Structure of 15884-86-3
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| CAS No. : | 15884-86-3 |
| Formula : | C4H7N3OS |
| M.W : | 145.18 |
| SMILES Code : | NC1=NN=C(COC)S1 |
| English Name : | 5-(Methoxymethyl)-1,3,4-thiadiazol-2-amine |
| MDL No. : | MFCD01203002 |
| InChI Key : | ZLDOCTTXAVVDHG-UHFFFAOYSA-N |
| Pubchem ID : | 660844 |
| Num. heavy atoms | 9 |
| Num. arom. heavy atoms | 5 |
| Fraction Csp3 | 0.5 |
| Num. rotatable bonds | 2 |
| Num. H-bond acceptors | 3.0 |
| Num. H-bond donors | 1.0 |
| Molar Refractivity | 35.17 |
| TPSA ? Topological Polar Surface Area: Calculated from |
89.27 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.15 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.3 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.12 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-1.12 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.3 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.23 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-0.83 |
| Solubility | 21.5 mg/ml ; 0.148 mol/l |
| Class? Solubility class: Log S scale |
Very soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-1.11 |
| Solubility | 11.2 mg/ml ; 0.0768 mol/l |
| Class? Solubility class: Log S scale |
Very soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.07 |
| Solubility | 12.3 mg/ml ; 0.0845 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
| BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
| P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
| CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
| CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
| CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
| CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
| CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
| Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-7.4 cm/s |
| Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
| Ghose? Ghose filter: implemented from |
None |
| Veber? Veber (GSK) filter: implemented from |
0.0 |
| Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
| Muegge? Muegge (Bayer) filter: implemented from |
2.0 |
| Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
| PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
| Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
| Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
| Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.87 |
* 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 |
|---|---|---|
| Thiosemicarbazid/Methoxyessigsaeure; | ||
| Thiosemicarbazid, Methoxyessigsaeure/POCl3; | ||
| With sulfuric acid at 80 - 90℃; Cooling with ice; | 1 General procedure: Add 0.3 mol acetic acid and 0.25 mol thiosemicarbazide into a 250 mL single-neck round bottom flask.Slowly add 31.5 mL of concentrated sulfuric acid dropwise while stirring in an ice bath (complete the addition within 30 minutes). Then the reaction was stirred to room temperature, and then slowly heated to 80-90°C for 7 hours. After the reaction solution is cooled to room temperature, slowly pour it into 500 mL of ice water. A large amount of colorless solid will form. Filter and wash the filter cake with cold water until neutral. Collect the filter cake, dry it with an infrared lamp, and then recrystallize it with ethanol to obtain 2-amino-5-methyl-1,3,4-thiadiazole. The preparation process of other such compounds is the same as that of 2-amino-5-methyl-1,3,4-thiadiazole. The structure and NMR data of this intermediate are shown in Table 1 below: |
| With sulfuric acid at 80 - 90℃; Cooling with ice; | 1 General procedure: Add 0.3 mol acetic acid and 0.25 mol thiosemicarbazide into a 250 mL single-neck round bottom flask.Slowly add 31.5 mL of concentrated sulfuric acid dropwise while stirring in an ice bath (complete the addition within 30 minutes). Then the reaction was stirred to room temperature, and then slowly heated to 80-90°C for 7 hours. After the reaction solution is cooled to room temperature, slowly pour it into 500 mL of ice water. A large amount of colorless solid will form. Filter and wash the filter cake with cold water until neutral. Collect the filter cake, dry it with an infrared lamp, and then recrystallize it with ethanol to obtain 2-amino-5-methyl-1,3,4-thiadiazole. The preparation process of other such compounds is the same as that of 2-amino-5-methyl-1,3,4-thiadiazole. The structure and NMR data of this intermediate are shown in Table 1 below: |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 56 EXAMPLE 56 EXAMPLE 56 Addition of phosphonyl chloride to a mixture of thiosemicarbazide and methoxyacetic acid at 60°-95° and working up of the product yields 5-amino-2-methoxymethyl-(1,3,4)-thiadiazole, m.p. 177°-179° (from water). | ||
| 86 EXAMPLE 86 EXAMPLE 86 Addition of phosphonyl chloride to a mixture of thiosemicarbazide and methoxyacetic acid at 60°-95° and working up of the product yields 5-amino-2-methoxymethyl-(1,3,4)-thiadiazole, m.p. 177°-179° (from water). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 89% | With trichlorophosphate In 1,4-dioxane at 70 - 80℃; for 6h; Large scale; | |
| 81% | With trichlorophosphate In 1,4-dioxane at 20 - 80℃; for 1.5h; | 2.1 Synthesis of 5-(methoxymethyl)-1 ,3,4-thiadiazol-2-amine a25.To a suspension of thiosemicarbazide a24 (40 g, 0.44 mol, 1 eq) in dioxane (400 ml) at room temperature is added methoxyacetic acid (39.56 g, 0.44mol, 1 eq) in one portion, and the reaction mixture is heated at 80°C then phosphorous oxychloride (67.54 g, 0.44 mol, 1 eq) is carefully added over 1.5 hours. After reaction completion (4 hours), water is added and the solution is neutralised to pH=6-7 with sodium hydroxyde pellets. After extraction EtOAc/iPrOH (9/1 ) and evaporation under vacuum, the residue is recrystallized from MeTHF/iPrOH to afford 51 g of pure 5-(methoxymethyl)-1 ,3,4- thiadiazol-2-amine a25.Yield: 81 %. LC-MS (MH+): 146. |
| With sodium hydroxide; trichlorophosphate In water monomer; Petroleum ether | 6.a EXAMPLE 6 a. Phosphoryl chloride (87 ml) was added dropwise to a vigorously stirred mixture of thiosemicarbazide (100 g), methoxyacetic acid (100 g) and petroleum ether b.p. 80°-100° (200 ml) maintained at 60°-70°. The temperature of the mixture was slowly raised to 95° and was kept at this temperature until the evolution of gas ceased. The solvent was evaporated and the residual syrup was dissolved in water (200 ml) to give a yellow solution which was adjusted to pH 7 by the addition of 10N NaOH. The mixture was filtered to give 5-amino-2-methoxymethyl-(1,3,4)-thiadiazole (111.25 g). Recrystallisation from water gave compound with m.p. 177°-179°. (Found: C, 32.9; H, 4.8; N, 29.1; S, 22.0; C4 H7 N3 OS requires: C, 33.1; H, 4.9; N, 29.0; S, 22.1%). |
| With trichlorophosphate at 75℃; for 1h; | 4.1.2. General procedure for the preparation 5-substituted-1,3,4-thiadiazol-2-amines 4a-4f General procedure: To a round-bottom flask were added thiosemicarbazide (10 mmol,1.0 eq.), carboxylic acid (11 mmol, 1.1 eq.) and POCl3 (5 mL). The resulting mixture was heated to 75 °C and stirred for 1 h. The reaction mixture was then cooled to room temperature, to which tepid water(10 mL) was slowly added, and it was further heated to reflux and stirred for 1 h. After cooling, the reaction mixture was neutralized with 50% NaOH and the precipitated solid was collected by filtration and washed with water. The crude product was then recrystallized from ethanol. Yield 70-80%. |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With hydrogen bromide; copper(I) bromide; sodium nitrite | 6.b EXAMPLE 6 b. An intimate dry mixture of 5-amino-2-methoxymethyl-(1,3,4)-thiadiazole (34.8 g) and sodium nitrite (75.9 g) was added over 1.5 hours to a stirred mixture of hydrobromic acid (48%, 270 ml) and cuprous bromide (2 g) maintained at -7°. The mixture was stirred at -6° for 1 hour and at room temperature for 1.5 hours. The mixture was neutralised with 10M NaOH, treated with sodium metabisulphite, warmed to 60° for 20 min., reneutralised with sodium hydroxide and filtered. The filtrate was extracted with cyclohexane for 13 hours, and the cyclohexane extract was dried over calcium sulphate, filtered and evaporated to give 5-bromo-2-methoxymethyl(1,3,4)thiadiazole (30.35 g) as an oil. (Found: C, 23.0; H, 2.7; Br 38.0; N, 13.5; S, 15.1; C4 H5 BrN2 OS requires C, 23.0; H, 2.4; Br 38.2; N, 13.4; S, 15.3 %). |
| 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 |
|---|---|---|
| 88.1% | With dmap In dichloromethane at 20℃; | 3.1 3.1 Synthesis of tert-butyl [5-(methoxymethyl)-1 ,3,4-thiadiazol-2-yl]carbamate a31.To a suspension of 5-(methoxymethyl)-1 ,3,4-thiadiazol-2-amine a25 (100 g, 0.69 mol, 1 eq) in dichloromethane (1 I) at room temperature is added, successively and each in one portion, di-tert-butyl dicarbonate (132 g, 0.76 mol, 1.1eq,) and N,N-dirnethylamino- pyridine (8.35 g, 0.069 mol, 0.1 eq). After overnight stirring at room temperature, the reaction mixture is washed with 1 N HCI (pH 5) to remove N,N-dimethylaminopyridine. The solvent is then removed under reduced pressure and the residue is recrystallized from di-isopropyl ether to afford 148.9 g of pure tert-butyl [5-(methoxymethyl)-1 ,3,4- thiadiazol-2-yl]carbamate a31.Yield: 88.1 %.LC-MS (MH+): 246. |
| 88% | With dmap In dichloromethane at 20℃; | 2.1 2.1 Synthesis of tert-butyl [5-(methoxymethyl)-1 ,3,4-thiadiazol-2-yl]carbamate a13. To a suspension of 5-(methoxymethyl)-1 ,3,4-thiadiazol-2-amine a1 (100 g, 0.69 mol, 1 eq) in dichloromethane (1 I) at room temperature are added, successively and each in one portion, di-tert-butyl dicarbonate (132 g, 0.76 mol, 1.1 eq,) and N,N-dimethylamino- pyridine (8.35 g, 0.069 mol, 0.1 eq). After overnight stirring at room temperature, the reaction mixture is washed with 1 N HCI (pH 5) to remove N,N-dimethylaminopyridine. The solvent is removed under reduced pressure and the residue is recrystallized from di-isopropyl ether to afford 148.9 g of pure tert-butyl [5-(methoxymethyl)-1 ,3,4-thiadiazol-2-yl]carbamate a13.Yield: 88 %. LC-MS (MH+): 246. |
| 88% | With dmap In dichloromethane at 20℃; | 2.1 2.1 Synthesis of tert-butyl [5-(methoxymethyl)- ,3,4-thiadiazo.-2-y.]carbamate a4. To a suspension of 5-(methoxymethyl)-1 ,3,4-thiadiazol-2-amine a1 (100 g, 0.69 mol, 1 eq) in dichloromethane (1 I) at room temperature are added, successively and each in one portion, di-tert-butyl dicarbonate (132 g, 0.76 mol, 1.1 eq,) and N,N-dimethylamino- pyridine (8.35 g, 0.069 mol, 0.1 eq). After overnight stirring at room temperature, the reaction mixture is washed with 1 N HCI (pH 5) to remove Ν,Ν-dimethylaminopyridine. The solvent is removed under reduced pressure and the residue is recrystallized from di-isopropyl ether to afford 148.9 g of pure tert-butyl [5-(methoxymethyl)-1 ,3,4-thiadiazol- 2-yl]carbamate a4.Yield: 88 %.LC-MS (MH+): 246 |
| 88% | With dmap In dichloromethane at 20℃; | 2.1 2.1 Synthesis of tert-butyl [5-(methoxymethyl)-1,3,4-thiadiazol-2-yl]carbamate XIV. To a suspension of 5-(methoxymethyl)-1,3,4-thiadiazol-2-amine (CAS: 15884-86-33, 100 g, 0.69 mol, 1 eq) in dichloromethane (1 I) at room temperature are added, successively and each in one portion, di-tert-butyl dicarbonate (132 g, 0.76 mol, 1.1 eq,) and N,N-dimethylamino-pyridine (8.35 g, 0.069 mol, 0.1 eq). After overnight stirring at room temperature, the reaction mixture is washed with 1 N HCI (pH 5) to remove N,N- dimethylaminopyridine. The solvent is removed under reduced pressure and the residue is recrystallized from di-isopropyl ether to afford 148.9 g of pure tert-butyl [5- (methoxymethyl)-l,3,4-thiadiazol-2-yl]carbamate XIV. Yield: 88 %. LC-MS (MH+): 246. |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 91% | In pyridine at 20℃; for 2h; | To a solution of 5-(methoxymethyl)-1,3,4-thiadiazol-2-amine (500mg, 3.444mmol) in pyridine (5mL) was added 4-nitrobenzene-l-sulfonyl chloride (1.5g, 6.888mmol). The mixture was stirred at RT for two hours. The solvent was removed under reduced pressure to give a solid. The solid was purified by column chromatography to give N-(5- (methoxymethyl)-l,3,4-thiadiazol-2-yl)-4-nitrobenzenesulfonamide (l .Og, 91%). MS (ESI) m/z 329 [M-H]~. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 47% | In 1,2-dimethoxyethane at 20 - 80℃; | 1.1 Example 1. Synthesis of r2-(methoxymethyl)-6-(trifluoromethyl)imidazor2,1- blf1.3.41thiadiazol-5-vHmethanol a3.1.1 Synthesis of 2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1 -b][1 ,3,4]thiadia- zole 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. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 20% | With N-ethyl-N,N-diisopropylamine In toluene at 120℃; for 16h; Sealed tube; | 4.6. General procedure for synthesis of triazopyridines 7 General procedure: A mixture of 6 (1.55 mmol), 2 (0.77 mmol), and i-Pr2NEt(1.55 mmol) in toluene (unless otherwise stated) (0.77 ml) was stirred at 120 °C in a sealed tube for 16 h. The mixture was allowed to cool to room temperature. Purification method A: the mixture was concentrated and the residue was purified by reverse phase automatedpreparative HPLC. Purification method B: the mixture was concentrated and the residue was purified by flash column chromatography (SiO2). Purification method C: the mixture was diluted(DCM), washed (satd Na2CO3), dried (filtered through a Biotage phase separator), and concentrated. The residue was purified by reverse phase automated preparative HPLC. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 29% | With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 140℃; for 16h; Sealed tube; | 4.4. General procedure for synthesis of triazoles 4 General procedure: A mixture of 1 (1.55 mmol, unless otherwise stated), 2 (0.77 mmol), and i-Pr2NEt (1.55 mmol) in NMP (0.77 mL) was stirred at 140 °C in a sealed tube for 16 h. The mixture was allowed to cool to room temperature, diluted (DCM), washed (satd Na2CO3), dried (filtered through a Biotage phase separator), and concentrated. Purification method A: the residue was purifiedby reverse phase automated preparative HPLC. Purification method B: the residue was purified by flash column chromatography (SiO2). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| In toluene at 120℃; Molecular sieve; Sealed tube; | ||
| In toluene at 120℃; Molecular sieve; Sealed tube; | 4.1.1. Typical experimental procedure for ethers 1-7, 11-20 General procedure: A screw-capped V-shaped vial (2.0 mL) was charged with 2-aminothiazole (0.36 mmol, 1.0 equiv), aldehyde (0.40 mmol, 1.1equiv), freshly activated 4 Å molecular sieves (300 mg) and dry toluene(1.5 mL). The vial was capped with a pressure cap and stored at 120 °C for 14-24 h until complete consumption of 2-aminothiazole (monitoredby 1H NMR). The resulting mixture containing imine was cooled to room temperature and the solvent was removed under reduced pressure. Under inert atmosphere, the residue was redissolved in dry toluene(1 mL) and then CuOTf*C6H6 (18 mg, 0.036 mmol, 10 mol %), Cu(OTf)2 (13 mg, 0.036 mmol, 10 mol %), alkyne (0.72 mmol, 2 equiv) and 4 Å molecular sieves (100 mg) were added. The reaction mixture was additionally stirred in the vial capped with a pressure cap at 120 °C for 2 h. After the completion of the reaction, the mixture was filtered through a plug of neutral aluminum oxide (eluent - EtOAc). The filtrate was concentrated under reduced pressure to give a crude material,which was purified by column chromatography on silica gel (eluentEt3N:EtOAc/petroleum ether) or neutral aluminum oxide (eluent EtOAc/petroleum ether) to give product. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 40% | In N,N-dimethyl-formamide at 100℃; | 1.1.7 To a solution of 5-(methoxymethyl)-1 ,3,4-thiadiazol-2-amine (CAS: 15884-86-3, 1.0 eq., 6.5 g, 45 mmol) in DMF (100 ml_), at 100°C, was added dropwise a solution of 3-bromo- 1 ,1-difluoro-propan-2-one (CAS: 883233-85-0, 1.05 eq., 8.1 g, 47 mmol) in DMF (5 ml_). The reaction mixture was heated at 100°C during 3 h and the completion was checked by LC/MS. A saturated aqueous solution of NaHCC>3 was added and the organic layer was extracted with ethyl acetate (three times). The combined organic layers were washed with water (five times), dried over MgSCU, filtered and evaporated to dryness to give a brown solid (7.6 g). The crude was purified by flash chromatography Biotage Isolera Four (100 g KP-SNAP silica gel column in a gradient of 0% to 5% methanol in dichloromethane over 12 CV) and the pure fractions were combined and evaporated under high vacuum to give 6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1- b][1 ,3,4]thiadiazole VII (3.95 g, 17.8 mmol) as an orange solid. Yield: 40% LC/MS: [M+H]+ = 220.2 1H NMR (400 MHz, DMSO-c/6): δ 8.53 (t, J = 2.2 Hz, 1 H), 7.01 (t, J = 54.6 Hz, 1 H), 4.83 (s, 2H), 3.43 (s, 3H). |
| 40% | In N,N-dimethyl-formamide at 100℃; for 3h; | 2.1.5 1.5 Synthesis of 6-(difluoromethyl)-2-(methoxymethyl)imidazo[2, 1 b][1 ,3,4]thiadiazole VII To a solution of 5-(methoxymethyl)-1 ,3,4-thiadiazol-2-amine VI (CAS: 15884-86-3, 1 .0 eq., 6.5 g, 45 mmol) in DMF (100 ml_), at 100°C, was added dropwise a solution of 3- bromo-1 , 1 -difluoro-propan-2-one (CAS: 883233-85-0, 1.05 eq., 8.1 g, 47 mmol) in DMF (5 ml_). The reaction mixture was heated at 100°C during 3 h and the completion was checked by LC/MS. A saturated aqueous solution of NaHC03 was added and the organic layer was extracted with ethyl acetate (three times). The combined organic layers were washed with water (five times), dried over MgS04, filtered and evaporated to dryness to give a brown solid (7.6 g). The crude was purified by flash chromatography Biotage Isolera Four (100 g KP-SNAP silica gel column in a gradient of 0% to 5% methanol in dichloromethane over 12 CV) and the pure fractions were evaporated under high vacuum to give 6-(difluoromethyl)-2-(methoxymethyl)imidazo[2, 1 - b][1 ,3,4]thiadiazole VII (3.95 g, 17.8 mmol) as an orange solid. Yield: 40% LC/MS: [M+H]+ = 220.2 1H NMR (400 MHz, DMSO-cfe): δ 8.53 (t, J = 2.2 Hz, 1 H), 7.01 (t, J = 54.6 Hz, 1 H), 4.83 (s, 2H), 3.43 (s, 3H). |
| 40% | In water; N,N-dimethyl-formamide at 100℃; for 3h; | C.1 C.1. Synthesis of 6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazole VI To a solution of 5-(methoxymethyl)-1,3,4-thiadiazol-2-amine (CAS: 15884-86-3, 1.0 eq., 6.5 g, 45 mmol) in DMF (100 ml_), at 100°C, was added dropwise a solution of 3-bromo- 1,1-difluoro-propan-2-one (CAS: 883233-85-0, 1.05 eq., 8.1 g, 47 mmol) in DMF (5 ml_). The reaction mixture was heated at 100°C during 3 h and the completion was checked by LC/MS. A saturated aqueous solution of NaHCC>3 was added and the organic layer was extracted with ethyl acetate (three times). The combined organic layers were washed with water (five times), dried over MgS04, filtered and evaporated to dryness to give a brown solid (7.6 g). The crude was purified by flash chromatography Biotage Isolera Four (100 g KP-SNAP silica gel column in a gradient of 0% to 5% methanol in dichloromethane over 12 CV) and the pure fractions were combined and evaporated under high vacuum to give 6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1- b][1,3,4]thiadiazole VI (3.95 g, 17.8 mmol) as an orange solid. Yield: 40% LC/MS: [M+H]+ = 220.2 1H NMR (400 MHz, DMSO-de): d 8.53 (t, J = 2.2 Hz, 1H), 7.01 (t, J = 54.6 Hz, 1H), 4.83 (s, 2H), 3.43 (s, 3H). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 52% | In N,N-dimethyl-formamide at 100℃; for 3h; | 1.1 1.1 Synthesis of 2-(methoxymethyl)-6-methyl-imidazo[2, 1 -b][1 ,3,4]thiadiazole II To a solution of 5-(methoxymethyl)-1 ,3,4-thiadiazol-2-amine I (CAS: 15884-86-3, WO201 1/047860, 1.0 eq., 7.0 g, 48.2 mmol) in DMF (95 ml_), at 100 °C, was added dropwise a solution of bromoacetone (1.0 eq., 4.2 ml_, 46.2 mmol, 97% purity) in DMF (5 mL). The reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was cooled to room temperature (RT) and the solvent was evaporated until dryness under high vacuum to give a brown oil. 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 14CV) and the pure fractions were evaporated to dryness to give 2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1 ,3,4]thiadiazole II (5.0 g, 25.1 1 mmol) as a yellow/orange solid. (0154) Yield: 52% (0155) LC/MS: [M+H]+ = 184.0 1H NMR (400 MHz, DMSO -cfe): d 8.53 (m, 1 H), 4.76 (s, 2H), 3.40 (s, 3H), 2.25 (d, J = 1 .0 Hz, 3H). |
| 52% | In N,N-dimethyl-formamide at 100℃; for 3h; | B.1 B.1 Synthesis of 2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazole IV To a solution of 5-(methoxymethyl)-1,3,4-thiadiazol-2-amine (CAS: 15884-86-3, WO2011/047860, 1.0 eq., 7.0 g, 48.2 mmol) in DMF (95 ml_), at 100°C, was added dropwise a solution of bromoacetone (1.0 eq., 4.2 ml_, 46.2 mmol, 97% purity) in DMF (5 ml_). The reaction mixture was stirred at 100°C for 3 h. The reaction mixture was cooled to room temperature (RT) and the solvent was evaporated until dryness under high vacuum to give a brown oil. 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 14CV) and the pure fractions were evaporated to dryness to give 2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazole IV (5.0 g, 25.1 1 mmol) as a yellow/orange solid. Yield: 52% LC/MS: [M+H]+ = 184.0 1H NMR (400 MHz, DMSO-de): d 8.53 (m, 1H), 4.76 (s, 2H), 3.40 (s, 3H), 2.25 (d, J = 1.0 Hz, 3H). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 28% | In N,N-dimethyl-formamide at 100 - 110℃; | 4.2 . 4.2 B. Synthesis of 2-(methoxymethyl)-6-(trideuteriomethyl)imidazo[2,1- b][1 ,3,4]thiadiazole IX. To a solution of 5-(methoxymethyl)-1 ,3,4-thiadiazol-2-amine | (1.0 eq., 8.0 g, 55.1 mmol) in DMF (100 ml_), at 100 °C, was added dropwise a solution of 1-bromo- 1 ,1 ,3,3,3-pentadeuterio-propan-2-one VIII (1.05 eq., 8.22 g, 57.9 mmol) in DMF (20 ml_). The reaction mixture was stirred at 1 10 °C for 2 h 30. The mixture was then cooled to RT, a saturated solution of NaHCC>3 was added and the solvent was evaporated until dryness. The obtained crude was then diluted in EtOAc, filtered and the filtrate was evaporated until dryness to give a brown oil (9.5 g). 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 14CV) and the pure fractions were evaporated to dryness to give 2-(methoxymethyl)-6-(trideuteriomethyl)imidazo[2,1- b][1 ,3,4]thiadiazole IX (3.05 g, 15.6 mmol) as a yellow solid. (0190) Yield: 28% (0191) LC/MS: [M+H]+ = 187.2 1H NMR (400 MHz, DMSO-d6) d 7.45 (s, 1 H), 4.70 (s, 2H), 3.48 (s, 3H) |

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