368-16-1

Basic information

• Product Name: 3-METHYL-L-HISTIDINE N-HYDRATE
• Synonyms: 3-methylhistidine;3-METHYL-L-HISTIDINE N-HYDRATE;π-methyl-l-histidine;(2S)-2-amino-3-(3-methylimidazol-4-yl)propanoic acid;METHYL-L-HISTIDINE, 1-(RG);METHYL-L-HISTIDINE, 3-(RG);1-METHYL-L-HISTIDINE CRYSTALLINE;H-His(p-Me)-OH
• CAS NO: 368-16-1
• Molecular Formula: C₇H₁₁N₃O₂
• Molecular Weight: 187.2
• EINECS: 206-704-6
• Product Categories: Amino Acids;Chiral Compound;amino acid
• Mol File: 368-16-1.mol
• Article Data: 7

Chemical Properties

• Melting Point: 248～252℃
• Boiling Point: 298.47°C (rough estimate)
• Flash Point: 204.8 °C
• Appearance: /
• Density: 1.37
• Vapor Pressure: 1.25E-07mmHg at 25°C
• Refractive Index: 1.5950 (estimate)
• Storage Temp.: Store at RT.
• PKA: 2.04±0.10(Predicted)
• CAS DataBase Reference: 3-METHYL-L-HISTIDINE N-HYDRATE(CAS DataBase Reference)
• NIST Chemistry Reference: 3-METHYL-L-HISTIDINE N-HYDRATE(368-16-1)
• EPA Substance Registry System: 3-METHYL-L-HISTIDINE N-HYDRATE(368-16-1)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26-36
• WGK Germany: 3
• Hazardous Substances Data: 368-16-1(Hazardous Substances Data)

Usage

Description

3-METHYL-L-HISTIDINE N-HYDRATE is a L-histidine derivative that is L-histidine substituted by a methyl group at position 3 on the imidazole ring. It is a white to off-white powder in appearance.

Uses

Used in Pharmaceutical Industry:
3-METHYL-L-HISTIDINE N-HYDRATE is used as a pharmacological PPARα agonist for stimulating the ubiquitin proteasome pathway and myofibrillar protein breakdown in skeletal muscle of rodents. This application is particularly relevant in the development of treatments targeting muscle-related conditions and disorders.
Used in Research and Development:
3-METHYL-L-HISTIDINE N-HYDRATE serves as a valuable compound in the field of research and development, particularly in the study of histidine derivatives and their potential applications in various biological and medical contexts. Its unique structure allows researchers to explore its interactions with other molecules and its potential effects on cellular processes.

Biochem/physiol Actions

3-Methyl-L-histidine is a non-proteinogenic amino acid and an index of muscle breakdown.

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

Synthetic route

3-methyl-5-(phenylthio)-L-histidine (141524-71-2) → 3-methyl-L-histidine (368-16-1)

Conditions	Yield
With water; nickel In ethanol for 8h; Heating;	87%

3-methyl-5-(1-naphthalenylthio)-L-histidine (141524-84-7) → 3-methyl-L-histidine (368-16-1)

Conditions	Yield
With water; nickel In ethanol for 8h; Heating;	83%

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

Nα,Nα-phthaloyl-L-histidine-methyl ester (65092-36-6) + methyl iodide (74-88-4) → 3-methyl-L-histidine (368-16-1)

Conditions	Yield
With N,N-dimethyl-formamide und anschliessendes Erwaermen mit wss.HCl;

trimethoxonium tetrafluoroborate (420-37-1) + N(α)-benzyloxycarbonyl-N(τ)-(4-tolylsulphonyl)-L-histidine methyl ester (95485-21-5) → 3-methyl-L-histidine (368-16-1)

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

imbricatine (105372-70-1) → (1S,3S)-6,8-Dihydroxy-1-(4-hydroxy-benzyl)-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (105372-72-3, 133761-44-1) + 3-methyl-L-histidine (368-16-1)

Conditions	Yield
With nickel for 1h; Heating;	A 8 mg B n/a
With nickel for 1h; Heating;

N(α)-benzyloxycarbonyl-N(τ)-piperidinocarbonyl-L-histidine methyl ester (20793-93-5) + methyl iodide (74-88-4) → 3-methyl-L-histidine (368-16-1)

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

(S)-2-Benzyloxycarbonylamino-3-(1-tert-butoxymethyl-1H-imidazol-4-yl)-propionic acid methyl ester (99523-92-9) + methyl iodide (74-88-4) → 3-methyl-L-histidine (368-16-1)

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-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-methoxyethoxy)methyl-L-histidine methyl ester (99523-89-4) + methyl iodide (74-88-4) → 3-methyl-L-histidine (368-16-1)

Conditions	Yield
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-acetyl-N3-methyl-L-histidine (37841-04-6) → 3-methyl-L-histidine (368-16-1)

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

aneserine → 3-methyl-L-histidine (368-16-1)

Conditions	Yield
With sulfuric acid; water

1-methyl-4-bromo-5-hydroxymethyl-1H-imidazole (141524-73-4) → 3-methyl-L-histidine (368-16-1)

Conditions	Yield
Multi-step reaction with 8 steps 1: 96 percent / active γ-MnO2 / CHCl3 / 1 h / Heating 2: 83 percent / NaH / dimethylformamide / 3 h / 100 °C 3: 97 percent / NaBH4 / methanol / 0.33 h / Ambient temperature 4: 98 percent / SOCl2 / 1.) 0 deg C, 30 min, 2.) RT, 30 min 5: 1.) butyllithium / 1.) hexane, THF, -78 deg C, 10 min, 2.)a) hexane, THF, -78 deg C, 1 h, b) -50 deg C, 20 h 6: 84 percent / 0.25 N aq. HCl / methanol / 1.5 h / Ambient temperature 7: 86 percent / 6 N aq. HCl / 1 h / Heating 8: 83 percent / H2O / Raney Ni / ethanol / 8 h / Heating View Scheme
Multi-step reaction with 8 steps 1: 96 percent / active γ-MnO2 / CHCl3 / 1 h / Heating 2: 73 percent / NaH / dimethylformamide / 3 h / 120 °C 3: 97 percent / NaBH4 / methanol / 0.5 h / Ambient temperature 4: 97 percent / SOCl2 / 1.) 0 deg C, 30 min, 2.) RT, 30 min 5: 1.) butyllithium / 1.) hexane, THF, -78 deg C, 15 min, 2.)a) hexane, THF, -78 deg C, 1 h, b) -50 deg C, 18 h 6: 98 percent / 0.25 N aq. HCl / methanol / 1.5 h / Ambient temperature 7: 83 percent / 6 N aq. HCl / 1 h / Heating 8: 87 percent / H2O / Raney Ni / ethanol / 8 h / Heating View Scheme

4-bromo-1-methyl-1H-imidazole-5-carbaldehyde (141524-74-5) → 3-methyl-L-histidine (368-16-1)

Conditions	Yield
Multi-step reaction with 7 steps 1: 83 percent / NaH / dimethylformamide / 3 h / 100 °C 2: 97 percent / NaBH4 / methanol / 0.33 h / Ambient temperature 3: 98 percent / SOCl2 / 1.) 0 deg C, 30 min, 2.) RT, 30 min 4: 1.) butyllithium / 1.) hexane, THF, -78 deg C, 10 min, 2.)a) hexane, THF, -78 deg C, 1 h, b) -50 deg C, 20 h 5: 84 percent / 0.25 N aq. HCl / methanol / 1.5 h / Ambient temperature 6: 86 percent / 6 N aq. HCl / 1 h / Heating 7: 83 percent / H2O / Raney Ni / ethanol / 8 h / Heating View Scheme
Multi-step reaction with 7 steps 1: 73 percent / NaH / dimethylformamide / 3 h / 120 °C 2: 97 percent / NaBH4 / methanol / 0.5 h / Ambient temperature 3: 97 percent / SOCl2 / 1.) 0 deg C, 30 min, 2.) RT, 30 min 4: 1.) butyllithium / 1.) hexane, THF, -78 deg C, 15 min, 2.)a) hexane, THF, -78 deg C, 1 h, b) -50 deg C, 18 h 5: 98 percent / 0.25 N aq. HCl / methanol / 1.5 h / Ambient temperature 6: 83 percent / 6 N aq. HCl / 1 h / Heating 7: 87 percent / H2O / Raney Ni / ethanol / 8 h / Heating View Scheme

1-methyl-4-(phenylthio)-1H-imidazole-5-methanol (141524-76-7) → 3-methyl-L-histidine (368-16-1)

Conditions	Yield
Multi-step reaction with 5 steps 1: 97 percent / SOCl2 / 1.) 0 deg C, 30 min, 2.) RT, 30 min 2: 1.) butyllithium / 1.) hexane, THF, -78 deg C, 15 min, 2.)a) hexane, THF, -78 deg C, 1 h, b) -50 deg C, 18 h 3: 98 percent / 0.25 N aq. HCl / methanol / 1.5 h / Ambient temperature 4: 83 percent / 6 N aq. HCl / 1 h / Heating 5: 87 percent / H2O / Raney Ni / ethanol / 8 h / Heating View Scheme

1-methyl-4-(phenylthio)-1H-imidazole-5-carbaldehyde (141524-75-6) → 3-methyl-L-histidine (368-16-1)

Conditions

Yield

Multi-step reaction with 6 steps 1: 97 percent / NaBH4 / methanol / 0.5 h / Ambient temperature 2: 97 percent / SOCl2 / 1.) 0 deg C, 30 min, 2.) RT, 30 min 3: 1.) butyllithium / 1.) hexane, THF, -78 deg C, 15 min, 2.)a) hexane, THF, -78 deg C, 1 h, b) -50 deg C, 18 h 4: 98 percent / 0.25 N aq. HCl / methanol / 1.5 h / Ambient temperature 5: 83 percent / 6 N aq. HCl / 1 h / Heating 6: 87 percent / H2O / Raney Ni / ethanol / 8 h / Heating View Scheme

1-methyl-4-(1-naphthalenylthio)-1H-imidazole-5-methanol (141524-80-3) → 3-methyl-L-histidine (368-16-1)

Conditions	Yield
Multi-step reaction with 5 steps 1: 98 percent / SOCl2 / 1.) 0 deg C, 30 min, 2.) RT, 30 min 2: 1.) butyllithium / 1.) hexane, THF, -78 deg C, 10 min, 2.)a) hexane, THF, -78 deg C, 1 h, b) -50 deg C, 20 h 3: 84 percent / 0.25 N aq. HCl / methanol / 1.5 h / Ambient temperature 4: 86 percent / 6 N aq. HCl / 1 h / Heating 5: 83 percent / H2O / Raney Ni / ethanol / 8 h / Heating View Scheme

1-methyl-4-(1-naphthalenylthio)-1H-imidazole-5-carbaldehyde (141524-61-0) → 3-methyl-L-histidine (368-16-1)

Conditions

Yield

Multi-step reaction with 6 steps 1: 97 percent / NaBH4 / methanol / 0.33 h / Ambient temperature 2: 98 percent / SOCl2 / 1.) 0 deg C, 30 min, 2.) RT, 30 min 3: 1.) butyllithium / 1.) hexane, THF, -78 deg C, 10 min, 2.)a) hexane, THF, -78 deg C, 1 h, b) -50 deg C, 20 h 4: 84 percent / 0.25 N aq. HCl / methanol / 1.5 h / Ambient temperature 5: 86 percent / 6 N aq. HCl / 1 h / Heating 6: 83 percent / H2O / Raney Ni / ethanol / 8 h / Heating View Scheme

3-methyl-5-(phenylthio)-L-histidine methyl ester (141524-79-0) → 3-methyl-L-histidine (368-16-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 83 percent / 6 N aq. HCl / 1 h / Heating 2: 87 percent / H2O / Raney Ni / ethanol / 8 h / Heating View Scheme

3-methyl-5-(1-naphthalenylthio)-L-histidine methyl ester (141524-83-6) → 3-methyl-L-histidine (368-16-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 86 percent / 6 N aq. HCl / 1 h / Heating 2: 83 percent / H2O / Raney Ni / ethanol / 8 h / Heating View Scheme

5-(chloromethyl)-1-methyl-4-(phenylthio)-1H-imidazole hydrochloride → 3-methyl-L-histidine (368-16-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) butyllithium / 1.) hexane, THF, -78 deg C, 15 min, 2.)a) hexane, THF, -78 deg C, 1 h, b) -50 deg C, 18 h 2: 98 percent / 0.25 N aq. HCl / methanol / 1.5 h / Ambient temperature 3: 83 percent / 6 N aq. HCl / 1 h / Heating 4: 87 percent / H2O / Raney Ni / ethanol / 8 h / Heating View Scheme

5-(chloromethyl)-1-methyl-4-(1-naphthalenylthio)-1H-imidazole hydrochloride → 3-methyl-L-histidine (368-16-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) butyllithium / 1.) hexane, THF, -78 deg C, 10 min, 2.)a) hexane, THF, -78 deg C, 1 h, b) -50 deg C, 20 h 2: 84 percent / 0.25 N aq. HCl / methanol / 1.5 h / Ambient temperature 3: 86 percent / 6 N aq. HCl / 1 h / Heating 4: 83 percent / H2O / Raney Ni / ethanol / 8 h / Heating View Scheme

(2R-trans)-2,5-dihydro-3,6-dimethoxy-2-(1-methylethyl)-5-<<1-methyl-4-(phenylthio)-1H-imidazol-5-yl>methyl>pyrazine (141524-78-9) → 3-methyl-L-histidine (368-16-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: 98 percent / 0.25 N aq. HCl / methanol / 1.5 h / Ambient temperature 2: 83 percent / 6 N aq. HCl / 1 h / Heating 3: 87 percent / H2O / Raney Ni / ethanol / 8 h / Heating View Scheme

(2R-trans)-2,5-dihydro-3,6-dimethoxy-2-(1-methylethyl)-5-<<1-methyl-4-(1-naphthalenylthio)-1H-imidazol-5-yl>methyl>pyrazine (141524-82-5) → 3-methyl-L-histidine (368-16-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: 84 percent / 0.25 N aq. HCl / methanol / 1.5 h / Ambient temperature 2: 86 percent / 6 N aq. HCl / 1 h / Heating 3: 83 percent / H2O / Raney Ni / ethanol / 8 h / Heating View Scheme

Z-His-OMe (15545-10-5) → 3-methyl-L-histidine (368-16-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 39 percent / triethylamine / benzene / 2 h / Heating 2: 2.) 'constant boiling' hydrochloric acid / 1.) (DMF), 24 h, room temp., 2.) reflux, 24 h View Scheme
Multi-step reaction with 2 steps 1: 70 percent / pyridine / 24 h / Ambient temperature 2: 2.) 'constant boiling' hydrochloric acid / 1.) methylene dichloride, 24 h, room temp., 2.) reflux, 24 h View Scheme
Multi-step reaction with 2 steps 1: 32 percent / triethylamine / CH2Cl2 / 2 h / Ambient temperature View Scheme
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-Histidine methyl ester (1499-46-3) → 3-methyl-L-histidine (368-16-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: methanol / und anschliessendes Behandeln mit SOCl2 in Benzol 2: DMF / und anschliessendes Erwaermen mit wss.HCl View Scheme

3-methyl-L-histidine (368-16-1) → [αR-3H]-Nτ-methylhistamine (1205535-88-1)

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;	81%

3-methyl-L-histidine (368-16-1) → [αR-2H]-Nτ-methylhistamine (1205535-87-0)

Conditions	Yield
With histidine decarboxylase; pyridoxal 5'-phosphate; water-d2 at 37℃; for 192h; pH=4.7; aq. phosphate buffer; Enzymatic reaction;	66%

3-methyl-L-histidine (368-16-1) + 3-(tert-butyloxycarbonyl)-4,5-dihydro-1,3-oxazine-2,6-dione (357610-30-1) → C15H24N4O5

Conditions	Yield
With sodium hydroxide In water at 0 - 10℃; for 0.5h; Solvent; Reagent/catalyst;	65%

methanol (67-56-1) + toluene-4-sulfonic acid (104-15-4) + 3-methyl-L-histidine (368-16-1) → 2-amino-3-(3-methyl-3H-imidazol-4-yl)-propionic acid methyl ester; compound with toluene-4-sulfonic acid

Conditions	Yield
for 24h; Heating;	45%

bufotalin 3-hemisuberate p-nitrophenyl ester (61507-75-3) + 3-methyl-L-histidine (368-16-1) → bufotalin 3-suberoyl-L-1-methylhistidine ester (95210-87-0)

Conditions	Yield
In pyridine; water for 12h; Ambient temperature;	16 mg

[13C]-formaldehyde (3228-27-1) + 3-methyl-L-histidine (368-16-1) → C7(13)C2H15N3O2

Conditions	Yield
With sodium cyanoborohydride In acetate buffer at 37℃; for 0.166667h; pH=5.3;

paraformaldehyde-d2 (1664-98-8) + 3-methyl-L-histidine (368-16-1) → C9H11(2)H4N3O2

Conditions	Yield
With sodium cyanoborohydride In acetate buffer at 37℃; for 0.166667h; pH=5.3;

formaldehyd (50-00-0) + 3-methyl-L-histidine (368-16-1) → C9H15N3O2

Conditions	Yield
With sodium cyanoborohydride In acetate buffer at 37℃; for 0.166667h; pH=5.3;

Upstream product

• 71-00-1 L-histidine 
• 74-88-4 methyl iodide 
• 65092-36-6 N^α,N^α-phthaloyl-L-histidine-methyl ester 
• 420-37-1 trimethoxonium tetrafluoroborate 
• 95485-21-5 N(α)-benzyloxycarbonyl-N(τ)-(4-tolylsulphonyl)-L-histidine methyl ester 
• 105372-70-1 imbricatine 
• 20793-93-5 N(α)-benzyloxycarbonyl-N(τ)-piperidinocarbonyl-L-histidine methyl ester 
• 99523-92-9 (S)-2-Benzyloxycarbonylamino-3-(1-tert-butoxymethyl-1H-imidazol-4-yl)-propionic acid methyl ester 
• 90653-43-3 N(α)-benzyloxycarbonyl-N(?)-t-butoxymethyl-L-histidine methyl ester 
• 99523-90-7 N(α)-benzyloxycarbonyl-N(?)-(2-trimethylsilylethoxy)methyl-L-histidine methyl ester 
• 99523-89-4 N(α)-benzyloxycarbonyl-N(τ)-(2-methoxyethoxy)methyl-L-histidine methyl ester 
• 99523-91-8 N(α)-benzyloxycarbonyl-N(τ)-(2-trimethylsilylethoxy)methyl-L-histidine methyl ester 
• 141524-71-2 3-methyl-5-(phenylthio)-L-histidine 
• 141524-84-7 3-methyl-5-(1-naphthalenylthio)-L-histidine 

Downstream Products

• 584-85-0 L-anserine 
• 37841-04-6 N-acetyl-N³-methyl-L-histidine 
• 118891-69-3 (S)-3-(3-Methyl-3H-imidazol-4-yl)-2-(trityl-amino)-propionic acid 

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