94790-37-1

Basic information

• Product Name: HBTU
• Synonyms: O-(1H-BENZOTRIAZOL-1-YL)-N,N,N',N'-TETRAMETHYLURONIUM HEXAFLUOROPHOSPHATE;O-(BENZOTRIAZOL-1-YL)-N,N,N',N'-TETRAMETHYLURONIUM HEXAFLUOROPHOSPHATE;O-(BENZOTRIAZOL-1-YL)-N-N-N ,N -TETRAMETHYLURONIUM HEXAFLUOROPHOSPHATE;O-BENZOTRIAZOL-1-YL-N,N,N',N'-TETRAMETHYLURONIUM HEXAFLUOROPHOSPHATE POLYMER BOUND;O-BENZOTRIAZOL-1-YL-TETRAMETHYLURONIUM HEXAFLUOROPHOSPHATE;O-BENZOTRIAZOLE-1-YL-N,N,N',N'-TETRAMETHYLURONIUM HEXAFLUOROPHOSPHATE;O-BENZOTRIAZOLE-N,N,N',N'-TETRAMETHYL-URONIUM;O-BENZOTRIAZOLE-N,N,N',N'-TETRAMETHYL-URONIUM-HEXAFLUORO-PHOSPHATE
• CAS NO: 94790-37-1
• Molecular Formula: C₁₁H₁₆N₅O*F₆P
• Molecular Weight: 379.24
• EINECS: 423-020-5
• Product Categories: Peptide coupling agents;Amino Acid Derivatives;Starting Raw Materials & Intermediates;PROTECTED AMINO ACID & PEPTIDES;Peptide Coupling Reagents;Biochemistry;Condensation & Active Esterification;Coupling Reactions (Peptide Synthesis);Peptide Synthesis;Synthetic Organic Chemistry;Peptide;peptides
• Mol File: 94790-37-1.mol
• Article Data: 4

Chemical Properties

• Melting Point: 200 °C (dec.)(lit.)
• Flash Point: 200°C
• Appearance: /Powder
• Storage Temp.: 2-8°C
• Solubility: acetonitrile: 0.1 g/mL, clear
• Stability: Stable. Incompatible with oxidizing agents.
• BRN: 7328329
• CAS DataBase Reference: HBTU(CAS DataBase Reference)
• NIST Chemistry Reference: HBTU(94790-37-1)
• EPA Substance Registry System: HBTU(94790-37-1)

Safety Data

• Hazard Codes: Xi,Xn
• Statements: 36/37/38-20/21/22-42/43
• Safety Statements: 26-36/37/39-36-22
• WGK Germany: 3
• F: 8-10-21
• Hazardous Substances Data: 94790-37-1(Hazardous Substances Data)

Usage

Chemical Properties

white to light yellow powder

Uses

Different sources of media describe the Uses of 94790-37-1 differently. You can refer to the following data:
1. HBTU is a coupling reagent used in peptide synthesis. HBTU has been shown to effectively suppress racemization.
2. peptide coupling reagent that reduces racemization

Biological Activity

hbtu (2-(1h-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexauorophosphate), a coupling reagent commonly used in solid phase peptide synthesis. after being introduced in 1978, this agent shows popularity in chemistry and industry use due to its mild activating properties. moreover, it also shows resistance against racemization. low tendency for racemization is a key requirement for peptide synthesis. especially for solid phase peptide synthesis, quantitative yields with short reaction times are crucial in order to make the synthesis of large peptides feasible. [1]

in vitro

peptide synthesis relied mostly on efficient and safe coupling reagents. hbtu was proved to transform carboxylic acids into azides efficiently and practically. the process might be applied to a wide range of carboxylic acids including n-protected amino acids. in addition, hbtu was of great value in one-pot synthesis of dipeptidyl urea esters, ureas, and carbamates from acids. the advantages of hbtu included the following points: 1) non-explosive and therefore more suitable for solution/solid phase peptide synthesis. 2) high solubility and stability in classical solvents. 3) feasible for colorimetric reaction monitoring. [2]

Purification Methods

Wash the salt with H2O (3x), CH2Cl2 (3x), dry and recrystallise it from MeCN. Dry it in a vacuum and store it cold in the dark [Dourtoglou et al. Tetrahedron Lett 1269 1978, NMR: Dourtoglou and Gross Synthesis 572 1984]. Benzoxazolinone (2 -hydroxybenzoxazole) [59 -49 -4] M 135.1, m 137 -139o, 142 -143o(corrected), b 121-213o/17mm, 335-337o/760mm. Benzoxazolinone is purified by recrystallisation from aqueous Me2CO followed by distillation at atmospheric pressure, then in a vacuum. The methyl mercury salt recrystallises from aqueous EtOH and has m 156-158o. [Bywater et al. J Am Chem Soc 67 905 1945, Beilstein 27 III/IV 2677.]

references

[1]adam s. hbtu: a mild activating ageiw of muramic acid. bioorg med chem lett. 1992 mar; 2(6): 571-4.[2]knorr r, trzeciak a, bannwarth w and gillessen d. new coupling reagents in peptide chemistry. tetrahedron lett. 1989; 30(15): 1927-30.

InChI:InChI=1/C11H16N5O.F6P/c1-14(2)11(15(3)4)17-16-10-8-6-5-7-9(10)12-13-16;1-7(2,3,4,5)6/h5-8H,1-4H3;/q+1;-1

Synthetic route

benzotriazol-1-ol (2592-95-2) + N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate → O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1)

Conditions	Yield
With triethylamine In dichloromethane	100%

N,N,N',N'-tetramethylchlorformamidinium chloride (56043-45-9, 13829-06-6) + 1-Hydroxy-1,2,3-benzotriazole potassium salt (62244-77-3) → O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1)

Conditions	Yield
With potassium hexafluorophosphate; potassium chloride

tetramethylurea (632-22-4) → O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: phosgene / toluene / 0.25 h 2: aq. ammonium hexafluorophosphate / CH2Cl2 3: 100 percent / N(C2H5)3 / CH2Cl2 View Scheme
Multi-step reaction with 2 steps 1: oxalyl chloride 2: KPF6,KCl View Scheme

C11H13N2O2Pol + O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1) → C16H25N4O3(1+)

Conditions	Yield
Stage #1: C11H13N2O2Pol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 0.166667h; 2-chlorotrityl chloride resin; Stage #2: With trifluoroacetic acid In dichloromethane	100%

1-{[(3aR,4R,6aS)-5-(tert-butoxycarbonyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyrrol-4-yl]methyl}-1H-pyrrole-2-carboxylic acid + O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1) → tert-butyl (3aR,4R,6aS)-4-{[2-{[(1H-benzo[d][1,2,3]triazol-1-yl)oxy]carbonyl}-1H-pyrrol-1-yl]methyl}-2,2-dimethyltetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 20℃;	100%

1-{[(3aR,4R,6aS)-5-(tert-butoxycarbonyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyrrol-4-yl]methyl}-4-(4-methoxyphenyl)-1H-pyrrole-2-carboxylic acid + O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1) → tert-butyl (3aR,4R,6aS)-4-[(2-{[(1H-benzo[d][1,2,3]triazol-1-yl)oxy]carbonyl}-4-(4-methoxyphen-yl)-1Hpyrrol-1-yl)methyl]-2,2-dimethyltetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 20℃;	98%

4-(4-methoxyphenyl)-1-methyl-1H-pyrrole-2-carboxylic acid + O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1) → 1H-benzo[d][1,2,3]triazol-1-yl 4-(4-methoxyphenyl)-1-methyl-1H-pyrrole-2-carboxylate

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 20℃;	96%

2-Nitrobenzenesulfonamide (5455-59-4) + O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1) → N-(bis-dimethylamino-methylene)-2-nitro-benzenesulfonamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1h;	95%

N-benzoyl-p-toluenesulfonimidamide (18512-85-1) + O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1) → N-(N',N',N'',N''-tetramethyl)[(N'''-benzoyl-p-tolyl)sulfonimidoyl]guanidine

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1h;	95%

sulindac sulfide (49627-27-2) + O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1) → (Z)-N-(2-(dimethylamino)ethyl)-2-(5-fluoro-2-methyl-1-(4-(methylsulfonyl)benzylidene)-1H-inden-3-yl)acetamide (944159-30-2)

Conditions	Yield
With (4-aminomethylphenyl)dimethylamine In N,N-dimethyl-formamide at 0 - 20℃;	94%

Ursolic acid (174291-94-2) + O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1) → C36H51N3O3

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 5h; Inert atmosphere;	94%

(+)-N-benzoyl-p-toluenesulfonimidamide + O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1) → (+)-N-(N',N',N'',N''-tetramethyl)[(N'''-benzoyl-p-tolyl)sulfonimidoyl]guanidine

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1h;	93%

Betulinic acid (472-15-1) + O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1) → 1-benzotriazolyl 3β-hydroxy-lup-20(29)-en-28-oate

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 5h; Inert atmosphere;	93%

O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1) + 18α-oleanolic acid (6880-10-0) → C36H51N3O3

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 5h; Inert atmosphere;	93%

Oleanolic acid (508-02-1) + O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1) → 1-benzotriazolyl 3β-hydroxyolean-12-en-28-oate (1596377-01-3)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 2h;	93%

O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1) + toluene-4-sulfonamide (70-55-3) → N-bis(dimethylamino)methylene-4-methylbenzenesulfonamide (1823-69-4)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1h;	92%

1-{[(3aS,4S,6aR)-5-(tert-butoxycarbonyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyrrol-4-yl]methyl}-4-(4-methoxyphenyl)-1H-pyrrole-2-carboxylic acid + O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1) → tert-butyl (3aS,4S,6aR)-4-{[2-{[(1H-benzo[d][1,2,3]triazol-1-yl)oxy]carbonyl}-4-(4-methoxyphenyl)-1H-pyrrol-1-yl]methyl}-2,2-dimethyltetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 20℃;	92%

3-nitrophenylsulfonamide (121-52-8) + O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1) → N-(bis-dimethylamino-methylene)-3-nitro-benzenesulfonamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1h;	90%

chenodeoxycholic acid (474-25-9) + O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1) → CDCA-OBt ester (1161010-74-7)

Conditions	Yield
With benzotriazol-1-ol; triethylamine In N,N-dimethyl-formamide at 20℃; for 4h;	90%

4-(2,4-dimethoxyphenyl)-1-methyl-1H-pyrrole-2-carboxylic acid + O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1) → 1H-benzo[d][1,2,3]triazol-1-yl 4-(2,4-dimethoxyphenyl)-1-methyl-1H-pyrrole-2-carboxylate

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 20℃;	90%

(rac)-(-)-N-(p-toluenesulfonyl)-p-toluenesulfonimidamide (94892-50-9) + O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1) → N-(N',N',N'',N''-tetramethyl)[(N'''-p-toluenesulfonyl-p-tolyl)sulfonimidoyl]guanidine

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1h;	89%

4-Chlorobenzenesulfonamide (98-64-6) + O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1) → 1,1,3,3-Tetra-methyl-2-(p-chlor-benzolsulfonyl)-guanidin (16816-86-7)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1h;	88%

N,O-dimethylhydroxylamine*hydrochloride (6638-79-5) + O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1) + 3-methylindole-2-carboxylic acid (10590-73-5) → N-methoxy-N,3-dimethyl-1H-indole-2-carboxamide (1352805-50-5)

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide	88%

methyl 6-aminocaproate hydrochloride (1926-80-3) + O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1) → 6-(N,N,N',N'-teramethylguanidinium chloride)-hexanoic acid methyl ester (1379001-37-2)

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 20℃; for 1h;	87%

1-{[(3aR,4R,6aS)-5-(tert-butoxycarbonyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyrrol-4-yl]methyl}-4-(2,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid + O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1) → tert-butyl (3aR,4R,6aS)-4-{[2-{[(1H-benzo[d][1,2,3]triazol-1-yl)oxy]carbonyl}-4-(2,4-dimethoxyphenyl)-1H-pyrrol-1-yl]methyl}-2,2-dimethyltetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 20℃;	86%

O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1) + 3,16-dihydroxy-(3β,16α)-olean-12-en-28-oic acid (1192133-72-4) → C36H51N3O4

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 5h; Inert atmosphere;	86%

2-(2,4-dichlorophenyl)-1-(4-methoxyphenyl)-5-methyl-1H-imidazole-4-carboxylic acid (505073-87-0) + sodium hydrogencarbonate (144-55-8) + O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1) + cyclohexylamine (108-91-8) → N-(1-cyclohexyl)-2-(2,4-dichlorophenyl)-5-methyl-1-(4-methoxyphenyl)-1H-imidazole-4-carboxamide (505073-88-1)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dichloromethane; acetonitrile	85%

Indole-2-carboxylic acid (1477-50-5) + N,O-dimethylhydroxylamine*hydrochloride (6638-79-5) + O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1) → N-methoxy-N-methyl-1H-indole-2-carboxamide (156571-69-6)

Conditions	Yield
With triethylamine In hexane; N,N-dimethyl-formamide	85%

2-chlorothiophene-5-sulfonamide (53595-66-7) + O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1) → 5-chloro-thiophene-2-sulfonic acid bis-dimethylamino-methyleneamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1h;	81%

2,2,5-trimethyltetrahydro-3aH-cyclopenla[d][1,3]dioxole-5-carboxylic acid + O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1) → 1H-benzo[d][1,2,3]triazol-1-yl-2,2,5-trimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-5-carboxylate

Conditions	Yield
With triethylamine In dichloromethane; acetonitrile	80%

N,O-dimethylhydroxylamine*hydrochloride (6638-79-5) + O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1) + 7-azaindole-2-carboxylic acid (136818-50-3) → N-methoxy-N-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (1352805-43-6)

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide	79%

p-nitrobenzenesulfonamide (6325-93-5) + O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94790-37-1) → N,N,N',N'-tetramethyl-N''-(4-nitro-benzenesulfonyl)-guanidine

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1h;	78%

Upstream product

• 632-22-4 tetramethylurea 
• 2592-95-2 benzotriazol-1-ol 
• 56043-45-9 N,N,N',N'-tetramethylchlorformamidinium chloride 
• 62244-77-3 1-Hydroxy-1,2,3-benzotriazole potassium salt 

Downstream Products

• 16816-86-7 N?[bis(dimethylamino)methylene]?4?chlorobenzenesulfonamide 
• 1823-69-4 N-bis(dimethylamino)methylene-4-methylbenzenesulfonamide 
• 415905-40-7 N-{5-[5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]pentyl}acetamide, formate 
• 206266-96-8 2-((tert-butoxy)carbonylamino)-N-(6-(4,6-diphenyl(2-pyridyloxy))-2,2-dimethylhexyl)-3-((fluoren-9-ylmethoxy)carbonylamino)propanamide 
• 248922-03-4 (S)-1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-4-methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentan-1-one 
• 248921-61-1 (S)-Azepane-1-carboxylic acid [1-(3,3-diphenyl-propylcarbamoyl)-3-methyl-butyl]-amide 
• 248921-85-9 (S)-4-Methyl-2-piperidin-1-yl-pentanoic acid (3,3-diphenyl-propyl)-amide monohydrochloride 

Relevant articles and documents

Radiofluorination methods

The present invention relates to radiolabelled substitute benzene compounds for diagnostic imaging. The present invention provides methods for preparation of such compounds, in particular, preparation of novel compounds which serve as precursors for 18F-labeling, and the use of thus 18F-labeled compounds for diagnostic imaging.

NEW COUPLING REAGENTS IN PEPTIDE CHEMISTRY

2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) has been applied as coupling reagent to solid phase peptide synthesis.Furthermore, a general synthetic procedure for new derivatives of different N-hydroxy compounds has been developed.They either act as excellent activating reagents causing low racemization during condensation of peptide segments or are useful tools for the formation of active esters suitable for couplings in mixed aqueous / organic media, respectively.