Structure of 64837-53-2
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CAS No. : | 64837-53-2 |
Formula : | C5H7N3O2S |
M.W : | 173.19 |
SMILES Code : | O=C(C1=NN=C(N)S1)OCC |
MDL No. : | MFCD03093787 |
InChI Key : | YVKRWIVXIPGKTL-UHFFFAOYSA-N |
Pubchem ID : | 2756556 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 5 |
Fraction Csp3 | 0.4 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 40.4 |
TPSA ? Topological Polar Surface Area: Calculated from |
106.34 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.31 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.57 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.3 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.55 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.1 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.55 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.41 |
Solubility | 6.72 mg/ml ; 0.0388 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.38 |
Solubility | 0.729 mg/ml ; 0.00421 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.04 |
Solubility | 15.8 mg/ml ; 0.0912 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 |
-6.95 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 |
1.0 |
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) |
2.76 |
* 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 |
---|---|---|
24% | at 70℃; for 5 h; | Step 1 ethyl 5-amino-l,3,4-thiadiazole-2-carboxylate To a solution of hydrazinecarbothioamide (10 g, 54.8 mmol) in POCI3 (25 mL) was added ethyl 2-chloro-2-oxacetate (6.1 mL, 54.8 mmol). The reaction was heated to 70°C and stirred for 5 h. POCI3 was completely removed from the reaction mixture under vacuum. The residue was diluted with ice cold water (150 mL) and basified to pH 8 with saturated sodium bicarbonate solution and then extracted with ethyl acetate (200 mL). The organic layer was separated and dried over a2S04, and the solvent was evaporated to obtain crude product. The crude product was purified by flash chromatography (silica gel 100-200?, 2percent methanol and dichloromethane) to afford ethyl 5-amino-l,3,4-thiadiazole-2-carboxylate as a yellow solid (3.1 g, 24percent yield). ? NMR (400 MHz, DMSO-d6): ? 7.94 (s, 2H), 4.29 (q, 2H), 1.27 (t, 3H); LC- MS m/z calcd for [M+H]+ 174.03, found 174.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With trichlorophosphate; at 70℃; for 5h; | Step 1 ethyl 5-amino-l,3,4-thiadiazole-2-carboxylate To a solution of hydrazinecarbothioamide (10 g, 54.8 mmol) in POCI3 (25 mL) was added ethyl 2-chloro-2-oxacetate (6.1 mL, 54.8 mmol). The reaction was heated to 70°C and stirred for 5 h. POCI3 was completely removed from the reaction mixture under vacuum. The residue was diluted with ice cold water (150 mL) and basified to pH 8 with saturated sodium bicarbonate solution and then extracted with ethyl acetate (200 mL). The organic layer was separated and dried over a2S04, and the solvent was evaporated to obtain crude product. The crude product was purified by flash chromatography (silica gel 100-200?, 2percent methanol and dichloromethane) to afford ethyl 5-amino-l,3,4-thiadiazole-2-carboxylate as a yellow solid (3.1 g, 24percent yield). ? NMR (400 MHz, DMSO-d6): ? 7.94 (s, 2H), 4.29 (q, 2H), 1.27 (t, 3H); LC- MS m/z calcd for [M+H]+ 174.03, found 174.1. |
at 160℃; for 5h; | EXAMPLE 67-( { [5-( 1 -Ethyl- 1 -hvdroxypropyl)- 1.3.4-thiadiazol-2-yl]amino 1 methyl)-4-phenylquinoline-2-carbonitrile Step 1: Ethyl 5-amino-1.3.4-thiadiazole-2-carboxylateN-NQ S NH,EtOA mixture of ethyl chloro(oxo)acetate (0.5 g, 3.68 mmol) and hydrazinecarbothioamide (0.335 g, 3.68 mmol) was heated to 160° C for 5 h. The solvent was removed under reduce pressure and the crude purified on silica gel (eluting with 3percent methanol in DCM) to give the title product. 1H NMR (400 MHz, acetone-ds): delta 7.28 (bs, IH), 9.67 (bs, IH), 4.39 (q, 2H), 1.38 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 2: 3-(5-Amino-1.3.4-thiadiazol-2-yl)pentan-3-olTo a solution of ethyl 5-amino-l,3,4-thiadiazole-2-carboxylate (0.95 g, 5.5 mmol) in 18 mL of THF at 0° C was added slowly a 3.0M solution of EtMgBr (14.6 mL; 43.9 mmol). The mixture was allowed to warm to rt overnight and quenched with 25percent NH4OAc. The solvent was removed and the residue stirred in ethyl acetate. The solid was filtered and the filtrate concentrated and purified over silica gel (eluting with 8percent MeOH in DCM) to yield the title compound. 1H NMR (400 MHz, acetone- d6): delta 6.39 (br, 2H), 1.9 (q, 4H), 0.89 (t, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.4% | With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 20 - 60℃; for 1.33333h; | To a stirred solution of compound 59 (21 g, 121.38 mmol) in ACN (400 mL), CuBr2 (53.3 g, 239.01 mmol) was added and stirred at room temperature for 15 min. To this solution, tert- butyl nitrite (24.65 g, 239.04 mmol) was added drop wise over a period of 20 min. The resulting reaction mixture was stirred at room temperature for 30 min. and then heated at 60 C for 30 min. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water; ethyl acetate and filtered through Celite bed. The organic layer was separated; washed with brine; dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound 60 (25 g, 87.40percent) as a yellow solid. TLC: 20percent EtOAc/hexane (Rf: 0.7); 1H NMR (400 MHz, DMSO-d6): delta 4.45-4.40 (m, 2H), 1.34 (t, J= 6.8 Hz, 3H). |
82% | With hydrogen bromide; copper(I) bromide; sodium nitrite; In water; at 3 - 20℃; for 2.75h; | A 500 mL (three neck) round-bottom flask with a stir bar, needle inlet, and a gas outlet to a trap containing a 10percent solution of Na2S203 was charged with CuBr (1.24g, 8.67 mmol, 0.1 equiv.) and HBr (48percent aqueous solution, 108 mL). The purple solution was cooled to 3°C (internal, ice bath), to which was added portion- wise a solid mixture of 5-amino-[l,3,4]thiadiazole-2-carboxylic acid ethyl ester (15.0 g, 86.6 mmol) and sodium nitrite (27.0 g, 391.3 mmol, 4.5 equiv.) over the course of 30 min. The reaction mixture was allowed to warm to room temperature for 2 h 15 min. The reaction mixture was diluted with CH2C12 and 10percent aqueous Na2S203 and the layers were separated. The aqueous layer was extracted 3 times with CH2C12. The combined organic layers were washed with Brine, dried over MgS04, and concentrated. The crude product was purified by column chromatography (ISCO XL, 330g Si02 column, 20-25percent EtOAc/Hexanes) to provide an off-white solid that was triturated with 5percent EtOAc/Hexanes. Filtration provided 5-bromo-[l ,3,4]thiadiazole-2-carboxylic acid ethyl ester (14.5 g, 71percent) as white needles. Concentration and trituration of the mother liquor provided an additional product (2.3 g, 11percent). |
79% | Step l:5-Bromo-[l,3,4]thiadiazole-2-carboxylic acid ethyl ester (3_39_2) [00332] CuBr2 (18.06 g, 80.1 mmol) was added to a suspension of 5-amino- [l,3,4]thiadiazole-2-carboxylic acid ethyl ester 3_39_1 (7 g, 40.5 mmol) in 150 mL of acetonitrile, the mixture was stirred for 15 min, t-BuONO (9.6 mL, 80.1 mmol) was added over 20 min., and the mixture was heated at 60°C for 0.5 h. Water and ethyl acetate were added, the mixture was stirred until the dark color disappeared and filtered through celite, and the organic layer was washed with brine, dried over Na2S04, filtrated and concentrated to give compound 3_39_2 (7.56 g, 79 percent yield) as a yellow solid. [00333] NMR (400 MHz, DMSO-d6): delta = 1.32 (t, J = 7.14 Hz, 3 H), 4.41 (q, J = 7.30 Hz, 2 H); |
74% | With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 20 - 60℃; for 0.666667h; | Step 2: ethyl 5-bromo-l,3,4-thiadiazole-2-carboxylate ter-BuONOTo a stirred solution of ethyl 5-amino-l,3,4-thiadiazole-2-carboxylate (3.1 g, 17.8 mmol) in acetonitrile (50 mL) at room temperature was added copper (II) bromide (7.95 g, 35.6 mmol) and the mixture was stirred for 20 min. Tertiary butyl nitrite (3.67 g, 35.63 mmol) was then added drop wise for 10 min, and the reaction mixture was heated to 60°C for 30 min. The reaction mixture was concentrated under reduced pressure, diluted with water (300 mL), and then extracted with ethyl acetate (500 m:). The organic layer was separated and dried over anhydrous sodium sulphate, and evaporated to afford ethyl 5-bromo-l,3,4-thiadiazole-2-carboxylate as a brown solid (3.0 g, 74percent yield). XH NMR (400 MHz, CDC13): ? 4.53-4.51 (m, 2H), 1.45-1.43 (m, 3H); LC-MS m/z calcd for [M+H]+ 238.92, found 238.9. |
With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 20 - 60℃; for 1.08333h; | Step 1: Ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate To a suspension of <strong>[64837-53-2]ethyl 5-amino-1,3,4-thiadiazole-2-carboxylate</strong> (10 g, 58 mmol) in CH3CN (180 mL) was added CuBr2 (25.7 g, 115 mmol). The mixture turned dark green and was further stirred for 15 min at room temperature. t-BuONO, 90percent (13.8 mL, 115 mmol) was added dropwise over 15-20 min. The mixture became slightly warm and gas was evolved after 5 min and then throughout the addition. After completion of the addition and gas evolution subsided, the mixture was heated at 60° C. for 30 min. Solvent was then evaporated in vacuo. Water and EtOAc were added and the mixture was agitated in the flask until the dark green color disappeared. The organic phase became light brown and the aqueous was green with insoluble material. The whole mixture was filtered through celite and washed with EtOAc. The EtOAc layer was separated, washed with dilute brine solution, dried (Na2SO4) and concentrated to give the title compound. 1H NMR (400 MHz, acetone-d6): delta4.52 (q, 2H), 1.43 (t, 3H). | |
To a suspension of ethyl 5-amino-l,3,4- thiadiazole-2-carboxylate in CH3CN (0.32 M) was added CuBr2 (2 equiv). The mixture turned dark green and was stirred for 15 min at room temperature. t-BuONO, 90percent (2 equiv) was added dropwise over 15 - 20 min. The mixture became slightly warm and gas evolved after about 5 min and then throughout the addition. After completion of the addition and after gas evolution subsided, the mixture was heated at 60 °C for 30 min. Solvent was then evaporated in vacuo. Water and EtOAc were added and the mixture was stirred until the dark green color disappeared. The organic phase became light brown and the aqueous phase was green with insoluble material. The entire mixture was filtered through Celite.(TM). and washed with EtOAc. The EtOAc layer was separated, washed with diluted brine, dried (Na2SO4) and concentrated to give the title compound. lH NMR (400 MHz, acetone-^): delta 4.52 (q, 2H), 1.43 (t, 3H). | ||
To a suspension of ethyl 5-amino- l,3,4-thiadiazole-2-carboxylate in CH3CN (0.32 M) was added CuBr2 (2 equiv). The mixture turned dark green and was stirred for 15 min at room temperature. Then /-BuONO (2 equiv, 90percent) was added dropwise over 15 - 20 min. The mixture became slightly warm and gas evolved after about 5 min and then throughout the addition. After completion of the addition and after gas evolution subsided, the mixture was heated at 60 °C for 30 min. Solvent was then evaporated in vacuo. Water and EtOAc were added and the mixture was stirred until the dark green color disappeared. The mixture was filtered through Celite.(TM). and washed with EtOAc. The EtOAc layer was separated, washed with diluted brine, dried (Na2SO4) and concentrated to give the title compound. lH NMR (400 MHz, acetone-t/6): delta 4.52 (q, 2H), 1.43 (t, 3H). | ||
Step 1 Ethyl 5-bromo-l ,3,4-thiadiazole-2-carboxylateTo a suspension of ethyl 5-ammo-l ,3,4-thiadiazole-2-carboxylate in CH3CN (0 32 M) was added CuBr2 (2 equiv) The mixture turned dark green and was stirred for 15 mm at room temperature ^-BuONO, 90percent (2 equiv) was added dropwise over 15 - 20 mm The mixture became slightly warm and gas was evolved after about 5 min and then throughout the addition After completion of the addition and gas evolution subsided, the mixture was heated at 60 0C for 30 mm Solvent was then evaporated under diminished pressure Water and EtOAc were added and the mixture was stirred until the dark green color disappeared The organic phase became light brown and the aqueous phase was green with insoluble material The entire mixture was filtered through celite and washed with EtOAc The EtOAc layer was separated, washed with diluted bpine, dpied (Na2SO4) and concentrated to give the title compound lH NMR (400 MHz, acetone-d) delta 4 52 (q, 2H), 1 43 (t, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 84 g of acetic acid, 72 g of phosphoric acid, and 28 g of sulfuric acid was dissolved 12.2 g of 2-amino-5-ethoxycarbonyl-1,3,4-thiadiazole (structural formula 1a). This solution was cooled to 5°C or lower. Thereto was added dropwise 22 g of 43percent nitrosylsulfuric acid. Thus, a solution of a diazo compound of 2-amino-5-ethoxycarbonyl-1,3,4-thiadiazole was prepared. Subsequently, the diazo compound solution obtained above was added dropwise to a solution composed of 8.6 g of the compound represented by the following structural formula 1b and 172 mL of methanol under the conditions of 5°C or lower, and the resultant mixture was stirred for 2 hours. This mixture was then neutralized with 28percent ammonia water. Thereafter, the crystals precipitated were taken out by filtration and purified to obtain 20 g of the azo compound represented by the following structural formula 1c. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | To a suspension of ethyl 5-amino-l,3,4-thiadiazole-2-carboxylate (200 mg, 1.155 mmol) in EtOH (3 mL) was added dimethylamine (1 mL, 7.90 mmol). The mixture was stirred at 90 0C for 2 h and concentrated. The residue was purified by reverse phase HPLC, using Sunfire SlO 30x250 mm column and eluting with 0-40percent solvent B (90percent MeOH-10percent H2O-0.1percent TFA) in solvent A (10percent MeOH-90percent H2O- 0.1percent TFA) to provide the expected product as TFA salt (50 mg, 15percent yield). MS (ES+) m/z: 173 (M+H); LC retention time: 0.66 min (analytical HPLC Method A). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | In methanol; at 20 - 70℃; for 6.83h; | To a suspension of ethyl 5-amino-l,3,4-thiadiazole-2-carboxylate (2 g, 11.55 mmol) in methanol (15 mL) was added cyclopropylamine (1.5 mL, 21.65 mmol). The mixture was stirred at room temperature for 1 h and at 40 0C for 1.5 h. Additional cyclopropylamine (2 mL) was added. After 3 h at 40 0C, 1 h at 50 0C and 20 min at 70 0C, the mixture was concentrated to half the volume, diluted with water (2.5 mL), heated to boil to give a clear solution and cooled to room temperature. The solid was filtered, washed with cold methanol, and dried to give 5-amino-N- cyclopropyl-l,3,4-thiadiazole-2-carboxamide as yellow crystals (1.52 g, 72 percent yield). MS (ES+) m/z: 185 (M+H); LC retention time: 0.87 min (analytical HPLC Method A). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; ethanol; at 20 - 70℃; | To a suspension of ethyl 5-amino-l,3,4-thiadiazole-2-carboxylate (106 mg, 0.612 mmol) in methanol (1.5 mL) was added 33 wt percent ethanol solution of <n="108"/>methylamine (0.5 mL, 4.00 mmol). The mixture was stirred at room temperature for 6 h, heated to 70 0C and cooled. The mixture was concentrated, mixed with water and lyophilized to give 5-amino-N-methyl-l,3,4-thiadiazole-2-carboxamide as a white solid (99 mg). 1H NMR (400 MHz, DMSO-d6) delta ppm 8.69 (q, J=4.8 Hz, 1 H), 7.70 (s, 2 H) 2.73 (d, J=4.78 Hz, 3 H); MS (ES+) m/z: 159 (M+H); LC retention time: 0.44 min (analytical HPLC Method A). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; water; at 20℃; | To a suspension of ethyl 5-amino-l,3,4-thiadiazole-2-carboxylate (200 mg, 1.155 mmol) in methanol (1.5 mL) was added a 70percent aqueous solution of ethylamine (0.5 mL, 6.29 mmol). The mixture was stirred at room temperature overnight, concentrated, mixed with water and lyophilized to give 5-amino-N-ethyl- l,3,4-thiadiazole-2-carboxamide as a yellowish solid (200 mg). MS (ES+) m/z: 173 (M+H); LC retention time: 0.70 min (analytical HPLC Method A). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With pyridine; at 20 - 95℃; for 48.25h; | General procedure: A suspension of ethyl 2-(5-amino-1,3,4-thiadiazol-2-yl)acetate29 (2.0 g, 11.2 mmol) in pyridine (50 mL) was stirred and cooled in an ice bath while p-dodecylbenzenesulfonyl chloride (4.7 g, 13.5 mmol) was added slowly. The mixture was stirred at rt for 48 h, then heated in an oil bath at 90 °C for 15 min. The reaction mixture was then cooled to rt, poured into aqueous 10percent HCl, and extracted with EtOAc (3 .x. 75 mL). The combined extracts were washed with water (2 .x. 50 mL), brine (2 .x. 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was subjected to chromatography on silica gel (70-230 mesh) eluted with CH2Cl2/MeOH 95:5 to give the product 37 (2.9 g, 5.9 mmol, 53percent) |
34% | With pyridine; at 20℃; for 4.5h; | To a solution of /?-dodecylbenzenesulfonyl chloride (260 mg, 0.75 mmol) in pyridine (3 mL) was added ethyl 5-amino-l,3,4-thiadiazole-2-carboxylate (100 mg, 0.58 mmol). The reaction mixture was stirred at room temperature for 4.5 h, then 2 M HCl was added to quench the reaction. The mixture was extracted with ethyl acetate (3 x 40 mL). The organic extracts were washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography over silica gel (70-230 mesh) eluted with CH2Cl2 methanol 49:1 to give the product as a solid, mp 96-97 0C, in 34percent yield (95 mg, 0.20 mmol); 1H NMR (300 MHz, CDCl3) delta 0.85 (t, 3H, J = 6.6 Hz), 1.20-1.35 (m, <n="90"/>21H), 1.57 (m, 2H), 2.60 (t, 2H, J = 7.0 Hz), 4.43 (q, 2H, J = 7.2 Hz), 7.26 (d, 2H, J = 8.0 Hz), 7.77 (d, 2H, J = 7.7 Hz); 13C NMR (300 MHz, CDCl3) delta 14.1, 22.7, 29.3, 29.4, 29.6, 29.6, 31.1, 31.9, 35.9, 63.4, 126.6, 128.9, 136.9, 145.8, 159.9, 163.7, 167.9; MS (LCQ, ESI+) Calcd for C23H36N3O4S2 482.2, found 482.1 (M+H)+; HRMS (ESI+, m/z) Calcd for C23H36N3O4S2 482.2140, found 482.2134 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | General procedure: To a solution of p-acetamidobenzenesulfonyl chloride (275 mg, 1.18 mmol) in pyridine (5 mL) was added ethyl 2-(5-amino-1,3,4-thiadiazol-2-yl)acetate (200 mg, 1.07 mmol). The reaction mixture was stirred at rt for 4.5 h, then 2 M HCl (10 mL) was added and the mixture extracted with EtOAc (3 ' 50 mL). The organic extracts were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was subjected to chromatography on silica gel (70-230 mesh) eluted with CH2Cl2:MeOH 19:1, affording the product 13 (312 mg, 0.81 mmol, 76percent yield), | |
73% | With pyridine; at 20℃; for 4.5h; | To a solution of /?-acetamidobenzenesulfonyl chloride (1.98 g, 8.47 mmol) in pyridine (20 rnL) was added ethyl 5-amino-l,3,4-thiadiazole-2-carboxylate (1.2 g, 7.06 mmol). The reaction mixture was stirred at room temperature for 4.5 h, than 2 M HCl (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3 x 60 mL). The organic extracts were washed with water (50 mL), brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel (70-230 mesh) eluted with CH2Cl2 methanol 19:1 to give the product as a solid, mp 201-202 0C, in 73percent yield (1.91 g, 5.15 mmol); 1H NMR (300 MHz, DMSO-^) delta 1.29 (t, 3H, J = 6.9 Hz), 2.08 (s, 3H), 4.37 (q, 2H, J = 7.8 Hz), 7.74 (m, 4H), 10.32 (s, IH); 13C NMR (75 MHz, OMSO-d6) delta 13.9, 14.0, 24.1, 62.9, 118.6, 127.1, 134.9, 143.2, 147.2, 157.5, 167.6, 169.0; MS (LCQ, ESI+) Calcd for Ci3Hi5N4O5S2 371.0, found 371.0 (M+H)+; HRMS (ESI+, m/z) Calcd for Ci3Hi5N4O5S2 371.0484, found 371.0472 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With pyridine; at 20℃; for 4.5h; | General procedure: To a solution of 4-decanamidobenzenesulfonyl chloride (608 mg, 1.76 mmol) in pyridine (8 mL) was added ethyl 2-(5-amino-1,3,4-thiadiazol-2-yl)acetate (300 mg, 1.60 mmol). The reaction mixture was stirred at rt for 4.5 h, then 2 M HCl was added to quench the reaction. The mixture was extracted with EtOAc (3 ' 40 mL), the organic extracts washed with water (30 mL), brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was subjected to chromatography on silica gel (70-230 mesh) eluted with CH2Cl2:MeOH 19:1 to give the product 22 (500 mg, 1.01 mmol, 63percent yield), |
65% | With pyridine; at 20℃; for 4.5h; | To a solution of 4-decanamidobenzenesulfonyl chloride (220 mg, 0.64 mmol) in pyridine (4 mL) was added ethyl 5-amino-l,3,4-thiadiazole-2-carboxylate (100 mg, 0.58 mmol). The reaction mixture was stirred at room temperature for 4.5 h, then 2 M HCl (10 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3 x 30 mL). The organic extracts were washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel (70-230 mesh) eluted with CH2Cl2 methanol 9:1 to give the product as a solid, mp 101-102 0C, in 65percent yield (183 mg, 0.38 mmol); 1H NMR (300 MHz, OMSO-d6) delta 0.83 (t, 3H, J = 6.6 Hz), 1.22-1.32 (m, 15H), 1.56 (m, 2H), 2.3 l(t, 2H, J = 6.0 Hz), 4.33 (q, 2H, J = 7.6 Hz), 7.71 (m, 4H), 10.19 (s, IH); 13C NMR (75 MHz, OMSO-d6) delta 14.6, 14.6, 22.8, 25.6, 29.3, 29.4, 29.5, 29.6, 31.3, 31.9, 37.1, 62.8, 119.1, 127.6, 136.8, 143.2, 147.7, 159.2, 170.3, 172.5; MS (LCQ, ESI+) Calcd for C2iH3iN4O5S2 483.2, found 483.1 (M+H)+; HRMS (ESI+, m/z) Calcd^+ for C2iH3iN4O5S2 483.1736, found 483.1728 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9% | With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;palladium diacetate; In 1,4-dioxane; at 20℃;Microwave irradiation; | To a stirred solution of Int-1 (2.0 g, 8.23 mmol) in 1,4-dioxane (30 mL) were added palladium (II) acetate (0.298 g, 1.31 mmol), Xanthophos (0.696 g, 1.31 mmol) and Int-2 (1.42 g, 8.23 mmol) followed by cesium carbonate (4.0 g, 12.34 mmol) at room temperature. The reaction mixture was thoroughly degassed and subjected to microwave irradiation (800 W) for 7 minutes. The volatiles were concentrated under reduced pressure; the residue was diluted with water (50 mL) and stirred for 30 minutes. The precipitated solid was filtered and dried to get crude material. The crude material was purified by column chromatography eluting with 3percent MeOH/DCM to afford Int-3 (0.3 g, 9percent) as yellowish solid. Mass (m/z): 381 [M++1]. 1H NMR (500 MHz, CDCl3): delta 12.3 (brs, 1H), 8.51-8.21 (m, 2H), 7.6 (d, J=12 Hz, 1H), 7.22-7.40 (m, 3H), 6.95 (t, J=10 Hz, 1H), 4.35-4.45 (q, 2H), 1.38 (t, J=12 Hz, 3H). To a stirred solution of Int-3 (0.4 g, 1.05 mmol) in methanol (16 mL), CH2Cl2 (16 mL) was added 50percent aqueous solution of NH2OH (50percent) at 0° C., and then stirred for 30 minutes. Then NaOH (0.32 g) in water (4 mL) was added to the reaction mixture at 0° C. The reaction mixture was allowed to room temperature, and then stirred for 16 hours. The volatiles were concentrated under vacuum. The residue was diluted with water (50 mL) and neutralized to about pH 7 using 2 N HCl. The precipitated solid was filtered, washed with water (30 mL) and dried under vacuum to afford the title compound (0.27 g, 69percent) as light brown solid. Mass (m/z): 367.9 [M++1]. 1H NMR (200 MHz, dmso-d6): delta 11.0 (bs, 1H), 8.52 (d, J=6.0 Hz, 2H), 7.59 (d, J=8.8 Hz, 1H), 7.37-7.25 (m, 3H), 6.96 (t, 1H), 2.46 (s, 3H). 13C NMR (125 MHz, dmso-d6): 162.18, 156.59, 155.81, 150.91, 147.48, 144.69, 142.51, 138.92, 125.53, 124.11, 118.24, 116.59, 116.31, 112.82, 109.89, 14.28. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Building block A1 (80 mg) was dissolved in DCM (2 ml), oxalylchloride (0.07 ml) was added and the mixture was stirred at room temperature for 0.75 h and then concentrated in vacuum. Pyridine (1 ml), 4-dimethylaminopyridine (2 mg) and 5-Amino-1,3,4-thiadiazole-2-carboxylic acid ethyl ester (60 mg) were added and the mixture was further stirred for 1 h, then concentrated, dissolved in acetonitrile and separated via reversed phase HPLC to give example 3 (17 mg). HPLC: 1.34 min (method D) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.28 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 100℃; for 0.5h;Microwave irradiation; Sealed tube; | [0377] 0.8 g of trans-4-(4-tert-butoxycarbonylmethylcyclohexyl)benzoic acid (2.51 mmol, 1 eq.) is placed in 12 mL of dimethylformamide at room temperature in a microwave tube. 0.769 g of hydroxybenzotriazole (5.02 mmol, 2 eq.), 0.962 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.02 mmol, 2 eq.) and 0.522 g of <strong>[64837-53-2]ethyl 5-amino[1.3.4]thiadiazole-2-carboxylate</strong> (3.01 mmol, 1.2 eq.) are successively added with stirring. The tube is sealed and the reaction mixture is heated for 30 minutes at 100° C. The reaction medium is diluted with ethyl acetate, washed three times with brine, dried over sodium sulfate, filtered and evaporated. The residue is chromatographed on silica gel, eluting with a gradient of methanol in dichloromethane ranging from 0percent to 2percent. The fractions of interest are evaporated and triturated in ethyl acetate. The solid obtained is dried to give 0.28 g of ethyl trans-5-[4-(4-tert-butoxy-carbonylmethylcyclohexyl)benzoylamino][1.3.4]thiadiazole-2-carboxylate, [0378] M+H+=475. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In dimethyl sulfoxide; at 20℃; | Step 1 :To a solution of 22a1 (100 mg, 0.6 mmol, Oakwood) in DMSO (3.0 mL) is added 1 N NaOH (3.5 mL, 3.5 mmol). The resulting mixture is stirred at RT overnight, then acidified with 1 N HCI (-1.5 mL) and extracted with EtOAc (3x). The organic extracts are combined, washed with brine, dried over MgS04, filtered and concentrated to provide 22a2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75 mg | With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃; for 1h;Cooling with ice; | 0239-1 A solution of <strong>[64837-53-2]ethyl 5-amino-1,3,4-thiadiazole-2-carboxylate</strong> (340 mg) in tetrahydrofuran (10 mL) was cooled by ice, and lithium aluminum hydride (a 10percent tetrahydrofuran solution, about 2.5 mol/L, 1 mL) was added dropwise thereto, followed by stirring at room temperature for 1 hour. After the reaction mixture was cooled by ice, ethyl acetate (2 mL) was added thereto, followed by stirring for 15 minutes under ice-cooling, and methanol (1 mL) was added thereto, followed by stirring for 5 minutes under ice-cooling. Anhydrous sodium sulfate aqueous solution (anhydrous sodium sulfate: 100 mg, water: 2 mL) was added to the reaction mixture, followed by neutralizing with 2 mol/L hydrochloric acid. The solid matter was separated by filtration, ethyl acetate was added thereto, and liquid-liquid separation was performed. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol), thereby obtaining (5-amino-1,3,4-thiadiazol-2-yl)methanol (75 mg). 1H-NMR (DMSO-d6) delta: 7.07 (2H, s), 5.74 (1H, t, J=6.1 Hz), 4.55 (2H, d, J=5.9 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44 mg | With sodium tris(acetoxy)borohydride; trifluoroacetic acid; In isopropyl alcohol; at 20 - 70℃; for 18h; | A suspension of 5-amino-[1 ,3,4]thiadiazole-2-carboxylic acid ethyl ester (0.30 g, 1 .75 mmol), TFA (0.27 mL, 3.50 mmol), 4-chlorobenzaldehyde (0.27 g, 1 .93 mmol) and sodium triacetoxyborohydride (0.45 g, 2.10 mmol) in isopropanol (3.5 mL) was stirred at room temperature for 2 hours and then at 70°C for 1 6 hours. After this time the reaction mixture wasconcentrated under reduced pressure and purified by flash column chromatography, eluting with EtOAc/cyclohexane (0-50percent) to afford the title compound (44 mg). LCMS method: Method 3, RT: 4.81 mm, Ml: 298 [M+1] 1H NMR (500 MHz, CDCI3) O 7.32 (d, 2H), 7.29 (d, 2H), 4.53 (5, 2H), 4.41 (q, 2H), 1 .39 (t, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | In N,N-dimethyl-formamide; at 100℃; for 2h; | To a solution of 5-amino-1 ,3,4-thiadiazole-2-carboxylic acid ethyl ester (1.0 eq., 8.8 g, 50 mmol) in DMF (105 ml_), at 100°C, was added (slow dropwise) a solution of 3-bromo- 1 ,1-difluoro-propan-2-one (1.05 equiv., 9.0 g, 52 mmol) in DMF (5 ml_). The reaction mixture was heated at 100°C during 2 h. 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 (9.0 g). The crude was purified by flash chromatography Biotage Isolera Four (100 g KP-SNAP silica gel column in a gradient of 0percent to 10percent methanol in dichloromethane over 14 CV) and the pure fractions were evaporated under high vacuum to give ethyl 6-(difluoromethyl)imidazo[2,1- b][1 ,3,4]thiadiazole-2-carboxylate XIV (4.48 g, 18.1 mmol) as a beige solid. Yield: 36percent LC/MS: [M+H]+ = 248.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In N,N-dimethyl-formamide; at 110℃; for 36h;Schlenk technique; Inert atmosphere; | General procedure: A 10-ml Schlenk tube equipped with a stir-bar was charged with compound 1 (0.2 mmol), compound 4 (0.3 mmol), Pd(OAc)2 (0.02 mmol), Xantphos (0.04 mmol), NaOtBu (0.3 mmol), anhydrous DMF (2 mL).The reaction tube was purged with argon. The Schlenk tube was placed in an oil-bath at 110 oC for 36 hours and then cooled to room temperature. The reaction mixture was extracted with EtOAc (3 × 20 mL). The combined organic phase was dried over MgSO4 and concentrated under reduced pressure and the crude residue purified by flash chromatography on silica gel (n-hexane:ethyl acetate = 1:1). The purified material was dried in vacuo to afford the corresponding product 5a-g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In N,N-dimethyl-formamide; at 110℃; for 36h;Schlenk technique; Inert atmosphere; | General procedure: A 10-ml Schlenk tube equipped with a stir-bar was charged with compound 1 (0.2 mmol), compound 4 (0.3 mmol), Pd(OAc)2 (0.02 mmol), Xantphos (0.04 mmol), NaOtBu (0.3 mmol), anhydrous DMF (2 mL).The reaction tube was purged with argon. The Schlenk tube was placed in an oil-bath at 110 oC for 36 hours and then cooled to room temperature. The reaction mixture was extracted with EtOAc (3 × 20 mL). The combined organic phase was dried over MgSO4 and concentrated under reduced pressure and the crude residue purified by flash chromatography on silica gel (n-hexane:ethyl acetate = 1:1). The purified material was dried in vacuo to afford the corresponding product 5a-g. |
Tags: 64837-53-2 synthesis path| 64837-53-2 SDS| 64837-53-2 COA| 64837-53-2 purity| 64837-53-2 application| 64837-53-2 NMR| 64837-53-2 COA| 64837-53-2 structure
A189756 [64837-49-6]
Ethyl 5-chloro-1,3,4-thiadiazole-2-carboxylate
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A307899 [15884-86-3]
5-(Methoxymethyl)-1,3,4-thiadiazol-2-amine
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A710744 [108-33-8]
2-Amino-5-methyl-1,3,4-thiadiazole
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A307899 [15884-86-3]
5-(Methoxymethyl)-1,3,4-thiadiazol-2-amine
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A189756 [64837-49-6]
Ethyl 5-chloro-1,3,4-thiadiazole-2-carboxylate
Similarity: 0.72
A293805 [1030613-07-0]
Ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate
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A710744 [108-33-8]
2-Amino-5-methyl-1,3,4-thiadiazole
Similarity: 0.57
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