332-80-9

Basic information

• Product Name: 1-Methyl-L-histidine
• Synonyms: METHYLHISTIDINE, L-1-;METHYLHISTIDINE, L-3-;1-METHYL-L-HISTIDINE;1-METHYLHISTIDINE;3-(1-METHYLIMIDAZOL-4-YL)-L-ALANINE;3-(1-METHYLIMIDAZOL-5-YL)-L-ALANINE;3-METHYL-L-HISTIDINE;P-METHYL-L-HISTIDINE
• CAS NO: 332-80-9
• Molecular Formula: C₇H₁₁N₃O₂
• Molecular Weight: 169.18
• EINECS: 206-368-0
• Product Categories: Pharmaceutical Raw Materials;Histidine [His, H];Amino Acids and Derivatives;Amino acids methyl、ethyl、t-butyl series;Amino Acids & Derivatives;Heterocycles;Inhibitors
• Mol File: 332-80-9.mol

Chemical Properties

• Melting Point: ~240 °C (dec.)(lit.)
• Boiling Point: 298.47°C (rough estimate)
• Flash Point: 204.8 °C
• Appearance: /
• Density: 1.2509 (rough estimate)
• Vapor Pressure: 1.25E-07mmHg at 25°C
• Refractive Index: 1.5950 (estimate)
• Storage Temp.: 2-8°C(protect from light)
• Solubility: Methanol (Slightly), Water (Slightly, Sonicated)
• PKA: 1.69(at 25℃)
• Stability: Hygroscopic
• BRN: 9727
• CAS DataBase Reference: 1-Methyl-L-histidine(CAS DataBase Reference)
• NIST Chemistry Reference: 1-Methyl-L-histidine(332-80-9)
• EPA Substance Registry System: 1-Methyl-L-histidine(332-80-9)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26-36-24/25-22
• WGK Germany: 3
• Hazardous Substances Data: 332-80-9(Hazardous Substances Data)

Usage

Uses

Used in Medical Research:
1-Methyl-L-histidine is used as a biomarker for skeletal muscle toxicity. Its presence in urine, particularly as a metabolite, is highly correlated with the sex-, dose-, and time-dependent development of myotoxicity, which is muscle toxicity often associated with the use of certain medications like cerivastatin.
Used in Muscle Metabolism Studies:
As an index of muscle protein breakdown, 1-Methyl-L-histidine is employed in the study of muscle metabolism. Understanding its role in this process can help researchers and medical professionals develop better strategies for managing muscle wasting conditions and muscle-related diseases.
Used in Pharmaceutical Development:
Given its correlation with muscle toxicity and its role in protein breakdown, 1-Methyl-L-histidine may also be used in the development of pharmaceuticals aimed at treating or preventing muscle-related disorders, particularly those that involve muscle wasting or myotoxicity.

InChI:InChI=1/C7H11N3O2/c1-10-3-5(9-4-10)2-6(8)7(11)12/h3-4,6H,2,8H2,1H3,(H,11,12)

Synthetic route

(S)-7-(methoxycarbonyl)-2-methyl-5-oxo-5,6,7,8-tetrahydroimidazo[1,5-c] pyrimidin-2-ium iodide (69618-95-7) → His(1-CH3) (332-80-9)

Conditions	Yield
With hydrogenchloride Heating;	99%

Nα-Trityl-Nτ-methyl-L-histidin (118891-68-2) → His(1-CH3) (332-80-9)

Conditions	Yield
With acetic acid In water; ethyl acetate for 1h; Heating;	71%

L-histidine (71-00-1) + methyl iodide (74-88-4) → 3-methyl-L-histidine (368-16-1) + His(1-CH3) (332-80-9)

Conditions	Yield
With ammonia; sodium

(S)-2-Amino-3-{5-[5-((S)-2-amino-2-carboxy-ethyl)-3-methyl-3H-imidazol-4-yldisulfanyl]-1-methyl-1H-imidazol-4-yl}-propionic acid (83471-81-2) → His(1-CH3) (332-80-9)

Conditions	Yield
With nickel In ethanol for 0.5h; Heating;

1-methyl<2-(3)H>-L-histidine (124017-72-7) → His(1-CH3) (332-80-9)

Conditions	Yield
With methylmercuric nitrate In water at 85℃; Rate constant; Mechanism; effect of pH; variation of concentration of MeHgNO3;

N-[(1,1-dimethylethoxy)carbonyl]-3-[(phenylmethoxy)methyl]-L-histidine (79950-65-5) + methyl iodide (74-88-4) → His(1-CH3) (332-80-9)

Conditions	Yield
With hydrogenchloride 1.) (DMF), 24 h, room temp., 2.) reflux, 24 h; Multistep reaction;

N(α)-benzyloxycarbonyl-N(ϖ)-t-butoxymethyl-L-histidine methyl ester (90653-43-3) + methyl iodide (74-88-4) → 3-methyl-L-histidine (368-16-1) + His(1-CH3) (332-80-9)

Conditions	Yield
With hydrogenchloride 1.) (DMF), 24 h, room temp., 2.) reflux, 24 h; Multistep reaction;

N(α)-benzyloxycarbonyl-N(ϖ)-(2-methoxyethoxy)methyl-L-histidine methyl ester (99523-88-3) + methyl iodide (74-88-4) → His(1-CH3) (332-80-9)

Conditions	Yield
Multistep reaction;

N(α)-benzyloxycarbonyl-N(ϖ)-(2-trimethylsilylethoxy)methyl-L-histidine methyl ester (99523-90-7) + methyl iodide (74-88-4) → 3-methyl-L-histidine (368-16-1) + His(1-CH3) (332-80-9)

Conditions	Yield
With hydrogenchloride 1.) (DMF), 24 h, room temp., 2.) reflux, 24 h; Multistep reaction;

N(α)-benzyloxycarbonyl-N(τ)-(2-trimethylsilylethoxy)methyl-L-histidine methyl ester (99523-91-8) + methyl iodide (74-88-4) → 3-methyl-L-histidine (368-16-1) + His(1-CH3) (332-80-9)

Conditions	Yield
With hydrogenchloride 1.) (DMF), 24 h, room temp., 2.) reflux, 24 h; Multistep reaction;

N(α)-benzyloxycarbonyl-N(ϖ)-(2,4,6-trimethylbenzyloxy)methyl-L-histidine methyl ester + methyl iodide (74-88-4) → His(1-CH3) (332-80-9)

Conditions	Yield
With hydrogenchloride 1.) (DMF), 24 h, room temp., 2.) reflux, 24 h; Multistep reaction;

1-Me-AcHis → His(1-CH3) (332-80-9)

Conditions	Yield
With (2)H8O4Pd(2+); deuteroperchloric acid In water-d2 at 40℃; Rate constant;

N(α)-benzyloxycarbonyl-N(τ)-tert-butyloxycarbonyl-L-histidine methyl ester (90653-42-2) → His(1-CH3) (332-80-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 81 percent / CH2Cl2 / 1.) 0 deg C, 1 h, 2.) room temp., 3 h View Scheme

Z-His-OMe (15545-10-5) → His(1-CH3) (332-80-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 27 percent / triethylamine / ethyl acetate / 1.) 0 deg C, 1 h, 2.) room temp., 6 h. 2: 2.) 'constant boiling' hydrochloric acid / 1.) (DMF), 24 h, room temp., 2.) reflux, 24 h View Scheme

L-5-sulfanyl-1-methylhistidine (62982-24-5) → His(1-CH3) (332-80-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: air, iodide / H2O / 24 h 2: Raney Nickel / aq. ethanol / 0.5 h / Heating View Scheme

n-butyllithium (109-72-8, 29786-93-4) + His(1-CH3) (332-80-9) → (S)-methyl 2-amino-3-(1-methyl-1H-imidazol-4-yl)propanoate (57519-09-2)

Conditions	Yield
With hydrogenchloride at 20℃;	95%

formaldehyd (50-00-0) + His(1-CH3) (332-80-9) → (S)-3-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylic acid

Conditions	Yield
With hydrogenchloride In water at 0℃; Reflux;	80%

His(1-CH3) (332-80-9) → (S)-2-Amino-3-{5-[5-((S)-2-amino-2-carboxy-ethyl)-3-methyl-3H-imidazol-4-yldisulfanyl]-1-methyl-1H-imidazol-4-yl}-propionic acid (83471-81-2)

Conditions	Yield
Stage #1: His(1-CH3) With hydrogenchloride; N-Bromosuccinimide In water at 1℃; for 0.05h; Stage #2: With tiolacetic acid In water at 0℃; for 0.5h; Stage #3: With 3-mercaptopropionic acid In water at 100℃; for 20h;	65%

His(1-CH3) (332-80-9) → [αR-2H]-Nτ-methylhistamine (1205535-89-2)

Conditions	Yield
With histidine decarboxylase; pyridoxal 5'-phosphate; water-d2 at 37℃; for 192h; pH=4.7; aq. phosphate buffer; Enzymatic reaction;	58%

Dimethoxymethane (109-87-5) + His(1-CH3) (332-80-9) → 3-methylspinacine dihydrochloride (114787-98-3)

Conditions	Yield
With hydrogenchloride 1) RT, overnight, 2) 3h, steam-bath;	45%

His(1-CH3) (332-80-9) → [αR-3H]-Nτ-methylhistamine (1205535-90-5)

Conditions	Yield
With (1)H,(3)H-water; histidine decarboxylase; pyridoxal 5'-phosphate at 37℃; for 192h; pH=4.7; aq. phosphate buffer; Enzymatic reaction;	35%

chloro-trimethyl-silane (75-77-4) + His(1-CH3) (332-80-9) → C10H19N3O2Si*ClH (118891-70-6)

Conditions	Yield
In chloroform for 1h; Heating;

peridoxal (19804-21-8) + His(1-CH3) (332-80-9) → N-pyridoxylidene-L-Nτmethylhistidine (83984-06-9)

Conditions	Yield
In methanol

bufotalin 3-hemisuberate p-nitrophenyl ester (61507-75-3) + His(1-CH3) (332-80-9) → bufotalin 3-suberoyl-L-3-methylhistidine ester (90038-13-4)

Conditions	Yield
In pyridine; water for 12h; Ambient temperature;	11 mg

His(1-CH3) (332-80-9) → 1-methyl<2-(3)H>-L-histidine (124017-72-7)

Conditions	Yield
With tritium oxide at 85℃; for 408h;

methanol (67-56-1) + His(1-CH3) (332-80-9) → L-Nτ-methylhistidine methyl ester dihydrochloride

Conditions	Yield
With thionyl chloride at 0℃; for 3h; Heating / reflux;

His(1-CH3) (332-80-9) → (S)-3-(1-Methyl-1H-imidazol-4-yl)-2-[((R)-3-oxo-cyclopentanecarbonyl)-amino]-propionic acid methyl ester

Conditions	Yield
Multi-step reaction with 2 steps 1: 95 percent / HCl gas / 20 °C 2: ethyl acetate / 24 h / 20 °C View Scheme

His(1-CH3) (332-80-9) → (S)-3-(1-Methyl-1H-imidazol-4-yl)-2-[((S)-3-oxo-cyclopentanecarbonyl)-amino]-propionic acid methyl ester

Conditions	Yield
Multi-step reaction with 2 steps 1: 95 percent / HCl gas / 20 °C 2: ethyl acetate / 24 h / 20 °C View Scheme

His(1-CH3) (332-80-9) → (S)-3-(1-Methyl-1H-imidazol-4-yl)-2-[((R)-3-oxo-cyclopentanecarbonyl)-amino]-propionic acid (406939-49-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: 95 percent / HCl gas / 20 °C 2: ethyl acetate / 24 h / 20 °C 3: 0.5N NaOH / methanol / 0.5 h / 20 °C View Scheme

His(1-CH3) (332-80-9) → (S)-3-(1-Methyl-1H-imidazol-4-yl)-2-[((S)-3-oxo-cyclopentanecarbonyl)-amino]-propionic acid (406939-48-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: 95 percent / HCl gas / 20 °C 2: ethyl acetate / 24 h / 20 °C 3: 0.5N NaOH / methanol / 0.5 h / 20 °C View Scheme

His(1-CH3) (332-80-9) → (S)-1-{(S)-3-(1-Methyl-1H-imidazol-4-yl)-2-[((R)-3-oxo-cyclopentanecarbonyl)-amino]-propionyl}-pyrrolidine-2-carboxylic acid amide

Conditions	Yield
Multi-step reaction with 4 steps 1: 95 percent / HCl gas / 20 °C 2: ethyl acetate / 24 h / 20 °C 3: 0.5N NaOH / methanol / 0.5 h / 20 °C 4: 36 percent / HOBt; DCC / dimethylformamide / 0.8 h / 20 °C View Scheme

His(1-CH3) (332-80-9) → (S)-1-{(S)-3-(1-Methyl-1H-imidazol-4-yl)-2-[((S)-3-oxo-cyclopentanecarbonyl)-amino]-propionyl}-pyrrolidine-2-carboxylic acid amide

Conditions	Yield
Multi-step reaction with 4 steps 1: 95 percent / HCl gas / 20 °C 2: ethyl acetate / 24 h / 20 °C 3: 0.5N NaOH / methanol / 0.5 h / 20 °C 4: 23 percent / HOBt; DCC / dimethylformamide / 0.8 h / 20 °C View Scheme

Upstream product

• 69618-95-7 (S)-7-(methoxycarbonyl)-2-methyl-5-oxo-5,6,7,8-tetrahydroimidazo[1,5-c] pyrimidin-2-ium iodide 
• 62982-24-5 L-5-sulfanyl-1-methylhistidine 
• 15545-10-5 Z-His-OMe 
• 90653-42-2 N(α)-benzyloxycarbonyl-N(τ)-tert-butyloxycarbonyl-L-histidine methyl ester 
• 74-88-4 methyl iodide 
• 99523-91-8 N(α)-benzyloxycarbonyl-N(τ)-(2-trimethylsilylethoxy)methyl-L-histidine methyl ester 
• 99523-90-7 N(α)-benzyloxycarbonyl-N(?)-(2-trimethylsilylethoxy)methyl-L-histidine methyl ester 
• 99523-88-3 N(α)-benzyloxycarbonyl-N(?)-(2-methoxyethoxy)methyl-L-histidine methyl ester 
• 90653-43-3 N(α)-benzyloxycarbonyl-N(?)-t-butoxymethyl-L-histidine methyl ester 
• 79950-65-5 N-[(1,1-dimethylethoxy)carbonyl]-3-[(phenylmethoxy)methyl]-L-histidine 
• 124017-72-7 1-methyl<2-(3)H>-L-histidine 
• 118891-68-2 N^α-Trityl-N^τ-methyl-L-histidin 
• 83471-81-2 (S)-2-Amino-3-{5-[5-((S)-2-amino-2-carboxy-ethyl)-3-methyl-3H-imidazol-4-yldisulfanyl]-1-methyl-1H-imidazol-4-yl}-propionic acid 
• 71-00-1 L-histidine 

Downstream Products

• 57519-09-2 (S)-methyl 2-amino-3-(1-methyl-1H-imidazol-4-yl)propanoate 
• 118891-68-2 N^α-Trityl-N^τ-methyl-L-histidin 

Relevant articles and documents

Immunomodulatory peptides

The invention relates to peptides derivatized with a hydrophilic polymer which, in some embodiments, bind to human FcRn and inhibit binding of the Fc portion of an IgG to an FcRn, thereby modulating serum IgG levels. The disclosed compositions and methods may be used in some embodiments, for example, in treating autoimmune diseases and inflammatory disorders. The invention also relates, in further embodiments, to methods of using and methods of making the peptides of the invention.

New regioselectivity in the cleavage of histidine-containing peptides by palladium(II) complexes studied by kinetic experiments and molecular dynamics simulations

Palladium(II) complexes promote hydrolytic cleavage of amide bonds in N- acetylhistidylglycine (AcHis-Gly), N-acetylhistidine (AcHis), and their derivatives methylated at the N-1 or N-3 atom of imidazole. Methylation controls coordination of imidazole to palladium(II) and allows stereochemical analysis of the reactions. The complex [PdCl4]2- regioselectively cleaves the amide bond involving the carboxylic group of histidine, the bond His- Gly; the rate constants of cleavage are virtually the same when the peptides coordinate to palladium(II) via the N-1 and the N-3 atom. The complex [Pd(H2O)4]2+ cleaves, at comparable rates, the amide bonds involving both the carboxylic (His-Gly) and the amino (AcHis) groups of histidine in the acetylated dipeptide. This unprecedented reactivity is examined by theoretical calculations in which molecular dynamics and solution of Poisson- Boltzmann equation are combined in a new way. When the Pd(H2O)32+ group is attached to the N-1 atom, both scissile bonds can be cleaved by internal delivery of aqua ligands. When the Pd(H2O)32+ group is attached to the N- 3 atom, both scissile bonds can be cleaved by internal delivery of aqua ligands and by external attack of water; in some conformers the two modes of cleavage may be combined in the reaction mechanism. In both N-1 and N-3 linkage isomers internal delivery seems to be assisted by weak hydrogen bonding. The rate constants for cleavage by [Pd(H2O)4]2+ are approximately 10 times greater than those for cleavage by [PdCl4]2-. This difference is explained semiquantitatively by consideration of the aquation equilibria involving [PdCl4]2-. This study shows that kinetics and regioselectivity of peptide cleavage may be controlled simply by choosing ligands in palladium(II) complexes. This is another step in our development of simple metal complexes as artificial metallopeptidases.

Regiospecific alkylation of histidine and histamine at N-1 (τ)

Series of 1-alkyl histidines and histamines have been synthesized by the alkylation of the corresponding 5,6,7,8-tetrahydro-5-oxomidazo[1,5-c]pyrimidines with alkyl halides in aprotic solvents. The method of conversion of the intermediate quaternary salt to the amino acid or amino depends on the nature of the alkyl group.

Metal ion - biomolecule interactions. Part 14. Methylmercury and hydrogen ion catalysis of C(2)-H isotopic exchange in 1-methylhistidine

The rate constants for detritiation from the C(2) position of 1-methyl-histidine have been determined in a series of aqueous buffers at 85 deg C.The resulting sigmoidal rate - pH profile was indicative of a mechanism involving hydroxide ion attack on the N(3)-protonated (4) and the amino protonated (5) forms of 1-methylhistidine, and dissection of the kinetic data allowed the extraction of the second-order rate constants for the two pathways, k and k'.The unusually large value of k' for a species not protonated at N(3) of the imidazole ring suggested the involvement of a kinetically eqiuvalent zwitterionic form of the substrate (7).Comparison of the rate constant k with values determined previously for closely related substrates, such as histidine, 1-methylimidazole, and imidazole, led to the use of FMO theory to explain the effect of the various structural changes, e.g., the effect of methylation and a positively charged side chain on k and k'.The addition of MeHgNO3 resulted in a decrease in the pseudo-first-order rate constant for detritiation.The rate retardation was discussed in terms of two mechanisms (Schemes 2 and 3).Analysis of the data in terms of the various metal-ion-coordinated species present under the experimental conditions showed that the reactivity of the protonated substrate greatly exceeds that of the metal-coordinated species.The difference in the catalytic ability of H(1+) vs.MeHg(1+) is discussed in terms of the extent of positive charge developed on the ligating heteroatom in the ylide (carbenoid) reaction intermediate. Keywordws: methylmercury; 1-methylhistidine; isotopic exchange; proton transfer; metal ion catalysis.

A Simple Preparation of Nτ-Methyl-L-histidine.

Nτ-Methyl-L-histidine is efficiently prepared in two steps starting from Nα-trityl-L-histidine.

The Differentiation of ?- and τ- Derivatised Histidines

Two simple methods of differentiating ?- and τ-derivatised histidines unambiguously are described.The first involves conversion into the two known im-methyl-L-histidines, which, to avoid all possible confusion arising from ambiguous nomenclature and previous work, have been correlated with N(α)-t-butyloxycarbonyl-N(?)-benzyloxymethyl-L-histidine, whose structure has been established by X-ray crystallography.The second method, which is appropriate for im-substituents of type RCH2-, involves the measurement of nuclear Overhauser effects.If the substituent is at the ?-position, the CH2 signal is enhanced if the low-field adjacent proton between the heterocyclic nitrogens is irradiated, but not if the high-field, more distant, ring proton is irradiated.If the substituent is at the τ-position, the CH2 signal is enhanced whichewer of the equidistant ring protons is irradiated.

ISOLATION AND STRUCTURE OF A NEW SULPHUR-CONTAINING AMINOACID FROM SEA URCHIN EGGS

Unfertilized sea urchin eggs (Paracentrotus lividus) contain, in addition to glutathione, a new low molecular weight thiol, 1-methyl-5-thiol-L-histidine (l) which was isolated and characterized as the disulphide 2 by spectral and chemical evidence.