16652-76-9

Basic information

• Product Name: L-Valine benzyl ester 4-toluenesulfonate
• Synonyms: BENZYL L-VALINATE P-TOLUENESULFONATE;H-VAL-OBZL P-TOSYLATE;H-VAL-OBZL TOS;H-VAL-OBZL TOS-OH;L-VALLINE BENZYL ESTER P-TOLUENESULFONATE SALT;L-VALINE BENZYL ESTER 4-TOLUENESULFONATE SALT;L-VALINE BENZYL ESTER P-TOLUENESULFONATE;L-VALINE BENZYL ESTER P-TOLUENESULFONATE SALT
• CAS NO: 16652-76-9
• Molecular Formula: C₇H₈O₃S*C₁₂H₁₇NO₂
• Molecular Weight: 379.47
• EINECS: 240-702-6
• Product Categories: Amino Acid Derivatives;Amino Acids;Valine [Val, V];Amino ester;Amino Acid Derivatives;Peptide Synthesis;Valine;Amino Acids;I - ZPeptide Synthesis;Modified Amino Acids
• Mol File: 16652-76-9.mol
• Article Data: 9

Chemical Properties

• Melting Point: 160-162 °C
• Boiling Point: 160-162°C
• Flash Point: 160-162°C
• Appearance: Crystalline
• Vapor Pressure: 0.0028mmHg at 25°C
• Storage Temp.: −20°C
• BRN: 3643436
• CAS DataBase Reference: L-Valine benzyl ester 4-toluenesulfonate(CAS DataBase Reference)
• NIST Chemistry Reference: L-Valine benzyl ester 4-toluenesulfonate(16652-76-9)
• EPA Substance Registry System: L-Valine benzyl ester 4-toluenesulfonate(16652-76-9)

Safety Data

• Safety Statements: 22-24/25
• WGK Germany: 3
• Hazardous Substances Data: 16652-76-9(Hazardous Substances Data)

Usage

Chemical Properties

Crystalline

Uses

Val-OBzl TosOH is a L-Valine derivative useful as intermediate for the preparation of peptides.

InChI:InChI=1/C12H17NO2.C7H8O3S/c1-9(2)11(13)12(14)15-8-10-6-4-3-5-7-10;1-6-2-4-7(5-3-6)11(8,9)10/h3-7,9,11H,8,13H2,1-2H3;2-5H,1H3,(H,8,9,10)/t11-;/m0./s1

Synthetic route

toluene-4-sulfonic acid (104-15-4) + (S)-2-(Benzhydrylidene-amino)-3-methyl-butyric acid benzyl ester (138892-14-5) → L-valine benzyl ester p-toluenesulfonate salt (16652-76-9)

Conditions	Yield
In water; acetonitrile Ambient temperature;	99%

L-valine (72-18-4) + toluene-4-sulfonic acid (104-15-4) + benzyl alcohol (100-51-6) → L-valine benzyl ester p-toluenesulfonate salt (16652-76-9)

Conditions	Yield
In toluene for 5h; Reflux;	91%
In benzene Heating;	90%
In cyclohexane; water for 4h; Dean-Stark; Reflux;	88%
In benzene for 23h; Reflux;
In water; toluene for 24h; Reflux; Dean-Stark;

L-Valine methyl ester (4070-48-8) → L-valine benzyl ester p-toluenesulfonate salt (16652-76-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: 87 percent 2: 1) 20percent aq.NaOH, Bu4NHSO4 / 1) MeCN, r.t., 16 h, 2) CH2Cl2, r.t., 6 h 3: 99 percent / acetonitrile; H2O / Ambient temperature View Scheme

Methyl N-(diphenylmethylene)-L-valinate (138892-08-7) → L-valine benzyl ester p-toluenesulfonate salt (16652-76-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1) 20percent aq.NaOH, Bu4NHSO4 / 1) MeCN, r.t., 16 h, 2) CH2Cl2, r.t., 6 h 2: 99 percent / acetonitrile; H2O / Ambient temperature View Scheme

L-valine benzyl ester (21760-98-5) + toluene-4-sulfonic acid (104-15-4) → L-valine benzyl ester p-toluenesulfonate salt (16652-76-9)

Conditions	Yield
In diethyl ether

BOC-glycine (4530-20-5) + L-valine benzyl ester p-toluenesulfonate salt (16652-76-9) → N-t-butoxycarbonylglycyl-L-valine benzyl ester (66415-00-7)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine	100%
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 0 - 20℃; for 12h; Inert atmosphere;	94%
With benzotriazol-1-ol; triethylamine; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide 1.) 0 deg C, 2.) overnight, 4 deg C;	89%
With 4-methyl-morpholine; isobutyl chloroformate 1.) THF, -15 deg C, 2.) DMF, a) -15 deg C, 30 min, b) r.t., 30 min.; Yield given. Multistep reaction;

t-Boc-L-valine (13734-41-3) + L-valine benzyl ester p-toluenesulfonate salt (16652-76-9) → (S)-benzyl 2-((S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)-3-methylbutanoate (77443-49-3)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine	100%
With benzotriazol-1-ol; dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃;	99%
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 0 - 20℃; for 12h;	87%
With triethylamine; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃; for 5h;	26%
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 0 - 20℃; for 12h; Inert atmosphere;

L-N-Boc-Ala (15761-38-3) + L-valine benzyl ester p-toluenesulfonate salt (16652-76-9) → Boc-L-Ala-L-Val-OBzl (116798-35-7)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine	100%

L-valine benzyl ester p-toluenesulfonate salt (16652-76-9) + 4'-(bromomethyl)-1,1'-biphenyl-2-carbonitrile (114772-54-2) → (S)-2-[(2'-cyanobiphenyl-4-ylmethyl)amino]-3-methylbutyric acid benzyl ester hydrochloride (137864-24-5)

Conditions	Yield
Stage #1: L-valine benzyl ester p-toluenesulfonate salt With sodium hydroxide In 5,5-dimethyl-1,3-cyclohexadiene; water at 20℃; pH=< 8.5 - 9; Large scale; Stage #2: 4'-(bromomethyl)-1,1'-biphenyl-2-carbonitrile In 5,5-dimethyl-1,3-cyclohexadiene at 60℃; for 3.41667h; Large scale; Stage #3: With hydrogenchloride In 5,5-dimethyl-1,3-cyclohexadiene; water at 72℃; for 2h; Dean-Stark; Large scale;	98%
Stage #1: L-valine benzyl ester p-toluenesulfonate salt; 4'-(bromomethyl)-1,1'-biphenyl-2-carbonitrile With tetrabutylammomium bromide; potassium carbonate; potassium iodide In water; toluene at 50 - 55℃; for 25h; Stage #2: With hydrogenchloride In water; toluene pH=1 - 2; Product distribution / selectivity;	90%
Stage #1: L-valine benzyl ester p-toluenesulfonate salt; 4'-(bromomethyl)-1,1'-biphenyl-2-carbonitrile With tetrabutylammomium bromide; potassium carbonate; potassium iodide In water; toluene Stage #2: With hydrogenchloride In water; toluene pH=1 - 2; Product distribution / selectivity;	90%

L-valine benzyl ester p-toluenesulfonate salt (16652-76-9) + (R)-Boc-leucine hydrate + benzotriazol-1-ol (2592-95-2) + 1-ethyl-3-(3-(dimethylammonio)propyl)carbodiimide perchlorate (56218-01-0) + citric acid (77-92-9) → Boc-D-Leu-Val-OBn (135219-63-5)

Conditions	Yield
With triethylamine In dichloromethane; water	97.8%

L-valine benzyl ester p-toluenesulfonate salt (16652-76-9) + Boc-Val-OPyCl (122751-34-2) → (S)-benzyl 2-((S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)-3-methylbutanoate (77443-49-3)

Conditions	Yield
	97%

L-valine benzyl ester p-toluenesulfonate salt (16652-76-9) + 1',3'-dohexadecyl N--L-glutamate (171195-66-7) → 1',3'-dihexadecyl N-<1-(M-valinyl-O-benzyl ester)succinyl>-L-glutamate

Conditions	Yield
With triethylamine In ethyl acetate for 24h; Ambient temperature;	97%

L-valine benzyl ester p-toluenesulfonate salt (16652-76-9) + benzoic acid anhydride (93-97-0) → N-benzyl-L-valinol (42807-42-1)

Conditions	Yield
Stage #1: L-valine benzyl ester p-toluenesulfonate salt; benzoic acid anhydride With triethylamine In dichloromethane for 1h; Inert atmosphere; Stage #2: With lithium aluminium tetrahydride In tetrahydrofuran for 2.25h; Inert atmosphere; Reflux;	97%

N-(Phenylacetyl)-L-alanine (718-07-0) + L-valine benzyl ester p-toluenesulfonate salt (16652-76-9) → N-(Phenylacetyl)-L-alanyl-L-valin-benzylester (116912-11-9)

Conditions	Yield
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 24h;	96%

L-valine benzyl ester p-toluenesulfonate salt (16652-76-9) + n-valeryl chloride (638-29-9) → 3-methyl-2-(pentanoylamino)butyric acid benzyl ester

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 10℃; for 1.75h;	96%

L-valine benzyl ester p-toluenesulfonate salt (16652-76-9) + (S)-2-(benzyloxy)propanoic acid (33106-32-0) → (S)-benzyl 2-((S)-2-(benzyloxy)propanamido)-3-methylbutanoate (1239425-90-1)

Conditions	Yield
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃;	95%

L-valine benzyl ester p-toluenesulfonate salt (16652-76-9) + N-tert-butyloxycarbonyl di-L-tryptophan (90826-08-7) → Boc-Trp-Trp-Val-OBzl (1311414-53-5)

Conditions	Yield
With 4-methyl-morpholine; benzotriazol-1-ol; dicyclohexyl-carbodiimide In tetrahydrofuran at 0℃; for 24h; pH=8;	95%
With 4-methyl-morpholine; benzotriazol-1-ol; dicyclohexyl-carbodiimide In tetrahydrofuran at 0 - 20℃; for 26h; pH=8;	95%

L-valine benzyl ester p-toluenesulfonate salt (16652-76-9) + Boc-L-Abu(CN)ONSu (91126-95-3) → Boc-Abu(CN)-Val-OBzl (91126-99-7)

Conditions	Yield
With 4-methyl-morpholine In dichloromethane for 20h; Ambient temperature;	94%

9-(2-Propenyl)-9H-fluorene-9-carboxylic acid (101451-35-8) + L-valine benzyl ester p-toluenesulfonate salt (16652-76-9) → (S)-2-[(9-Allyl-9H-fluorene-9-carbonyl)-amino]-3-methyl-butyric acid benzyl ester

Conditions	Yield
With 4-methyl-morpholine; benzotriazol-1-ol; dicyclohexyl-carbodiimide In dichloromethane for 18h; Ambient temperature;	94%

L-valine benzyl ester p-toluenesulfonate salt (16652-76-9) + Cyclohexyl(isopropyl)ammonium (SS)-N-(N-tert-butyloxycarbonyl)-S-methyl S-phenyl sulfonimidoyl acetate → C25H32N2O6S (188633-67-2)

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide	93%

N-Boc-D-Leu (16937-99-8) + L-valine benzyl ester p-toluenesulfonate salt (16652-76-9) → Boc-D-Leu-Val-OBn (135219-63-5)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃; for 6h;	93%

N-[2-chloro-9-(tetrahydropyran-2-yl)-9H-purin-6-yl]-N-cyclopropylglycine (1185198-27-9) + L-valine benzyl ester p-toluenesulfonate salt (16652-76-9) → N-[2-chloro-9-(tetrahydropyran-2-yl)-9H-purin-6-yl]-N-cyclopropylglycyl-L-valine benzyl ester (1185198-46-2)

Conditions	Yield
Stage #1: N-[2-chloro-9-(tetrahydropyran-2-yl)-9H-purin-6-yl]-N-cyclopropylglycine With benzotriazol-1-ol; dicyclohexyl-carbodiimide In tetrahydrofuran at 0℃; Stage #2: L-valine benzyl ester p-toluenesulfonate salt With 4-methyl-morpholine In tetrahydrofuran at 20℃; for 0.333333h; pH=9; Stage #3: In tetrahydrofuran at 0 - 20℃; for 50h;	93%

9H-fluoren-9-ylmethyl (2-chloro-2-oxoethyl)carbamate (103321-49-9) + L-valine benzyl ester p-toluenesulfonate salt (16652-76-9) → Fmoc-Gly-Val-OBzl (221174-14-7)

Conditions	Yield
With 1-Hydroxy-1,2,3-benzotriazole potassium salt In dichloromethane for 0.5h; Ambient temperature;	92%
With silver cyanide; triethylamine In toluene at 60℃; 10-15 min;	80%

C22H19BrN4O (1307853-49-1) + L-valine benzyl ester p-toluenesulfonate salt (16652-76-9) → C34H35N5O3 (1307853-60-6)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 50℃; for 3h; Product distribution / selectivity;	92%
With N-ethyl-N,N-diisopropylamine In acetonitrile at 50℃; for 2h;

L-valine benzyl ester p-toluenesulfonate salt (16652-76-9) + treprostinil (81846-19-7) → C35H49NO6

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane; water at 20℃; for 2h;	90.3%

BOC-L-aspartic acid 4-benzyl ester (7536-58-5) + L-valine benzyl ester p-toluenesulfonate salt (16652-76-9) → Boc-Asp(OBzl)-Val-OBzl (110863-06-4)

Conditions	Yield
Stage #1: BOC-L-aspartic acid 4-benzyl ester With benzotriazol-1-ol; dicyclohexyl-carbodiimide In tetrahydrofuran at 0℃; under 750.075 Torr; for 0.5h; Inert atmosphere; Stage #2: L-valine benzyl ester p-toluenesulfonate salt With 4-methyl-morpholine In tetrahydrofuran at 0 - 20℃; under 750.075 Torr; pH=8.5; Inert atmosphere;	90%
Stage #1: BOC-L-aspartic acid 4-benzyl ester With benzotriazol-1-ol; dicyclohexyl-carbodiimide In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: L-valine benzyl ester p-toluenesulfonate salt With 4-methyl-morpholine In tetrahydrofuran at 0 - 20℃; pH=8.5; Inert atmosphere;	90%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine at 0 - 20℃; for 16h; Inert atmosphere; Green chemistry;	70%

N-tert-butoxycarbonyl-L-phenylalanine (13734-34-4) + L-valine benzyl ester p-toluenesulfonate salt (16652-76-9) → benzyl (tert-butoxycarbonyl)-L-phenylalanyl-L-valinate (136282-23-0)

Conditions	Yield
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 0 - 20℃; for 12h; Inert atmosphere;	90%

N-tert-butyloxycarbonyl-L-tert-leucine (62965-35-9) + L-valine benzyl ester p-toluenesulfonate salt (16652-76-9) → benzyl ((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-L-valinate

Conditions	Yield
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 0 - 20℃; for 12h; Inert atmosphere;	90%

L-valine benzyl ester p-toluenesulfonate salt (16652-76-9) + 2-Bromoacetyl bromide (598-21-0) → bromoacetyl valine benzyl ester (77434-37-8)

Conditions	Yield
With triethylamine In tetrahydrofuran at 5℃;	88%

L-Lactic acid (79-33-4) + L-valine benzyl ester p-toluenesulfonate salt (16652-76-9) → benzyl (2S)-2-{[(2S)-2-hydroxypropanoyl]amino}-3-methylbutanoate (1181104-59-5)

Conditions	Yield
With benzotriazol-1-ol; triethylamine; diisopropyl-carbodiimide In dichloromethane at 0 - 20℃;	88%

pent-4-enoic acid (591-80-0) + L-valine benzyl ester p-toluenesulfonate salt (16652-76-9) → N-(4-pentenoyl)-(S)-valine benzyl ester

Conditions	Yield
With 4-methyl-morpholine; benzotriazol-1-ol; dicyclohexyl-carbodiimide In dichloromethane for 18h; Ambient temperature;	87%

L-valine benzyl ester p-toluenesulfonate salt (16652-76-9) + (2S,3R)-3-[(tert-butoxycarbonyl) amino]-2-hydroxy-4-phenyl-butanoic acid (62023-65-8) → 6-tert-butoxycarbonylamino-5-hydroxy-2-isopropyl-4-oxo-7-phenyl-3-azaheptanoic acid benzyl ester (246506-77-4)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; for 12h;	87%

diethylphosphinic chloride (1112-37-4) + L-valine benzyl ester p-toluenesulfonate salt (16652-76-9) → Nα-diethylphosphinoylvaline benzyl ester (98748-17-5)

Conditions	Yield
With 4-methyl-morpholine In dichloromethane at 0℃; for 1h;	86%

Upstream product

• 104-15-4 toluene-4-sulfonic acid 
• 138892-14-5 (S)-2-(Benzhydrylidene-amino)-3-methyl-butyric acid benzyl ester 
• 640-68-6 D-Val-OH 
• 100-51-6 benzyl alcohol 
• 21760-98-5 L-valine benzyl ester 
• 138892-08-7 Methyl N-(diphenylmethylene)-L-valinate 
• 4070-48-8 L-Valine methyl ester 
• 72-18-4 L-valine 

Downstream Products

• 221174-14-7 Fmoc-Gly-Val-OBzl 
• 188633-69-4 C₃₀H₄₁N₃O₇S 
• 188633-67-2 C₂₅H₃₂N₂O₆S 
• 178034-81-6 (S)-2-[((2S,6R)-2,6-Dimethyl-piperidine-1-carbonyl)-amino]-3-methyl-butyric acid benzyl ester 
• 135219-63-5 Boc-D-Leu-Val-OBn 
• 160940-50-1 Bn-L-Val-(diketo-L-Asp)-L-Val-Bn 
• 77328-25-7 (S)-2-(Benzyloxycarbonylmethyl-amino)-3-methyl-butyric acid benzyl ester 
• 99909-22-5 Z-Pro-Val-OBzl 

Relevant articles and documents

Design, synthesis, and evaluation of cystargolide-based β-lactones as potent proteasome inhibitors

The peptidic β-lactone proteasome inhibitors (PIs) cystargolides A and B were used to conduct structure-activity relationship (SAR) studies in order to assess their anticancer potential. A total of 24 different analogs were designed, synthesized and evaluated for proteasome inhibition, for cytotoxicity towards several cancer cell lines, and for their ability to enter intact cells. X-ray crystallographic analysis and subunit selectivity was used to determine the specific subunit binding associated with the structural modification of the β-lactone (P1), peptidic core, (Px and Py), and end-cap (Pz) of our scaffold. The cystargolide derivative 5k, structurally unique at both Py and P1, exhibited the most promising inhibitory activity for the β5 subunit of human proteasomes (IC50 = 3.1 nM) and significant cytotoxicity towards MCF-7 (IC50 = 416 nM), MDA-MB-231 (IC50 = 74 nM) and RPMI 8226 (IC50 = 41 nM) cancer cell lines. Cellular infiltration assays revealed that minor structural modifications have significant effects on the ability of our PIs to inhibit intracellular proteasomes, and we identified 5k as a promising candidate for continued therapeutic studies. Our novel drug lead 5k is a more potent proteasome inhibitor than carfilzomib with mid-to-low nanomolar IC50 measurements and it is cytotoxic against multiple cancer cell lines at levels approaching those of carfilzomib.

Enantiomeric resolution of p-toluenesulfonate of valine benzyl ester by preferential crystallizaion

Preferential crystallization of amino acid derivatives by seeding a pure enantiomer into racemic amino acid solutions has been studied for many years. However, few examples of valine derivatives have been reported so far. Although there have been some reports using valine hydrogen chloride with preferential crystallization, it is difficult to obtain optical isomers for valine derivatives using preferential crystallization. In this study, repeated preferential crystallization of p-toluenesulfonate valine benzyl ester with a 20% e.e. in 2-propanol gave a 94% e.e. on sonication. Sonication accelerated crystallization rate, but there was not a big difference in e.e. between with and without sonication. However, this research demonstrates the first preferential crystallization of p-toluenesulfonate of valine benzyl esters with an acceleration of crystallization using sonication.

A mild Boc deprotection and the importance of a free carboxylate

We report a facile and rapid removal of Boc protecting groups using microwave heating in H2O, with deprotection only requiring a free carboxylic acid group in the starting material. Unlike previous approaches, no additional reagents are required.