Synthesis method of bronchial drug intermediate

Abstract

The invention provides an efficient and economical method for catalytically synthesizing a bronchial drug intermediate. The synthesis method is simple and efficient, post-treatment is convenient, starting materials are cheap and easy to obtain, and industrial production is easy. # imgabs0 #

Description

Technical Field

[0001] This application relates to the field of drug intermediate synthesis, and specifically, to a method for synthesizing a drug intermediate. Background Art

[0002] The investigational drug Brensocatib of AstraZeneca is an oral, reversible dipeptidyl peptidase 1 (DPP1) inhibitor, mainly used for the treatment of non-cystic fibrosis bronchiectasis (NCFBE). Brensocatib reduces neutrophil-mediated lung injury and inflammation by inhibiting DPP1, thereby reducing the rate of pulmonary exacerbation in patients.

[0003] 。

[0004] This candidate drug molecule is prepared by condensation reaction and protecting group transformation from key intermediate compound 4 and compound 6.

[0005] The main synthetic routes of compound 4 in the prior art such as literature are as follows.

[0006] The route design of directly coupling the 4-iodophenylalanine derivative prepared from phenylalanine with a borate compound, as reported in patents such as WO2010128324, WO2013041497, WO2015110826, etc., has the following synthetic routes: , In the process of preparing compound A3 from compound A2, the literature uses relatively expensive reagents such as Burgess reagent or methyl (chlorosulfonyl)carbamate as dehydrating agents to complete the preparation of the cyano compound A3. Although there is also literature mentioning the condition of TFAA / TEA, the reaction yield is not given. In the reaction of preparing compound 4 from compound A3 and A5, the use equivalent of the palladium catalyst is 10% mol, and the catalyst dosage is relatively high. In addition, the synthesis of compound A5 also uses the Suzuki-Miyaura reaction catalyzed by transition metal Pd, so the cost of A5 is high, further driving up the cost of A8.

[0007] The following synthetic route is reported in patent WO2015110826. Compound A2 and A5 can undergo coupling and subsequent deprotection reactions under the condition of 1.36 mol% palladium catalyst to obtain compound A8 with a two-step yield of 68%. Although this route reduces the catalytic amount, the preparation of A5 still requires the noble metal-catalyzed coupling reaction of its chloro precursor with bis(pinacolato)diboron, and the material cost of A8 is still relatively high; , This case shows that although the catalytic efficiency in the later coupling stage has been optimized, the preparation of the precursor borate ester still has the problem of high cost. Therefore, developing a more economical method for synthesizing borate esters or exploring a non-noble metal catalytic system still has important research value.

[0008] There is also a route design for preparing 4-halophenylalanine derivatives derived from phenylalanine and then further derivatizing them into borate esters for coupling with aryl halides. For example, Haisco reported such a transformation in patent WO2022042591, where A6 was coupled with the corresponding arylboronic acid under palladium-catalyzed conditions. It should be noted that this reaction requires the use of approximately 10 mol% of palladium catalyst, and only bromides have been reported to achieve a yield of 72 - 95%, with no examples of coupling with less reactive chlorides. The general formula of the synthetic route is shown as follows: , .

[0009] The synthetic methods reported in the existing literature have obvious limitations in terms of the supply of key raw materials or catalytic efficiency: some routes rely on high-cost borate ester precursors, while others require the use of high-load noble metal catalysts. These technical defects significantly affect the feasibility of industrial production of related intermediates. Therefore, developing a new synthetic route with cost-effectiveness, high catalytic efficiency, and process scalability not only has important academic research value but also provides a practical solution for the industrial production of related pharmaceutical intermediates. Summary of the Invention

[0010] The purpose of this application is to provide a method for preparing compound 4.

[0011] , (1) Compound 1 reacts with an ammonium salt through a dehydration reaction to prepare the corresponding amide compound 2; (2) Compound 2 undergoes a transition metal-catalyzed coupling reaction to prepare compound 3; (3) Compound 3 undergoes a dehydration reaction to obtain compound 4.

[0012] Compared with the prior art, the method for synthesizing compound 4 in this application has the following advantages: (1) Selecting compound 1 (such as the synthesis scheme reported in CN118994222 or US5157149) and compound 5 (such as the synthesis scheme reported in US9522894) as starting materials, both of which have preparation methods that do not involve noble metal coupling, can effectively control the cost of raw materials; (2) Changing the coupling substrate, the amide substrate effectively reduces the equivalent amount of noble metal catalyst used compared to the cyano substrate; (3) The route has relatively high atom economy, the selected substrates are more inexpensive and readily available, and it is more in line with the concept of current green chemistry and environmentally friendly synthesis processes. Detailed Description of the Invention

[0013] The embodiments of the present application will be described below through examples. Those skilled in the art should recognize that these specific examples only represent the implementation technical solutions selected to achieve the purpose of the present application, and do not limit the technical solutions. According to the teachings of the present application, it is obvious to improve the technical solutions of the present application in combination with the prior art, and all belong to the scope protected by the present application.

[0014] The implementation conditions adopted in the examples can be further adjusted according to specific requirements. The implementation conditions not specified are usually the conditions in conventional experiments. The starting materials are commercially available compounds or prepared by referring to the existing literature.

[0015] Example 1 , Compound 1 (CAS#119771-23-2, 1.0 eq, 20.0 g), ammonium bicarbonate (2.0 eq), di-tert-butyl dicarbonate (1.3 eq), pyridine (3.0 eq), and N,N-dimethylformamide (5 vol) were added to a reaction flask and reacted at room temperature (25 °C) for 2 - 3 h. After the reaction was complete, water (40 vol) was added to the reaction system and stirred for another hour. The product precipitated to obtain a white solid; it was filtered and dried by suction, and then dried at 50 °C; 17.94 g was obtained, with a yield of 90% and a purity of 98.90%.

[0016] Mass spectrometry data of Compound 2: ESI[M - Boc + H] + = 209.15.

[0017] Nuclear magnetic data of Compound 2: 1 H NMR (400 MHz, DMSO) δ 7.94 (s, 2H), 7.69 (d, J = 7.6 Hz, 2H), 7.37 (s, 1H), 7.22 (d, J = 7.6 Hz, 2H), 7.02 (s, 1H), 6.79 (d, J = 8.6 Hz, 1H), 4.13~4.04 (m, 1H), 2.98~2.93 (m, 1H), 2.77~2.68 (m, 1H), 1.31(s, 9H).

[0018] Example 2 , Under nitrogen protection, compound 2 (1.0 eq, 5.0 g), compound 5 (1.05 eq), palladium acetate (0.005 eq), X-Phos (0.02 eq), potassium carbonate (2.0 eq), 1,4-dioxane (5 vol) and water (1 vol) were added to the reaction flask. The reaction was carried out at 80 °C for 3 h. After the reaction was complete, water (5 vol) and EA (5 vol) were added, stirred and separated. The aqueous phase was further extracted with EA (5 vol) once; the EA phase was concentrated to dryness at 40 °C to obtain a brown solid; column chromatography using n-heptane / ethyl acetate = 1 / 1~1 / 3 gave 5.68 g of the product. The yield was 85% and the purity was 99.12%.

[0019] The mass spectrometry data of compound 3: [M+H-56] + = 356.09

[0020] The NMR data of compound 3: 1 H NMR (400 MHz, DMSO) δ 7.67~7.59 (m, 2H), 7.56(t, J J = 1.2 Hz, 1H), 7.48~7.31 (m, 5H), 7.04 (s, 1H), 6.86 (d, J J = 8.6 Hz,1H), 4.16~4.10 (m, 1H), 3.40 (s, 3H), 3.03~2.98 (m, 1H), 2.81~2.75 (m, 1H),1.31 (s, 10H).

[0021] In this example, different palladium catalysts (Pd(dppf)Cl2, Pd(dtbpf)Cl2, Pd(PPh3)4, Pd(OAc)2, X-Phos Pd G2) and different ligands (X-Phos, dppf) were screened for combination, which could all reduce the amount of catalyst used to varying degrees. The results showed that the combination of Pd(OAc)2 and X-Phos and the combination of X-Phos Pd G2 and X-Phos had the best reaction effect, and Pd(OAc)2 and X-Phos with lower usage cost were used as the most preferred catalysts.

[0022] Example 3 , Add trifluoroacetic anhydride (2.2 eq), pyridine (6.0 eq), and THF (5 vol) to the reaction flask. While controlling the temperature in the reaction flask at 0 - 10 °C, add a THF (5 vol) solution of compound 3 (1.0 eq, 0.5 g). React at room temperature for 2 - 3 h. After the reaction is complete, add 0.1 M HCl (10 vol) and EA (10 vol), stir and separate the layers. Extract the aqueous phase with EA (5 vol) one more time. Concentrate the EA phase to dryness at 40 °C to obtain a white solid. Use a normal heptane / ethyl acetate = 4 / 1 - 2 / 3 column chromatography to obtain 0.43 g of product compound 4, with a yield of 90% and a purity of 99.10%.

[0023] Mass spectrometry data of compound 4: [M+H] + = 394.14

[0024] NMR data of compound 4: 1 H NMR (400 MHz, DMSO) δ 7.88 (d, J = 8.2 Hz, 1H), 7.71~7.63 (m, 2H), 7.58 (d, J = 1.6 Hz, 1H), 7.46~7.35 (m, 4H), 4.73~4.67 (m, 1H), 3.40 (s, 3H), 3.09 (s, 2H), 1.37 (s, 9H).

[0025] This application includes but is not limited to the above embodiments. Any equivalent substitution or partial improvement carried out under the principle of the spirit of this application will be regarded as within the protection scope of this application.

Claims

1. A method for preparing compound 4, , Step (1): React compound 1 with an ammonium salt or ammonia under the action of a dehydrating agent to prepare the corresponding amide compound 2; Step (2): Catalyze the coupling reaction of compound 2 and compound 5 with a palladium catalyst to prepare compound 3; Step (3): Perform a dehydration reaction on compound 3 under the action of a dehydrating agent and a base to obtain compound 4.

2. As described in claim 1, the dehydrating agent in step (1) is di-tert-butyl dicarbonate.

3. As described in claim 1, the palladium catalyst in step (2) is composed of a palladium metal salt and a ligand.

4. As described in claim 3, the equivalent amount of the palladium metal salt used is not higher than 0.5% mol, and the equivalent amount of the ligand used is not higher than 2% mol.

5. As described in claim 4, the palladium metal salt is palladium acetate, and the ligand is X-Phos.

6. As described in claim 1, the dehydrating agent in step (3) is trifluoroacetic anhydride, and the base is pyridine.

7. As described in claim 1, in step (1), compound 1 (1.0 eq), ammonium bicarbonate (2.0 eq), di-tert-butyl dicarbonate (1.3 eq), pyridine (3.0 eq), and N,N-dimethylformamide (5 vol) react completely at room temperature. Add (40 vol) water to the reaction system to precipitate the white solid compound 2.

8. As described in claim 1, in step (2), compound 2 (1.0 eq), compound 5 (1.05 eq), palladium acetate (0.005 eq), X-Phos (0.02 eq), and potassium carbonate (2.0 eq) are used in 1,4-dioxane (5 vol) and water (1 vol), and react at 80 °C to prepare compound 3.

9. As described in claim 1, in step (3), in a solution of trifluoroacetic anhydride (2.2 eq) and pyridine (6.0 eq) in THF (5 vol), control the temperature at 0 - 10 °C and add a solution of compound 3 (1.0 eq) in THF (5 vol), and react at room temperature to obtain compound 4.

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