Structure of 1294001-16-3
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| CAS No. : | 1294001-16-3 |
| Formula : | C7H6F3N3OS |
| M.W : | 237.20 |
| SMILES Code : | FC(C1=CN2C(SC(COC)=N2)=N1)(F)F |
| English Name : | 2-(Methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole |
| MDL No. : | MFCD30803541 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 47% | In 1,2-dimethoxyethane at 20 - 80℃; for 24h; | 2.2 2.2 Synthesis of 2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1 - bJ[1 ,3,4]thiadiazole a28.Bromotrifluoroacetone (478 g, 1.05 eq) is added on a suspension of 5- (methoxymethyl)-1 ,3,4-thiadiazol-2-amine a25 (346 g, 1 eq) in 1 ,2-dimethoxyethane (6 I) at 20°C. The reaction mixture is heated to 80°C until maximum conversion (<24 h). Water (4 I) is added to the reaction mixture at 32°C and the expected compound crystallized out of the reaction mixture. The crystalline suspension is cooled to 10°C to complete the crystallization process, filtered and the crystalline precipitate is washed with water (1 ,5 I) to afford 266 g of pure 2-(methoxymethyl)-6- (trifluoromethyl)imidazo[2, 1 -b][1 ,3,4]thiadiazole a28.Yield: 47 %.LC-MS (MH+): 238. |
| 47% | In 1,2-dimethoxyethane at 20 - 80℃; for 24h; | 1.1 1.1 Synthesis of 2-(methoxymethyl)-6-(trifluoromethyl)imiclazo[2,1-b][1 ,3,4]thia- diazole a2.Bromotrifluoroacetone (478 g, 2.5 mol, 1.05 eq) is added on a suspension of 5- (methoxymethyl)-1 ,3,4-thiadiazol-2-amine a1 (346 g, 2.4 mol, 1 eq) in 1 ,2- dimethoxyethane (6 I) at 20°C. The reaction mixture is heated to 80°C until maximum conversion (<24 h). Water (4 I) is added to the reaction mixture at 32°C and the expected compound crystallized out of the reaction mixture. The crystalline suspension is cooled to 10°C to complete the crystallization process, filtered and the crystalline precipitate is washed with water (1 ,5 I) to afford 266 g of pure 2-(methoxymethyl)-6- (trifluoromethyl)imidazo[2,1 -b][1 ,3,4]thiadiazole a2.Yield: 47 %.LC-MS (MH+): 238. |
| 47% | In 1,2-dimethoxyethane; water at 80℃; for 24h; | 1.1 1.1 Synthesis of 2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole VIII. 3-Bromo-1,1,1-trifluoroacetone (CAS: 431-35-6, 478 g, 2.5 mol, 1.05 eq) is added on a suspension of 5-(methoxymethyl)-1,3,4-thiadiazol-2-amine (CAS: 15884-86-33, 46 g, 2.4 mol, 1 eq) in 1,2-dimethoxyethane (6 I) at 20°C. The reaction mixture is heated to 80°C until maximum conversion (<24 h). Water (4 I) is added to the reaction mixture at 32°C and the expected compound crystallized out of the reaction mixture. The crystalline suspension is cooled to 10°C to complete the crystallization process, filtered and the crystalline precipitate is washed with water (1,5 I) to afford 266 g of pure 2- (methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole VIII. Yield: 47 %. LC-MS (MH+): 238. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: zinc(II) chloride / 1,4-dioxane / 216 h / 80 - 90 °C / Reflux 2: Chiralpak AS-V / n-heptane; ethanol / 30 °C / Resolution of racemate |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 74% | With zinc(II) chloride In 1,4-dioxane at 80 - 90℃; for 216h; Reflux; | 2.3 2.3 Synthesis of 4-(2-chloro-2,2-difluoroethyl)-1-[2-(methoxymethyl)-6-(trifluoro- methyl)imidazo[2,1 -b][1 ,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-one 4 and enantiomers 5 and 6.To a hot solution (80°C) of ZnCl2 (0.23 g, 1.69 mmol, 10 mol%) and 2- (methoxymethyl)-6-(trifluoromethyl)imidazo[2, 1-b][1 ,3,4]thiadiazole a28 (4 g, 16.96 mmol) in dioxane (200 ml) is added a solution of 4-(2-chloro-2,2-difluoroethyl)-1- (chloromethyl)pyrrolidin-2-one a18 in dioxane (5 ml). The reaction mixture is heated at 85°C for 5 days, then a further 2 g of pyrrolidinone a18 is added in one portion and the reaction mixture is kept under agitation at 90°C for 1 day. A further addition of pyrrolidinone a18 (2 g) in order to insure complete conversion of compound a28 and further heating of the reaction mixture at reflux for 3 days increased significatively the conversion of imidazo[2,1 -b][1 ,3,4]thiadiazole a28. After cooling and hydrolysis (250 ml of water), the crude mixture is extracted by CH2CI2 (2 x 250ml). The cumulated organic layers are dried over MgS04, filtered and condensed under reduced pressure. The residue is purified over silicagel (eluent: Ch^C^/MeOH/ h^OH 99/1/0.1) to afford 4-(2-chloro-2,2-difluoroethyl)-1 -[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1 - b][1 ,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-one 4.Yield: 74 %.LC- S (MH+): 433/435. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 30% | With zinc(II) chloride In 1,4-dioxane at 90℃; for 120h; | 8.3 8.3 Synthesis of (4R)-4-(2-chloro-2,2-dif luoroethyl)-1 -[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1 -b][1 ,3,4]thiadiazol-5-yl](2H2)methyl}pyrrolidin-2-one 32.(4R)-4-(2-chloro-2,2-difluoroethyl)-1 -[chloro(2H2)methyl]pyrrolidin-2-one §46 is redissolved in dry dioxane (3.4 ml) and is added at 90°C to a mixture of 2- (methoxymethyl)-6-(trifluoromethyl)imidazo[2,1 -b][1 ,3,4]thiadiazole a28 (0.85 g, 1.0 eq mol) and zinc chloride (0.27 g, 0.55 eq mol) in dioxane (5 ml). The reaction mixture is stirred for 5 days at this temperature. After reaction completion and extractive work-up, the product is purified by preparative reverse phase chromatography (eluent: CH3CN/H2O/NH4OH 30/70/0.1 ) followed by a chromatography over normal phase (eluant: CH2CI2/EtOH/NH4OH 99.5/0.5/0.05) to afford 0.46 g of (4R)-4-(2-chloro-2,2- difluoroethyl)-1 -[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1 -b][1 ,3,4]thiadiazol-5- yl](2H2)methyl}pyrrolidin-2-one 32.Yield: 30 %.LC-MS (MH+): 435/437. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 58% | Stage #1: formaldehyd; 2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole With hydrogenchloride In sulfolane; water at 110℃; Stage #2: With water In sulfolane at 50℃; for 2h; | 1.2 1.2 Synthesis of [2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1 ,3,4]thiadiazol -5-yl]methanol a3.2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1 ,3,4]thiadiazole a2 (10 g, 42.16 mmol, 1 eq), formaldehyde (16 g, 421.6 mmol, 10 eq) and hydrochloric acid (37 %,8.2 ml, 2 eq) are diluted in sulfolane (250 ml). The reaction mixture is heated at 110°C overnight. Water (500 ml) is added and the mixture is heated at 50°C for 2h. The solvent is then removed under reduced pressure. The residue is purified by chromatography over silicagel (gradient; eluent: Ch^C^/MeOH/NI-^OH from 100/0/0 to 99/1/0.1 ) to afford 6.5 g of [2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1 ,3,4]thiadiazol-5- yljmethanol a3 as a yellow solid.Yield: 58 %.LC-MS (MH+): 268. |
| 58% | With hydrogenchloride In sulfolane; water at 110℃; | 1.2 1.2 Synthesis of [2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol -5-yl]methanol IX. 2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole VIII (10 g, 42.16 mmol, 1 eq), formaldehyde (16 g, 421.6 mmol, 10 eq) and hydrochloric acid (37 %, 8.2 ml, 2 eq) are diluted in sulfolane (250 ml). The reaction mixture is heated at 1 10°C overnight. Water (500 ml) is added and the mixture is heated at 50°C for 2h. The solvent is then removed under reduced pressure. The residue is purified by chromatography over silicagel (gradient; eluent: ChC/MeOH/NhOH from 100/0/0 to 99/1/0.1) to afford 6.5 g of [2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5- yl]methanol IX as a yellow solid. Yield: 58 %. LC-MS (MH+): 268. |
| 41% | With hydrogenchloride In 1,4-dioxane; water at 100℃; for 18h; Sealed tube; | 1.4 1.4 Synthesis of [2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2, 1- b][1 ,3,4]thiadiazol-5-yl]methanol V In a sealed tube, 2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2, 1-b][1 ,3,4]thiadiazole IV (CAS: 1294001-16-3, patent application WO 2012/1431 17, 1 eq., 2.0 g, 8.4 mmol), paraformaldehyde (6.0 eq., 1 .52 g, 50.6 mmol) and an aqueous solution of hydrochloric acid (2N) (1 .0 equiv., 4.2 ml_, 8.4 mmol) were mixed in 1 ,4-dioxane (4 ml_). The mixture was stirred at 100°C for 18 h and the reaction was checked by LC/MS. The crude mixture was cooled to RT and an aqueous saturated solution of NaHC03 was added until pH=6-7. The aqueous layer was extracted with ethyl acetate (three times) and the combined organic layers were washed with brine, dried over MgSC , filtered and evaporated to dryness. The crude was purified by flash chromatography Biotage Isolera Four (100 g KP-SNAP silica gel column in a gradient of 0% to 10% methanol in dichloromethane over 15 CV) to give [2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2, 1 - b][1 ,3,4]thiadiazol-5-yl]methanol (1.06 g, 3.5 mmol) V as a beige solid. The compound was used directly in the next step without any further purification. Yield: 41 %LC/MS: [M+H]+ = 268.2 1H NMR (400 MHz, CDCI3): δ 5.04 (d, J = 5.2 Hz, 2H), 4.77 (s, 2H), 3.53 (s, 3H), 2.32 (t, J = 6.3 Hz, 1 H). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1.1: hydrogenchloride / sulfolane; water / 110 °C 1.2: 2 h / 50 °C 2.1: toluene-4-sulfonic acid / toluene / 110 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1.1: hydrogenchloride / sulfolane; water / 110 °C 1.2: 2 h / 50 °C 2.1: toluene-4-sulfonic acid / toluene / 110 °C 3.1: Chiralpak IC / isopropyl alcohol; n-heptane / 30 °C / Resolution of racemate |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1.1: hydrogenchloride / sulfolane; water / 110 °C 1.2: 2 h / 50 °C 2.1: N-ethyl-N,N-diisopropylamine; methanesulfonyl chloride; sodium azide / dichloromethane; N,N-dimethyl-formamide / 0 - 20 °C | ||
| Multi-step reaction with 2 steps 1: hydrogenchloride / water; sulfolane / 110 °C 2: N-ethyl-N,N-diisopropylamine; sodium azide; methanesulfonyl chloride / N,N-dimethyl-formamide; dichloromethane / 0 - 20 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1.1: hydrogenchloride / sulfolane; water / 110 °C 1.2: 2 h / 50 °C 2.1: N-ethyl-N,N-diisopropylamine; methanesulfonyl chloride; sodium azide / dichloromethane; N,N-dimethyl-formamide / 0 - 20 °C 3.1: triphenylphosphine; water / tetrahydrofuran / 60 h / 20 °C | ||
| Multi-step reaction with 3 steps 1: hydrogenchloride / water; sulfolane / 110 °C 2: N-ethyl-N,N-diisopropylamine; sodium azide; methanesulfonyl chloride / N,N-dimethyl-formamide; dichloromethane / 0 - 20 °C 3: triphenylphosphine / water; tetrahydrofuran / 60 h / 20 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 6 steps 1.1: hydrogenchloride / sulfolane; water / 110 °C 1.2: 2 h / 50 °C 2.1: N-ethyl-N,N-diisopropylamine; methanesulfonyl chloride; sodium azide / dichloromethane; N,N-dimethyl-formamide / 0 - 20 °C 3.1: triphenylphosphine; water / tetrahydrofuran / 60 h / 20 °C 4.1: sodium carbonate / N,N-dimethyl-formamide / 20 °C 5.1: N,N-dimethyl-formamide 6.1: potassium <i>tert</i>-butylate / N,N-dimethyl-formamide / 4 h / 75 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 4 steps 1.1: hydrogenchloride / sulfolane; water / 110 °C 1.2: 2 h / 50 °C 2.1: N-ethyl-N,N-diisopropylamine; methanesulfonyl chloride; sodium azide / dichloromethane; N,N-dimethyl-formamide / 0 - 20 °C 3.1: triphenylphosphine; water / tetrahydrofuran / 60 h / 20 °C 4.1: sodium carbonate / N,N-dimethyl-formamide / 20 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 5 steps 1.1: hydrogenchloride / sulfolane; water / 110 °C 1.2: 2 h / 50 °C 2.1: N-ethyl-N,N-diisopropylamine; methanesulfonyl chloride; sodium azide / dichloromethane; N,N-dimethyl-formamide / 0 - 20 °C 3.1: triphenylphosphine; water / tetrahydrofuran / 60 h / 20 °C 4.1: sodium carbonate / N,N-dimethyl-formamide / 20 °C 5.1: N,N-dimethyl-formamide |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 7 steps 1.1: hydrogenchloride / sulfolane; water / 110 °C 1.2: 2 h / 50 °C 2.1: N-ethyl-N,N-diisopropylamine; methanesulfonyl chloride; sodium azide / dichloromethane; N,N-dimethyl-formamide / 0 - 20 °C 3.1: triphenylphosphine; water / tetrahydrofuran / 60 h / 20 °C 4.1: sodium carbonate / N,N-dimethyl-formamide / 20 °C 5.1: N,N-dimethyl-formamide 6.1: potassium <i>tert</i>-butylate / N,N-dimethyl-formamide / 4 h / 75 °C 7.1: hydrogenchloride / water / 168 h / 80 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 8 steps 1.1: hydrogenchloride / sulfolane; water / 110 °C 1.2: 2 h / 50 °C 2.1: N-ethyl-N,N-diisopropylamine; methanesulfonyl chloride; sodium azide / dichloromethane; N,N-dimethyl-formamide / 0 - 20 °C 3.1: triphenylphosphine; water / tetrahydrofuran / 60 h / 20 °C 4.1: sodium carbonate / N,N-dimethyl-formamide / 20 °C 5.1: N,N-dimethyl-formamide 6.1: potassium <i>tert</i>-butylate / N,N-dimethyl-formamide / 4 h / 75 °C 7.1: hydrogenchloride / water / 168 h / 80 °C 8.1: Chiralpak AS-V / isopropyl alcohol; n-heptane / 30 °C / Resolution of racemate |