Structure of 348-40-3
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Novel amides of mycophenolic acid and some heterocyclic derivatives as immunosuppressive agents
Walczak, Juliusz Maksymilian ; Iwaszkiewicz-Grzes, Dorota ; Ziomkowska, Michalina ; Sliwka-Kaszynska, Magdalena ; Dasko, Mateusz ; Trzonkowski, Piotr , et al.
Abstract: The group of 18 new amide derivatives of mycophenolic acid (MPA) and selected heterocyclic amines was synthesised as potential immunosuppressive agents functioning as inosine-5′-monophosphate dehydrogenase (IMPDH) uncompetitive inhibitors. The synthesis of 14 of them employed uronium-type activating system (TBTU/HOBt/DIPEA) while 4 of them concerned phosphonic acid anhydride method (T3P/Py) facilitating amides to be obtained in moderate to excellent yields without the need of phenolic group protection. Most of optimised protocols did not require complicated reaction work-ups, including chromatographic, solvent-consuming methods. The biological activity assay was performed on the T-Jurkat cell line and peripheral mononuclear blood cells (PBMCs) which are both dedicated for antiproliferative activity determination. Each of designed derivatives was characterised by reduced cytotoxicity and benzoxazole analogue (A2) revealed the most promising activity. Subsequently, an observed structure-activity relationship was discussed.
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Keywords: Mycophenolic acid ; amide derivatives ; heterocycles ; benzoxazole ; IMPDH inhibition
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Purchased from AmBeed: 934-32-7 ; 1477-42-5 ; 5464-79-9 ; 5464-79-9 ; 136-95-8 ; 95-24-9 ; 533-30-2 ; 1123-93-9 ; 6285-57-0 ; 15864-32-1 ; 29927-08-0 ; 348-40-3 ; 58-63-9 ; 4570-41-6 ; 75985-45-4 ; 24280-93-1 ; 2536-91-6 ; 19952-47-7 ; 1747-60-0 ; 777-12-8 ; 63837-12-7 ; 58-63-9
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CAS No. : | 348-40-3 |
Formula : | C7H5FN2S |
M.W : | 168.19 |
SMILES Code : | C1=CC(=CC2=C1N=C(N)S2)F |
MDL No. : | MFCD00013336 |
InChI Key : | CJLUXPZQUXVJNF-UHFFFAOYSA-N |
Pubchem ID : | 319954 |
GHS Pictogram: | ![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 9 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 43.98 |
TPSA ? Topological Polar Surface Area: Calculated from | 67.15 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from | 1.67 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by | 2.06 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from | 2.45 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from | 1.69 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by | 2.85 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions | 2.14 |
Log S (ESOL):? ESOL: Topological method implemented from | -2.79 |
Solubility | 0.275 mg/ml ; 0.00164 mol/l |
Class? Solubility class: Log S scale | Soluble |
Log S (Ali)? Ali: Topological method implemented from | -3.1 |
Solubility | 0.134 mg/ml ; 0.000796 mol/l |
Class? Solubility class: Log S scale | Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by | -2.88 |
Solubility | 0.22 mg/ml ; 0.00131 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 | Yes |
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) | Yes |
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 | -5.86 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) | 2.15 |
* 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 |
---|---|---|
89% | With hydrogenchloride; hydrazine hydrate; In water; at 5℃; for 5h;Reflux; | 6-Fluoro-2-hydrazinobenzothiazole (2). Hydrochloric acid (10 mL) was added dropwise to hydrazine hydrate 99% (10 g, 0.2 mol) at 5-10 C, followed by addition of a solution of 2-amino-6-fluorobenzothiazole (1) (3.364 g, 0.02 mol) in ethylene glycol (40 mL). The mixture was heated at reflux temperature for 5 h. On cooling, the precipitated solid was collected by filtration, washed with water, dried and crystallized from ethanol. Yield 89%, m.p. 194-196 C [1]. |
With hydrazine hydrochloride; hydrazine hydrate; In ethylene glycol; at 140℃; for 2h; | General procedure: The substituted aniline (1eq.) and ammonium thiocyanate (2eq.) in 150mL glacial acetic acid were cooled in an ice bath and stirred mechanically. To the sulution, bromine (2eq.) in 25ml glacial acetic acid was added dropwise at such arate to keep the temperature below 10oC throughout the addition. Stirring was continued for additional 30 min after the bromine addition. The precipitate was collected and recrystallization from ethanol to give 2-aminobenzthiazoles. Then, the substituted 2-aminobenzthiazoles (1eq) in ethylene glycol were added hydrazine hydrate (2eq.) and hydrazine dihydrochloride (2eq). The mixture was heated at 140 oC for 2h. After cooling, the precipitate was filtered to give used directly for next step without further purification. Then, the hydrazino compound was added to thionyl chloride (1eq.) for 2h at 50 oC. After evaporated under reduced pressure, the residue was taken up in ethyl acetate and washed with 1 M NaHCO3 and brine each for twice. The organic layer was dried and evaporated to give the crude final product. The crude product was purified by silica gel column chromatography using PE-EA as an eluent. | |
With hydrogenchloride; hydrazine hydrate; In water; ethylene glycol; at 5℃; for 5h;Reflux; | Hydrochloric acid (10 mL) was added dropwise to hydrazine hydrate 99% (10 g, 0.2 mol) at 5-10 C, followed by addition of a solution of 2-amino-6-fluorobenzothiazole (1) (3.364 g, 0.02 mol) in ethylene glycol (40 mL). The mixture was heated at reflux temperature for 5 h. On cooling, the precipitated solid was collected by filtration, washed with water, dried and crystallized from ethanol. Yield 89%, m.p. 194-196 C [1]. |
With hydrogenchloride; hydrazine hydrate; In water; ethylene glycol; at 5℃;Reflux; | Concentrated hydrochloric acid (0.067 mol) was added dropwise with stirring tohydrazine hydrate (0.12 mol) at 5-6 C followed by ethylene glycol (30 mL);thereafter, 6-uorobenzo[d]thiazol-2-amine (1) (20 mmol) was added in portionsand the resultant mixture was reuxed for 2-3 h and cooled at room temperature.The reaction progress was monitored by TLC using toluene:ethylacetate (75:25) asmobile phase. The reaction mixture was ltered and the resulting precipitates werewashed with distilled water. The resulting crude was recrystallized from ethanol. IR(KBr) mmax: 3010 (=C-H str), 1645 (C=C str), 1398 (C=N str). The 1HNMR(DMSO-d6) spectrum of this product showed signals: d 7.2-7.4 (3H, m, Ar C-H), at4.0 (1H, br, NH) and 4.75 (2H, br, NH2) ppm. The peaks in its 13CNMR (DMSO-d6)d: 106.1, 112.4, 115.5, 129.7, 145.5, 157.5, 171.2 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With tert.-butylnitrite; In hexane; ethyl acetate; acetonitrile; | (Step 1) Synthesis of 2-bromo-6-fluorobenzothiazole Copper (I) bromide (619 mg, 4.32 mmol) was suspended in acetonitrile (10 ml). To the resulting suspension was added tert-butyl nitrite (640 ael, 5.38 mmol), followed by stirring at 60ØC for 5 minutes. To the reaction mixture was added 2-amino-6-fluorobenzothiazole (605 mg, 3.60 mmol). The resulting mixture was stirred at 60ØC for 10 minutes. After cooling to the room temperature, the reaction mixture was diluted with ethyl acetate. The ethyl acetate solution was washed with 1N HCl, saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ ethyl acetate (5:1, v/v) eluate fractions, 2-bromo-6-fluorobenzothiazole (330 mg, 40%) was obtained as a brown solid. 1H-NMR (CDCl3) delta: 7.19-7.24 (m, 1H), 7.49-7.52 (m, 1H), 7.92-7.96 (m, 1H). MS (ESI) m/z 273.8 (M++1+MeCN). |
With sodium nitrite; In water; hydrogen bromide; | EXAMPLE 28 [(2-(6-Fluorobenzothiazolyl))carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester STR36 Slurry 2-amino-6-fluorobenzothiazole (0.255 mol) in water (325 mL), heat to reflux and add 48% hydrobromic acid (130 mL). Maintain at reflux for 20 minutes, cool to 0 C. and add a solution of sodium nitrite (17.56 g, 0.255 mol) water (90 mL), maintaining a temperature of 0 C. Stir at 0 C. for 15 minutes and add by dropwise addition (while keeping cold) to a rapidly stirring mixture of copper (I) bromide (42.03 g, 0.293 mol) in 48% hydrobromic acid (86 mL) and water (225 mL). Stir at room temperature for 20 minutes. Allow to stand overnight, extract into methylene chloride and dry (MgSO4). Evaporate the solvent in vacuo and purify by chromatography to give 2-bromo-6-fluorobenzothiazole. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With tert.-butylnitrite; copper(I) bromide; In acetonitrile; at 60.0℃; for 1.0h; | General procedure: To a stirred suspension of CuBr (1.57 g, 10.9 mmol) in MeCN (25 ml) was added tBuONO (1.63 ml, 13.7 mmol) and the mixture was stirred at 60 C for 10 min. Then 2-amino-6-methylbenzothiazole (14b) (1.50 g, 9.13 mmol) was added to the mixture, and the reaction mixture was stirred at 60 C for 1 h. After cooled to room temperature, the mixture was poured into 1 N HCl. The resulting precipitate was dissolved into EtOAc, washed with 1 N HCl, brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (7:1, v/v) as eluent to give the title compound (703 mg, 34%) as a brown oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In dichloromethane; ethyl acetate; at 0 - 20℃; for 3.0h; | General procedure: To a stirred solution of 5-amino-1-naphthol (126 mg, 0.792 mmol) and <strong>[70395-35-6]sodium chlorofluoroacetate</strong> (159 mg,1.18 mmol) in dichloromethane (8 mL) was added T3P (50 wt%solution in AcOEt, 701 μL, 1.18 mmol) and N,N-diisopropylethylamine(DIPEA) (273 μL, 1.57 mmol) at 0C. Afterstirred at ambient temperature for 1 h, the reaction mixturewas diluted with water and extracted thrice with CHCl3. Thecombined organic layers were washed with brine, dried overNa2SO4, filtered and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (hexane/AcOEt = 3 : 1) to afford the title compound (37.2 mg, 18% yield) as a pale purple solid. |
Tags: 348-40-3 synthesis path| 348-40-3 SDS| 348-40-3 COA| 348-40-3 purity| 348-40-3 application| 348-40-3 NMR| 348-40-3 COA| 348-40-3 structure
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