A method for preparing 2-(8-bromoimidazolo[1,5-a]pyridin-3-yl)propane-2-amine

Abstract

The application discloses a preparation method of 2-(8-bromimidazo[1,5-a]pyridine-3-yl)propane-2-amine and belongs to the technical field of synthesis of pharmaceutical intermediates. The preparation method of 2-(8-bromimidazo[1,5-a]pyridine-3-yl)propane-2-amine comprises the following steps: step one, condensation of compound I and compound II to obtain compound III; step two, dehydration and ring closure of compound III to obtain compound IV; and step three, hydrazinolysis of compound IV to obtain compound V. The compound V is prepared by adopting a new route, the use of HATU and the Burgess reagent is avoided, product purification is simple, the yield is high, the cost is low, and the method is very suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis technology, and more specifically, to a method for preparing 2-(8-bromoimidazolo[1,5-a]pyridin-3-yl)propane-2-amine. Background Technology

[0002] Patent WO 2024 / 102754 A reports 2-(8-bromoimidozolo[1,5-a]pyridin-3-yl)propane-2-amine (CAS: 1781347-65-6), a pharmaceutical intermediate used as an important structural fragment in new drug development, primarily for the preparation of somatostatin receptor 4 (SSTR4) agonists. These agonists exhibit a significant ability to bind to the SSTR4 receptor, demonstrating potent agonistic activity and modulating SSTR4 receptor activity. Binding at this site is considered a potential treatment for conditions such as pain, addiction, depression, stress, anxiety, autoimmune diseases, and neurological disorders. The structure of the somatostatin receptor 4 (SSTR4) agonist is as follows... Figure 3 As shown, the synthesis of somatostatin receptor subtype 4 (SSTR4) agonists requires the use of compounds with the following structures: Figure 4 As shown, its synthetic route is as follows Figure 5 As shown, patent WO 2024 / 102754 A2 from 2024 uses compound I and compound VI to condense under the action of HATU to obtain compound VII. Then, through Burgess reagent, dehydration and cyclization are performed to obtain compound VIII in a 30% molar yield. Finally, the Boc protecting group is removed by ethanol / hydrochloric acid to obtain compound V in a 90% molar yield. This process uses HATU and Burgess reagent, which are expensive and costly. The mentioned patent route is as follows: Figure 6 As shown.

[0003] In conclusion, 2-(8-bromoimidazolo[1,5-a]pyridin-3-yl)propane-2-amine, as a novel drug synthesis intermediate, has a wider range of applications in the future. Therefore, it is essential to develop an efficient, inexpensive, and simple industrial synthesis method. Summary of the Invention

[0004] 1. Technical problem to be solved:

[0005] The purpose of this invention is to provide a novel route for the preparation of 2-(8-bromoimidazolo[1,5-a]pyridin-3-yl)propane-2-amine, which is simple, mild, efficient, and suitable for industrial production, in order to solve the technical problems existing in the background art.

[0006] 2. Technical Solution:

[0007] To solve the above problems, the present invention adopts the following technical solution.

[0008] A method for preparing 2-(8-bromoimidazolo[1,5-a]pyridin-3-yl)propane-2-amine, characterized by comprising the following steps:

[0009] S1, compound I and compound II were condensed to obtain compound III;

[0010] S2, compound III was dehydrated and cyclized to obtain compound IV;

[0011] S3, compound IV was hydrazinoly synthesized to obtain compound V.

[0012] A further improvement is that the specific operation in step S1 is as follows: add a solution of compound I and an alkali to the reaction flask, add a solution of compound II dropwise, and after the reaction is complete, add water to the phase, dry the organic phase, and concentrate it for use in the next reaction.

[0013] A further improvement is that the acid-binding agent in step S1 is triethylamine, pyridine, or DIPEA, and the optimal base is triethylamine.

[0014] A further improvement is that the molar ratio of compound I to compound II in step S1 is 1.0:(1.0~2.0), and the optimal molar ratio is 1:1.2.

[0015] A further improvement is that the specific operation in step S2 is as follows: compound III, solvent, molecular sieve, and dehydrating agent are added to the reaction flask. After the reaction is completed, water is added as the phase phase, and the product spot is collected by organic phase column chromatography.

[0016] Further, the dehydrating agent in step S2 is methyl (chlorosulfonyl) carbamate or ethyl (chlorosulfonyl) carbamate.

[0017] Furthermore, in step S2, the molar ratio of compound III to the dehydrating agent is 1:(1~6), and the optimal molar ratio is 1:1.1.

[0018] Furthermore, the solvent in step S2 is dichloromethane, dichloroethane, or trichloromethane, with 1,2-dichloroethane being the most preferred.

[0019] Furthermore, the heating reaction in step S2 is 10-70°C, with the optimal temperature being 40°C.

[0020] Further, the specific operation in step S3 is as follows: add compound IV, solvent, and hydrazine hydrate to the reaction flask, heat the reaction, filter after the reaction is completed, concentrate the mother liquor, extract with water and organic solvent, and dry and concentrate the organic phase.

[0021] Furthermore, in step S3, the molar ratio of compound V to hydrazine hydrate is 1:(2~6), and the optimal molar ratio is 1:4.

[0022] Furthermore, the solvent in step S3 is methanol, ethanol, or isopropanol, with ethanol being the most preferred.

[0023] 3. Beneficial effects:

[0024] Compared with the prior art, the technical solution provided by this invention has the following advantages:

[0025] The present invention is rationally designed, and the technical solution provided by the present invention has the following beneficial effects compared with the prior art:

[0026] A novel route was used to synthesize compound V, avoiding the use of HATU and Burgess reagents. This method offers high yields, low costs, and is highly suitable for industrial production.

[0027] It should be noted that the structures not described in this invention are not related to the design points and improvement directions of this invention, and are the same as or can be implemented using existing technologies, so they will not be elaborated here. Attached Figure Description

[0028] Figure 1 This is a flowchart of the synthesis process of the present invention;

[0029] Figure 2 This is a purity graph for compound V;

[0030] Figure 3 This is a structural diagram of a somatostatin receptor 4 subtype (SSTR4) agonist;

[0031] Figure 4 This is a structural diagram of compounds used in the synthesis of somatostatin receptor subtype 4 (SSTR4) agonists;

[0032] Figure 5 for Figure 4 Schematic diagram of the synthetic route in the middle;

[0033] Figure 6 This is a schematic diagram of the route for compound V in the prior art. Detailed Implementation

[0034] To facilitate understanding of the present invention, a more complete description of the invention will be given below with reference to the accompanying drawings, which illustrate several embodiments of the invention. However, the invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that the disclosure of the invention will be more thorough and complete.

[0035] Example 1: Preparation of Compound III: N-((3-bromopyridin-2-yl)methyl)-2-(1,3-dioxaisoindol-2-yl)-2-methylpropionamide

[0036] Under nitrogen protection, 52 g (1 eq) of compound I, 260 ml of dichloromethane (5V), and 84.4 g of triethylamine (3 eq) were added to a reaction flask. 83.9 g (1.2 eq) of compound II was slowly added dropwise at 5-20 °C after dilution with 160 ml of dichloromethane. After the addition was complete, the mixture was stirred. Once the reaction was finished, hydrochloric acid was added to adjust the pH to neutral. The mixture was washed twice with water, and the phases were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and then slurried with toluene for 2 hours. After filtration and drying, 106.23 g of off-white crystals were obtained, with a calculated molar yield of 95%.

[0037] 1 H NMR (400 MHz, DMSO-d6 ) δ 8.51 – 8.40 (m, 2H), 8.03 (dd, J = 8.0,1.5 Hz, 1H), 7.83 (s, 4H), 7.25 (dd, J = 8.0, 4.6 Hz, 1H), 4.42 (d, J = 5.4Hz, 2H), 1.73 (s, 6H). MS: m / z 402.4[M+H] +

[0038] Example 2: Preparation of compound IV: 2-(2-(8-bromoimidazolo[1,5-a]pyridin-3-yl)propyl-2-yl)isoindoline-1,3-dione

[0039] Add 50 g (1 eq) of compound III, 750 ml (15 V) of dichloroethane, and 150 g of 4A molecular sieve to a reaction flask. Stir at 40 °C for 30 min, then add 24 g (1.1 eq) of methyl (chlorosulfonyl) carbamate. React at 40 °C for 1 h. After the reaction is complete, filter the solution, add 150 ml of water to the filtrate to separate the phases, wash the organic phase with 150 ml of saturated brine, concentrate to dryness, and perform column chromatography. Collect the product and concentrate to dryness to obtain 23.82 g of yellow solid. Calculate the molar yield as 50%.

[0040] 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J = 7.2 Hz, 1H), 7.86 – 7.75 (m,4H), 7.39 (d, J = 0.9 Hz, 1H), 7.06 (d, J = 6.8 Hz, 1H), 6.43 (t, J = 7.0 Hz,1H), 2.05 (s, 6H). MS: m / z 384.4[M+H] +

[0041] Example 3: Preparation of compound V: 2-(2-(8-bromoimidazolo[1,5-a]pyridin-3-yl)propyl-2-yl)isoindoline-1,3-dione

[0042] 50 g (1 eq) of compound III, 750 ml of dichloroethane, and 150 g of 4A molecular sieve were added to a reaction flask. After stirring at 40 °C for 30 min, 67.63 g (3.1 eq) of methyl (chlorosulfonyl) carbamate was added, and the mixture was reacted at 40 °C for 1 h. After the reaction was completed, the mixture was filtered, and 150 ml of water phase was added to the filtrate. The organic phase was washed with 150 ml of saturated brine, concentrated to dryness, and subjected to column chromatography. The product was collected and concentrated to dryness as a yellow solid of 22.76 g. The molar yield was calculated to be 48%.

[0043] Example 4: Preparation of Compound V: 2-(8-bromoimidazolo[1,5-a]pyridin-3-yl)propane-2-amine

[0044] 15 g (1 eq) of compound IV and 300 ml of anhydrous ethanol were added to a reaction flask. 9.77 g (4 eq) of hydrazine hydrate was added dropwise at 60-70 °C. The mixture was heated to reflux and the reaction was stopped. After the reaction was completed, the mixture was cooled to about 0 °C and filtered. The mother liquor was concentrated and water was added and distilled twice. 30 ml of water and dichloromethane were added, and the phases were separated. The organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated to obtain 9.44 g of white crystals. The molar yield was calculated to be 95%.

[0045] 1 H NMR (400 MHz, DMSO-d6 ) δ 9.08 (d, J = 7.3 Hz, 1H), 7.27 (s, 1H),7.07 (d, J = 6.9 Hz, 1H), 6.57 – 6.49 (m, 1H), 2.14 (s, 2H), 1.55 (s, 6H)

[0046] The total yield of 2-(8-bromoimidazolo[1,5-a]pyridin-3-yl)propane-2-amine prepared by the above steps was 45%, and the purity was greater than 99% as determined by HPLC (high performance liquid chromatography).

[0047] The foregoing description fully demonstrates that the present invention has excellent applicability, high yield, and is very suitable for industrial-scale production. The embodiments only illustrate certain implementations of the present invention, and their descriptions are relatively specific and detailed, but they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this patent should be determined by the appended claims.

[0048] The above-described embodiments are merely illustrative of certain implementations of the present invention, and are described in a relatively specific and detailed manner. However, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements are all within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the appended claims.

Claims

1. A method for preparing 2-(8-bromoimidazolo[1,5-a]pyridin-3-yl)propane-2-amine, characterized in that, Includes the following steps: S1, compound I and compound II were condensed to obtain compound III; S2, compound III was dehydrated and cyclized to obtain compound IV; S3, compound IV was hydrazinoly synthesized to obtain compound V; 。 2. The method for preparing 2-(8-bromoimidazolo[1,5-a]pyridin-3-yl)propane-2-amine according to claim 1, characterized in that: The specific operation in step S1 is as follows: add a solution of compound I and an acid-binding agent and solvent to the reaction flask, add compound II, add water after the reaction is complete, dry the organic phase, concentrate it to dryness for the next reaction. The molar ratio of compound I to compound II is 1.0:(1-2). The acid-binding agent is one of triethylamine, DIPEA, or pyridine.

3. The method for preparing 2-(8-bromoimidazolo[1,5-a]pyridin-3-yl)propane-2-amine according to claim 1, characterized in that: The specific operation in step S2 is as follows: compound III, solvent, molecular sieve, and dehydrating agent are added to the reaction flask. After the reaction is completed, water is added as the phase phase, and the product spot is collected by organic phase column chromatography.

4. The method for preparing 2-(8-bromoimidazolo[1,5-a]pyridin-3-yl)propane-2-amine according to claim 1, characterized in that: The specific operation in step S3 is as follows: add compound IV, solvent, and hydrazine hydrate to the reaction flask, heat the reaction, filter after the reaction is completed, concentrate the mother liquor, add water and organic solvent for extraction, and dry and concentrate the organic phase.

5. The method for preparing 2-(8-bromoimidazolo[1,5-a]pyridin-3-yl)propane-2-amine according to claim 3, characterized in that: The dehydrating agent in step S2 is methyl (chlorosulfonyl) carbamate or ethyl (chlorosulfonyl) carbamate.

6. The method for preparing 2-(8-bromoimidazolo[1,5-a]pyridin-3-yl)propane-2-amine according to claim 3, characterized in that: In step S2, the molar ratio of compound III to the dehydrating agent is 1:(1~6).

7. The method for preparing 2-(8-bromoimidazolo[1,5-a]pyridin-3-yl)propane-2-amine according to claim 3, characterized in that: The solvent in step S2 is one of dichloromethane, dichloroethane, or trichloromethane.

8. The method for preparing 2-(8-bromoimidazolo[1,5-a]pyridin-3-yl)propane-2-amine according to claim 1, characterized in that: The reaction temperature in step S3 is 20-70℃.

9. The method for preparing 2-(8-bromoimidazolo[1,5-a]pyridin-3-yl)propane-2-amine according to claim 4, characterized in that: In step S3, the molar ratio of compound IV to hydrazine hydrate is 1.0:(1-6).

10. The method for preparing 2-(8-bromoimidazolo[1,5-a]pyridin-3-yl)propane-2-amine according to claim 4, characterized in that: The solvent in step S3 is one of methanol, ethanol, or isopropanol.

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