165727-45-7

Basic information

• Product Name: (1S, 2S)-(1-BENZYL-3-CHLORO-2-HYDROXY-PROPYL)-CARBAMIC ACID TERT-BUTYL ESTER
• Synonyms: (1S, 2S)-(1-BENZYL-3-CHLORO-2-HYDROXY-PROPYL)-CARBAMIC ACID TERT-BUTYL ESTER;(1S,2S)-[3-CHLORO-2-HYDROXY-1-(PHENYLMETHYL)PROPYL]CARBAMIC ACID 1,1-DIMETHYLETHYL ESTER;(1S, 2S)-[3-CHLORO-2-HYDROXY-1-(PHENYLMETHYL)-PROPYL]CARBAMIC ACID, 1,1-DIMETHYLETHYL ETHER;(2S,3S)-(-)-3-T-BUTOXYCARBONYLAMINO-1-CHLORO-4-PHENYL-BUTAN-2-OL;(1S, 2S)-[3-Chloro-2-hydroxy-1-(phenylmethyl)-;Tert-Butyl (2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-ylcarbamate;(2S,3S)-N-t-butyloxycarbonyl-3-amino-1-chloro-2-phenylbutanol;Carbamic acid, N-[(1S,2S)-3-chloro-2-hydroxy-1-(phenylmethyl)propyl]-, 1,1-dimethylethyl ester
• CAS NO: 165727-45-7
• Molecular Formula: C15H22ClNO3
• Molecular Weight: 299.79
• EINECS: 1312995-182-4
• Mol File: 165727-45-7.mol
• Article Data: 30

Chemical Properties

• Boiling Point: 460.5 °C at 760 mmHg
• Flash Point: 232.3 °C
• Appearance: White to off-white powder
• Density: 1.153 g/cm³
• Vapor Pressure: 2.83E-09mmHg at 25°C
• Refractive Index: 1.527
• Storage Temp.: 2-8°C
• PKA: 11.92±0.46(Predicted)
• CAS DataBase Reference: (1S, 2S)-(1-BENZYL-3-CHLORO-2-HYDROXY-PROPYL)-CARBAMIC ACID TERT-BUTYL ESTER(CAS DataBase Reference)
• NIST Chemistry Reference: (1S, 2S)-(1-BENZYL-3-CHLORO-2-HYDROXY-PROPYL)-CARBAMIC ACID TERT-BUTYL ESTER(165727-45-7)
• EPA Substance Registry System: (1S, 2S)-(1-BENZYL-3-CHLORO-2-HYDROXY-PROPYL)-CARBAMIC ACID TERT-BUTYL ESTER(165727-45-7)

Safety Data

• Hazardous Substances Data: 165727-45-7(Hazardous Substances Data)

Usage

General Description

The chemical compound, (1S, 2S)-(1-benzyl-3-chloro-2-hydroxy-propyl)-carbamic acid tert-butyl ester, is a derivative of carbamic acid with a tert-butyl ester group and a benzyl and chloro substituent. It is a chiral compound with stereocenters at positions 1 and 2. This chemical has potential biological and pharmaceutical applications due to its carbamic acid functional group and the presence of a benzyl group, which are both commonly found in bioactive compounds. The tert-butyl ester moiety can also improve the compound's lipophilicity and stability. Its specific properties make it a valuable compound for research and potential drug development.

InChI:InChI=1/C15H22ClNO3/c1-15(2,3)20-14(19)17-12(13(18)10-16)9-11-7-5-4-6-8-11/h4-8,12-13,18H,9-10H2,1-3H3,(H,17,19)/t12-,13+/m0/s1

Synthetic route

(S)-tert-butyl (4-chloro-3-oxo-1-phenylbutan-2-yl)carbamate (102123-74-0) → tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7)

Conditions	Yield
With isopropyl alcohol; aluminum tri-tert-butoxide In dichloromethane at 50℃; Product distribution / selectivity; Meerwein-Ponndorf-Verley Reduction; Inert atmosphere;	95%
With aluminum sec-butoxide In 2-methyl-propan-1-ol; toluene at 15 - 20℃; Large scale;	95%
With C38H40ClN2O3RhS In dichloromethane at 25℃; for 1h; Catalytic behavior; Schlenk technique; diastereoselective reaction;	93%

(S)-tert-butyl (4-chloro-3-oxo-1-phenylbutan-2-yl)carbamate (102123-74-0) + isopropyl alcohol (67-63-0) → tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7)

Conditions	Yield
With diisobutylaluminium hydride In toluene	90%

(S)-tert-butyl (4-chloro-3-oxo-1-phenylbutan-2-yl)carbamate (102123-74-0) → tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7) + (2R,3S)-1-Chloro-2-hydroxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane (162536-40-5) + (1R,2R)[3-chloro-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid 1,1-dimethylethyl ester + (1R,2S)[3-chloro-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid 1,1-dimethylethyl ester (923601-69-8)

Conditions	Yield
With potassium phosphate buffer; Streptomyces nodosus SC 13149 at 28℃; for 48h; pH=6.8; microbial reduction;	A 62% B n/a C n/a D n/a

(S)-tert-butyl (4-chloro-3-oxo-1-phenylbutan-2-yl)carbamate (102123-74-0) → tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7) + (2R,3S)-1-Chloro-2-hydroxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane (162536-40-5)

Conditions	Yield
With sodium tetrahydroborate In tetrahydrofuran; water at 0℃; for 0.75h;	A 50% B n/a
With sodium tetrahydroborate In tetrahydrofuran; water at 0℃; for 0.75h;	A n/a B 50%
With sodium tetrahydroborate In ethanol; toluene at -78 - 0℃; for 8h;	A 7.8 g B n/a

potassium bisulfite + (S)-tert-butyl (4-chloro-3-oxo-1-phenylbutan-2-yl)carbamate (102123-74-0) → tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7)

Conditions	Yield
With sodium borohydrid In tetrahydrofuran; water; ethyl acetate	50%

di-tert-butyl dicarbonate (24424-99-5) + (S)-3-amino-(S)-2-hydroxy-4-phenyl-1-chlorobutane hydrochloride → tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7)

Conditions	Yield
With triethylamine
With triethylamine In tetrahydrofuran at 20℃; Cooling with ice;

(S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester (51987-73-6) → tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: LDA / tetrahydrofuran / 0.5 h / -78 °C 2: 7.8 g / NaBH4 / toluene; ethanol / 8 h / -78 - 0 °C View Scheme

N-t-butoxycarbonyl-L-phenylalanine 4-nitrophenyl ester (7535-56-0) → tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: t-BuOK / tetrahydrofuran / 2 h / Heating 1.2: tetrahydrofuran / 4 h / 0 °C 2.1: 81 percent / LiCl; MeSO3H / tetrahydrofuran / 2 h / 70 °C 3.1: 50 percent / NaBH4 / tetrahydrofuran; H2O / 0.75 h / 0 °C View Scheme

tert-butyl (S)-(4-(dimethyl(oxo)-λ6-sulfanylidene)-3-oxo-1-phenylbutan-2-yl)carbamate (400611-25-8) → tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 81 percent / LiCl; MeSO3H / tetrahydrofuran / 2 h / 70 °C 2: 50 percent / NaBH4 / tetrahydrofuran; H2O / 0.75 h / 0 °C View Scheme

(2S)-N,N-dibenzylphenylalaninal (123054-12-6, 123808-74-2, 136370-73-5, 111060-64-1) → tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: Li / tetrahydrofuran / -55 °C 2: 97 percent / H2 / Pd(OH)2/C / 760 Torr 3: Et3N View Scheme
Multi-step reaction with 3 steps 1: lithium / tetrahydrofuran / 3 h / -65 °C / Inert atmosphere 2: palladium hydroxide on carbon; hydrogen / methanol / 4 h / 20 °C / 760.05 Torr 3: triethylamine / tetrahydrofuran / 20 °C / Cooling with ice View Scheme

N,N-dibenzyl-(S)-3-amino-(S)-2-hydroxy-4-phenyl-1-chlorobutane hydrochloride → tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 97 percent / H2 / Pd(OH)2/C / 760 Torr 2: Et3N View Scheme
Multi-step reaction with 2 steps 1: palladium hydroxide on carbon; hydrogen / methanol / 4 h / 20 °C / 760.05 Torr 2: triethylamine / tetrahydrofuran / 20 °C / Cooling with ice View Scheme

(S)-2-(dibenzylamino)-3-phenylpropan-1-ol (111060-52-7) → tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: 99 percent / pyridine*SO3, DMSO, Et3N / 10 °C 2: Li / tetrahydrofuran / -55 °C 3: 97 percent / H2 / Pd(OH)2/C / 760 Torr 4: Et3N View Scheme
Multi-step reaction with 4 steps 1: sulfur trioxide pyridine complex; triethylamine / dimethyl sulfoxide / 1.08 h / 15 °C / Cooling with ice 2: lithium / tetrahydrofuran / 3 h / -65 °C / Inert atmosphere 3: palladium hydroxide on carbon; hydrogen / methanol / 4 h / 20 °C / 760.05 Torr 4: triethylamine / tetrahydrofuran / 20 °C / Cooling with ice View Scheme

N-tert-butoxycarbonyl-L-phenylalanine (13734-34-4) → tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: 4-methylmorpholine / tetrahydrofuran / 0.33 h / -25 - -20 °C 2: diethyl ether / a) 0 deg C, 2 h, b) RT, overnight 3: 92 percent / HCl / dioxane; diethyl ether / 1 h / 0 °C 4: NaBH4 / tetrahydrofuran; H2O / 0.75 h / 0 °C View Scheme
Multi-step reaction with 2 steps 1: triethylamine 2: aluminum sec-butoxide / toluene; 2-methyl-propan-1-ol / 15 - 20 °C / Large scale View Scheme

(3S)-tert-butyl 1-benzyl-3-diazo-2-oxopropylcarbamate (60398-41-6) → tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 92 percent / HCl / dioxane; diethyl ether / 1 h / 0 °C 2: NaBH4 / tetrahydrofuran; H2O / 0.75 h / 0 °C View Scheme

Boc-Phe-O-COO-isoBu (67729-36-6, 60398-40-5) → tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: diethyl ether / a) 0 deg C, 2 h, b) RT, overnight 2: 92 percent / HCl / dioxane; diethyl ether / 1 h / 0 °C 3: NaBH4 / tetrahydrofuran; H2O / 0.75 h / 0 °C View Scheme

triisobutylaluminum (100-99-2) + (S)-tert-butyl (4-chloro-3-oxo-1-phenylbutan-2-yl)carbamate (102123-74-0) + isopropyl alcohol (67-63-0) → tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7)

Conditions	Yield
In hexane; toluene

Triisopropyl borate (5419-55-6) + triisobutylaluminum (100-99-2) + (S)-tert-butyl (4-chloro-3-oxo-1-phenylbutan-2-yl)carbamate (102123-74-0) → tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7)

Conditions	Yield
In hexane; toluene

diethyl(ethoxy)aluminum (1586-92-1) + (S)-tert-butyl (4-chloro-3-oxo-1-phenylbutan-2-yl)carbamate (102123-74-0) → tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7)

Conditions	Yield
With hydrogenchloride In toluene

1,1-Diphenylmethanol (91-01-0) + triisobutylaluminum (100-99-2) + (S)-tert-butyl (4-chloro-3-oxo-1-phenylbutan-2-yl)carbamate (102123-74-0) → tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7)

Conditions	Yield
With methanesulfonic acid In hexane; toluene

(2S,3R)-2-amino-4-chloro-1-phenylbutan-3-ol hydrochloride (369362-96-9) + di-tert-butyl dicarbonate (24424-99-5) → tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7) + (2R,3S)-1-Chloro-2-hydroxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane (162536-40-5)

Conditions	Yield
With sodium hydroxide In methanol; water; toluene at 25℃; for 3h; pH=7; Product distribution / selectivity;

L-phenylalanine (63-91-2) → tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: sodium tetrahydroborate; iodine / tetrahydrofuran / Cooling with ice; Reflux 2.1: potassium carbonate / methanol; water / 0.17 h / Reflux 2.2: 1 h / Heating 3.1: sulfur trioxide pyridine complex; triethylamine / dimethyl sulfoxide / 1.08 h / 15 °C / Cooling with ice 4.1: lithium / tetrahydrofuran / 3 h / -65 °C / Inert atmosphere 5.1: palladium hydroxide on carbon; hydrogen / methanol / 4 h / 20 °C / 760.05 Torr 6.1: triethylamine / tetrahydrofuran / 20 °C / Cooling with ice View Scheme

L-Phenylalaninol (3182-95-4) → tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: potassium carbonate / methanol; water / 0.17 h / Reflux 1.2: 1 h / Heating 2.1: sulfur trioxide pyridine complex; triethylamine / dimethyl sulfoxide / 1.08 h / 15 °C / Cooling with ice 3.1: lithium / tetrahydrofuran / 3 h / -65 °C / Inert atmosphere 4.1: palladium hydroxide on carbon; hydrogen / methanol / 4 h / 20 °C / 760.05 Torr 5.1: triethylamine / tetrahydrofuran / 20 °C / Cooling with ice View Scheme

C15H20N3O3(1+) (910642-68-1) → tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride 2: aluminum isopropoxide / isopropyl alcohol / 3 h / Reflux View Scheme

(S)-3-(tert-butoxycarbonyl)amino-4-phenyl-2-butanone (85613-64-5) → tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride / ethyl acetate; water / 2.5 h / 20 °C 2: sodium carbonate; hydrogen; C44H48FeIrNO2P(1+)*C32H12BF24(1-) / methanol / 2 h / 20 °C View Scheme

tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7) → (1-oxiranyl-2-phenylethyl)carbamic acid tert-butyl ester (98760-08-8, 98818-34-9, 98818-35-0, 103127-56-6, 98737-29-2)

Conditions	Yield
With potassium carbonate In methanol	100%
With potassium tert-butylate In tetrahydrofuran; isopropyl alcohol at 16℃; for 0.5h;	96%
With potassium carbonate; citric acid In ethanol; n-heptane; water; toluene	95%

methanesulfonyl chloride (124-63-0) + tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7) → (1S,2S)-(1-benzyl-3-chloro-2-methanesulfonyloxypropyl)carbamate tert-butyl ester

Conditions	Yield
With triethylamine In toluene at 35℃; for 2h; Temperature; Inert atmosphere;	99.1%

isobutylamine (78-81-9) + tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7) → (2R,3S)-3-tert-butoxycarbonylamino-1-isobutylamino-4-phenyl-2-butanol (160232-08-6)

Conditions	Yield
With potassium hydroxide In ethanol at 15 - 20℃; Large scale;	97.3%
With sodium carbonate In water at 60 - 65℃; for 3h;	105 g
With sodium carbonate In water at 60 - 65℃; for 3h;	105 g

isopropyl alcohol (67-63-0) + tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7) + citric acid (77-92-9) → (1-oxiranyl-2-phenylethyl)carbamic acid tert-butyl ester (98760-08-8, 98818-34-9, 98818-35-0, 103127-56-6, 98737-29-2)

Conditions	Yield
With sodium hydroxide In water	87%

tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7) → (2R,3S)-3-[N-(tert-butyloxycarbonyl)amino]-1,2-epoxy-4-phenylbutane (98760-08-8)

Conditions	Yield
With sodium hydroxide In methanol; ethanol at 0 - 20℃; for 4.5h; Time;	74%
Multi-step reaction with 3 steps 1: thionyl chloride / tert-butyl methyl ether / 8 h / 10 - 55 °C 2: triethylamine; dmap / tert-butyl methyl ether / 8 h / 10 - 20 °C 3: potassium hydroxide / ethanol / 0.5 h / 5 °C View Scheme
Multi-step reaction with 3 steps 1: triethylamine / toluene / 2 h / 35 °C / Inert atmosphere 2: 18-crown-6 ether / toluene / 3 h / 70 °C 3: potassium hydroxide / tetrahydrofuran; ethanol / 2 h / -15 °C / Inert atmosphere View Scheme

tetrabutylammonium acetate (10534-59-5) + tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7) → (2S, 3S)-1-acetoxy-3-(t-butoxycarbonylamino)-2-hydroxy-4-phenylbutane (180713-67-1)

Conditions	Yield
In acetonitrile for 18h; Heating / reflux;	70%
In methanol; water; ethyl acetate; acetonitrile

tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7) → (4R)-4-{1-[(S)-(tert-butoxycarbonyl)amino]-2-phenylethyl}-γ-butyrolactone (135130-98-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: 89 percent / KOH / ethanol / 2 h / 20 °C 2: 90 percent / EtONa / ethanol / 20 °C 3: LiOH / dimethylformamide; H2O / 6 h / 50 °C 4: toluene / 5 h / Heating View Scheme

tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7) → 3-carbethoxy-5(R)-<1'-(S)-<(tert-butyloxycarbonyl)amino>-2-phenylethyl>dihydrofuran-2(3H)-one (338462-91-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 89 percent / KOH / ethanol / 2 h / 20 °C 2: 90 percent / EtONa / ethanol / 20 °C View Scheme

tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7) → (R)-5-((S)-1-tert-Butoxycarbonylamino-2-phenyl-ethyl)-2-oxo-tetrahydro-furan-3-carboxylic acid

Conditions	Yield
Multi-step reaction with 3 steps 1: 89 percent / KOH / ethanol / 2 h / 20 °C 2: 90 percent / EtONa / ethanol / 20 °C 3: LiOH / dimethylformamide; H2O / 6 h / 50 °C View Scheme

tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7) → {(S)-1-[(2R,4R)-4-(4-Benzyl-benzyl)-5-oxo-tetrahydro-furan-2-yl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester

Conditions	Yield
Multi-step reaction with 6 steps 1.1: 89 percent / KOH / ethanol / 2 h / 20 °C 2.1: 90 percent / EtONa / ethanol / 20 °C 3.1: LiOH / dimethylformamide; H2O / 6 h / 50 °C 4.1: toluene / 5 h / Heating 5.1: LDA / tetrahydrofuran / 0.5 h / -78 °C 5.2: tetrahydrofuran / 0.5 h / -78 °C 5.3: 80 percent / Ac2O; Et3N / 1 h / 120 °C 6.1: H2 / Pd/C / ethyl acetate / 24 h / 20 °C View Scheme

tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7) → tert-butyl (S)-(1-((R)-4-(2-phenyl-1,3-dioxolan-2-yl)benzylidene)-tetrahydro-5-oxofuran-2-yl)-2-phenylethylcarbamate (794525-84-1)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: 89 percent / KOH / ethanol / 2 h / 20 °C 2.1: 90 percent / EtONa / ethanol / 20 °C 3.1: LiOH / dimethylformamide; H2O / 6 h / 50 °C 4.1: toluene / 5 h / Heating 5.1: LDA / tetrahydrofuran / 0.5 h / -78 °C 5.2: tetrahydrofuran / 0.5 h / -78 °C 5.3: 80 percent / Ac2O; Et3N / 1 h / 120 °C View Scheme

tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7) → tert-butyl (S)-(1-((2R,4R)-4-(2-phenyl-1,3-dioxolan-2-yl)benzyl)-tetrahydro-5-oxofuran-2-yl)-2-phenylethylcarbamate (794525-86-3)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: 89 percent / KOH / ethanol / 2 h / 20 °C 2.1: 90 percent / EtONa / ethanol / 20 °C 3.1: LiOH / dimethylformamide; H2O / 6 h / 50 °C 4.1: toluene / 5 h / Heating 5.1: LDA / tetrahydrofuran / 0.5 h / -78 °C 5.2: tetrahydrofuran / 0.5 h / -78 °C 5.3: 80 percent / Ac2O; Et3N / 1 h / 120 °C 6.1: 90 percent / H2 / PtO2 / ethyl acetate / 2 h / 20 °C View Scheme

tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7) → (2R,4R,5S)-5-tert-Butoxycarbonylamino-4-hydroxy-6-phenyl-2-[4-(2-phenyl-[1,3]dioxolan-2-yl)-benzyl]-hexanoic acid (1026641-14-4)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: 89 percent / KOH / ethanol / 2 h / 20 °C 2.1: 90 percent / EtONa / ethanol / 20 °C 3.1: LiOH / dimethylformamide; H2O / 6 h / 50 °C 4.1: toluene / 5 h / Heating 5.1: LDA / tetrahydrofuran / 0.5 h / -78 °C 5.2: tetrahydrofuran / 0.5 h / -78 °C 5.3: 80 percent / Ac2O; Et3N / 1 h / 120 °C 6.1: 90 percent / H2 / PtO2 / ethyl acetate / 2 h / 20 °C 7.1: LiOH / dimethylformamide; H2O / 20 °C View Scheme

tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7) → 5(S)-tert-butoxycarbonylamino-4(R)-(tert-butyldimethylsilanyloxy)-6-phenyl-2-(4-(2-phenyl-1,3-dioxolan-2-yl)-benzyl)hexanoic acid (794525-87-4)

Conditions

Yield

Multi-step reaction with 8 steps 1.1: 89 percent / KOH / ethanol / 2 h / 20 °C 2.1: 90 percent / EtONa / ethanol / 20 °C 3.1: LiOH / dimethylformamide; H2O / 6 h / 50 °C 4.1: toluene / 5 h / Heating 5.1: LDA / tetrahydrofuran / 0.5 h / -78 °C 5.2: tetrahydrofuran / 0.5 h / -78 °C 5.3: 80 percent / Ac2O; Et3N / 1 h / 120 °C 6.1: 90 percent / H2 / PtO2 / ethyl acetate / 2 h / 20 °C 7.1: LiOH / dimethylformamide; H2O / 20 °C 8.1: imidazole / dimethylformamide / 20 °C 8.2: MeOH / dimethylformamide / 2 h View Scheme

tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7) → {1S-benzyl-4R-[1-(1S-carbamoyl-2-phenyl-ethylcarbamoyl)-3-(1S)-methyl-butylcarbamoyl]-2R-hydroxy-5-[4-(2-phenyl-[1.3]dioxolan-2-yl)phenyl]-pentyl}carbamic acid tert-butyl ester (794525-90-9)

Conditions

Yield

Multi-step reaction with 10 steps 1.1: 89 percent / KOH / ethanol / 2 h / 20 °C 2.1: 90 percent / EtONa / ethanol / 20 °C 3.1: LiOH / dimethylformamide; H2O / 6 h / 50 °C 4.1: toluene / 5 h / Heating 5.1: LDA / tetrahydrofuran / 0.5 h / -78 °C 5.2: tetrahydrofuran / 0.5 h / -78 °C 5.3: 80 percent / Ac2O; Et3N / 1 h / 120 °C 6.1: 90 percent / H2 / PtO2 / ethyl acetate / 2 h / 20 °C 7.1: LiOH / dimethylformamide; H2O / 20 °C 8.1: imidazole / dimethylformamide / 20 °C 8.2: MeOH / dimethylformamide / 2 h 9.1: 88 percent / 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; 1-hydroxybenzotriazole; Hunig's base / dimethylformamide / 20 °C 10.1: 71 percent / tetrabutylammonium fluoride / tetrahydrofuran / 20 °C View Scheme

tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7) → {1S-benzyl-2R-(tert-butyldimethylsilanyloxy)-4R-[1-(1S-carbamoyl-2-phenyl-ethylcarbamoyl)-3-(1S)-methyl-butylcarbamoyl]-5-[4-(2-phenyl-[1.3]dioxolan-2-yl)phenyl]-pentyl}carbamic acid tert-butyl ester (794525-88-5)

Conditions

Yield

Multi-step reaction with 9 steps 1.1: 89 percent / KOH / ethanol / 2 h / 20 °C 2.1: 90 percent / EtONa / ethanol / 20 °C 3.1: LiOH / dimethylformamide; H2O / 6 h / 50 °C 4.1: toluene / 5 h / Heating 5.1: LDA / tetrahydrofuran / 0.5 h / -78 °C 5.2: tetrahydrofuran / 0.5 h / -78 °C 5.3: 80 percent / Ac2O; Et3N / 1 h / 120 °C 6.1: 90 percent / H2 / PtO2 / ethyl acetate / 2 h / 20 °C 7.1: LiOH / dimethylformamide; H2O / 20 °C 8.1: imidazole / dimethylformamide / 20 °C 8.2: MeOH / dimethylformamide / 2 h 9.1: 88 percent / 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; 1-hydroxybenzotriazole; Hunig's base / dimethylformamide / 20 °C View Scheme

tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7) → (2S,4R)-1-((2R,3S)-3-Amino-2-hydroxy-4-phenyl-butyl)-4-hydroxy-piperidine-2-carboxylic acid tert-butylamide

Conditions	Yield
Multi-step reaction with 2 steps 1: KOH / methanol 2: 1.) basic alumina, 2.) conc. HCl / 1.) THF, 45-50 deg C, 23 h, 2.) H2O, 1 h View Scheme

tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7) → (2S,4R)-1-((2R,3S)-3-Amino-2-hydroxy-4-phenyl-butyl)-4-(pyridin-4-ylmethoxy)-piperidine-2-carboxylic acid tert-butylamide (190508-37-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: KOH / methanol 2: 1.) basic alumina, 2.) conc. HCl / 1.) THF, 45-50 deg C, 23 h, 2.) H2O, 1 h View Scheme

tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (165727-45-7) → [(1S,2R)-1-Benzyl-3-((2S,4R)-2-tert-butylcarbamoyl-4-hydroxy-piperidin-1-yl)-2-hydroxy-propyl]-carbamic acid tert-butyl ester

Conditions	Yield
Multi-step reaction with 2 steps 1: KOH / methanol 2: basic alumina / tetrahydrofuran / 50 °C View Scheme

Upstream product

• 5419-55-6 Triisopropyl borate 
• 100-99-2 triisobutylaluminum 
• 102123-74-0 (S)-tert-butyl (4-chloro-3-oxo-1-phenylbutan-2-yl)carbamate 
• 910642-68-1 C₁₅H₂₀N₃O₃⁽¹⁺⁾ 
• 1586-92-1 diethyl(ethoxy)aluminum 
• 85613-64-5 (S)-3-(tert-butoxycarbonyl)amino-4-phenyl-2-butanone 
• 3182-95-4 L-Phenylalaninol 
• 63-91-2 L-phenylalanine 
• 67-63-0 isopropyl alcohol 
• 67729-36-6 Boc-Phe-O-COO-isoBu 
• 60398-41-6 (3S)-tert-butyl 1-benzyl-3-diazo-2-oxopropylcarbamate 
• 13734-34-4 N-tert-butoxycarbonyl-L-phenylalanine 
• 111060-52-7 (S)-2-(dibenzylamino)-3-phenylpropan-1-ol 
• 123054-12-6 (2S)-N,N-dibenzylphenylalaninal 

Downstream Products

• 190508-37-3 (2S,4R)-1-((2R,3S)-3-Amino-2-hydroxy-4-phenyl-butyl)-4-(pyridin-4-ylmethoxy)-piperidine-2-carboxylic acid tert-butylamide 
• 98760-08-8 (1-oxiranyl-2-phenylethyl)carbamic acid tert-butyl ester 
• 180713-67-1 (2S, 3S)-1-acetoxy-3-(t-butoxycarbonylamino)-2-hydroxy-4-phenylbutane 
• 160232-08-6 (2R,3S)-3-tert-butoxycarbonylamino-1-isobutylamino-4-phenyl-2-butanol 
• 169280-56-2 4-amino-N-(2R,3S)(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutylbenzenesulfonamide 
• 206361-99-1 darunavir 
• 191226-98-9 [(1S,2R)-3-[(4-nitrophenylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid tert-butyl ester 
• 147976-16-7 (4S,5S)-5-hydroxymethyl-4-phenylmethyloxazolidinone 
• 98760-08-8 (2R,3S)-3-[N-(tert-butyloxycarbonyl)amino]-1,2-epoxy-4-phenylbutane 
• 183004-94-6 3-S-(N-tert-butyloxyformamido)-[2R-hydroxy-1-[(4-aminophenylsulfonyl)(2-methylpropyl)]amino]-4-phenylbutane 
• 206361-99-1 darunavir 
• 478866-50-1 (4S,5R)-4-benzyl-5-(chloromethyl)oxazolidin-2-one 
• 162538-06-9 {(1S,2R)-1-Benzyl-3-[benzyl-((2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-amino]-2-hydroxy-propyl}-carbamic acid tert-butyl ester 
• 162677-31-8 {(1S,2R)-1-Benzyl-3-[benzyl-((2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-amino]-2-hydroxy-propyl}-carbamic acid tert-butyl ester 

Relevant articles and documents

Preparation of chiral synthon for HIV protease inhibitor: Stereoselective microbial reduction of N-protected α-aminochloroketone

The chiral intermediate (1S,2R) [3-chloro-2-hydroxy-1-(phenylmethyl)propyl] carbamic acid, 1,1-dimethylethyl ester 2a was prepared for the total synthesis of an HIV protease inhibitor, BMS-186318. The stereoselective reduction of (1S) [3-chloro-2-oxo-1-(phenylmethyl)propyl] carbamic acid, 1,1-dimethyl-ethyl ester 1 was carried out using microbial cultures among which Streptomyces nodosus SC 13149 efficiently reduced 1 to 2a. A reaction yield of 80% was obtained. The optical purity of 99.8% and the diastereomeric purity of 99% were obtained for chiral alcohol 2a.

Preparation method of anti-HIV protease inhibitor intermediate

The invention relates to the technical field of medicine preparation, in particular to a preparation method of an anti-HIV protease inhibitor intermediate. According to the invention, the anti-HIV protease inhibitor intermediate disclosed as a formula II or a formula III shown in the description is obtained by reacting a compound shown in a formula I defined in the description as a raw material, a catalyst A or catalyst B serving as a catalyst and dichloromethane and an aprotic polar solvent serving as a mixed solvent in the presence of formate. Firstly, the preparation method of the novel anti-HIV protease inhibitor intermediate, which is mild in condition, safe in process and suitable for industrial production, is created, and the reaction conditions are further explored and optimized, so that the reaction yield and purity are greatly improved.

Rh(iii)-Catalyzed diastereoselective transfer hydrogenation: An efficient entry to key intermediates of HIV protease inhibitors

A highly efficient diastereoselective transfer hydrogenation of α-aminoalkyl α′-chloromethyl ketones catalyzed by a tethered rhodium complex was developed and successfully utilized in the synthesis of the key intermediates of HIV protease inhibitors. With the current Rh(iii) catalyst system, a series of chiral 3-amino-1-chloro-2-hydroxy-4-phenylbutanes were produced in excellent yields and diastereoselectivities (up to 99% yield, up to 99?:?1 dr). Both diastereomers of the desired products could be efficiently accessed by using the two enantiomers of the Rh(iii) catalyst.