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CAS No. : | 66211-46-9 | MDL No. : | MFCD00798261 |
Formula : | C3H9NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | KQIGMPWTAHJUMN-GSVOUGTGSA-N |
M.W : | 91.11 | Pubchem ID : | 6994409 |
Synonyms : |
|
Num. heavy atoms : | 6 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 3.0 |
Molar Refractivity : | 21.57 |
TPSA : | 66.48 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -8.29 cm/s |
Log Po/w (iLOGP) : | 0.43 |
Log Po/w (XLOGP3) : | -2.02 |
Log Po/w (WLOGP) : | -1.7 |
Log Po/w (MLOGP) : | -1.51 |
Log Po/w (SILICOS-IT) : | -1.2 |
Consensus Log Po/w : | -1.2 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 3.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | 1.0 |
Solubility : | 911.0 mg/ml ; 9.99 mol/l |
Class : | Highly soluble |
Log S (Ali) : | 1.15 |
Solubility : | 1280.0 mg/ml ; 14.1 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | 0.87 |
Solubility : | 669.0 mg/ml ; 7.35 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.29 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P501-P264-P280-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338+P310-P405 | UN#: | 3259 |
Hazard Statements: | H314 | Packing Group: | Ⅲ |
GHS Pictogram: |
* 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 |
---|---|---|
21% | -((R)-2,3-Hydroxypropylamino)-3-(2-trifluoromethoxyphenyl)-2H-isoquinolin-1-one; [Show Image] 7-Chloro-3-(2-trifluoromethoxyphenyl)-2H-isoquinolin-1-one (340 mg, 1.00 mmol), (R)-(+)-3-amino-1,2-propanediol (273 mg, 3.00 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (47.2 mg, 0.12 mmol), and tris(dibenzylideneacetone)dipalladium (45.8 mg, 0.05 mmol) were dissolved in THF (5 ml). Thereafter, to the obtained solution, a 1 M lithium bis(trimethylsilyl)amide THF solution (7 ml, 7.00 mmol) was added. The obtained mixture was stirred under heating to reflux for 14 hours. The reaction solution was cooled to a room temperature, and a saturated ammonium chloride aqueous solution was then added thereto, followed by extraction with ethyl acetate. The extract was washed with a saturated saline solution, and was then dried over anhydrous sodium sulfate. The residue obtained by concentration of the extract was purified by silica gel column chromatography (dichloromethane : methanol = 50 : 1 to 20 : 1), so as to obtain 7-((R)-2,3-hydroxypropylamino)-3-(2-trifluoromethoxyphenyl)-2H-isoquinolin-1-one (83.4 mg, 21%) in the form of a Mars yellow solid. 1H-NMR (270MHz, CDCl3) delta (ppm): 3.30 (1H, dd, J=13.0, 7.5Hz), 3.45 (1H, dd, J=13.0, 4.0Hz), 3.69 (1H, dd, J=11.0, 6.0Hz), 3.81 (1H, dd, J=11.0, 3.5Hz), 4.03-4.12 (1H, m), 6.61 (1H, s), 7.03 (1H, dd, J=8.5, 2.5Hz), 7.34-7.45 (4H, m), 7.52 (1H, d, J=2.0Hz), 7.55 (1H, dd, J=7.5, 2.0Hz), 9.03 (1H, brs) ESI (LC-MS positive mode) m/z 395 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | In ethanol; at 130℃; for 0.166667h;Microwave irradiation; | EXAMPLE 368; 5-Bromo-3-[6-((R)-2,3-dihydroxy-propylamino)-2-propyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one; Example 188 (40 mg, 0.0983 mmol) and (R)-(+)-3-amino-1,2-propanediol (89 mg, 0.983 mmol) were heated in 1 mL EtOH at 130 C. in microwave for 10 min. Upon cooling, the product precipitated in the reaction tube. The resulting solid was filtered and pumped dry to afford 32 mg (71%) of a yellow solid. mp 293-296 C.; MS (ES+calculated: 461.32; found: 461.60, 462.75 M+H). HPLC (93%) purity, retention time 9.155 minutes-Method B); 1H NMR (400 MHz, TFA) delta 8.74 (s, 1H), 7.90 (s, 1H), 7.53 (d, J=8 Hz, 1H), 7.17 (d, J=8 Hz, 1H), 4.52 (m, 1H), 4.44 (m, 2H), 4.18 (m, 2H), 3.99 (m, 2H), 2.12 (q, J=7 Hz, 2H), 1.36 (m, 1H), 1.12 (t, J=7 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | In isopropyl alcohol; for 18h;Heating / reflux; | 5- [3, 4-Difluoro-2- (2-fluoro-4-iodo-phenylamino)-phenyl]-3H- [1, 3,4] oxadiazol-2- one (16.0 g, 37 mmol) and (R)- (+)-3-AMINO-1, 2-propanediol (4.25 g, 46.7 mmol) were combined in isopropanol (150 ML) and heated to reflux under a nitrogen atmosphere. After 18 h, the reaction mixture was cooled to ambient temperature and concentrated to about 1/4 volume. The crude reaction mixture was diluted with an approximately equal volume of ether, and crystallization was induced by scratching with a glass rod. The crystals were filtered, washed with ether, and dried in vacuo to afford the urea product as a crystalline solid (16.37 g, 84% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In butan-1-ol; at 112℃; for 48h; | A mixture of 5,6-dichloro-N4-(5-ethoxy-1H-pyrazol-3-yl)-N2-[(1S)-1-(4- fluorophenyl) ethyl] pyrimidine-2,4-diamine (Example 191;188 mg, 0.46 mmol), (2R)-3- aminopropane-1, 2-diol (96 mg, 1.05 mmol) in n-butanol (2.5 ml) was heated at112 C for 2 days. The mixture was concentrated. Reverse phase HPLC (Gilson) purification gave the title compound (18 mg). 1H NMR(CDCl3) : 8 1.29 (t, 3 H), 1.40 (d, 3 H), 3.18-3. 61 (m, 5 H), 4. 08 (q, 2 H), 4.93 (m, 1 H), 5.44 (s, 1 H), 6.59 (br s,1 H), 7.11 (m, 2 H), 7.38 (m, 2 H), 7.86 (br s,1 H), 9.27 (br s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 110℃; for 10h; | To a mixture of tert-butyl 4-(2-chloro-6-ethylthieno[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (EXA 16; 2.0 g) in NMP (5 mL) was added DIEA (1.42 g) and <strong>[66211-46-9](R)-3-amino-1,2-propanediol</strong> (1 g). The mixture was heated at 110 0C for 6 hours, then cooled and stirred at room temperature overnight. The mixture was again heated to 110 0C for 4 hours and cooled to room temperature. The mixture was then partitioned between brine and ethyl acetate. The layers were separated and the aqueous layer extracted with ethyl acetate. The ethyl acetate extracts were combined and washed three times with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel using ethyl acetate as elupsilonent to give 1.5 g of the title compound: 1H NMR (400 MHz, CDCl3) delta 1.3 (t, 3 H), 1.48 (s, 9 H), 2.8 (q, 2 H), 3.6 (m, 8 H), 3.77 (m, 6 H), 5.2 (m, 1 H), 6.8 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 100℃; for 29h; | A mixture of 4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-chloro-6-ethylthieno[2,3- d]pyrimidine (EXA 18, 0.150 g), R-(+)-3-amino-1 ,2-propanediol (0.0885 g), N, N- diisopropylethylamine (0.0461 g), and N-methylpyrrolidinone (1 mL) was stirred at 100 0C for 29 hours. After cooling and standing at room temperature overnight, the mixture was partitioned between ethyl acetate, aq. sodium bicarbonate, and brine. The organic layer was dried over magnesium sulfate, concentrated, and the residue chromatographed on silica gel using MeOH- dichloromethane (6/94) to give 0.0832 g of the title compound. MS [m+H] 518.2; 1H NMR (400 MHz, CDCI3) delta 1.30 (t, 3H), 2.79 (q, 2H), 3.5-3.9 (m, 15H), 5.1 (m, 1H), 6.76 (s, 1H), 7.35-7.65 (m, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 105℃; for 24h; | A mixture of 4-[4-(1 ,1 '-biphenyl-3-ylcarbonyl)piperazin-1-yl]-2-chloro-6-ethylthieno[2,3- d]pyrimidine (EXA 33, 0.101 g), R-(+)-3-amino-1 ,2-propanediol (0.0595 g), N, N- diisopropylethylamine (0.0338 g), and N-methylpyrrolidinone (1 mL) was stirred at 105 0C for 24 hours. After cooling, the mixture was partitioned between ethyl acetate, aq. sodium bicarbonate, and brine. The organic layer was dried over magnesium sulfate, concentrated, and the residue chromatographed on silica gel using MeOH-ethyl acetate (2/99) to give 0.036 g of the title compound. MS [m+H] 518.3; 1H NMR (400 MHz, CDCl3) delta 1.29 (t, 3H), 2.79 (q, 2H), 3.5-4.0: (m, 15H), 5.10 (m, 1H), 6.74 (s, 1H), 7.36-7.68 (m, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate; isopropyl alcohol; | 3-(t-Butoxycarbonyl)-6-[(R)-propane-1,2-diol-3-yl]aminopyridine A mixture of <strong>[115309-57-4]t-butyl 6-chloronicotinate</strong> (4.69 g, 0.0220 mol) and (R)-3-amino-1,2-propanediol (5.00 g, 0.0549 mol) in isopropanol (20 ml) was heated at 100 C. overnight. Solvent was removed under vacuum, and the residue taken up in ethyl acetate, washed with water, brine, dried (MgSO4), and evaporated to give nearly pure product as a yellow oil. Yield 5.90 g (99%). 1H NMR. MS: 269 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.80 g (65.6%) | With ammonium hydroxide; In methanol; ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 17 Preparation of (R)-4-[[(2,3-Dihydroxypropyl)amino]methyl]-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]benzeneacetamide hydrochloride <strong>[66211-46-9](R)-3-Amino-1,2-propanediol</strong> (5.0 g, 54.9 mmol, 10.5 eq) was dissolved in 50 mL of N,N-dimethylformamide under N2. 4-(Bromomethyl)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]benzeneacetamide (2.50 g, 5.20 mmol, 1 eq) was added in small portions and the reaction mixture was stirred for 2 h at rt. The mixture was diluted with ethyl acetate (250 mL) and washed with water and 10% aqueous LiCl. The aqueous phase was back-extracted twice with ethyl acetate. The organic extracts were dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography on silica gel eluding with a gradient of 10-20% methanol in ethyl acetate with 0.5% ammonium hydroxide provided 1.80 g (65.6%) of (R)-4-[[(2,3-dihydroxypropyl)amino]methyl]-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]benzeneacetamide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With triethylamine; In methanol; acetonitrile; at -10 - 20℃; for 16.5h; | Triethylamine (1.83 mL, 13.2 mmol) was added to a solution of (R)-3-amino-1 ,2- propanediol (1.00 g, 11.0 mmol) in a mixture CH3CN / MeOH (36 mL / 16 mL) at -10 0C under nitrogen. Chloroacetyl chloride (0.98 ml, 12.0 mmol) was added dropwise at -10 0C over 30 min. The reaction mixture was allowed to reach room temperature and stirred for 16 h. The mixture was concentrated and purified by flash column chromatography on silica gel, eluting with methanol / ethyl acetate (8 / 92), to give the title compound as a white solid (1.43 g, 78%).1H NMR (Acetone-d6, 500 MHz,) delta 7.59 (s, 1 H), 4.12 (s, 2H), 4.08 (brs, 1 H), 3.84 (s, 1 H), 3.73 (q, 1 H, J = 5.4 Hz), 3.50 (q, 1 H, J = 5.4 Hz), 3.47-3.42 (m, 1H), 3.32-3.27 (m, 1H). |
52% | With triethylamine; In methanol; acetonitrile; at -10 - 20℃; for 18.75h; | Step a) (R)-2-chloro-N-(2,3-dihydroxy-propyl)-acetamide An oven-dried flask was charged with (R)-3-amino-1 ,2-propanediol (1.73g, 19mmol), methanol (11ml) and acetonitrile (60ml). The flask was purged with argon, cooled to -1O0C in a salt ice bath and triethylamine (3.2ml, 22.8mmol) added. Chloroacetyl chloride (1.7ml, 20.9mmol) was then added dropwise over a period of 45 minutes. The reaction was then allowed to reach room temperature and stirred for 18h. Solvent was removed in vacuo and the residue purified by flash chromatography (silica gel, 0-7% MeOH in EtOAc) to give the desired product as a colourless oil (1.67g, 52%), m/z = 168 (M+H) in MS ES+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In 2-ethoxy-ethanol; | Example 18 (R)-3-(Acridin-9-ylamino)propane-1,2-diol (Compound 5a) 9-chloro-acridine (1 g, 4.68 mmol) and (R)-3-amino-propane-1,2-diol (0.42 g, 4.68 mmol) in 2-ethoxyethanol (40 ml) was heated at 120 C. for 30 min. Removal of the solvent yielded the desired compound (0.9 g, 75%) as a yellow solid. HPLC (conditions in example 1) single peak of retention time 8.4 min. 1H-NMR [MeOD delta, ppm]: 8.01 (m, 2H), 7.84 (m, 2H), 7.60 (m, 2H), 4.37-4.28 (m, 2H, (CH2NH), 4.17 (m, 1H, CHOH), 3.82-3.75 (m, 2H, CH2OH). MS (Cl/NH3) found 269.1, expected for C16H16N2O2 268.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of 5.89 g (64.7 mmol) (R)-3-amino-propane-1,2-diol, 9.58 g (64.7 mmol) 3-isopropyl-benzaldehyde in 30 ml toluene and 30 ml cyclohexane containing 1 ml EtOH is refluxed with azeotropic removal of water. The residual clear solution is concentrated in vacuum, dissolved in 200 ml EtOH and cooled to +4 C. A solution of 4.9 g NaBH4 in 10 ml water is slowly added so that the reaction temperature does not exceed +10 C. The mixture is stirred at 25 C. for 16 h. Excess hydride is quenched through the dropwise addition of 55 ml 4N HCl. After 1 h the mixture is evaporated to dryness. After addition of toluene/EtOH this is repeated twice. The residue is taken up in 200 ml EtOH, filtered and concentrated in vacuo to yield 16.6 g of the hydrochloride salt of the title compound as a colorless oil, which is used in the next step without purification.LC (Nucleosil C-18HD, 4×70 mm, 3 mum, 20-100% AcCN (6 min), 100% AcCN (1.5 min)): 2.503 min MS (ES) MH+=2241H-NMR (400 MHz, CD3OD): 7.43-7.34 (m, 4H), 4.25 (s, 2H), 4.00-3.93 (m, 1H), 3.65-3.54 (m, 2H), 3.22-2.94 (m, 3H), 1.28 (d, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | 19a. (2R) -2, 3-Bis (nitrooxy) PROPYLAMINE, hydrochloride salt Fuming nitric acid (4.5 ML, 113.7 mmol) and acetic anhydride (Aldrich, Wisconsin, U. S. , 17.2 ML, 181.9 mmol) were combined at 0 C and stirred for 15 minutes. The mixture was then added to a solution of (R)-3-AMINO-1, 2-propandiol (Aldrich, Wisconsin, U. S. , 2. 1 g, 22.7 mmol) and fuming nitric acid (2. 7 ML, 68. 2 mmol) in EtOAc (10 ML) cooled to 0 C, and the resulting mixture stirred at 0 C for 3 hours. The solvent was removed under reduced pressure and the resulting residue triturated in ether to give the title compound (1. 1 g, 23% yield) as a solid which was collected via filtration : 1H NMR (300 MHz, CDC13) 8 8.08-8. 06 (br s, 3H), 5.66-5. 59 (M, 1H), 5.00-4. 94 (m, 1H), 4.82-4. 75 (m, 1H), 3.45-3. 37 (m, 1H), 3.32-3. 20 (m, 1H). Mass spectrum API-TIS-M/Z 182 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In dichloromethane; at 20℃; for 8h; | A mixture of 2-methyl-5-[(Z)-(2-oxo-l,2-dihydro-3H-i?dol-3-yl(de?e)metriyl]-4-plienyl-1 H-pyrrole-3-carboxylic acid (500 mg, 1 45mmol.), O-(benzotriazol-1-yl)-N,N,NN'- tetramethyluronium tetrafluoborate (TBTU1 1 39 g, 435 mmol ), triethylami?e (1 02 mL, 435 mmol) and (R)-3-amino-1,2-propandiol (396 mg, 4 35 mmol ) in dichloromethane (20 mL) was stirred at room temperature for 8h The reaction mixture was treated with 2N HCI, and extracted with AcOEt (4x20 mL) The organic phases were combined, washed with water (2x15 mL), dried on anhydrous Na2SO4, filtered and evaporated to dryness The crude residue was chromatographed on silica gel, using dichloromethane-ethanol 20:1 as eluant, to give 240 mg (40% yield) of the desired product as yellow solid 1 H-NMR (400 MHz), delta (ppm, DMSOd6): 1386 (bs, 1H), 11 02 (bs, 1H), 7.56-739 (m, 5H), 727-724 (d, 1H, J=762 Hz)1 723-7 19 (m. 1H), 722 (s, IH)1 7 19-7 15 (td, 1H, J=1 06 Hz, J=762 Hz), 7 00-696 (td, 1H, J=O 76 Hz1 J=746 Hz), 6 95-6.92 (d, IH, J=7 76 Hz)1 4 92-3 98 (m, 2H), 3 57-2 97 (m, 5H),2 57-2 51 (m, 3H) [alpha]D= -4 5 (20 mg/mL, DMF) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In tetrahydrofuran; at 60℃; for 20h; | A. Preparation of 2-[4,5-bis(benzyloxy)pyridin-2-yl]carbonyl}-N-[(2R)-2,3-dihydroxypropyl]hydrazinecarboxamide (C19). (2R)-3-Aminopropane-1,2-diol (0.291 g, 3.19 mmol) was added to a suspension of C6 (1.0 g, 2.66 mmol) in tetrahydrofuran (50 mL), and the mixture was heated to 60 C. for 20 hours. After cooling to room temperature, the suspension was filtered, and the solid was washed with tetrahydrofuran (3*5 mL) to afford C19 as a white solid. Yield: 1.07 g, 2.29 mmol, 86%. LCMS m/z 467.2 (M+1). 1H NMR (400 MHz, DMSO-d6) delta 2.93 (m, 1H), 3.19 (m, 1H), 3.27 (m, 2H), 3.44 (m, 1H), 4.53 (t, J=5.8 Hz, 1H), 4.77 (d, J=4.8 Hz, 1H), 5.33 (s, 4H), 6.31 (t, J=5.5 Hz, 1H), 7.31-7.48 (m, 10H), 7.69 (s, 1H), 8.01 (br s, 1H), 8.28 (s, 1H), 10.04 (br s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General Procedure O: Synthesis of compounds in Table O; Compounds in Table O were produced as part of a one dimensional array with the only variant being the aldehyde monomer which is given in Table O. The amines were purchased pre- weighed from the Sigma Aldrich Custom Packaged Reagent service.; In a 20 mL vial a solution of 4-(trimethylsilyl)ethynylbenzaldehyde (1.2 eq) dissolved in MeOH:DCM (1.5 mL) was added, followed by the addition of amine core (20 mg, leq.) dissolved in MeOH:DCM (1.0 mL), and HOAc (3 eq.). The mixture was shaken at about 50 C for about 2 h and MP-cyanoborohydride resin (5 eq.) (Biotage) was added. This reaction mixture was allowed to stir overnight at about 50 C. The reaction was checked by LC/MS and concentrated to dryness. The residue was dissolved in 1 : 1 DMSO/MeOH and purified by reverse phase HPLC. Product was characterized by MS and LC/MS (Table 2, Method a). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 100℃; | A mixture of Intermediate 23 (150 mg, 0.44 mmol), (R)-3 -amino- 1 ,2-propanediol (200 mg, 2.19 mmol) and DIPEA (0.4 mL, 2.19 mmol) in NMP (3 mL) was heated at 1000C overnight. The reaction mixture was cooled and partitioned between water (30 mL) and EtOAc (100 mL). The organic layer was washed with water (5 x 20 mL), separated, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 75-100% EtOAc in isohexane) to give the title compound (147 mg, 85%) as a white solid. deltaH (CDCl3) 7.75 (IH, s), 7.64 (IH, dd, J 7.6, 1.2 Hz), 7.49 (IH, dd, J8.0, 1.2 Hz), 7.13 (IH, t, J7.8 Hz), 7.00-6.90 (IH, m), 5.26-5.20 (IH, m), 4.98- 4.90 (IH, m), 4.41 (IH, d, J 10.0 Hz), 3.90-3.75 (3H, m), 3.61-3.56 (2H, m), 3.38-3.32 (IH, m), 1.67 (3H, d, J 6.8 Hz), 1.45 (9H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With pyridine; In dichloromethane; ethyl acetate; N,N-dimethyl-formamide; for 0.333333h; | Step 1-Synthesis of (R)-1-(4-bromophenyl)-3-(2,3-dihydroxypropyl)urea (ac). A solution of 1-bromo-4-isocyanatobenzene (aa, 430 mg, 2.17 mmol) and 1,2-dichloroethane (2 mL) was added dropwise to a suspension of (R)-3-aminopropane-1,2-diol (ab, 268 mg, 2.94 mmol) in a mixture of DMF:pyridine:1,2-dichloroethane (1:1:2, 4 mL). The mixture solidified upon completion of addition. Ethyl acetate (30 mL) was added, and stirred for 20 min. The solid was collected on paper, rinsed with ethyl acetate, and dried under vacuum to afford 492 mg (78%) of (R)-1-(4-bromophenyl)-3-(2,3-dihydroxypropyl)urea (ac) as a colorless solid: 1H NMR (400 MHz, DMSO) delta 8.72 (s, 1H), 7.43-7.25 (m, 4H), 6.15 (t, J=5.6 Hz, 1H), 4.82 (d, J=4.9 Hz, 1H), 4.56 (t, J=5.6 Hz, 1H), 3.55-3.46 (m, 1H), 3.37-3.33 (m, 1H), 3.00-2.94 (m, 1H); LC-MS: m/z=+290 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chiral stationary phase including isopropyl-functionalized CF6; In methanol; acetic acid; triethylamine; acetonitrile; at 20℃;Purification / work up; | In addition to the foregoing, numerous other chromatographic separations using a column bonded with a CSP including a derivatized cyclofructan residue were carried out. Tables 5-9 list some additional examples of chromatographic separations using a column bonded with a CSP of the present invention. AU examples of chromatographic separations using columns bonded with CSPs of the present invention were carried out using the following experimental conditions and procedures.|0132| The high performance liquid chromatography (HPLC) column packing system was composed of an air driven fluid pump (HASKEL, DSTV- 122), an air compressor, a pressure regulator, a low pressure gauge, two high-pressure gauges (10,000 and 6,000 psi), a slurry chamber, check valves, and tubings. The CSPs were slurry packed into a 25 cm x 0.46 cm (inner diameter, I. D.) stainless steel column.|0133| The HPLC system was an Agilent 1 100 system (Agilent Technologies, Palo Alto,CA), which consisted of a diode array detector, an autosampler, a binary pump, a temperature- controlled column chamber, and Chemstation software. All chiral analytes were dissolved in ethanol, methanol, or other appropriate mobile phases, as indicated. For the LC analysis, the injection volume and flow rate were 5 muL and 1 mL/min, respectively. Separations were carried out at room temperature (~20 0C) if not specified otherwise. The wavelengths of UV detection were 195, 200, 210, and 254 nm. The mobile phase was degassed by ultrasonication under vacuum for 5 min. Each sample was analyzed in duplicate. Three operation modes (the normal phase mode, polar organic mode, and reversed phase mode) were tested, unless indicated otherwise. In the normal phase mode, heptane with ethanol or isopropanol was used as the mobile phase. In some cases, trifluoroacetic acid (TFA) was used as an additive, as indicated. The mobile phase of the polar organic mode was composed of acetonitrile/methanol and small amounts of acetic acid and triethylamine. Water/acetonitrile or acetonitrile/acetate buffer (20 mM, pH = 4.1 ) was used as the mobile phase in the reversed-phase mode.|0134| Two different supercritical fluid chromatographic instruments were used. One was a Berger SFC unit with an FCM 1200 flow control module, a TCM 2100 thermal column module, a dual pump control module, and a column selection valve. The flow rate was 4 mL/min. The cosolvent was composed of methanol/ethanol/isopropanol = 1 : 1 : 1 and 0.2% diethylamine (DEA). The gradient mobile phase composition was 5% cosolvent hold during 0- 0.6 min, 5-60% during 0.6-4.3 min, 60% hold during 4.3-6.3 min, 60%-5% during 6.3-6.9 min, and 5% hold during 6.9-8.0 min. The other SFC system was a Jasco (MD, USA) system comprised of an autosampler unit (AS-2059-SF Plus), a dual pump module (PU-2086 Plus), a column thermostat module (CO-2060 Plus), a UV/Vis detector (UV-2075 Plus), and a back pressure regulator module (SCH-Vch-BP). Unless otherwise specified, the mobile phase was composed of CCVmethanol (0.1 % TFA or 0.1% diethylamine). The flow rate was 3 mL/min.|0135| For the calculations of chromatographic data, the "dead time" to was determined by the peak of the refractive index change due to the sample solvent or determined by injecting l ,3,5-tri-/e/-/-butylbenzene in the normal phase mode. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 10 2-(2R,3-Dihydroxy-propylamino)-5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one 2-(2R,3-Dihydroxy-propylamino)-5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one was prepared from 1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and (R)-3-amino-propane-1,2-diol following General Procedure C. 1H NMR (DMSO-d6): delta 8.28 (s, 1H), 8.02 (s, 1H), 7.69-7.73 (2H), 7.58 (d, 2H), 7.25 (s, 1H), 7.11 (m, 1H), 6.74 (d, 1H), 5.75 (s, 2H), 5.09 (m, 1H), 4.75 (br, 2H), 3.77 (s, 3H), 3.64-3.71 (2H). LC/MS: mass calcd. for C23H21F3N4O4S: 506.12, found 507.3 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | In tetrahydrofuran; at 20℃; for 2h; | Example 17 2-([2-(4-Chlorophenyl)-1,3-thiazol-4-yl]methylsulfanyl)-6-[(2R)-2,3-dihydroxypropyl]amino-4-(1,3-thiazol-5-yl)pyridine-3,5-dicarbonitrile 100 mg (0.206 mmol) of 2-chloro-6-([2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-4-(1,3-thiazol-5-yl)pyridine-3,5-dicarbonitrile, together with 38 mg (0.411 mmol) of (2R)-3-aminopropane-1,2-diol, were dissolved in 1.5 ml of THF. The mixture was stirred at room temperature for two hours, and the product was then purified by preparative HPLC (acetonitrile/water: 10:90?95:5, 0.1% TFA added). This gave 64 mg (58%/0 of theory) of the target compound. 1H-NMR (500 MHz, DMSO-d6): delta=9.41 (d, 1H), 8.31 (d, 1H), 8.10 (t, 1H), 7.96 (d, 2H), 7.73 (s, 1H), 7.57 (d, 2H), 4.92 (d, 1H), 4.78-4.68 (m, 3H), 3.81-3.71 (m, 2H), 3.58-3.48 (m, 1H), 3.44-3.40 (m, 2H). LC-MS (Method 2): Rt=2.42 min; MS (ESIpos): m/z=541 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h; | General procedure: To a solution of amines (2.5 equiv) and DIPEA (5 equiv) in CH2Cl2 at room temperature was added a solution of 3-[(E)-2-(4-chlorophenyl)vinyl]-4-methoxy-benzoyl chloride (1 equiv) in CH2Cl2 and the mixture was stirred for 1 h at room temperature. The reaction mixture was washed with saturated aqueous solution of NH4Cl and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, n-hexane/EtOAc) to give the desired products 32a-h. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | In a flame-dried flask equipped with a CaCl2 guard tube and an air condenser, kept at 0 C, dry CH2Cl2 (34 mL) and fuming HNO3 (d = 1.52) (3.30 mL) were mixed cautiously; to this mixture, powdered (R)-3-amino-1,2-propandiol (1.2 g; 13.2 mmol) was added portionwise. The mixture was stirred vigorously at 0 C for 2 h, then acetic anhydride (3.0 mL; 31.8 mmol) was added and the reaction stirred at 0 C for a further 45 min The resulting precipitate was filtered through a sintered glass funnel, collected and dried over P2O5, KOH overnight, to afford 2.60 g (81%) of an off-white solid. The product was recrystallized from iPrOH to obtain a white solid. 1H NMR (DMSO-d6): delta, 8.16 (s, br 3H, NH3+); 5.67-5.62 (m, 1H, CHONO2); 4.98 (dd, 2H, Jgem = 12.9 Hz; Jvic = 3.3 Hz, CHHONO2); 4.79 (dd, 2H, Jgem = 12.9; Jvic = 5.4 Hz, CHHONO2); 3.39-3.33 (m, 2H, CHHNH3+); 3.21 (dd, 2H, Jgem = 14.1; Jvic = 9.3 Hz, CHHNH3+). 13C NMR (DMSO-d6): delta, 76.4; 70; 37.3, spectral data are in agreement with those of an authentic sample [57]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 70℃; | General procedure: A mixture of 2-(4-bromo-3-fluorophenyl)-4-chloro-6-methylpyrimidine (14d, 241 mg), (S)-3-amino-1,2-propanediol (366 mg), N,N-diisopropylethylamine (0.14 mL) and acetonitrile (4 mL) was stirred at 70 C for 4 days. The reaction mixture was cooled down to room temperature. To the mixture was added water, and extracted with chloroform. The organic layer was dried, and the desiccant was removed by filtration, and then the solvent was evaporated in vacuo. The resulting residue was dissolved in ethanol (5 mL), and to the solution was added oxalic acid (108 mg). The mixture was evaporated in vacuo and the residue was recrystallized from acetonitrile and ethanol, and the crystal was dried in vacuo to obtain 24a (228 mg, 64%) as a colorless crystal. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 70℃; | General procedure: A mixture of 2-(4-bromo-3-fluorophenyl)-4-chloro-6-methylpyrimidine (14d, 241 mg), (S)-3-amino-1,2-propanediol (366 mg), N,N-diisopropylethylamine (0.14 mL) and acetonitrile (4 mL) was stirred at 70 C for 4 days. The reaction mixture was cooled down to room temperature. To the mixture was added water, and extracted with chloroform. The organic layer was dried, and the desiccant was removed by filtration, and then the solvent was evaporated in vacuo. The resulting residue was dissolved in ethanol (5 mL), and to the solution was added oxalic acid (108 mg). The mixture was evaporated in vacuo and the residue was recrystallized from acetonitrile and ethanol, and the crystal was dried in vacuo to obtain 24a (228 mg, 64%) as a colorless crystal. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 70℃; | General procedure: A mixture of 2-(4-bromo-3-fluorophenyl)-4-chloro-6-methylpyrimidine (14d, 241 mg), (S)-3-amino-1,2-propanediol (366 mg), N,N-diisopropylethylamine (0.14 mL) and acetonitrile (4 mL) was stirred at 70 C for 4 days. The reaction mixture was cooled down to room temperature. To the mixture was added water, and extracted with chloroform. The organic layer was dried, and the desiccant was removed by filtration, and then the solvent was evaporated in vacuo. The resulting residue was dissolved in ethanol (5 mL), and to the solution was added oxalic acid (108 mg). The mixture was evaporated in vacuo and the residue was recrystallized from acetonitrile and ethanol, and the crystal was dried in vacuo to obtain 24a (228 mg, 64%) as a colorless crystal. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 70℃; | General procedure: A mixture of 2-(4-bromo-3-fluorophenyl)-4-chloro-6-methylpyrimidine (14d, 241 mg), (S)-3-amino-1,2-propanediol (366 mg), N,N-diisopropylethylamine (0.14 mL) and acetonitrile (4 mL) was stirred at 70 C for 4 days. The reaction mixture was cooled down to room temperature. To the mixture was added water, and extracted with chloroform. The organic layer was dried, and the desiccant was removed by filtration, and then the solvent was evaporated in vacuo. The resulting residue was dissolved in ethanol (5 mL), and to the solution was added oxalic acid (108 mg). The mixture was evaporated in vacuo and the residue was recrystallized from acetonitrile and ethanol, and the crystal was dried in vacuo to obtain 24a (228 mg, 64%) as a colorless crystal. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 70℃; | General procedure: A mixture of 2-(4-bromo-3-fluorophenyl)-4-chloro-6-methylpyrimidine (14d, 241 mg), (S)-3-amino-1,2-propanediol (366 mg), N,N-diisopropylethylamine (0.14 mL) and acetonitrile (4 mL) was stirred at 70 C for 4 days. The reaction mixture was cooled down to room temperature. To the mixture was added water, and extracted with chloroform. The organic layer was dried, and the desiccant was removed by filtration, and then the solvent was evaporated in vacuo. The resulting residue was dissolved in ethanol (5 mL), and to the solution was added oxalic acid (108 mg). The mixture was evaporated in vacuo and the residue was recrystallized from acetonitrile and ethanol, and the crystal was dried in vacuo to obtain 24a (228 mg, 64%) as a colorless crystal. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Heating; | For the second reaction, intermediate b (0.1-1 mmol) was dissolved in an excess (1-5 mL) of the required amine, and the mixture was stirred at 100-150 C, until TLC analysis confirmed the absence of starting materials (typically 24-48 h). After the mixture was cooled, the crude product was precipitated by addition of H2O (30-50 mL) and collected by filtration and/or extraction with EtOAc. The product was purified by chromatography on silica (yields 97%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 16, Method C(2R)-3-[3-(1 -Benzofuran-2-yl)imidazo[1 ,2-b]pyridazin-6-yl]amino}propane-1 ,2- diolStep 1 : To a solution of 300 mg (3.29 mmol) (/?)-3-aminopropanol in 6 mL of DMF were added 1 .57 g (7.90 mmol) potassium bis(trimethylsilyl)amide and 2.1 g (7.24 mmol) ferf.-butyldiphenylsilylchloride. The reaction was stirred over night at room temperature. The crude mixture was used directly in the next step.Step 2: A second flask was charged with 317 mg (1 .17 mmol) 3-(1 -benzofur-2-yl)-6- chloroimidazo[1 ,2-b]pyridazine, 54 mg (0.06 mmol) tris(dibenzylidenacetone)- dipalladium, 75.5 mg (0.118 mmol) (Kac)-BINAP and 678 mg (7.06 mmol) NaO¾u. The crude mixture from step 1 was added and the resulting mixture was stirred at 100 C for 3 days.Step 3: The mixture was allowed to cool to room temperature. 5.88 mL (5.88 mmol) of a 1 M tetra-n-butylammoniumfluoride solution in THF was added. The reaction mixture was stirred for 30 min at room temperature. 20 mL of brine were added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and the solvent evaporated. The crude product was purified by preparative HPLC to give 42 mg (1 1 % over 3 steps) of the title compound as solid material.1 H-NMR (300 MHz, DMSO-d6), delta [ppm]= 2.54 (1 H), 3.16-3.27 (1 H), 3.45 (1 H), 3.64- 3.75 (1 H), 3.82-3.93 (1 H), 6.88 (1 H), 7.29 (2H), 7.58-7.64 (1 H), 7.71 (2H), 7.81 (1 H), 7.92 (1 H), 8.14 (2H).LCMS (Method 2): Rt = 0.77 min; MS (ESIpos) m/z = 325 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In tetrahydrofuran; at 20℃; | 61.5 mg (0.15 mmol) of 3-[(6-chloro-3,5-dicyano-4-phenylpyridin-2-yl)sulfanyl]methyl}benzene-carboxylic acid (Example 72A) were initially charged in 1.6 ml of THF. After addition of 27.6 mg (0.30 mmol) of (2R)-3-aminopropane-1,2-diol, the mixture was stirred at RT overnight. 2 ml of water were added, and the reaction mixture was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid). Yield: 52 mg (75% of theory) LC-MS (Method 3): Rt=2.21 min; MS (ESIpos): m/z=461 [M+H]+. 1H NMR (400 MHz, DMSO-d6): delta=13.07-12.98 (br s, 1H), 8.05 (s, 1H), 7.91 (t, 1H), 7.85 (d, 1H), 7.72 (d, 1H), 7.60-7.51 (m, 5H), 7.47 (t, 1H), 4.96-4.92 (br s, 1H), 4.75-4.69 (br s, 1H), 4.65 (d, 2H), 3.81-3.70 (m, 2H), 3.52-3.44 (m, 1H), 3.43-3.35 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | 50 mg (0.12 mmol) of 3-([6-amino-3,5-dicyano-4-(4-fluorophenyl)pyridin-2-yl]sulfanyl}methyl)-benzenecarboxylic acid Example 14 were initially charged in 1.2 ml of DMF. The reaction solution was cooled to 0 C. After addition of 94 mg (0.25 mmol) of HATU, the mixture was stirred at 0 C. for 20 min. 22.5 mg (0.25 mmol) of <strong>[66211-46-9](R)-3-amino-1,2-propanediol</strong> and 32 mg (0.25 mmol) of N,N-diisopropylethylamine were added, and the reaction solution was stirred at RT overnight. Water and tetrahydrofuran were added to the reaction mixture until a clear solution had formed. The solution was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid). Yield: 47 mg (80% of theory) LC-MS (Method 10): Rt=1.78 min; MS (ESIpos): m/z=478 [M+H]+. 1H NMR (400 MHz, DMSO-d6): delta=8.39 (t, 1H), 8.35-7.95 (br s, 2H), 7.99 (s, 1H), 7.77-7.68 (m, 2H), 7.65-7.58 (m, 2H), 7.45-7.37 (m, 3H), 4.81 (d, 1H), 4.61-4.53 (m, 3H), 3.69-3.60 (m, 1H), 3.44-3.31 (m, 3H), 3.24-3.15 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With toluene-4-sulfonic acid; In toluene; for 8h;Inert atmosphere; Reflux; | General procedure: To a solution of (S)-3-Amino-1,2-propanediol (400 mg, 4.39 mmol) and acetonylacetone (600 mg, 5.26 mmol) in 40 mLtoluene was added p-TsOH (17 mg, 0.0878 mmol). The resulting solution was heated to reflux,and the generated water was isolated via a dean stark apparatus. After 8-hour reaction, the solvent was removed under reduced pressure, and crude product was further purified via silicagel chromatography (EtOAc/Hexanes = 1/10) to afford a pale yellow solid, 570 mg. 77%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In ethanol; at 100℃; for 1h;Microwave irradiation; | A mixture of 6-(bromomethyl)-5-(3-chlorobenzoyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (2 g, 5.38 mmol), (R)-3-aminopropane-1,2-diol (0.490 g, 5.38 mmol) and triethylamine (0.750 ml, 5.38 mmol) in EtOH (17.94 ml) was heated under microwave irradiation at 100 C. for 1 hour. The mixture was evaporated under vacuum and the residue partitioned between DCM (20 mL) and 1M HCl (20 mL). The phases were separated and the organic phase was washed with water (2*20 mL). The organic phase was passed through a hydrophobic frit and evaporate under vacuum to afford the title compound. 1H NMR (400 MHz, CDCl3) delta 7.44 (3H, m), 7.37 (1H, m), 6.58 (1H, br s), 4.02 (2H, t), 3.94 (1H, m), 3.61 (1H, dd), 3.43 (4H, m), 3.36 (3H, s) LC-MS Rt 0.84 mins [M+H]+ 364.2 (Method 2minLowpHv01) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With Novozym 435 lipase on resin; In acetone; at 35℃; for 8h;Green chemistry; Enzymatic reaction; | General procedure: A representative synthetic procedure is given hereafter: To 500mg (1.5mmol) of DPA ethyl ester as an oil were added 100mg of Novozym 435 lipase on resin and 5 equiv (7.5mmol) of serinol. A minimum amount of acetone was then added to decrease viscosity (1mL). The mixture was magnetically stirred for 4-18h at 35C until TLC indicated complete disappearance of the ethyl ester (to be noted, LC-MS methods with UV detection are not useful to follow these reactions owing to the very low absorbance of the chromophores). The reaction was then filtered, acetone was evaporated then water added. The mixture was extracted with a minimal amount of diethyl ether (1mL) thrice. The organic phase was dried with magnesium sulfate, filtered then evaporated under reduced pressure. The crude product was purified by flash chromatography with hexane/ethyl acetate to give the desired amide 25 as a colorless oil in 60% yield (>90% purity by 1H NMR). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With Novozym 435 lipase on resin; In acetone; at 35℃; for 8h;Green chemistry; Enzymatic reaction; | General procedure: A representative synthetic procedure is given hereafter: To 500mg (1.5mmol) of DPA ethyl ester as an oil were added 100mg of Novozym 435 lipase on resin and 5 equiv (7.5mmol) of serinol. A minimum amount of acetone was then added to decrease viscosity (1mL). The mixture was magnetically stirred for 4-18h at 35C until TLC indicated complete disappearance of the ethyl ester (to be noted, LC-MS methods with UV detection are not useful to follow these reactions owing to the very low absorbance of the chromophores). The reaction was then filtered, acetone was evaporated then water added. The mixture was extracted with a minimal amount of diethyl ether (1mL) thrice. The organic phase was dried with magnesium sulfate, filtered then evaporated under reduced pressure. The crude product was purified by flash chromatography with hexane/ethyl acetate to give the desired amide 25 as a colorless oil in 60% yield (>90% purity by 1H NMR). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With Novozym 435 lipase on resin; In acetone; at 35℃; for 8h;Green chemistry; Enzymatic reaction; | General procedure: A representative synthetic procedure is given hereafter: To 500mg (1.5mmol) of DPA ethyl ester as an oil were added 100mg of Novozym 435 lipase on resin and 5 equiv (7.5mmol) of serinol. A minimum amount of acetone was then added to decrease viscosity (1mL). The mixture was magnetically stirred for 4-18h at 35C until TLC indicated complete disappearance of the ethyl ester (to be noted, LC-MS methods with UV detection are not useful to follow these reactions owing to the very low absorbance of the chromophores). The reaction was then filtered, acetone was evaporated then water added. The mixture was extracted with a minimal amount of diethyl ether (1mL) thrice. The organic phase was dried with magnesium sulfate, filtered then evaporated under reduced pressure. The crude product was purified by flash chromatography with hexane/ethyl acetate to give the desired amide 25 as a colorless oil in 60% yield (>90% purity by 1H NMR). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | In tetrahydrofuran; at 20℃; for 48h; | A mixture of the acid chloride derivative 8 (0.25 g, 0.9 mmol) and (R)-(-)-3-amino-1,2-propanediol (0.154 g, 1.7mmol) in THF (15 mL) were stirred at room temperature for 48 h. The THF was removed under reduced pressure and the resulting crude oil was extracted with chloroform (2×50 mL) and the extract was washed with water (2×50 mL) and brine (50 mL). The combined extracts were dried over Na2SO4 (10 g), filtered and concentrated under vacuum. The residue was purified by flash column chromatography (SiO2, CHCl3-MeOH, 9.4:0.6) to afford the product 12 as dark red crystals (0.17 g, 57 2%): mp 93-95C. 1H NMR (300MHz, CDCl3) delta 7.82 (d, J=8.2Hz, 2H), 7.24 (d, J=7.2Hz, 4H), 6.32 (s, 1H), 3.89 (d, J=5.0Hz, 1H), 3.65 (m, J=5.2Hz, 4H), 2.73 (s, 3H), 2.63 (t, J=7.6Hz, 2H), 1.61 (t, J=7.9Hz, 2H), 1.35 (q, J=7.5Hz, 2H), 0.92 (t, J=6.1Hz, 3H); ESIMS m/z (rel intensity) 349 (MH+, 100) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Example 516 N-[(2R)-2,3-Dihydroxypropyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (50 mg, 0.140 mmol) and (2R)-3-amino-1,2-propanediol (0.03 mL, 0.42 mmol) was prepared N-[(2R)-2,3-dihydroxypropyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (39 mg, 68% yield) as a white solid. 1H NMR (DMSO-d6) delta 10.44 (br s, 1H), 8.53 (s, 1H), 8.01 (s, 1H), 7.40-7.36 (m, 2H), 7.15-7.10 (m, 2H), 5.06 (m, 1H), 4.77 (m, 1H), 4.16 (s, 2H), 3.61-3.55 (m, 4H), 3.39 (m, 1H), 3.24 (m, 1H); MS m/z 402 (M+1). |
Tags: 66211-46-9 synthesis path| 66211-46-9 SDS| 66211-46-9 COA| 66211-46-9 purity| 66211-46-9 application| 66211-46-9 NMR| 66211-46-9 COA| 66211-46-9 structure
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P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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