863971-44-2

Basic information

• Product Name: (5S,9S,11S,12R)-11-((S)-sec-butyl)-1-(9H-fluoren-9-yl)-5,9-diisopropyl-12-Methoxy-4,10-diMethyl-3,6,8-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid
• Synonyms: (5S,9S,11S,12R)-11-((S)-sec-butyl)-1-(9H-fluoren-9-yl)-5,9-diisopropyl-12-Methoxy-4,10-diMethyl-3,6,8-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid;Fmoc-3AA-orl;Fmoc-3vvd-OH;Tripeptide (MMAE-3);Fmoc-Meval-val-dolaisoleucine-OH;(5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H-fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid;L-Valinamide, N-[(9H-fluoren-9-ylmethoxy)carbonyl]-N-methyl-L-valyl-N-[(1S,2S)-1-[(1R)-2-carboxy-1-methoxyethyl]-2-methylbutyl]-N-methyl-
• CAS NO: 863971-44-2
• Molecular Formula: C₃₆H₅₁N₃O₇
• Molecular Weight: 637.80604
• Product Categories: ADCs Linkers
• Mol File: 863971-44-2.mol
• Article Data: 6

Chemical Properties

• Appearance: /
• CAS DataBase Reference: (5S,9S,11S,12R)-11-((S)-sec-butyl)-1-(9H-fluoren-9-yl)-5,9-diisopropyl-12-Methoxy-4,10-diMethyl-3,6,8-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid(CAS DataBase Reference)
• NIST Chemistry Reference: (5S,9S,11S,12R)-11-((S)-sec-butyl)-1-(9H-fluoren-9-yl)-5,9-diisopropyl-12-Methoxy-4,10-diMethyl-3,6,8-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid(863971-44-2)
• EPA Substance Registry System: (5S,9S,11S,12R)-11-((S)-sec-butyl)-1-(9H-fluoren-9-yl)-5,9-diisopropyl-12-Methoxy-4,10-diMethyl-3,6,8-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid(863971-44-2)

Safety Data

• Hazardous Substances Data: 863971-44-2(Hazardous Substances Data)

Usage

General Description

The chemical compound "(5S,9S,11S,12R)-11-((S)-sec-butyl)-1-(9H-fluoren-9-yl)-5,9-diisopropyl-12-Methoxy-4,10-diMethyl-3,6,8-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid" is a complex organic molecule with several functional groups. It contains a fluorenyl and sec-butyl group, as well as multiple methyl and isopropyl groups. Additionally, the compound features an oxa and triazatetradecan ring, as well as a carboxylic acid functional group. This molecule has a molecular formula C38H49NO6 and is likely to have biological activity due to its complex structure and the presence of a carboxylic acid moiety. Further research is needed to fully understand its potential uses.

Synthetic route

tert-butyl (5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H-fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oate (474645-25-5) → (5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2)

Conditions	Yield
With trifluoroacetic acid In dichloromethane at 20℃; for 2h;	86%
With trifluoroacetic acid In dichloromethane
With trifluoroacetic acid In dichloromethane

(3R,4S,5S)-4-[(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-N,3-dimethylbutanamido]-3-methoxy-5-methylheptanoate (177423-00-6) → (5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 20 °C 2: trifluoroacetic acid / dichloromethane / 2 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 20 °C 2: trifluoroacetic acid / dichloromethane / 2 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; diethyl dicarbonate / ethyl acetate / 20 °C 2: trifluoroacetic acid / dichloromethane / 20 °C View Scheme

tert-Butyl (3R,4S,5S)-3-methoxy-4-(N-methylamino)-5-methylheptanoate (474645-22-2) → (5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: 2-bromo-1-ethylpyridin-1-ium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / dichloromethane / 20 h / -10 - 20 °C 2: palladium 10% on activated carbon; hydrogen / methanol / 1 h / 20 °C 3: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 20 °C 4: trifluoroacetic acid / dichloromethane / 2 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine; 2-bromo-1-ethylpyridinium tetrafluoroborate / dichloromethane / 20 h / -10 - 20 °C 2: palladium 10% on activated carbon; hydrogen / methanol / 1 h / 20 °C 3: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 20 °C 4: trifluoroacetic acid / dichloromethane / 2 h / 20 °C View Scheme

(S)-N-(benzyloxycarbonyl)valine (1149-26-4) → (5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: 2-bromo-1-ethylpyridin-1-ium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / dichloromethane / 20 h / -10 - 20 °C 2: palladium 10% on activated carbon; hydrogen / methanol / 1 h / 20 °C 3: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 20 °C 4: trifluoroacetic acid / dichloromethane / 2 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine; 2-bromo-1-ethylpyridinium tetrafluoroborate / dichloromethane / 20 h / -10 - 20 °C 2: palladium 10% on activated carbon; hydrogen / methanol / 1 h / 20 °C 3: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 20 °C 4: trifluoroacetic acid / dichloromethane / 2 h / 20 °C View Scheme

tert-butyl (3R,4S,5S)-4-[(2S)-2-[[(benzyloxy)carbonyl]amino]-N,3-dimethylbutanamido]-3-methoxy-5-methylheptanoate (120205-52-9) → (5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: palladium 10% on activated carbon; hydrogen / methanol / 1 h / 20 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 20 °C 3: trifluoroacetic acid / dichloromethane / 2 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: palladium 10% on activated carbon; hydrogen / methanol / 1 h / 20 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 20 °C 3: trifluoroacetic acid / dichloromethane / 2 h / 20 °C View Scheme

Fmoc-Val-OH (68858-20-8) → (5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: 2-chloro-4,6-dimethoxy-1 ,3,5-triazine / 20 °C 2: diethylamine / tetrahydrofuran / 20 °C 3: N-ethyl-N,N-diisopropylamine; diethyl dicarbonate / ethyl acetate / 20 °C 4: trifluoroacetic acid / dichloromethane / 20 °C View Scheme

tert-butyl (3R,4S,5S)-4-[(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-N,3-dimethylbutanamido]-3-methoxy-5-methylheptanoate (1375415-93-2) → (5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: diethylamine / tetrahydrofuran / 20 °C 2: N-ethyl-N,N-diisopropylamine; diethyl dicarbonate / ethyl acetate / 20 °C 3: trifluoroacetic acid / dichloromethane / 20 °C View Scheme

tert-Butyl (3R,4S,5S)-3-methoxy-4-(N-methylamino)-5-methylheptanoate hydrochloride (120205-48-3) → (5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: 2-chloro-4,6-dimethoxy-1 ,3,5-triazine / 20 °C 2: diethylamine / tetrahydrofuran / 20 °C 3: N-ethyl-N,N-diisopropylamine; diethyl dicarbonate / ethyl acetate / 20 °C 4: trifluoroacetic acid / dichloromethane / 20 °C View Scheme

(5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2) + (2R,3R)-3-methoxy-2-methyl-N-[(2S)-1-(1,2-oxazinan-2-yl)-1-oxo-3-phenylpropan-2-yl]-3-[(2S)-pyrrolidin-2-yl]propanamide, trifluoroacetic acid salt (1352201-70-7) → N-[(9H-fluoren-9-ylmethoxy)carbonyl]-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(2S)-1-(1,2-oxazinan-2-yl)-1-oxo-3-phenylpropan-2-yl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 3h;	100%
With N-ethyl-N,N-diisopropylamine; 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 20℃; for 3h;	100%

(5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2) + (2R,3R)-3-methoxy-2-methyl-N-[(2S,3S)-1-(1,2-oxazinan-2-yl)-1-oxo-3-phenylbutan-2-yl]-3-[(2S)-pyrrolidin-2-yl]propanamide, trifluoroacetic acid salt (1352201-95-6) → N-[(9H-fluoren-9-ylmethoxy)carbonyl]-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(2S,3S)-1-(1,2-oxazinan-2-yl)-1-oxo-3-phenylbutan-2-yl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	100%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	100%

(5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2) + (2R,3R)-3-methoxy-2-methyl-N-[(2S)-1-(2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)-1-oxo-3-phenylpropan-2-yl]-3-[(2S)-pyrrolidin-2-yl]propanamide trifluoroacetate → N-[(9H-fluoren-9-ylmethoxy)carbonyl]-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(2S)-1-(2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)-1-oxo-3-phenylpropan-2-yl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 1h;	98%
With N-ethyl-N,N-diisopropylamine; 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 20℃; for 1h;	98%

(5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2) + di-tert-butyl dicarbonate (24424-99-5) → N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(2R,3S,4S)-1-carboxy-2-methoxy-4-methylhexan-3-yl]-N-methyl-L-valinamide

Conditions	Yield
Stage #1: (5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H-fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid With piperidine In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: di-tert-butyl dicarbonate In 1,4-dioxane; water pH=11;	97%

(5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2) + dap-phe-OMe hydrochloride salt → C55H77N5O10

Conditions	Yield
With diethyl cyanophosphonate; N-ethyl-N,N-diisopropylamine In dichloromethane for 1h;	87%

(5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2) + (x)C2HF3O2*C25H40N2O7 → C61H89N5O13

Conditions	Yield
With diethyl cyanophosphonate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2h;	81%

(5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2) + (S)-tert-butyl 2-((2R,3R)-3-methoxy-2-methyl-3-((2S,5S)-5-methylpyrrolidin-2-yl)propanamido)-3-phenylpropanoate → (S)-tert-butyl 2-((2R,3R)-3-((2S,5S)-1-((5S,8S,11S,12R)-11-sec-butyl-1-(9H-fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecane)-5-methylpyrrolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoate

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane; N,N-dimethyl-formamide at 20 - 30℃; for 1h; Inert atmosphere;	81%

(5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2) + (S)-2,4-dimethoxybenzyl 2-((2R,3R)-3-((1S,3S,5S)-2-azabicyclo[3.1.0]hexan-3-yl)-3-methoxy-2-methylpropanamido)-3-(2-fluorophenyl)propanoate → (S)-2,4-dimethoxybenzyl 2-((2R,3R)-3-((1S,3S,5S)-2-((5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H-fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oyl)-2-azabicyclo[3.1.0]hexan-3-yl)-3-methoxy-2-methylpropanamido)-3-(2-fluorophenyl)propanoate

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane; N,N-dimethyl-formamide at 20℃; for 1h; Temperature; Solvent; Inert atmosphere;	75.8%

(5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2) + (2R,3R)-3-methoxy-2-methyl-N-[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]-3-[(2S)-pyrrolidin-2-yl]propanethioamide, trifluoroacetic acid salt (1438851-45-6) → N-[(9H-fluoren-9-ylmethoxy)carbonyl]-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}-3-thioxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide

Conditions	Yield
With triethylamine; HATU In dichloromethane; N,N-dimethyl-formamide	75%

(5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2) + benzyl N-{(2R,3R)-3-methoxy-2-methyl-3-[(2S)-pyrrolidin-2-yl]propanoyl}-L-phenylalaninate trifluoroacetate (1369426-89-0) → N-[(9H-fluoren-9-ylmethoxy)carbonyl]-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(benzyloxy)-1-oxo-3-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	68%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	68%

(5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2) + (2R,3R)-3-methoxy-2-methyl-N-(2-phenylethyl)-3-[(2S)-pyrrolidin-2-yl]propanethioamide hydrochloride → N-[(9H-fluoren-9-ylmethoxy)carbonyl]-N-methyl-L-valyl-N-{(3R,4S,5S)-3-methoxy-[(2S)-2-{(1R,2R)-methoxy-2-methyl-3-[(2-phenylethyl)amino]-3-thioxopropyl}pyrrolidin-1-yl]-5-methyl-1-oxoheptan-4-yl}-N-methyl-L-valinamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane; N,N-dimethyl-formamide for 2h;	66%

(5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2) + (S)-tert-butyl 2-((2R,3R)-3-((1S,3S,5S)-2-azabicyclo[3.1.0]hexan-3-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoate → (S)-tert-butyl 2-((2R,3R)-3-((1S,3S,5S)-2-((5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(1H-fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-yl)-2-azabicyclo[3.1.0]hexan-3-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoate

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane; N,N-dimethyl-formamide at 20 - 30℃; for 1h; Inert atmosphere;	54.9%

(5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2) + (2R,3R)-3-methoxy-2-methyl-3-[(2S)-pyrrolidin-2-yl]propanoic acid trifluoroacetate → N-[(9H-fluoren-9-ylmethoxy)carbonyl]-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-2-carboxy-1-methoxypropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 3.5h;	35%
Stage #1: (5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H-fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 1.5h; Stage #2: (2R,3R)-3-methoxy-2-methyl-3-[(2S)-pyrrolidin-2-yl]propanoic acid trifluoroacetate With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h;	35%

1-hydroxy-pyrrolidine-2,5-dione (6066-82-6) + (5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2) → Fmoc-MeVal-Val-Dil-OSu (920017-35-2)

Conditions	Yield
With dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 48h;

(5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2) + C37H37Cl2N2O4Pol → C73H86Cl2N5O10Pol

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide for 6h; not specified;

(5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2) + (2R,3R)-3-methoxy-2-methyl-N-[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]-3-[(2S)-pyrrolidin-2-yl]propanethioamide, trifluoroacetic acid salt (1438851-45-6) → N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}-3-thioxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide

Conditions	Yield
Multi-step reaction with 2 steps 1: HATU; triethylamine / dichloromethane; N,N-dimethyl-formamide 2: diethylamine / dichloromethane View Scheme

(5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2) → N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(benzyloxy)-3-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide

Conditions	Yield
Multi-step reaction with 4 steps 1.1: piperidine / N,N-dimethyl-formamide / 0.17 h / 20 °C 1.2: pH 11 2.1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 20 °C 3.1: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 0.5 h / 20 °C 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.5 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1: piperidine / N,N-dimethyl-formamide / 0.17 h / 20 °C 2: sodium hydroxide / 1,4-dioxane; water / pH 11 3: 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 / 0.08 h / 20 °C 4: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 0.5 h / 20 °C 5: N-ethyl-N,N-diisopropylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 0.5 h / 20 °C View Scheme

(5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2) → N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(benzyloxy)-3-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide trifluoroacetate

Conditions	Yield
Multi-step reaction with 5 steps 1.1: piperidine / N,N-dimethyl-formamide / 0.17 h / 20 °C 1.2: pH 11 2.1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 20 °C 3.1: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 0.5 h / 20 °C 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.5 h / 20 °C 5.1: dichloromethane / 0.5 h / 20 °C View Scheme
Multi-step reaction with 6 steps 1: piperidine / N,N-dimethyl-formamide / 0.17 h / 20 °C 2: sodium hydroxide / 1,4-dioxane; water / pH 11 3: 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 / 0.08 h / 20 °C 4: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 0.5 h / 20 °C 5: N-ethyl-N,N-diisopropylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 0.5 h / 20 °C 6: dichloromethane / 0.5 h / 20 °C View Scheme

(5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2) → [3H]-Vedotin (474645-27-7)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: piperidine / N,N-dimethyl-formamide / 0.17 h / 20 °C 1.2: pH 11 2.1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 20 °C 3.1: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 0.5 h / 20 °C 4.1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.08 h / 20 °C 5.1: trifluoroacetic acid / dichloromethane View Scheme
Multi-step reaction with 6 steps 1: piperidine / N,N-dimethyl-formamide / 0.17 h / 20 °C 2: sodium hydroxide / 1,4-dioxane; water / pH 11 3: 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 / 0.08 h / 20 °C 4: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 0.5 h / 20 °C 5: 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 / 0.08 h / 20 °C 6: dichloromethane 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; dichloromethane / 20 °C 2: diethylamine / dichloromethane / 20 °C View Scheme

(5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2) → C44H75N5O9

Conditions	Yield
Multi-step reaction with 4 steps 1.1: piperidine / N,N-dimethyl-formamide / 0.17 h / 20 °C 1.2: pH 11 2.1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 20 °C 3.1: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 0.5 h / 20 °C 4.1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.08 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1: piperidine / N,N-dimethyl-formamide / 0.17 h / 20 °C 2: sodium hydroxide / 1,4-dioxane; water / pH 11 3: 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 / 0.08 h / 20 °C 4: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 0.5 h / 20 °C 5: 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 / 0.08 h / 20 °C View Scheme

(5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2) → (S)-2-((2R,3R)-3-((S)-1-((6S,9S,12S,13R)-12-((S)-sec-butyl)-6,9-diisopropyl-13-methoxy-2,2,5,11-tetramethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoic acid (1369427-27-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: piperidine / N,N-dimethyl-formamide / 0.17 h / 20 °C 1.2: pH 11 2.1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.17 h / 20 °C 3.1: palladium 10% on activated carbon; hydrogen / methanol View Scheme
Multi-step reaction with 4 steps 1: piperidine / N,N-dimethyl-formamide / 0.17 h / 20 °C 2: sodium hydroxide / 1,4-dioxane; water / pH 11 3: 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 / 0.17 h / 20 °C 4: palladium 10% on activated carbon; hydrogen / methanol / 1 h / 20 °C View Scheme

(5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2) → C51H79N5O10

Conditions	Yield
Multi-step reaction with 2 steps 1.1: piperidine / N,N-dimethyl-formamide / 0.17 h / 20 °C 1.2: pH 11 2.1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.17 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: piperidine / N,N-dimethyl-formamide / 0.17 h / 20 °C 2: sodium hydroxide / 1,4-dioxane; water / pH 11 3: 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 / 0.17 h / 20 °C View Scheme

(5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2) → N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide

Conditions	Yield
Multi-step reaction with 4 steps 1.1: piperidine / N,N-dimethyl-formamide / 0.17 h / 20 °C 1.2: pH 11 2.1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 20 °C 3.1: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 0.5 h / 20 °C 4.1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: piperidine / N,N-dimethyl-formamide / 0.17 h / 20 °C 2.1: sodium hydroxide / 1,4-dioxane; water / pH 11 3.1: 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 / 0.08 h / 20 °C 4.1: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 0.5 h / 20 °C 5.1: 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 / 0.5 h / 20 °C 5.2: 20 °C View Scheme

(5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2) → N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide trifluoroacetate

Conditions	Yield
Multi-step reaction with 5 steps 1.1: piperidine / N,N-dimethyl-formamide / 0.17 h / 20 °C 1.2: pH 11 2.1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 20 °C 3.1: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 0.5 h / 20 °C 4.1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C View Scheme

(5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2) → N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(1S,2R)-1-(1,2-oxazinan-2-ylcarbonyl)-2-phenylcyclopropyl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide

Conditions	Yield
Multi-step reaction with 3 steps 1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 20 °C 2: piperidine / N,N-dimethyl-formamide / 0.5 h / 20 °C 3: sodium cyanoborohydride; hydrogenchloride / 1,4-dioxane; water / 6 h / 100 °C / pH 3 View Scheme
Multi-step reaction with 3 steps 1.1: 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 / 2 h / 20 °C 2.1: piperidine / N,N-dimethyl-formamide / 0.5 h / 20 °C 3.1: 1,4-dioxane; water / 1 h / 100 °C 3.2: 20 - 100 °C / pH 3 View Scheme

(5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2) → N-(5-carboxypentyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(1S,2R)-1-(1,2-oxazinan-2-ylcarbonyl)-2-phenylcyclopropyl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide

Conditions	Yield
Multi-step reaction with 3 steps 1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 20 °C 2: piperidine / N,N-dimethyl-formamide / 0.5 h / 20 °C 3: sodium cyanoborohydride; hydrogenchloride / 1,4-dioxane; water / 4 h / 100 °C / pH 3 View Scheme
Multi-step reaction with 3 steps 1.1: 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 / 2 h / 20 °C 2.1: piperidine / N,N-dimethyl-formamide / 0.5 h / 20 °C 3.1: 1,4-dioxane; water / 1 h / 100 °C 3.2: 20 - 100 °C / pH 3 View Scheme

(5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2) → N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(adamantan-1-ylmethoxy)-1-oxo-3-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide

Conditions	Yield
Multi-step reaction with 6 steps 1.1: piperidine / N,N-dimethyl-formamide / 0.17 h / 20 °C 1.2: pH 11 2.1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 20 °C 3.1: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 0.5 h / 20 °C 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C 5.1: dichloromethane / 0.5 h 6.1: sodium cyanoborohydride; hydrogenchloride / 1,4-dioxane; water / 5 h / 100 °C View Scheme
Multi-step reaction with 7 steps 1.1: piperidine / N,N-dimethyl-formamide / 0.17 h / 20 °C 2.1: sodium hydroxide / 1,4-dioxane; water / pH 11 3.1: 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 / 0.08 h / 20 °C 4.1: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 0.5 h / 20 °C 5.1: N-ethyl-N,N-diisopropylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 0.5 h / 20 °C 6.1: dichloromethane / 0.5 h 7.1: 1,4-dioxane; water / 1 h / 100 °C 7.2: 4 h / 100 °C / pH 3 View Scheme

(5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acid (863971-44-2) → N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(benzyloxy)-3-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide

Conditions	Yield
Multi-step reaction with 6 steps 1.1: piperidine / N,N-dimethyl-formamide / 0.17 h / 20 °C 1.2: pH 11 2.1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 20 °C 3.1: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 0.5 h / 20 °C 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.5 h / 20 °C 5.1: dichloromethane / 0.5 h / 20 °C 6.1: sodium cyanoborohydride; hydrogenchloride / 1,4-dioxane; water / 5 h / 100 °C View Scheme
Multi-step reaction with 7 steps 1.1: piperidine / N,N-dimethyl-formamide / 0.17 h / 20 °C 2.1: sodium hydroxide / 1,4-dioxane; water / pH 11 3.1: 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 / 0.08 h / 20 °C 4.1: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 0.5 h / 20 °C 5.1: N-ethyl-N,N-diisopropylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 0.5 h / 20 °C 6.1: dichloromethane / 0.5 h / 20 °C 7.1: 1,4-dioxane; water / 1 h / 100 °C 7.2: 4 h / 100 °C / pH 3 View Scheme

Upstream product

• 474645-25-5 tert-butyl (5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H-fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oate 
• 177423-00-6 (3R,4S,5S)-4-[(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-N,3-dimethylbutanamido]-3-methoxy-5-methylheptanoate 
• 474645-22-2 tert-Butyl (3R,4S,5S)-3-methoxy-4-(N-methylamino)-5-methylheptanoate 
• 1149-26-4 (S)-N-(benzyloxycarbonyl)valine 
• 120205-52-9 tert-butyl (3R,4S,5S)-4-[(2S)-2-[[(benzyloxy)carbonyl]amino]-N,3-dimethylbutanamido]-3-methoxy-5-methylheptanoate 
• 120205-48-3 tert-Butyl (3R,4S,5S)-3-methoxy-4-(N-methylamino)-5-methylheptanoate hydrochloride 
• 1375415-93-2 tert-butyl (3R,4S,5S)-4-[(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-N,3-dimethylbutanamido]-3-methoxy-5-methylheptanoate 
• 68858-20-8 Fmoc-Val-OH 

Downstream Products

• 474645-27-7 [3H]-Vedotin 
• 1369427-27-9 (S)-2-((2R,3R)-3-((S)-1-((6S,9S,12S,13R)-12-((S)-sec-butyl)-6,9-diisopropyl-13-methoxy-2,2,5,11-tetramethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoic acid 

Relevant articles and documents

An antibody-coupled drug targeting on EGFR, a preparation method thereof, and uses thereof

The invention discloses an antibody coupling drug targeting on EGFR, a preparation method thereof and uses thereof. The antibody-conjugated drug targeting EGFR is named LR004-VC-MMAE consisting of anantibody, a cytotoxic drug and a linker, wherein the antibody drug conjugate has a structure represented by the formula I, wherein mAb is an LR004 monoclonal antibody, n=2-8. The novel antibody-conjugated drug LR004-VC-MMAE can not only target EGFR antigen, but also has strong cytotoxicity to tumor cells. Compared with LR004 itself, it did not affect the affinity, endocytosis and targeting of theantibody, and better retained its biological function. Compared to LR004, the antitumor effect of LR004-VC-MMAE antibody-conjugated drug is significantly improved, and the tumor disappeared. Comparedto LR004, LR004-VC-MMAE antibody-conjugated total antibody showed longer half-life, slower clearance rate, lower concentration of free MMAE in plasma, shorter half-life and faster clearance rate, which is conducive to reduce toxicity.

NOVEL BINDER-DRUG CONJUGATES (ADCs) AND USE OF SAME

The present patent application relates to novel binder-drug conjugates (ADCs) of N,N-dialkylauristatins directed against the target epidermal growth factor receptor (EGFR, gene ID 1956), effective metabolites of these ADCs, methods for producing these ADCs, use of these ADCs for treatment and or prevention of diseases as well as the use of these ADCs to produce pharmaceutical drugs for treatment and/or prevention of diseases, in particular hyperproliferative and/or angiogenic diseases such as cancer, for example. Such treatments may be administered as monotherapy or in combination with other pharmaceutical drugs or other therapeutic measures.

SUBSTITUTED PEPTIDE ANALOGS

The present invention relates to peptide analogs, antibody-drug conjugates comprising such compounds, pharmaceutical compositions comprising such compounds and conjugates, and methods of treating cancer with such compounds and conjugates.