7554-65-6

Hazards Identification

Pictogram(s):

Signal:

Danger

GHS Hazard Statements:

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]
H312 (66.18%): Harmful in contact with skin [Warning Acute toxicity, dermal]
H314 (66.18%): Causes severe skin burns and eye damage [Danger Skin corrosion/irritation]
H315 (33.82%): Causes skin irritation [Warning Skin corrosion/irritation]
H318 (66.18%): Causes serious eye damage [Danger Serious eye damage/eye irritation]
H319 (33.82%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]
H335 (61.76%): May cause respiratory irritation [Warning Specific target organ toxicity, single exposure; Respiratory tract irritation]

Precautionary Statement Codes:

P260, P261, P264, P264+P265, P270, P271, P280, P301+P317, P301+P330+P331, P302+P352, P302+P361+P354, P304+P340, P305+P351+P338, P305+P354+P338, P316, P317, P319, P321, P330, P332+P317, P337+P317, P362+P364, P363, P403+P233, P405, and P501

Hazard Classes and Categories:

Acute Tox. 4 (100%)
Acute Tox. 4 (66.18%)
Skin Corr. 1C (66.18%)
Skin Irrit. 2 (33.82%)
Eye Dam. 1 (66.18%)
Eye Irrit. 2 (33.82%)
STOT SE 3 (61.76%)

Usage

Uses

Used in Antidote Applications:
4-Methylpyrazole is used as an antidote for methanol and ethylene glycol poisoning. It functions as an alcohol dehydrogenase inhibitor, preventing the formation of toxic metabolites responsible for severe metabolic acidosis and renal failure. In limited human studies, it has been shown to reverse the toxicity of potentially lethal doses of ethylene glycol.
Used in Pharmaceutical Industry:
4-Methylpyrazole is used as a reactant to prepare 4-methyl-1-phenyl-1H-pyrazole by reacting with bromobenzene via N-arylation using a copper catalyst. It is also used as a starting material for the synthesis of 4-methyl-3(5)-nitropyrazole by nitration.
Used in Chemical Research:
4-Methylpyrazole serves as a ligand in the preparation of gallium(III) complex of 4-methylpyrazole, which has potential applications as an antitumor and antiviral agent.
Brand Name:
The brand name for 4-Methylpyrazole is Antizol, which is marketed by Jazz Pharmaceuticals.

Originator

Orphan Medical (US)

Manufacturing Process

Preparation of 4-methylpyrazole 1.0 g (6.67 mmol) of sodium iodide is added to a suspension of 560 g (4.0 mol) of 70% strength sulfuric acid and 62.5 g (1.0 mol) of 80% strength hydrazine hydrate and, at 125°C, 86.4 g (1.2 mol) of isobutyraldehyde are pumped under the surface of the suspension over the course of 2 hours using a metering pump. During and up to 100 min after the addition of isobutyraldehyde, a total of 175 g of water was distilled out, with the temperature of the mixture rising to 135°C. The solution is cooled and adjusted to pH 8.6 with 820 g (5.125 mol) of 25% strength sodium isobutyraldehyde hydroxide solution and is extracted with isobutanol. The combined extracts are concentrated to 82 g in a rotary evaporator and then distilled. The main fraction (boiling point 82°C/7 mbar; 49 g) consists of 82% 4-methylpyrazole. Yield: 49% of theory.

Biochem/physiol Actions

Alcohol dehydrogenase inhibitor.

InChI:InChI=1/C4H6N2/c1-4-2-5-6-3-4/h2-3H,1H3,(H,5,6)

Synthetic route

1,1,3,3-tetraethoxy-2-methyl-propane (10602-37-6) → 4-methyl-1H-pyrazole (7554-65-6)

Conditions	Yield
Stage #1: 1,1,3,3-tetraethoxy-2-methyl-propane With hydrazinium sulfate In water at 80℃; for 3h; Stage #2: With sodium hydroxide In water at 3 - 30℃; pH=4 - 6; Stage #3: With sodium hydrogencarbonate In water at 27 - 30℃; pH=7;	84%
Stage #1: 1,1,3,3-tetraethoxy-2-methyl-propane With hydrazinium sulfate In water at 80℃; for 3h; Stage #2: With sodium hydroxide In water at 3 - 30℃; pH=4 - 6; Stage #3: With sodium hydrogencarbonate In water at 27℃; pH=7;	84%

4-Methyl-5-trimethylsilanyl-1H-pyrazole → 4-methyl-1H-pyrazole (7554-65-6)

Conditions	Yield
With potassium hydroxide In ethanol for 1h; Heating;	68%

4-methyl-1H-pyrazole-3,5-dicarboxylic acid (99968-85-1) → 4-methyl-1H-pyrazole (7554-65-6)

Conditions	Yield
bei der trocknen Destillation des Silbersalzes;

4-methyl-1H-pyrazole-3-carboxylic acid (82231-51-4) → 4-methyl-1H-pyrazole (7554-65-6)

Conditions	Yield
With soda lime Beim Destillieren;

C6H10N2O2 → 4-methyl-1H-pyrazole (7554-65-6) + methallyl acetate (820-71-3)

Conditions	Yield
With calcium carbonate In 1,4-dioxane at 85 - 110℃; Yield given;
With calcium carbonate In 1,4-dioxane at 85 - 110℃; Yields of byproduct given;

C12H14N2O2 → 4-methyl-1H-pyrazole (7554-65-6) + 2-methyl-2-propen-1-yl phenylacetate (128863-93-4)

Conditions	Yield
With calcium carbonate In 1,4-dioxane at 85 - 110℃; Yield given. Yields of byproduct given;

(+-)-α,β-dibromo-isobutyraldehyde → 4-methyl-1H-pyrazole (7554-65-6)

Conditions	Yield
With ethanol; hydrazine hydrate

4-methyl-1H-pyrazole-3-carboxylic acid (82231-51-4) + soda lime → 4-methyl-1H-pyrazole (7554-65-6)

formamide (77287-34-4, 77287-35-5, 60100-09-6) + 3-amino-2-methyl acrolein (30989-81-2) → 4-methyl-1H-pyrazole (7554-65-6)

Conditions	Yield
With tetrabutyl-ammonium chloride In water at 20 - 80℃; for 4h; Reagent/catalyst; Temperature;	82 g

4-methyl-1H-pyrazole (7554-65-6) → 1,4-dimethyl-1H-pyrazole (1072-68-0)

Conditions	Yield
	100%
	92.1%
phosphoric acid	68%
With sodium hydroxide; dimethyl sulfate
With sulfuric acid In methanol

4-methyl-1H-pyrazole (7554-65-6) + di-tert-butyl dicarbonate (24424-99-5) → 4-methylpyrazole-1-carboxylic acid tert-butyl ester (121669-69-0)

Conditions	Yield
With dmap In acetonitrile for 1h;	100%
With dmap In dichloromethane at 20℃; for 1h;	93%
With dmap In acetonitrile at 20℃;	84%

4-methyl-1H-pyrazole (7554-65-6) + 4'-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-fluoro-[1,1'-biphenyl]-2-carbonitrile → 4'-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(4-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-2-carbonitrile

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 18h; Sealed tube;	100%

4-methyl-1H-pyrazole (7554-65-6) + copper(II) choride dihydrate + tetrabutyl-ammonium chloride (1112-67-0) → [N(n-C4H9)4]2[Cu3(μ3-Cl)2(μ-4-methylpyrazolato)3Cl3]

Conditions	Yield
With NaOH In dichloromethane byproducts: NaCl; stirring of equimolar amts. of CuCl2*2H2O, 4-methylpyrazole, NaOH and N(C4H9)4Cl in CH2Cl2 for 12 h at ambient temp.; filtration, treatment with Et2O, filtration, washing with Et2O, recrystn. from CH2Cl2/Et2O; elem. anal.;	99%

4-methyl-1H-pyrazole (7554-65-6) + cyclohexylallene (5664-17-5) → (R)-1-(1-cyclohexylallyl)-4-methyl-1H-pyrazole

Conditions	Yield
With chloro(1,5-cyclooctadiene)rhodium(I) dimer; JoSPOPhos SL-J688-2; pyridinium p-toluenesulfonate In toluene at 80℃; for 16h; Inert atmosphere; Schlenk technique; Sealed tube; enantioselective reaction;	99%

4-methyl-1H-pyrazole (7554-65-6) + iodobenzene (591-50-4) → 4-methyl-1-phenyl-1H-pyrazole (14766-43-9)

Conditions	Yield
With hydroxybenzaldoxime; copper(I) oxide In acetonitrile at 82℃; for 24h;	98%

3,4-dihydro-2H-pyran (110-87-2) + 4-methyl-1H-pyrazole (7554-65-6) → 4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (1174132-49-0)

Conditions	Yield
With pyridinium p-toluenesulfonate In dichloromethane; toluene at 55℃; for 16h;	98%
With pyridinium p-toluenesulfonate In dichloromethane at 55℃; for 12h;	61%
With trifluoroacetic acid In toluene at 80℃; Large scale;

4-methyl-1H-pyrazole (7554-65-6) + 1,2,4,5-tetrafluoro-3-(1H-indol-1-yl)benzene (1448803-95-9) → 1-(2,3,5,6-tetrakis(4-methyl-1H-pyrazol-1-yl)phenyl)-1H-indole (1610894-52-4)

Conditions	Yield
With sodium t-butanolate In N,N-dimethyl acetamide at 20℃; for 24h;	98%

4-methyl-1H-pyrazole (7554-65-6) + (E)-2-(prop-1-en-1-yl)-1-tosylbenzimidazole → (S)-2-(2-(4-methylpyrazol-1-yl)propyl)-1-tosylbenzimidazole

Conditions	Yield
Stage #1: (E)-2-(prop-1-en-1-yl)-1-tosylbenzimidazole With (R)-3,3'-bis(9-anthracenyl)-1,1'-binaphthyl-2,2'-diyl hydrogenphosphate In tetrahydrofuran at -40℃; for 0.166667h; Michael Addition; Inert atmosphere; Stage #2: 4-methyl-1H-pyrazole In tetrahydrofuran at -40℃; for 48h; Michael Addition; Inert atmosphere; enantioselective reaction;	98%

4-methyl-1H-pyrazole (7554-65-6) + 2-phenyl-2H-indazole (3682-71-1) → 3-(4-methyl-1H-pyrazol-1-yl)-2-phenyl-2H-indazole

Conditions	Yield
With dipotassium peroxodisulfate In acetonitrile at 80℃; for 5h; Schlenk technique; regioselective reaction;	98%

4-methyl-1H-pyrazole (7554-65-6) + 2-bromo-pyridine (109-04-6) → 2-(4-methyl-1H-pyrazol-1-yl)pyridine

Conditions	Yield
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 120℃; for 24h; Inert atmosphere;	98%

4-methyl-1H-pyrazole (7554-65-6) + 1-(2,3,5,6-tetrafluorophenyl)-1H-benzo[d]imidazole (1448804-06-5) → 1-(2,3,5,6-tetrakis(4-methyl-1H-pyrazol-1-yl)phenyl)-1H-benzo[d]imidazole (1610894-50-2)

Conditions	Yield
With sodium t-butanolate In N,N-dimethyl acetamide at 20℃; for 24h;	97%

4-methyl-1H-pyrazole (7554-65-6) → 4-methyl-3-nitro-1H-pyrazole (38858-90-1)

Conditions	Yield
With silica-sulfuric acid impregnated with bismuth nitrate In tetrahydrofuran at 20℃; for 6h; Reagent/catalyst; Green chemistry;	96%
With bismuth(III) nitrate In tetrahydrofuran at 20℃; for 3.5h;	84%
With sulfuric acid; nitric acid at 30 - 105℃; for 2h;	55%
With sulfuric acid; nitric acid at 100℃; for 2h;	20 %Spectr.

4-methyl-1H-pyrazole (7554-65-6) + 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2) → 1,3,7-trimethyl-4,5,8-tris(4-methyl-1H-pyrazol-1-yl)-3,4,5,7-tetrahydro-1H-purine-2,6-dione

Conditions	Yield
With tetrabutylammonium tetrafluoroborate In acetonitrile at 45℃; for 10h; Inert atmosphere; Electrochemical reaction; Green chemistry; diastereoselective reaction;	96%

4-methyl-1H-pyrazole (7554-65-6) + 1-(5-fluoro-2-nitrophenyl)piperidine (854044-35-2) → 1-[5-(4-methyl-pyrazol-1-yl)-2-nitro-phenyl]-piperidine (885704-59-6)

Conditions	Yield
With sodium hydroxide In dimethyl sulfoxide at 90℃;	95%

4-methyl-1H-pyrazole (7554-65-6) + aniline (62-53-3) → 4-methyl-1-phenyl-1H-pyrazole (14766-43-9)

Conditions	Yield
Stage #1: aniline With tert.-butylnitrite; acetic acid In methanol at 0℃; for 0.5h; Schlenk technique; Inert atmosphere; Stage #2: 4-methyl-1H-pyrazole With copper diacetate In methanol at 0 - 20℃; for 14h; Schlenk technique; Inert atmosphere;	95%

4-methyl-1H-pyrazole (7554-65-6) + copper(II) choride dihydrate → trans-[CuCl2{4-(CH3)-(C3H3N2)}2]

Conditions	Yield
In water Sealed tube;	95%

4-methyl-1H-pyrazole (7554-65-6) + ethyl 4-chloro-6-methoxyquinolin-3-carboxylate (22931-71-1) → ethyl 6-methoxy-4-(4-methyl-1H-pyrazol-1-yl)quinoline-3-carboxylate

Conditions	Yield
With potassium carbonate In dimethyl sulfoxide at 100℃; for 2h; Sealed tube; Microwave irradiation;	95%

4-methyl-1H-pyrazole (7554-65-6) + phosgene (75-44-5) → bis(4-methylpyrazol-1-yl)ketone (1401660-67-0)

Conditions	Yield
With triethylamine In diethyl ether; toluene at 0℃; for 1h;	94%

4-methyl-1H-pyrazole (7554-65-6) + 9-(2,3,5,6-tetrafluorophenyl)-9H-carbazole (1035347-03-5) → 9-(2,3,5,6-tetrakis(4-methyl-1H-pyrazol-1-yl)phenyl)-9H-carbazole (1610894-53-5)

Conditions	Yield
With sodium t-butanolate In N,N-dimethyl acetamide at 20℃; for 24h;	94%

4-methyl-1H-pyrazole (7554-65-6) + C13H15NO2 (247043-64-7) → N-(3-(4-methyl-1H-pyrazol-1-yl)hexanoyl)benzamide

Conditions	Yield
With lithium chloride In acetonitrile for 9h; Schlenk technique; Reflux;	93%

4-methyl-1H-pyrazole (7554-65-6) + 2-bromo-5-methoxybenzyl bromide (19614-12-1) → 1-(2-bromo-5-methoxybenzyl)-4-methyl-1H-pyrazole (1252590-76-3)

Conditions	Yield
Stage #1: 2-bromo-5-methoxybenzyl bromide With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.5h; Stage #2: 4-methyl-1H-pyrazole In tetrahydrofuran; mineral oil at 20℃; for 12h;	92%

4-methyl-1H-pyrazole (7554-65-6) + 2-bromo-1-(bromomethyl)-3-methylbenzene (66790-58-7) → 1-(2-bromo-3-methylbenzyl)-4-methyl-1H-pyrazole (1252590-77-4)

Conditions	Yield
Stage #1: 2-bromo-1-(bromomethyl)-3-methylbenzene With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.5h; Stage #2: 4-methyl-1H-pyrazole In tetrahydrofuran; mineral oil at 20℃; for 12h;	92%

4-methyl-1H-pyrazole (7554-65-6) + 1-(2,3,5,6-tetrafluorophenyl)-1H-pyrazole (1262133-94-7) → 1,1',1'',1'''-(3-(1H-pyrazol-1-yl)benzene-1,2,4,5-tetrayl)tetrakis(4-methyl-1H-pyrazole) (1610894-51-3)

Conditions	Yield
With sodium t-butanolate In N,N-dimethyl acetamide at 20℃; for 24h;	92%

4-methyl-1H-pyrazole (7554-65-6) + para-nitrophenyl bromide (586-78-7) → 4-methyl-1-(4-nitrophenyl)-1H-pyrazole (13808-73-6)

Conditions	Yield
With C31H28NO6PPdS; caesium carbonate In water at 90℃; for 24h; Schlenk technique; Inert atmosphere;	92%
With potassium tert-butylate In dimethylsulfoxide-d6 at 60℃; for 5h;	80%

4-methyl-1H-pyrazole (7554-65-6) + dimethylamino sulfonyl chloride (13360-57-1) → N,N,4-trimethyl-1H-pyrazole-1-sulfonamide

Conditions	Yield
With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere;	92%

4-methyl-1H-pyrazole (7554-65-6) + trifluoromethyl trifluorovinyl ether (1187-93-5) → 4-methyl-1-[1,1,2-trifluoro-2-(trifluoromethoxy)ethyl]-1H-pyrazole

Conditions	Yield
Stage #1: 4-methyl-1H-pyrazole With sodium hydride In melt; mineral oil for 0.0833333h; Inert atmosphere; Stage #2: trifluoromethyl trifluorovinyl ether In melt; mineral oil	92%

Upstream product

• 99968-85-1 4-methyl-1H-pyrazole-3,5-dicarboxylic acid 
• 82231-51-4 4-methyl-1H-pyrazole-3-carboxylic acid 
• 77287-34-4 formamide 
• 30989-81-2 3-amino-2-methyl acrolein 
• 10602-37-6 1,1,3,3-tetraethoxy-2-methyl-propane 

Downstream Products

• 1072-68-0 1,4-dimethyl-1H-pyrazole 
• 37718-11-9 1H-pyrazole-4-carboxylic acid 
• 24086-18-8 3-iodo-4-methyl-1H-pyrazole 
• 138679-49-9 dihydro-5-[(4-methyl-1H-pyrazol-1-yl)methyl]-3,3-diphenyl-2(3H)-furanone 
• 172800-57-6 2,6-di{4-methylpyrazol-1-yl}pyridine 
• 121669-69-0 tert-butyl 4-methyl-1H-pyrazole-1-carboxylate 
• 220460-93-5 [2-chloro-4-(4-methyl-pyrazol-1-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone 
• 146456-97-5 4-methyl-1H-pyrazole-1-ylmethanol 
• 475578-45-1 [(Pt(CH2C6H4P(o-tolyl)2-κC,P)(μ-4-methylpyrazole))2] 

Relevant academic research and scientific papers

4-methylpyrazole preparation method

The invention discloses a 4-methylpyrazole preparation method. According to the preparation method, 3-amino-2-methylacrolein and formamide are utilized as main raw materials, methylbenzene is utilized as solvent, 4-methylpyrazole is prepared through normal-pressure reaction, and a 4-methylpyrazole finished product can be prepared by rectifying a crude product. The preparation method is simple, has moderate reaction conditions and avoids high-pressure reaction; the main raw materials are safe and environment-friendly; the product has high purity and is more favorable for industrial production.

ULTRAPURE 4-METHYLPYRAZOLE

Disclosed is an ultrapure 4-methylpyrazole containing less than 0.1% pyrazole and containing less than 10 ppm each of hydrazine and nitrobenzaldehyde. The ultrapure 4-methylpyrazole is prepared by a novel process so that less than 0.01% of ethylvinyl ether is present.

ULTRAPURE 4-METHYLPYRAZOLE

Disclosed is an ultrapure 4-methylpyrazole containing less than 0.1% pyrazole and containing less than 10 ppm each of hydrazine and nitrobenzaldehyde. The ultrapure 4-methylpyrazole is prepared by a novel process so that less than 0.01% of ethylvinyl ether is present.

Method for producing substituted pyrazoles

Pyrazole derivatives are prepared by reacting carbonyl compounds R1—C(O)—CH(R2)—CH2R3with hydrazine, its hydrate or its salts in 30 to 100% by weight sulfuric acid in the presence of catalytic amounts of iodine or of an iodine compound.

Preparation of pyrazole and its derivatives

A process for preparing pyrazole and its derivatives of the formula I STR1 where R1, R2, R3 and R4 are each hydrogen, halogen, nitro, carboxyl, sulfonyl or C-organic radicals, from alpha,beta-unsaturated carbonyl compounds of the formula II STR2 and hydrazine or hydrazine derivatives of the formula III wherein, initially without additional diluent, an alpha,beta-unsaturated carbonyl compound of the formula II is reacted with hydrazine or a hydrazine derivative of the formula III, and the resulting reaction mixture is reacted in another step with a mixture of sulfuric acid and iodine or a compound which liberates iodine or hydrogen iodide.

THE NITROGENATED ALLYLIC SYSTEM AS AN INTRAMOLECULAR NUCLEOPHILE: A NEW ROUTE TO PYRAZOLES

A new route to pyrazoles via the cyclization of N-allyl-N-nitrosoamides is described.

NEW METHODS AND REAGENTS IN ORGANIC SYNTHESIS. 41. LITHIUM TRIMETHYLSILYLDIAZOMETHANE. A NEW SYNTHON FOR THE PREPARATION OF PYRAZOLES FROM α,β-UNSATURATED NITRILES

Lithium trimethylsilyldiazomethane reacts smoothly with various α,β-unsaturated nitriles to give 3(or 5)-trimethylsilylpyrazoles in good yields.