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1025967-78-5

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1025967-78-5 Usage

Application

Lifitegrast is used for the treatment of signs and symptons of dry eye diseases. It also Inhibites corneal inflammation that is capable of causing pains, blurred vision and ocular discomfort in sufferer.

Description

Lifitegrast (Xiidra; lifitegrast sodium; SAR1118; SHP606; SPD606) is a lymphocyte functionassociated antigen-1 (LFA-1) antagonist. It inhibits T-cell inflammation by blocking the binding of two key surface proteins (LFA-1 and ICAM-1) that mediate the chronic inflammatory cascade associated with dry eye disease. In a phase III clinical trial, lifitegrast 5% ophthalmic solution (50 mg/mL) is administered as a single 0.2mL eye drop twice a day into each eye for an 84 day treatment period. Lifitegrast does not currently have Marketing Authorisation in the EU for any indication. Lifitegrast is licensed for use in the USA for treatment of the signs and symptoms of dry eye disease. The most common adverse reactions (incidence 5-25%) reported following the use of lifitegrast are instillation site irritation, dysgeusia, and decreased visual acuity.

Chemical Properties

Lifitegrast is a white to off-white powder which is soluble in water.

Uses

Lifitegrast is used for the treatment of signs and symptons of dry eye diseases. It also Inhibites corneal inflammation that is capable of causing pains, blurred vision and ocular discomfort in sufferer.

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.

Definition

ChEBI: An N-acyl-L-alpha-amino acid obtained by formal condensation of the carboxy group of N-[2-(1-benzofuran-6-carbonyl)]-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid with he amino group of 3-(methanesulfonyl)-L-phenylalanine. Used for treatment of keratoconjunctivitis sicca (dry eye syndrome).

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.

Check Digit Verification of cas no

The CAS Registry Mumber 1025967-78-5 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,0,2,5,9,6 and 7 respectively; the second part has 2 digits, 7 and 8 respectively.
Calculate Digit Verification of CAS Registry Number 1025967-78:
(9*1)+(8*0)+(7*2)+(6*5)+(5*9)+(4*6)+(3*7)+(2*7)+(1*8)=165
165 % 10 = 5
So 1025967-78-5 is a valid CAS Registry Number.

1025967-78-5SDS

SAFETY DATA SHEETS

According to Globally Harmonized System of Classification and Labelling of Chemicals (GHS) - Sixth revised edition

Version: 1.0

Creation Date: Aug 19, 2017

Revision Date: Aug 19, 2017

1.Identification

1.1 GHS Product identifier

Product name SAR1118

1.2 Other means of identification

Product number -
Other names SAR1118

1.3 Recommended use of the chemical and restrictions on use

Identified uses For industry use only.
Uses advised against no data available

1.4 Supplier's details

1.5 Emergency phone number

Emergency phone number -
Service hours Monday to Friday, 9am-5pm (Standard time zone: UTC/GMT +8 hours).

More Details:1025967-78-5 SDS

1025967-78-5Synthetic route

lifitegrast dicyclohexylamine salt

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

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

Conditions
ConditionsYield
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)-benzyl 2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-methylsulfonyl)phenyl)propanoate

(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

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

Conditions
ConditionsYield
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

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-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

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

Conditions
ConditionsYield
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

(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

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

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

Conditions
ConditionsYield
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

benzofuran-6-carboxylic acid

(S)-2-(5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid
851785-70-1

(S)-2-(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 acid
1025967-78-5

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

Conditions
ConditionsYield
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

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

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

Conditions
ConditionsYield
With water; lithium hydroxide In methanol at 25 - 30℃; for 3h; Reagent/catalyst; Solvent;80%
C19H12Cl3NO3

C19H12Cl3NO3

(S)-2-amino-3-(3-(methylsulphonyl)phenyl)propanoic acid hydrochloride

(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

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

Conditions
ConditionsYield
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

(2S)-3-(3-bromophenyl)-2-[(tert-butoxycarbonyl)amino]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

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

Conditions
ConditionsYield
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-((tert-butoxycarbonyl)amino)-3-((3-methylsulfonyl)phenyl)propanol

(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

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

Conditions
ConditionsYield
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)-benzyl 2-((tert-butoxycarbonyl)amino)-3-((3-methylsulfonyl)phenyl)propionate

(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

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

Conditions
ConditionsYield
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

(2S)-2-amino-3-(3-(methanesulfonyl)phenyl)propionic acid benzyl ester 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

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

Conditions
ConditionsYield
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

N-(2-chloroethyl)-3,5-dichlorobenzylamine 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

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

Conditions
ConditionsYield
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

C28H23Cl2N

(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

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

Conditions
ConditionsYield
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

5,7-dichloro-2-trityl-1,2,3,4-tetrahydroisoquinoline-6-carboxylic 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

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

Conditions
ConditionsYield
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

C46H40Cl2N2O5S

(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

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

Conditions
ConditionsYield
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

benzyl (S)-2-(5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-[3-(methylsulfonyl)phenyl]propanoate 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

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

Conditions
ConditionsYield
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

3,5-dichlorobenzaldehyde

(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

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

Conditions
ConditionsYield
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

5,7-dichloro-1,2,3,4-tetrahydroisoquinoline

(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

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

Conditions
ConditionsYield
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-amino-3-(3-bromophenyl)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

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

Conditions
ConditionsYield
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

(3,5-dichloro-benzylidene)-(2,2-diethoxy-ethyl)-amine

(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

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

Conditions
ConditionsYield
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

5,7-dichloro isoquinoline

(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

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

Conditions
ConditionsYield
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

6-hydroxy-1,2,3,4-tetrahydroisoquinoline

(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

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

Conditions
ConditionsYield
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

C15H16Cl2F3NO5S

(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

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

Conditions
ConditionsYield
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

2-(tert-butyl) 6-methyl 5,7-dichloro-3,4-dihydroisoquinoline-2,6(1Η)-dicarboxylate

(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

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

Conditions
ConditionsYield
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

2-(tert-butoxycarbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxylic 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

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

Conditions
ConditionsYield
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

C9H9Cl2NO*C7H8O3S

(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

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

Conditions
ConditionsYield
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

tert-butyl 5,7-dichloro-6-hydroxy-3,4-dihydroisoquinoline-2(1H)-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

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

Conditions
ConditionsYield
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

benzyl (S)-2-(5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-[3-(methylsulfonyl)phenyl]propanoate hydrochloride

benzofuran-6-carboxylic chloride

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

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

Conditions
ConditionsYield
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

6-hydroxybenzofuran-3-one

(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

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

Conditions
ConditionsYield
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

5,7-dichloro-1,2,3,4-tetrahydroisoquinoline 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

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

Conditions
ConditionsYield
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

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

N-cyclohexyl-cyclohexanamine
101-83-7

N-cyclohexyl-cyclohexanamine

lifitegrast dicyclohexylamine salt

lifitegrast dicyclohexylamine salt

Conditions
ConditionsYield
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

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

1-isobutyric acid chloromethyl ester
84674-32-8

1-isobutyric acid chloromethyl ester

1-(isobutyryloxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate

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
ConditionsYield
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

1-Chloroethyl methyl carbonate

(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

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

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

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
ConditionsYield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20 - 50℃; for 38h;42%
1-chloroethyl acetate
5912-58-3

1-chloroethyl acetate

(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

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

1-acetoxyethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate

1-acetoxyethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate

Conditions
ConditionsYield
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

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

methyl (2R)-2-(((1-chloroethoxy)carbonyl)oxy)propanoate

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

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
ConditionsYield
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

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

2-((((1-chloroethoxy)carbonyl)oxy)methyl)propane-1,3-diyl bis(2,2-dimethylpropanoate)

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)

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
ConditionsYield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 60℃; Sealed tube;36%
propanoic acid,1-chloroethyl ester
58304-44-2

propanoic acid,1-chloroethyl ester

(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

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

C34H32Cl2N2O9S

C34H32Cl2N2O9S

Conditions
ConditionsYield
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

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

2-((((1-chloroethoxy)carbonyl)oxy)methyl)propane-1,3-diyl diacetate

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

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
ConditionsYield
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

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

1-(isopropoxycarbonyloxy)ethyl chloride
98298-66-9

1-(isopropoxycarbonyloxy)ethyl chloride

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

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
ConditionsYield
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

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

1-chloroethyl pivalate
40258-80-8

1-chloroethyl pivalate

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

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
ConditionsYield
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

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

1-chloroethyl 5-((R)-1,2-dithiolan-3-yl)pentanoate

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

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
ConditionsYield
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

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

1-Chloroethyl ethyl carbonate
50893-36-2

1-Chloroethyl ethyl carbonate

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

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

1025967-78-5Downstream Products

1025967-78-5Relevant articles and documents

Preparation method of ritast and its intermediate compounds

-

Paragraph 0130-0135, (2022/01/12)

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.

PROCESS FOR PREPARING LIFITEGRAST AND INTERMEDIATES THEREOF

-

, (2019/01/15)

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.

PROCESS FOR THE PREPARATION OF LIFITEGRAST

-

, (2020/01/08)

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.

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