Preparation method of 2-(8-bromoimidazo [1, 5-a] pyridine-3-yl) propane-2-amine

Abstract

The invention discloses a preparation method of 2-(8-bromo-imidazo [1, 5-a] pyridine-3-yl) propane-2-amine, and belongs to the technical field of synthesis of drug intermediates, the preparation method of 2-(8-bromo-imidazo [1, 5-a] pyridine-3-yl) propane-2-amine comprises the following steps: 1, condensing a compound I and a compound II to obtain a compound III; 2, dehydrating and cyclizing the compound III to obtain a compound IV; and step 3, hydrazinolysis of the compound IV to prepare a compound V. The compound V is prepared by adopting a new route, the use of HATU and Burgi reagents is avoided, the 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] The present invention relates to the technical field of pharmaceutical intermediate synthesis, and more specifically to a method for preparing 2-(8-bromoimidazo[1,5-a]pyridin-3-yl)propane-2-amine. Background Art

[0002] Patent WO 2024 / 102754 A reports that 2-(8-bromoimidazo[1,5-a]pyridin-3-yl)propane-2-amine (CAS: 1781347-65-6) is a pharmaceutical intermediate. It is an important structural fragment in the process of new drug development, mainly used as an important structural fragment for the preparation of somatostatin receptor subtype 4 (SSTR4) agonists. The agonist has a significant ability to bind to the SSTR4 receptor, exhibits strong agonist activity on the SSTR4 receptor, and regulates the activity of the SSTR4 receptor. The binding of this site is considered to have the potential to treat pain, addiction, depression, stress, anxiety, autoimmune diseases or neurological diseases. The structure of the somatostatin receptor subtype 4 (SSTR4) agonist is as follows: Figure 3 As shown, in the process of synthesizing a somatostatin receptor subtype 4 (SSTR4) agonist, a compound is required, the structure of which is shown in Figure 4 Its synthetic route is as shown in Figure 5 As shown, the 2024 patent WO 2024 / 102754 A2 uses compound I and compound VI to condense under the action of HATU to obtain compound VII, and then uses Burgess reagent to dehydrate and cyclize to obtain compound VIII with a molar yield of 30%, and finally removes the Boc protecting group with ethanol / hydrochloric acid to obtain compound V with a molar yield of 90%. HATU and Burgess reagent are used, which are expensive and costly. The patent route mentioned is as follows Figure 6 shown.

[0003] In summary, 2-(8-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-amine, as a new drug synthesis intermediate, will have a wider range of applications in the future. Therefore, it is very necessary to develop an efficient, inexpensive and simple industrial synthesis method. Summary of the invention

[0004] 1. Technical problems to be solved: The purpose of the present invention is to provide a new route, a method for preparing 2-(8-bromoimidazo[1,5-a]pyridin-3-yl)propane-2-amine with simple process, mild conditions, high efficiency and suitable for industrial production, so as to solve the technical problems existing in the above-mentioned background technology.

[0005] 2. Technical solution: To solve the above problems, the present invention adopts the following technical solutions.

[0006] A method for preparing 2-(8-bromoimidazo[1,5-a]pyridin-3-yl)propane-2-amine, characterized in that it comprises the following steps: S1, compound I and compound II are condensed to prepare compound III; S2, compound III is dehydrated and cyclized to obtain compound IV; S3. Compound IV is subjected to hydrazinolysis to obtain compound V.

[0007] A further improvement is that the specific operation in step S1 is: adding compound I solution and base into the reaction bottle, adding compound II solution dropwise, after the dropwise addition is completed and the reaction is completed, adding water phase, drying the organic phase, and concentrating the dry phase for the next reaction.

[0008] A further improvement is that the acid binding agent in step S1 is triethylamine, pyridine, DIPEA, and the optimal base is triethylamine.

[0009] 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.

[0010] A further improvement is that the specific operation in the step S2 is: adding compound III, solvent, molecular sieve, and dehydrating agent into the reaction bottle, adding water to separate phases after the reaction is completed, and collecting product spots by organic phase column chromatography.

[0011] Furthermore, the dehydrating agent in step S2 is methyl (chlorosulfonyl) carbamate or ethyl (chlorosulfonyl) carbamate.

[0012] Furthermore, the molar ratio of compound III to the dehydrating agent in step S2 is 1:(1-6), and the optimal molar ratio is 1:1.1.

[0013] Furthermore, the solvent in step S2 is dichloromethane, dichloroethane, chloroform, and the most preferred solvent is 1,2-dichloroethane.

[0014] Furthermore, the temperature of the reaction in step S2 is 10-70°C, and the optimum temperature is 40°C.

[0015] Furthermore, the specific operation in the step S3 is: adding compound IV, solvent, and hydrazine hydrate into a reaction bottle, heating for reaction, completing the reaction, filtering, concentrating the mother liquor, adding water and an organic solvent for extraction, and drying and concentrating the organic phase.

[0016] Furthermore, in the step S3, the molar ratio of compound V to hydrazine hydrate is 1:(2-6), and the optimal molar ratio is 1:4.

[0017] Furthermore, the solvent in step S3 is methanol, ethanol, isopropanol, and ethanol is the most preferred.

[0018] 3. Beneficial effects: Compared with the prior art, the technical solution provided by the present invention has the following beneficial effects: The present invention is reasonably designed and has the following beneficial effects compared with the prior art: A new route is used to synthesize compound V, which avoids the use of HATU and Burgess reagent, has high yield and low cost, and is very suitable for industrial production.

[0019] It should be noted that the structures not introduced in the present invention are the same as the prior art or can be implemented by using the prior art, and are not described in detail here because they do not involve the design points and improvement directions of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 is a synthetic flow chart of the present invention; Figure 2 is the purity diagram of compound V; Figure 3 It is a structural diagram of the somatostatin receptor subtype 4 (SSTR4) agonist; Figure 4 The structure diagram of the compound used in the process of synthesizing the somatostatin receptor subtype 4 (SSTR4) agonist; Figure 5 for Figure 4 Structural schematic diagram of the synthetic route; Figure 6 Schematic diagram of the route of compound V in the prior art. DETAILED DESCRIPTION

[0021] To facilitate understanding of the present invention, the present invention will be described more comprehensively below with reference to the relevant drawings. Several embodiments of the present invention are shown in the drawings. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the present invention more thorough and comprehensive.

[0022] Example 1: Preparation of Compound III: N-((3-bromopyridin-2-yl)methyl)-2-(1,3-dioxoisoindole-2-yl)-2-methylpropanamide Under nitrogen protection, 52g (1eq) of compound Ⅰ, 260ml of dichloromethane (260ml) (5V) and 84.4g of triethylamine (3eq) were added to the reaction bottle, and 83.9g (1.2eq) of compound Ⅱ was slowly added dropwise at 5-20°C, diluted with 160ml of dichloromethane and added dropwise. After the addition, the reaction was stirred and the reaction was completed. Hydrochloric acid was added dropwise to adjust the pH to neutral, washed twice with water, separated, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to dryness, added toluene to pulp for 2h, filtered and dried to obtain 106.23g of off-white crystals, and the molar yield was calculated to be 95%.

[0023] 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] + Example 2: Preparation of Compound IV: 2-(2-(8-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-yl)isoindoline-1,3-dione Add 50 g (1 eq) of compound III, 750 ml (15V) of dichloroethane, and 150 g of 4A molecular sieves into 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 completed, filter and add 150 ml of water to the filtrate for phase separation. Wash the organic phase with 150 ml of saturated brine, concentrate and perform column chromatography. Collect the product and concentrate to 23.82 g of a yellow solid. The molar yield is 50%.

[0024] 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] + Example 3: Preparation of Compound V: 2-(2-(8-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-yl)isoindoline-1,3-dione Add 50g (1eq) of compound III, 750ml of dichloroethane, and 150g of 4A molecular sieves into a reaction flask, stir at 40°C for 30min, then add 67.63g (3.1eq) of methyl (chlorosulfonyl) carbamate, and react at 40°C for 1h. After the reaction is completed, filter, add 150ml of water to the filtrate, wash the organic phase with 150ml of saturated brine, concentrate and perform column chromatography, collect the concentrated product to 22.76g as a yellow solid, and the molar yield is calculated to be 48%.

[0025] Example 4: Preparation of Compound V: 2-(8-bromoimidazo[1,5-a]pyridin-3-yl)propane-2-amine Add 15g (1eq) of compound IV and 300ml of anhydrous ethanol to a reaction flask, add 9.77g (4eq) of hydrazine hydrate dropwise at 60-70°C, heat and reflux to react, cool to about 0°C, filter, concentrate the mother liquor and add water and evaporate twice, add 30ml of water and dichloromethane, separate the phases, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate and concentrate to obtain 9.44g of white crystals, with a calculated molar yield of 95%.

[0026] 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) The total yield of 2-(8-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-amine prepared through the above steps is 45%, and the purity is greater than 99% as detected by HPLC (high performance liquid chromatography).

[0027] The above fully illustrates that the present invention has good applicability, high yield, and is very suitable for industrial scale-up production. The examples only express a certain embodiment of the present invention, and the description is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention; it should be pointed out that for ordinary technicians in the field, without departing from the concept of the present invention, several modifications and improvements can be made, which all belong to the protection scope of the present invention; therefore, the protection scope of the patent of the present invention shall be based on the attached claims.

[0028] The above-described embodiments only express a certain implementation mode of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the patent scope of the present invention. It should be pointed out that, for ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be based on the attached claims.

Claims

1. A method for preparing 2-(8-bromoimidazo[1,5-a]pyridin-3-yl)propane-2-amine, characterized in that: The following steps are involved: S1, compound I and compound II are condensed to prepare compound III; S2, compound III is dehydrated and cyclized to obtain compound IV; S3. Compound IV is subjected to hydrazinolysis to obtain compound V.

2. The method for preparing 2-(8-bromoimidazo[1,5-a]pyridin-3-yl)propane-2-amine according to claim 1, characterized in that: The specific operation in step S1 is to add the solution of compound I and an acid-binding agent and a solvent into a reaction bottle, add compound II, and after the reaction is completed, add water to separate the phases, dry the organic phase, and concentrate it 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 and pyridine.

3. The method for preparing 2-(8-bromoimidazo[1,5-a]pyridin-3-yl)propane-2-amine according to claim 1, characterized in that: The specific operation in the step S2 is to add compound III, solvent, molecular sieve and dehydrating agent into the reaction bottle, add water to phase after the reaction is completed, and collect product spots by organic phase column chromatography.

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

5. The method for preparing 2-(8-bromoimidazo[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-bromoimidazo[1,5-a]pyridin-3-yl)propane-2-amine according to claim 3, characterized in that: In the 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.

7. The method for preparing 2-(8-bromoimidazo[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 and chloroform.

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

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

10. The method for preparing 2-(8-bromoimidazo[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 and isopropanol.

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