58909-39-0

Basic information

• Product Name: Tetrahydro-2-methyl-3-thioxo-1,2,4-triazine-5,6-dione
• Synonyms: 2,5-Dihydro-6-hydroxy-3-mercapto-2-methyl-1,2,4-triazine-5-one;2-AMINOPROPYL-4(7)-AZO-BENZIMIDAZOLE;TTZ,TTA,OHMMT;Thiotriazinone(TTZ);3-MERCAPTO-2-METHYL-5-OXO-6-HYDROXY-1,2,4-TRIAZINE[TTZ,OHMMT];2,5-DIHYDRO-3-MERCAPTO-2-METHYL-5-OXO-6-HYDROXY-1,2,4-TRIAZINE;Thiotriazinone, 98+%;2,5-DIHYDRO-3-MERCAPTO-2-METHYL-5-OXO-6-HYDROXY-1,2,4-TRIAZINE/TTZ
• CAS NO: 58909-39-0
• Molecular Formula: C₄H₅N₃O₂S
• Molecular Weight: 159.17
• EINECS: 261-490-1
• Product Categories: Building Blocks;Heterocyclic Building Blocks;Triazines;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Sulfur & Selenium Compounds
• Mol File: 58909-39-0.mol
• Article Data: 6

Chemical Properties

• Melting Point: 168-171 °C(lit.)
• Boiling Point: 272.3 °C at 760 mmHg
• Flash Point: 118.5 °C
• Appearance: /
• Density: 1.62 g/cm³
• Vapor Pressure: 0.000795mmHg at 25°C
• Refractive Index: 1.678
• Storage Temp.: Refrigerator
• Solubility: DMSO (Sparingly), Methanol (Slightly)
• PKA: 5.34±0.20(Predicted)
• CAS DataBase Reference: Tetrahydro-2-methyl-3-thioxo-1,2,4-triazine-5,6-dione(CAS DataBase Reference)
• NIST Chemistry Reference: Tetrahydro-2-methyl-3-thioxo-1,2,4-triazine-5,6-dione(58909-39-0)
• EPA Substance Registry System: Tetrahydro-2-methyl-3-thioxo-1,2,4-triazine-5,6-dione(58909-39-0)

Safety Data

• Hazard Codes: Xi
• Statements: 20/21/22-36
• Safety Statements: 36-26
• WGK Germany: 3
• Hazardous Substances Data: 58909-39-0(Hazardous Substances Data)

Usage

Chemical Properties

White Solid

Uses

Different sources of media describe the Uses of 58909-39-0 differently. You can refer to the following data:
1. Reagent used in the preparation of Cefalosporins.
2. Thiotriazinone can be used in the preparation of Cefalosporins.

General Description

Tetrahydro-2-methyl-3-thioxo-1,2,4-triazine-5,6-dione is an intermediate for synthesizing ceftriaxone.

InChI:InChI=1/C4H5N3O2S/c1-7-4(10)5-2(8)3(9)6-7/h1H3,(H,6,9)(H,5,8,10)

Synthetic route

2-methyl-thiosemicarbazide (6938-68-7) + oxalic acid diethyl ester (95-92-1) → 2-methyl-3-mercapto-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazine (58909-39-0)

Conditions	Yield
With dmap; N,N,N,N,-tetramethylethylenediamine; sodium methylate In methanol; ethanol at 15 - 55℃; for 4h; Temperature; Solvent; Reagent/catalyst;	92.7%
With sodium methylate In methanol; dimethyl sulfoxide at 0 - 45℃; Solvent;	91.6%

Dimethyl oxalate (553-90-2) + ammonium thiocyanate + methylhydrazine (60-34-4) → 2-methyl-3-mercapto-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazine (58909-39-0)

Conditions	Yield
Stage #1: ammonium thiocyanate; methylhydrazine In water at 95 - 100℃; Stage #2: Dimethyl oxalate With sodium methylate In methanol at 65 - 75℃; for 6h; Temperature;	75%

sodium salt of ceftriaxone → 2-methyl-3-mercapto-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazine (58909-39-0) + (6R,7S)-7-{2-(2-Amino-thiazol-4-yl)-2-[(Z)-methoxyimino]-acetylamino}-3-(6-hydroxy-2-methyl-5-oxo-2,5-dihydro-[1,2,4]triazin-3-ylsulfanylmethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid anion + C14H13N5O6S2(2-) (153470-19-0)

Conditions	Yield
With Carbonate buffer at 37℃; Rate constant; H/D-isotopic effect were studied too;

(6R,7S)-7-{2-(2-Amino-thiazol-4-yl)-2-[(Z)-methoxyimino]-acetylamino}-3-(6-hydroxy-2-methyl-5-oxo-2,5-dihydro-[1,2,4]triazin-3-ylsulfanylmethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid anion → 2-methyl-3-mercapto-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazine (58909-39-0) + sodium salt of ceftriaxone + C14H13N5O6S2(2-)

Conditions	Yield
With Carbonate buffer at 37℃; Rate constant; H/D-isotopic effect were studied too;

2-methyl-3-mercapto-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazine (58909-39-0) + 2-(2-amino-1,3-thiazol-4-yl)-1-(1,3-benzothiazol-2-ylsulfanyl)-2-(methoxyimino)ethan-1-one (94088-75-2) + 7-Aminocephalosporanic acid (957-68-6) → ceftriaxone sodium

Conditions	Yield
Stage #1: 2-methyl-3-mercapto-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazine; 7-Aminocephalosporanic acid With carbonic acid dimethyl ester at 35℃; for 1h; Stage #2: 2-(2-amino-1,3-thiazol-4-yl)-1-(1,3-benzothiazol-2-ylsulfanyl)-2-(methoxyimino)ethan-1-one for 0.166667h; Stage #3: With triethylamine at 10℃; for 4h; Concentration; Temperature;	99.5%

2-methyl-3-mercapto-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazine (58909-39-0) + 7-Aminocephalosporanic acid (957-68-6) → 7-aminoceftrizine (58909-56-1)

Conditions	Yield
With boron trifluoride dimethyl carbonate complex; methanesulfonic acid at 10 - 12℃; for 0.383333h; Reagent/catalyst;	95.1%
With boron trifluoride dimethyl carbonate complex; edetate disodium at 30℃; for 0.833333h; Time;	90%
With boron trifluoride In acetonitrile at 10 - 30℃; for 0.5h;	85.71%

2-methyl-3-mercapto-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazine (58909-39-0) + 7-Aminocephalosporanic acid (957-68-6) → 7-amino-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazine-3-mercapto)methyl]-3 cephalosporin-4-carboxylic acid (58909-56-1)

Conditions	Yield
With aluminum (III) chloride; boron trifluoride; carbonic acid dimethyl ester at 5 - 30℃; for 1h;	92%
With aluminum (III) chloride; boron trifluoride; carbonic acid dimethyl ester at 5 - 30℃; for 1h; Reagent/catalyst;	90%

2-methyl-3-mercapto-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazine (58909-39-0) + 7α-methoxy-8-oxo-2-(pyrrolidinocarbonyl)-3-(chloromethyl)-5-thia-1-azabicyclo<4.2.0>oct-2-ene 5,5-dioxide (143731-84-4) → L-659,286 (119742-06-2)

Conditions	Yield
With sodium hydrogencarbonate In water; acetone for 16h; Ambient temperature;	85%

2-methyl-3-mercapto-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazine (58909-39-0) + fipronilβ-cyclodextrin (7585-39-9) → C4H5N3O2S*C42H70O35

Conditions	Yield
In water at 30℃; for 24.5h;	83%

2-methyl-3-mercapto-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazine (58909-39-0) + 1,1-dimethylethyl 3-(chloromethyl)-7α-methoxy-8-oxo-5-thia-1-azabicyclo<4.2.0>oct-2-ene-2-carboxylate 5,5-dioxide (95672-05-2) → 1,1-dimethylethyl 7α-methoxy-3-{[(1,2,5,6-tetrahydro-5,6-dioxo-2-methyl-as-triazin-3-yl)thio]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 5,5-dioxide (116536-09-5)

Conditions	Yield
With sodium hydrogencarbonate In water; acetone	80%

2-methyl-3-mercapto-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazine (58909-39-0) + tert-butylchlorodiphenylsilane (58479-61-1) → 6-((tert-butyldiphenylsilyl)oxy)-3-mercapto-2-methyl-1,2,4-triazin-5(2H)-one

Conditions	Yield
With triethylamine In tetrahydrofuran at 20 - 25℃; for 1h;	78%
With triethylamine In tetrahydrofuran

2-methyl-3-mercapto-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazine (58909-39-0) + alpha cyclodextrin (10016-20-3) → C36H60O30*C4H5N3O2S

Conditions	Yield
In water at 30℃; for 24.5h;	50%

2-methyl-3-mercapto-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazine (58909-39-0) + N-methyl-N-<(tert-butoxycarbonyl)methyl>-3-(chloromethyl)-7α-methoxy-8-oxo-5-thia-1-azabicyclo<4.2.0>oct-2-ene-2-carboxamide 5,5-dioxide (116536-11-9) → N-methyl-N-[(tert-butoxycarbonyl)methyl]-7α-methoxy-8-oxo-3-{[(1,2,5,6-tetrahydro-5,6-dioxo-2-methyl-as-triazin-3-yl)thio]methyl}-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxamide 5,5-dioxide (116536-14-2)

Conditions	Yield
With sodium hydrogencarbonate In water; acetone for 16h; Ambient temperature;	45%

2-methyl-3-mercapto-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazine (58909-39-0) + [((6R,7S)-3-Chloromethyl-7-ethyl-5,5,8-trioxo-5λ6-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carbonyl)-methyl-amino]-acetic acid tert-butyl ester → {[(6R,7S)-7-Ethyl-3-(6-hydroxy-2-methyl-5-oxo-2,5-dihydro-[1,2,4]triazin-3-ylsulfanylmethyl)-5,5,8-trioxo-5λ6-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carbonyl]-methyl-amino}-acetic acid tert-butyl ester

Conditions	Yield
With sodium hydrogencarbonate In water; acetone for 16h; Ambient temperature;

2-methyl-3-mercapto-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazine (58909-39-0) + 3-[((6R,7S)-3-Chloromethyl-7-methoxy-5,5,8-trioxo-5λ6-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carbonyl)-methyl-amino]-propionic acid tert-butyl ester → 3-{[(6R,7S)-3-(6-Hydroxy-2-methyl-5-oxo-2,5-dihydro-[1,2,4]triazin-3-ylsulfanylmethyl)-7-methoxy-5,5,8-trioxo-5λ6-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carbonyl]-methyl-amino}-propionic acid tert-butyl ester

Conditions	Yield
With sodium hydrogencarbonate In water; acetone for 16h; Ambient temperature;

2-methyl-3-mercapto-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazine (58909-39-0) + (S)-1-((6R,7S)-3-Chloromethyl-7-methoxy-5,5,8-trioxo-5λ6-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carbonyl)-pyrrolidine-2-carboxylic acid tert-butyl ester → (S)-1-[(6R,7S)-3-(6-Hydroxy-2-methyl-5-oxo-2,5-dihydro-[1,2,4]triazin-3-ylsulfanylmethyl)-7-methoxy-5,5,8-trioxo-5λ6-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carbonyl]-pyrrolidine-2-carboxylic acid tert-butyl ester

Conditions	Yield
With sodium hydrogencarbonate In water; acetone for 16h; Ambient temperature;

2-methyl-3-mercapto-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazine (58909-39-0) + 2α-bromo-4-(tert-butylcarbonyl)-7α-methoxy-3-methylcephem 1,1-dioxide (138810-38-5) → 4-(tert-butylcarbonyl)-2α-<6-(hydroxy-2-methyl-5-oxo-2,5-dihydro-1,2,4-triazin-3-yl)thio>-7α-methoxy-3-methyl-Δ3-cephem 1,1-dioxide

Conditions	Yield
With TEA In acetonitrile for 0.5h;

cefotaxime (60846-21-1, 63527-52-6, 63527-53-7) + 2-methyl-3-mercapto-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazine (58909-39-0) → ceftriaxone (73384-59-5, 92143-31-2)

Conditions	Yield
With sodium acetate In methanol; dichloromethane; water

3-iodomethyl-3-cephem + 7β-[2-(2-Aminothiazol-4-yl)-(4-chlorobenzyloxyimino)acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid + 2-methyl-3-mercapto-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazine (58909-39-0) → 7β-[2-(2-Aminothiazol-4-yl)-2-(4-chlorobenzyloxyimino)acetamido]-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazin-3-yl)thiomethyl]-3-cephem-4-carboxylic acid

Conditions	Yield
With TMSI; acetic acid In tetrahydrofuran; dichloromethane; water; dimethyl sulfoxide; acetonitrile

7β-[2-(2-aminothiazol-4-yl)-2-(4-hydroxybenzyloxyimino)acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid + 2-methyl-3-mercapto-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazine (58909-39-0) → 7β-[2-(2-Aminothiazol-4-yl)-2-(4-hydroxybenzyloxyimino)acetamido]-3-[(2,5-dihydro-6-hydroxy-2-methyl5-oxo-1,2,4-triazin-3-yl)thiomethyl]-3-cephem-4carboxylic acid

Conditions	Yield
With TMSI; sodium hydrogencarbonate; acetic acid In tetrahydrofuran; dichloromethane; water; acetonitrile

4-picolylchloride hydrochloride (1822-51-1) + 2-methyl-3-mercapto-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazine (58909-39-0) → 2-methyl-3-(pyridin-4-ylmethylthio)-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazine

Conditions	Yield
With sodium hydrogencarbonate In water

2-methyl-3-mercapto-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazine (58909-39-0) + 7-aminocephalosporanic acid (108260-00-0) + N,N,N',N'-tetramethylguanidine (80-70-6) → C12H13N5O5S2*C5H13N3

Conditions	Yield
Stage #1: 2-methyl-3-mercapto-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazine; 7-aminocephalosporanic acid In acetonitrile Stage #2: N,N,N',N'-tetramethylguanidine With triethylamine In dichloromethane at -15℃;

Upstream product

• 553-90-2 Dimethyl oxalate 
• 60-34-4 methylhydrazine 
• 6938-68-7 2-methyl-thiosemicarbazide 
• 95-92-1 oxalic acid diethyl ester 

Downstream Products

• 58909-56-1 7-amino-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazine-3-mercapto)methyl]-3 cephalosporin-4-carboxylic acid 
• 58909-56-1 7-aminoceftrizine 
• 80819-15-4 tetrahydro-2-methyl-5,6-dioxo-3-thioxo-as-triazine-1(2H)-carboxylic acid benzyl ester 
• 73384-59-5 ceftriaxone 
• 119742-06-2 L-659,286 

Relevant articles and documents

Preparation method of triazine ring

The invention belongs to the technical field of preparation of organic intermediates, and particularly relates to a preparation method of a triazine ring. The method comprises the following steps: adding 2-methyl thiosemicarbazide, diethyl oxalate and a mixed alcohol solvent into a reaction flask, dropwise adding a mixed base catalyst, carrying out cyclization reaction at 45-55 DEG C, performing acidifying with hydrochloric acid, performing cooling to 0-5 DEG C, and carrying out suction filtration to obtain a triazine ring crude product; dissolving the triazine ring crude product in distilled water at 65-70 DEG C, performing cooling to 10-15 DEG C, crystallizing to obtain a triazine ring wet product, and drying at 90-100 DEG C for 3-5 hours to obtain a triazine ring dry product. According to the preparation method, a new solvent system is not introduced, the reaction selectivity is high, side reactions are few, the solvent system is easy to recycle, and the product yield is high; the adopted raw materials are cheap, easy to obtain, low in cost and suitable for industrial amplification.

The use of mixed solvent to synthesize triazine ring new method

The invention relates to a novel method for synthesizing thiotriazinone (TTZ) by using a mixed solvent. The synthetic process comprises the following steps: performing cyclization reaction on 2-methylthiosemicarbazide, the mixed solvent, diethyl oxalate and sodium methylate at 0-45 DEG C to generate triazine ring sodium salt, and acidifying through hydrochloric acid to obtain thiotriazinone. Due to the use of the mixed solvent, the system viscosity of the synthetic process is greatly improved, the TTZ cyclization yield is increased to be more than 90% (by 2-methylthiosemicarbazide), and the content of a byproduct-1-methyl-5-sulfydryl-1,2,4-triazole-3-methyl carboxylate is less than 0.002%, namely less than 20ppm.

Cephalosporin compounds and antibacterial agents

Cephalosporin compounds of the formula (I): STR1 wherein R1 and R2 may be the same or different and are a hydrogen atom or a lower alkyl group of 1-5 carbon atoms and A is a hydrogen atom or a nucleophilic compound residue or pharmacologically acceptable salts thereof have excellent antibacterial activity against Gram positive and Gram negative microorganisms.