868539-96-2

Basic information

• Product Name: Boc-HPh-Leu-Phe-OMe
• Synonyms: Boc-HPh-Leu-Phe-OMe;L-Phenylalanine, (αS)-α-[[(1,1-dimethylethoxy)carbonyl]amino]benzenebutanoyl-L-leucyl-, methyl ester;N-[(S)-2-(tert-Butoxycarbonylamino)-4-phenylbutanoyl]-L-leucyl-L-phenylalanine methyl ester;methyl ((S)-2-((tert-butoxycarbonyl)amino)-4-phenylbutanoyl)-L-leucyl-L-phenylalaninate;Methyl N-[(2S)-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)-4-phenylbutanoyl]-L-leucyl-L-phenylalaninate;(6S,9S,12S)-Methyl 12-benzyl-9-isobutyl-2,2-dimethyl-4,7,10-trioxo-6-phenethyl-3-oxa-5,8,11-triazatridecan-13-oate
• CAS NO: 868539-96-2
• Molecular Formula: C₃₁H₄₃N₃O₆
• Molecular Weight: 553.68962
• EINECS: -0
• Mol File: 868539-96-2.mol
• Article Data: 6

Chemical Properties

• Boiling Point: 753.4±60.0 °C(Predicted)
• Appearance: /
• Density: 1.123±0.06 g/cm3(Predicted)
• Storage Temp.: 2-8°C
• PKA: 11.22±0.46(Predicted)
• CAS DataBase Reference: Boc-HPh-Leu-Phe-OMe(CAS DataBase Reference)
• NIST Chemistry Reference: Boc-HPh-Leu-Phe-OMe(868539-96-2)
• EPA Substance Registry System: Boc-HPh-Leu-Phe-OMe(868539-96-2)

Safety Data

• Hazardous Substances Data: 868539-96-2(Hazardous Substances Data)

Usage

General Description

Boc-HPh-Leu-Phe-OMe is a chemical compound that consists of a Boc (tert-butoxycarbonyl) protecting group, followed by the amino acids phenylalanine, leucine, and phenylalanine, and ending with a methoxy (OMe) group. The Boc group is commonly used to protect the amine group of amino acids during peptide synthesis, while the amino acids leucine and phenylalanine are essential for protein synthesis and play important roles in various biological processes. The methoxy group is a common protective group for the carboxyl group of amino acids. Overall, Boc-HPh-Leu-Phe-OMe is a complex chemical compound with potential applications in peptide synthesis and biological research.

Synthetic route

Boc-L-homophenylalanine (82732-07-8, 108524-68-1, 142926-43-0, 100564-78-1) + Leu-Phe-OMe trifluoroacetate → (S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate (868539-96-2)

Conditions	Yield
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 0 - 20℃;
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 12h;

N-tert-butoxycarbonyl-L-phenylalanine (13734-34-4) + L-leucyl-L-phenylalanine methyl ester (38155-18-9) → (S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate (868539-96-2)

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 N,N-dimethyl-formamide at 20℃;

N-tert-butoxycarbonyl-L-leucine (13139-15-6) → (S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate (868539-96-2)

Conditions	Yield
Multi-step reaction with 3 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 / 20 °C 2: trifluoroacetic acid / dichloromethane / 3 h 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 / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate / N,N-dimethyl-formamide / 0 °C / Inert atmosphere 2.1: trifluoroacetic acid / dichloromethane / 2 h / 0 - 20 °C 2.2: 0 - 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: benzotriazol-1-ol; 4-methyl-morpholine; dicyclohexyl-carbodiimide / dichloromethane / 2 h / 0 - 30 °C / Inert atmosphere 2: hydrogenchloride / isopropyl alcohol / 2 h / 25 - 30 °C 3: benzotriazol-1-ol; 4-methyl-morpholine; dicyclohexyl-carbodiimide / dichloromethane / 2 h / 0 - 30 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C 2: trifluoroacetic acid / dichloromethane View Scheme

methyl (2S)-2-amino-3-phenylpropanoate hydrochloride (7524-50-7) → (S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate (868539-96-2)

Conditions	Yield
Multi-step reaction with 3 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 / 20 °C 2: trifluoroacetic acid / dichloromethane / 3 h 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 / 20 °C View Scheme
Multi-step reaction with 3 steps 1: benzotriazol-1-ol; 4-methyl-morpholine; dicyclohexyl-carbodiimide / dichloromethane / 2 h / 0 - 30 °C / Inert atmosphere 2: hydrogenchloride / isopropyl alcohol / 2 h / 25 - 30 °C 3: benzotriazol-1-ol; 4-methyl-morpholine; dicyclohexyl-carbodiimide / dichloromethane / 2 h / 0 - 30 °C / Inert atmosphere View Scheme

(N-(tert-butoxycarbonyl)-L-leucinyl)-L-phenylalanine methyl ester (15136-32-0, 87976-66-7, 120342-25-8, 5874-73-7) → (S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate (868539-96-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: trifluoroacetic acid / dichloromethane / 3 h 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 / 20 °C View Scheme
Multi-step reaction with 2 steps 1: hydrogenchloride / isopropyl alcohol / 2 h / 25 - 30 °C 2: benzotriazol-1-ol; 4-methyl-morpholine; dicyclohexyl-carbodiimide / dichloromethane / 2 h / 0 - 30 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: dichloromethane / 3 h / 0 - 20 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 0 - 20 °C View Scheme

(N-(tert-butoxycarbonyl)-L-leucinyl)-L-phenylalanine methyl ester (15136-32-0, 87976-66-7, 120342-25-8, 5874-73-7) + Boc-L-homophenylalanine (82732-07-8, 108524-68-1, 142926-43-0, 100564-78-1) → (S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate (868539-96-2)

Conditions	Yield
Stage #1: (N-(tert-butoxycarbonyl)-L-leucinyl)-L-phenylalanine methyl ester With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 2h; Stage #2: Boc-L-homophenylalanine With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere;	21.59 g
Stage #1: (N-(tert-butoxycarbonyl)-L-leucinyl)-L-phenylalanine methyl ester With trifluoroacetic acid In dichloromethane Stage #2: Boc-L-homophenylalanine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane	246 mg

methyl (2S)-2-amino-3-phenylpropanoate (2577-90-4) → (S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate (868539-96-2)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate / N,N-dimethyl-formamide / 0 °C / Inert atmosphere 2.1: trifluoroacetic acid / dichloromethane / 2 h / 0 - 20 °C 2.2: 0 - 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 0 - 20 °C 2: dichloromethane / 3 h / 0 - 20 °C 3: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 0 - 20 °C View Scheme

Boc-L-homophenylalanine (82732-07-8, 108524-68-1, 142926-43-0, 100564-78-1) + (S)-methyl 2-((S)-2-amino-4-methylpentanamido)-3-phenylpropanoate hydrochloride (6461-07-0) → (S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate (868539-96-2)

Conditions	Yield
With 4-methyl-morpholine; benzotriazol-1-ol; dicyclohexyl-carbodiimide In dichloromethane at 0 - 30℃; for 2h; Inert atmosphere;	121.0 g

L-leucine (61-90-5) → (S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate (868539-96-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium hydroxide / water / 20 h / 25 - 30 °C 2: benzotriazol-1-ol; 4-methyl-morpholine; dicyclohexyl-carbodiimide / dichloromethane / 2 h / 0 - 30 °C / Inert atmosphere 3: hydrogenchloride / isopropyl alcohol / 2 h / 25 - 30 °C 4: benzotriazol-1-ol; 4-methyl-morpholine; dicyclohexyl-carbodiimide / dichloromethane / 2 h / 0 - 30 °C / Inert atmosphere View Scheme

L-phenylalanine (63-91-2) → (S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate (868539-96-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: thionyl chloride / 8 h / 25 - 30 °C 2: benzotriazol-1-ol; 4-methyl-morpholine; dicyclohexyl-carbodiimide / dichloromethane / 2 h / 0 - 30 °C / Inert atmosphere 3: hydrogenchloride / isopropyl alcohol / 2 h / 25 - 30 °C 4: benzotriazol-1-ol; 4-methyl-morpholine; dicyclohexyl-carbodiimide / dichloromethane / 2 h / 0 - 30 °C / Inert atmosphere View Scheme

N-tert-butoxycarbonyl-L-phenylalanine (13734-34-4) → (S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate (868539-96-2)

Conditions

Yield

Multi-step reaction with 4 steps 1: thionyl chloride / 2 h / 0 - 20 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 0 - 20 °C 3: dichloromethane / 3 h / 0 - 20 °C 4: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 0 - 20 °C View Scheme

(S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate (868539-96-2) + trifluoroacetic acid (76-05-1) → C2HF3O2*C26H35N3O4 (868539-99-5)

Conditions	Yield
In dichloromethane at 20℃; for 1h; Product distribution / selectivity;
In dichloromethane at 0 - 20℃; for 3h;

(S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate (868539-96-2) → C44H61N7O8 (1545469-05-3)

Conditions

Yield

Multi-step reaction with 4 steps 1: lithium hydroxide monohydrate / tetrahydrofuran; methanol / 3 h / 0 - 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 / 20 °C 3: dichloromethane / 4 h / 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 / 20 °C View Scheme

(S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate (868539-96-2) → C39H50N6O6 (1545468-61-8)

Conditions

Yield

Multi-step reaction with 4 steps 1: lithium hydroxide monohydrate / tetrahydrofuran; methanol / 3 h / 0 - 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 / 20 °C 3: dichloromethane / 4 h / 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 / 20 °C View Scheme

(S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate (868539-96-2) → C36H49N4O10P(2-)*2Na(1+)

Conditions

Yield

Multi-step reaction with 5 steps 1: lithium hydroxide monohydrate / tetrahydrofuran; methanol / 3 h / 0 - 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 / 20 °C 3: dichloromethane / 4 h / 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 / 20 °C 5: palladium 10% on activated carbon; hydrogen / tetrahydrofuran; water / 2 h / 20 °C View Scheme

(S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate (868539-96-2) → C38H50N6O6S (1545468-62-9)

Conditions

Yield

Multi-step reaction with 4 steps 1: lithium hydroxide monohydrate / tetrahydrofuran; methanol / 3 h / 0 - 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 / 20 °C 3: dichloromethane / 4 h / 20 °C 4: triethylamine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate / N,N-dimethyl-formamide / 20 °C View Scheme

(S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate (868539-96-2) → C39H53N7O6 (1545468-63-0)

Conditions

Yield

Multi-step reaction with 5 steps 1: lithium hydroxide monohydrate / tetrahydrofuran; methanol / 3 h / 0 - 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 / 20 °C 3: dichloromethane / 4 h / 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 / 20 °C 5: trifluoroacetic acid / dichloromethane / 3 h / 20 °C View Scheme

(S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate (868539-96-2) → C39H52N6O6S (1545468-64-1)

Conditions

Yield

Multi-step reaction with 4 steps 1: lithium hydroxide monohydrate / tetrahydrofuran; methanol / 3 h / 0 - 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 / 20 °C 3: dichloromethane / 4 h / 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 / 20 °C View Scheme

(S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate (868539-96-2) → C30H41N3O6

Conditions	Yield
With lithium hydroxide monohydrate In tetrahydrofuran; methanol at 0 - 20℃; for 3h;

(S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate (868539-96-2) → C39H56N4O7

Conditions	Yield
Multi-step reaction with 2 steps 1: lithium hydroxide monohydrate / tetrahydrofuran; methanol / 3 h / 0 - 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 / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: hydrazine / methanol / Reflux 2.1: hydrogenchloride; tert-butyl nitrate / 1,4-dioxane; N,N-dimethyl-formamide / 0.17 h / -30 °C / Inert atmosphere 2.2: -30 - 20 °C View Scheme

(S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate (868539-96-2) → (S)-2-((S)-2-amino-4-phenylbutanamido)-4-methyl-N-((S)-1-(((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)pentanamide 2,2,2-trifluoroacetate

Conditions	Yield
Multi-step reaction with 3 steps 1: lithium hydroxide monohydrate / tetrahydrofuran; methanol / 3 h / 0 - 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 / 20 °C 3: dichloromethane / 4 h / 20 °C View Scheme

(S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate (868539-96-2) → C50H63N4O10P

Conditions

Yield

Multi-step reaction with 4 steps 1: lithium hydroxide monohydrate / tetrahydrofuran; methanol / 3 h / 0 - 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 / 20 °C 3: dichloromethane / 4 h / 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 / 20 °C View Scheme

(S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate (868539-96-2) + chloroacetyl chloride (79-04-9) → C28H36ClN3O5 (868540-08-3)

Conditions	Yield
Stage #1: (S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate With trifluoroacetic acid In dichloromethane at 20℃; for 1h; Stage #2: chloroacetyl chloride With N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere;	0.64 g

(S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate (868539-96-2) → (x)C6H8O7*C40H57N5O7

Conditions	Yield
Multi-step reaction with 5 steps 1.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 1.2: 0 - 20 °C / Inert atmosphere 2.1: potassium iodide / tetrahydrofuran / Inert atmosphere 3.1: lithium hydroxide / methanol; water / 12 h / 0 - 5 °C 4.1: benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / 1 h / 0 °C 5.1: tetrahydrofuran; acetonitrile / 2 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 1.2: 0 - 20 °C / Inert atmosphere 2.1: potassium iodide / tetrahydrofuran / Inert atmosphere 3.1: lithium hydroxide / methanol; water / 12 h / 0 - 5 °C 4.1: benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 1.5 h / 0 - 5 °C 5.1: tetrahydrofuran; acetonitrile / 2 h / 20 °C View Scheme

(S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate (868539-96-2) → C32H44N4O6

Conditions	Yield
Multi-step reaction with 2 steps 1.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 1.2: 0 - 20 °C / Inert atmosphere 2.1: potassium iodide / tetrahydrofuran / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: hydrogenchloride / ethyl acetate / 2 h / 25 - 30 °C 2: benzotriazol-1-ol; 4-methyl-morpholine; dicyclohexyl-carbodiimide / dichloromethane / 2 h / 0 - 30 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: dichloromethane / 3 h / 0 - 20 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 0 - 20 °C View Scheme

(S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate (868539-96-2) → (S)-2-((S)-4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamido)-3-phenyipropanoic acid (868540-16-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 1.2: 0 - 20 °C / Inert atmosphere 2.1: potassium iodide / tetrahydrofuran / Inert atmosphere 3.1: lithium hydroxide / methanol; water / 12 h / 0 - 5 °C View Scheme
Multi-step reaction with 3 steps 1: hydrogenchloride / ethyl acetate / 2 h / 25 - 30 °C 2: benzotriazol-1-ol; 4-methyl-morpholine; dicyclohexyl-carbodiimide / dichloromethane / 2 h / 0 - 30 °C / Inert atmosphere 3: lithium hydroxide monohydrate; water / tetrahydrofuran / 3 h / 25 - 30 °C View Scheme
Multi-step reaction with 3 steps 1: dichloromethane / 3 h / 0 - 20 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 0 - 20 °C 3: lithium hydroxide monohydrate / methanol / 3 h / 0 - 20 °C View Scheme

(S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate (868539-96-2) → carfilzomib

Conditions	Yield
Multi-step reaction with 4 steps 1.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 1.2: 0 - 20 °C / Inert atmosphere 2.1: potassium iodide / tetrahydrofuran / Inert atmosphere 3.1: lithium hydroxide / methanol; water / 12 h / 0 - 5 °C 4.1: benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / 1 h / 0 °C View Scheme
Multi-step reaction with 4 steps 1.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 1.2: 0 - 20 °C / Inert atmosphere 2.1: potassium iodide / tetrahydrofuran / Inert atmosphere 3.1: lithium hydroxide / methanol; water / 12 h / 0 - 5 °C 4.1: benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 1.5 h / 0 - 5 °C View Scheme
Multi-step reaction with 4 steps 1: hydrogenchloride / ethyl acetate / 2 h / 25 - 30 °C 2: benzotriazol-1-ol; 4-methyl-morpholine; dicyclohexyl-carbodiimide / dichloromethane / 2 h / 0 - 30 °C / Inert atmosphere 3: lithium hydroxide monohydrate; water / tetrahydrofuran / 3 h / 25 - 30 °C 4: benzotriazol-1-ol; 4-methyl-morpholine; HATU / N,N-dimethyl-formamide / 3 h / 0 - 5 °C / Inert atmosphere View Scheme

(S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate (868539-96-2) → Reaxys ID: 30386849

Conditions	Yield
Multi-step reaction with 4 steps 1: hydrogenchloride / ethyl acetate / 2 h / 25 - 30 °C 2: benzotriazol-1-ol; 4-methyl-morpholine; dicyclohexyl-carbodiimide / dichloromethane / 2 h / 0 - 30 °C / Inert atmosphere 3: lithium hydroxide monohydrate; water / tetrahydrofuran / 3 h / 25 - 30 °C View Scheme

(S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate (868539-96-2) → (S)-methyl 2-((S)-2-((S)-2-amino-4-phenyIbutanamido)-4-methylpentanamido)-3-phenylpropanoate hydrochloride

Conditions	Yield
With hydrogenchloride In ethyl acetate at 25 - 30℃; for 2h;	75.2 g

(S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate (868539-96-2) → (S)-perfluorophenyl 2-((S)-4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamido)-3-phenylpropanoate

Conditions	Yield
Multi-step reaction with 4 steps 1: hydrogenchloride / ethyl acetate / 2 h / 25 - 30 °C 2: benzotriazol-1-ol; 4-methyl-morpholine; dicyclohexyl-carbodiimide / dichloromethane / 2 h / 0 - 30 °C / Inert atmosphere 3: lithium hydroxide monohydrate; water / tetrahydrofuran / 3 h / 25 - 30 °C 4: 4-methyl-morpholine; HATU / dichloromethane / 6 h / 0 - 5 °C / Inert atmosphere View Scheme

(S)-methyl 2-((S)-2-tert.butoxycarbonyIamino-4-phenylbutanamido-4-methylpentanamido)-3-phenylpropanoate (868539-96-2) → (S)-2,5-dioxopyrrolidin-1-yl 2-((S)-4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamido)-3-phenylpropanoate

Conditions	Yield
Multi-step reaction with 4 steps 1: hydrogenchloride / ethyl acetate / 2 h / 25 - 30 °C 2: benzotriazol-1-ol; 4-methyl-morpholine; dicyclohexyl-carbodiimide / dichloromethane / 2 h / 0 - 30 °C / Inert atmosphere 3: lithium hydroxide monohydrate; water / tetrahydrofuran / 3 h / 25 - 30 °C 4: diisopropyl-carbodiimide / dichloromethane / 6 h / 0 - 30 °C / Inert atmosphere View Scheme

Upstream product

• 13734-34-4 N-tert-butoxycarbonyl-L-phenylalanine 
• 63-91-2 L-phenylalanine 
• 61-90-5 L-leucine 
• 82732-07-8 Boc-L-homophenylalanine 
• 6461-07-0 methyl (S)-2-[(S)-2-amino-4-methylpentanamido]-3-phenylpropanoate hydrochloride 
• 2577-90-4 methyl (2S)-2-amino-3-phenylpropanoate 
• 15136-32-0 (N-(tert-butoxycarbonyl)-L-leucinyl)-L-phenylalanine methyl ester 
• 7524-50-7 methyl (2S)-2-amino-3-phenylpropanoate hydrochloride 
• 13139-15-6 N-tert-butoxycarbonyl-L-leucine 
• 38155-18-9 L-leucyl-L-phenylalanine methyl ester 

Downstream Products

• 868540-08-3 C₂₈H₃₆ClN₃O₅ 
• 1140908-89-9 C₃₂H₄₄N₄O₆ 
• 868540-16-3 (S)-2-((S)-4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamido)-3-phenyipropanoic acid 
• 868540-17-4 carfilzomib 
• 868539-99-5 C₂HF₃O₂*C₂₆H₃₅N₃O₄ 

Relevant articles and documents

Preparation and biological evaluation of soluble tetrapeptide epoxyketone proteasome inhibitors

A series of novel tetrapeptidyl epoxyketone inhibitors of 20S proteasome was designed and synthesized. To fully understand the SAR, various groups at R1, R2, R3, R4 and R5 positions, including aromatic and aliphatic substituents were designed, synthesized and biologically assayed. Based on the enzymatic results, seven compounds were selected to evaluate their cellular activities and soluble compound 36 showed strong potency against human multiple myeloma (MM) cell lines. Microsomal stability results indicated that compound 36 was more stable in mice, rat and human microsomes than marketed carfilzomib. The in vivo activities of this compound were evaluated with the xenograft mice models of MM cell lines ARH77 and RPMI-8226 with luciferase expression and the T/C value of the two models were 49.5% and 37.6%, respectively. To evaluate the potential cardiovascular toxicity, inhibition of hERG ion channel in HEK293 cells by compound 36 and carfilzomib was carried out. The results indicated that 36 had no binding affinity for the hERG ion channel while carfilzomib could bind it with IC50 of 92.1 μM.

PROCESS FOR THE PREPARATION OF (2S)-N-((S)-1-((S)-4-METHYL-1-((R)-2-METHYL OXIRAN-2-YL)-1-OXOPENTAN-2-YLCARBAMOYL)-2-PHENYLETHYL)-2-((S)-2-(2-MORPHOLINO ACETAMIDO)-4-PHENYLBUTANAMIDO)-4-METHYLPENTANAMIDE

The present invention relates to process for the preparation of (2S)-N-((S)-l -((S)-4-methyl-1 -((R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-4 -methylpentanamide represented by the following structural formula-1.

PEPTIDE EPOXYKETONE COMPOUNDS

The present disclosure relates to novel compounds and pharmaceutical compositions thereof which are useful as inhibitors of proteasomes. The compounds provided herein are capable of inhibiting all three of CT-L, T-L, and PGPH activities of proteasomes, and are useful in treating various conditions or diseases associated with proteasomes.