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CAS No. : | 546-88-3 | MDL No. : | MFCD00009994 |
Formula : | C2H5NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | RRUDCFGSUDOHDG-UHFFFAOYSA-N |
M.W : | 75.07 | Pubchem ID : | 1990 |
Synonyms : |
N-Hydroxyacetamide;AHA;NSC 408425;NSC 176136;NSC 5073
|
Num. heavy atoms : | 5 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.5 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 15.46 |
TPSA : | 49.33 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) : | -7.89 cm/s |
Log Po/w (iLOGP) : | 0.63 |
Log Po/w (XLOGP3) : | -1.59 |
Log Po/w (WLOGP) : | -0.49 |
Log Po/w (MLOGP) : | -0.96 |
Log Po/w (SILICOS-IT) : | -0.98 |
Consensus Log Po/w : | -0.68 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | 0.76 |
Solubility : | 434.0 mg/ml ; 5.78 mol/l |
Class : | Highly soluble |
Log S (Ali) : | 1.06 |
Solubility : | 867.0 mg/ml ; 11.6 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | 0.44 |
Solubility : | 206.0 mg/ml ; 2.75 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.3 |
Signal Word: | Danger | Class: | N/A |
Precautionary Statements: | P501-P202-P201-P280-P308+P313-P405 | UN#: | N/A |
Hazard Statements: | H360 | Packing Group: | N/A |
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 |
---|---|---|
53.7% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; | 2- fluorobenzonitrile (6.1g, 50.0mmol), acetohydroxamic acid (5.6g, 75.0mmol) and potassium carbonate (10.4g, 75mmol) was dissolved in DMF (40mL), the mixture was stirred overnight and heated to 80 .With ethyl acetate (100mL × 2) and extracted.The combined organic phases were washed with water (100 mL × 2), saturated brine (100 mL), dried over anhydrous sodium sulfate.Filtered, and the solvent was evaporated under reduced pressure and the crude product purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 4/1), as a white solid (3.6g, 53.7percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 0.5 h; Stage #2: for 4.5 h; |
To a solution of N-hydroxyacetamide (3.1 g, 41 mmol) in dry N,N-dimethylformamide (60 mL) at room temperature was added potassium t-butoxide (4.6 g, 41 mmol). After stirring for 30 minutes, 4-chloro-2-nitrobenzonitrile (5.0 g, 27 mmol) was added, and stirring was continued for another 4.5 hours. On completion, the reaction mixture was poured into a mixture of brine (60 mL) and ethyl acetate (60 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by silica gel chromatography [petroleum ether: ethyl acetate = 3:11 to afford compound B-l (3.1 g, 66percent yield) as a pale yellow solid. ‘H-NMR (DM50-cl6, 400 MHz): 7.84-7.82 (d, J=8.8 Hz, 1H), 7.65-7.64 (d, J=1.2 Hz, 1H), 7.33-7.3 1 (dd, J=1.2 Hz, J=8.8 Hz, 1H), 6.52 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | Stage #1: With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide for 0.5 h; Stage #2: at 20℃; for 240 h; |
Step A: 6-bromobenzo[d]isoxazol-3-ol: N-hydroxyacetamide (0.99 g, 12.9 mmol) was dissolved in DMF (20 mL). To this was added KOt-Bu (1.44 g, 12.9 mmol) and the reaction was stirred for 30 minutes before addition of methyl 4-bromo-2-fluorobenzoate (2.0 g, 8.58 mmol). The reaction mixture was stirred at ambient temperature for 10 days, then diluted with ethyl acetate (50 mL) and 1N NaOH (50 mL). The aqueous layer was washed with ethyl acetate, then acidified with 2N HCl (30 mL). The desired product was collected by filtration (570 mg, 31percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Stage #1: With potassium <i>tert</i>-butylate In 1,2-dimethoxyethane at 20℃; for 2 h; Inert atmosphere Stage #2: at 20℃; for 25 h; Inert atmosphere |
Method 1. Representative example Isoxazolo[5,4-b]pyridin-3-amine (2) From 2-chloronicotinonitrile in 1,2-dimethoxyethane in 48percent yield |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | Stage #1: With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 0.5 h; Stage #2: at 50℃; for 5 h; |
Synthesis of intermediate VX001: Isoxazolo[5,4-b]pyridin-3-amine 909 mg (8.1 mmol) of KO-t-Bu were added, with vigorous stirring, to a suspension of 668 mg (8.9 mmol) of acethydroxamic acid in DMF (20 ml), and the mixture was stirred for 30 min at RT. 990 mg (8.1 mmol) of 2-fluoro-nicotinonitrile were then added, and stirring was carried out for a further 5 h at 50° C. The mixture was then extracted with EA and the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 7:3) of the residue yielded 305 mg (2.3 mmol, 28percent) of isoxazolo[5,4-b]pyridin-3-amine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; | Intermediate 1 : lsoxazolo[5,4-cipyridin-3-ylamine.; To a solution of 3-chloro-isonicotinitrile (1.13 g, 8.36 mmol) in DMF (6.0 mL) were added potassium carbonate (1.69 g, 12.2 mmol) and acetohydroxamic acid (0.91 g, 12.2 mmol). The reaction mixture was stirred at rt overnight, diluted with EtOAc (200 mL) and extracted with saturated aqueous NaHCO3 (200 mL) then saturated aqueous NaCI (100 mL). The aqueous layers were back extracted with EtOAc (200 mL) and the combined organic layers were dried (MgSO4) and concentrated. The crude residue was purified (FCC, 2 N NH3 in MeOH/DCM) to give isoxazolo[5,4-c]pyhdin-3-ylamine (0.447 g, 41 percent). MS (ESI+): calcd for C6H5N3O m/z 135.04, found 136.2 (M+H)+. 1H NMR (d6-DMSO): 8.93 (d, J = 0.8, 1 H), 8.45 (d, J = 5.2, 1 H), 7.88-7.86 (dd, J = 5.2, 1.2, 1 H), 6.72 (br s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | Stage #1: With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide for 0.5 h; Stage #2: at 20℃; for 2 h; |
Step A: 6-Bromobenzo[d]isoxazol-3-amine: N-hydroxyacetamide (1.13 g, 15.0 mmol) was dissolved in DMF (20 mL). To this was added KOt-Bu (1.68 g, 15.0 mmol) and the reaction was stirred for 30 minutes before addition of 4-bromo-2-fluorobenzonitrile (2.0 g, 10.0 mmol). The reaction mixture was left at ambient temperature for 2 hours, then diluted with ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate The combined organics were washed with water, dried, filtered and concentrated. The crude product was purified by flash column chromatography, eluting with ethyl acetate/hexanes (1:4), ethyl acetate/hexanes (1:3) to give the desired product (1.35 g, 63percent). MS (APCI) m/z 215.2, 217.1 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | Stage #1: With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 30℃; Stage #3: With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide |
The title compound was prepared by a modification of the literature procedure as described in Palermo, M. G., Tetrahedron Lett, 37:2885 (1996). A single neck 50 mL flask equipped with a magnetic stirred was charged with N-hydroxyacetamide (2.63 g, 35.0 mmol) and DMF (100 mL). Then, KOtBu (3.93 g, 35.0 mmol) was added in one portion. The temperature rose to 300C. The mixture was stirred for Ih and, 5-bromo~2-fluorobenzonitrile (7 g, 35.0 mmol) was added. The reaction mixture was stirred for overnight. A further portion of KOtBu (1.96 g, 17.5mmo) was added and the solution was again stirred overnight. The mixture was poured into brine and CH2CI2 and the layers were separated. The organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (BIOTAGE.(R)., eluting with a gradient of 0 to 40percent EtOAc in hexanes) to afford the title compound (4.59 g, 62percent) as a colorless solid. 1H NMR (500 MHz, DMSOd6) δ 8.09 (d, J = 1.8 HZ, IH), 7.65 (dd, J = 2.1, 8.9 Hz, IH), 7.45 (d, J = 8.9 Hz5 IH), 6.49 (s, 2H). LCMS: Anal. Calcd. for C7H5BrN2O: 2115 213; found: 212, 214 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With hydroxylamine monohydrate In water at 20 - 80℃; | To a stirred 50% solution of hydroxylamine hydrate (25 ml, 0.42 mole) and 25 ml of waterin a beaker stirred using magnetic stir bar, was added dropwise 45ml (49.3g, 0.42 mol) ofacetic anhydride; the temperature of reaction mixture rose to 80o during the addition. Afterthe addition of acetic anhydride was complete, the clear liquid obtained was allowed to coolto room temperature with continued stirring. The reaction mixture was then extracted withethyl acetate (4 × 70 mL). The combined extracts were concentrated in vacuo to a volumeof 90 mL and cooled to 0C for 16 hrs. The resulting precipitate (20.0 g, 88% pure) wascollected and recrystallized from acetone to give 17.0 g. (55%) of 98% AHA as a colorlesssolid, mp. 86-88C, lit.18 88-89C. |
With hydroxylamine hydrochloride | ||
With hydroxylamine hydrochloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.1% | With hydroxylammonium sulphate; potassium etoxide In ethanol at 25℃; for 2h; | 2 To the reactor was added 16.4 g (0.1 mol) of hydroxylamine sulfate, 68.0 g of an ethanol solution of 20% sodium ethoxide was added dropwise at room temperature, and the molar ratio of sodium ethoxide to hydroxylamine sulfate was 2: 1 and stirred for about 0.5 hours. (0.1 mol) of ethyl acetate was added dropwise. After about 1 h, the reaction was carried out for 1 hour. The reaction temperature was maintained at 25 ° C. After completion of the reaction, the reaction was continued until the concentrated sulfuric acid was added to the final pH = 6, filtered, concentrated, concentrated solution about 10ml, mixed with chloroform and ethanol 60ml, the volume ratio of 9: 1 crystallization, needle-like crystal acetohydroxamic acid 14.6g, the yield of 97.1%. |
84.6% | With hydroxyamino hydrochloride; sodium hydroxide In methanol; lithium hydroxide monohydrate at 40℃; for 3h; Large scale; | 1.1-1.9; 1-5 1) Add 2.6L of methanol and 1300g of hydroxylamine hydrochloride to the three-necked reaction flask (10L), place the reaction flask in an ice-water bath, and keep stirring;2) Dissolve 748g of sodium hydroxide in 1.3L of water, and then pour the sodium hydroxide solution into the reaction bottle to neutralize hydrochloric acid;3) Will 1978gEthyl acetate was added to the reaction flask, the temperature of the reaction system was raised to 40 ° C, and stirring was continued for 1 h;4) Dissolve the remaining 748g of sodium hydroxide in 1.3L of water, add it to the reaction flask at 40 ° C, and continue the reaction at this temperature for 2h;5) The reaction solution was concentrated on a rotary evaporator to remove methanol;6) In an ice-water bath, adjust the reaction system to pH = 4-5 with concentrated hydrochloric acid;7) Evaporate the water in the reaction system to dryness;8) Add a total of 6.5L of ethyl acetate to the reaction system, heat and extract 5 times, and then concentrate the extract to 2L;9) Add 10 ml of acetone to the concentrate, stir at low temperature for 30 min at 0 ° C, filter to obtain a white solid, and dry at 40 ° C to obtain 1000 g of the product. The calculated yield is 84.6%.During the reaction, ultraviolet light was used to track the progress of the reaction. The purity of the compound was detected by liquid chromatography. From the test results, the purity of the product was 98.0%. The structure of the product was confirmed by nuclear magnetic resonance and carbon spectrum. As shown in Fig. 1, it was confirmed that the obtained product was acetoxyhydroxamic acid. |
With hydroxylamine; potassium etoxide |
With sodium hydroxide; hydroxylamine | ||
With methanol; hydroxylamine | ||
With potassium hydroxide; hydroxyamino hydrochloride In methanol for 5h; temp. < 30 deg C; | ||
With hydroxylamine Ambient temperature; | ||
With hydroxylamine In aq. buffer at 40℃; for 1.75h; Micellar solution; Enzymatic reaction; | 2.3.1. Acyltransferase activity assay of immobilized P. aeruginosa cells in the reverse micellar system General procedure: The activity assays in the reverse micellar medium were performed using intact cells from P. aeruginosa L10 strain containing amidase and according to a methodology previously described [3], in a thermostatic water bath at 40°C. Briefly, the acyltransferase activity was investigated in a 5mL stirred reverse micellar system of 200mM TTAB in heptane/octanol (80/20%, v/v) containing P. aeruginosa cells (0.050g cells/mL in 10mM HEPES buffer at pH 7.2), hydroxylamine solution (freshly neutralized to pH 7). The water content in the system, usually defined through the parameter w0=[H2O]/[surfactant], was controlled by adjusting the added volume of buffer 10mM HEPES at pH 7.2 and established to a value of 10. The amide or ester substrate solution in 10mM HEPES buffer at pH 7.2 was injected in order to initiate the reaction. The rate of reaction was determined by following the increase in the concentration of the reaction product a, hydroxamic acid derivative, during the course of the reaction as described in [3]. Calibration curves with acetohydroxamate, benzohydroxamate, butyrylhydroxamate, glycine hydroxamate and alanine hydroxamate were established and values for the extinction coefficient (ε) were obtained of 0.105mM-1 (R2=0.993), 0.1210mM-1 (R2=0.964), 0.038mM-1 (R2=0.993), 0.0072mM-1 (R2=0.965), 0.0057mM-1 (R2=0.972), respectively. One enzyme unit (U) is defined as the amount of enzyme required to produce 1 μmol of hydroxamic acid derivative per min under these experimental conditions. | |
With hydroxyamino hydrochloride; sodium hydroxide In lithium hydroxide monohydrate Cooling with ice; | 2 Example 2 (E)-Glutazol-4-ene-3β-mercapto-methyl-6-one (Compound 3) and (E)-Glutosyl-3β,6β-mercapto-methyl-4-ene (Compound 4) Hydroxylamine hydrochloride (100.0 mg), ethyl acetate (240 μl),Sodium hydroxide (126.0 mg), dissolved in 500 μl of deionized water,The reaction was carried out under ice bath conditions, and TLC (thin layer silica gel plate) was monitored until the reaction was completed. After completion of the reaction, methyl bromide (114.1 μl) was added and the reaction was carried out in an ice bath.TLC (thin layer silica gel plate) was monitored until the reaction was complete. After the reaction is completed,After extracting by-products with petroleum ether, the lower layer solution is taken.Extract three times with ethyl acetate and take an ethyl acetate layer.The solvent was evaporated to dryness under reduced pressure to yield white crystals,Further, ethanol (10.0 ml) and hydrochloric acid (15 μl) were added, and the reaction was carried out at 65 ° C, and the reaction was completed by TLC (thin layer silica gel).After the reaction is completed,Evaporation of the solvent gave pale yellow crystals of 2:m.p.(81.3 mg, yield is 69.3%) | |
With hydroxyamino hydrochloride; sodium hydroxide In lithium hydroxide monohydrate at 0℃; for 4h; | (E)-4-ene-sitosterol-3β-oxime group-methyl-6-one (3) and (E)-sitosterol-3β,6β-hydroxyimino-methyl-4-ene (31). To a 50 mL round bottomflask was added hydroxylamine hydrochloride (100.0 mg), ethyl acetate(240.0 μL), sodium hydroxide (126.0 mg) and pure water (500.0 μL).The reaction was stirred in 0 °C for 4 h. TLC (thin layer of silica gelplate) detected complete reaction. The methyl bromide (114.1 μL) wasadded in the solvent and continue reacted for 2 h at 0 °C. TLC alsodetected complete reaction. After extraction of the by-product withpetroleum ether, the solution was taken out and extracted three timeswith ethyl acetate. The ethyl acetate layer was evaporated and thesolvent was evaporated under reduced pressure to give white crystals ofmethoxycarboxamide. Then add ethanol (10.0 mL), hydrochloric acid(15.0 μL), 65 °C reaction, TLC (thin layer of silica gel plate) to the reactionis complete. After completion of the reaction, the solvent wasevaporated to dryness to give pale yellow crystals of methoxyaminehydrochloride (81.3 mg, yield 69.3%). After that, 2 (50.0 mg), methoxylaminehydrochloride (29.1 mg) and sodium acetate (10.0 mg) wereplaced in a 50 mL round bottom flask and dissolved in 10 mL of ethanolat 45 °C, TLC monitoring to complete reaction. The solvent is evaporatedunder reduced pressure. And the residue was purified by silica gelcolumn chromatography with a Petroleum Ether : EtOAc=10:1 (V/V)gradient to give (E)-4-ene-sitosterol-3β-oxime group-methyl-6-one(23.0 mg, 50.3 mmol, 43.0% yield). | |
With hydroxyamino hydrochloride; sodium hydroxide In ethanol; lithium hydroxide monohydrate at 20℃; Cooling with ice; | ||
With hydroxyamino hydrochloride; sodium hydroxide In lithium hydroxide monohydrate at 0 - 20℃; for 1h; | 3.2.2. General Procedure for Synthesis of O-substituted hydroxylamines 3d-3j General procedure: The water (5 mL) mixing hydroxylamine hydrochloride (0.10 mol), ethyl acetate(0.18 mol) and 28% sodium hydroxide aqueous solution (25 mL) were stirred at 0 C.The resultant mixture was then stirred at room temperature for 1 h. After that, halogenated hydrocarbon (0.11 mol) was dropwise added and the reaction was stirred at 60 C for further 6 h. Subsequently, the reaction mixture was extracted with petroleum ether and ethyl acetate. The organic layer was combined and dried by anhydrous sodium sulfate,then the solvent was removed under reduced pressure and oily product was obtained.The obtained oily product was dissolved in ethyl alcohol, and 36% aqueous hydrochloric acid was added to the solution. The mixture was stirred at 50 C for 4 h. Finally, the reactionwas neutralized to pH 7.0 by saturated sodium bicarbonate aqueous solution, and thenextracted with dichloromethane. The extracts were dried over anhydrous sodium sulfate,and concentrated under vacuum to obtain the title compounds 3d-3j | |
With ammonia; dihydrogen peroxide In lithium hydroxide monohydrate; <i>tert</i>-butyl alcohol at 60℃; for 4.5h; Molecular sieve; | 1-4 Embodiment 1, the synthetic method of acetohydroxamic acid: Taking ethyl acetate (CH3COOC2H5) as the reaction raw material, the selected catalyst is titanium-silicon molecular sieve TS-1, ammonia is liquid ammonia, that is, ammonia water with a mass concentration of 25%, and the solvent is an aqueous solution of tert-butanol with a volume content of 10% of tert-butanol ; That is, the solvent used is a mixed solvent of 10% tert-butanol and 90% water by volume.Specifically, perform the following steps in sequence:1. Method 1 (ammonia is added at one time):1.1), add catalyzer, solvent, reaction raw material and ammonia to the reactor, stir, form reaction system;Described reaction raw material: the weight ratio of catalyst=1:0.1; Reaction raw material: the mol ratio of ammonia=1:1.5;Described reaction raw material: solvent=1g:10g material-liquid ratio.1.2), set reaction temperature to be 60 ;After the reaction system was heated to 60°C, a hydrogen peroxide solution with a mass concentration of 30% was added dropwise for 4 hours, and the reaction was continued for 0.5 hours at a temperature of 60°C after the dropwise addition;Described reaction raw material: the mol ratio of hydrogen peroxide=1:1;2. The reaction product obtained in step 1.2) is filtered to separate out the catalyst, that is, the obtained filter residue is a solid catalyst (returnable to the system for reuse), and the obtained filtrate is a reaction solution containing substances such as hydroxamic acid, solvent, water, and ammonia. The filtrate is subjected to conventional post-treatments such as conventional rectification, evaporation, and crystallization to obtain the product acethydroxamic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | To a solution of N-hydroxyacetamide (3.1 g, 41 mmol) in dry N,N-dimethylformamide (60 mL) at room temperature was added potassium t-butoxide (4.6 g, 41 mmol). After stirring for 30 minutes, <strong>[34662-32-3]4-chloro-2-nitrobenzonitrile</strong> (5.0 g, 27 mmol) was added, and stirring was continued for another 4.5 hours. On completion, the reaction mixture was poured into a mixture of brine (60 mL) and ethyl acetate (60 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by silica gel chromatography [petroleum ether: ethyl acetate = 3:11 to afford compound B-l (3.1 g, 66% yield) as a pale yellow solid. ?H-NMR (DM50-cl6, 400 MHz): 7.84-7.82 (d, J=8.8 Hz, 1H), 7.65-7.64 (d, J=1.2 Hz, 1H), 7.33-7.3 1 (dd, J=1.2 Hz, J=8.8 Hz, 1H), 6.52 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.7% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; | 2- fluorobenzonitrile (6.1g, 50.0mmol), acetohydroxamic acid (5.6g, 75.0mmol) and potassium carbonate (10.4g, 75mmol) was dissolved in DMF (40mL), the mixture was stirred overnight and heated to 80 .With ethyl acetate (100mL × 2) and extracted.The combined organic phases were washed with water (100 mL × 2), saturated brine (100 mL), dried over anhydrous sodium sulfate.Filtered, and the solvent was evaporated under reduced pressure and the crude product purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 4/1), as a white solid (3.6g, 53.7%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | Step A: 6-Bromobenzo[d]isoxazol-3-amine: N-hydroxyacetamide (1.13 g, 15.0 mmol) was dissolved in DMF (20 mL). To this was added KOt-Bu (1.68 g, 15.0 mmol) and the reaction was stirred for 30 minutes before addition of 4-bromo-2-fluorobenzonitrile (2.0 g, 10.0 mmol). The reaction mixture was left at ambient temperature for 2 hours, then diluted with ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate The combined organics were washed with water, dried, filtered and concentrated. The crude product was purified by flash column chromatography, eluting with ethyl acetate/hexanes (1:4), ethyl acetate/hexanes (1:3) to give the desired product (1.35 g, 63%). MS (APCI) m/z 215.2, 217.1 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide | |
62% | Stage #1: acetylhydroxamic acid With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 2-fluoro-4-(methoxymethyl)benzonitrile In N,N-dimethyl-formamide at 20 - 40℃; | xxvi.b b) 6-(Methoxymethyl)benzo[d]isoxazol-3-amine I62 b) 6-(Methoxymethyl)benzo[d]isoxazol-3-amine I62 To a solution of acetohydroxamic acid (1.5 g, 9.1 mmol) in DMF (50 mL) was added t-BuOK (3.06 g, 27.2 mmol) and the mixture was stirred at RT for 1 h. 2-Fluoro-4- (methoxymethyl)benzonitrile I61 (1.5 g, 9.1 mmol) was then added and the mixture was heated at 40 °C overnight. [93] The mixture was diluted with water and extracted with EtOAc. The organic extract was concentrated under reduced pressure and the residue was purified by silica gel chromatography (Pet. ether/EtOAc = 100/1 to 10/1) to give the title compound (1 g, 62%) as a yellow solid. LCMS-D: Rt 0.95 min, m/z 179.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With sodium periodate In methanol; water Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With potassium carbonate In DMF (N,N-dimethyl-formamide); water at 20℃; | 37.J Part J: Acetohydroxamic acid (0.096 g, 1.28 mmol), potassium carbonate (0.35 g, 2.57 mmol), 3 mL of DMF and 1 mL of water were stirred together for 10 minutes at rt then the product from above (0.21 g, 0.43 mmol) in 2 mL of DMF was added and the reaction stirred overnight. Next EtOAc was added and the mixture transferred to a separatory funnel where it was washed 5×with water then brine and dried over sodium sulfate to give the amino benzisoxazole compound (0.16 g, 76% yield) LRMS (ES+) 505.5 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.5% | With thionyl chloride; potassium carbonate; In ethyl acetate; N,N-dimethyl-formamide; toluene; | Example 3-1 Synthesis of O-{1-(3-trifluoromethylphenyl)ethyl}-acetohydroxamate A 20 mg portion of DMF was added to 5 ml of toluene solution containing 3 g (15.8 mmol) of 1-(3-trifluoromethylphenyl)ethylalcohol. Then, 2.25 g (18.9 mmol) of thionyl chloride was added under ice-cooling. After 2 hours of stirring at 10C or less, this was concentrated under a reduced pressure on a water bath at temperature of 50 to 60C. After cooling to room temperature, 8 ml of DMF, 3.3 g (23.9 mmol) of anhydrous potassium carbonate and 2.15 g (20.5 mmol) of acetohydroxamic acid were added, and the mixture was stirred for 6 hours while heating at 120 to 130C. After cooling, ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated brine in that order and then dried over anhydrous sodium sulfate. This was concentrated under a reduced pressure, and the resulting residue was purified by a silica gel column chromatography (n-Hex:AcOEt = 1:1 ? 1:2) to give 2.32 g of the title compound (yield = 59.5%). Melting point; 75.3 - 76.5C 1H-NMR delta (CDCl3); 1.57 (3H, d), 1.8 - 2.2 (3H, br), 4.8 - 5.15 (1H, br), 7.45 - 7.55 (4H, m), 7.8 - 8.0 (1H, br) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Stage #1: acetylhydroxamic acid With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 0.333333h; Stage #2: 2-fluoro-5-(6-(2-isobutoxyphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)benzonitrile In N,N-dimethyl-formamide at 20℃; for 16h; Stage #3: In N,N-dimethyl-formamide Acidic conditions; | 23 EXAMPLE 23 4-(3-amino-l,2-benzisoxazol-5-yl)-6-{2-[(2-methylpropyl)oxy]phenyl}pyrimidin-2(lH)-one [00203] To a solution of acetohydroxamic acid (53 mg, 0.7 mmol) in DMF (5 mL) was added potassium ter/-butoxide (80 mg, 1.76 mmol). The mixture was stirred at room temperature for 20 min, followed by the addition of solution of 2-fluoro-5-(6-(2-isobutoxyphenyl)-2-oxo-l,2- dihydropyrimidin-4-yl)benzonitrile (100 mg, 0.27 mmol) (Example l^Step 4) in DMF (4 mL). The reaction was stirred at room temperature for 16h. The mixture was quenched by acid and the product was purified by Prep-HPLC to give 75 mg (74%) of 4-(3 -amino- 1 ,2-benzisoxazol- 5-yl)-6-{2-[(2-methylpropyl)oxy]phenyl} pyrimidin-2(lH)-one. 1H NMR (400 MHz, d6- DMSO): δ 1 1.80 (s, br, 2H), 8.78 (s, IH), 8.37 (d, IH), 7.66-7.45 (m, 3H), 7.24-7.00 (m, 3H), 6.60 (s, 2H), 3.83 (d, 2H), 2.05-1.97 (m, IH), 0.98 (d, 6H). MS (EI) for C21H20N4O3: 377 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | Stage #1: acetylhydroxamic acid With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 0.5h; Inertt atmosphere; Stage #2: 2-fluoro-3-iodo-4-methylbenzonitrile In N,N-dimethyl-formamide at 20℃; | 11 INTERMEDIATE 11 7-lodo-6-methyl-1,2-benzisoxazol-3-amine [Show Image] Potassium tert-butoxide (3.58 g, 31.87 mmol) was added to a stirred suspension of N-hydroxyacetamide (2.39 g, 31.87 mmol) in N,N'-dimethylformamide (44 mL) at room temperature under argon. After 30 minutes, 2-fluoro-3-iodo-4-methylbenzonitrile (Intermediate 10b, 3.33 g, 12.75 mmol) was added to the stirred reaction mixture at room temperature. After stirring overnight, the solvent was evaporated under reduced pressure, and the residue was partitioned between satured aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried (MgS04) and evaporated. Purification of the residue by flash chromatography (4:1 hexanes/ethyl acetate to 1:1 hexanes/ethyl acetate) gave the title compound (2.21 g, 63%) as a pale yellow solid. LRMS (m/z): 275 (M+1)+.1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.59 (s, 3 H) 4.39 (br. s., 2 H) 7.15 (d, J=7.97 Hz, 1 H) 7.37 (d, J=7.97 Hz, 1 H) |
63% | Stage #1: acetylhydroxamic acid With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 0.5h; Inert atmosphere; Stage #2: 2-fluoro-3-iodo-4-methylbenzonitrile In N,N-dimethyl-formamide at 20℃; | 11 INTERMEDIATE 11; 7-lodo-6-methyl-1,2-benzisoxazol-3-amine; Potassium tert-butoxide (3.58 g, 31.87 mmol) was added to a stirred suspension of N- hydroxyacetamide (2.39 g, 31.87 mmol) in Λ/,Λ/'-dimethylformamide (44 mL) at room temperature under argon. After 30 minutes, 2-fluoro-3-iodo-4-methylbenzonitrile (Intermediate 10b, 3.33 g, 12.75 mmol) was added to the stirred reaction mixture at room temperature. After stirring overnight, the solvent was evaporated under reduced pressure, and the residue was partitioned between satured aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried (MgS04) and evaporated. Purification of the residue by flash chromatography (4:1 hexanes/ethyl acetate to 1 :1 hexanes/ethyl acetate) gave the title compound (2.21 g, 63%) as a pale yellow solid.LRMS (m/z): 275 (M+1)+.1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.59 (s, 3 H) 4.39 (br. s., 2 H) 7.15 (d, J=7.97 Hz, 1 H) 7.37 (d, J=7.97 Hz, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium periodate In methanol at 20℃; | |
With sodium periodate In methanol; water at 20℃; for 16.0833h; | 11 Example 11: (24)To a stirred solution of 22 (5 g, 27.1 mmol) in 2,2-dimethoxypropane (80 ml_) was added p-toluenesulfonic acid (catalytic amount) at room temperature. After complete consumption of starting material (TLC analysis), the solution was cooled 0 °C before the addition of H2O (10 ml_). On a preparative scale the intermediate acetonide was not isolated (analytical samples were purified via flash column chromatography with a solvent system of 3:1 (hexanes-ethyl acetate)). Data for the intermediate 23: Rf 0.56 (1 :1 hexanes/ethyl acetate); [α]D23 +74.6 (c 4.02, CHCI3); IR (film): v 3018, 2987, 2936, 1712, 1651 , 1425, 1380, 1259, 1155, 1031 , 917, 856, 697, 667, 512 cm"1; 1H NMR (300 MHz, CDCI3) δ 7.06 (dd, J = 5.3, J = 3.1 Hz, 1 H), 4.84 (d, J = 5.7 Hz, 1 H), 4.28-4.41 (m, 1 H), 4.07-4.26 (m, 2H), 2.21-2.45 (m, 1 H), 1.99-2.16 (m, 1 H), 1.86-1.99 (m, 1 H), 1.58-1.72 (m, 1 H), 1.33 (d, J = 10.2 Hz, 6H), 1.24 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (75 MHz, CDCI3) δ 166.2, 142.3, 130.0, 108.5, 72.6, 70.4, 60.5, 27.8, 26.2, 25.1 , 20.9, 14.2 ppm; MS (El) m/z (%): 226 (M+-CH3), 211 (77), 181(15), 169(17), 123(100), 105(17), 95(13), 83(11), 79(76), 67(14), 59(10), 55(11), 43(82), 41 (14); HRMS (M+-CH3) calcd for Ci2H16O4 211.0970, found 211.0969; Anal, calcd: C 64.27; H 7.19. Found C 64.52; H 7.08.NaIO4 (5.80 g, 27.1 mmol) was added to the reaction vessel prior to the addition of a solution of acetohydroxamic acid (2.03 g, 27.1 mmol) in MeOH (25 mL) dropwise over 5 minutes. The resulting solution was stirred at room temperature for 16 h, quenched by the slow addition of sat. NaHSO3 (10 mL) and extracted into Et2O (3 x 100 mL). The combined organic layers were washed with brine (2 x 30 mL) and dried over Na2SO4. The crude material was purified via flash column chromatography with a solvent system of 2:8 (hexanes-ethyl acetate) to yield 24 (5.65 g, 70% over 2 steps) as a white solid: Rf 0.33 (3:7 hexanes- ethyl acetate); mp 89-90 °C (hexanes-ethyl acetate); [α]D23 -18.0 (c 0.54, CHCI3); IR (film) v 3466, 2938, 2987, 1747, 1684, 1620, 1372, 1275, 1086 cnT1; 1H NMR (600 MHz, CDCI3) δ 6.57-6.65 (m, 2H), 5.47-5.52 (m, 1 H), 4.71 (d, J = 6.8 Hz, 1 H), 4.56 (dd, J = 4.7, 6.6 Hz, 1 H), 4.38 (q, J = 7.2 Hz, 2H), 2.01 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H), 1.32 (s, 3H), 1.30 (s, 3H) ppm; 13C NMR (150 MHz, CDCI3) δ 173.9, 166.6, 132.4, 128.4, 111.7, 79.2, 76.1 , 72.8, 62.7, 50.0, 25.6, 25.4, 21.7, 14.1 ppm; MS (El) m/z (%): 297 (M), 43(100), 96(30), 100(32), 105(35), 124(52); HRMS calcd for C14H19NO6 297.1212, found 297.1215. | |
5.65 g | With sodium periodate In methanol at 20℃; for 16.2h; Inert atmosphere; regioselective reaction; |
5.65 g | With sodium periodate In methanol at 20℃; for 16h; Inert atmosphere; | |
With sodium periodate In methanol at 20℃; for 16h; | 2 NalO4 (5.80 g, 27.1 mmol) was added to the reaction mixture above prior to the dropwise addition of a solution of acetohydroxamic acid (2.03 g, 27.1 mmol) in MeOH (25 mL) over 5 minutes. The resulting solution was stirred at room temperature for 16 h then diluted with ethyl acetate (300 mL). Inorganic precipitate was filtered off and resulting solution was washed with saturated solution of NaHCO3(2 x 20 mL). Organic layer was dried over Mg2SO4 and evaporated. The crude material was purified via flash column chromatography [hexane-ethyl acetate (1 :4)] to yield oxazine 5 (5.65 g, 70% over 2 steps) as a white solid; mp 89-90 °C (hexanes-ethyl acetate): Rf 0.33 (3:7 hexane- ethyl acetate); [a]23D = -18.0 (c 0.54, CHCI3); IR (film, cm"1) v 3466, 2938, 2987, 1747, 1684, 1620, 1372, 1275, 1086; 1H NMR (600 MHz, CDCI3) δ 6.57-6.65 (m, 2H), 5.47-5.52 (m, 1 H), 4.71 (d, J = 6.8 Hz, 1 H), 4.56 (dd, J = 4.7, 6.6 Hz, 1 H), 4.38 (q, J = 7.2 Hz, 2H), 2.01 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H), 1.32 (s, 3H), 1.30 (s, 3H); 13C NMR (150 MHz, CDCI3) δ 173.9, 166.6, 132.4, 128.4, 1 1 1.7, 79.2, 76.1 , 72.8, 62.7, 50.0, 25.6, 25.4, 21.7, 14.1 ; MS (El) m/z (%): 297 (M+), 124(52), 105(35), 100(32), 96(30), 43(100); HRMS. Calcd for Ci4H19NO6: 297.1212. Found: 297.1215. | |
5.65 g | With sodium periodate In methanol at 20℃; for 16h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: acetylhydroxamic acid With 4-methyl-morpholine; dimethylbromosulphonium bromide In 1,2-dichloro-ethane at 0℃; for 2h; Inert atmosphere; Stage #2: benzylamine In 1,2-dichloro-ethane at 0 - 80℃; | General procedure for the synthesis of unsymmetrical urea derivatives 6: To a solution of hydroxamic acid 1 (1 mmol) in DCE (2 mL) at 0 °C under nitrogen atmosphere, N-methylmorpholine (NMM) (2.6 mmol) then bromodimethylsulfonium bromide 2 (BDMS) (1.3 mmol) were added and the mixture was stirred at 0 °C for 2 h. The amine 5 (1.2 mmol) was then added and the temperature of reaction mixture was raised to 80 °C and stirred at the same temperature for 7-18 h (Table 2). Upon completion of the reaction as indicated by TLC, the reaction mixture was cooled to rt and acidified with 2 mL HCl (0.1 N) and the solution was extracted with DCM (2 × 10 mL) and EtOAc (1 × 10 mL). The combined organic phase was dried over MgSO4, filtered, and evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography using a gradient mixture of hexane/ethyl acetate as eluent to give the corresponding pure urea derivatives 6. All the products are known compounds and were characterized by the comparison of their mp and spectral data with those of reported in the literature. [10] and [12] |
76% | Stage #1: acetylhydroxamic acid With 4-methyl-morpholine; 1,3,5-trichloro-2,4,6-triazine In dichloroethane at 0℃; for 1.5h; Inert atmosphere; Stage #2: benzylamine In dichloroethane at 0 - 84℃; for 15h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | Intermediate 1 : lsoxazolo[5,4-cipyridin-3-ylamine.; To a solution of 3-chloro-isonicotinitrile (1.13 g, 8.36 mmol) in DMF (6.0 mL) were added potassium carbonate (1.69 g, 12.2 mmol) and acetohydroxamic acid (0.91 g, 12.2 mmol). The reaction mixture was stirred at rt overnight, diluted with EtOAc (200 mL) and extracted with saturated aqueous NaHCO3 (200 mL) then saturated aqueous NaCI (100 mL). The aqueous layers were back extracted with EtOAc (200 mL) and the combined organic layers were dried (MgSO4) and concentrated. The crude residue was purified (FCC, 2 N NH3 in MeOH/DCM) to give isoxazolo[5,4-c]pyhdin-3-ylamine (0.447 g, 41 %). MS (ESI+): calcd for C6H5N3O m/z 135.04, found 136.2 (M+H)+. 1H NMR (d6-DMSO): 8.93 (d, J = 0.8, 1 H), 8.45 (d, J = 5.2, 1 H), 7.88-7.86 (dd, J = 5.2, 1.2, 1 H), 6.72 (br s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | xv) 5-Bromobenzo[d]isoxazol-3-amine I40 To a solution of acetohydroxamic acid (23.7 g, 0.315 mol) in DMF (800 ml.) at 0 C under N2 was added t-BuOK (35.4 g, 0.315 mol) and the mixture was stirred at 15 C for 2 h. 5-Bromo-2-fluorobenzonitrile (21.0 g, 0.105 mol) was then added and the mixture was stirred at RT overnight. The mixture was diluted with EtOAc (1.5 L) and washed with water (400 ml. x 4). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure. The residue was purified by column chromatography (Pet. ether/EtOAc = 50/1 to 3/1) to give the title compound (19 g, 86%) as a white solid. LCMS-D: Rt2.13 min; m/z 212.9/214.9 [M+H]+. | |
62% | The title compound was prepared by a modification of the literature procedure as described in Palermo, M. G., Tetrahedron Lett, 37:2885 (1996). A single neck 50 mL flask equipped with a magnetic stirred was charged with N-hydroxyacetamide (2.63 g, 35.0 mmol) and DMF (100 mL). Then, KOtBu (3.93 g, 35.0 mmol) was added in one portion. The temperature rose to 300C. The mixture was stirred for Ih and, 5-bromo~2-fluorobenzonitrile (7 g, 35.0 mmol) was added. The reaction mixture was stirred for overnight. A further portion of KOtBu (1.96 g, 17.5mmo) was added and the solution was again stirred overnight. The mixture was poured into brine and CH2CI2 and the layers were separated. The organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (BIOTAGE, eluting with a gradient of 0 to 40% EtOAc in hexanes) to afford the title compound (4.59 g, 62%) as a colorless solid. 1H NMR (500 MHz, DMSOd6) delta 8.09 (d, J = 1.8 HZ, IH), 7.65 (dd, J = 2.1, 8.9 Hz, IH), 7.45 (d, J = 8.9 Hz5 IH), 6.49 (s, 2H). LCMS: Anal. Calcd. for C7H5BrN2O: 2115 213; found: 212, 214 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | Synthesis of intermediate VX001: Isoxazolo[5,4-b]pyridin-3-amine 909 mg (8.1 mmol) of KO-t-Bu were added, with vigorous stirring, to a suspension of 668 mg (8.9 mmol) of acethydroxamic acid in DMF (20 ml), and the mixture was stirred for 30 min at RT. 990 mg (8.1 mmol) of 2-fluoro-nicotinonitrile were then added, and stirring was carried out for a further 5 h at 50 C. The mixture was then extracted with EA and the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 7:3) of the residue yielded 305 mg (2.3 mmol, 28%) of isoxazolo[5,4-b]pyridin-3-amine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | Synthesis of intermediate VX007: Isoxazolo[5,4-b]quinolin-3-amine 2.52 g (22.5 mmol) of KO-t-Bu were added to a solution of 1.69 g (22.5 mmol) of acethydroxamic acid in THF (45 ml), and stirring was carried out for 30 min at RT. The mixture was then cooled to 0 C., and 2.85 g (15.0 mmol) of <strong>[95104-21-5]2-chloroquinoline-3-carbonitrile</strong> and 1.22 g (3.8 mmol) of Cs2CO3 were added in succession. The reaction solution was stirred for 3 h at RT and then diluted with EA, and washing with water and brine was carried out. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. CC (DCM/MeOH 97:3) of the residue yielded 700 mg (3.8 mmol, 25%) of isoxazolo[5,4-b]quinolin-3-amine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: acetylhydroxamic acid With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 0.75h; Stage #2: 2,6 difluorobenzonitrile In N,N-dimethyl-formamide at 50℃; for 16h; | 4 4.00 g (35.65 mmol) of potassium tert-butoxide and 2.60 g (34.64 mmol) of acetohydroxamic acid are dissolved in 50 ml of dry dimethylformamide and stirred at room temperature for 45 minutes. After the addition of 3.30 g (23.72 mmol) of 2,6-difluorobenzonitrile, the mixture is stirred at 50° C. for 16 hours. The mixture is concentrated under reduced pressure, and the residue is dissolved in dichloromethane and washed with water. After drying and concentration of the organic phase, 3.2 g of a yellow resin are obtained, which, according to 1H NMR, is about 85% pure |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: acetylhydroxamic acid With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 2-(difluoromethoxy)-6-fluorobenzonitrile In N,N-dimethyl-formamide at 20 - 60℃; for 19h; | 5 8.00 g (71.29 mmol) of potassium tert-butoxide and 5.20 g (69.27 mmol) of acetohydroxamic acid are dissolved in 50 ml of dry dimethylformamide and stirred at room temperature for 1 hour. After the addition of 4.40 g (23.51 mmol) of 2-(difluoromethoxy)-6-fluorobenzonitrile, the mixture is stirred first at room temperature for 3 hours and then at 60° C. for 16 hours. The mixture is concentrated under reduced pressure, the residue is stirred with water and the pale olive-coloured precipitate is filtered off with suction. This gives 4.4 g of product, which, according to LC-MS, is about 89% pure |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | Step A: 6-bromobenzo[d]isoxazol-3-ol: N-hydroxyacetamide (0.99 g, 12.9 mmol) was dissolved in DMF (20 mL). To this was added KOt-Bu (1.44 g, 12.9 mmol) and the reaction was stirred for 30 minutes before addition of methyl 4-bromo-2-fluorobenzoate (2.0 g, 8.58 mmol). The reaction mixture was stirred at ambient temperature for 10 days, then diluted with ethyl acetate (50 mL) and 1N NaOH (50 mL). The aqueous layer was washed with ethyl acetate, then acidified with 2N HCl (30 mL). The desired product was collected by filtration (570 mg, 31%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.7% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; | 2-Fluoro-5-trifluoro-benzonitrile (Matrix, 5 g, 26.4 mmol), N-hydroxy-acetamide (Aldrich, 2.9 g, 39.7 mmol) and K2CO3 (5.48 g, 39.7 mmol) in DMF (20 mL) were heated at 80 C overnight. The reaction was partitioned between ethyl acetate and water. The aqueous layer was extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude material, which was purified by silica gel column (hexanes: ethyl acetate 2:1 ) to afford the title compound as white solid (4.1 g, 76.7%). MS: 203 (MH+). |
76.6% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; | Step A 5-Trifluoromethyl-benzo[d]isoxazol-3-ylamine 2-Fluoro-5-trifluoro-benzonitrile (Matrix, 5 g, 26.4 mmol), N-hydroxy-acetamide (Aldrich, 2.9 g, 39.7 mmol) and K2CO3 (5.48 g, 39.7 mmol) in DMF (20 mL) were heated at 80 C. overnight. The reaction was partitioned between ethyl acetate and water. The aqueous layer was extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude material, which was purified by silica gel column (hexanes:ethyl acetate 2:1) to afford the title compound as white solid (4.1 g, 76.7%). MS: 203 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: acetylhydroxamic acid With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 0 - 20℃; for 1h; Inert atmosphere; Stage #2: 2-fluoro-4-((tetrahydro-2 H-pyran-2-yl)oxy)benzonitrile In N,N-dimethyl-formamide at 20℃; Inert atmosphere; | xi.b 6-((Tetrahydro-2H-pyran-2-yl)oxy)benzo[d]isoxazol-3-amine I30 [78] To a solution of acetohydroxamic acid (13.7 g, 182.3 mmol) in DMF (60 ml.) at 0 °C under N2was added potassium tert- butoxide (20.4 g, 182.3 mmol) and the mixture was stirred at RT for 1 h. 2-Fluoro-4-((tetrahydro-2H-pyran-2-yl)oxy)benzonitrile I29 (13.4 g, 60.8 mmol) was then added and the mixture was stirred at RT overnight. EtOAc (500 ml.) was added and the mixture was washed with water (100 ml. x 5). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. ether/EtOAc = 100/1 to 5/1) to give the title compound (12.1 g, 85%) as a white solid. LCMS-D: Rt2.31 min; m/z 235.1 [M+H]+. |
69% | Stage #1: acetylhydroxamic acid With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 2-fluoro-4-((tetrahydro-2 H-pyran-2-yl)oxy)benzonitrile In N,N-dimethyl-formamide at 20℃; for 24h; | 3.85.2 Step 2: 6-(Tetrahydro-pyran-2-yloxy)-benzo[d]isoxazol-3-ylamine (3_85_3) Step 2: 6-(Tetrahydro-pyran-2-yloxy)-benzo[d]isoxazol-3-ylamine (3_85_3) [00540] Potassium tert-butoxide (8.96 g, 80 mmol) was added in portions to a solution of N-hydroxy acetamide (6.00 g, 80 mmol) in N,N-dimethylformamide (40 mL). After the addition was complete, the resulting mixture was stirred at room temperature for 1 hour. A solution of 2-fluoro-4-(tetrahydro-2H-pyran-2-yloxy)benzo- nitrile 3_85_2 (8.90 g, 40 mmol) in ,Ν-dimethylformamide (20 mL) was added and the resulting mixture was stirred at room temperature for 24 hours and concentrated. The residue was diluted with ethyl acetate (200 mL), washed with water (20 mL) and brine (20 mL), dried and concentrated. The residue was purified by column chromatography to give compound 3_85_3 (6.5 g, 69 % yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: acetylhydroxamic acid With sodium hydride In N,N-dimethyl-formamide; mineral oil for 0.333333h; Cooling with ice; Stage #2: methyl (2R)-2-bromo-3-(2-naphthyl)propanoate In N,N-dimethyl-formamide; mineral oil at 20℃; for 16h; | 6 Synthesis of KOK2015 (Step 6) Acetohydroxamic acid (31 mg, 0.41 mmol) was dissolved in N,N-dimethylformamide (3 ml). To this, sodium hydride (60%) (16 mg, 0.41 mmol) was added under ice cooling and stirred for 20 minutes. To the mixture, an N,N-dimethylformamide (3 ml) solution containing KOK1164 (100 mg, 0.34 mmol) obtained in Step 2 was added dropwise and stirred at room temperature for 16 hours. To the mixture, water was added and the mixture was extracted three times with ethyl acetate, washed three times with water and then washed with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. This was filtered and concentrated under reduced pressure. Thereafter, the residue was purified by silica gel column chromatography (hexane : ethyl acetate = 1 : 1) to obtain the titled compound (colorless oily substance: 79 mg, 81 %). 1H-NMR (DMSO-d6, 270 MHz) δ ppm: 1.72 (3H, s), 3.21 (2H, d, J = 6.3 Hz), 3.61 (3H, s), 4.71 (1H, t, J = 6.3 Hz), 7.34-7.54 (3H, m), 7.73-7.92 (4H, m), 11.12 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: (1S,2R)-2-Amino-1,2-diphenylethanol; 2-hydroxy-4,6-dimethoxybenzaldehyde; acetylhydroxamic acid In ethanol for 1h; Reflux; Stage #2: vanadium(V) oxytriethoxide In ethanol at 20℃; for 2h; Overall yield = 80 %; | 14 Synthesis of vanadium(V) complexes General procedure: 2.4. Synthesis of vanadium(V) complexesThe complexes were obtained in the following exampleprocedure. A solution of 5 mmol of 1S,2R(+)-2-amino-1,2-diphenylethanol in absolute ethanol (10 ml) was added withstirring to 5 mmol of an aromatic o-hydroxyaldehyde (salicy-laldehyde, 3-methoxysalicylaldehyde, 5-methoxysalicylaldehyde,4,6-dimethoxysalicylaldehyde, 5-methylsalicylaldehyde, 5-bromosalicylaldehyde, 5-nitrosalicylaldehyde, 2,4-dihydroxyben-zaldehyde, 3-tert-butylsalicylaldehyde, 2-hydroxy-1-naphthal-dehyde) in absolute EtOH (20 ml) and heated under reflux for 1 h. Incase of 1b-10b, acetohydroxamic acid (5 mmol) in absolute EtOH(10 ml) was also added with an aldehyde. Then a vanadium(V)oxytriethoxide (5 mmol) in absolute EtOH (10 ml) was added andstirred at room temperature for 2 h. After cooling in a fridge a solid was separated and filtered off, washed several times andrecrystallized from absolute EtOH. 2.4.14 (Acetohydroxamato-κ2O,O'){1S,2R(+)-2-[(1-oxido-1,2-diphenylethyl)iminomethyl]-3,5-dimethoxyphenolato-κ3N,O,O'}oxidovanadium(V) (4b) Yield 80%. Anal. Calc. for C25H25N2O7V: C, 58.1; H, 4.9; N, 5.4. Found: C, 58.2; H, 5.0; N, 5.3%. IR (KBr, cm-1): 3428 (νN-H); 1601, 1573 (νC=O, νC=N); 959 (νV=O). UV-vis spectrum in DMSO [λmax (nm), ɛ (M-1 cm-1)]: 320 (17 850), 489 (3670). CD spectrum in MeOH [λmax (nm), Δɛ (M-1 cm-1)]: 273 (0.24), 322 (-3.95), 371 (3.74), 465 (0.57). 1H NMR (CD3OD, ppm) major (60%): 8.88 (1H, s) (azomethine); 7.51 (2H, dd, 3J = 8 Hz, 4J = 3 Hz), 7.01-7.12 (8H, m), 6.05 (1H, d, 3J = 8 Hz), 5.98 (1H, d, 3J = 8 Hz) (aromatic); 6.47 (1H, d, 3J = 6 Hz), 5.58 (1H, d, 3J = 6 Hz) (methine); 3.84 (3H, s), 3.78 (3H, s) (methoxy); 2.01 (3H, s) (acetyl); minor (40%): 8.83 (1H, s) (azomethine); 7.43 (2H, m), 6.99-7.10 (8H, ov), 6.02 (1H, d, 3J = 8 Hz), 5.97 (1H, ov) (aromatic); 6.71 (1H, d, 3J = 6 Hz), 5.80 (1H, d, 3J = 6 Hz) (methine); 3.87 (3H, s), 3.81 (3H, s) (methoxy); 2.21 (3H, s) (acetyl). 51V NMR (CD3OD, ppm) major (60%): -266.1; minor (40%): -238.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With zinc trifluoromethanesulfonate In toluene at 110℃; for 6h; | Typical procedure for preparation of quinazoline 3-oxides 2a-2h & 4a-4h: General procedure: Ina 50ml round bottom flask fitted with condenser and calcium chloride guard tubea mixture of 2-aminoacetophenone 1a (500 mg, 3.7mmol), acetohydroxamic acid (332 mg, 4.4 mmol) and 5ml toluene were taken. To this zinc(II) triflate (67 mg, 0.18 mmol) was added and stirred the reaction mixture at 110 °C for 6 hours. After completion of reaction by TLC, the crude mixture was concentrated under vacuum and the crude product was purified by normal column chromatography (silica gel 100-200 mesh, ethyl acetate/hexane = 1:2) to obtain 2,4- dimethylquinazoline 3-oxide 2a as a yellow solid (610 mg, 95%, m.p.101-102 °C) and it was characterized by the following spectral data:1HNMR (300 MHz, CDCl3): δ = 7.92 (d, J = 8.3 Hz, 1H), 7.87 (d, J =8.3 Hz, 1H), 7.75-7.69 (m, 1H), 7.65-7.60 (m, 1H), 2.90 (s, 3H), 2.89 (s, 3H); 13CNMR (75 MHz, CDCl3): δ = 157.1, 150.6, 139.7, 130.7, 128.4, 128.3,123.0, 20.5, 12.9; IR (KBr): υ 3442, 3397, 3227, 2983, 2839, 1544, 1459, 1322,1232, 1141, 1028 cm-1; MS(ESI) 175(M+H). ESI-HRMS obtained for C10H11N2O(M+H) =175.0871 (calculated: 175.0864). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With zinc trifluoromethanesulfonate In toluene at 110℃; for 10h; | Typical procedure for preparation of quinazoline 3-oxides 2a-2h & 4a-4h: General procedure: Ina 50ml round bottom flask fitted with condenser and calcium chloride guard tubea mixture of 2-aminoacetophenone 1a (500 mg, 3.7mmol), acetohydroxamic acid (332 mg, 4.4 mmol) and 5ml toluene were taken. To this zinc(II) triflate (67 mg, 0.18 mmol) was added and stirred the reaction mixture at 110 °C for 6 hours. After completion of reaction by TLC, the crude mixture was concentrated under vacuum and the crude product was purified by normal column chromatography (silica gel 100-200 mesh, ethyl acetate/hexane = 1:2) to obtain 2,4- dimethylquinazoline 3-oxide 2a as a yellow solid (610 mg, 95%, m.p.101-102 °C) and it was characterized by the following spectral data: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With zinc trifluoromethanesulfonate In toluene at 110℃; for 8h; | Typical procedure for preparation of quinazoline 3-oxides 2a-2h & 4a-4h: General procedure: Ina 50ml round bottom flask fitted with condenser and calcium chloride guard tubea mixture of 2-aminoacetophenone 1a (500 mg, 3.7mmol), acetohydroxamic acid (332 mg, 4.4 mmol) and 5ml toluene were taken. To this zinc(II) triflate (67 mg, 0.18 mmol) was added and stirred the reaction mixture at 110 °C for 6 hours. After completion of reaction by TLC, the crude mixture was concentrated under vacuum and the crude product was purified by normal column chromatography (silica gel 100-200 mesh, ethyl acetate/hexane = 1:2) to obtain 2,4- dimethylquinazoline 3-oxide 2a as a yellow solid (610 mg, 95%, m.p.101-102 °C) and it was characterized by the following spectral data: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With zinc trifluoromethanesulfonate In toluene at 110℃; for 8h; | Typical procedure for preparation of quinazoline 3-oxides 2a-2h & 4a-4h: General procedure: Ina 50ml round bottom flask fitted with condenser and calcium chloride guard tubea mixture of 2-aminoacetophenone 1a (500 mg, 3.7mmol), acetohydroxamic acid (332 mg, 4.4 mmol) and 5ml toluene were taken. To this zinc(II) triflate (67 mg, 0.18 mmol) was added and stirred the reaction mixture at 110 °C for 6 hours. After completion of reaction by TLC, the crude mixture was concentrated under vacuum and the crude product was purified by normal column chromatography (silica gel 100-200 mesh, ethyl acetate/hexane = 1:2) to obtain 2,4- dimethylquinazoline 3-oxide 2a as a yellow solid (610 mg, 95%, m.p.101-102 °C) and it was characterized by the following spectral data: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With zinc trifluoromethanesulfonate In toluene at 110℃; for 12h; | Typical procedure for preparation of quinazoline 3-oxides 2a-2h & 4a-4h: General procedure: Ina 50ml round bottom flask fitted with condenser and calcium chloride guard tubea mixture of 2-aminoacetophenone 1a (500 mg, 3.7mmol), acetohydroxamic acid (332 mg, 4.4 mmol) and 5ml toluene were taken. To this zinc(II) triflate (67 mg, 0.18 mmol) was added and stirred the reaction mixture at 110 °C for 6 hours. After completion of reaction by TLC, the crude mixture was concentrated under vacuum and the crude product was purified by normal column chromatography (silica gel 100-200 mesh, ethyl acetate/hexane = 1:2) to obtain 2,4- dimethylquinazoline 3-oxide 2a as a yellow solid (610 mg, 95%, m.p.101-102 °C) and it was characterized by the following spectral data: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With zinc trifluoromethanesulfonate In toluene at 110℃; for 12h; | Typical procedure for preparation of quinazoline 3-oxides 2a-2h & 4a-4h: General procedure: Ina 50ml round bottom flask fitted with condenser and calcium chloride guard tubea mixture of 2-aminoacetophenone 1a (500 mg, 3.7mmol), acetohydroxamic acid (332 mg, 4.4 mmol) and 5ml toluene were taken. To this zinc(II) triflate (67 mg, 0.18 mmol) was added and stirred the reaction mixture at 110 °C for 6 hours. After completion of reaction by TLC, the crude mixture was concentrated under vacuum and the crude product was purified by normal column chromatography (silica gel 100-200 mesh, ethyl acetate/hexane = 1:2) to obtain 2,4- dimethylquinazoline 3-oxide 2a as a yellow solid (610 mg, 95%, m.p.101-102 °C) and it was characterized by the following spectral data: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With zinc trifluoromethanesulfonate In toluene at 110℃; for 12h; | Typical procedure for preparation of quinazoline 3-oxides 2a-2h & 4a-4h: General procedure: Ina 50ml round bottom flask fitted with condenser and calcium chloride guard tubea mixture of 2-aminoacetophenone 1a (500 mg, 3.7mmol), acetohydroxamic acid (332 mg, 4.4 mmol) and 5ml toluene were taken. To this zinc(II) triflate (67 mg, 0.18 mmol) was added and stirred the reaction mixture at 110 °C for 6 hours. After completion of reaction by TLC, the crude mixture was concentrated under vacuum and the crude product was purified by normal column chromatography (silica gel 100-200 mesh, ethyl acetate/hexane = 1:2) to obtain 2,4- dimethylquinazoline 3-oxide 2a as a yellow solid (610 mg, 95%, m.p.101-102 °C) and it was characterized by the following spectral data: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With zinc trifluoromethanesulfonate In toluene at 110℃; for 12h; | Typical procedure for preparation of quinazoline 3-oxides 2a-2h & 4a-4h: General procedure: Ina 50ml round bottom flask fitted with condenser and calcium chloride guard tubea mixture of 2-aminoacetophenone 1a (500 mg, 3.7mmol), acetohydroxamic acid (332 mg, 4.4 mmol) and 5ml toluene were taken. To this zinc(II) triflate (67 mg, 0.18 mmol) was added and stirred the reaction mixture at 110 °C for 6 hours. After completion of reaction by TLC, the crude mixture was concentrated under vacuum and the crude product was purified by normal column chromatography (silica gel 100-200 mesh, ethyl acetate/hexane = 1:2) to obtain 2,4- dimethylquinazoline 3-oxide 2a as a yellow solid (610 mg, 95%, m.p.101-102 °C) and it was characterized by the following spectral data: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In dichloromethane at 20℃; for 0.5h; | |
83% | In dichloromethane at 20℃; | |
83% | In dichloromethane at 20℃; |
83% | In dichloromethane at 25℃; for 0.333333h; Inert atmosphere; | |
82.12% | In dichloromethane at 30℃; for 0.75h; | 1.B; 2.B B. Dissolve 21.58g of acetylhydroxamic acid with 130ml of dichloromethane, add N,N'-carbonyldiimidazole prepared in step A, stir while adding, react at 30°C for 45min, and extract with dichloromethane after the reaction is completed, Dry over anhydrous sodium sulfate, remove the solvent under reduced pressure, and recrystallize from a mixture of n-hexane and acetone with a mass ratio of 8:1 to obtain 20.76 g of the product 3-methyl-1,2,4-dioxazol-5-one, Yield 82.12%. |
75% | In dichloromethane at 20℃; for 1h; | |
69% | In dichloromethane at 20℃; for 0.5h; | |
In dichloromethane at 20℃; for 0.5h; | ||
In dichloromethane at 20℃; for 0.5h; | ||
In dichloromethane at 20℃; for 0.5h; | ||
In dichloromethane at 25 - 30℃; for 0.5h; Inert atmosphere; | ||
In dichloromethane at 20℃; | ||
In dichloromethane at 20℃; for 0.5h; | 2. General procedures for the synthesis of dioxazolones 2 General procedure: Hydroxamic acids were commercially available or prepared according to reported synthetic procedures. Dioxazolones 2 were prepared using the literature method.[2] To a stirred solution of a hydroxamic acid (5.0 mmol) in dichloromethane (50 mL) was added 1,1′-carbonyl diimidazole (CDI) (0.81 g, 5.0 mmol) in one portion at room temperature. After stirring for 30 min, the reaction mixture was quenched with 1 N HCl (30 mL), the reaction mixture was extracted with dichloromethane three times (50 mL x 3) and the combined organic layers were dried over magnesium sulfate. After filtration, the solvent in the filtrate was removed under the reduced pressure to afford dioxazolone 2. Dioxazolone 2 could be recrystallized from acetone/hexanes, if necessary. | |
In dichloromethane at 20℃; for 16h; | 1 Preparation of 3-methyl-1,4,2-dioxoazol-5-one The synthesis was carried out as described by S. Chang et al. in J. Am. Chem. Soc. 2015, 137, pages 4534-4542. For this purpose, 50 mmol of acetohydroxamic acid (Sigma-Aldrich) were dissolved in 500 ml of dichloromethane. 50 mmol of 1,1′-carbonyldiimidazole (Combi-Blocks) were added thereto all at once at room temperature (20° C.±2° C.). After stirring for 16 hours, the reaction mixture was quenched with 300 ml of 1 M HCl, extracted three times with 150 ml in each case of dichloromethane and dried over magnesium sulfate. The solvent was removed under reduced pressure and 3-methyl-1,4,2-dioxoazol-5-one was obtained as a colorless, slightly yellowish oil. | |
In ethyl acetate at 20℃; for 1.5h; | ||
In dichloromethane at 20℃; | ||
In dichloromethane at 20℃; | ||
In dichloromethane at 20℃; for 0.5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With 1,4-diaza-bicyclo[2.2.2]octane In acetonitrile at 20℃; for 1h; | General procedure: To a test tube charged with a stir bar, 0.20 mmol of1a and 0.20 mmol of BPO weresequentially added MeCN 1.0 mL and 0.20 mmol of DABCO. The resulting reactionmixture was stirred at room temperature for 3 h and diluted by addition of EtOAc,the organic layer was briefly washed by saturated aqueous sodium bicarbonatesolution, brine and dried over anhydrous sodium sulfate. The bulk solvent wasremoved in vacuo, and the residue waspurified by silica gel flash chromatography (hexane/EtOAc = 5:1) to affordproduct 2a 48.8 mg, 90% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | Stage #1: acetylhydroxamic acid With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 2-fluoro-6-(3-aminophenoxy)benzonitrile In N,N-dimethyl-formamide for 72h; | 2 4.1.1 Preparation of 4-(4-aminophenoxy)benzo[d]isoxazol-3-amine (5a) General procedure: To a solution of acetohydroxamic acid (316mg, 4.21mmol) in DMF (10mL) was added t-BuOK (472mg, 4.21mmol) and the resulting mixture was stirred at room temperature for 30min. Then the precursor 2-(4-aminophenoxy)-6-fluorobenzonitrile 4a (480mg, 2.10mmol) was added and the reaction mixture was stirred for 3days. After the completion of the reaction, the mixture was treated with EtOAc (100mL), washed successively with water (4×30mL) and brine (30mL), and then dried over Na2SO4. The mixture was filtered and concentrated to dryness. The crude product was purified by chromatograph (0-30% acetoacetate/petroleum) to give the title compound as a white solid (220mg, 43%). 1H NMR (300MHz, DMSO-d6) δ: 7.33 (t, J=8.2Hz, 1H), 7.02 (d, J=8.1Hz, 1H), 6.90 (d, J=8.6Hz, 2H), 6.63 (d, J=8.7Hz, 2H), 6.25 (d, J=7.9Hz, 1H), 6.00 (s, 2H), 5.10 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3% | 6-Chloro-5-fluoroisoxazolo[5,4-b]pyridin-3-amine (66) From <strong>[40381-92-8]2,5,6-trichloronicotinonitrile</strong> and acetohydroxamic acid in N- methylmorpholine at room temperature for 3 days to give 67 (3% yield). 1H NMR [(CD3)2SO] delta 8.58 (s, 1H), 6.82 (brs, 2H), HPLC 96.5%, LCMS [M + H] = 204/206. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Method 1. Representative example 5-Bromo-4,6-di methyl isoxazolo[5,4-b]pyridin-3-amine (1) To a solution of acetohydroxamic acid (0.61 g, 8.13 mmol) in dry DMF (10 ml_) under nitrogen was added potassium terf-butoxide (0.91 g, 8.14 mmol). The reaction mixture was stirred at 20 C for 2 hr. 5-Bromo-2-chloro-4,6- dimethylnicotinonitrile (1.00 g, 4.07 mmol) was then added and the resulting mixture was stirred at 20C for 24 hr, then diluted with H20 (150 ml) and stirred for 1 hr. The resulting white precipitate was filtered and washed with water. The filtrate was extracted with EtOAc (30 ml_ x 3). Combined organic fractions were dried (Na2S04), and the solvent evaporated under vacuum to give further material. Both the isolated solid and the extracted material were combined and chromatographed on Si02 eluting with a 0-50 % gradient of petroleum ether/EtOAc. The column purified product was recrystallized from DCM/petroleum ether to give 5-bromo-4,6-dimethylisoxazolo[5,4- b]pyridin-3-amine (1) (0.68 g, 69% ) as a white solid, mp (DCM/petroleum ether) 208-211 C, *H NMR [(CD3)2SO] delta 6.24 (s, 2H, NH2), 2.66 (6H, 2 x CH3), LCMS [M + H] = 242 and 244. Calc. for C8H8BrN30: C, 36.7; H, 3.3; N, 17.4; found C, 36.9; H, 3.2, N, 17.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.2% | 6-Chloro-5-fluoroisoxazolo[5,4-b]pyridin-3-amine (66) To a solution of acetohydroxamic acid (589 mg, 7.85 mmol) in N- methylmorpholine (10 ml.) at 20C was added dry K2C03 (1.08 g, 7.83 mmol) and the mixture was stirred for 1 hr at this temperature. This mixture was cooled in ice and 2,6-dichloro-5-fluoronicotinonitrile (1.00 g, 5.24 mmol) was added and the reaction mixture was allowed to warm up slowly to 20C and stirred at this temperature for 3 days. The reaction mixture was then diluted with H20 and basified with K2CO3 , extracted into EtOAc and dried (Na2S04 ). Evaporation of the solvents gave a semisolid, which was chromatographed (Si02/X4/EtOAc, 0-20%). The fractions with the correct mass were combined and the solvents were evaporated. The resulting residue was triturated with DCM and MeOH to give (66) (2.0 mg, 0.2% yield), mp 243-245 C; *H NMR [(CD3)2SO] delta 8.32 (d, J = 7.6 Hz, 1H), 6.77 (brs, 2H); HPLC 99.4%; Anal, calcd. for C6H3CIFN3O.0.25 MeOH : C, 38.38, H, 2.06; N, 21.49; found C, 38.32; H, 1.85, N, 21.54%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4% | at 120℃; for 20h; | General procedure: 6-Chloro-4-(trifluoromethyl)isoxazolo[5,4-b]pyridin-3-amine (68) A neat mixture of <strong>[13600-42-5]2,6-dichloro-4-(trifluoromethyl)nicotinonitrile</strong> (102 mg, 0.42 mmol) and acetohydroxamic acid (315 mg 4.2 mmol) was heated to 120 C for 20 hr. The cooled reaction mixture was then diluted with H20, basified with K2C03, extracted into EtOAc, and the solution dried (Na2S04). Evaporation of the solvents and the chromatography of the residue (Si02/pet. ether/EtOAc 0-20%) gave 68 (4.0 mg, 4% yield), *H NMR [(CD3)2SO] delta 7.95 (d, J = 0.6 Hz, 1H), 6.24 (brs, 2H), HPLC 99.5%, LCMS [M + H] = 238. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Method 1. Representative example Isoxazolo[5,4-b]pyridin-3-amine (2) From 2-chloronicotinonitrile in 1,2-dimethoxyethane in 48% yield |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With sodium periodate; potassium carbonate In ethanol; water at 20℃; for 3.16667h; Sonication; | 4.2.3 Synthesis of N-hydroxy-N-(3,4-dimethyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-4-yl)-N-acetamide (NHPY 3b) To a solution of acetohydroxamic acid (210 mg, 2.80 mmol) and pyrazolone 2b (105 mg, 0.56 mmol) in 50% aqueous ethanol (7 mL), was added potassium carbonate (12 mg, 0.09 mmol) to adjust the pH to 7-8. Sodium periodate (599 mg, 2.80 mmol) was added to the reaction mixture, which was sonicated for 10 min, and then stirred for 3 h at room temperature. The reaction mixture was diluted with ethanol (12 mL) and the solid was filtered. The filtrate was concentrated via rotary evaporation and the resulting solid was redissolved in ethylacetate (50 mL) and washed three times with a saturated solution of ammonium chloride (30 mL). The organic phase was collected, dried over MgSO4, and concentrated in vacuo. Recrystallization from dichloromethane and hexane gave the title compound (73% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With sodium periodate; potassium carbonate In ethanol; water at 20℃; for 3.16667h; | 11 Example 11: Compound 11 - N-hydroxy-N-(3,4-dimethyl-5-oxo-1-phenyl-4,5-dihydro- 1H-pyrazol-4-yl)-acetamide: To a solution of 3,4-dimethyl-1-phenyl-1H-pyrazol-5(4H)-one (0.105 g, 0.56 mmol) and acetohydroxamic acid (0.210 g, 2.80 mmol) in 50 % aqueous ethanol (8 mL), potassium carbonate (0.012 g, 0.09 mmol) was added to adjust the pH to 7-8. Sodium periodate (0.599 g, 2.80 mmol) was added to the reaction mixture, which was sonicated for 10 min and then stirred for 3 h at room temperature. The reaction mixture was diluted with ethanol (12 mL) and the solid was filtered. The filtrate was concentrated via rotary evaporation, redissolved in ethylacetate (50 mL), and washed three times with saturated solution of ammonium chloride (30 mL). The organic phase was collected, dried over MgSO4, filtered and concentrated in vacuo. Recrystalization from dichloromethane and hexane gave the title compound as white solid (0.107 g, 73%). 1H NMR (400 MHz, CDCl3) δ: 9.08 (s, 1H), 7.86 (m, 2H), 7.44 (m, 2H), 7.23 (m, 1H), 2.18 (s, 3H), 2.10 (s, 3H), 1.68 (s, 3H). [0176] Crystallographic Analysis: Fw = 261.28, colorless irregular shaped crystal, 0.23 ^ 0.09 ^ 0.08 mm3, orthorhombic, Pna21 (no. 33), a = 10.0574(8), b = 11.5181(9), c = 11.6390(10) Å, V = 1348.29(19) Å3, Z = 4, Dx = 1.287 g cm-3, ^ = 0.774 mm-1, abs. corr. range: 0.893 ^0.961. 8035 Reflections were measured up to a resolution of (sin ^/ ^)max = 0.62 Å-1. 2530 Reflections were unique (Rint = 0.0310), of which 2346 were observed [I > 2 ^(I)]. 177 Parameters were refined using 1 restraint. R1/wR2 [I > 2 ^(I)]: 0.0561/0.1561. R1/wR2 [all refl.]: 0.0597/0.1603. S = 1.090. Residual electron density found between ^0.22 and 0.33 e Å-3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With sodium periodate; potassium carbonate In ethanol; water at 20℃; for 3.16667h; | 1 According to Method B, acetohydroxamic acid (0.161 g, 2.14 mmol) was added to a solution of 4-(acetyl-O-methoxyoxime)-N-phenyl-3-methyl-pyrazolone (0.105 g, 0.43 mmol) in 50 % aqueous ethanol (7 mL), and potassium carbonate (0.012 g, 0.09 mmol) was added to adjust the pH to 7-8. Sodium periodate (0.458 g, 2.14 mmol) was added to the reaction mixture, sonciated for 10 min, and then stirred for 3 h at room temperature. The reaction mixture was diluted with ethanol (10 mL) and the solid was filtered. The filtrate was concentrated via rotary evaporation and the resulting solid was redissolved in ethylacetate (50 mL) and washed three times with a saturated solution of ammonium chloride (30 mL). The organic phase was collected, dried over MgSO4, filtered and concentrated in vacuo. Recrystallization from dichloromethane and hexane gave the title compound as white solid (0.1 g, 73%). 1H NMR (400 MHz, CDCl3) δ: 7.86 (m, 2H), 7.51 (s, 1H), 7.42 (m, 2H), 7.22 (m, 1H), 3.95 (s, 3H), 2.25 (s, 3H), 2.19 (s, 3H), 2.01 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 167.8, 159.0, 157.0, 151.4, 137.8, 128.8, 125.8, 119.5, 76.3, 62.5, 21.0, 15.4, 11.4. HR-MS (FAB): found m/z = 319.14094 (MH+); calc. for C15H18O4N4: 319.14063. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: acetylhydroxamic acid; (1R,5S,8s)-8-((5-(3-fluorophenoxy)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)amino)-3-azabicyclo[3.2.1]octane-3-carbonitrile With zinc(II) chloride In ethanol at 20 - 25℃; for 16h; Stage #2: With hydrogenchloride In ethanol; water at 65℃; for 5h; | 29 Example 29 (1R,5S,8s)-N-(5-(3-fluorophenoxy)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)-3-(3-methyl-1,2,4-oxadiazol-5-yl)-3-azabicyclo[3.2.1]octan-8-amine In a 2 mL flask, (1R,5S,8s)-8-((5-(3-fluorophenoxy)-1-(2,2,2-trifluoroethyl)-1H-1,2,4- triazol-3-yl)amino)-3-azabicyclo[3.2.1]octane-3-carbonitrile (lnt-131, 21.2 mg, 51.7 μιηο) was dissolved in ethanol (0.5 mL) and N-hydroxyacetamide (4.7 mg, 62 μιηο) was added, followed by a solution of carefully dried zinc chloride (8.6 mg, 62 μιηο) in ethanol (250 L). The reaction mixture was stirred at room temperature for 16 h. Then, concentrated hydrochloric acid (12.9L) was added and the mixture was stirred for 5 h at 65 °C. After cooling, it was concentrated in vacuo. The resulting crude product was directly purified by column chromatography (amino modified silica gel, 50 g, eluting with ethyl acetate / n-heptane, gradient 0: 100 to 1: 1 v/v) to yield the title compound as a white solid (18.1 mg, 75%). 1H NMR (CDCl3, 300 MHz): δ 1.57- 1.67 (m, 2 H), 1.81-1.91 (m, 2 H), 2.22 (s, 3 H), 2.39-2.46 (m, 2 H), 3.30-3.39 (m, 2 H), 3.72 (d, J = 6.1 Hz, 1 H), 3.89 (dd, J = 3.4, 12.9 Hz, 2 H), 3.99 (d, J = 5.8 Hz, 1 H), 4.52 (q, J = 8.2 Hz, 2 H), 6.95-7.03 (m, 1 H), 7.05-7.12 (m, 2 H), 7.34-7.43 (m, 1 H). MS (ES+) m/z 468.3 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With potassium carbonate In dimethyl sulfoxide at 80℃; for 2h; | 120.1 2-hydroxy-8-{4-(trifluoromethyl)phenoxy}quinoline-5-carbonitrile (Compound 120-1) Compound 60-2 (0.050 g, 0.14 μMol) was dissolved in DMSO (3 mL), and N-hydroxyacetamide (0.022 g, 0.29μMol) and potassium carbonate (0.059 g, 0.43 μMol) were added to the solution. The mixture was stirred at 80°C for2 hours. The mixture was cooled to room temperature, and water was added to the mixture. The organic layer wasextracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate = 100/0-> 50/50) to obtain compound 120-1 (0.043 g, 91%).ESIMS m/z: [M + H]+ 331. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Stage #1: acetylhydroxamic acid With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 2-fluoro-6-methoxy-4-((2,2,2-trifluoroethoxy)methyl)benzonitrile In N,N-dimethyl-formamide at 20℃; | lv.b b) 4-Methoxy-6-((2,2,2-trifluoroethoxy)methyl)benzo[d]isoxazol-3-amine I118 b) 4-Methoxy-6-((2,2,2-trifluoroethoxy)methyl)benzo[d]isoxazol-3-amine I118 A suspension of acetohydroxamic acid (86 mg, 1.14 mmol) and t-BuOK (128 mg,1.14 mmol) in anhydrous DMF (10 ml.) was stirred at RT for 1 h. 2-Fluoro-6-methoxy-4-((2,2,2-trifluoroethoxy)methyl)benzonitrile I117 (100 mg, 0.38 mmol) was then added and the mixture was stirred at RT overnight. The mixture was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The reaction was scaled up accordingly using 2-fluoro-6-methoxy-4-((2,2,2- trifluoroethoxy)methyl)benzonitrile I117 (400 mg, 1.52 mmol) and the two batches were combined and purified by column chromatography (Pet. ether/EtOAc = 20/1 to 5/1) to give the title product (350 mg, 67%) as a yellow solid. LCMS-C: Rt 2.08 min; m/z 277.0 [M+H]+. 1H NMR (400 MHz, DMSO -cfe) d 6.96 (s, 1H), 6.68 (s, 1H), 5.94 (s, 2H), 4.74 (s, 2H), 4.13 (q, J = 9.4 Hz, 2H), 3.90 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Stage #1: acetylhydroxamic acid With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: 2-fluoro-5-methyl-4-(pyridin-2-yl)benzonitrile In N,N-dimethyl-formamide at 0 - 20℃; | lviii.c c) 5-Methyl-6-(pyridin-2-yl)benzo[d]isoxazol-3-amine I124 c) 5-Methyl-6-(pyridin-2-yl)benzo[d]isoxazol-3-amine I124 A suspension of acetohydroxamic acid (255 mg, 3.39 mmol) and t-BuOK (381 mg, 3.39 mmol) in anhydrous DMF (30 mL) was stirred at 0 °C for 1 h. 2-Fluoro-5-methyl-4-(pyridin-2-yl)benzonitrile I123 (240 mg, 1.13 mmol) was then added and the mixture was allowed to warm to RT and stirred overnight. Water was added and the mixture was extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. ether/EtOAc =8/1 to 3/1) to give the title compound (180 mg, 73%) as a white solid. LCMS-C: Rt 0.50 min; m/z 226.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: acetylhydroxamic acid With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 0 - 30℃; for 1h; Inert atmosphere; Stage #2: 3-ethoxy-2-fluorobenzonitrile In N,N-dimethyl-formamide at 30℃; | ix.d d) 7-Ethoxybenzo[d]isoxazol-3-amine I26 To a solution of acetohydroxamic acid (300 mg, 4.0 mmol) in DMF (15 mL) at 0 °C under N2was added potassium tert-butoxide (450 mg, 4.0 mmol) and the mixture was heated at 30 °C for 1 h. A solution of 3-ethoxy-2-fluorobenzonitrile I25 (220 mg, 1.3 mmol) in DMF (10 mL) was added and the mixture was heated at 30 °C overnight. EtOAc (80 mL) was added and the mixture was washed with water (50 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to give the title compound (170 mg, 70%) as a yellow solid. LCMS-D: Rt 1.68 min; m/z 179.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | To a solution of ethanehydroxamic acid (0.263 g, 3.50 mmol) in N,N- dimethylformamide (5 mL) was added t-BuOK (393 mg, 3.50 mmol) and the reaction was stirred for 30 minutes. 4-Bromo-2-fluoro-5-methylbenzonitrile (0.50 g, 2.3 mmol) was added to the reaction which was stirred for a further 2 hours at room temperature. The reaction was diluted with ethyl acetate (50 mL) and water (50 mL), the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water, dried, filtered and concentrated. The crude material was purified by silica gel chromatography (12 g S1O2 cartridge, 0-50% EtOAc in petroleum benzine 40-60 C) to give the title compound (0.30 g, 56% yield) as a white solid. 1H NMR (400 MHz, CDCI3) d 7.68 (s, 1H), 7.37 (s, 1H), 4.35 (br s, 2H), 2.49 (s, 3H). LCMS-B: rt 3.18 min, m/z 229.8 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With potassium carbonate; In water; N,N-dimethyl-formamide; at 70℃; for 19h; | To a solution of <strong>[143306-27-8]2-fluoro-6-nitrobenzonitrile</strong> (1.0 g, 6.17 mmol) in DMF/H2O (32 mL/32 ml.) was added acetohydroxamic acid (2.78 g, 37.0 mmol) and K2CO3 (10.23 g, 74.0 mmol) and the mixture was heated at 70 C for 19 h. Water (200 mL) was added and the mixture was extracted with EtOAc (100 ml. x 3). The combined organic extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. ether/EtOAc = 30/1 to 1/1) to give the title compound (380 mg, 35%) as a yellow solid. LCMS-D: Rt 2.82 min; m/z 180.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | xxix) 7-Bromobenzo[d]isoxazol-3-amine I66 To a solution of acetohydroxamic acid (3.75 g, 0.05 mol) in DMF (60 ml.) at 0 C was added t-BuOK (5.6 g, 0.05 mol) and the mixture was stirred at RT for 1 h. A solution of <strong>[840481-82-5]3-bromo-2-fluorobenzonitrile</strong> (5.0 g, 0.025 mol) in DMF (90 mL) was then added dropwise and stirred was continued at RT overnight. The mixture was diluted with DCM (300 mL), washed with water (250 mL x 4), brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (4.0 g, 63%) as a white solid. LCMS-D: Rt2.09 min, m/z 213.0/215.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | xvi) 4-Bromobenzo[d]isoxazol-3-amine I41 To a solution of acetohydroxamic acid (11.25 g, 0.15 mol) in DMF (220 ml.) at 0 C under N2 was added t-BuOK (16.8 g, 0.15 mol) and the mixture was stirred at 25 C for 1 h. A solution of 2-bromo-6-fluorobenzonitrile (10.0 g, 0.05 mol) in DMF (80 ml.) was then added dropwise and stirring was continued at 25 C overnight. The mixture was diluted with water (200 ml.) and extracted with EtOAc (400 ml_). The organic extract was washed with water (400 ml. x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (7.0 g, 66 %) as a light red solid. LCMS-D: Rt2.05 min; m/z 212.9/214.9 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | xvii) 4-(Trifluoromethyl)benzo[d]isoxazol-3-amine I42 [84] To a solution of acetohydroxamic acid (2.25 g, 30 mmol) in DMF (80 ml.) at 0 C under N2 was added t-BuOK (3.37 g, 30 mmol) and the mixture was heated at 30 C for 1 h. A solution of <strong>[133116-83-3]2-fluoro-6-(trifluoromethyl)benzonitrile</strong> (1.89 g, 10 mmol) in DMF (20 ml.) was then added and heating was continued at 30 C overnight. The mixture was partitioned between EtOAc (300 ml.) and water (100 ml_), the layers were separated and the organic layer was washed with water (100 ml. c 3), brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. ether/ EtOAc = 50/1 to 1/1) to give the title compound (1.3 g, 64%) as a white solid LCMS-D: Rt2.19 min; m/z 203.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | xxii) 5-Methoxybenzo[d]isoxazol-3-amine I54 To a solution of acetohydroxamic acid (1.49 mg, 19.8 mmol) in DMF (35 ml.) at 0 C under N2was added t-BuOK (2.23 mg, 19.8 mmol) and the mixture was heated at 30 C for 1 h. A solution of <strong>[127667-01-0]2-fluoro-5-methoxybenzonitrile</strong> (1.0 g, 6.6 mmol) in DMF (5 ml.) was then added and the mixture was heated at 30 C overnight. The mixture was diluted with water (70 ml.) and extracted with EtOAc (100 ml. x 3). The combined organic extracts were washed with water (200 ml. x 3) then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (110 mg, 11 %) as a yellow solid, which was used directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | xxv) 5-Methylbenzo[d]isoxazol-3-amine I60 To a solution of acetohydroxamic acid (8.33 g, 0.11 mol) in DMF (200 ml.) was added t-BuOK (12.5 g, 0.11 mol) and the mixture was stirred at RT for 1 hour. 2-Fluoro-5-methylbenzonitrile (5 g, 0.37 mol) was then added and the mixture was heated at 60 C overnight. The mixture was diluted with water and extracted with EtOAc. The organic extract was concentrated under reduced pressure and the residue was purified by a silica gel chromatography (DCM/MeOH = 200/1 to 50/1) to give the title compound (3.0 g, 55%) as a white solid. LCMS-D: Rt 1.75 min, m/z 149.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | xxvii) 5-(Trifluoromethoxy)benzo[d]isoxazol-3-amine I63 To a solution of acetohydroxamic acid (2.2 g, 0.029 mol) in DMF (50 ml.) was added t-BuOK (3.28 g, 0.029 mol) and the mixture was stirred RT for 1 hour. 2-Fluoro-5-(trifluoromethoxy)benzonitrile (2 g, 9.75 mmol) was then added and the mixture was heated at 60 C overnight. The mixture was diluted with water and extracted with EtOAc. The organic extract was concentrated under reduced pressure to give the title compound (1.6 g, 75%) as a yellow solid. LCMS-D: Rt2.43 min; m/z 219.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: acetylhydroxamic acid With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 0 - 20℃; for 2h; Inert atmosphere; Stage #2: 2-fluoro-4-(1H-1,2,3-triazol-1-yl)benzonitrile In N,N-dimethyl-formamide at 20℃; Inert atmosphere; | xiii.c 6-(1H-1,2,3-Triazol-1-yl)benzo[d]isoxazol-3-amine I36 To a solution of acetohydroxamic acid (239 mg, 3.16 mmol) in DMF (25 ml.) at 0 °C under N2was added potassium tert-butoxide (357 mg, 3.18 mmol) and the mixture was stirred at RT for 2 h. A solution of 2-fluoro-4-(1H-1,2,3-triazol-1-yl)benzonitrile I35 (200 mg, 1.06 mmol) in DMF (15 ml.) was then added and stirring was continued at RT overnight. EtOAc (100 ml.) was added and the mixture was washed with water (x 5). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. ether/EtOAc = 100/1 to 2/1) to give the title compound (150 mg, 70%) as a white solid. LCMS-D: Rt 0.47 min; m/z 202.1 [M+H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | a) 5-Chlorobenzo[d]isoxazol-3-amine A1 Potassium tert-butoxide (793 mg, 7.07 mmol) was added to a suspension of acetohydroxamic acid (531 mg, 7.07 mmol) in DMF (10 ml.) and stirred at room temperature for 30 minutes. <strong>[57381-34-7]5-Chloro-2-fluorobenzonitrile</strong> (1.00 g, 6.43 mmol) was added and the reaction heated to 50 C for 1 hour. Upon cooling, the reaction mixture was diluted with an aqueous saturated solution of NaCI (15 ml_), the aqueous layer was extracted with EtOAc (3 x 100 ml_), the organics were combined, dried (Na2SO4), filtered and the volatiles were removed in vacuo. The residue was loaded onto silica gel and the product purified by column chromatography (Biotage Isolera, 40 g S1O2 cartridge, 0-40% EtOAc in petroleum benzine 40-60 C) to yield the title compound as a white solid (507 mg, 47%). 1H NMR (400 MHz, DMSO-cfe) d = 7.94 (dd, J = 2.1, 0.6, 1H), 7.59 - 7.48 (m, 1H), 6.51 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | a) 7-Fluorobenzo[d]isoxazol-3-amine A3 Potassium tert-butoxide (887 mg, 7.91 mmol) was added to a suspension of acetohydroxamic acid (594 mg, 7.91 mmol) in DMF (10 ml.) and the reaction was stirred at room temperature for 30 minutes. 2,3-Difluorobenzonitrile (1.00 g, 7.19 mmol) was added and the reaction was heated to 50 C for 1 hour. Upon cooling, the reaction mixture was diluted with an aqueous saturated solution of NaCI (15 ml_), the aqueous layer was extracted with EtOAc (3 x 100 ml.) the organics were combined, dried (Na2SO4) and filtered and the volatiles were removed in vacuo. The resulting gum was loaded onto silica gel and purified by column chromatography (Biotage Isolera, 24g S1O2 cartridge, 0-100% EtOAc in petroleum benzine 40-60 C) to yield the title compound as a white solid (303 mg, 27%). 1H NMR (400 MHz, CDCI3) d = 7.33 (dd, J= 7.6, 1.3, 1H), 7.30 - 7.26 (m, 1H), 7.26 - 7.19 (m, 1H), 4.45 (s, 2H). [187] LCMS-B: rt 3.371 min, m/z 153.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | To a solution of ethanehydroxamic acid (0.629 g, 8.37 mmol) in DMF (5 ml.) was added potassium 2-methylpropan-2-olate (0.94 g, 8.4 mmol) and the reaction was stirred for 30 minutes. Methyl 4-cyano-3-fluorobenzoate (1.0 g, 5.6 mmol) was added followed by DMF (2 ml.) and the reaction was stirred for a further 2 hours at room temperature. The reaction was diluted with ethyl acetate (50 ml.) and water (50 ml_), the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water, dried, filtered and concentrated. The crude material was purified by silica gel chromatography (12 g Si02 cartridge, 0-50% EtOAc in petroleum benzine 40-60 C) to give the title compound (0.55 g, 51% yield) as a white solid. 1H NMR (400 MHz, CDCIs) d 8.12 (d, J = 1.02 Hz, 1H), 7.96 (dd, J = 1.24, 8.29 Hz, 1H), 7.59 (dd, J = 0.77, 8.25 Hz, 1H), 3.98 (s, 3H). LCMS: rt 2.97 min, m/z 193.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Stage #1: acetylhydroxamic acid With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 0 - 30℃; for 1h; Inert atmosphere; Stage #2: 2-fluoro-4-(pyrimidin-2-yl)benzonitrile In N,N-dimethyl-formamide at 30℃; Inert atmosphere; | xiv.c c) 6-(Pyrimidin-2-yl)benzo[d]isoxazol-3-amine I39 c) 6-(Pyrimidin-2-yl)benzo[d]isoxazol-3-amine I39 To a solution of acetohydroxamic acid (306 mg, 4.07 mmol) in DMF (20 ml.) at 0 °C under N2 was added potassium tert-butoxide (457 mg, 4.07 mmol) and the mixture was heated at 30 °C for 1 h. A solution of 2-fluoro-4-(pyrimidin-2-yl)benzonitrile I38 (270 mg, 1.36 mmol) in DMF (10 ml.) was then added and heating was continued at 30 °C overnight. The mixture was diluted with EtOAc (100 ml.) and washed with water (50 ml. x 3). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and the residue was purified by column chromatography (Pet. ether/ EtOAc = 50/1 to 2/1) to give the title compound (200 mg, 69%) as a white solid. LCMS-D: Rt 0.38 min; m/z 213.1 [M+H]+, 235.1 [M+Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: acetylhydroxamic acid With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 0 - 20℃; for 1.5h; Inert atmosphere; Stage #2: 3-bromo-6-fluoro-2-methoxybenzonitrile In N,N-dimethyl-formamide at 70℃; Inert atmosphere; | xix.d d) 5-Bromo-4-methoxybenzo[d]isoxazol-3-amine I48 d) 5-Bromo-4-methoxybenzo[d]isoxazol-3-amine I48 To a solution of acetohydroxamic acid (3.4 g, 45.7 mmol) in DMF (150 ml.) at 0 °C under N2was added t-BuOK (5.1 g, 45.7 mmol) and the mixture was stirred at RT for 90 min. A solution of 3-bromo-6-fluoro-2-methoxybenzonitrile I47 (3.5 g, 15.2 mmol) in DMF (30 ml.) was then added and the mixture was heated at 70 °C overnight. The mixture was diluted with EtOAc (1000 ml.) and washed with water (x 3), brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. ether/EtOAc = 50/1 to 3/1) to give the title compound (3.2 g, 86%) as a white solid. LCMS-D: Rt2.24 min; m/z 243.0/244.9 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | b) 4-Ethoxybenzo[d]isoxazol-3-amine I53 To a solution of acetohydroxamic acid (2.18 g, 29 mmol) in DMF (40 ml.) at 0 C under N2was added t-BuOK (3.26 g, 29 mmol) and the mixture was stirred at RT for 1 h. 2-Ethoxy-6-fluorobenzonitrile I52 (1.6 g, 9.7 mmol) was then added and the mixture was stirred at RT overnight. The mixture was diluted with DCM (80 ml_), washed with water (60 ml. x 4), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet.ether/EtOAc = 5/1) to give the title compound (240 mg, 15%) as a white solid. LCMS- E: Rt5.05 min; m/z 179.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: acetylhydroxamic acid With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 0 - 30℃; for 1h; Inert atmosphere; Stage #2: 5-ethoxy-2-fluorobenzonitrile In N,N-dimethyl-formamide at 30℃; Inert atmosphere; | xxiii.c c) 5-Ethoxybenzo[d]isoxazol-3-amine I57 c) 5-Ethoxybenzo[d]isoxazol-3-amine I57 To a solution of acetohydroxamic acid (645 mg, 8.7 mmol) in DMF (35 ml.) at 0 °C under N2was added t-BuOK (978 mg, 8.7 mmol) and the mixture was heated at 30 °C for 1 h. A solution of 5-ethoxy-2-fluorobenzonitrile I56 (480 mg, 2.9 mmol) in DMF (5 ml.) was then added and the mixture was heated at 30 °C overnight. The mixture was diluted with water (60 ml.) and extracted with EtOAc (80 ml. x 2). The combined organic extracts were washed with water (150 ml. x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (400 mg, 77%) as a light yellow solid. LCMS-D: Rt2.02 min; m/z 179.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: acetylhydroxamic acid With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 0 - 20℃; for 2h; Stage #2: 2-fluoro-4-(methoxymethyl)-5-methylbenzonitrile In N,N-dimethyl-formamide at 60℃; | i.d 6-(Methoxymethyl)-5-methylbenzo[d]isoxazol-3-amine I4 To a solution of acetohydroxamic acid (792 mg, 10.6 mmol) in anhydrous DMF (20 ml.) at 0 °C was added potassium tert-butoxide (1.2 g, 10.6 mmol) and the mixture was stirred at RT for 2 h. 2-Fluoro-4-(methoxymethyl)-5-methylbenzonitrile I3 (630 mg, 3.5 mmol) was then added and the mixture was heated at 60 °C overnight. Water was added and the mixture was extracted with EtOAc (80 ml. x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (DCM/MeOH = 20/1 to 10/1) to give the title compound (1.0 g, 77%) as a yellow solid. LCMS-D: Rt 1.75 min; m/z 193.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Stage #1: acetylhydroxamic acid With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 0℃; for 1h; Inert atmosphere; Stage #2: 2-fluoro-3-(pyrimidin-2-yl)benzonitrile In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; | xxx b) 7-(Pyrimidin-2-yl)benzo[d]isoxazol-3-amine I68 b) 7-(Pyrimidin-2-yl)benzo[d]isoxazol-3-amine I68 To a solution of acetohydroxamic acid (243 mg, 3.2 mmol) in DMF (15 ml.) at 0 °C under N2 was added t-BuOK (363 mg, 3.2 mmol) and the mixture was stirred for 1 h. A solution of 2-fluoro-3-(pyrimidin-2-yl)benzonitrile I67 (400 mg, 1.6 mmol) in DMF (5 ml.) was then added dropwise and the mixture was stirred at RT overnight. The mixture was diluted with EtOAc (80 ml.) and washed with water (60 ml. x 3). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (230 mg, 67%) as a yellow solid. LCMS- D: Rt 0.80 min, m/z 213.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: acetylhydroxamic acid With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 2-fluoro-4-methoxy[1,1'-biphenyl]-3-carbonitrile In N,N-dimethyl-formamide at 20 - 60℃; | xxxvi.c c) 4-Methoxy-7-phenylbenzo[d]isoxazol-3-amine I80 c) 4-Methoxy-7-phenylbenzo[d]isoxazol-3-amine I80 To a solution of acetohydroxamic acid (533 mg, 7.1 1 mmol) in anhydrous DMF (30 mL) at RT was added potassium tert-butoxide (797 mg, 7.11 mmol) and the mixture was stirred at RT for 1 h. 2-Fluoro-4-methoxy-[1,1'-biphenyl]-3-carbonitrile I79 (538 mg, 2.37 mmol) was then added and the mixture was heated at 60 °C overnight. Water was added and the mixture was extracted with EtOAc (30 mL c 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. ether/EtOAc = 10/1 to 5/1) to give the title compound (413 mg, 72%) as an orange solid. LCMS-C: Rt 1.33 min; m/z 209.0 [M+H]+. 1H NMR (400 MHz, CDCIs) d 7.84 - 7.79 (m, 2H), 7.61 (d, J = 8.1Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.38 - 7.32 (m, 1H), 6.67 (d, J = 8.2 Hz, 1H), 4.00 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: acetylhydroxamic acid With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: 4-cyano-N-(2,2-dimethoxyethyl)-3-fluorobenzamide In N,N-dimethyl-formamide at 40℃; | xl.c c) 3-Amino-N-(2,2-dimethoxyethyl)benzo[d]isoxazole-6-carboxamide I89 c) 3-Amino-N-(2,2-dimethoxyethyl)benzo[d]isoxazole-6-carboxamide I89 To a solution of acetohydroxamic acid (448 mg, 5.95 mmol) in DMF (30 ml.) at 0 °C was added t-BuOK (889 mg, 7.92 mmol) portion-wise and the mixture was stirred for 1 h. 4-Cyano-N-(2,2-dimethoxyethyl)-3-fluorobenzamide I88 (500 mg, 1.98 mmol) was then added and the mixture was heated at 40 °C overnight. The mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet.ether/EtOAc = 1/1, v/v) to give the title compound (380 mg, 72%) as a yellow solid. LCMS-D: Rt 0.59 min, m/z 287.9 [M+Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.07% | With sodium hydroxide In dimethyl sulfoxide at 60℃; for 12h; | 2 Preparation Example 2: Preparation of compound a1 Add the compound represented by formula (II-1-1) (0.5mol), the compound represented by formula (II-2-1) (0.85mol), and DMSO (600ml) into the reaction flask,After stirring and dissolving, add sodium hydroxide (2mol), and react at 60°C for 12h. After HPLC detects that the compound represented by formula (II-1-1) is basically unchanged, DMSO is distilled off, and the remaining organic phase in the bottle is dissolved in water , Extracted three times with dichloromethane, and removed the dichloromethane to obtain compound a1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.2% | Stage #1: acetylhydroxamic acid With potassium carbonate In tetrahydrofuran at 20℃; for 1h; Stage #2: 1-bromo-4-(bromomethyl)-2-(trifluoromethyl)benzene In tetrahydrofuran at 20℃; | 1.c Step c, synthesis of N-((4-bromo-3-(trifluoromethyl)benzyl)oxy)acetamide Dissolve acetohydroxamic acid (0.12g, 1.58mmol) in THF (5ml), Add potassium carbonate (0.22g, 1.58mmol) and stir at room temperature for 1h, Add a solution of 4-bromo-3-trifluoromethylbenzyl bromide (0.5g, 1.58mmol) in THF (5ml), React overnight at room temperature. The reaction liquid is filtered, The filtrate was concentrated to dryness to obtain a yellow oil (0.52g), then, Using EA/PE system to recrystallize to obtain 0.44g of white solid, the yield is 89.2%, The purity was determined to be 98.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.3% | Stage #1: acetylhydroxamic acid; dimethyl sulfate With sodium hydrogencarbonate; sodium hydroxide In water at 20℃; for 3.5h; Stage #2: With hydrogenchloride In water; isopropyl alcohol at 20℃; for 0.5h; | 1-3 The preparation method of methoxyamine hydrochloride of this embodiment includes the following steps: 1) Add 0.2 mol sodium bicarbonate and 2.3 mol sodium hydroxide to 200 g of water and mix uniformly to obtain a composite alkali aqueous solution (ie, mixed aqueous solution);2) Add 108g (1.44mol) of acetohydroxamic acid and 252g of water to the reaction flask and mix to obtain a reaction solution. Control the temperature of the reaction solution to 20°C, add 163.4g (1.30mol) dimethyl sulfate dropwise, and add the compound dropwise at the same time. Alkaline aqueous solution, control the pH of the reaction system = 7.5-8.0, after 2 hours of dripping, the dimethyl sulfate dripping is completed and stirred for 0.5h. Then continue to add 18.1g (0.14mol) dimethyl sulfate dropwise, and at the same time add the composite alkali aqueous solution, control the pH of the reaction system = 7.5-8.0, stir for 0.5h after dropping, and then add 27.2g (0.22mol) dimethyl sulfate dropwise At the same time, the composite alkali aqueous solution was added dropwise, the pH of the reaction system was controlled to be 7.5-8.0, the dropping was completed and the reaction was stirred for 0.5 h, TLC monitored the completion of the reaction, and the reaction product liquid was obtained.3) The above reaction product liquid was heated to 60°C, kept for 1 hour (quenching dimethyl sulfate), and dropped to room temperature. 156.8g 90% concentrated sulfuric acid (containing 1.44mol H2SO4) was added dropwise, and reacted at 73°C. After 3 hours, the acetic acid was distilled off under reduced pressure at 60°C, and 500g ethanol was added to disperse the remainder. After that, alkali was added to adjust pH=10, stirred for 0.5h, filtered, and the filtrate was distilled at atmospheric pressure to collect 80-95°C. Then add 115g of 30% mass fraction of concentrated hydrochloric acid to adjust pH<2, evaporate to dryness, then add 60g of isopropanol, stir at room temperature for half an hour, filter, and dry the obtained solid at 50 to obtain 116.4g of finished product. The rate is 96.3%, and the gas phase detection purity is 99.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.3% | With sodium hydrogencarbonate; sodium hydroxide In water at 20℃; for 3.5h; | 4-6 The preparation method of methoxyamine hydrochloride of this embodiment includes the following steps: General procedure: 1) Add 0.2 mol sodium bicarbonate and 2.3 mol sodium hydroxide to 200 g of water and mix uniformly to obtain a composite alkali aqueous solution (ie, mixed aqueous solution);2) Add 108g (1.44mol) of acetohydroxamic acid and 252g of water to the reaction flask and mix to obtain a reaction solution. Control the temperature of the reaction solution to 20°C, add 163.4g (1.30mol) dimethyl sulfate dropwise, and add the compound dropwise at the same time. Alkaline aqueous solution, control the pH of the reaction system = 7.5-8.0, after 2 hours of dripping, the dimethyl sulfate dripping is completed and stirred for 0.5h. Then continue to add 18.1g (0.14mol) dimethyl sulfate dropwise, and at the same time add the composite alkali aqueous solution, control the pH of the reaction system = 7.5-8.0, stir for 0.5h after dropping, and then add 27.2g (0.22mol) dimethyl sulfate dropwise At the same time, the composite alkali aqueous solution was added dropwise, the pH of the reaction system was controlled to be 7.5-8.0, the dropping was completed and the reaction was stirred for 0.5 h, TLC monitored the completion of the reaction, and the reaction product liquid was obtained.3) The above reaction product liquid was heated to 60°C, kept for 1 hour (quenching dimethyl sulfate), and dropped to room temperature. 156.8g 90% concentrated sulfuric acid (containing 1.44mol H2SO4) was added dropwise, and reacted at 73°C. After 3 hours, the acetic acid was distilled off under reduced pressure at 60°C, and 500g ethanol was added to disperse the remainder. After that, alkali was added to adjust pH=10, stirred for 0.5h, filtered, and the filtrate was distilled at atmospheric pressure to collect 80-95°C. Then add 115g of 30% mass fraction of concentrated hydrochloric acid to adjust pH<2, evaporate to dryness, then add 60g of isopropanol, stir at room temperature for half an hour, filter, and dry the obtained solid at 50 to obtain 116.4g of finished product. The rate is 96.3%, and the gas phase detection purity is 99.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Stage #1: hydroxylamine hydrochloride With sodium hydroxide In water at 20 - 25℃; for 0.15h; Stage #2: ethyl acetate at 30 - 35℃; for 0.25h; | In this application, during application, 69.5g (1mol) of hydroxylamine hydrochloride is preferably dissolved in 85g of water at room temperature, and 306g of 30% sodium hydroxide aqueous solution is prepared. Hydroxylamine hydrochloride solution and sodium hydroxide solution are fed into flux at the same time. The first microchannel reactor is 100ml, the flow rate of hydroxylamine hydrochloride is controlled to 13.4ml/min, the flow rate of sodium hydroxide solution is 24.6ml/min, the reaction temperature is 20-25, the reaction is over after 9min, and then the reaction liquid is collected .Pass the collected reaction liquid and ethyl acetate into the second microchannel reactor with a flux of 100ml at the same time, the flow rate of the reaction liquid is 22.92ml/min, the flow rate of ethyl acetate is 8.3ml/min, and the reaction temperature is 30- 35°C.The 15min reaction is over.After the reaction, the yield can be determined by tracking and analyzing the content of hydroxylamine hydrochloride by TLC. The yield of the two-step reaction is 98%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium carbonate In dimethyl sulfoxide at 80℃; for 18h; | 1 [00793] Step 1 - Ethyl 6-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate [00794] To a solution of ethyl 6-bromopyrazolo[1,5-a]pyrimidine-3-carboxylate (500 mg, 1.85 mmol, Intermediate BMT) in the DMSO (4 mL) was added ethanehydroxamic acid (417 mg, 5.55 mmol) and K2CO3 (1.28 g, 9.26 mmol), and the mixture was stirred at 80 °C for 18 hrs. On completion, the reaction mixture was diluted with EA (50 mL) and washed with HCl (1 M, 50 mL), and brine (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (300 mg, 78% yield) as yellow solid.1H NMR (400 MHz, DMSO-d6) δ8.61 (d, J = 2.7 Hz, 1H), 8.52 (d, J = 2.7 Hz, 1H), 8.40 (s, 1H), 4.27 (q, J = 7.1Hz, 2H), 1.32 - 1.28 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.1% | Stage #1: 2-fluoro-[1,1'-biphenyl]-3-carbonitrile With potassium-t-butoxide In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: acetylhydroxamic acid In N,N-dimethyl-formamide at 60℃; for 10h; | 4.1.2 General procedure for preparation of intermediates 12, 14 and 17a-17e 4.1.2.1 7-phenylbenzo[d]isoxazol-3-amine (12) t-BuOK (2.98g, 26.56mmol) was added to a solution of intermediate 11 (3.50g, 17.75mmol) in DMF (30mL) in batches, and the mixture was stirred for 1h at room temperature. Acetohydroxamic acid (2.00g, 26.64mmol) was added to the mixture and stirred for 10h at 60. When TLC showed the completion of the reaction, water (150mL) was added. The mixture was extracted 3 times with ethyl acetate (each 60mL). The organic phases were combined, washed with brine, dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure and then purified by column chromatography on silica gel (petroleum ether : ethyl acetate=5 : 2) to give intermediate 12 (2.28g, yield 61.1%). It was obtained as a white solid. 1H NMR (400MHz, DMSO-d6) δ 7.90 - 7.86 (dd, J=1.2, 8.3Hz, 2H), 7.86 - 7.82 (dd, J=1.1, 7.8Hz, 1H), 7.81 - 7.76 (dd, J=1.1, 7.5Hz, 1H), 7.57 - 7.49 (t, J=7.6Hz, 2H), 7.47 - 7.40 (t, J=7.4Hz, 1H), 7.39 - 7.35 (t, J=7.6Hz, 1H), 6.51 - 6.46 (s, 2H). ESI-MS: m/z=211.1 [M+H]+. |
61.1% | Stage #1: 2-fluoro-[1,1'-biphenyl]-3-carbonitrile With potassium-t-butoxide In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: acetylhydroxamic acid In N,N-dimethyl-formamide at 60℃; for 10h; | 4.1.2 General procedure for preparation of intermediates 12, 14 and 17a-17e 4.1.2.1 7-phenylbenzo[d]isoxazol-3-amine (12) t-BuOK (2.98g, 26.56mmol) was added to a solution of intermediate 11 (3.50g, 17.75mmol) in DMF (30mL) in batches, and the mixture was stirred for 1h at room temperature. Acetohydroxamic acid (2.00g, 26.64mmol) was added to the mixture and stirred for 10h at 60. When TLC showed the completion of the reaction, water (150mL) was added. The mixture was extracted 3 times with ethyl acetate (each 60mL). The organic phases were combined, washed with brine, dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure and then purified by column chromatography on silica gel (petroleum ether : ethyl acetate=5 : 2) to give intermediate 12 (2.28g, yield 61.1%). It was obtained as a white solid. 1H NMR (400MHz, DMSO-d6) δ 7.90 - 7.86 (dd, J=1.2, 8.3Hz, 2H), 7.86 - 7.82 (dd, J=1.1, 7.8Hz, 1H), 7.81 - 7.76 (dd, J=1.1, 7.5Hz, 1H), 7.57 - 7.49 (t, J=7.6Hz, 2H), 7.47 - 7.40 (t, J=7.4Hz, 1H), 7.39 - 7.35 (t, J=7.6Hz, 1H), 6.51 - 6.46 (s, 2H). ESI-MS: m/z=211.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.7% | With potassium ethanolate In ethanol at 30℃; for 12h; Inert atmosphere; | 1; 4 Example 4 Under nitrogen protection, add absolute ethanol (100ml) to a dry 250ml four-necked flask, Slowly add potassium ethoxide solid (16.8g, 0.2mol), stir to dissolve, then add N-hydroxyacetamide (7.5g, 0.1mol), methyl 3-methyl-3-((methylsulfonyl)oxy)butyrate (21 g, 0.1 mol) was added dropwise, and after the dropwise addition was completed, the mixture was stirred at 30 °C for 12 h. After the reaction, the by-products were removed by suction filtration, the filtrate was evaporated under reduced pressure to remove ethanol, water (100ml) was added to the residue, stirred at room temperature until completely dissolved, and the pH was adjusted to 2 with hydrochloric acid (2mol/L). dichloromethane (60ml) was added for extraction, then the organic phase was separated and the organic phase was evaporated under reduced pressure to remove the dichloromethane to obtain a white solid 5,5-dimethylisoxazolidin-3-one (10.2g), which was detected by HPLC , the product has a purity of 98.9% and a yield of 87.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.5% | With potassium methanolate In methanol at 20℃; for 24h; Inert atmosphere; | 2; 5 Example 5 Under nitrogen protection, add anhydrous methanol (100ml) to a dry 250ml four-necked flask, Slowly add potassium methoxide solid (14g, 0.2mol), stir to dissolve, then add N-hydroxyacetamide (7.5g, 0.1mol), methyl 3-methyl-3-((trifluoromethyl)sulfonyl)oxy)butyrate (26.4 g, 0.1 mol) was added dropwise, and after the dropwise addition was completed, the mixture was stirred at 20 °C for 24 h. After the reaction, the by-product was removed by suction filtration, the filtrate was evaporated under reduced pressure to remove methanol, water (100ml) was added to the residue, stirred at room temperature until completely dissolved, adjusted to pH 2 with hydrochloric acid (2mol/L), and dichloromethane (60ml) extraction. Then, the organic phase was separated and the organic phase was evaporated under reduced pressure to remove the dichloromethane to obtain a white solid 5,5-dimethylisoxazolidin-3-one (10.3g). The yield was 88.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium methanolate In methanol at 50℃; for 8h; Inert atmosphere; | 3; 6 Example 6 Under nitrogen protection, add anhydrous methanol (100ml) to a dry 250ml four-necked flask, Slowly add potassium methoxide solid (14g, 0.2mol), stir to dissolve, then add N-hydroxyacetamide (7.5g, 0.1mol), methyl 3-methyl-3-(p-methylbenzenesulfonyloxy)butyrate (28.6 g, 0.1 mol) was added dropwise, and after the dropwise addition was completed, the mixture was stirred at 50 °C for 8 h. After the reaction, the by-products were removed by suction filtration, the filtrate was evaporated under reduced pressure to remove methanol, water (100ml) was added to the residue, stirred at room temperature until completely dissolved, and the pH was adjusted to 2 with hydrochloric acid (2mol/L). dichloromethane (60ml) was added for extraction, then the organic phase was separated and the organic phase was evaporated under reduced pressure to remove the dichloromethane to obtain a white solid 5,5-dimethylisoxazolidin-3-one (10.1g), which was detected by HPLC, the product has a purity of 99.1% and a yield of 87.0%. |
Tags: 546-88-3 synthesis path| 546-88-3 SDS| 546-88-3 COA| 546-88-3 purity| 546-88-3 application| 546-88-3 NMR| 546-88-3 COA| 546-88-3 structure
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