A process for the synthesis of 4,6-dichloro-1h-pyrrolo[3,2-c]pyridine and intermediates thereof

Abstract

The application relates to the technical field of pharmaceutical intermediates, in particular to a synthesis method of 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine and intermediates thereof, wherein the intermediate is 2-(ethoxycarbonylmethyl)pyrrole-3-carboxylic acid ethyl ester, a synthesis route of which is shown in the figure; the starting material of the synthesis method is cheap; the preparation method of the key intermediate can adopt a one-pot method, the key intermediate can be used for the next reaction without additional purification, the machine time and the working hours of equipment and personnel are reduced, and the method is especially suitable for industrial production. In the method, the reaction yield of the key intermediate is high; the volume concentration of the reaction is large, which is beneficial to improving the production capacity and reducing the generation of waste.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediates, specifically to a method for synthesizing 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine and its intermediates. Background Technology

[0002] 4,6-Dichloro-1H-pyrrolo[3,2-c]pyridine is an important drug molecule cleavage and a synthetic intermediate for many drugs. For example, this compound can be used to synthesize ribonucleoside analogs, which have broad application prospects in antitumor, antiviral, and ATR kinase inhibitors. In addition, this compound is also an intermediate in the synthesis of a class of pyridinyl and pyrimidinyl-substituted thiazole and thiadiazole derivatives, used in pesticide production.

[0003] With the clinical recommendations of the aforementioned drugs and the continuous discovery of new similar structures, the demand for 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine is constantly increasing, especially as this analogue is widely used in insecticides. However, current laboratory preparation methods for this compound severely limit its production capacity, necessitating the development of a safe, environmentally friendly, and inexpensive industrial preparation process to meet this demand.

[0004] Currently, the synthesis of 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine involves five steps, as detailed below:

[0005]

[0006] The preparation of the key intermediate Key Int. (i.e., ethyl 2-(ethoxycarbonylmethyl)pyrrole-3-carboxylate) is as follows: First, 1,3-propanone dicarboxylic acid diethyl ester is condensed with α-amino acetal to obtain an imine intermediate; Second, the imine intermediate is cyclized by intramolecular condensation under alkaline conditions. The first and second steps are the key factors restricting the synthesis of the final target product, and they have the following disadvantages: (1) The yield of the key intermediate Key Int. is low, only 15% (J. Chem. SOC. (C), 1970, 285); (2) Column chromatography purification is required, which is not suitable for industrial production requirements; (3) The reaction concentration is low, which limits the production capacity and generates a large amount of waste liquid.

[0007] After the key intermediate is prepared, the subsequent reaction steps are all common methods in the existing technology (Journal of Medicinal Chemistry, 1978, Vol. 21, No. 9991), and a mature process method has been formed.

[0008] Therefore, the key to optimizing the process route of 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine is to find a novel synthetic method for a key intermediate. Summary of the Invention

[0009] To address the aforementioned problems in the prior art, the present invention aims to provide a method for synthesizing 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine, and in particular a method for synthesizing the key intermediate, ethyl 2-(ethoxycarbonylmethyl)pyrrole-3-carboxylate.

[0010] To achieve the above objectives, the present invention provides the following technical solution:

[0011] A method for synthesizing an intermediate of 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine, wherein the intermediate is ethyl 2-(ethoxycarbonylmethyl)pyrrole-3-carboxylate, and the synthetic route is as follows:

[0012]

[0013] The first step in the synthesis of this intermediate is the nucleophilic substitution of an enamine with an α-haloaldehyde, and the second step is the intramolecular condensation of the amino group with the aldehyde to obtain the key intermediate.

[0014] The preparation method of compound 2a is as follows: at room temperature, HBr solution is added to an aqueous solution of bromoacetaldehyde diethanol condensate, the resulting mixture is heated and stirred, cooled, and then NaOAc is added to obtain 2-bromoacetaldehyde, i.e., compound 2a. The heating temperature of the aqueous solution of bromoacetaldehyde diethanol condensate and the HBr solution is 40℃, the stirring time is 3h, and the cooling temperature is 0℃.

[0015] The preparation method of compound 3 is as follows: a solution of 3-amino-2-pentene-1,5-diacid diethyl ester is added to a solution of 2-bromoacetaldehyde, and the resulting mixture is stirred at room temperature. After the reaction is completed, the reaction solution is extracted with ethyl acetate, and the combined organic phases are washed with saturated brine to separate the layers. The mixture is then concentrated to dryness under reduced pressure to obtain a yellow oily crude product of 2-(ethoxycarbonylmethyl)pyrrole-3-carboxylic acid ethyl ester, i.e., compound 3. Preferably, in the preparation of compound 3, a solution of 3-amino-2-pentene-1,5-diacid diethyl ester is added to a solution of 2-bromoacetaldehyde at 0°C, and the resulting mixture is stirred at room temperature for 16 hours.

[0016] The synthetic route for compound 2b is as follows:

[0017]

[0018] The preparation method of compound 2b is as follows: NH4HCO3 is added to a methanol solution of diethyl 1,3-acetone dicarboxylate, and the resulting mixture is heated and stirred; then the mixture is concentrated under reduced pressure, and the resulting yellow oily substance is dissolved in acetone to obtain a solution of diethyl 3-amino-2-pentene-1,5-diacid, i.e., compound 2b. Preferably, the heating temperature is 40°C and the stirring time is 4 hours.

[0019] This invention also provides a method for synthesizing 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine, the synthetic route of which is as follows:

[0020]

[0021] The intermediate 2-(ethoxycarbonylmethyl)pyrrole-3-carboxylate was prepared using the above-described synthetic method.

[0022] Compared with the prior art, the beneficial effects of the present invention are:

[0023] The starting materials used in the synthesis method of this invention are inexpensive, costing only half the price of those used in traditional routes. Furthermore, the preparation of key intermediates can be achieved using a one-pot process, eliminating the need for additional purification before use in the next reaction, thus reducing equipment and personnel time, making it particularly suitable for industrial production. In the method of this invention, the reaction yield of key intermediates is high; the reaction volume concentration is large, which is beneficial for increasing production capacity and reducing waste generation. Attached Figure Description

[0024] Figure 1 The image shows the HNMR spectrum of the product from Example 1.

[0025] Figure 2 The image shows the HNMR spectrum of the product from Example 3.

[0026] Figure 3 The 1H NMR spectrum of 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine, the product of Example 4. Detailed Implementation

[0027] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0028] Example 1: Preparation of ethyl 2-(ethoxycarbonylmethyl)pyrrole-3-carboxylate

[0029]

[0030] Prepare 2-bromoacetaldehyde solution and 3-amino-2-pentene-1,5-dicitoxate diethyl ester solution. The two solutions should be prepared as simultaneously as possible and used immediately after preparation.

[0031] (1) Preparation of 2-bromoacetaldehyde solution

[0032] A 15 L solution of bromoacetaldehyde diethanol(4.87 kg, 3.81 L, 24.73 mol, 1 eq) in water was added at room temperature. HBr solution (4.17 kg, 48%, 1.34 L, 24.73 mol, 1 eq) was then added. The resulting mixture was stirred at 40 °C for 3 hours. The mixture was cooled to 0 °C, and then NaOAc (4.06 kg, 2.80 L, 49.46 mol, 2 eq) was added to obtain an aqueous solution of bromoacetaldehyde, which was then set aside for later use.

[0033] (2) Preparation of diethyl 3-amino-2-pentene-1,5-dicarboxylic acid solution

[0034] In another reaction vessel, a methanol (5 L) solution of 1,3-acetone dicarboxylic acid diethyl ester (5 kg, 4.50 L, 24.73 mol, 1 eq) was added to NH4HCO3 (2.44 kg, 1.54 L, 30.91 mol, 1.25 eq). The resulting mixture was heated to 40 °C and stirred for 4 hours. The mixture was then concentrated under reduced pressure, and the resulting yellow oily substance was dissolved in acetone (5 L x 3) to give a solution of 3-amino-2-pentene-1,5-diacid diethyl ester.

[0035] (3) Preparation of ethyl 2-(ethoxycarbonylmethyl)pyrrole-3-carboxylate

[0036] At 0°C, a solution of diethyl 3-amino-2-penten-1,5-diacid was added to a solution of bromoacetaldehyde, and the resulting mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was extracted three times with ethyl acetate (5 L x 3). The combined organic phases were washed with saturated brine (3 L x 2) to separate the layers, and then concentrated to dryness under reduced pressure to obtain a yellow oily crude product of ethyl 2-(ethoxycarbonylmethyl)pyrrole-3-carboxylate (5.57 kg, yield: 100%). The purity of this crude product was greater than 90%, and it was directly used as a starting material for the next synthesis. The relevant spectra of the product are shown below. Figure 1 As shown.

[0037] MS = 225.8(M+1). 1 H NMR (400MHz, Chloroform-d) δ9.58 (s, 1H), 6.67 (t, J = 2.7Hz,

[0038] 1H), 6.59 (t, J = 2.9Hz, 1H), 4.31-4.22 (m, 4H), 4.12 (s, 2H), 1.37-1.29 (m, 6H).

[0039] Example 2 Preparation of ethyl 2-carbamoylmethyl-3-pyrrolecarboxylate

[0040]

[0041] A solution of ethyl 2-(ethoxycarbonylmethyl)pyrrole-3-carboxylate (4.10 kg, 18.20 mol, 1 eq) in ammonia water (11.39 kg, 28%, 12.66 L, 91.01 mol, 5 eq) was heated to 40 °C and stirred for 18 hours. TLC (petroleum ether / ethyl acetate = 1 / 1, Rf = 0.2) showed the disappearance of the starting material. The resulting reaction solution was an ammonia water solution containing 3.57 kg of ethyl 2-carbamoylmethyl-3-pyrrolecarboxylate (reaction yield 99.9%, confirmed by quantitative NMR), which was directly used in the next step of the reaction.

[0042] Example 3 Preparation of 1-Hydropyrrolo[3,2-c]-4,6-dihydroxypyridine

[0043]

[0044] NaOH (2.18 kg, 54.58 mol, 3 eq) was dissolved in 8 L of water and cooled to 0 °C. The solution was then kept below 15 °C, and the alkali solution was slowly added dropwise to the ammonia solution of ethyl 2-carbamoylmethyl-3-pyrrolecarboxylate from the previous step. After the addition was complete, the reaction mixture was heated to 40 °C and stirred for 1 hour. After the reaction was accepted, the reaction mixture was cooled to 0 °C, and the pH was adjusted to 2-3 with 6 M hydrochloric acid solution. A large amount of solid precipitated, forming a suspension. The suspension was stirred at 0 °C for 16 hours, filtered, and the solid was collected and vacuum dried at 40 °C for 48 hours to obtain crude 1-hydro-pyrrolo[3.2-c]-4,6-dihydroxypyridine. The crude product was suspended in 10 times its volume of methanol, heated to 70 °C and stirred for 2 hours, then cooled to room temperature, filtered, and the filtrate was collected. The filter cake was washed with 1 volume of methanol, filtered, and the filtrate was collected. The combined filtrates were concentrated to dryness under reduced pressure to obtain pure 1-hydro-pyrrolo[3.2-c]-4,6-dihydroxypyridine (1.10 kg, Yield: 40.27%). The relevant spectra of the product are shown below. Figure 2 As shown.

[0045] 1H NMR (400MHz, DMSO-d6) δ11.49(s,1H),10.53(s,1H),6.86(t,J=2.5Hz,1H),6.42-6.29(m,1H),3.86(s,2H).MS=150.6(M+1).

[0046] Example 4 Preparation of 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine

[0047]

[0048] A mixture of 1-hydro-pyrrolo[3,2-c]pyridine-4,6-dihydroxy (2.20 kg, 14.65 mol, 1 eq) and phenylphosphine oxychloride (9.17 kg, 6.60 L, 47.05 mol, 3.21 eq) was heated to 160 °C and stirred for 4 hours. After the reaction was complete, the reaction solution was cooled to 70 °C and then diluted with 5 L of tetrahydrofuran. The resulting mixture was slowly added to 20 L of ice water and stirred at 0 °C for 16 hours, resulting in the precipitation of a dark, waxy solid. The mixture settled, and the aqueous phase was slowly removed by decantation. The remaining mixture was added to an ethyl acetate / methanol mixture (ethyl acetate / methanol = 3 / 1, 15 L), rapidly stirred to break up the mixture, and filtered to collect the filtrate. The filter cake was then added to an ethyl acetate / tetrahydrofuran mixture (ethyl acetate / tetrahydrofuran = 3 / 1, 5 L), rapidly stirred to break up the mixture, and filtered to collect the filtrate. The filtrates were combined and concentrated under reduced pressure to approximately 8 L, resulting in the precipitation of a large amount of yellow solid. The suspension was filtered, and the solid was collected to obtain a deep yellow 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine (2.30 kg, Yield: 83.93%).

[0049] NaOH pulping:

[0050] 4,6-Dichloro-1H-pyrrolo[3,2-c]pyridine (2.20 kg, 11.76 mol, 1 eq) was dispersed in an aqueous NaOH solution (264.02 g, 6.60 L, 6.60 mol, 0.5611 eq, 1 M). The suspension was stirred at 20 °C for 16 hours and then filtered. The filter cake was washed three times with water (1 L x 3), collected, and vacuum dried at 40 °C for 24 hours to obtain a deep yellow crude product of 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine (2.10 kg, Yield: 95.45%).

[0051] Activated carbon decolorization, EtOAc pulping:

[0052] 4,6-Dichloro-1H-pyrrolo[3,2-c]pyridine (2 kg, 10.69 mol, 1 eq) was dissolved in a mixed solvent of ethyl acetate (20 L) and tetrahydrofuran (10 L) to obtain a dark brown solution. Activated carbon (500 g, 200 mesh) was added. The resulting mixture was heated to 65 °C and stirred for 1 hour, until the solution turned pale yellow. The suspension was filtered, and the filtrate was collected. The filter cake was washed with 8 L of a mixed solution of ethyl acetate / tetrahydrofuran (ethyl acetate / tetrahydrofuran = 2 / 1), and then filtered to collect the filtrate. The filtrates were combined and concentrated to approximately 4 L, resulting in the precipitation of a yellow solid. The solid was collected by filtration, and the filter cake was washed with 4 times its volume of ethyl acetate to obtain white 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine (1.10 kg, Yield: 55%). The relevant spectra of the product are shown below. Figure 3 As shown.

[0053] MS = 187.0(M+1). 1 H NMR (400MHz, DMSO-d6) δ12.04 (s, 1H), 7.62 (dd, J = 3.3, 2.4Hz,

[0054] 1H), 7.53 (d, J=0.9Hz, 1H), 6.59 (ddd, J=3.1, 2.0, 1.0Hz, 1H).

[0055] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing an intermediate of 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine, characterized in that: The intermediate is ethyl 2-(ethoxycarbonylmethyl)pyrrole-3-carboxylate, and its synthetic route is as follows: ； The preparation method of compound 3 is as follows: a solution of 3-amino-2-pentene-1,5-diacid diethyl ester is added to a solution of 2-bromoacetaldehyde, and the resulting mixture is stirred at room temperature; after the reaction is completed, the reaction solution is extracted with ethyl acetate, the combined organic phases are washed with saturated brine to separate the layers, and then concentrated to dryness under reduced pressure to obtain a yellow oily crude product of 2-(ethoxycarbonylmethyl)pyrrole-3-carboxylic acid ethyl ester, namely compound 3.

2. The method for synthesizing the intermediate of 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine according to claim 1, characterized in that: The preparation method of compound 2a is as follows: at room temperature, HBr solution is added to an aqueous solution of bromoacetaldehyde diethanol, the resulting mixture is heated, stirred, cooled, and then NaOAc is added to obtain 2-bromoacetaldehyde, i.e., compound 2a.

3. The method for synthesizing the intermediate of 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine according to claim 2, characterized in that: In the preparation of compound 2a, the aqueous solution of bromoacetaldehyde diethanol and the HBr solution were heated to 40°C and stirred for 3 hours; the temperature was then cooled to 0°C.

4. The method for synthesizing the intermediate of 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine according to claim 1, characterized in that: In the preparation of compound 3, a solution of 3-amino-2-pentene-1,5-diacid diethyl ester was added to a solution of 2-bromoacetaldehyde at 0 °C, and the resulting mixture was stirred at room temperature for 16 hours.

5. The method for synthesizing the intermediate of 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine according to claim 1, characterized in that: The synthetic route for compound 2b is as follows: 。 6. The method for synthesizing the intermediate of 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine according to claim 5, characterized in that: The preparation method of compound 2b is as follows: NH4HCO3 is added to a methanol solution of diethyl 1,3-acetone dicarboxylic acid, and the resulting mixture is heated and stirred; then the mixture is concentrated under reduced pressure, and the resulting yellow oily substance is dissolved in acetone to obtain a solution of diethyl 3-amino-2-pentene-1,5-diacid, which is compound 2b.

7. The method for synthesizing the intermediate of 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine according to claim 6, characterized in that: In the preparation of compound 2b, the heating temperature was 40℃ and the stirring time was 4h.

8. A method for synthesizing 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine, characterized in that: Its synthetic route is as follows: ； The preparation method of compound 3 is as follows: a solution of 3-amino-2-pentene-1,5-diacid diethyl ester is added to a solution of 2-bromoacetaldehyde, and the resulting mixture is stirred at room temperature; after the reaction is completed, the reaction solution is extracted with ethyl acetate, the combined organic phases are washed with saturated brine to separate the layers, and then concentrated to dryness under reduced pressure to obtain a yellow oily crude product of 2-(ethoxycarbonylmethyl)pyrrole-3-carboxylic acid ethyl ester, namely compound 3.

9. The method for synthesizing 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine according to claim 8, characterized in that: wherein, The preparation method of ethyl 2-(ethoxycarbonylmethyl)pyrrole-3-carboxylate, an intermediate of 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine, is performed by the synthetic method described in any one of claims 1-8.

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