1025967-78-5

Basic information

• Product Name: lifitegrast
• Synonyms: lifitegrast;Lifitegrast, SAR 1118;L-Phenylalanine,N-[[2-(6-benzofuranylcarbonyl)-5,7-dichloro-1,2,3,4-tetrahydro-6-isoquinolinyl]carbonyl]-3-(methylsulfonyl)-;N-[[2-(6-Benzofuranylcarbonyl)-5,7-dichloro-1,2,3,4-tetrahydro-6-isoquinolinyl]carbonyl]-3-(methylsulfonyl)-L-phenylalanine;SAR 1118;(S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid;(S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic;liftegrast
• CAS NO: 1025967-78-5
• Molecular Formula: C₂₉H₂₄Cl₂N₂O₇S
• Molecular Weight: 615.48106
• EINECS: -0
• Product Categories: API
• Mol File: 1025967-78-5.mol

Chemical Properties

• Boiling Point: 811.9±65.0 °C(Predicted)
• Appearance: /
• Density: 1.479±0.06 g/cm3(Predicted)
• Storage Temp.: Hygroscopic, -20°C Freezer, Under inert atmosphere
• Solubility: DMSO (Slightly, Heated, Sonicated), Methanol (Slightly, Sonicated)
• PKA: 3.14±0.10(Predicted)
• Stability: Hygroscopic
• CAS DataBase Reference: lifitegrast(CAS DataBase Reference)
• NIST Chemistry Reference: lifitegrast(1025967-78-5)
• EPA Substance Registry System: lifitegrast(1025967-78-5)

Safety Data

• Hazardous Substances Data: 1025967-78-5(Hazardous Substances Data)

Usage

Indications

Topical lifitegrast was approved by the FDA for the treatment of dry eye. Lifitegrast decreases inflammation by blocking the interaction between intercellular adhesion molcule 1 and lymphocyte function- -associated antigen 1. In four, large, multicellular, randomized clinical trials, lifitegrast was shown to be effective in improving the signs and symptoms of dry eye. The side effects of lifitegrast include transient ocular irritation and dysgeusia. Further studies are needed to explore the effectiveness of combination therapy such as the concomitant use of topical cyclosporine and topical liftegrast.

Mechanism of action

Lifitegrast binds to the integrin lymphocyte function-associated antigen-1 (LFA-1), a cell surface protein found on leukocytes and blocks the interaction of LFA-1 with its cognate ligand intercellular adhesion molecule-1 (ICAM-1). ICAM-1 may be overexpressed in corneal and conjunctival tissues in dry eye disease. LFA-1/ICAM-1 interaction can contribute to the formation of an immunological synapse resulting in T-cell activation and migration to target tissues. In vitro studies demonstrated that lifitegrast may inhibit T-cell adhesion to ICAM-1 in a human T-cell line and may inhibit secretion of inflammatory cytokines in human peripheral blood mononuclear cells. The exact mechanism of action of lifitegrast in dry eye disease is not known.

Pharmacokinetics

In a subset of dry eye disease patients (n=47) enrolled in a Phase 3 trial, the pre-dose (trough) plasma concentrations of lifitegrast were measured after 180 and 360 days of topical ocular dosing (1 drop twice daily) with Xiidra (lifitegrast ophthalmic solution) 5%. A total of nine (9) of the 47 patients (19%) had plasma lifitegrast trough concentrations above 0.5 ng/mL (the lower limit of assay quantitation). Trough plasma concentrations that could be quantitated ranged from 0.55 ng/mL to 3.74 ng/mL.

Side effects

A multicenter, randomized, double-masked, placebo-controlled phase 3 study (n = 331) evaluating the safety of lifitegrast ophthalmic solution for the treatment of dry eye disease reported the most common non-ocular effect was dysgeusia (change in taste) occurring in 16.4% of patients in the lifitegrast group and 1.8% of the placebo group.

Synthesis

After Boc protection, reaction with sodium methanesulfinate in the presence of copper iodide, K2CO3, and L-proline gave rise to sulfonate 176. Esterification of 176 with benzyl alcohol followed by removal of the Boc group within 177 yielded the corresponding HCl salt of the aminoester 178. Amide bond coupling with acid 179 furnished amide 180, which was then subjected to 4 N HCl in dioxane resulting in trityl removal and arrival at HCl salt 181 in 88% yield over two steps. Tetrahydroisoquinoline 181 was then coupled with commercial benzofuranyl acid 182 to give rise to lifitegrast benzyl ester in 90% yield. Finally, saponification delivered lifitegrast (XIX) in 88% yield.Tetrahydroisoquinoline-6-carboxylic acid 179 was prepared starting from commercial 3,5-dichlorobenzaldehyde 183. Reductive amination with 1-chloro-2-aminoethane 184 gave chloroethyl amine 185, which underwent an efficient intramolecular Friedel-Crafts reaction using AlCl3 to generate the corresponding tetrahydroisoquinoline 186 in 91% yield. N-Tritylation of 186 proceeded in 89% yield, and this was followed by a directed o-metalation reaction and carbon dioxide quench to furnish the requisite acid 179 in 75% yield.

Synthetic route

lifitegrast dicyclohexylamine salt → (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5)

Conditions	Yield
With phosphoric acid In dichloromethane; water at 50℃; for 0.5h;	96%

((S)-benzyl 2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-methylsulfonyl)phenyl)propanoate (1194550-67-8) → (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5)

Conditions	Yield
With formic acid; palladium 10% on activated carbon; triethylamine In tetrahydrofuran; methanol at 20℃; for 4h;	95%
With formic acid; palladium 10% on activated carbon; triethylamine In tetrahydrofuran; methanol Reagent/catalyst; Solvent;	n/a
With lithium hydroxide monohydrate In water; acetone at -5 - 0℃; for 1h; Reagent/catalyst; Solvent; Temperature;
With hydrogenchloride In water; acetonitrile at 3 - 25℃; for 19.5h; Solvent; Temperature; Reagent/catalyst; Inert atmosphere;	3.8 g

2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3 ,4-tetrahydroisoquinoline-6-carboxylic acid + (S)-2-amino-3-(3-(methylsulfonyl)phenyl)propanoic acid → (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5)

Conditions	Yield
Stage #1: 2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3 ,4-tetrahydroisoquinoline-6-carboxylic acid With [2-(1H-indol-3-yl)-ethyl]-methylamine; N-ethyl-N,N-diisopropylamine; HATU In tetrahydrofuran at 40℃; for 2h; Inert atmosphere; Stage #2: (S)-2-amino-3-(3-(methylsulfonyl)phenyl)propanoic acid In tetrahydrofuran at 20 - 30℃;	92%
Stage #1: 2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3 ,4-tetrahydroisoquinoline-6-carboxylic acid With triethylamine In N,N-dimethyl-formamide at 28℃; for 0.166667h; Stage #2: With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 5 - 8℃; for 2h; Stage #3: (S)-2-amino-3-(3-(methylsulfonyl)phenyl)propanoic acid In N,N-dimethyl-formamide at 8℃; for 1h;

(S)-2-amino-3-(3-(methylsulfonyl)phenyl)propanoic acid + 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl 2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxylate → (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5)

Conditions	Yield
Stage #1: (S)-2-amino-3-(3-(methylsulfonyl)phenyl)propanoic acid; 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl 2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxylate With N-ethyl-N,N-diisopropylamine In acetonitrile at 40 - 45℃; Stage #2: With hydrogenchloride In water at 0 - 5℃; for 1h; pH=5;	87%
With N-ethyl-N,N-diisopropylamine In water; acetonitrile at 20 - 45℃; for 4h;

benzofuran-6-carboxylic acid (77095-51-3) + (S)-2-(5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (851785-70-1) → (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -10 - 20℃; Reagent/catalyst; Solvent; Temperature;	83.8%
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 10 - 20℃; for 1.5h;

C30H26Cl2N2O7S → (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5)

Conditions	Yield
With water; lithium hydroxide In methanol at 25 - 30℃; for 3h; Reagent/catalyst; Solvent;	80%

C19H12Cl3NO3 + (S)-2-amino-3-(3-(methylsulphonyl)phenyl)propanoic acid hydrochloride → (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5)

Conditions	Yield
Stage #1: (S)-2-amino-3-(3-(methylsulphonyl)phenyl)propanoic acid hydrochloride With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; Inert atmosphere; Stage #2: C19H12Cl3NO3 In dichloromethane at 0 - 5℃; Temperature; Inert atmosphere;	77%

(2S)-3-(3-bromophenyl)-2-[(tert-butoxycarbonyl)amino]propanoic acid (82278-73-7) → (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5)

Conditions	Yield
Multi-step reaction with 7 steps 1: copper(l) iodide; caesium carbonate; L-proline / dimethyl sulfoxide / 9 h / 100 °C 2: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 20 °C 3: hydrogenchloride / 1,4-dioxane; dichloromethane; water / 0 °C 4: triethylamine; HATU / N,N-dimethyl-formamide / 18 h / 20 °C 5: hydrogenchloride / 1,4-dioxane; water / 2 h / 20 °C 6: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 0 °C 7: palladium 10% on activated carbon; formic acid; triethylamine / tetrahydrofuran; methanol / 4 h / 20 °C View Scheme
Multi-step reaction with 7 steps 1.1: copper(l) iodide; caesium carbonate; L-proline; sodium methansulfinate / dimethyl sulfoxide / 9 h / 95 - 100 °C 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap 3.1: hydrogenchloride / dichloromethane; 1,4-dioxane / 0 °C 4.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 0.17 h 4.2: 18 h / 20 °C 5.1: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 6.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 7.1: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme
Multi-step reaction with 7 steps 1: copper(l) iodide; caesium carbonate; L-proline; sodium methansulfinate / dimethyl sulfoxide / 9 h / 95 - 100 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap 3: hydrogenchloride / dichloromethane; 1,4-dioxane / 0 °C 4: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide 5: hydrogenchloride / water; 1,4-dioxane 6: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 7: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme

(S)-2-((tert-butoxycarbonyl)amino)-3-((3-methylsulfonyl)phenyl)propanol (1289646-76-9) → (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5)

Conditions	Yield
Multi-step reaction with 6 steps 1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 20 °C 2: hydrogenchloride / 1,4-dioxane; dichloromethane; water / 0 °C 3: triethylamine; HATU / N,N-dimethyl-formamide / 18 h / 20 °C 4: hydrogenchloride / 1,4-dioxane; water / 2 h / 20 °C 5: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 0 °C 6: palladium 10% on activated carbon; formic acid; triethylamine / tetrahydrofuran; methanol / 4 h / 20 °C View Scheme
Multi-step reaction with 6 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap 2.1: hydrogenchloride / dichloromethane; 1,4-dioxane / 0 °C 3.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 0.17 h 3.2: 18 h / 20 °C 4.1: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 5.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 6.1: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme
Multi-step reaction with 6 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap 2: hydrogenchloride / dichloromethane; 1,4-dioxane / 0 °C 3: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide 4: hydrogenchloride / water; 1,4-dioxane 5: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 6: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme
Multi-step reaction with 6 steps 1.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 0.25 h / 25 - 35 °C 1.2: 5 h / 25 - 45 °C 2.1: hydrogenchloride / 1,4-dioxane; dichloromethane / 2 h / 25 - 35 °C 3.1: triethylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 0.25 h / 25 - 35 °C 3.2: 5 h / 25 - 45 °C 4.1: hydrogenchloride / 1,4-dioxane; dichloromethane / 25 - 35 °C 5.1: triethylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 0.25 h / 25 - 35 °C 5.2: 5 h / 25 - 45 °C 6.1: lithium hydroxide monohydrate / tetrahydrofuran; water / 25 - 35 °C View Scheme

(S)-benzyl 2-((tert-butoxycarbonyl)amino)-3-((3-methylsulfonyl)phenyl)propionate (1289646-78-1) → (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5)

Conditions	Yield
Multi-step reaction with 5 steps 1: hydrogenchloride / 1,4-dioxane; dichloromethane; water / 0 °C 2: triethylamine; HATU / N,N-dimethyl-formamide / 18 h / 20 °C 3: hydrogenchloride / 1,4-dioxane; water / 2 h / 20 °C 4: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 0 °C 5: palladium 10% on activated carbon; formic acid; triethylamine / tetrahydrofuran; methanol / 4 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: hydrogenchloride / dichloromethane; 1,4-dioxane / 0 °C 2.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 0.17 h 2.2: 18 h / 20 °C 3.1: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 4.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 5.1: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme
Multi-step reaction with 5 steps 1: hydrogenchloride / dichloromethane; 1,4-dioxane / 0 °C 2: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide 3: hydrogenchloride / water; 1,4-dioxane 4: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 5: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme

(2S)-2-amino-3-(3-(methanesulfonyl)phenyl)propionic acid benzyl ester hydrochloride (1194550-59-8) → (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: triethylamine; HATU / N,N-dimethyl-formamide / 18 h / 20 °C 2: hydrogenchloride / 1,4-dioxane; water / 2 h / 20 °C 3: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 0 °C 4: palladium 10% on activated carbon; formic acid; triethylamine / tetrahydrofuran; methanol / 4 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 0.17 h 1.2: 18 h / 20 °C 2.1: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 3.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 4.1: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme
Multi-step reaction with 4 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide 2: hydrogenchloride / water; 1,4-dioxane 3: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 4: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme

N-(2-chloroethyl)-3,5-dichlorobenzylamine hydrochloride (14046-52-7) → (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: aluminum (III) chloride / 185 °C 2.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 4 h / 20 °C 3.1: n-butyllithium; N,N,N,N,-tetramethylethylenediamine / tetrahydrofuran / -78 - 20 °C 3.2: -78 - 20 °C 4.1: triethylamine; HATU / N,N-dimethyl-formamide / 18 h / 20 °C 5.1: hydrogenchloride / 1,4-dioxane; water / 2 h / 20 °C 6.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 0 °C 7.1: palladium 10% on activated carbon; formic acid; triethylamine / tetrahydrofuran; methanol / 4 h / 20 °C View Scheme
Multi-step reaction with 7 steps 1.1: aluminum (III) chloride; ammonium chloride / 185 °C 2.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 10 - 25 °C 3.1: n-butyllithium; N,N,N,N,-tetramethylethylenediamine 4.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 0.17 h 4.2: 18 h / 20 °C 5.1: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 6.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 7.1: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme
Multi-step reaction with 9 steps 1: aluminum (III) chloride; ammonium chloride / 185 °C 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 10 - 25 °C 3: n-butyllithium; N,N,N,N,-tetramethylethylenediamine 4: hydrogenchloride / 1,4-dioxane 5: sodium hydrogencarbonate 6: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide 7: hydrogenchloride / water; 1,4-dioxane 8: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 9: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme

C28H23Cl2N (1289646-72-5) → (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: n-butyllithium; N,N,N,N,-tetramethylethylenediamine / tetrahydrofuran / -78 - 20 °C 1.2: -78 - 20 °C 2.1: triethylamine; HATU / N,N-dimethyl-formamide / 18 h / 20 °C 3.1: hydrogenchloride / 1,4-dioxane; water / 2 h / 20 °C 4.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 0 °C 5.1: palladium 10% on activated carbon; formic acid; triethylamine / tetrahydrofuran; methanol / 4 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: n-butyllithium; N,N,N,N,-tetramethylethylenediamine 2.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 0.17 h 2.2: 18 h / 20 °C 3.1: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 4.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 5.1: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme
Multi-step reaction with 7 steps 1: n-butyllithium; N,N,N,N,-tetramethylethylenediamine 2: hydrogenchloride / 1,4-dioxane 3: sodium hydrogencarbonate 4: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide 5: hydrogenchloride / water; 1,4-dioxane 6: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 7: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme

5,7-dichloro-2-trityl-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (1194550-56-5) → (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: triethylamine; HATU / N,N-dimethyl-formamide / 18 h / 20 °C 2: hydrogenchloride / 1,4-dioxane; water / 2 h / 20 °C 3: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 0 °C 4: palladium 10% on activated carbon; formic acid; triethylamine / tetrahydrofuran; methanol / 4 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 0.17 h 1.2: 18 h / 20 °C 2.1: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 3.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 4.1: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme
Multi-step reaction with 6 steps 1: hydrogenchloride / 1,4-dioxane 2: sodium hydrogencarbonate 3: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide 4: hydrogenchloride / water; 1,4-dioxane 5: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 6: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme
Multi-step reaction with 3 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 20 h / 28 °C 2: sodium hydroxide / 1,4-dioxane; water / 2 h / 28 °C 3: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 1.5 h / 10 - 20 °C View Scheme

C46H40Cl2N2O5S (1194550-63-4) → (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride / 1,4-dioxane; water / 2 h / 20 °C 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 0 °C 3: palladium 10% on activated carbon; formic acid; triethylamine / tetrahydrofuran; methanol / 4 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 3: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme
Multi-step reaction with 2 steps 1: sodium hydroxide / 1,4-dioxane; water / 2 h / 28 °C 2: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 1.5 h / 10 - 20 °C View Scheme

benzyl (S)-2-(5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-[3-(methylsulfonyl)phenyl]propanoate hydrochloride (1194550-65-6) → (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 0 °C 2: palladium 10% on activated carbon; formic acid; triethylamine / tetrahydrofuran; methanol / 4 h / 20 °C View Scheme

3,5-dichlorobenzaldehyde (10203-08-4) → (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5)

Conditions	Yield
Multi-step reaction with 8 steps 1.1: methanol; sodium cyanoborohydride / 20 °C 2.1: aluminum (III) chloride / 185 °C 3.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 4 h / 20 °C 4.1: n-butyllithium; N,N,N,N,-tetramethylethylenediamine / tetrahydrofuran / -78 - 20 °C 4.2: -78 - 20 °C 5.1: triethylamine; HATU / N,N-dimethyl-formamide / 18 h / 20 °C 6.1: hydrogenchloride / 1,4-dioxane; water / 2 h / 20 °C 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 0 °C 8.1: palladium 10% on activated carbon; formic acid; triethylamine / tetrahydrofuran; methanol / 4 h / 20 °C View Scheme
Multi-step reaction with 10 steps 1: sodium cyanoborohydride 2: aluminum (III) chloride; ammonium chloride / 185 °C 3: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 10 - 25 °C 4: n-butyllithium; N,N,N,N,-tetramethylethylenediamine 5: hydrogenchloride / 1,4-dioxane 6: sodium hydrogencarbonate 7: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide 8: hydrogenchloride / water; 1,4-dioxane 9: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 10: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme
Multi-step reaction with 11 steps 1.1: ethanol / 2 h / 20 - 78 °C 2.1: sulfuric acid / dichloromethane / 7 h / 120 - 125 °C 2.2: 5 h / 0 - 50 °C / pH 12 3.1: platinum(IV) oxide / methanol / 0.17 h / 20 °C / Inert atmosphere 3.2: 25 h / 20 °C / 6464.52 Torr / Inert atmosphere 3.3: 0 - 40 °C 4.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 10 - 25 °C 5.1: n-butyllithium; N,N,N,N,-tetramethylethylenediamine 6.1: hydrogenchloride / 1,4-dioxane 7.1: sodium hydrogencarbonate 8.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide 9.1: hydrogenchloride / water; 1,4-dioxane 10.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 11.1: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme
Multi-step reaction with 8 steps 1.1: sodium cyanoborohydride 2.1: aluminum (III) chloride; ammonium chloride / 185 °C 3.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 10 - 25 °C 4.1: n-butyllithium; N,N,N,N,-tetramethylethylenediamine 5.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 0.17 h 5.2: 18 h / 20 °C 6.1: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 8.1: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme
Multi-step reaction with 9 steps 1.1: ethanol / 2 h / 20 - 78 °C 2.1: sulfuric acid / dichloromethane / 7 h / 120 - 125 °C 2.2: 5 h / 0 - 50 °C / pH 12 3.1: platinum(IV) oxide / methanol / 0.17 h / 20 °C / Inert atmosphere 3.2: 25 h / 20 °C / 6464.52 Torr / Inert atmosphere 3.3: 0 - 40 °C 4.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 10 - 25 °C 5.1: n-butyllithium; N,N,N,N,-tetramethylethylenediamine 6.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 0.17 h 6.2: 18 h / 20 °C 7.1: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 8.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 9.1: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme

5,7-dichloro-1,2,3,4-tetrahydroisoquinoline (89315-56-0) → (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 4 h / 20 °C 2.1: n-butyllithium; N,N,N,N,-tetramethylethylenediamine / tetrahydrofuran / -78 - 20 °C 2.2: -78 - 20 °C 3.1: triethylamine; HATU / N,N-dimethyl-formamide / 18 h / 20 °C 4.1: hydrogenchloride / 1,4-dioxane; water / 2 h / 20 °C 5.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 0 °C 6.1: palladium 10% on activated carbon; formic acid; triethylamine / tetrahydrofuran; methanol / 4 h / 20 °C View Scheme
Multi-step reaction with 6 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 10 - 25 °C 2.1: n-butyllithium; N,N,N,N,-tetramethylethylenediamine 3.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 0.17 h 3.2: 18 h / 20 °C 4.1: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 5.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 6.1: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme
Multi-step reaction with 8 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 10 - 25 °C 2: n-butyllithium; N,N,N,N,-tetramethylethylenediamine 3: hydrogenchloride / 1,4-dioxane 4: sodium hydrogencarbonate 5: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide 6: hydrogenchloride / water; 1,4-dioxane 7: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 8: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme

(S)-2-amino-3-(3-bromophenyl)propanoic acid (82311-69-1) → (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5)

Conditions	Yield
Multi-step reaction with 8 steps 1: sodium hydrogencarbonate / 1,4-dioxane; water / 20 °C 2: copper(l) iodide; caesium carbonate; L-proline / dimethyl sulfoxide / 9 h / 100 °C 3: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 20 °C 4: hydrogenchloride / 1,4-dioxane; dichloromethane; water / 0 °C 5: triethylamine; HATU / N,N-dimethyl-formamide / 18 h / 20 °C 6: hydrogenchloride / 1,4-dioxane; water / 2 h / 20 °C 7: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 0 °C 8: palladium 10% on activated carbon; formic acid; triethylamine / tetrahydrofuran; methanol / 4 h / 20 °C View Scheme
Multi-step reaction with 8 steps 1.1: sodium hydrogencarbonate / water; 1,4-dioxane 2.1: copper(l) iodide; caesium carbonate; L-proline; sodium methansulfinate / dimethyl sulfoxide / 9 h / 95 - 100 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap 4.1: hydrogenchloride / dichloromethane; 1,4-dioxane / 0 °C 5.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 0.17 h 5.2: 18 h / 20 °C 6.1: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 8.1: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme
Multi-step reaction with 8 steps 1: sodium hydrogencarbonate / water; 1,4-dioxane 2: copper(l) iodide; caesium carbonate; L-proline; sodium methansulfinate / dimethyl sulfoxide / 9 h / 95 - 100 °C 3: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap 4: hydrogenchloride / dichloromethane; 1,4-dioxane / 0 °C 5: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide 6: hydrogenchloride / water; 1,4-dioxane 7: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 8: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme

(3,5-dichloro-benzylidene)-(2,2-diethoxy-ethyl)-amine (1000210-73-0) → (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5)

Conditions	Yield
Multi-step reaction with 10 steps 1.1: sulfuric acid / dichloromethane / 7 h / 120 - 125 °C 1.2: 5 h / 0 - 50 °C / pH 12 2.1: platinum(IV) oxide / methanol / 0.17 h / 20 °C / Inert atmosphere 2.2: 25 h / 20 °C / 6464.52 Torr / Inert atmosphere 2.3: 0 - 40 °C 3.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 10 - 25 °C 4.1: n-butyllithium; N,N,N,N,-tetramethylethylenediamine 5.1: hydrogenchloride / 1,4-dioxane 6.1: sodium hydrogencarbonate 7.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide 8.1: hydrogenchloride / water; 1,4-dioxane 9.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 10.1: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme
Multi-step reaction with 8 steps 1.1: sulfuric acid / dichloromethane / 7 h / 120 - 125 °C 1.2: 5 h / 0 - 50 °C / pH 12 2.1: platinum(IV) oxide / methanol / 0.17 h / 20 °C / Inert atmosphere 2.2: 25 h / 20 °C / 6464.52 Torr / Inert atmosphere 2.3: 0 - 40 °C 3.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 10 - 25 °C 4.1: n-butyllithium; N,N,N,N,-tetramethylethylenediamine 5.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 0.17 h 5.2: 18 h / 20 °C 6.1: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 8.1: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme

5,7-dichloro isoquinoline (73075-58-8) → (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: platinum(IV) oxide / methanol / 0.17 h / 20 °C / Inert atmosphere 1.2: 25 h / 20 °C / 6464.52 Torr / Inert atmosphere 1.3: 0 - 40 °C 2.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 10 - 25 °C 3.1: n-butyllithium; N,N,N,N,-tetramethylethylenediamine 4.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 0.17 h 4.2: 18 h / 20 °C 5.1: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 6.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 7.1: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme
Multi-step reaction with 9 steps 1.1: platinum(IV) oxide / methanol / 0.17 h / 20 °C / Inert atmosphere 1.2: 25 h / 20 °C / 6464.52 Torr / Inert atmosphere 1.3: 0 - 40 °C 2.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 10 - 25 °C 3.1: n-butyllithium; N,N,N,N,-tetramethylethylenediamine 4.1: hydrogenchloride / 1,4-dioxane 5.1: sodium hydrogencarbonate 6.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide 7.1: hydrogenchloride / water; 1,4-dioxane 8.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 9.1: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme

6-hydroxy-1,2,3,4-tetrahydroisoquinoline (14446-24-3) → (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5)

Conditions

Yield

Multi-step reaction with 9 steps 1: N-chloro-succinimide / acetonitrile / 20 °C 2: sodium carbonate / methanol / 20 °C 3: pyridine / dichloromethane / 0.17 h / 0 - 2 °C 4: N-ethyl-N,N-diisopropylamine; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / N,N-dimethyl-formamide / 20 °C / Reflux 5: sodium hydroxide / methanol / Reflux 6: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide 7: hydrogenchloride / water; 1,4-dioxane 8: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 9: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme

C15H16Cl2F3NO5S (851784-78-6) → (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5)

Conditions

Yield

Multi-step reaction with 6 steps 1: N-ethyl-N,N-diisopropylamine; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / N,N-dimethyl-formamide / 20 °C / Reflux 2: sodium hydroxide / methanol / Reflux 3: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide 4: hydrogenchloride / water; 1,4-dioxane 5: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 6: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme

2-(tert-butyl) 6-methyl 5,7-dichloro-3,4-dihydroisoquinoline-2,6(1Η)-dicarboxylate (851784-80-0) → (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5)

Conditions	Yield
Multi-step reaction with 5 steps 1: sodium hydroxide / methanol / Reflux 2: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide 3: hydrogenchloride / water; 1,4-dioxane 4: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 5: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme
Multi-step reaction with 3 steps 1: lithium hydroxide; water / methanol / 20 °C 2: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0 - 20 °C 3: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 - 5 °C View Scheme
Multi-step reaction with 3 steps 1: lithium hydroxide; water / methanol / 20 °C 2: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0 - 20 °C 3: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / tetrahydrofuran / -10 - 20 °C View Scheme

2-(tert-butoxycarbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (851784-82-2) → (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide 2: hydrogenchloride / water; 1,4-dioxane 3: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 4: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0 - 20 °C 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 - 5 °C View Scheme
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0 - 20 °C 2: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / tetrahydrofuran / -10 - 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: sodium carbonate / N,N-dimethyl-formamide / 2 h / 25 - 35 °C 1.2: 2 h / 25 - 35 °C 2.1: triethylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / tetrahydrofuran / 0.5 h / 25 - 35 °C 2.2: 3 h / 25 - 35 °C 3.1: pyridine; lithium iodide hydrate / 100 - 105 °C 4.1: triethylamine; HATU / N,N-dimethyl-formamide / 0.5 h / 25 - 35 °C 4.2: 2 h / 25 - 35 °C View Scheme

C9H9Cl2NO*C7H8O3S (1609545-55-2) → (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5)

Conditions

Yield

Multi-step reaction with 8 steps 1: sodium carbonate / methanol / 20 °C 2: pyridine / dichloromethane / 0.17 h / 0 - 2 °C 3: N-ethyl-N,N-diisopropylamine; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / N,N-dimethyl-formamide / 20 °C / Reflux 4: sodium hydroxide / methanol / Reflux 5: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide 6: hydrogenchloride / water; 1,4-dioxane 7: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 8: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme

tert-butyl 5,7-dichloro-6-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (851784-76-4) → (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5)

Conditions	Yield
Multi-step reaction with 7 steps 1: pyridine / dichloromethane / 0.17 h / 0 - 2 °C 2: N-ethyl-N,N-diisopropylamine; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / N,N-dimethyl-formamide / 20 °C / Reflux 3: sodium hydroxide / methanol / Reflux 4: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide 5: hydrogenchloride / water; 1,4-dioxane 6: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 7: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme
Multi-step reaction with 5 steps 1: pyridine / -20 - 20 °C 2: 1,3-bis-(diphenylphosphino)propane; N-ethyl-N,N-diisopropylamine; palladium diacetate / N,N-dimethyl acetamide / 20 °C 3: lithium hydroxide; water / methanol / 20 °C 4: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0 - 20 °C 5: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 - 5 °C View Scheme
Multi-step reaction with 5 steps 1: pyridine / -20 - 20 °C 2: 1,3-bis-(diphenylphosphino)propane; N-ethyl-N,N-diisopropylamine; palladium diacetate / N,N-dimethyl acetamide / 20 °C 3: lithium hydroxide; water / methanol / 20 °C 4: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0 - 20 °C 5: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / tetrahydrofuran / -10 - 20 °C View Scheme

benzyl (S)-2-(5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-[3-(methylsulfonyl)phenyl]propanoate hydrochloride (1194550-65-6) + benzofuran-6-carboxylic chloride → (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 2: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme

6-hydroxybenzofuran-3-one (6272-26-0) → (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5)

Conditions

Yield

Multi-step reaction with 9 steps 1: triethylamine / acetone 2: sodium tetrahydroborate / methanol / 20 °C 3: hydrogenchloride; water / tetrahydrofuran / 28 °C / Inert atmosphere; Darkness 4: dichloromethane / 72 h 5: 1,3-bis-(diphenylphosphino)propane; palladium diacetate; triethylamine / N,N-dimethyl-formamide / 6 h / 70 °C / 6000.6 Torr / Autoclave 6: lithium hydroxide; water / methanol 7: oxalyl dichloride / N,N-dimethyl-formamide / 5.5 h 8: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 9: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme

5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride (73075-47-5) → (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 10 - 25 °C 2.1: n-butyllithium; N,N,N,N,-tetramethylethylenediamine 3.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 0.17 h 3.2: 18 h / 20 °C 4.1: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 5.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 6.1: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme
Multi-step reaction with 8 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 10 - 25 °C 2: n-butyllithium; N,N,N,N,-tetramethylethylenediamine 3: hydrogenchloride / 1,4-dioxane 4: sodium hydrogencarbonate 5: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide 6: hydrogenchloride / water; 1,4-dioxane 7: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 5 °C 8: triethylamine; palladium 10% on activated carbon; formic acid / tetrahydrofuran; methanol View Scheme

(S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5) + N-cyclohexyl-cyclohexanamine (101-83-7) → lifitegrast dicyclohexylamine salt

Conditions	Yield
In tetrahydrofuran at 20℃; for 24h;	70%

(S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5) + 1-isobutyric acid chloromethyl ester (84674-32-8) → 1-(isobutyryloxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 60℃; for 16h; Sealed tube;	61%

1-Chloroethyl methyl carbonate (80196-03-8) + (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5) → 1-((methoxycarbonyl)oxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20 - 50℃; for 38h;	42%

1-chloroethyl acetate (5912-58-3) + (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5) → 1-acetoxyethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 60℃; for 16h; Sealed tube;	39%

(S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5) + methyl (2R)-2-(((1-chloroethoxy)carbonyl)oxy)propanoate → 1-(((((R)-1-methoxy-1-oxopropan-2-yl)oxy)carbonyl)oxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 60℃; for 16h; Sealed tube;	37%

(S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5) + 2-((((1-chloroethoxy)carbonyl)oxy)methyl)propane-1,3-diyl bis(2,2-dimethylpropanoate) → 2-((8S)-10-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-methyl-8-(3-(methylsulfonyl)benzyl)-3,7,10-trioxo-2,4,6-trioxa-9-azadecyl)propane-1,3-diyl bis(2,2-dimethylpropanoate)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 60℃; Sealed tube;	36%

propanoic acid,1-chloroethyl ester (58304-44-2) + (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5) → C34H32Cl2N2O9S

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 60℃; for 18h; Inert atmosphere;	35%

(S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5) + 2-((((1-chloroethoxy)carbonyl)oxy)methyl)propane-1,3-diyl diacetate → 2-((8S)-10-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-methyl-8-(3-(methylsulfonyl)benzyl)-3,7,10-trioxo-2,4,6-trioxa-9-azadecyl)propane-1,3-diyl diacetate

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 60℃; for 72h;	34%

(S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5) + 1-(isopropoxycarbonyloxy)ethyl chloride (98298-66-9) → 1-((isopropoxycarbonyl)oxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 55℃; for 2h;	24%

(S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5) + 1-chloroethyl pivalate (40258-80-8) → 1-(((S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoyl)oxy)ethyl pivalate

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 40℃; for 72h; Inert atmosphere;	22%

(S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5) + 1-chloroethyl 5-((R)-1,2-dithiolan-3-yl)pentanoate → 1-(((S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoyl)oxy)ethyl 5-((R)-1,2-dithiolan-3-yl)pentanoate

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 60℃; for 16h;	4%

(S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (1025967-78-5) + 1-Chloroethyl ethyl carbonate (50893-36-2) → 1-((ethoxycarbonyl)oxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 40℃; for 20h; Inert atmosphere;	3%

Upstream product

• 82278-73-7 (2S)-3-(3-bromophenyl)-2-[(tert-butoxycarbonyl)amino]propanoic acid 
• 1289646-76-9 (S)-2-((tert-butoxycarbonyl)amino)-3-((3-methylsulfonyl)phenyl)propanol 
• 1289646-78-1 (S)-benzyl 2-((tert-butoxycarbonyl)amino)-3-((3-methylsulfonyl)phenyl)propionate 
• 1194550-59-8 (2S)-2-amino-3-(3-(methanesulfonyl)phenyl)propionic acid benzyl ester hydrochloride 
• 14046-52-7 N-(2-chloroethyl)-3,5-dichlorobenzylamine hydrochloride 
• 1289646-72-5 C₂₈H₂₃Cl₂N 
• 1194550-56-5 5,7-dichloro-2-trityl-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid 
• 1194550-63-4 C₄₆H₄₀Cl₂N₂O₅S 
• 1194550-65-6 benzyl (S)-2-(5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-[3-(methylsulfonyl)phenyl]propanoate hydrochloride 
• 1194550-67-8 ((S)-benzyl 2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-methylsulfonyl)phenyl)propanoate 
• 77095-51-3 benzofuran-6-carboxylic acid 
• 851784-92-4 C₂₀H₁₅Cl₂NO₄ 
• 851784-90-2 dichloro quinoline ester 
• 851785-70-1 (S)-2-(5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid 

Relevant articles and documents

Preparation method of ritast and its intermediate compounds

The present invention relates to a method of preparation of ritast and an intermediate compound thereof. In particular, the present invention relates to a method of synthesis of ritast, a key intermediate for synthesizing tast, a solvate thereof, and a method for hydrolyzing it under alkaline conditions to prepare lithast.

NOVEL PROCESS FOR THE PREPARATION OF LIFITEGRAST

The present invention relates to a novel process for the preparation of lifitegrast of Formula (I). The present invention further provides a novel process for the purification of lifitegrast of Formula (I).

PROCESSES FOR THE PREPARATION OF (S)-2-(2-(BENZOFURAN-6-CARBONYL)-5,7-DICHLORO-1,2,3,4-TETRAHYDROISOQUINOLINE-6-CARBOXAMIDO)-3-(3-(METHYLSULFONYL)PHENYL) PROPANOIC ACID AND POLYMORPHS THEREOF

The present invention relates to various processes for the preparation of (S)-2-(2- (benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3- (methylsulfonyl)phenyl)propanoic acid represented by the following structural formula-1. The said processes for the preparation of compound of formula-1 proceed through various novel intermediate compounds. The present invention also relates to novel crystalline polymorphs of compound of formula-1 and processes for preparation thereof.

PROCESS FOR THE PREPARATION OF LIFITEGRAST

The invention relates to a process for the preparation of Lifitegrast of formula (I), which comprises: a) condensation of the compound of formula (II) with the compound of formula (III) to give the compound of formula (IV) wherein R1, R2 and R3 are independently selected from straight or branched C1- C6 alkyl groups; b) chlorination of compound (IV) in the presence of a chlorinating agent (IV), (V), c) condensation of compound (V) with amino acid (VI) to give compound (I), c) condensation of compound (V) with amino acid (VI) to give compound (I), d) optional purification of the crude Lifitegrast in mixtures of polar aprotic solvents and water.

PROCESS FOR PREPARING LIFITEGRAST AND INTERMEDIATES THEREOF

The present disclosure provides efficient, economical, and improved processes for synthesizing lifitegrast and intermediates thereof. The currently discloses processes provide a direct synthetic route, avoiding protection or deprotection steps. The currently disclosed process also provides processes for synthesizing lifitegrast using a reduced number of synthetic steps.

PROCESSES FOR PREPARATION OF LIFITEGRAST AND INTERMEDIATES THEREOF

The present invention provides process for preparation of lifitegrast, amine salts of lifitegrast, process for preparation of amine salts of lifitegrast and their use in purification of lifitegrast, and also provided are process for preparation of amorphous lifitegrast and pharmaceutical compositions comprising lifitegrast prepared by the processes of the present invention.

AN IMPROVED PROCESS FOR THE PREPARATION OF LIFITEGRAST OR SALTS THEREOF

Disclosed herein is an improved process for the synthesis of lifitegrast or salts thereof with high yields and purity and its use in the therapy.

A PROCESS FOR THE PREPARATION OF LIFITEGRAST

The present invention provides dibenzylamine salt of Lifitegrast (XV), and diphenylamine salt of Lifitegrast (XVI) and the use of the above salts in the purification process of Lifitegrast (I). The present invention relates to a process for the preparation of Lifitegrast (I).

PROCESS FOR PREPARATION OF LIFITEGRAST

The present invention relates to a process for the preparation of lifitegrast, a compound of formula I, the process comprising deprotecting a compound of formula III using a Lewis acid. The present invention also relates to lifitegrast organic amine salt, a compound of formula II, process for its preparation and conversion thereof to lifitegrast.

PROCESS FOR PREPARING AND PURIFYING THE LFA-1 ANTAGONIST LIFITEGRAST

The invention relates to a process for the preparation of lifitegrast (I) comprising a) reacting benzofuran-6-carboxylic acid (II) with a non- chlorinated carboxyl activating agent; and b) reacting the activated compound obtained in step a) with compound (III) or a salt thereof to give lifitegrast. It also relates to a process for the purification of lifitegrast (I) by i) reacting lifitegrast with dicyclohexylamine to give the dicyclohexylamine salt of lifitegrast (la); ii) isolating the salt from the reaction medium; iii) converting the isolated salt into lifitegrast by treatment with an acid; and iv) isolating lifitegrast from the reaction medium. It also relates to the dicyclohexylamine salt of lifitegrast (la) and to a process for its preparation. (Formula I, III)