A process for the preparation of the DPP1 inhibitor brivaninitide

Abstract

This invention discloses a method for preparing the DPP1 inhibitor bresocarte, belonging to the field of pharmaceutical synthesis. Specifically, the method includes the following steps: N-tert-butoxycarbonyl-L-4-bromophenylalanine reacts with methanesulfonyl chloride or 4-nitrobenzenesulfonyl chloride in the presence of a base, followed by amination substitution to obtain intermediate 1; then, it undergoes dehydration in the presence of trifluoroacetic anhydride to obtain intermediate 2; next, it undergoes a coupling reaction with pinacol diboronate to obtain intermediate 3; then, it undergoes a coupling reaction with bromide compound 4 to obtain intermediate 5; then, it undergoes cyclization with di-tert-butyl dicarbonate in the presence of sodium methoxide to obtain intermediate 6; then, it undergoes deprotection in the presence of hydrogen chloride to obtain intermediate 7; next, it undergoes condensation with compound 8 to obtain intermediate 9; finally, it undergoes deprotection in the presence of hydrogen chloride to obtain the inhibitor bresocarte. This method provides a new synthetic approach, with low overall cost, simple operation, high yield, and suitability for industrial production.

Description

Technical Field

[0001] This invention relates to a method for preparing the DPP1 inhibitor bresocarte, belonging to the field of pharmaceutical synthesis technology. Background Technology

[0002] AZD7986 (generic name: bresocatib) is a dipeptidyl peptidase 1 (DPP1) inhibitor. Its English name is (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, and its Chinese name is (S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[D]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide. Its primary use is to inhibit the activation of neutrophil serine proteases (NSPs), thereby modulating the inflammatory response. Originally developed by AstraZeneca, this drug is currently primarily focused on treating chronic inflammatory lung disease, namely chronic obstructive pulmonary disease (COPD). The mechanism of action of this drug also provides new insights into stroke and lung metastasis of breast cancer.

[0003] Existing US patent US2015 / 210655, 2015, A1 reports a reaction using chlorzoxazone as a starting material. First, compound II is reacted with iodomethane in the presence of cesium carbonate to give compound IV. Then, compound IV is coupled with pinacol diboronate to give compound IV. Next, compound IV is coupled with tert-butyl (S)-(1-amino-3-(4-iodophenyl)-1-oxopropyl-2-yl)carbamate to give compound VI. Following deprotection with hydrogen chloride, compound VII is given. Then, compound IX is condensed with (S)-4-(tert-butoxycarbonyl)-1,4-oxazetane-2-carboxylic acid to give compound IX. Finally, compound X is deprotected with trifluoroacetic acid. The reaction route is shown below:

[0004] This method has high raw material and production costs, and the coupling reaction can cause a lot of oxazole structure decomposition, making it difficult to purify the final compound. Summary of the Invention

[0005] To address the problems existing in the prior art, this invention provides a method for preparing bresocarte, specifically comprising the following steps: N-tert-butoxycarbonyl-L-4-bromophenylalanine reacts with methanesulfonyl chloride or 4-nitrobenzenesulfonyl chloride in the presence of a base, followed by amination substitution to obtain intermediate 1; then, it undergoes a dehydration reaction in the presence of trifluoroacetic anhydride to obtain intermediate 2; subsequently, it undergoes a coupling reaction with pinacol diboronate to obtain intermediate 3; then, it undergoes a coupling reaction with brominated compound 4 to obtain intermediate 5; then, it undergoes cyclization with di-tert-butyl dicarbonate in the presence of sodium methoxide to obtain intermediate 6; then, it undergoes deprotection in the presence of hydrogen chloride to obtain intermediate 7; then, it undergoes condensation with compound 8 to obtain intermediate 9; finally, it undergoes deprotection in the presence of hydrogen chloride to obtain the inhibitor bresocarte. This method provides a new synthetic approach, with lower overall cost, simple operation, high yield, and suitability for industrial production.

[0006] The preparation method of the DPP1 inhibitor bresocarte of the present invention includes the following steps: Step 1: N-tert-butoxycarbonyl-L-4-bromophenylalanine reacts with methanesulfonyl chloride or 4-nitrobenzenesulfonyl chloride in the presence of an organic base, followed by substitution with an amination reagent to give intermediate 1; Step 2: Intermediate 1 undergoes a dehydration reaction in the presence of trifluoroacetic anhydride to obtain intermediate 2; Step 3: Intermediate 2 and pinacol diboronic acid ester are coupled together in the presence of K2CO3 and PdCl2dppf to obtain intermediate 3; Step 4: Intermediate 3 and bromide product 4 are coupled in the presence of K2CO3, X-phos and Pd2(dba)3 to obtain intermediate 5; Step 5: Intermediate 5 is cyclized with di-tert-butyl dicarbonate in the presence of triethylamine and sodium methoxide to obtain intermediate 6; Step 6: Intermediate 6 is deprotected in the presence of hydrogen chloride to obtain intermediate 7; Step 7: Intermediate 7 and compound 8 undergo condensation to obtain intermediate 9; Step 8: Intermediate 6 is deprotected in the presence of hydrogen chloride to give bresocarte.

[0007] The preparation method of the DPP1 inhibitor bresocarte described in this invention is represented by the following reaction equation:

[0008] In a preferred embodiment, in the first step, the organic base is selected from diisopropylethylamine or N-methylmorpholine.

[0009] In a preferred embodiment, in the first step, the molar ratio of N-tert-butoxycarbonyl-L-4-bromophenylalanine, methanesulfonyl chloride or 4-nitrobenzenesulfonyl chloride, organic base and amination reagent is 1:1:1.8-2.0:2.0-3.0.

[0010] In a preferred embodiment, in the second step, the molar ratio of intermediate 1 to TFAA is 1:1.5-2.0.

[0011] In a preferred embodiment, in the third step, the molar ratio of intermediate 2, pinacol diboronate, potassium carbonate, and PdCl2dppf is 1:1.1:2.0-2.5:0.01-0.05.

[0012] In a preferred embodiment, in the fourth step, the molar ratio of intermediate 3, bromide 4, potassium carbonate, Xphos and Pd2(dba)3 is 1:1-1.1:2.0:0.01-0.022:0.006-0.01.

[0013] In a preferred embodiment, in step five, the molar ratio of intermediate 5, di-tert-butyl dicarbonate, triethylamine, and sodium methoxide is 1:1-1.2:1.25-1.30:1.5.

[0014] In a preferred embodiment, in step six, the molar ratio of intermediate 6 to hydrogen chloride is 1:3.0-3.5.

[0015] In a preferred embodiment, in step seven, the molar ratio of intermediate 7, methanesulfonyl chloride, compound 8 and NMM (4-methylmorpholine) is 1:1:1.0-1.05:3.2-3.5.

[0016] In a preferred embodiment, in step eight, the molar ratio of intermediate 9 to hydrogen chloride is 1:2.0-3.5.

[0017] Compared to the synthetic route reported in US Patent US2015 / 210655, 2015, A1, this invention makes the following improvements: 1. Using p-bromophenylalanine instead of 4-iodophenylalanine reduces costs and side reactions. 2. By changing the assembly order, the amino acid is made into a borate ester before condensation with the brominated product, which reduces the large-scale decomposition of the cyclic structure during coupling in the original route, resulting in a highly mixed product. 3. Synthesizing the cyclic structure with Boc₂O in the presence of excess base results in a clean and rapid reaction with significantly reduced costs. Detailed Implementation

[0018] The present invention will be further described below through specific embodiments, but this is not a limitation of the present invention. Those skilled in the art can make various modifications or improvements based on the basic idea of ​​the present invention, but as long as they do not depart from the basic idea of ​​the present invention, they are all within the scope of the present invention. Example 1

[0019]

[0020] 172.1 g (0.5 mol, 1 eq) of N-tert-butoxycarbonyl-L-4-bromophenylalanine was dissolved in 1300 mL of dichloromethane, cooled to -10 °C, and 116.3 g (0.9 mol, 1.8 eq) of DIPEA was added. 57.3 g (0.5 mol, 1 eq) of methanesulfonyl chloride was added dropwise, and the reaction was carried out at this temperature for 2 hours. Then, 178.6 mL (1.25 mol, 2.5 eq) of 7M ammonia-methanol solution was added, the temperature was slowly raised to room temperature, and the reaction was carried out overnight. HPLC analysis showed that the remaining starting material was ≤0.5%. The mixture was cooled to 0 °C, and the organic phase was washed successively with 5% hydrochloric acid, 5% sodium bicarbonate, and water. The organic phase was concentrated under reduced pressure, and MTBE and n-heptane were added and slurryed to obtain 156.7 g of N-tert-butoxycarbonyl-L-4-bromophenylalanine amide, with a yield of 91.3%. Example 2

[0021]

[0022] 172.1 g (0.5 mol, 1 eq) of N-tert-butoxycarbonyl-L-4-bromophenylalanine was dissolved in 1100 mL of dichloromethane. The solution was cooled to -10 °C, and 101.2 g (1.0 mol, 2.0 eq) of NMM was added. 110.8 g (0.5 mol, 1 eq) of 4-nitrobenzenesulfonyl chloride was added dropwise in 300 mL of dichloromethane solution. The reaction was carried out at this temperature for 2 hours. Then, 178.6 mL (1.25 mol, 2.5 eq) of 7M ammonia-methanol solution was added, and the solution was slowly heated to room temperature and reacted overnight. HPLC analysis showed that the remaining starting material was ≤0.5%. The solution was cooled to 0 °C, and the organic phase was washed successively with 5% hydrochloric acid, 5% sodium bicarbonate, and water. The organic phase was concentrated under reduced pressure, and MTBE and n-heptane were added to slurry to obtain 158.1 g of N-tert-butoxycarbonyl-L-4-bromophenylalanine amide, with a yield of 92.1%. Example 3

[0023]

[0024] 154.5 g (0.45 mol, 1 eq) of N-tert-butoxycarbonyl-L-4-bromophenylalanine amide was dissolved in 1200 mL of tetrahydrofuran. The solution was cooled to -10 °C, and 170.1 g (0.81 mol, 1.8 eq) of TFAA was added dropwise. The solution was slowly heated to room temperature and reacted for 6 hours. The starting material was ≤1.0% by HPLC. The solution was concentrated under reduced pressure at 35-40 °C until it did not flow. 1200 mL of ethyl acetate was added for dilution, and the pH was adjusted to 8-9 by adding 10% potassium bicarbonate aqueous solution. The solution was then washed twice with brine. The organic phase was concentrated under reduced pressure at 35-40 °C, and then slurryed with n-heptane to obtain 125.4 g of N-tert-butoxycarbonyl-L-4-bromophenylalanine nitrile, with a yield of 85.7%. Example 4

[0025]

[0026] Under nitrogen protection, 113.8 g (0.35 mol, 1 eq) of N-tert-butoxycarbonyl-L-4-bromophenylalanine nitrile, 97.8 g (0.385 mol, 1.1 eq) of pinacol diboronate, 680 mL of DMF, 108.8 g (0.7875 mol, 2.25 eq) of potassium carbonate, and 12.8 g of 1,1-bis(diphenylphosphine)diberberine palladium dichloride were added. Mix (0.0175 mol, 0.05 eq), heat to 90 °C, react for 8 hours, cool the reaction solution to room temperature, filter through diatomaceous earth, wash the filter cake with 1000 mL of DCM, wash the filtrate successively with 5% hydrochloric acid, 5% sodium bicarbonate, and water, concentrate the organic phase under reduced pressure, add n-heptane and slurry to obtain 115.1 g of (S)-(1-cyano-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)ethyl)carbamate tert-butyl, yield 88.3%. Example 5

[0027]

[0028] 75.2 g (0.4 mol, 1 eq) of 2-amino-4-bromophenol and 35.7 g (0.44 mol, 1.10 eq) of 37% formaldehyde aqueous solution were mixed in 450 mL of hexafluoroisopropanol. 52.3 g (0.8 mol, 2.0 eq) of zinc powder was added in portions. The mixture was heated to 55-60 °C and reacted for 4 hours. HPLC showed no residue of raw materials. The mixture was filtered, and the filter cake was washed with 50 mL of hexafluoroisopropanol. The filtrate was concentrated under reduced pressure at 35-40 °C until it no longer flowed (the concentrated hexafluoroisopropanol can be recycled up to 3 times). 400 mL of ethyl acetate was added, and the mixture was washed twice with water. After concentration under reduced pressure at 30-40 °C, n-heptane was added and the mixture was slurried to obtain 73.4 g of 4-bromo-2-(methylamino)-phenol, with a yield of 90.8%.

[0029]

[0030] Under nitrogen protection, 111.7 g (0.3 mol, 1 eq) of N-[(1S)-1-cyano-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]ethyl]carbamate tert-butyl ester, 60.6 g (0.3 mol, 1 eq) of 4-bromo-2-(methylamino)-phenol, 750 mL of DMF, 82.9 g (0.6 mol, 2 eq) of powdered potassium carbonate, 1.72 g (0.0036 mol, 0.012 eq) of X-PHOS and 1.65 g (0.0018 mol, 0.006 eq) of tris(dibenzylacetone)dipalladium were mixed, heated to 80 °C, and reacted for 10 hours. The reaction solution was cooled to room temperature and filtered through diatomaceous earth. The filter cake was washed with 750 mL of 2-MeTHF. The filtrate was washed with 5% hydrochloric acid, 5% sodium bicarbonate, and water, respectively. The organic phase was concentrated under reduced pressure, and the filtrate was concentrated under reduced pressure. Isopropyl ether was added and the mixture was slurried to obtain 103.3 g of tert-butyl(S)-(1-cyano-2-(4'-hydroxy-3'-(methylamino)-[1,1'-biphenyl]-4-yl)ethyl)carbamate, with a yield of 93.7%.

[0031] Example 6

[0032] Under nitrogen protection, 91.9 g (0.25 mol, 1 eq) of tert-butyl (S)-(1-cyano-2-(4'-hydroxy-3'-(methylamino)-[1,1'-biphenyl]-4-yl)ethyl)carbamate was dissolved in 730 mL of 2-MeTHF, and 65.5 g (0.3 mol, 1.2 eq) of ditert-butyl dicarbonate and 31.6 g (0.3125 mol, 1 eq) of triethylamine were added. 1.25 eq), then cooled to 0℃, added 24.3 g (0.45 mol, 1.5 eq) of sodium methoxide, HPLC analysis showed the remaining raw material was ≤0.8%, quenched with 5% hydrochloric acid, allowed to stand and separate, washed the organic phase with brine, concentrated the organic phase under reduced pressure, added n-heptane and slurry to obtain 89.2 g of tert-butyl N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzo[D]oxazol-5-yl)phenyl]ethyl]carbamate, yield 90.7%. Example 7

[0033]

[0034] 78.7 g (0.2 mol, 1 eq) of tert-butyl N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamate was mixed with 470 mL of acetonitrile. The mixture was cooled to 0-5 °C, and 146 g (0.6 mol, 3.0 eq) of 15% hydrogen chloride / acetonitrile solution was added dropwise. The mixture was slowly heated to room temperature and reacted for 3 hours. HPLC analysis showed that the remaining starting material was ≤0.2%. Ethyl acetate was added and the mixture was stirred to obtain 61.9 g of (S)-2-amino-3-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[D]oxazol-5-yl)phenyl)propionitrile hydrochloride, with a yield of 93.8%.

[0035] Example 8

[0036] 36.8 g (0.15 mol, 1 eq) of (S)-4-(tert-butoxycarbonyl)-1,4-oxazacycloheptan-2-carboxylic acid was mixed with 300 mL of 2-MeTHF, cooled to -10 °C, and 53.1 g (0.525 mol, 1 eq) of NMM was added. 3.5 eq), add dropwise 17.2 g (0.15 mol, 1 eq) of methanesulfonyl chloride / 100 mL of 2-MeTHF solution, and react at this temperature for 2 hours. Add 49.5 g (0.15 mol, 1 eq) of (S)-2-amino-3-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[D]oxazol-5-yl)phenyl)propionitrile hydrochloride in portions, slowly raise the temperature to room temperature and react overnight. HPLC analysis showed that the remaining starting material was ≤1.0%. Cool to 0℃, wash the organic phase sequentially with 5% hydrochloric acid, 5% sodium bicarbonate, and water. Concentrate the organic phase under reduced pressure, replace with ethanol, then dissolve in ethanol again. Add water dropwise to precipitate the solid, and filter to obtain tert-butyl(2S)- 68 g of 2-({(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydrobenzo[D]oxazol-5-yl)phenyl]ethyl}aminoyl)-1,4-oxazolidine-4-carboxylic acid ester, yield 87.1%.

[0037]

[0038] 52.1 g (0.1 mol) of tert-butyl(2S)-2-({(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydrobenzo[D]oxazol-5-yl)phenyl]ethyl}aminoyl)-1,4-oxazolidine-4-carboxylic acid ester were prepared. 1 eq) was mixed in 300 mL of acetonitrile solvent, cooled to 0 °C, and 300 mL of 1 mol / L hydrogen chloride / ethyl acetate solution (0.3 mol, 3 eq) was added dropwise. The mixture was slowly heated to room temperature and reacted for 3 hours. After filtration, the filter cake was added to ethanol and water, and lithium hydroxide was added to adjust the pH to 9.0-9.5. The mixture was heated to 35 °C and reacted for 1 hour until the pH was stable at 9.0-9.5. After cooling to 10 °C, the mixture was filtered to obtain 40.1 g of (S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[D]oxazol-5-yl)phenyl)ethyl)-1,4-oxazhecycloheptane-2-carboxamide, with a yield of 95.4% and an HPLC yield of 98.9%.

[0039] The above description is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make several modifications and improvements without departing from the inventive concept of the present invention, and these all fall within the protection scope of the present invention.

Claims

1. A process for the preparation of the DPP1 inhibitor brivanacet, characterized in that, Includes the following steps: ； Step 1: N-tert-butoxycarbonyl-L-4-bromophenylalanine reacts with methanesulfonyl chloride or 4-nitrobenzenesulfonyl chloride in the presence of an organic base, followed by substitution with an amination reagent to give intermediate 1; Step 2: Intermediate 1 undergoes a dehydration reaction in the presence of trifluoroacetic anhydride to obtain intermediate 2; Step 3: Intermediate 2 and pinacol diboronic acid ester are coupled together in the presence of K2CO3 and PdCl2dppf to obtain intermediate 3; Step 4: Intermediate 3 and bromide product 4 are coupled in the presence of K2CO3, X-phos and Pd2(dba)3 to obtain intermediate 5; Step 5: Intermediate 5 is cyclized with di-tert-butyl dicarbonate in the presence of triethylamine and sodium methoxide to obtain intermediate 6; Step 6: Intermediate 6 is deprotected in the presence of hydrogen chloride to obtain intermediate 7; Step 7: Intermediate 7 and compound 8 undergo condensation to obtain intermediate 9; Step 8: Intermediate 6 is deprotected in the presence of hydrogen chloride to give bresocarte.

2. Process for the preparation of the DPP1 inhibitor brivaninitide according to claim 1, characterized in that: In the first step, the organic base is selected from diisopropylethylamine or N-methylmorpholine.

3. Process for the preparation of the DPP1 inhibitor brivaninitide according to claim 1, characterized in that: In the first step, the molar ratio of N-tert-butoxycarbonyl-L-4-bromophenylalanine, methanesulfonyl chloride or 4-nitrobenzenesulfonyl chloride, organic base and amination reagent is 1:1:1.8-2.0:2.0-3.

0.

4. A process for the preparation of the DPP1 inhibitor brivaninitide according to claim 1, characterized in that: In the second step, the molar ratio of intermediate 1 to TFAA is 1:1.5-2.

0.

5. A process for the preparation of the DPP1 inhibitor brivaninitide according to claim 1, characterized in that: In the third step, the molar ratio of intermediate 2, pinacol diboronate, potassium carbonate and PdCl2dppf is 1:1.1:2.0-2.5:0.01-0.

05.

6. A process for the preparation of the DPP1 inhibitor brivaninitide according to claim 1, characterized in that: In the fourth step, the molar ratio of intermediate 3, bromide 4, potassium carbonate, Xphos and Pd2(dba)3 is 1:1-1.1:2.0:0.01-0.022:0.006-0.

01.

7. A process for the preparation of the DPP1 inhibitor brivaninitide according to claim 1, characterized in that: In the fifth step, the molar ratio of intermediate 5, di-tert-butyl dicarbonate, triethylamine and sodium methoxide is 1:1-1.2:1.25-1.30:1.

5.

8. A process for the preparation of the DPP1 inhibitor brivaninitide according to claim 1, characterized in that: In step six, the molar ratio of intermediate 6 to hydrogen chloride is 1:3.0-3.

5.

9. A process for the preparation of the DPP1 inhibitor brivaninitide according to claim 1, characterized in that: In step seven, the molar ratio of intermediate 7, methanesulfonyl chloride, compound 8 and NMM is 1:1:1.0-1.05:3.2-3.

5.

10. A process for the preparation of the DPP1 inhibitor brivaninitide according to claim 1, characterized in that: In step 8, the molar ratio of intermediate 9 to hydrogen chloride is 1:2.0-3.5.

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