723286-98-4

Usage

Uses

Used in Pharmaceutical Industry:
2-Chloromethyl-5-trifluoromethyl-[1,3,4]oxadiazole is used as an intermediate in the synthesis of Sitagliptin, a medication that is particularly effective in the treatment of diabetes and hypertension. Its role in the pharmaceutical industry is crucial for the development of drugs that can help manage and treat these prevalent health conditions.
Used in Chemical Synthesis:
As a versatile chemical intermediate, 2-Chloromethyl-5-trifluoromethyl-[1,3,4]oxadiazole can be utilized in the synthesis of various other compounds, contributing to the advancement of chemical research and development. Its unique properties make it a valuable building block for creating new molecules with potential applications in different fields.

InChI:InChI=1/C4H2ClF3N2O/c5-1-2-9-10-3(11-2)4(6,7)8/h1H2

Synthetic route

N'-(2-chloroacetyl)trifluoroacetohydrazide (762240-99-3) → 2-trifluoromethyl-1,3,4-oxadiazol-5-ylmethyl chloride (723286-98-4)

Conditions	Yield
With trichlorophosphate In 1,2-dichloro-ethane at 80 - 85℃; Reagent/catalyst; Temperature;	90.2%
With trichlorophosphate In acetonitrile at 100℃; Temperature;	87.73%
With trichlorophosphate In acetonitrile at 80℃; for 24h;	86%

5-chloromethyltetrazole + trifluoroacetic anhydride (407-25-0) → 2-trifluoromethyl-1,3,4-oxadiazol-5-ylmethyl chloride (723286-98-4)

Conditions	Yield
In dichloromethane at 20℃;	49%

2,2,2-trifluoroacetohydrazide (1538-08-5) + chloroacetyl chloride (79-04-9) → 2-trifluoromethyl-1,3,4-oxadiazol-5-ylmethyl chloride (723286-98-4)

Conditions	Yield
Stage #1: 2,2,2-trifluoroacetohydrazide; chloroacetyl chloride With triethylamine In acetonitrile at -5 - 5℃; for 3h; Stage #2: With trichlorophosphate In acetonitrile at 0 - 85℃;

2-trifluoromethyl-1,3,4-oxadiazol-5-ylmethyl chloride (723286-98-4) + ethylene-d4-diamine (37164-19-5) → C6H5(2)H4F3N4O

Conditions	Yield
With oxazepine In methanol at -20 - -10℃; for 2h;	80.44%

2-trifluoromethyl-1,3,4-oxadiazol-5-ylmethyl chloride (723286-98-4) + ethylenediamine (107-15-3) → 2,2,2-trifluoro-N’-[(2Z)-piperazin-2-ylidene]acetohydrazide (763105-70-0)

Conditions	Yield
In methanol at -20℃; for 1h;	74%
In methanol; ethanol at -20 - -5℃; for 2h;	72%
In methanol at -20℃; for 1h;	72%

2-trifluoromethyl-1,3,4-oxadiazol-5-ylmethyl chloride (723286-98-4) + N-methyl-ethane-1,2-diamine (109-81-9) → 2,2,2-trifluoro-N'-[(2Z)-4-methylpiperazin-2-ylidene]acetohydrazide (763105-73-3, 849944-46-3)

Conditions	Yield
In methanol at -20℃; for 1h;	74%

2-trifluoromethyl-1,3,4-oxadiazol-5-ylmethyl chloride (723286-98-4) + N-benzylethylenediamine (4152-09-4) → N'-[(2Z)-4-benzylpiperazin-2-ylidene]-2,2,2-trifluoroacetohydrazide (763105-74-4, 849944-48-5)

Conditions	Yield
In methanol at -20℃; for 1h;	67%

2-trifluoromethyl-1,3,4-oxadiazol-5-ylmethyl chloride (723286-98-4) + theobromine / (83-67-0) → 3,7-dimethyl-1-((5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)methyl)-1H-purine-2,6(3H,7H)-dione

Conditions	Yield
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 120℃; for 3h;	34%

2-trifluoromethyl-1,3,4-oxadiazol-5-ylmethyl chloride (723286-98-4) + 1,1-dimethylethylenediamine (811-93-8) → 5,5-dimethyl-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (723286-97-3)

Conditions	Yield
Stage #1: 2-trifluoromethyl-1,3,4-oxadiazol-5-ylmethyl chloride; 1,1-dimethylethylenediamine With N-ethyl-N,N-diisopropylamine In methanol at 0 - 20℃; for 2.5h; Stage #2: With superphosphoric acid at 110℃; for 18h; Further stages.;	8%
Stage #1: 2-trifluoromethyl-1,3,4-oxadiazol-5-ylmethyl chloride; 1,1-dimethylethylenediamine With N-ethyl-N,N-diisopropylamine In methanol at 0 - 20℃; for 2.5h; Stage #2: With superphosphoric acid at 110℃; for 18h;

2-trifluoromethyl-1,3,4-oxadiazol-5-ylmethyl chloride (723286-98-4) + dibutylamine (111-92-2) → dibutyl-(5-trifluoromethyl-[1,3,4]oxadiazol-2-ylmethyl)-amine

Conditions	Yield
In methanol at -40℃;

2-trifluoromethyl-1,3,4-oxadiazol-5-ylmethyl chloride (723286-98-4) + (S)-1,2-diaminopropane (15967-72-3) + di-tert-butyl dicarbonate (24424-99-5) → tert-butyl (5S)-5-methyl-3-(trifluoromethyl)-5,6-dihydro-1,2,4-triazolo[4,3-a]pyrazine-7(8H)-carboxylate (1013657-13-0) + tert-butyl (6S)-6-methyl-3-(trifluoromethyl)-5,6-dihydro-1,2,4-triazolo[4,3-a]pyrazine-7(8H)-carboxylate (1013657-14-1)

Conditions	Yield
Stage #1: 2-trifluoromethyl-1,3,4-oxadiazol-5-ylmethyl chloride; (S)-1,2-diaminopropane With N-ethyl-N,N-diisopropylamine In methanol for 22h; Stage #2: di-tert-butyl dicarbonate In dichloromethane at 20℃; for 1h; Further stages.;	A 103 mg B 243 mg

2-trifluoromethyl-1,3,4-oxadiazol-5-ylmethyl chloride (723286-98-4) + (R)-1,2-diaminopropane (78-90-0, 6852-78-4, 10424-38-1, 15967-72-3) + di-tert-butyl dicarbonate (24424-99-5) → tert-butyl (5R)-5-methyl-3-(trifluoromethyl)-5,6-dihydro-1,2,4-triazolo[4,3-a]pyrazine-7(8H)-carboxylate (1013656-80-8) + tert-butyl (6R)-6-methyl-3-(trifluoromethyl)-5,6-dihydro-1,2,4-triazolo[4,3-a]pyrazine-7(8H)-carboxylate (1013656-81-9)

Conditions	Yield
Stage #1: 2-trifluoromethyl-1,3,4-oxadiazol-5-ylmethyl chloride; (R)-1,2-diaminopropane With N-ethyl-N,N-diisopropylamine In methanol for 22h; Stage #2: di-tert-butyl dicarbonate In dichloromethane at 20℃; for 1h; Further stages.;

2-trifluoromethyl-1,3,4-oxadiazol-5-ylmethyl chloride (723286-98-4) + potassium ethyl xanthogenate (140-89-6) → O-ethyl S-[(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)methyl]xanthate

Conditions	Yield
In acetone at 0℃; for 1h;

2-trifluoromethyl-1,3,4-oxadiazol-5-ylmethyl chloride (723286-98-4) + {(R)-2-[3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-5-piperazin-1-yl-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester (1308375-93-0) → C34H36F7N7O5

Conditions	Yield
With potassium carbonate In acetonitrile at 20 - 60℃; for 3h;

2-trifluoromethyl-1,3,4-oxadiazol-5-ylmethyl chloride (723286-98-4) + 6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (42869-47-6) → 2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(trifluoromethyl)-1,3,4-oxadiazole

Conditions	Yield
Stage #1: 6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine With potassium tert-butylate In tetrahydrofuran at 45℃; for 0.5h; Stage #2: 2-trifluoromethyl-1,3,4-oxadiazol-5-ylmethyl chloride With tetra-(n-butyl)ammonium iodide In tetrahydrofuran at 45℃; for 1h;	0.094 g

2-trifluoromethyl-1,3,4-oxadiazol-5-ylmethyl chloride (723286-98-4) + tert-butyl (5S)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate → tert-butyl (5S)-3-oxo-2-{[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]methyl}-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate

Conditions	Yield
With caesium carbonate In acetonitrile

Upstream product

• 407-25-0 trifluoroacetic anhydride 
• 1538-08-5 2,2,2-trifluoroacetohydrazide 
• 79-04-9 chloroacetyl chloride 
• 762240-99-3 N'-(2-chloroacetyl)trifluoroacetohydrazide 

Downstream Products

• 763105-70-0 2,2,2-trifluoro-N’-[(2Z)-piperazin-2-ylidene]acetohydrazide 
• 763105-74-4 N'-[(2Z)-4-benzylpiperazin-2-ylidene]-2,2,2-trifluoroacetohydrazide 
• 723286-97-3 5,5-dimethyl-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine 

Relevant academic research and scientific papers

Radical-based route to 2-(trifluoromethyl)-1,3,4-oxadiazoles and trifluoromethyl -substituted polycyclic 1,2,4-triazoles and dihydrofurans

O-Ethyl S-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]methyl xanthate was readily prepared on a large scale and shown to undergo very efficient intermolecular radical additions to unactivated alkenes. The products were further elaborated by exploiting both

Preparation method of 5-(chloromethyl)-2-(trifluoromethyl)-1, 3, 4 oxadiazole

The invention relates to a preparation method of a sitagliptin intermediate 5-(chloromethyl)-2-(trifluoromethyl)-1, 3, 4 oxadiazole. The preparation method comprises the following steps: by taking 1-(chloroacetyl)-2-(trifluoroacetyl) hydrazine as a raw material, carrying out heating reaction with phosphorus oxychloride in the presence of a solvent to obtain a product solution, cooling, dropwise adding water for cracking, layering, washing an organic layer with a sodium bicarbonate aqueous solution until the organic layer is neutral, and finally concentrating and recovering the solvent to obtain the 5-(chloromethyl)-2-(trifluoromethyl)-1, 3, 4 oxadiazole. Aiming at the defects of the existing production process, the method provided by the invention has the advantages of obvious improvement,simple operation, convenient solvent recovery, easy scale-up production, good product purity and high yield.

Use of silicon compounds in cyclization reaction

The invention relates to the field of organic chemistry, and in particular, relates to an application of silicon compounds in cyclization reaction. On one hand, the invention provides a preparation method of 2-chloro-5-chloromethylpyridine, and the preparation method comprises the steps: carrying out cyclization reaction on 4-formyl-4,5-dichlorovaleronitrile in the presence of a silicon compound and an amide compound to provide the 2-chloro-5-chloromethylpyridine. On the other hand, the invention provides a preparation method of 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole, and the preparation method comprises the steps: carrying out cyclization reaction on 1-(chloracetyl)-2-(trifluoroacetyl)hydrazine in the presence of a silicon compound and an amide compound to provide the 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole. By using the silicon compound or/and amide provided by the invention as a cyclization reagent, cyclization synthesis can be efficiently carried out.

Design, synthesis, biological evaluation and computational study of novel triazolo [4,3-a]pyrazin analogues

The triazolo [4,3-a]pyrazin analogues are of interest due to their potential activity against various infectious and non-infectious disease. In search of suitable potent drug candidate, we report here the design, synthesis, characterization, biological activities and computation study of novel triazolo [4,3-a]pyrazin analogues. The synthesized molecules were characterized by various spectroscopic studies such as IR, Mass, 1H NMR, 13C NMR and elemental analysis. The newly synthesized compounds were evaluated for their in vitro biological activities such as anti-malarial, anti-tuberculosis, anti-bacterial and anti-fungal activities against plasmodium falciparum, H37Rv, various bacterial and fungal strains, respectively. The molecular docking study was carried out with enzyme aspartic proteinase zymogen proplasmepsin II from plasmodium falciparum to analyze their binding orientation in the active site of the aspartic proteinase enzyme. The best docking complex was subjected to molecular dynamics simulation to illustrate the stability of these complexes and the most prominent interactions during the simulated trajectory. We have also calculated ADMET properties of all the synthesized compounds to predict the pharmacokinetic properties for the selection of the active and bioavailability of compounds.

plants the deuterium mark sitagliptin a process for the preparation of

The present invention discloses a method for preparing deuterium-labeled sitagliptin. The deuterium-labeled sitagliptin-D4 is synthesized by an eight-step reaction with hydrazine hydrate as a starting material and ethylene-D4 as a deuterium-labeled initiator. The optimal preparation steps and reaction conditions are screened through a plurality of experiments in the invention and the entire process is reasonable in design and high in operability. The deuterium-labeled sitagliptin prepared by the invention has purity of over 98% and the yield up to 70% or more, and isotopic abundance is greater than 99%. The deuterium-labeled sitagliptin prepared by the invention can provide test samples for a research on the metabolic mechanism of sitagliptin and has important application value.

PROCESS FOR THE PREPARATION OF SITAGLIPTIN AND ITS INTERMEDIATES

The present invention relates to novel and improved processes for the preparation of Sitagliptin compound of formula (1) and its intermediates.

PROCESSES FOR THE PREPARATION OF SITAGLIPTIN AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF

There is provided salts and polymorphs of sitagliptin, processes for the preparation thereof, and pharmaceutical compositions comprising the same.

Reaction of 5-Substituted tetrazoles with trifluoroacetic anhydride

5-Substituted tetrazoles readily react with trifluoroacetic anhydride at 20-25°C to give the corresponding 2-substituted 5-trifluoromethyl-1,3,4- oxadiazoles, in contrast to published data according to which the title compounds are converted into 1,3,4-oxadiazole derivatives on heating with carboxylic acid anhydrides or chlorides at 100-120°C. The reaction is governed not only by the rate of acylation of the tetrazole ring and temperature conditions but also by the stability of intermediate N-acyltetrazoles.

COMBINATION OF A DIPEPTIDYL PEPTIDASE-4 INHIBITOR AND AN ANTI-HYPERTENSIVE AGENT FOR THE TREATMENT OF DIABETES AND HYPERTENSION

The present invention relates to pharmaceutical compositions comprising a combination of a particular dipeptidyl peptidase-4 (DPP-4) inhibitor and an anti-hypertensive agent selected from the group consisting of an angiotensin II receptor antagonist and an angiotensin converting enzyme inhibitor, kits containing such combinations and methods of using such compositions for the treatment of diabetes, diabetes-related disorders, hypertension, and hypertension-related disorders.

DODECYLSULFATE SALT OF A DIPEPTIDYL PEPTIDASE-IV INHIBITOR

The dodecylsulfate salt of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl) butan-2-amine is a potent inhibitor of dipeptidyl peptidase-IV and is useful for the treatment of Type 2 diabetes. The invention also relates to a crystalline anhydrate of the dodecylsulfate salt as well as a process for its preparation, pharmaceutical compositions containing this novel form and methods of use for the treatment of Type 2 diabetes, hyperglycemia, insulin resistance, and obesity.