{"id":49,"date":"2026-06-16T05:25:23","date_gmt":"2026-06-16T05:25:23","guid":{"rendered":"https:\/\/astinovabiolabs.com\/blog\/?p=49"},"modified":"2026-06-16T05:25:23","modified_gmt":"2026-06-16T05:25:23","slug":"synthesis-of-brensocatib-brinsupri","status":"publish","type":"post","link":"https:\/\/astinovabiolabs.com\/blog\/synthesis-of-brensocatib-brinsupri\/","title":{"rendered":"Synthesis of Brensocatib (BRINSUPRI)"},"content":{"rendered":"\n

Compiled:<\/strong> 2026-06-16 \u00b7 Trigger event:<\/strong> FDA approval, 2025-08-12 Innovator:<\/strong> Insmed Incorporated (originator AstraZeneca; AZD7986, worldwide-licensed to Insmed Oct 2016 as INS1007) Status:<\/strong> Approved NME<\/p>\n\n\n\n

INN:<\/strong> brensocatibBrand (US):<\/strong> BRINSUPRICAS:<\/strong> 1802148-05-5ChEMBL:<\/strong> CHEMBL3900409MW:<\/strong> 420.5 g\/molNDA #:<\/strong> NDA 217673Approval:<\/strong> 2025-08-12<\/p>\n\n\n\n

Mechanism:<\/strong>\u00a0Brensocatib is a competitive, reversible (reversible-covalent, via a nitrile warhead engaging the catalytic Cys) inhibitor of dipeptidyl peptidase 1 (DPP1, cathepsin C; ChEMBL target CHEMBL2252). DPP1 activates pro-inflammatory neutrophil serine proteases (NSPs) \u2014 neutrophil elastase, cathepsin G, proteinase 3 \u2014 during neutrophil maturation in the bone marrow. By blocking DPP1, brensocatib lowers the activity of mature-neutrophil NSPs that drive the airway-damage cycle of neutrophil-mediated NCFB inflammation. Refs: PMID 27690432 (discovery), PMID 29484635.<\/p>\n\n\n\n

Synthesis Route of the Originator<\/strong><\/p>\n\n\n\n

Convergent synthesis disclosed in the AstraZeneca discovery paper (Doyle et al., J. Med. Chem. 2016, 59, 9457-9472; AZD7986 = compound 30). The eastern warhead precursor is built from 4-bromo-L-phenylalaninamide (N-Boc): Suzuki\u2013Miyaura coupling with 3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-ylboronate (SM-2) forms the biaryl (INT-2). Boc removal (INT-3), then amide coupling with N-Boc-(2S)-1,4-oxazepane-2-carboxylic acid (SM-3) builds the central amide (INT-4, the penultimate bis-amide). The terminal primary amide is then dehydrated (Burgess reagent, or TFAA\/Et\u2083N, cold) to the reversible-covalent nitrile warhead (INT-5); final Boc removal and crystallisation from aqueous ethanol give brensocatib monohydrate. The amide\u2192nitrile dehydration is intentionally the last C-modifying step to avoid epimerising the (1S) alpha-amino-nitrile centre. Both stereocentres are (S): the warhead centre derives from L-phenylalanine and the oxazepane is the (2S) building block. Conditions are representative for the named transformations \u2014 verify against originator\/process literature before scale-up.<\/p>\n\n\n\n

\"\"<\/figure>\n\n\n\n
\"\"<\/figure>\n\n\n\n
\"\"<\/figure>\n\n\n\n

a<\/sup>Reagents and conditions: (1) 3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-ylboronic acid pinacol ester (1.1 eq), Pd(dppf)Cl\u2082 (3\u20135 mol%), K\u2083PO\u2084 or K\u2082CO\u2083 (2\u20133 eq), 1,4-dioxane\/H\u2082O 4:1, 80\u201390 \u00b0C, 4\u201312 h; (2) HCl (4 M in 1,4-dioxane) or TFA\/CH\u2082Cl\u2082, rt, 1\u20132 h; free-base on workup; (3) N-Boc-(2S)-1,4-oxazepane-2-carboxylic acid (1.05 eq), T3P (1.5 eq) or HATU (1.2 eq), DIPEA (2\u20133 eq), DMF or EtOAc, 0 \u00b0C \u2192 rt, 2\u20136 h; (4) Burgess reagent (1.3 eq), THF, 40\u201360 \u00b0C; or TFAA (1.2 eq)\/Et\u2083N, CH\u2082Cl\u2082, \u221210 \u00b0C \u2192 0 \u00b0C. Mild, low-temperature dehydration selective for the 1\u00b0 amide; preserves the (1S) alpha-amino-nitrile stereocentre; (5) HCl\/dioxane or TFA\/CH\u2082Cl\u2082, rt; free-base, then crystallise from aqueous EtOH to give brensocatib monohydrate (drug-substance form, C\u2082\u2083H\u2082\u2084N\u2084O\u2084\u00b7H\u2082O, MW 438.48).<\/p>\n\n\n\n

Key intermediates<\/strong><\/p>\n\n\n\n

\"\"<\/figure>\n\n\n\n
\"\"<\/figure>\n\n\n\n

Key patent filings<\/strong><\/p>\n\n\n\n

atent \/ Application<\/th>Type<\/th>Assignee<\/th>Filed<\/th>Expiry (~)<\/th><\/th><\/tr><\/thead>
AstraZeneca composition-of-matter family \u2014 oxazepane amidoacetonitrile DPP1 series [VERIFY exact WO\/US no. on Espacenet]<\/strong><\/td>Composition of matter (originator)<\/td>AstraZeneca AB<\/td>Priority ~2014\u20132015 (the 2nd-generation reversible-covalent DPP1 inhibitor series described in Doyle et al., J. Med. Chem. 2016)<\/td>~2034\u20132036 nominal (20 yr from filing), before any PTE<\/td><\/td><\/tr>
Insmed-era patents \u2014 ‘Reversible DPP1 inhibitors and uses thereof’ \/ formulation & method-of-use [VERIFY exact nos.]<\/strong><\/td>Formulation \/ method-of-use \/ polymorph<\/td>Insmed Incorporated<\/td>~2019\u20132024<\/td>~2039\u20132044 nominal<\/td><\/td><\/tr>
Process patent(s) \u2014 building-block routes<\/strong><\/td>Process<\/td>AstraZeneca \/ Insmed \/ CDMO [VERIFY]<\/td>~2015\u20132022<\/td>~2035\u20132042<\/td><\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n

Approved indication<\/h3>\n\n\n\n