyrimidine compounds and their derivatives, and includes the following steps.

[0054] Step 1) Under the assumption that other process conditions and steps are the same as in Example 1, the 6-amino-5-(2-hydroxyethyl)pyrimidine-4-ol compound or its derivatives was synthesized at different reaction temperatures and reaction times using different amounts of cyanoacetate compound, alkylene oxide compound, formamidine acetate compound and alkaline substance (specifically, sodium ethoxide solution), and the reaction conditions and yields are shown in the table below. [Table 1]

[0055] Using Step 2) and Step 1), prepare the 6-amino-5-(2-hydroxyethyl)pyrimidine-4-ol compound or its derivatives. Under the assumption that the other process conditions and steps are the same as in Example 3, synthesize 4-hydroxylpyrrolopyrimidine or its derivatives using different amounts of the 6-amino-5-(2-hydroxyethyl)pyrimidine-4-ol compound or its derivatives, an oxidizing agent (specifically, a PCC oxidizing agent), different reaction temperatures, and different reaction times. The reaction conditions and yields are shown in the table below. [Table 2]

[0056] Using Step 3) and Step 2), a 4-hydroxypyrrolopyrimidine compound or its derivatives was prepared. Under the assumption that other process conditions and steps were the same as in Example 6, different amounts of the 4-hydroxypyrrolopyrimidine compound or its derivatives, POCl3, DIPEA, different reaction temperatures, and different reaction times were used to synthesize the 4-chloropyrrolopyrimidine compound or its derivatives, and the yields are shown in the table below. [Table 3]

[0057] From the above examples, it can be seen that the method for synthesizing 4-chloropyrrolopyrimidine according to the present invention is simple to operate, easy to purify, yields high yields, and uses inexpensive raw materials. As a result, the yield of 4-chloropyrrolopyrimidine is significantly improved and costs are reduced.

[0058] Although specific embodiments of the present invention have been described in detail above, these are merely illustrative, and the present invention is not limited to the above-described specific embodiments. It will be clear to those skilled in the art that any equivalent modifications and substitutions to the present invention are also within the scope of the invention. Accordingly, all equivalent changes and modifications made without departing from the spirit and scope of the invention shall be included within the scope of the invention.

Claims

1. A 6-amino-5-(2-hoseethyl)pyrimidine-4-ol compound or its derivative, wherein the structural formula of the above compound is shown as formula III, 【Chemistry 12】 Here, R ２ It is selected from the hydrogen, methyl, and ethyl groups. R ３ It is characterized by being selected from the group of hydrogen, methyl, amino, and ol.

2. A method for producing a 6-amino-5-(2-hydroxyethyl)pyrimidine-4-ol compound or its derivatives, comprising the following steps: Step S1: Using an alkaline substance as a catalyst, the alkylene oxide compound and the cyanoacetate compound are reacted to obtain the compound of formula I. The structural formula of the compound of formula I is shown below. 【Chemistry 13】 The compound of formula I above undergoes a ring-closing reaction to obtain the compound of formula II, and the structural formula of the compound of formula II is shown below. 【Chemistry 14】 Step S2, using an alkaline substance as a catalyst, formamidine acetate compound, compound I, and compound II are reacted in a one-pot reaction to obtain compound III. Compound III is an amino-5-(2-hydroxyethyl)pyrimidine-4-ol compound, and the structural formula of compound III is shown below. 【Chemistry 15】 And, Here, the structural formula of the alkylene oxide compound is, 【Chemistry 16】 And, The structural formula of the above cyanoacetate compound is, 【Chemistry 17】 The structural formula of the above formamidine acetate compound is, [Chemistry 18] And, R １ The group is selected from methyl, ethyl, methylsulfonyl, p-toluenesulfonyl, and propyl. R ２ These are selected from the hydrogen, methyl, and ethyl groups. R ３ It is characterized by being selected from the group of hydrogen, methyl, amino, and hydroxyl.

3. In the manufacturing method described in claim 2, the molar ratio of the cyanoacetate compound, alkylene oxide compound, formamidine acetate compound and alkaline substance is 1:1 to 1.87:1 to 2.14:1 to 9.

2. The reaction temperature of steps S1 and S2 is 45 to 80°C, and the total reaction time is 16 to 26 hours.

4. In the production method described in claim 2, the alkylene oxide compound is added as a mixed solution obtained by dissolving one or more of n-heptane and tetrahydrofuran, and / or, the above alkaline substance is selected from one or more of sodium ethoxide, sodium methoxide, potassium tert-butoxide, sodium hydride, n-butyllithium, sodium hydroxide, and potassium hydroxide. and / or, the reactions of steps S1 and S2 are carried out in a first solvent, the first solvent being selected from one or more of a sodium ethoxide solution, tetrahydrofuran, and sodium methoxide solution.

5. A method for producing pyrrolopyrimidine compounds or derivatives thereof, wherein a 6-amino-5-(2-hydroxyethyl)pyrimidine-4-ol compound or a derivative thereof is used as a raw material, and a pyrrolopyrimidine compound or derivative thereof is obtained by further reaction, Here, the above-mentioned 6-amino-5-(2-hydroxyethyl)pyrimidine-4-ol compound is the compound of formula III described in claim 1, or is produced using the production method described in any one of claims 2 to 4. The above pyrrolopyrimidine compounds are selected from 4-hydroxypyrrolopyrimidine compounds or their derivatives, 4-chloropyrrolopyrimidine compounds or their derivatives, The structural formula of the above 4-hydroxypyrrolopyrimidine compound is, 【Chemistry 19】 And, The structural formula of the above 4-chloropyrrolopyrimidine compound is, 【Chemistry 20】 It is characterized by being such.

6. In the manufacturing method described in claim 5, when producing a 4-hydroxypyrrolopyrimidine compound or its derivatives, the above manufacturing method is The present invention is characterized by comprising step S3, in which an oxidizing agent is used to react a 6-amino-5-(2-hydroxyethyl)pyrimidine-4-ol compound or a derivative thereof in a one-pot reaction to oxidize it to an aldehyde, and then a ring-closing reaction is carried out to obtain 4-hydroxypyrrolopyrimidine or a derivative thereof.

7. In the production method according to claim 6, the molar ratio of the 6-amino-5-(2-hydroxyethyl)pyrimidine-4-ol compound or its derivative to the oxidizing agent is 1:1 to 3. and / or, the oxidizing agent is selected from one or more of the following: pyridinium chlorochromate, Dess-Martin oxidizing agent, Jones reagent, pyridine sulfur trioxide, hydrogen peroxide, manganese dioxide, sodium tungstate, tetramethylpiperidine oxide, diacetoxyiodobenzene, and sodium hypochlorite. and / or, the reaction in step S3 is carried out in a second solvent, the second solvent being selected from one or more of dichloromethane, water, acetone, and 1,4-dioxane. And / or, the reaction temperature in step S3 is 20 to 30°C, and the reaction time is 0.5 to 3 hours.

8. The manufacturing method according to any one of claims 6 to 7 is characterized by comprising step S4, in which a 4-hydroxypyrrolopyrimidine compound or a derivative thereof is further reacted to produce a 4-chloropyrrolopyrimidine compound or a derivative thereof.

9. In the manufacturing method described in claim 8, step S4 specifically includes a process of adding an organic base as an acid binder to chlorinate 4-hydroxypyrrolopyrimidine or a derivative thereof with phosphorus oxychloride to obtain a 4-chloropyrrolopyrimidine compound or a derivative thereof.

10. In the manufacturing method according to claim 9, the molar ratio of the above-mentioned organic base, phosphorus oxychloride, and 4-hydroxypyrrolopyrimidine compound or derivative thereof is 1 to 2.5:1 to 2.0:

1. and / or the above 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, the third solvent being toltoluene, And / or, the reaction temperature in step S4 is 50 to 60°C, and the reaction time is 6 to 10 hours.

Images