1149-26-4

Basic information

• Product Name: N-Carbobenzyloxy-L-valine
• Synonyms: Z-L-VALINE;Z-L-VAL-OH;Z-VAL;Z-VALINE;Z-VAL-OH;N-CBZ-L-VALINE CRYSTALLINE;N-Carbobenzyloxy-L-valine, 99+%;N-[(Benzyloxy)(carbonyl)]-L-va
• CAS NO: 1149-26-4
• Molecular Formula: C₁₃H₁₇NO₄
• Molecular Weight: 251.28
• EINECS: 214-562-1
• Product Categories: Miscellaneous Biochemicals;chiral;PROTECTED AMINO ACID & PEPTIDES;Valine [Val, V];Z-Amino Acids and Derivatives;Amino Acids;Amino Acids (N-Protected);Biochemistry;Cbz-Amino Acids;Chiral Compounds;Cbz-Amino acid series
• Mol File: 1149-26-4.mol
• Article Data: 75

Chemical Properties

• Melting Point: 62-64 °C(lit.)
• Boiling Point: 394.43°C (rough estimate)
• Flash Point: 215.4 °C
• Appearance: White to off-white/Crystalline Powder
• Density: 0,926g/cm
• Vapor Pressure: 2.99E-08mmHg at 25°C
• Refractive Index: -4.3 ° (C=2, AcOH)
• Storage Temp.: 2-8°C
• Solubility: Acetic Acid, DMSO (Slightly), Ethanol (Slightly)
• PKA: 4.00±0.10(Predicted)
• BRN: 2056617
• CAS DataBase Reference: N-Carbobenzyloxy-L-valine(CAS DataBase Reference)
• NIST Chemistry Reference: N-Carbobenzyloxy-L-valine(1149-26-4)
• EPA Substance Registry System: N-Carbobenzyloxy-L-valine(1149-26-4)

Safety Data

• Hazard Codes: Xi,Xn
• Statements: 38-43-36/37/38-20/21/22
• Safety Statements: 36/37-36-26
• WGK Germany: 3
• Hazardous Substances Data: 1149-26-4(Hazardous Substances Data)

Usage

Chemical Properties

white to light yellow crystal powde

Uses

Different sources of media describe the Uses of 1149-26-4 differently. You can refer to the following data:
1. Imatinib intermediate
2. Valaciclovir intermediate
3. N-Cbz-L-valine is an N-Cbz-protected form of L-Valine (V094205). L-Valine is an essential amino acid that is used as an ingredient in cosmetic formulations, pharmaceuticals, and animal feed products. L-valine is also important for growth and ammonia detoxification in humans.

Synthesis Reference(s)

Synthesis, p. 738, 1985 DOI: 10.1055/s-1985-31329

InChI:InChI=1/C13H17NO4/c1-9(2)11(12(15)16)14-13(17)18-8-10-6-4-3-5-7-10/h3-7,9,11H,8H2,1-2H3,(H,14,17)(H,15,16)/p-1/t11-/m0/s1

Synthetic route

L-valine (72-18-4) + benzyl chloroformate (501-53-1) → (S)-N-(benzyloxycarbonyl)valine (1149-26-4)

Conditions	Yield
With sodium hydrogencarbonate In water Inert atmosphere;	100%
With sodium hydroxide In water at 0 - 20℃;	100%
With potassium carbonate In water at 0 - 2℃; pH=1.5 - Ca. 2; Reagent/catalyst; pH-value; Temperature; Solvent;	99%

C13H15N2O2(1+)*CF3O3S(1-) (1431461-34-5) + (L)-valine methyl ester triflate (1428647-69-1) → (S)-N-(benzyloxycarbonyl)valine (1149-26-4)

Conditions	Yield
Stage #1: C13H15N2O2(1+)*CF3O3S(1-); (L)-valine methyl ester triflate With 1,1’-carbonylbis-(3-ethylimidazolium) triflate In nitromethane at 20℃; for 60h; Inert atmosphere; Stage #2: With water; sodium hydroxide In nitromethane at 20℃; for 2h; Inert atmosphere;	80%

N-benzyloxycarbonyl-L-valinol (6216-65-5) → (S)-N-(benzyloxycarbonyl)valine (1149-26-4)

Conditions	Yield
With 2-hydroxypyridin; 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In dimethyl sulfoxide at 20℃; for 72h;	79%

(S)-2-Benzyloxycarbonylamino-3-methyl-butyric acid 3-methyl-but-2-enyl ester → (S)-N-(benzyloxycarbonyl)valine (1149-26-4)

Conditions	Yield
With cerium(III) chloride; sodium iodide In acetonitrile for 2h; Heating;	92%
With sodium hydrogen sulfate; silica gel In dichloromethane at 20℃; for 5h;	91%
With sodium iodide; zirconium(IV) chloride In acetonitrile for 2h; Heating;	91%

4-isopropyl-2,5-dioxo-oxazolidine-3-carboxylic acid benzyl ester (394210-42-5) → (S)-N-(benzyloxycarbonyl)valine (1149-26-4)

Conditions	Yield
Stage #1: 4-isopropyl-2,5-dioxo-oxazolidine-3-carboxylic acid benzyl ester With methanol; 4 A molecular sieve In diethyl ether at 0℃; for 22h; Stage #2: With water Further stages.;	40%

benzyl (S)-1-(tert-butoxycarbonyl)-2-methylpropylcarbamate (16874-02-5) → (S)-N-(benzyloxycarbonyl)valine (1149-26-4)

Conditions	Yield
In dichloromethane at 0 - 20℃; for 1.08333h;

DL-Val/PyS + benzyl chloroformate (501-53-1) → N-[(benzyloxy)carbonyl]-D-valine (1685-33-2) + (S)-N-(benzyloxycarbonyl)valine (1149-26-4)

Conditions	Yield
Stage #1: DL-Val/PyS With alpha cyclodextrin In ethanol; dimethyl sulfoxide at 30℃; for 24h; Stage #2: benzyl chloroformate

(S)-2-Benzyloxycarbonylamino-3-methyl-butyric acid 2,2-dibromo-1-tert-butylcarbamoyl-propyl ester (78031-88-6) → (S)-N-(benzyloxycarbonyl)valine (1149-26-4)

Conditions	Yield
With sodium metaborate; cobalt(II) phthalocyanine In ethanol at 20℃; for 1h;	64%

(S)-2-Benzyloxycarbonylamino-3-methyl-butyric acid allyl ester (122665-04-7) → (S)-N-(benzyloxycarbonyl)valine (1149-26-4)

Conditions	Yield
With morpholine; 1,8-diazabicyclo[5.4.0]undec-7-ene; triphenylphosphine; bis(dibenzylideneacetone)-palladium(0) In acetonitrile at 30℃; for 12h;	79%

L-valine hydrochloride (17498-50-9, 25616-14-2, 31320-20-4) + benzyl chloroformate (501-53-1) → (S)-N-(benzyloxycarbonyl)valine (1149-26-4)

Conditions	Yield
With sodium carbonate In tetrahydrofuran; water at 0 - 20℃; for 16h; Solvent; Temperature;

methyl (2S)-3-methyl-[(benzyloxy)carbonylamino]butanoate (24210-19-3) → (S)-N-(benzyloxycarbonyl)valine (1149-26-4)

Conditions	Yield
With 2C33H37N*H2O7S2; water at 80℃; for 9h; optical yield given as %ee;	86%
With sodium hydroxide In methanol

potassium ethyl xanthogenate (140-89-6) + (S)-2-Benzyloxycarbonylamino-3-methyl-butyric acid 5-methoxy-1,2-dimethyl-4,7-dioxo-4,7-dihydro-1H-indol-3-ylmethyl ester (210578-20-4) → (S)-N-(benzyloxycarbonyl)valine (1149-26-4) + Dithiocarbonic acid O-ethyl ester S-(5-methoxy-1,2-dimethyl-4,7-dioxo-4,7-dihydro-1H-indol-3-ylmethyl) ester

Conditions	Yield
With sodium dithionite In tetrahydrofuran; water	A 67% B 72%

N-(Benzyloxycarbonyloxy)succinimide (13139-17-8) + L-valine (72-18-4) → (S)-N-(benzyloxycarbonyl)valine (1149-26-4)

Conditions	Yield
With sodium hydroxide; sodium hydrogencarbonate In 1,4-dioxane; water at 0℃;
With sodium hydrogencarbonate In acetone at 20℃;

L-valine (72-18-4) + N-(benzyloxycarbonyl)benzothiazolin-2-thione (91285-92-6) → (S)-N-(benzyloxycarbonyl)valine (1149-26-4)

Conditions	Yield
With sodium hydroxide In 1,4-dioxane for 12h; Ambient temperature;	90%

L-valine (72-18-4) + 1-Benzyloxycarbonylbenzimidazoline-2-thione (91285-93-7) → (S)-N-(benzyloxycarbonyl)valine (1149-26-4)

Conditions	Yield
With sodium hydroxide In 1,4-dioxane for 12h; Ambient temperature;	91%

L-valine (72-18-4) + dimethylsulfonium methyl sulfate → (S)-N-(benzyloxycarbonyl)valine (1149-26-4)

Conditions	Yield
With triethylamine In water Ambient temperature;	82%

benzyl chloroformate (501-53-1) → (S)-N-(benzyloxycarbonyl)valine (1149-26-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: 90 percent / Et3N / acetonitrile / 2 h / 5 °C 2: 82 percent / Et3N / H2O / Ambient temperature View Scheme
Multi-step reaction with 2 steps 1: 89 percent / quinoline; CH2Cl2 / 12 h / Ambient temperature 2: 74 percent / triethylamine; CHCl3; H2O / 18 h / Ambient temperature View Scheme
Multi-step reaction with 2 steps 1: 38 percent / NaHCO3 / CH2Cl2; H2O / Ambient temperature 2: Jones' reagent / acetone / 3 h / 0 °C View Scheme

L-valine (72-18-4) + O-benzyl S-(pyridin-2-yl)carbonothioate (91285-94-8) → (S)-N-(benzyloxycarbonyl)valine (1149-26-4)

Conditions	Yield
With sodium hydroxide In 1,4-dioxane for 12h; Ambient temperature;	82%

L-valine (72-18-4) + benzyl 2-thioxobenzo[d]oxazol-3(2H)-carboxylate (91285-91-5) → (S)-N-(benzyloxycarbonyl)valine (1149-26-4)

Conditions	Yield
With sodium hydroxide In 1,4-dioxane for 12h; Ambient temperature;	81%

4-isopropyl-2,5-oxazolidinedione (2816-12-8, 24601-74-9) → (S)-N-(benzyloxycarbonyl)valine (1149-26-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: NMM / tetrahydrofuran / -25 - 20 °C 2.1: 20 mol percent DHQD-PHN; 4 Angstroem molecular sieves; methanol / diethyl ether / 22 h / 0 °C 2.2: 40 percent / H2O View Scheme

Z-L-Val p-chlorophenyl ester → (S)-N-(benzyloxycarbonyl)valine (1149-26-4) + 4-chloro-phenol (106-48-9)

Conditions	Yield
With thiolsubtilisin In water; N,N-dimethyl-formamide Ambient temperature; pH 8.0 phosphate buffer containing PhB(OH)2 traces;

(2S)-amino-4-methylpentanamide hydrochloride (10466-61-2) + Z-L-Val carbamoylmethyl ester (203640-53-3) → (S)-N-(benzyloxycarbonyl)valine (1149-26-4) + Z-L-Val-L-Leu-NH2 (95303-78-9)

Conditions	Yield
With α-chymotripsin on Celite; Tris buffer; TEA In acetonitrile at 30℃; for 48h;	A 6.8% B 13.6%

sodium phenyl-methanolate (20194-18-7) → (S)-N-(benzyloxycarbonyl)valine (1149-26-4) + S-benzyl-L-cysteine benzyl ester-toluene-4-sulfonate

Conditions	Yield
Multi-step reaction with 2 steps 1: 85 percent / tetrahydrofuran / 6 h / 30 °C 2: aq. NaOH / methanol View Scheme
Multi-step reaction with 2 steps 1: 72 percent / tetrahydrofuran / 6 h / 30 °C 2: 79 percent / DBU, morpholine / Pd(dba)2, PPh3 / acetonitrile / 12 h / 30 °C View Scheme

(S)-N-[Bis(methylthio)methylene]valine allyl ester (192930-84-0) → (S)-N-(benzyloxycarbonyl)valine (1149-26-4) + S-benzyl-L-cysteine benzyl ester-toluene-4-sulfonate

Conditions	Yield
Multi-step reaction with 2 steps 1: 72 percent / tetrahydrofuran / 6 h / 30 °C 2: 79 percent / DBU, morpholine / Pd(dba)2, PPh3 / acetonitrile / 12 h / 30 °C View Scheme

picolyl N-Cbz-L-valinate (21844-69-9) → (S)-N-(benzyloxycarbonyl)valine (1149-26-4)

Conditions	Yield
With magnesium In methanol at 20℃; for 4h;

N-benzyloxycarbonyl-L-valinol (6216-65-5) → N-[(benzyloxy)carbonyl]-D-valine (1685-33-2) + (S)-N-(benzyloxycarbonyl)valine (1149-26-4)

Conditions	Yield
With jones' reagent In acetone at 0℃; for 3h; Yield given. Yields of byproduct given;

Z-Val-ONp (10512-93-3) → 4-nitro-phenol (100-02-7) + (S)-N-(benzyloxycarbonyl)valine (1149-26-4)

Conditions	Yield
With cetyltrimethylammonim bromide; Dec-L-His In acetonitrile at 25℃; Rate constant; 0.02M phosphate buffer, pH=7.3; other catalysts;
With papain (preactivated with 2E-3M ethylenediaminotetraacetic acid (tetrasodium salt) and 5E-3M L-cysteine); water In acetonitrile at 21℃; Kinetics; pH=3.4-4.0 (formate and acetate buffers); pre-steady-state and steady-state parameters describing papain action;
With water at 21℃; Rate constant; Mechanism; pH dependence of the rate constant and catalytic effect of amino acid;

L-valine (72-18-4) + benzyl pyridin-2-yl carbonate (96452-48-1) → (S)-N-(benzyloxycarbonyl)valine (1149-26-4)

Conditions	Yield
In chloroform; water; triethylamine for 18h; Ambient temperature;	74%

benzyl alcohol (100-51-6) → (S)-N-(benzyloxycarbonyl)valine (1149-26-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1) NaH / 1) THF, reflux, 2h, 2) room temperature, 1h 2: tetrahydrofuran / 3 h / Ambient temperature 3: 92 percent / standard pH stat conditions View Scheme

L-valine (72-18-4) + dibenzyl pyrocarbonate → (S)-N-(benzyloxycarbonyl)valine (1149-26-4)

Conditions	Yield
standard pH stat conditions;	92%

diazomethane (186581-53-3, 908094-01-9) + (S)-N-(benzyloxycarbonyl)valine (1149-26-4) → methyl (2S)-3-methyl-[(benzyloxy)carbonylamino]butanoate (24210-19-3)

Conditions	Yield
In diethyl ether	100%
With diethyl ether

(S)-N-(benzyloxycarbonyl)valine (1149-26-4) → Z-(L)-Val-Cl (87052-60-6)

Conditions	Yield
With oxalyl dichloride In chloroform; N,N-dimethyl-formamide at 20℃; for 5h; Cooling with ice; Reflux;	100%
With diethyl ether; phosphorus pentachloride
With thionyl chloride In N,N,N,N,N,N-hexamethylphosphoric triamide; acetonitrile at -5 - 0℃; for 0.25h;

L-Valine methyl ester (4070-48-8) + (S)-N-(benzyloxycarbonyl)valine (1149-26-4) → methyl (S)-2-((S)-2-benzyloxycarbonyl-amino-3-methylbutyrylamino)-3-methylbutyrate (1999-88-8)

Conditions	Yield
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In ethyl acetate at 20℃;	100%
With N-ethyl-N,N-diisopropylamine; <4-nitro-6-(trifluoromethyl)benzotriazol-1-yloxy>tris(pyrrolidino)phosphonium hexafluorophosphate at 20℃; for 1h;	98%
With 3,3'-Dicyano-4,4',6,6'-tetramethyl-2,2'-dipyridinyl-disulfid; triphenylphosphine In dichloromethane at -20 - -15℃; for 12h;	84%

(S)-N-(benzyloxycarbonyl)valine (1149-26-4) + methyl N-methyl-L-valinate hydrochloride (3339-44-4) → N--L-N-methylvaline methyl ester (128892-28-4)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate In dichloromethane 1) 1 min in the cold, 2) 1 h at r.t.; other coupling reagents;	100%
With N-ethyl-N,N-diisopropylamine; chlorotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate In dichloromethane for 3h; Ambient temperature;	96%
With N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate In dichloromethane 1.) 0 deg C, 1 min, 2.) r.t., 3 h;	90%
With bromo-tris-dimethylamino-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane for 1h; Ambient temperature;	71%
With N-ethyl-N,N-diisopropylamine; <6-(trifluoromethyl)benzotriazol-1-yloxy>tris(dimethylamino)phosphonium hexafluorophosphate In dichloromethane at 35℃; for 1h;	49%

(S)-N-(benzyloxycarbonyl)valine (1149-26-4) + (2S,3S)-2,3-Bis-(tert-butyl-dimethyl-silanyloxy)-butane-1,4-diol (155336-09-7) → (S)-2-Benzyloxycarbonylamino-3-methyl-butyric acid (2S,3S)-4-((S)-2-benzyloxycarbonylamino-3-methyl-butyryloxy)-2,3-bis-(tert-butyl-dimethyl-silanyloxy)-butyl ester

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane for 24h; Ambient temperature;	100%

(S)-N-(benzyloxycarbonyl)valine (1149-26-4) → N-benzyloxycarbonyl-L-valinol (6216-65-5)

Conditions	Yield
Stage #1: (S)-N-(benzyloxycarbonyl)valine With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at -15℃; for 0.25h; Stage #2: With sodium tetrahydroborate In tetrahydrofuran; water at -15℃; for 1h;	100%
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 25℃;
Multi-step reaction with 2 steps 1: DCC / ethyl acetate / 20 h / 20 °C 2: NaBH4; AcOH / methanol; dioxane View Scheme

(S)-N-(benzyloxycarbonyl)valine (1149-26-4) + benzylamine (100-46-9) → (S)-benzyl (1-(benzylamino)-3-methyl-1-oxobutan-2-yl)carbamate (20998-83-8)

Conditions	Yield
With N,N'-Bis(2-oxo-3-oxazolidinyl)phosphorodiamidic azide; triethylamine In dichloromethane	100%
Stage #1: (S)-N-(benzyloxycarbonyl)valine With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at 0℃; for 0.75h; Stage #2: benzylamine at 0 - 20℃; for 17h;	89%
With triethylamine; isobutyl chloroformate In tetrahydrofuran for 16h; Ambient temperature;

(S)-N-(benzyloxycarbonyl)valine (1149-26-4) + (R)-2-N-(tert-butoxycarbonyl)amino-2-methyl-3-hydroxypropanoic acid methyl ester (188476-28-0) → (S)-2-Benzyloxycarbonylamino-3-methyl-butyric acid (R)-2-tert-butoxycarbonylamino-2-methoxycarbonyl-propyl ester

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃;	100%

(S)-N-(benzyloxycarbonyl)valine (1149-26-4) + (1R,2S)-1-tert-Butoxycarbonylamino-2-hydroxy-cyclohexanecarboxylic acid methyl ester → (1R,2S)-2-((S)-2-Benzyloxycarbonylamino-3-methyl-butyryloxy)-1-tert-butoxycarbonylamino-cyclohexanecarboxylic acid methyl ester (209127-52-6)

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃;	100%

(S)-N-(benzyloxycarbonyl)valine (1149-26-4) + 2-(3,4-dimethoxyphenyl)-ethylamine (120-20-7) → benzyl (1S)-1-({[2-(3,4-dimethoxyphenyl)ethyl]amino}carbonyl)-2-methylpropylcarbamate (143491-22-9)

Conditions	Yield
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In tetrahydrofuran at 20℃;	100%
With 1,1'-carbonyldiimidazole In tetrahydrofuran; dichloromethane

(S)-N-(benzyloxycarbonyl)valine (1149-26-4) + N4-(4-ethyl-6-methoxy-5-propoxy-quinolin-8-yl)-pentane-1,4-diamine (672912-23-1) → {(S)-1-[4-(4-Ethyl-6-methoxy-5-propoxy-quinolin-8-ylamino)-pentylcarbamoyl]-2-methyl-propyl}-carbamic acid benzyl ester

Conditions	Yield
With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 4h;	100%

(S)-N-(benzyloxycarbonyl)valine (1149-26-4) + N4-(4-ethyl-5-hexyloxy-6-methoxy-quinolin-8-yl)-pentane-1,4-diamine (672912-26-4) → {(S)-1-[4-(4-Ethyl-5-hexyloxy-6-methoxy-quinolin-8-ylamino)-pentylcarbamoyl]-2-methyl-propyl}-carbamic acid benzyl ester

Conditions	Yield
With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 4h;	100%

(S)-N-(benzyloxycarbonyl)valine (1149-26-4) + Dimethyl-(3-methyl-2-butenyl)-sulfonium tetrafluoroborate → Cbz-Val-OH 1,1-dimethylallyl ester

Conditions	Yield
With potassium carbonate; copper(I) bromide In dichloromethane at 20℃;	100%

(S)-N-(benzyloxycarbonyl)valine (1149-26-4) + (2R,3R,11bR)-dihydrotetrabenazine → (S)-2-benzyloxycarbonyl-amino-3-methylbutyric acid-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester (1025504-76-0)

Conditions	Yield
Stage #1: (2R,3R,11bR)-dihydrotetrabenazine With dmap In dichloromethane Stage #2: (S)-N-(benzyloxycarbonyl)valine In dichloromethane for 0.0833333h; Stage #3: With dicyclohexyl-carbodiimide In dichloromethane	100%
With dmap; dicyclohexyl-carbodiimide In dichloromethane	95.7 g

(S)-N-(benzyloxycarbonyl)valine (1149-26-4) + L-2-hydroxy-3-methylbutanoic acid allyl ester (178113-56-9) → C21H29NO6

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 3h; Inert atmosphere;	100%

(S)-N-(benzyloxycarbonyl)valine (1149-26-4) + glycine ethyl ester hydrochloride (623-33-6) → ethyl N-(benzyloxycarbonyl)-L-valylglycinate (2766-17-8)

Conditions	Yield
With 3,3'-(phenylphosphinylidene)bis<2(3H)-benzothiazolone; triethylamine In dichloromethane for 2h; Ambient temperature;	99%
With TEA; diphenyl (2,3-dihydro-2-thioxo-3-benzoxazolyl)phosphonate In dichloromethane for 2h; Ambient temperature;	99%
With TEA; 1,2-benzisoxazol-3-yl diphenyl phosphate In dichloromethane for 2h; Ambient temperature;	95%

(S)-Leu-OMe (2666-93-5) + (S)-N-(benzyloxycarbonyl)valine (1149-26-4) → (S)-methyl 2-((S)-2-(((benzyloxy)carbonyl)amino)-3-methylbutanamido)-4-methylpentanoate (4817-93-0)

Conditions	Yield
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane	99%
With dicyclohexyl-carbodiimide In N,N-dimethyl-formamide

(S)-N-(benzyloxycarbonyl)valine (1149-26-4) + L-α-hydroxyisovaleric acid t-butyl ester (3519-30-0) → benzyloxycarbonyl-L-valyl-L-α-hydroxyisovaleric acid t-butyl ester (13516-17-1)

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane for 24h; Ambient temperature;	99%
(i) PhSO2Cl, Py, (ii) /BRN= 4658890/; Multistep reaction;

(S)-N-(benzyloxycarbonyl)valine (1149-26-4) + L-alanine benzyl ester hydrochloride (5557-81-3, 5557-83-5, 34404-37-0) → Z-(S)-Val-(S)-Ala-OBzl (118234-89-2)

Conditions	Yield
With TEA; diphenyl (2,3-dihydro-2-thioxo-3-benzoxazolyl)phosphonate In dichloromethane for 2h; Ambient temperature;	99%

(S)-N-(benzyloxycarbonyl)valine (1149-26-4) + Isopropenyl Succinimido Carbonate (96935-01-2) → 2,5-dioxopyrrolidin-1-yl (2S)-2-(((benzyloxy)carbonyl)amino)-3-methylbutanoate (3496-11-5)

Conditions	Yield
With dmap In acetonitrile for 4h; Ambient temperature;	99%

(S)-N-(benzyloxycarbonyl)valine (1149-26-4) + Carbonic acid 3,5-dioxo-4-aza-tricyclo[5.2.1.02,6]dec-8-en-4-yl ester isopropenyl ester (137283-63-7) → N-(benzyloxycarbonyl)-L-valine N-hydroxy-5-norbornene-2,3-dicarboximide ester (53666-01-6)

Conditions	Yield
With dmap In acetonitrile for 4h; Ambient temperature;	99%

(S)-N-(benzyloxycarbonyl)valine (1149-26-4) + N,O-dimethylhydroxylamine*hydrochloride (6638-79-5) → Nα-(benzyloxycarbonyl)-N-methoxy-N-methyl-L-valinamide (114744-84-2)

Conditions	Yield
Stage #1: (S)-N-(benzyloxycarbonyl)valine With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; 1,8-diazabicyclo[5.4.0]undec-7-ene In ethyl acetate; acetonitrile at 0℃; for 0.166667h; Stage #2: N,O-dimethylhydroxylamine*hydrochloride With triethylamine In ethyl acetate; acetonitrile at 0℃; for 0.5h;	99%
Stage #1: (S)-N-(benzyloxycarbonyl)valine With triethylamine; HATU In dichloromethane at 20℃; for 0.25h; Stage #2: N,O-dimethylhydroxylamine*hydrochloride In dichloromethane at 20℃;	85.4%
Stage #1: (S)-N-(benzyloxycarbonyl)valine With triethylamine; HATU In dichloromethane at 20℃; for 0.25h; Stage #2: N,O-dimethylhydroxylamine*hydrochloride In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran at 20℃;	85.4%

(S)-N-tert-butoxycarbonyl-2-[bis(2-methylphenyl)phosphinomethyl]pyrrolidine (1190207-25-0) + (S)-N-(benzyloxycarbonyl)valine (1149-26-4) → benzyl N-{1-(R)-[(2-(S)-bis(2-methylphenyl)phosphinomethyl)pyrrolidine-1-carbonyl]-2-methylpropyl}carbamate

Conditions	Yield
Stage #1: (S)-N-tert-butoxycarbonyl-2-[bis(2-methylphenyl)phosphinomethyl]pyrrolidine With hydrogenchloride In 1,4-dioxane at 0 - 20℃; Inert atmosphere; Stage #2: (S)-N-(benzyloxycarbonyl)valine With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; N,N-dimethyl-formamide at -20 - 20℃; for 19.5h;	99%

(S)-N-(benzyloxycarbonyl)valine (1149-26-4) + 1-(2',3'-di-O-isopropylidene-β-D-ribofuranosyl)<1,2,4>triazole-3-carboxamide (52663-90-8) → C24H31N5O8

Conditions	Yield
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	99%

(S)-N-(benzyloxycarbonyl)valine (1149-26-4) + methyl (L)-leucinate hydrochloride (7517-19-3) → (S)-methyl 2-((S)-2-(((benzyloxy)carbonyl)amino)-3-methylbutanamido)-4-methylpentanoate (4817-93-0)

Conditions	Yield
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; for 12h;	99%
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 0 - 20℃; for 12h;	69%

(S)-N-(benzyloxycarbonyl)valine (1149-26-4) → (S)-N-benzyloxycarbonylvalinamide (13139-28-1)

Conditions	Yield
Stage #1: (S)-N-(benzyloxycarbonyl)valine With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0℃; for 0.25h; Stage #2: With ammonium chloride In N,N-dimethyl-formamide at 23℃; for 16h;	98%
Stage #1: (S)-N-(benzyloxycarbonyl)valine With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at 0℃; for 0.5h; Stage #2: With ammonium chloride In tetrahydrofuran; water at 0℃; for 0.5h;	93%
With hexamethylphosphorous triamide dichloride; ammonia In dichloromethane 1) 30 min, -20 deg C, 2) 4 h, r.t.;	87.5%

(S)-N-(benzyloxycarbonyl)valine (1149-26-4) + Penciclovir (39809-25-1) → (S)-2-Benzyloxycarbonylamino-3-methyl-butyric acid 4-(2-amino-6-oxo-1,6-dihydro-purin-9-yl)-2-((S)-2-benzyloxycarbonylamino-3-methyl-butyryloxymethyl)-butyl ester

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide for 32h; Ambient temperature;	98%

(S)-N-(benzyloxycarbonyl)valine (1149-26-4) + 3,5-Dimethylphenol (108-68-9) → N-benzyloxycarbonyl-L-valine 3,5-dimethylphenyl ester (619337-54-1)

Conditions	Yield
With 4-methyl-morpholine; (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexaflu; orophosphate In dichloromethane at 20℃;	98%

phenyl (3S)-3-amino-4-phenylbut-1-enyl sulfone hydrochloride + (S)-N-(benzyloxycarbonyl)valine (1149-26-4) → phenyl (3S)-3-(N-carbobenzyloxyvalyl)amino-4-phenylbut-1-enyl sulfone

Conditions	Yield
With 4-methyl-morpholine; isobutyl chloroformate In dichloromethane at -15 - 20℃;	98%

Upstream product

• 516-06-3 D,L-valine 
• 501-53-1 benzyl chloroformate 
• 91806-74-5 3,5-dimethyl-pyrazole-1-carboxylic acid benzyl ester 
• 20314-88-9 tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-methylbutanoate 
• 100-51-6 benzyl alcohol 
• 72-18-4 L-valine 
• 91285-94-8 O-benzyl S-(pyridin-2-yl)carbonothioate 
• 91285-91-5 benzyl 2-thioxobenzo[d]oxazol-3(2H)-carboxylate 
• 91285-92-6 N-(benzyloxycarbonyl)benzothiazolin-2-thione 
• 91285-93-7 1-Benzyloxycarbonylbenzimidazoline-2-thione 
• 96452-48-1 benzyl pyridin-2-yl carbonate 
• 10512-93-3 Z-Val-ONp 
• 6216-65-5 N-benzyloxycarbonyl-L-valinol 
• 122665-04-7 (S)-2-Benzyloxycarbonylamino-3-methyl-butyric acid allyl ester 

Downstream Products

• 4108-18-3 N-benzyloxycarbonyl-valine 4-nitro-phenyl ester 
• 10512-93-3 Z-Val-ONp 
• 24210-19-3 methyl (2S)-3-methyl-[(benzyloxy)carbonylamino]butanoate 
• 15149-72-1 N-(N-benzyloxycarbonyl-L-valyl)-L-tyrosine methyl ester 
• 122241-38-7 N-(N-benzyloxycarbonyl-L-valyl)-L-aspartic acid-4-benzyl ester-1-tert-butyl ester 
• 2766-17-8 ethyl N-(benzyloxycarbonyl)-L-valylglycinate 
• 28130-09-8 S-benzyl-N-(N-benzyloxycarbonyl-L-valyl)-L-cysteine benzyl ester 
• 66919-37-7 N²-(N-benzyloxycarbonyl-L-valyl)-N⁶-(toluene-4-sulfonyl)-L-lysine methyl ester 
• 3867-61-6 S-benzyl-N-(N-benzyloxycarbonyl-L-valyl)-L-cysteine ethyl ester 
• 79598-35-9 benzyloxycarbonylvalyltyrosine ethyl ester 
• 87052-60-6 Z-(S)-Val-Cl 
• 103209-78-5 Z-Val-Tyr-OBzl 
• 122445-78-7 N-[N-(N-benzyloxycarbonyl-L-valyl)-L-α-glutamyl]-L-valine 
• 6461-15-0 N²-(N-benzyloxycarbonyl-L-valyl)-N⁵-(toluene-4-sulfonyl)-L-ornithine methyl ester 

Relevant articles and documents

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Design and synthesis of novel symmetric fluorene-2,7-diamine derivatives as potent hepatitis C virus inhibitors

Hepatitis C virus (HCV) is an international challenge. Since the discovery of NS5A direct-acting antivirals, researchers turned their attention to pursue novel NS5A inhibitors with optimized design and structure. Herein we explore highly potent hepatitis C virus (HCV) NS5A inhibitors; the novel analogs share a common symmetrical prolinamide 2,7-diaminofluorene scaffold. Modification of the 2,7-diaminofluorene backbone included the use of (S)-prolinamide or its isostere (S,R)-piperidine-3-caboxamide, both bearing different amino acid residues with terminal carbamate groups. Compound 26 exhibited potent inhibitory activity against HCV genotype (GT) 1b (effective concentration (EC50) = 36 pM and a selectivity index of >2.78 × 106). Compound 26 showed high selectivity on GT 1b versus GT 4a. Interestingly, it showed a significant antiviral effect against GT 3a (EC50 = 1.2 nM). The structure-activity relationship (SAR) analysis revealed that picomolar inhibitory activity was attained with the use of S-prolinamide capped with R- isoleucine or R-phenylglycine residues bearing a terminal alkyl carbamate group.

Synthesis, characterization and docking studies of anti-HCV molecules

The present study reports the synthesis and characterization of novel molecules inhibiting the spread of hepatitis C. The molecules were designed as to block the NS3/4A protease enzyme on HCV RNA. The molecules were synthesized using usual peptide synthesis techniques. Compounds with purity more than 95% were characterized and docking studies were also performed. All the compounds were characterized using physico-chemical techniques such as determination of melting point by DSC and NMR, mass, IR spectral studies. The docking studies were also conducted to assess the activity of molecules for inhibition of hepatitis C virus.