198904-86-8

Basic information

• Product Name: Des-N-(methoxycarbonyl)-L-tert-leucine Bis-Boc Atazanavir
• Synonyms: 2-[(2S,3S)-3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl] -2-[[4-(2-pyridinyl)phenyl]methyl]hydrazinecarboxylic Acid 1,1-Dimethylethyl Ester;Des-N-(methoxycarbonyl)-L-tert-leucine Bis-Boc Atazanavir;dimethylethoxy)carbonyl]amino]-2-hydroxy-4-;Hydrazinecarboxylic acid, 2-[(2S,3S)-3-[[(1,1-;phenylbutyl]-2-[[4-(2-pyridinyl)phenyl]methyl]-,1,1-dimethylethyl ester;Hydrazinecarboxylic acid, 2-[(2S,3S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]-2-[[4-(2-pyridinyl)phenyl]methyl]-, 1,1-dimethylethyl ester;1-[4-(Pyridin-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)-amino]-4(S)-hydroxyl-6-phenyl-2-azahexane;2-[(2S,3S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]-2-[[4-(2-pyridi
• CAS NO: 198904-86-8
• Molecular Formula: C₃₂H₄₂N₄O₅
• Molecular Weight: 562.69968
• EINECS: 1592732-453-0
• Product Categories: Aromatics Compounds;Aromatics;Chiral Reagents;Heterocycles
• Mol File: 198904-86-8.mol
• Article Data: 12

Chemical Properties

• Melting Point: 185-186℃
• Appearance: /
• Density: 1.157
• Vapor Pressure: 0-0Pa at 25℃
• Refractive Index: 1.567
• Storage Temp.: Refrigerator
• Solubility: Chloroform (Slightly), DMSO (Slightly), Methanol (Slightly)
• PKA: 10.05±0.50(Predicted)
• CAS DataBase Reference: Des-N-(methoxycarbonyl)-L-tert-leucine Bis-Boc Atazanavir(CAS DataBase Reference)
• NIST Chemistry Reference: Des-N-(methoxycarbonyl)-L-tert-leucine Bis-Boc Atazanavir(198904-86-8)
• EPA Substance Registry System: Des-N-(methoxycarbonyl)-L-tert-leucine Bis-Boc Atazanavir(198904-86-8)

Safety Data

• Hazardous Substances Data: 198904-86-8(Hazardous Substances Data)

Usage

Description

Des-N-(methoxycarbonyl)-L-tert-leucine Bis-Boc Atazanavir is a white solid intermediate compound that plays a crucial role in the synthesis of Atazanavir (A790051) and the preparation of certain peptide analogs. It is a chemical derivative of Atazanavir, a protease inhibitor used in the treatment of HIV.

Uses

Used in Pharmaceutical Industry:
Des-N-(methoxycarbonyl)-L-tert-leucine Bis-Boc Atazanavir is used as an intermediate in the synthesis of Atazanavir, a potent protease inhibitor for the treatment of HIV. Its role in the pharmaceutical industry is to facilitate the production of Atazanavir, which is an essential medication for HIV management.
Additionally, Des-N-(methoxycarbonyl)-L-tert-leucine Bis-Boc Atazanavir is used as a building block in the preparation of various peptide analogs. These analogs have potential applications in the development of new drugs and therapies, particularly in the fields of medicine and biotechnology.

InChI:InChI=1/C32H42N4O5/c1-31(2,3)40-29(38)34-27(20-23-12-8-7-9-13-23)28(37)22-36(35-30(39)41-32(4,5)6)21-24-15-17-25(18-16-24)26-14-10-11-19-33-26/h7-19,27-28,37H,20-22H2,1-6H3,(H,34,38)(H,35,39)/t27-,28-/m0/s1

Synthetic route

(2R,3S)-3-[N-(tert-butyloxycarbonyl)amino]-1,2-epoxy-4-phenylbutane (98760-08-8) + N-1-(tert-butoxycarbonyl)-N-2-[4-(pyridine-2-yl)benzyl]hydrazine (198904-85-7) → 1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane (198904-86-8)

Conditions	Yield
In isopropyl alcohol for 24h; Inert atmosphere; Reflux; Large scale;	85.4%
In isopropyl alcohol Heating / reflux;	75%
In isopropyl alcohol for 16h; Heating;	69%

1-(4-(pyridin-2-yl)-phenyl)-1-oxo-5(S)-2,5-di[(tert-butoxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane (198905-10-1) → 1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane (198904-86-8)

Conditions	Yield
With diisobutylaluminium hydride at 0℃; for 2.5h;	60%

(1-oxiranyl-2-phenylethyl)carbamic acid tert-butyl ester (98760-08-8, 98818-34-9, 98818-35-0, 103127-56-6, 98737-29-2) + N-1-(tert-butoxycarbonyl)-N-2-[4-(pyridine-2-yl)benzyl]hydrazine (198904-85-7) → 1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane (198904-86-8)

Conditions	Yield
In isopropyl alcohol at 65℃; for 16h;	57%
In isopropyl alcohol at 65 - 85℃; for 16h; Product distribution / selectivity;	35%
In isopropyl alcohol at 85℃; for 16h;	35%

2-bromo-pyridine (109-04-6) → 1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane (198904-86-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) Mg, I2, 2.) <1,3-bis(diphenylphosphino)propane>nickel(II) chloride, diisobutylaluminum hydride, 3.) aq. HCl 2: 93 percent / ethanol / 4 h / Heating 3: 89 percent / H2 / 10percent Pd/C / methanol 4: 69 percent / propan-2-ol / 16 h / Heating View Scheme
Multi-step reaction with 4 steps 1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / toluene; ethanol / 20 h / 76 °C / Inert atmosphere 2: toluene; isopropyl alcohol / 2 h / 80 - 85 °C / Inert atmosphere; Large scale 3: palladium 10% on activated carbon; sodium formate / water; ethanol / 1.5 h / 57 °C 4: isopropyl alcohol / 24 h / Inert atmosphere; Reflux; Large scale View Scheme

2-(4-formylphenyl)pyridine (127406-56-8) → 1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane (198904-86-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: 93 percent / ethanol / 4 h / Heating 2: 89 percent / H2 / 10percent Pd/C / methanol 3: 69 percent / propan-2-ol / 16 h / Heating View Scheme
Multi-step reaction with 3 steps 1: toluene; isopropyl alcohol / 2 h / 80 - 85 °C / Inert atmosphere; Large scale 2: palladium 10% on activated carbon; sodium formate / water; ethanol / 1.5 h / 57 °C 3: isopropyl alcohol / 24 h / Inert atmosphere; Reflux; Large scale View Scheme

1,1-dimethoxy-1-(4-bromophenyl)methane (24856-58-4) → 1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane (198904-86-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) Mg, I2, 2.) <1,3-bis(diphenylphosphino)propane>nickel(II) chloride, diisobutylaluminum hydride, 3.) aq. HCl 2: 93 percent / ethanol / 4 h / Heating 3: 89 percent / H2 / 10percent Pd/C / methanol 4: 69 percent / propan-2-ol / 16 h / Heating View Scheme

N-(tert-butoxycarbonyl)-N'-[4-(pyridin-2-yl)phenylmethylidene]hydrazine (857904-11-1) → 1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane (198904-86-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 89 percent / H2 / 10percent Pd/C / methanol 2: 69 percent / propan-2-ol / 16 h / Heating View Scheme

t-butoxycarbonylhydrazine (870-46-2) → 1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane (198904-86-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: 53 percent / H2, AcOH / Raney Ni / methanol / 750.06 Torr / Ambient temperature 2: NaBH3CN, TsOH / 1,2-dimethoxy-ethane / Ambient temperature 3: 1.) aq. borax; 2.) MTBD 4: 60 percent / DIBAH / 2.5 h / 0 °C View Scheme

Boc-L-phenylalaninal (72155-45-4) → 1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane (198904-86-8)

Conditions	Yield
Multi-step reaction with 5 steps 1: 39 percent / BnEt3N(1+)*Cl(1-) / H2O; CH2Cl2 / 0 °C 2: 53 percent / H2, AcOH / Raney Ni / methanol / 750.06 Torr / Ambient temperature 3: NaBH3CN, TsOH / 1,2-dimethoxy-ethane / Ambient temperature 4: 1.) aq. borax; 2.) MTBD 5: 60 percent / DIBAH / 2.5 h / 0 °C View Scheme

4-Pyridin-2-yl-benzoic acid (1R,2S)-2-tert-butoxycarbonylamino-1-(tert-butoxycarbonyl-hydrazonomethyl)-3-phenyl-propyl ester (198905-09-8) → 1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane (198904-86-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: NaBH3CN, TsOH / 1,2-dimethoxy-ethane / Ambient temperature 2: 1.) aq. borax; 2.) MTBD 3: 60 percent / DIBAH / 2.5 h / 0 °C View Scheme

4-Pyridin-2-yl-benzoic acid (1S,2S)-2-tert-butoxycarbonylamino-1-(N'-tert-butoxycarbonyl-hydrazinomethyl)-3-phenyl-propyl ester → 1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane (198904-86-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) aq. borax; 2.) MTBD 2: 60 percent / DIBAH / 2.5 h / 0 °C View Scheme

4-Pyridin-2-yl-benzoic acid (1R,2S)-2-tert-butoxycarbonylamino-1-cyano-3-phenyl-propyl ester (198905-08-7) → 1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane (198904-86-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: 53 percent / H2, AcOH / Raney Ni / methanol / 750.06 Torr / Ambient temperature 2: NaBH3CN, TsOH / 1,2-dimethoxy-ethane / Ambient temperature 3: 1.) aq. borax; 2.) MTBD 4: 60 percent / DIBAH / 2.5 h / 0 °C View Scheme

(2R,3S)-3-[N-(tert-butyloxycarbonyl)amino]-1,2-epoxy-4-phenylbutane (98760-08-8) + N-1-(tert-butoxycarbonyl)-N-2-[4-(pyridine-2-yl)benzyl]hydrazine (198904-85-7) → C47H63N5O9 (1140968-73-5) + 1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane (198904-86-8)

Conditions	Yield
In isopropyl alcohol Reflux;

(2S,3S)-3-(t-butoxycarbonylamino)-4-phenylbutane-1,2-diol (149451-80-9) → 1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane (198904-86-8)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: dmap; triethylamine / toluene / 3 h / 50 °C / Large scale 1.2: 3 h / 0 - 5 °C / Large scale 2.1: ammonium fluoride; acetic acid / methanol / 11 h / 20 °C / Large scale 3.1: potassium tert-butylate / isopropyl alcohol; tetrahydrofuran / 1.83 h / 17 °C 4.1: isopropyl alcohol / 24 h / Inert atmosphere; Reflux; Large scale View Scheme

methanesulfonic acid 2-tert-butoxycarbonylamino-1-(tert-butyl-dimethyl-silanyloxymethyl)-3-phenyl-propyl ester (437713-03-6) → 1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane (198904-86-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: ammonium fluoride; acetic acid / methanol / 11 h / 20 °C / Large scale 2: potassium tert-butylate / isopropyl alcohol; tetrahydrofuran / 1.83 h / 17 °C 3: isopropyl alcohol / 24 h / Inert atmosphere; Reflux; Large scale View Scheme

4-formylphenylboronic acid, (87199-17-5) → 1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane (198904-86-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / toluene; ethanol / 20 h / 76 °C / Inert atmosphere 2: toluene; isopropyl alcohol / 2 h / 80 - 85 °C / Inert atmosphere; Large scale 3: palladium 10% on activated carbon; sodium formate / water; ethanol / 1.5 h / 57 °C 4: isopropyl alcohol / 24 h / Inert atmosphere; Reflux; Large scale View Scheme

C16H25NO6S → 1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane (198904-86-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium tert-butylate / isopropyl alcohol; tetrahydrofuran / 1.83 h / 17 °C 2: isopropyl alcohol / 24 h / Inert atmosphere; Reflux; Large scale View Scheme

2-[4-(2-pyridinyl)phenyl]methylenehydrazinecarboxylic acid tert-butyl ester (198904-84-6) → 1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane (198904-86-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: palladium 10% on activated carbon; sodium formate / water; ethanol / 1.5 h / 57 °C 2: isopropyl alcohol / 24 h / Inert atmosphere; Reflux; Large scale View Scheme

1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane (198904-86-8) → 1-[4-(pyridin-2-yl)phenyl]-4(S)-hydroxy-5(S)-2,5-diamino-6-phenyl-2-azahexane trihydrochloride

Conditions	Yield
With hydrogenchloride In tetrahydrofuran at 50℃; for 4h;	100%
With hydrogenchloride In tetrahydrofuran at 22 - 55℃; for 3h; Large scale;	95%
With hydrogenchloride In dichloromethane at 0 - 40℃; for 1.5h;
With hydrogenchloride In dichloromethane; water at 0.5 - 40℃;

1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane (198904-86-8) → 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-diamino-6-phenyl-2-azahexane hydrochloride (1313358-78-9)

Conditions	Yield
With hydrogenchloride; water In tetrahydrofuran at 60℃; for 3h;	100%
In 1,4-dioxane; hydrogenchloride; methanol; N,N-dimethyl-formamide; toluene
With hydrogenchloride In 1,4-dioxane; dichloromethane at 20℃; for 0.333333h;

1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane (198904-86-8) → 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-diamino-6-phenyl-2-azahexane (437713-06-9)

Conditions	Yield
With hydrogenchloride In dichloromethane; water at 40 - 45℃; for 3h; Solvent; Temperature; Concentration;	96.1%
Stage #1: 1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane With hydrogenchloride; water In tetrahydrofuran at 60℃; for 3h; Stage #2: With sodium hydrogencarbonate In tetrahydrofuran; water at 25℃; for 3h;	61%
Stage #1: 1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane With hydrogenchloride In tetrahydrofuran; water at 60℃; for 3h; Stage #2: With ethanol In tetrahydrofuran; water Stage #3: With sodium hydrogencarbonate In tetrahydrofuran; water at 25℃; for 3h;	61%
With hydrogenchloride In 1,4-dioxane at 50℃; for 4h;
With hydrogenchloride In dichloromethane

di-tert-butyl dicarbonate (24424-99-5) + 1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane (198904-86-8) → Tert-butyl (1S,2S)-1-benzyl-2-hydroxy-3-{1-[4-(2-pyridinyl)benzyl]hydrazino}propylcarbamate (857904-20-2)

Conditions	Yield
Stage #1: 1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane With hydrogenchloride In tetrahydrofuran; water at 60℃; for 3h; Stage #2: di-tert-butyl dicarbonate With sodium hydrogencarbonate In tetrahydrofuran; water at 25℃; for 3h;	72%

1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane (198904-86-8) → C42H40N6O7

Conditions	Yield
Multi-step reaction with 2 steps 1: HCl / dioxane / 4 h / 50 °C 2: Et3N / tetrahydrofuran / 8 h / 0 - 20 °C View Scheme

1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane (198904-86-8) → C46H44N6O9

Conditions	Yield
Multi-step reaction with 2 steps 1: HCl / dioxane / 4 h / 50 °C 2: Et3N / tetrahydrofuran / 8 h / 0 - 20 °C View Scheme

1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane (198904-86-8) → 1-[4-(Pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-bis[N-(N-methoxycarbonyl-(L)-valyl)amino]-6-phenyl-2-azahexane

Conditions	Yield
Multi-step reaction with 2 steps 1: 100 percent / aq. HCl / tetrahydrofuran / 4 h / 50 °C 2: 1.) N-ethyl-N'-<3-(dimethylamino)propyl>carbodiimide hydrochloride, 1-hydroxybenzotriazole, Et3N / 1.) DMF, 0 deg C, 20 min, 2.) DMF, RT, overnight View Scheme

1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane (198904-86-8) → atazanavir (198904-31-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 100 percent / aq. HCl / tetrahydrofuran / 4 h / 50 °C 2: 1.) O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, N-ethyldiisopropylamine / 1.) CH2Cl2, 0 deg C, 20 min, 2.) CH2Cl2, overnight View Scheme
Multi-step reaction with 2 steps 1: hydrogenchloride / tetrahydrofuran / 3 h / 22 - 55 °C / Large scale 2: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 22 - 25 °C / Large scale View Scheme
Multi-step reaction with 2 steps 1: hydrogenchloride / dichloromethane; water / 0.5 - 40 °C 2: dipotassium hydrogenphosphate / water / 5 - 40 °C View Scheme

1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane (198904-86-8) → 1-[4-(Pyridin-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane.3hydrochloride

Conditions	Yield
Stage #1: 1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane With hydrogenchloride In dichloromethane; water at 5 - 40℃; Stage #2: Stage #3: With water for 0.25h;

1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane (198904-86-8) → (2S,3S)-3-amino-4-phenyl-1-(1-(4-(pyridin-2-yl)benzyl)hydrazinyl)butan-2-ol hydrochloride

Conditions	Yield
With hydrogenchloride; water In tetrahydrofuran at 45 - 55℃; for 3h;
With hydrogenchloride; water In dichloromethane Reflux;

1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane (198904-86-8) → C22H26N4O*3HI

Conditions	Yield
With trimethylsilyl iodide In tetrahydrofuran

1-[4-(pyridine-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane (198904-86-8) → atazanavir sulphate

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride / tetrahydrofuran / 3 h / 22 - 55 °C / Large scale 2: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 22 - 25 °C / Large scale 3: sulfuric acid / ethanol / 22 °C / Large scale View Scheme
Multi-step reaction with 3 steps 1: hydrogenchloride / dichloromethane; water / 0.5 - 40 °C 2: dipotassium hydrogenphosphate / water / 5 - 40 °C 3: sulfuric acid / acetone; 1-methyl-pyrrolidin-2-one / 0.5 h / 40 - 50 °C View Scheme

Upstream product

• 98760-08-8 (2R,3S)-3-[N-(tert-butyloxycarbonyl)amino]-1,2-epoxy-4-phenylbutane 
• 198904-85-7 N-1-(tert-butoxycarbonyl)-N-2-[4-(pyridine-2-yl)benzyl]hydrazine 
• 198905-10-1 1-(4-(pyridin-2-yl)-phenyl)-1-oxo-5(S)-2,5-di[(tert-butoxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane 
• 109-04-6 2-bromo-pyridine 
• 127406-56-8 4-(2'-pyridyl)benzaldehyde 
• 24856-58-4 1,1-dimethoxy-1-(4-bromophenyl)methane 
• 857904-11-1 N-(tert-butoxycarbonyl)-N'-[4-(pyridin-2-yl)phenylmethylidene]hydrazine 
• 870-46-2 t-butoxycarbonylhydrazine 
• 72155-45-4 Boc-L-phenylalaninal 
• 198905-09-8 4-Pyridin-2-yl-benzoic acid (1R,2S)-2-tert-butoxycarbonylamino-1-(tert-butoxycarbonyl-hydrazonomethyl)-3-phenyl-propyl ester 
• 198905-08-7 4-Pyridin-2-yl-benzoic acid (1R,2S)-2-tert-butoxycarbonylamino-1-cyano-3-phenyl-propyl ester 
• 98760-08-8 (1-oxiranyl-2-phenylethyl)carbamic acid tert-butyl ester 
• 149451-80-9 (2S,3S)-3-(t-butoxycarbonylamino)-4-phenylbutane-1,2-diol 
• 437713-03-6 methanesulfonic acid 2-tert-butoxycarbonylamino-1-(tert-butyl-dimethyl-silanyloxymethyl)-3-phenyl-propyl ester 

Downstream Products

• 198904-87-9 1-[4-(pyridin-2-yl)phenyl]-4(S)-hydroxy-5(S)-2,5-diamino-6-phenyl-2-azahexane trihydrochloride 
• 1313358-78-9 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-diamino-6-phenyl-2-azahexane hydrochloride 
• 437713-06-9 1-[4-(pyridine-2-yl)phenyl]-(5S)-2,5-diamino-(4S)-hydroxy-6-phenyl-2-azahexane 
• 198904-22-2 1-[4-(Pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-bis[N-(N-methoxycarbonyl-(L)-valyl)amino]-6-phenyl-2-azahexane 
• 198904-31-3 atazanavir 
• 857904-20-2 Tert-butyl (1S,2S)-1-benzyl-2-hydroxy-3-{1-[4-(2-pyridinyl)benzyl]hydrazino}propylcarbamate 
• 198904-87-9 (2S,3S)-3-amino-4-phenyl-1-(1-(4-(pyridin-2-yl)benzyl)hydrazinyl)butan-2-ol hydrochloride 
• 229975-97-7 atazanavir sulphate 

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A minor side product in a manufacturing batch of the intermediate 4 was observed and separated. The minor side product 5 was purified by preparative HPLC and its structure was determined by the analysis of comprehensive NMR and MS data. The structure of 5

Design and synthesis of HIV-1 protease inhibitors incorporating oxazolidinones as P2/P2′ ligands in pseudosymmetric dipeptide isosteres

A series of novel HIV-1 protease inhibitors based on two pseudosymmetric dipeptide isosteres have been synthesized and evaluated. The inhibitors were designed by incorporating N-phenyloxazolidinone-5-carboxamides into the hydroxyethylene and (hydroxyethyl)hydrazine dipeptide isosteres as P2 and P2′ ligands. Compounds with (S)-phenyloxazolidinones attached at a position proximal to the central hydroxyl group showed low nM inhibitory activities against wild-type HIV-1 protease. Selected compounds were further evaluated for their inhibitory activities against a panel of multidrug-resistant protease variants and for their antiviral potencies in MT-4 cells. The crystal structures of lopinavir (LPV) and two new inhibitors containing phenyloxazolidinone-based ligands in complex with wild-type HIV-1 protease have been determined. A comparison of the inhibitor-protease structures with the LPV-protease structure provides valuable insight into the binding mode of the new inhibitors to the protease enzyme. Based on the crystal structures and knowledge of structure-activity relationships, new inhibitors can be designed with enhanced enzyme inhibitory and antiviral potencies.