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CAS No. : | 39499-34-8 | MDL No. : | MFCD00085127 |
Formula : | C5H4ClNO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XMVNMWDLOGSUSM-UHFFFAOYSA-N |
M.W : | 145.54 | Pubchem ID : | 2736894 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.2 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 31.65 |
TPSA : | 43.1 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.01 cm/s |
Log Po/w (iLOGP) : | 1.82 |
Log Po/w (XLOGP3) : | 1.66 |
Log Po/w (WLOGP) : | 1.36 |
Log Po/w (MLOGP) : | 0.02 |
Log Po/w (SILICOS-IT) : | 1.77 |
Consensus Log Po/w : | 1.33 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.13 |
Solubility : | 1.07 mg/ml ; 0.00736 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.18 |
Solubility : | 0.964 mg/ml ; 0.00662 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.17 |
Solubility : | 0.989 mg/ml ; 0.00679 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.21 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P280-P301+P330+P331-P302+P352-P304+P340-P305+P351+P338-P310 | UN#: | 3265 |
Hazard Statements: | H314 | Packing Group: | Ⅱ |
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 |
---|---|---|
92% | With triethylamine; In dichloromethane; for 0.5h; | General procedure: The steps of synthesizing UTLOH-4a, -4b, and -4c can be described below.In short,The starting material (5-methylisoxazole-3-carboxylic acid) (1.27 g, 10 mmol) in 30 mL of dichloromethane was refluxed with thionyl chloride (10 mL) for 3 hr.Excess thionyl chloride was removed in vacuo to afford compound 2.Slowly add anisidine to the compound 2 of 10 ml of dichloromethane (o-,M- or p-anisidine (1.23 g 10 mmol).Then 5 ml of dichloromethane in triethylamine was added to the mixture.The mixture was then stirred for 30 minutes and the dichloromethane was removed in vacuo.Diluted HCl was added and the crude product was extracted three times with ethyl acetate.The organic layers were combined, dried over Na 2 SO 4 , filtered and then recrystallised.Compound 3a, 3b or 3c is obtained. |
With triethylamine; In dichloromethane; at 20℃; for 0.166667h; | EXAMPLE 1; Synthesis of Compound 3a, 3b, Or 3c; Compound 1 (5-methylisoxazole-3-carboxylic acid) (1.27 g, 10 mmole) was refluxed in 10 mL of toluene with thionyl chloride (10 mL) for 3 hr. The excess thionyl chloride was removed in vacuo to make compound 2. Anisidines (1.23 g, 10 mmole) and triethylamine (TEA)(1.39 mL, 10 mmole) were added to compound 2 in 10 mL of dichloromethane. The mixture was stirred at room temp for 10 min and the solvent was removed in vacuo. After acidification with diluted HCl, the mixture was poured into water and then extracted with ethyl acetate a couple times. The combined organic layers were dried by Molecular Sieve and concentrated. Recrystallization in ethanol afforded compound 3a-c. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In toluene; | EXAMPLE 1: Preparation of 3-(2,6-dimethyl phenylcarbamoyl) 5-methyl isoxazole (compound 1) 27 g (0.2 mole) of 2,6-dimethyl aniline are dissolved in 100 ml of toluene, 14.5 g (0.1 mole) of 5-methyl isoxazole 3-carboxylic acid chloride are added drop wise with stirring and the mixture is refluxed for 2h. The mixture is cooled and the hydrochloride formed is filtered off. The organic phase is washed with 10% sodium bicarbonate. After filtration and removal of the solvent, the product is recrystallized from cyclohexane or pentane. M.p.=100. The yield is about 90%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | To a suspension of 5-methylisoxazole-3-carboxylic acid (130 mg, 0.89 mmol, CAS: 3405-77-4) in DCM (5 mL) was added oxalyl chloride (0.5 mL) and THF (0.1 mL). After 30 min, to the reaction mixture was added oxalyl chloride (0.5 mL) and DMF (0.05 mL). After a further 30 min the reaction mixture was concentrated in vacuo, azeotroping twice with toluene to give 5-methylisoxazole-3-carbonyl chloride (150 mg, 100%). To a stirred solution of benzyl (1 S,2R)-2-((S)-1 -((1 ,3-dioxoisoindolin-2-yl)methyl)- 8-(((S)-pyrrolidin-3-yl)oxy)-1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1- carboxylate (92 mg, 0.14 mmol) and triethylamine (0.10 mL, 0.70 mmol) in DCM (1 mL) was added portionwise a solution of 5-methylisoxazole-3-carbonyl chloride (150 mg, 0.91 mmol) in DCM (2 mL). After 30 min saturated aqueous NaHCC>3 (2 mL) was added and the organic layer separated and dried over MgSCL,filtered and concentrated in vacuo. The residue was passed through an SCX-2 cartridge (1 g, methanolic ammonia) and concentrated in vacuo to give (1 S,2R)-benzyl 2-((S)-1-((1 ,3-dioxoisoindolin-2-yI)methyl)- 8-(((S)-1-(5-methylisoxazole-3-carbonyl)pyrrolidin-3-yl)oxy)-1 ,2,3,4-tetrahydroiso- quinoline-2-carbonyl)cyclohexanecarboxylate (34 mg, 33%), used without further purification. LCMS (Method 4a): 3.07 min, 748.6 [M+NH4f. | |
80% | With thionyl chloride; In N,N-dimethyl-formamide; toluene; for 5h;Reflux; | A mixture of 5-methylisoxazole-3-carboxylic acid (3.81 g, 0.03 mol) in 150 mL of toluene was dried via azeotropic distillation of some of the toluene into a two-neck 500 mL round bottom flask fitted with a Dean-Stark trap and a magnetic stirrer. The mixture was allowed to cool to about 90 C, and dimethylformamide, 1 mL, was added. Thionyl chloride (4.8 g, 0.04 mol) was added dropwise over 15 min and the mixture was refluxed for 5 h with continuous stirring. The reaction was allowed to cool to room temperature, and then the solvent was evaporated in vacuo to yield the product, a dark-brown oil, 80%, which crystallized on standing. It was kept under vacuum until further use. |
With thionyl chloride; In toluene; for 3h;Heating / reflux; | EXAMPLE 1; Synthesis of Compound 3a, 3b, Or 3c; Compound 1 (5-methylisoxazole-3-carboxylic acid) (1.27 g, 10 mmole) was refluxed in 10 mL of toluene with thionyl chloride (10 mL) for 3 hr. The excess thionyl chloride was removed in vacuo to make compound 2. Anisidines (1.23 g, 10 mmole) and triethylamine (TEA)(1.39 mL, 10 mmole) were added to compound 2 in 10 mL of dichloromethane. The mixture was stirred at room temp for 10 min and the solvent was removed in vacuo. After acidification with diluted HCl, the mixture was poured into water and then extracted with ethyl acetate a couple times. The combined organic layers were dried by Molecular Sieve and concentrated. Recrystallization in ethanol afforded compound 3a-c. |
With thionyl chloride; In dichloromethane; for 6h;Heating / reflux; | EXAMPLE 87. Synthesis of S-fS-Methylisoxazole-θ-CarboxamidoV^-ChlorobenzoicAcid (Intermediate 42)42[0280] Ethyl S-methylisoxazole-S-carboxylate (500 mg, 3.22 mmol) was suspended in MeOH-THF-H2O (2OmL, 1:1:1) and lithium hydroxide monohydrate (1.35 g, 32.2 mmol) was added. The reaction mixture was stirred for 16 h at room temperature, and acidified with IN HCl. The crude product was extracted with ethyl acetate, and ethyl acetate layer was dried (Na2SO4) and solvent evaporated. The white solid thus obtained, was suspended in dichloromethane (30 mL) and treated with thionyl chloride (2.35 mL, 32.3 mmol) at reflux for 6 hr. The reaction mixture was evaporated, and the residue was dissolved in hexane-ethyl acetate mixture (100 mL, 6:4) and quickly filtered through a short silica plug. On evaporation of solvent, 5-methylisoxazole-3-carbonyl chloride was obtained as a colorless syrup (330 mg, 70%).[0281] qTo a solution of 5-amino-2-chlorobenzoic acid (342 mg, 2.0 mmol) and TEA (1.39 mL, 10 mmol), was added 5-methylisoxazole-3-carbony. chloride (300 mg, 2.06 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 16 hr, and triturated with aqueous sodium bicarbonate. The organic layer was separated, dried <n="105"/>(Na2SO4) and evaporated. The residue on filtered through a silica plug to give the title compound as a cream colored solid (330 mg, 57%). | |
With thionyl chloride; In N,N-dimethyl-formamide; toluene; for 5h;Reflux; | 5-Methylisoxazole-3-carboxylic acid (150 mg, 1.18 mmol) dissolved in toluene (2 mL) was treated with DMF (1 drop) and thionyl chloride (1.42 mmol, 103 Ι then heated to reflux for 5 h. The solvent was removed in vacuo to afford crude 5-methylisoxazole-3- carbonyl chloride (155 mg, 1.06 mmol) as a brown oil. The crude acid chloride without purification was dissolved in THF (4 mL), treated with Et3N (155 μ, i.o6 mmol) and stirred for 5 min, before adding 4-(2-aminoethyl)benzenesulfonamide (220 mg, 1.10 mmol) and stirring at room temperature for 15 h under N2 atmosphere. The reaction mixture was concentrated in vacuo and purified by MPLC, affording the titled compound as an amorphous white solid (205 mg, 62%): NMR (600 MHz, DMSO- d6) δ 8.79 (t, J = 5-8 Hz, lH), 7-74 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 8.3 Hz, 2H), 7.30 (s, 2H), 6.50 (q, J= 0.8 Hz, lH), 3.49 (m, 2H), 2.91 (t, J = 7.2 Hz, 2H), 2.45 (d, J= 0.8 Hz, 3H); ^C NMR (151 MHz, DMSO-d6) δ 171.0, 158.8, 158.5, 143-3, 142.0, 129.0, 125. 6, 101.1, 39-8, 34-3, H-7; HRMS (ESI-TOF) m/z calcd for C13H14N304S [M-H]- 308.0711, found 308.0708; LC-MS m/z 308.0 [M+H]+, purity >99% (ELSD). | |
With thionyl chloride; In dichloromethane; for 3h;Reflux; | The steps of synthesizing UTLOH-4a, -4b, and -4c can be described below.In short,The starting material (5-methylisoxazole-3-carboxylic acid) (1.27 g, 10 mmol) in 30 mL of dichloromethane was refluxed with thionyl chloride (10 mL) for 3 hr.Excess thionyl chloride was removed in vacuo to afford compound 2.Slowly add anisidine to the compound 2 of 10 ml of dichloromethane (o-,M- or p-anisidine (1.23 g 10 mmol).Then 5 ml of dichloromethane in triethylamine was added to the mixture.The mixture was then stirred for 30 minutes and the dichloromethane was removed in vacuo.Diluted HCl was added and the crude product was extracted three times with ethyl acetate.The organic layers were combined, dried over Na 2 SO 4 , filtered and then recrystallised.Compound 3a, 3b or 3c is obtained. | |
With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; for 3h;Reflux; | Dissolve 5mmol 5-methylisoxazole-3-carboxylic acid in 5ml of anhydrous dichloromethane, slowly add 1.5ml of thionyl chloride, and add a small amount of DMF for catalysis, and reflux for 3h. After the reaction is completed, the excess thionyl chloride and dichloromethane are removed by rotary evaporation, and a light yellow acid chloride is obtained for the next reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With triethylamine; In dichloromethane; at 20℃; for 1h; | Example B 8; Preparation of compound 8A mixture of intermediate 12 (0.000552 mol), 5-methyl-3-isoxazolecarbonyl chloride (0.000552 mol) and Et3N (0.001104 mol) in CH2Cl2 (5 ml) was stirred for 1 hour at room temperature. The solvent was evaporated. Then Na2CO3 aqueous solution (1 ml) and CH2Cl2 were added to the residue. The mixture was filtered through an Extrelute filter and the filtrate's solvent was evaporated. The residue was purified by HPLC method A. The product fractions were collected and the solvent was evaporated. The residue was dried, yielding 0.097 g (37 %) of compound 8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; for 1h; | Example B22; Preparation of compound 54A mixture of (0.00250 mol), 5-methyl-3-isoxazolecarbonyl chloride(0.00250 mol) and Et3N (0.00225 mol) in CH2Cl2 (50 ml) was stirred for 1 hour at room temperature. The reaction was quenched with an aqueous Na2CO3 solution. The mixture was extracted with CH2Cl2. The separated organic layer was dried (MgSO4), filtered and the solvent was evaporated. DIPE was added to precipitate some product. The precipitate was filtered off and dried, yielding 0.30 g of compound 54. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With triethylamine; In dichloromethane; at 20℃; for 16h; | EXAMPLE 87. Synthesis of S-fS-Methylisoxazole-psi-CarboxamidoV^-ChlorobenzoicAcid (Intermediate 42)42[0280] Ethyl S-methylisoxazole-S-carboxylate (500 mg, 3.22 mmol) was suspended in MeOH-THF-H2O (2OmL, 1:1:1) and lithium hydroxide monohydrate (1.35 g, 32.2 mmol) was added. The reaction mixture was stirred for 16 h at room temperature, and acidified with IN HCl. The crude product was extracted with ethyl acetate, and ethyl acetate layer was dried (Na2SO4) and solvent evaporated. The white solid thus obtained, was suspended in dichloromethane (30 mL) and treated with thionyl chloride (2.35 mL, 32.3 mmol) at reflux for 6 hr. The reaction mixture was evaporated, and the residue was dissolved in hexane-ethyl acetate mixture (100 mL, 6:4) and quickly filtered through a short silica plug. On evaporation of solvent, 5-methylisoxazole-3-carbonyl chloride was obtained as a colorless syrup (330 mg, 70percent).[0281] qTo a solution of <strong>[89-54-3]5-amino-2-chlorobenzoic acid</strong> (342 mg, 2.0 mmol) and TEA (1.39 mL, 10 mmol), was added 5-methylisoxazole-3-carbony. chloride (300 mg, 2.06 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 16 hr, and triturated with aqueous sodium bicarbonate. The organic layer was separated, dried <n="105"/>(Na2SO4) and evaporated. The residue on filtered through a silica plug to give the title compound as a cream colored solid (330 mg, 57percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sodium azide; In water; acetone; at 0 - 25℃; for 1h; | A solution of <strong>[39499-34-8]5-methylisoxazole-3-carbonyl chloride</strong> (4.9 g, 33.3 mmol) in 50 mL acetone is cooled to 0 C. and treated with sodium azide (2.5 g, 38.5 mmol) dissolved in 3 mL water. The solution is allowed to warm to RT. After 1 h, the solvent is removed, suspended in water, filtered and dried in vacuo to provide 4.65 g (92% yield) of 5-methylisoxazole-3-carbonyl azide. 1H NMR (CDCl3, 400 MHz) δ 2.51, 6.46 ppm. A solution of 5-methylisoxazole-3-carbonyl azide (166 mg, 1.09 mmol) and 5-chloro-2,4-dimethoxyaniline (204 mg, 1.09 mmol) in 15 mL CH3CN is heated under reflux. After 16 h, the reaction is cooled. The white precipitate is filtered, washed with ether and dried in vacuo to provide 264 mg (78% yield) of Example 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With triethylamine; In acetonitrile; at 20℃; for 84h; | [2-(1-METHYL-4-PHENYL-LH-IMIDAZOL-5-YL) [1,] 3] thiazolo [5,4-d] [PYRIMIDIN-7-AMINE] (Example 2) (50 mg) and 5-methyl-isoxazole-3-carbonyl chloride (140 mg) were stirred in MeCN (4 [ML)] for 15 minutes then triethylamine (0.14 mL) added and stirred at ambient temperature for 3.5 days under an inert atmosphere. The reaction mixture was concentrated in vacuo, 7N [NH3] in MeOH (5 mL) /concentrated aqueous [NH3] (5 mL) added then heated at 55 C for 2.5 hours. The reaction mixture was concentrated in vacuo and purified on [RPHPLC] to give the title compound as a pale yellow solid (12 mg, [18%)] ; 1H NMR (DMSO-d6) 8 2.56 (s, 3H), 4.19 (s, 3H), 7.01 (s, 1H), 7.40-7. 45 (m, [3H),] 7.63-7. 68 (m, 2H), 8.01 (bs, 2H), 8.37 (s, 1H) ; MS m/e MH+ 418. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | Example 20 { (S)-3- [3- (4-Fluoro-phenyl)- [ 1, 2,4] oxadiazol-5-yl]-piperidin-1-yl}- (5-methyl- isoxazol-3-yl)-methanone The compound was prepared following the procedure described in the Example 13, using <strong>[39499-34-8]5-methylisoxazole-3-carbonyl chloride</strong> as the acyl chloride of choice and S-3- [3- (4-fluoro-phenyl)- [1, 2,4] oxadiazol-5-yl] -piperidine hydrochloride (prepared as described in the Example 12). Yield: 32 % (colourless oil); [a] D=+112 (c=1.2, CHCl3) ; LCMS (Tr): 7.23 min (Method A); MS (ES+) gave m/z: 357. 1. 1H-NMR (CDC13, 333K, 300 MHz), b (ppm): 8.14-7. 96 (m, 2H); 7.20-7. 09 (m, 2H); 6.26 (s, 1H); 5.04-4. 24 (m br, 2H); 3.97-3. 58 (m br, 1H); 3.46-3. 13 (m, 2H); 2.45 (s, 3H); 2.41-2. 27 (m, 1H); 2.11-1. 88 (m, 2H); 1. 83-1. 67 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 0.333333h;pH 9.0; | To a solution of the compound of Step 12 (2.09 g, 4.01 mmol) in CH2C12 (12 mL) at 0 C was added <strong>[39499-34-8]5-methylisoxazole-3-carbonyl chloride</strong> (0.875 g, 6.02 mmol). DIPEA was added to adjust pH of the reaction mixture to 9. The reaction mixture was stirred at 0 C for another 20 minutes and partitioned between EtOAc and water. The organic extract was washed with water and brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography and eluted with 0-50% EtOAc in hexanes to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion of 557.08 for M+H+. 1H NMR (400 MHz, DMSO-d6) 8 9.23 (s, 1H), 8.48 (s, 1H), 8.11-8. 09 (d, J = 7. 7 Hz, 1H), 7.94-7. 91 (m, 1H), 7.81-7. 80 (d, J = 2. 6 Hz, 1H), 7.63- 7.62 (d, J = 2.6 Hz, 1H), 6.56 (s, 1H), 6.15-5. 87 (m, 1H), 5.34-5. 27 (m, 1H), 3.99-3. 90 (m, 2H), 2.46 (s, 3H), 1. 40-1. 28 (m, SH), 1.08-0. 97 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With acetic acid; In diethyl ether; hexane; | a 2-Diazo-1-(5-methylisoxazol-3-yl)ethanone 5-Methylisoxazole-3-carboxylic acid chloride (15.7 g, 0.108 mol) was dissolved in diethyl ether (100 ml) and added dropwise to a cooled solution of trimethylsilyldiazomethane (2M in hexane, 56.3 ml, 0.112 mol). The solution was stirred at 0 C. for 1 hour, then allowed to warm up to room temperature and stirred for 1 hour. Acetic acid (1.5 ml) was added and the solution was stirred for 15 min. The solution was then washed with water and brine, and dried (Na2SO4). The solution was evaporated to dryness and the residue purified by chromatography on silica gel, eluding with ethyl acetate/hexane (1:2), to yield the required diazoketone (7.4 g, 45%). 1H NMR (360 MHz, CDCl3) 2.48 (3H, s), 6.19 (1H, s), 6.42 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; | This crude material was suspended in CH3CN (170 mL) and cooled to 0 C. 5-Methylisoxazole-3-carbonyl chloride (8.00 g, 55.0 mmol, 1 equiv) was added in one portion. After 25 min at 0 C., the reaction mixture was allowed to warm to 23 C. and stirred for an additional 75 min. The thick mixture was then poured into dilute HCl (0.02 M, 150 mL) and mixed thoroughly. The undissolved solid was collected by filtration and washed with H2O (2*20 mL) then dried under vacuum overnight to provide the title intermediate (7.1 g, 65%): 1H NMR (DMSO-d6) δ 2.48 (s, 3H), 6.29 (dd, 1H, J=7.2, 6.6), 6.69 (s, 1H), 7.19 (dd, 1H, J=6.6, 1.8), 8.26 (dd, 1H, J=7.2, 1.8), 9.43 (s, 1H), 12.20 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With NMM; In ethanol; dichloromethane; acetonitrile; | Preparation of Intermediate 5-Methylisoxazole-3-carboxylic Acid (2'-hydroxy-4'-methylpyridin-3'-yl)amide A sample of 10% Pd on C (0.35 g) was added to a solution of <strong>[6332-56-5]2-hydroxy-3-nitropyridine</strong> (2.03 g, 14.5 mmol, 1 equiv) in EtOH. The reaction mixture was stirred at room temperature under H2 atmosphere (balloon) overnight and then was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was dissolved in CH3CN (100 mL), cooled to 0 C., and 5-methylisoxazole-3-carbonyl chloride (2.11 g, 14.5 mmol, 1 equiv) and NMM (1.51 mL, 14.5 mmol, 1 equiv) were added sequentially. The resulting mixture was stirred at 0 C. for 20 min, and then was partitioned between water (400 mL) and 10% CH3OH in CH2Cl2 (2*400 mL). The organic layers were dried over Na2SO4, concentrated and the resulting residue was recrystallized from CH2Cl2/hexanes to afford the title intermediate as an off-white solid (2.42 g, 76%): IR (cm-1) 3330, 1650, 1536; 1H NMR (DMSO-d6) delta 3.34 (s, 3H), 6.31 (t, 1H, J=6.6), 6.73 (s, 1H), 7.21 (d, 1H, J=7.2), 8.29 (s, 1H, J=7.2), 9.46 (s, br. 1H), 12.23 (s, br. 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With ammonium acetate; In pyridine; | cis-N3-(4-{4-Amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-5-methyl-3-isoxazolecarboxamide 5-Methyl-3-isoxazolecarbonyl chloride (20 mg, 0.137 mmol) was added to a solution of cis-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.067 mmol) in pyridine (0.5 mL). After 5 hours, the solvent was evaporated and the residue was purified by preparative HPLC (Hypersil BSD C18, 5 um, 100*21 mm, 0%-100% acetonitrile/0.05M ammonium acetate over 10 min, 25.0 mL/min). The resulting products were further purified by partitioning between dichloromethane (4 ml) and 1.0 N sodium hydroxide (2 ml) and passing through an Empore high performance extraction disk cartridge (C18-SD octadecyl) to give cis-N3-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-5-methyl-3-isoxazolecarboxamide (14 mg, 38%). 1H NMR (DMSO-d6) δ 1.81 (m, 2H), 2.14 (m, 2H), 2.35 (m, 2H), 2.53 (s, 3H), 2.76 (m, 3H), 3.37 (bm, 8H), 3.99 (s, 3H), 4.93 (m, 1H), 6.74 (s, 1H), 7.36 (m, 2H), 8.26 (m, 1H), 9.48 (s, 1H); LCMS (Finigan-Column: Pecosphere, C18, 3 um, 33*4.6 mm. Eluents: 0% B/A to 100% B/A in 4 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.0 mL/min.): MH+=546.4, Rt=1.82 min. |
38% | With ammonium acetate; In pyridine; | Example 399 cis-N3-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-5-methyl-3-isoxazolecarboxamide 5-methyl-3-isoxazolecarbonyl chloride (20 mg, 0.137 mmol) was added to a solution of cis-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.067 mmol) in pyridine (0.5 mL). After 5 hours, the solvent was evaporated and the residue was purified by preparative HPLC (Hypersil BSD C18, 5 um, 100*21 mm, 0%-100% acetonitrile/0.05M ammonium acetate over 10 min, 25.0 mL/min). The resulting products were further purified by partitioning between dichloromethane (4 ml) and 1.0 N sodium hydroxide (2 ml) and passing through an Empore high performance extraction disk cartridge (C18-SD octadecyl) to give cis-N3-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-5-methyl-3-isoxazolecarboxamide (14 mg, 38%). 1H NMR (DMSO-d6) δ 1.81 (m, 2H), 2.14 (m, 2H), 2.35 (m, 2H), 2.53 (s, 3H), 2.76 (m, 3H), 3.37 (bm, 8H), 3.99 (s, 3H), 4.93 (m, 1H), 6.74 (s, 1H), 7.36 (m, 2H), 8.26 (m, 1H), 9.48 (s, 1H); LCMS (Finigan-Column: Pecosphere, C18, 3 um, 33*4.6 mm. Eluents: 0% B/A to 100% B/A in 4 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.0 mL/min.): MH+=546.4, Rt=1.82 min. |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine; In 1,2-dimethoxyethane; | Example 57 Preparation of N-[9-(2,5-Dichlorobenzyl)-9H-β-carbolin-3-yl]methyl}-5-methyl-3-isoxazolecarboxamide A solution of <strong>[39499-34-8]5-methylisoxazole-3-carbonyl chloride</strong> in DCE (0.25M) was treated with a solution of [9-(2,5-dichlorobenzyl)-9H-β-carbolin-3-yl]methylamine in DME (0.25M, 1 equiv), followed by a solution of triethylamine in DME (1.0M, 1 equiv). The mixture was agitated, and allowed to stand overnight. The solvent was evaporated and the residue purified by preparative HPLC. 1H NMR (300 MHz, DMSO-d6) δ9.5 (br t, 1H), 9.40 (s, 1H), 8.74 (s, 1H), 8.60 (d,J=7.8 Hz, 1H) 7.78 (m, 1H), 7.66-7.60 (m, overlap, 2H), 7.50-7.41 (m, overlap, 2H), 6.69 (s, 1H), 6.65 (s, 1H), 5.97 (s, 1H), 4.96 (d, J=5.4Hz, 2H), 2.49 (s, overlap with DMSO peak). A peak at 13.7 ppm in the 13C NMR spectrum is consistent with the methyl group, which presumably overlaps with the solvent in the 1H NMR spectrum. Monoisotopic mass calcd for C24H18Cl2N4O2: 464.1, (M+H) found 465.4. |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine; In dichloromethane; at 20℃; for 0.5h; | EXAMPLE 3; Synthesis of Compound 14a, 14b, Or 14c; 5-methylisoxazole-3-carboxylic acid (1.27 g, 10 mmole) was refluxed with thionyl chloride (10 mL) in 10 mL toluene for 3 hr. The excess thionyl chloride was removed in vacuo to provide compound 2 (as shown in example 1). Phenylethylenediamine (1.1 g, 10 mmole) and TEA (1.39 mL, 10 mmole) were added to compound 2 in dichloromethane (10 mL). The mixture was stirred at room temp for 30 min and dichloromethane was removed in vavuo. After acidification with dilute HCl, the mixture was poured into water to precipitate the product. Recrystallizaiton in ethanol afforded pure compound 14a-c. |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine; In dichloromethane; at 20℃; for 0.5h; | EXAMPLE 4; Synthesis of Compound 15 a, 15b, Or 15c; 5-methylisoxazole-3-carboxylic acid (1.27 g, 10 mmole) was refluxed with thionyl chloride (10 mL) in 10 mL toluene for 3 hr. The excess thionyl chloride was removed in vacuo to provide compound 2 (as shown in example 1). Phenyldiol (1.1 g, 10 mmole) and TEA (1.39 mL, 10 mmole) were added to compound 2 in dichloromethane (10 mL). The mixture was stirred at room temp for 30 min and dichloromethane was removed in vacuo. After acidification with dilute HCl, the mixture was poured into water to precipitate the product. Recrystallizaiton in ethanol afforded pure compound 15a-c. |
Yield | Reaction Conditions | Operation in experiment |
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50.3% | With sodium hydroxide; In dichloromethane; water; Petroleum ether; | Example 3 Preparation of N-(1-ethyl-3-piperidinyl)-5-methylisoxazole-3carboxamide (compound No. 14) To a solution of <strong>[6789-94-2]3-amino-N-ethylpiperidine</strong> (4.61 g; 36 mmols) in methylene chloride (20 ml) and water (10 ml), a solution of 5-methyl-3-isoxazole-carbonyl chloride (5.68 g; 39 mmols) in methylene chloride (35 ml) and 1N NaOH (39 ml) were added contemporaneously at the temperature of 3C. After 30 minutes the temperature was allowed to raise to the room value and after 1-3 h the phases were separated; the aqueous phase was extracted again with methylene chloride. After drying and evaporation of the solvent, a crude product (7.1 g) was obtained which was then crystallyzed from a mixture of isopropyl ether/petroleum ether (ratio 1:1; 160 ml). N-(1-ethyl-3-piperidinyl)-5-methylisoxazole-3-carboxamide was obtained (4.3 g; yield 50.3%) m.p. 84-86C. 1H-NMR (200 MHz, CDCl3): delta (ppm): 1.04 (t, 3H, C H 3-CH2); 1.51-2.61 (m, 8H); 2.38 (q, 2H, CH3-C H 2); 2.46 (d, 1H, CH3-C); 4.20 (m, 1H, CH-N); 6.41 (q, 1H, CH=C); 7.29 (d, 1H, NH). |
50.3% | With sodium hydroxide; In dichloromethane; water; Petroleum ether; | EXAMPLE 3 Preparation of N-(1-ethyl-3-piperidinyl)-5-methylisoxazole-3-carboxamide (compound No. 14) To a solution of <strong>[6789-94-2]3-amino-N-ethylpiperidine</strong> (4.61 g; 36 mmols) in methylene chloride (20 ml) and water (10 ml), a solution of 5-methyl-3-isoxazole-carbonyl chloride (5.68 g; 39 mmols) in methylene chloride (35 ml) and 1N NaOH (39 ml) were added contemporaneously at the temperature of 3 C. After 30 minutes the temperature was allowed to raise to the room value and after 1-3 h the phases were separated; the aqueous phase was extracted again with methylene chloride. After drying and evaporation of the solvent, a crude product (7.1 g) was obtained which was then crystallyzed from a mixture of isopropyl ether/petroleum ether (ratio 1:1; 160 ml). N-(1-ethyl-3-piperidinyl)-5-methylisoxazole-3-carboxamide was obtained (4.3 g; yield 50.3%) m.p. 84-86 C. 1 H--NMR (200 MHz, CDCl3): delta (ppm): 1.04 (t, 3H, CH3 --CH2); 1.51-2.61 (m, 8H); 2.38 (q, 2H, CH3 --CH2); 2.46 (d, 1H, CH3 --C); 4.20 (m, 1H, CH--N); 6.41 (q, 1H, CH=C); 7.29 (d, 1H, NH). |
Yield | Reaction Conditions | Operation in experiment |
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With potassium carbonate; In diethyl ether; dichloromethane; acetonitrile; | Example 2 Preparation of 5-methylisoxazole-3-carboxylic acid 3-(1-methylpiperidinyl) ester hydrochloride (compound No. 10) A solution of 5-methyl-3-isoxazolecarbonylchloride (5.33 g; 36.6 mmols) in methylene chloride (15 ml) was poured dropwise into a solution of 3-hydroxy-1-methylpiperidine (4.21 g; 36.6 mmols) in methylene chloride (50 ml), cooled to 5C. After 1 hour at room temperature, the reaction mixture was poured into an aqueous solution of potassium carbonate and the phases were separated. The aqueous phase was extracted with methylene chloride. The combined organic extracts were washed with water, made anhydrous and evaporated under vacuum. The residue (8 g) was crystallized from isopropyl ether/petroleum ether (ratio 1:3; 80 ml) thus obtaining 5-methylisoxazole-3-carboxylic acid 3-(1-methylpiperidinyl) ester (4.7 g; yield 49.3%); m.p. 59.3-61.5C. By dissolution in acetonitrile (30 ml) and diethyl ether (30 ml) followed by acidification with hydrochloric acid in ether, the 5-methylisoxazole-3-carboxylic acid 3-(1-methylpiperidinyl) ester hydrochloride was obtained (4.37 g; yield 45.8%) showing the same characteristics as the sample obtained as described in example 1. | |
With potassium carbonate; In diethyl ether; dichloromethane; acetonitrile; | EXAMPLE 2 Preparation of 5-methylisoxazole-3-carboxylic acid 3-(1-methylpiperidinyl) ester hydrochloride (compound No. 10) A solution of 5-methyl-3-isoxazolecarbonylchloride (5.33 g; 36.6 mmols) in methylene chloride (15 ml) was poured dropwise into a solution of 3-hydroxy-1-methylpiperidine (4.21 g; 36.6 mmols) in methylene chloride (50 ml), cooled to 5 C. After 1 hour at room temperature, the reaction mixture was poured into an aqueous solution of potassium carbonate and the phases were separated. The aqueous phase was extracted with methylene chloride. The combined organic extracts were washed with water, made anhydrous and evaporated under vacuum. The residue (8 g) was crystallized from isopropyl ether/petroleum ether (ratio 1:3; 80 ml) thus obtaining 5-methylisoxazole-3-carboxylic acid 3-(1-methylpiperidinyl) ester (4.7 g; yield 49.3%); m.p. 59.3-61.5 C. By dissolution in acetonitrile (30 ml) and diethyl ether (30 ml) followed by acidification with hydrochloric acid in ether, the 5-methylisoxazole-3-carboxylic acid 3-(1-methylpiperidinyl) ester hydrochloride was obtained (4.37 g; yield 45.8%) showing the same characteristics as the sample obtained as described in example 1. |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride;AlCl3; In CS2; | EXAMPLE 1 [3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl](5-methyl-3-isoxazolyl)methanon To a solution of 20.6 g (0.1 mole) of 2,6-di-tert-butylphenol and 15.6 g (0.107 mole) of 5-methylisoxazole-3-carboxylic acid chloride in 100 mL of CS2 is added 14.3 g (0.107 mole) of AlCl3 at +5 C. Vigorous stirring is maintained at that temperature for 1 hour and then at room temperature for 1 hour. The CS2 is decanted off and the residue treated with 350 mL of ice cold 1N HCl and extracted with Et2 O. The extracts are washed with saturated NaHCO3 solution and brine, dried with Na2 SO4 and evaporated to give a mixture of products. The desired product is separated by flash chromatography (0% to 50% CH2 Cl2 /n-hexane) on silica gel to give 4.4 g of the crude ketone which is recrystallized from n-pentane to give 2.3 g (14%) of pale yellow crystals, [3,5-bis(1,1-dimethylethyl)-4 -hydroxyphenyl(5-methyl-3-isoxazolyl)methanone, mp 120 C.; 1 H NMR (CDCl3) δ 1.48 (s, 18H, tert-butyl), 2.52 (s, 3H, CH3), 5.85 (s, 1H, OH), 6.48 (s, 1H, isoxazole aromatic), 8.23 (s, 2H, phenyl aromatics); IR (KBr) 1590, 1600, 1650, 3600 cm-1; MS (DEI) m/e 315 (M+), 300 (M-CH3). Anal. for C19 H25 NO3: Calcd: C, 72.35; H, 7.99; N, 4.44. Found: C, 71.96; H, 8.08; N, 4.34. |
Yield | Reaction Conditions | Operation in experiment |
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In 1,4-dioxane; | Example 97 4-Amino-6,7-dimethoxy-2-[4-(5-methylisoxazole-3-carbonyl)-piperazin-1-yl]quinazoline Hydrochloride A solution of <strong>[39499-34-8]5-methylisoxazole-3-carbonyl chloride</strong> (0.41 g., 2.83 mmole) in dioxane was added to a solution of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (0.82 g., 2.83 mmole) in dioxane. The mixture was treated as described in the previous example to give the title compound having a m.p. of 271-273 C. with decomposition. Anal. Calcd. for C19H22N6O4HCl H2O: C, 50.38; H, 5.56; N, 18.56; H2O, 3.92. Found: C, 50.58; H, 5.40; N, 18.86; H2O, 3.72. | |
In 1,4-dioxane; | EXAMPLE 4 4-Amino-6,7-dimethoxy-2-[4-(5-methylisoxazole-3-carbonyl)piperazin-1-yl]quinazoline Hydrochloride A solution of <strong>[39499-34-8]5-methylisoxazole-3-carbonyl chloride</strong> (0.41 g., 2.83 mmole) in dioxane was added to a solution of 4-amino-6,7-dimethoxy-2-(1-piperazinyl) quinazoline (0.82 g., 2.83 mmole) in dioxane. The mixture was treated as described in the previous example to give the title compound having a m.p. of 271-273 C. with decomposition. Anal. Calcd. for C19 H22 N6 O4. HCl H2 O: C, 50.38; H, 5.56; N, 18.56; H2 O, 3.92. Found: C, 50.58; H, 5.40; N, 18.86; H2 O, 3.72. |
Yield | Reaction Conditions | Operation in experiment |
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In potassium carbonate; acetone; | Part A Preparation of 3'-acetyl-5-methyl-3-isoxazolecarboxanilide. 1/4 hydrate STR8 A solution of 5-methyl-3-isoxazolecarbonyl chloride (14.5 g) in acetone (30 ml) was added to a solution of m-aminoacetophenone (13.8 g) in acetone (280 ml) in the presence of anhydrous potassium carbonate (21.0 g). The mixture was stirred for 1/2hour, and then diluted with water. The precipitated product was filtered, washed with water and dried. Yield = 20.5 g (83%), m.p. 188-190. Analysis %: Found: C, 62.77; H, 5.00; N, 10.89. Calculated for C13 H12 N2 O3.1/4H2 O: C, 62.77; H, 5.03; N, 11.26. |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride; In water; acetone; | EXAMPLE 6 Preparation of dl-6-{m-(5-methylisoxazole-3-carboxamido)phenyl}-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole monohydrochloride monohydrate dl-6-(m-aminophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole (14.5 g) was stirred in acetone (100 ml) and water (25 ml) and 2.5N HCl (27 ml) added to give a clear solution of pH approximately 5. This solution was stirred and cooled to 5 and a solution of 5-methyl-3-isoxazolecarbonyl chloride (14.5 g) in acetone (30 ml) added over 1/2 hour at 5-10. The resulting mixture was stirred at 10 for 1/2 hour and the precipitated solid filtered, washed with acetone and dried. Yield = 21 g (87.5%), m.p. 118-121 (d). N.M.R., I.R. and T.L.C. analyses showed the product to be identical with the product of Example 1 Part C. |
Yield | Reaction Conditions | Operation in experiment |
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97% | With triethylamine; In dichloromethane; for 1.5h; | 96 mg of N-(2'-chloro-4'-fluoro-5'-aminobenzoyl)-4-(p~fluorophenoxy)- piperidine (0.261 mmol) (as described in Example 14, step 2) and triethylamine (100 μL, 0.718 mmol) was dissolved in anhydrous dichloromethane (5 ml_) and 5-methyl-isoxazole-3-carbonyl chloride 140 mg (0.959 mmol) was added in one portion. The mixture was stirred for 114 hours, quenched with 0.5M sodium carbonate (30 ml_) and stirred vigorously for an additional hour. The work-up of the reaction mixture and purification was identical to Example 24. (The purified amorphous product crystallized upon re-dissolution in methanol (0.5 ml_). The supernatant was decanted and the product dried under high vacuum). Y = 120.5 mg of a white crystalline solid (97%). Physical Data: LC/MS(+ESI): M+1=476, 478. 1H (cfe-DMSO, 400MHz): δ 10.573 (s, 1H), 7.685 (m, 2H), 7.115 (m, 2H), 7.023 (m, 2H), 6.685 (S1 1H), 4.605 (m, 1h), 4.096-3.947 (m, 1 H), 3.548-3.309 (m, 2H), 3.166 (m, 1 H), 2.511 (s, 3H), 2.006 (br m, 1 H), 1.904 (br m, 1 H), 1.621 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
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With triphenylphosphine; In dichloromethane; at 45℃; for 4h; | Methyl 5-(4-aminophenyl)-3-[[(frans-4-methylcyclohexyl)carbonyl](1-methylethyl)amino]-2- thiophenecarboxylate (200 mg, a synthesis of which is described as Intermediate 9) was dissolved in DCM (5 ml_), then triphenylphosphine (317 mg) and 5-methyl-3- isoxazolecarbonyl chloride (140 mg) were added. The reaction was stirred at 450C for 4 h.The mixture was diluted with DCM and sodium bicarbonate solution was added. The mixture was stirred at room temperature for 5 mins, then the organic phases were separated, dried using a hydrophobic frit and evaporated in vacuo. The crude material was purified by ISCOCompanion silica chromatography, eluting with a gradient 5-100% EtOAc in cyclohexane to give the title compound.MS calcd for (C28H33N3O5S + H)+: 524 MS found (electrospray): (M+H)+ = 524 |
Yield | Reaction Conditions | Operation in experiment |
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39% | Step 3. To a solution of methyl 1-(2-amino-4-formylphenyl)piperidine-4-carboxylate 59 (0.488 g, 1.9 mmol) in DCM (10 mL) at 0 C. was added pyridine (0.300 mL, 3.7 mmol) and <strong>[39499-34-8]5-methylisoxazole-3-carbonyl chloride</strong> (0.185 g, 1.3 mmol). The reaction mixture was stirred at 0 C. for 30 min, additional acid chloride (88 mg) was added and stirring was continued at 0 C. After 30 min, the reaction mixture was diluted with EtOAc, washed with saturated NaHCO3 (1*), brine (1*), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 20% to 50% EtOAc in hexanes) gave methyl 1-(4-formyl-2-(5-methylisoxazole-3-carboxamido)phenyl)piperidine-4-carboxylate 60 (0.268 g, 39% yield) as a pale yellow solid. Mass spectrum: calculated for C19H21N3O5 371.2; found 372.2 (M++1). |
Yield | Reaction Conditions | Operation in experiment |
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89% | In N,N-dimethyl-formamide; at 20℃; for 0.5h; | To a solution of 88 (46 mg, 0.1 mmol) in 2 rnL of anhydrous DMF was added 5- methyl-isoxazole-3-carbonyl chloride (12 mg, 0.12 mmol). The reaction mixture was stirred at ambient temperature for 30 min, then filtered through 0.2 u syringe filter and purified by reverse-phase preparative ηPLC in Cη3CN/η2O system containing 0.1% of TFA. Fractions, containing the product, were combined and poured into EtOAc (50 mL). The solution was treated with saturated aqueous NaHCO3 (2 x 10 mL), washed with brine (2 x 10 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the title compound as a bright- yellow solid (50 mg, 89% yield).[0427] 1H NMR (500 MHz, DMSO-J6, 80 0C): δ 1.72 (br s, 4H), 2.61 (br s, 4H), 2.84 (t, J = 5.9 Hz, 2H), 3.00 (br s, 2H), 3.97 (br s, 2H), 4.08 (t, J = 5.9 Hz, 2H), 4.82 (s, 2H), 6.45 (s, IH), 6.78 (s, IH), 6.89 (d, J = 8.9 Hz, 2H), 7.18 (s, IH), 7.73 (d, J = 8.8 Hz, 2H), 7.83 (br s, IH), 8.54 (s, IH), 11.25 (s, IH)MS (ES+): m/z 570 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
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Intermediate 15: 5-(5-methyl-3-isoxazolvn-1.2-dihvdro-3H-1.2.4-triazole-3-thioneTo 5-methyl-3-isoxazolecarbonyl chloride (commercially available from Maybridge Chemical Co., Ltd.) (291 mg, 2.000 mmol) in acetone (5 ml) was added hydrazinecarbothioamide (182 mg, 2 mmol). The reaction mixture was heated in a microwave reactor at 8O0C for 10min, then evaporated to dryness. Ethanol (2 ml) was added, then aqueous NaOH 2M (8.00 ml). The reaction mixture was heated in a microwave reactor at 15O0C for 10min. Water was added and then aqueous 5M HCI until the evolution of gas was no longer observed. The aqueous phase was extracted <n="40"/>with ethyl acetate three times, and the combined organic phases were dried over MgSC>4 and the solvent removed to give the title compound. |
Yield | Reaction Conditions | Operation in experiment |
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17% | N-(4-Fluorobenzyl)-3-hydroxy-10-(methyl((5-methyl-3-isoxazolyl)carbonyl)amino)-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide. To a solution of N-(4-fluorobenzyl)-3-hydroxy-10-(methylamino)-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide (25 mg, 0.061 mmol) in CH2Cl2 (2 mL) was added triethylamine (0.051 mL, 0.365 mmol) followed by <strong>[39499-34-8]5-methylisoxazole-3-carbonyl chloride</strong> (17.69 mg, 0.122 mmol) and the resulting mixture was stirred at room temperature. After 16 at room temperature the reaction mixture was concentrated to give crude product which was dissolved in methanol (2 mL) and treated with 2M dimethylamine in methanol (0.5 mL). The resulting reaction mixture was stirred at 60 C. for 2 h, then cooled and purified by preparative HPLC to afford the title compound (5 mg, 17% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ: 11.81 (1H, brs), 8.70 (1H, d, J=5.19 Hz), 7.31 (2H, dd, J=8.55, 5.49 Hz), 6.92-7.01 (2H, m), 6.09 (1H, s), 4.75-4.86 (1H, m), 4.58-4.67 (1H, m), 4.38-4.47 (1H, m), 3.67 (1H, d, J=15.56 Hz), 3.35-3.46 (1H, m), 3.13 (3H, s), 2.50 (1H, brs), 2.41 (3H, s), 2.07-2.16 (3H, m), 1.95-2.05 (1H, m), 1.72-1.86 (2H, m), 1.37-1.50 (1H, m). LCMS (M+H)=496.66. HPLC purity: >95%. |
Yield | Reaction Conditions | Operation in experiment |
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49% | N-(4-Fluorobenzyl)-3-hydroxy-10-(((4-((5-methyl-3-isoxazolyl)carbonyl)-1-piperazinyl)(oxo)acetyl)amino)-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide. To a suspension N-(4-fluorobenzyl)-3-hydroxy-4-oxo-10-((oxo(1-piperazinyl)acetyl)amino)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide (0.024 g, 0.038 mmol) in dichloromethane (1 mL) was added diisopropyl ethylamine (0.027 mL, 0.153 mmol). After stirring for 5 min, <strong>[39499-34-8]5-methylisoxazole-3-carbonyl chloride</strong> (0.011 g, 0.077 mmol) was added and the solution stirred at room temperature for 1 h. Dimethylamine (0.192 mL, 0.383 mmol) (2 M in methanol) was added and the solution stirred at room temperature for 1 h then concentrated. The residue was purified by preparative HPLC: Solvent A=10% methanol/90% H2O/0.1% trifluoroacetic acid; Solvent B=90% methanol/10% H2O/0.1% trifluoroacetic acid; Start % B=10; Final % B=100; Gradient time=20 min; Stop time=25 min; Column=XTERRA 19×50 mm, C18, 5 μm (product elutes at 12.6 min) to give the title compound as a pale lavender solid (12.1 mg, 49% yield). 1H NMR (500 MHz, CDCl3) δ: 12.00 (1H, brs), 8.51 (1H, d, J=5.80 Hz), 8.40 (1H, d, J=5.19 Hz), 7.28-7.50 (2H, m), 6.88-7.12 (2H, m), 6.33 (1H, d, J=2.14 Hz), 4.55 (2H, t, J=6.26 Hz), 4.16 (2H, brs), 4.02-4.14 (2H, m), 3.89-4.00 (2H, m), 3.80 (2H, dt, J=18.08, 5.00 Hz), 3.50-3.68 (2H, m), 2.53-2.77 (2H, m), 2.48 (4H, d, J=7.93 Hz), 1.87-2.15 (4H, m), 1.72 (2H, brs). LCMS (M+H) calcd for C30H33FN7O7: 622.24; found: 622.78. |
Yield | Reaction Conditions | Operation in experiment |
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63% | A solution of (S)-N- [2-OXO-3- (5-OXO-2, 3,4, 5-tetrahydro-benzo [b] oxepin-8- yl) -oxazolidin-5-ylmethyl]-acetamide 7-11 (458 mg, 1.44 mmol) in THF (15 mL) was cooled to 0 C and a 1 M solution of LIHIVDS in THF (3.02 mL, 3.02 mmol) was added. The mixture was stirred at 0 C for 30 minutes then a solution of 5- methyl-isoxazole-3-carbonyl chloride (214 mg, 1.73 mmol) in THF (10 mL) was added dropwise over 1 h. After warming to room temperature overnight, the mixture was treated with saturated ammonium chloride and extracted with dichloromethane. The organic layer was dried over NA2S04 and concentrated in vacuo. The resultant oil was subjected to silica gel chromatography to result in the title compound. Isolated yield: 388 mg (63%). MS-APCI (m/z+): 384,428 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
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40% | A solution of (S)-N- [2-oxo-3- (6-oxo-6, 7,8, 9-TETRAHYDRO-5H- BENZOCYCLOHEPTEN-2-YL)-OXAZOLIDIN-5-YLMETHYL]-ACETAMIDE (46) (500 mg, 1.58 mmol) in THF (15 mL) was cooled to 0 C and 1 M solution OF LIHMDS in THF (3.32 ML, 3.32 mmol) was added. The mixture was stirred at 0 C for 30 minutes, and then 5-methyl-isoxazole-3-carbonyl chloride (276 mg, 1.90 mmol) was added dropwise as a solution in THF (10 ML) over 50 minutes After warming to room temperature overnight, the mixture was worked up with saturated ammonium chloride, extracted with dichloromethane, dried over sodium sulfate and concentrated in vacuo. The resulting oil was purified with column chromatography to result in the title compound. Isolated yield: 269 mg (40% Y). MS-APCI (M/Z+) : 426 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
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58%; 20% | N- {3-[4-Fluoro-6(R,S)-(5-methyl-isoxazole-3-carbonyl)-5-oxo-6,7,8,9- TETRAHYDRO-5H-BENZOCYCLOHEPTEN-2-YLL-2-OXO-OXAZOLIDIN-5 (S)-YLMETHYLL- acetamide (Step 1) : A solution of (S)-N- [3- (4-FLUORO-5-OXO-6, 7,8, 9-tetrahydro-5H- benzocyclohepten-2-yl) -2-oxo-oxazolidin-5-ylmethyl]-acetamide (504 mg, 1.51 mmol) in THF (15 mL) was cooled to 0 C and 1 M solution of LIHMDS in THF (2.70 mL, 2.70 mmol) was added. The mixture was stirred at 0 C for 30 minutes then 5-methyl-isoxazole-3-carbonyl chloride (224 mg, 1.73 mmol) was added dropwise as a solution in THF (10 mL) over 1 hour. After warming to room temperature overnight, the mixture was worked up with saturated ammonium chloride, extracted with dichloromethane, dried over sodium sulfate and concentrated in vacuo. The resulting oil was purified with column chromatography to result in the title compound. Isolated yield: 388 mg (58% Y). 5-METHYL-ISOXAZOLE-3-CARBOXVLIC ACID {3-R4-FLUORO-6 (R, S)- 5-METHYL-ISOXAZOLE-3-CARBOXYLIC ACID {3-[4-FLUORO-6(R,S)-(5-METHYL-ISOXAZOLE- 3-CARBONYL)-5-OXO-6, 7, 8, 9-TETRAHYDRO-5H-BENZOCYCLOHEPTEN-2-YLL-2-OXO- oxazolidin-5 (S)-YLMETHVL}-AMIDE (STEP 1) : The title compound was isolated as another product in the synthesis of N- {3- [4-FLUORO-6 (R, S)- (5-METHYL-ISOXAZOLE-3-CARBONYL)-5-OXO-6, 7,8, 9-tetrahydro- 5H-BENZOCYCLOHEPTEN-2-YL]-2-OXO-OXAZOLIDIN-5 (S)-YLMETHYL}-ACETAMIDE. Isolated yield: 152 mg (20 %). MS-APCI (m/z+): 511 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
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To a solution of 1-(CYCLOBUTYLMETHYL)-2-[(4-ETHOXYPHENYL) METHYL]-LH-PYRROLO [2,3- B] PYRIDIN-5-AMINE (57 mg, 0.16 mmol) in dichloromethane (5 ml) at 0C was added diisopropylethylamine (84 µL, 0.48 mmol) followed by 5-methyl-3-isoxazolecarbonyl chloride (48 mg, 0.33 mmol). The mixture was stirred overnight at room temperature. The reaction was then quenched by 2M Na2CO3 aqueous solution (10 mL). The phases were separated and the aqueous phase was back-extracted with additional dichloromethane (10 mL). The organic phases were combined, dried with MGSO4, filtered and concentrated in vacuo. The residue was purified using HPLC (10 to 70% [0.1% TFA in ACCN solution] in 0.1% TFA aqueous solution) to provide 25 mg of the TFA salt OF 3-ISOXAZOLECARBOXAMIDE N [1-(cyclobutylmethyl)-2-[(4-ethoxyphenyl)methyl]-1H-pyrrolo [2, 3-B] pyridin-5-yl]-N, 5- DIMETHYL-3-ISOXAZOLECARBOXAMIDE. H NMR (400 MHz, METHANOL-D4) 8 1.26 (M, 3 H) 1.71 (M, 6 H) 2.12 (s, 3 H) 2.61 (M, 1 H) 3.37 (s, 3 H) 3.90 (q,. J=6. 96 Hz, 2 H) 3.99 (s, 2 H) 4.08 (d,. J=7. 23 Hz, 2 H) 5.84 (s, 1 H) 5.99 (s, 1 H) 6.75 (M, 2 H) 7.01 (d,. J=8. 59 Hz, 2 H) 7.63 (d, J=2. 34 Hz, 1 H) 7.86 (D, J=2. 34 Hz, 1 H). MS (ESI) (M+H) + : 460 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With triethylamine; In dichloromethane; at 20℃; for 2h; | To a stirred solution of 3-(2-tert-butylphenoxy)azetidine (0.18 g, 0.80 mmol) and triethylamine (0.24 g, 2.4 mmol) in methylene chloride (4.0 mL) was added <strong>[39499-34-8]5-methylisoxazole-3-carbonyl chloride</strong> (0.12 g, 0.80 mmol) at room temperature. After 2 h the reaction mixture was directly purified by flash column chromatography (silica gel, 80:20 heptane/ethyl acetate) to provide (3-(2-tert-butylphenoxy)azetidin-1-yl)(5-methylisoxazol-3-yl)methanone (0.21 g, 83%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.26 (dd, J = 7.8, 1.6 Hz, 1H), 7.17 (dt, J = 7.4, 1.6 Hz, 1H), 6.92 (t, J = 7.6 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 6.55 (d, J = 0.78 Hz, 1H), 5.17-5.12 (m, 1H), 4.94-4.88 (m, 1H), 4.60-4.54 (m, 1H), 4.37-4.32 (m, 1H), 4.04-3.98 (m, 1H), 2.45 (s, 3H), 1.35 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | 5.120 5-METHYL-ISOXAZOLE-3-CARBOXYLIC ACID [2-(2,6-DIOXO-PIPERIDIN-3-YL)-1,3-DIOXO-2,3-DIHYDRO-1H-ISOINDOL-4-YLMETHYL]-AMIDE 1,8-Diazabicyclo[5.4.0]undec-7-ene (1.0 g, 6.6 mmol) was added to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.0 mmol) in acetonitrile (40 mL). After stirring for 10 minutes, <strong>[39499-34-8]5-methylisoxazole-3-carbonyl chloride</strong> (0.4 g, 2.6 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was dissolved in CH2Cl2 (80 mL). The CH2Cl2 solution was washed with water (2×40 mL) and brine (40 mL), and dried (MgSO4). Solvent was removed, and the residue was purified by chromatography (SiO2, CH2Cl2:CH3OH 97.5:2.5) to give 5-methyl-isoxazole-3-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide (0.4 g, 44%) as a light brown solid: mp 207-209 C.; 1H NMR (DMSO-d6) δ 2.05-2.09 (m, 1H), 2.48 (s, 3H), 2.50-2.64 (m, 2H), 2.84-2.98 (m, 1H), 4.91 (d, J=6.0 Hz, 2H), 5.13-5.20 (dd, J=5.4 and 12.6 Hz, 1H), 6.58 (s, 1H), 7.69-7.87 (m, 3H), 9.35 (t, J=6.0 Hz, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 11.82, 21.97, 30.92, 38.00, 48.88, 101.35, 121.99, 127.18, 131.55, 132.87, 134.84, 138.39, 158.61, 159.15, 166.93, 167.47, 169.81, 171.36, 172.84; Anal. calcd. for C19H16N4O6+0.2H2O: C, 57.03; H, 4.14; N, 14.00. Found: C, 57.34; H, 3.99; N, 13.70. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; at -10 - 20℃; | Intermediate P 5-Methyl-isoxazole-3-carboxylic acid (R)-pyrrolidin-3-ylamideTEA (0.42 ml, 3.0 mmol) is added to a cooled (-10 C.) solution of 5-methyl isoxazole-3-carbonyl chloride (0.44 g, 2.95 mmol) in THF (5 ml). To this turbid mixture is added dropwise, (R)-3-amino-1-N-pyrrolidine (0.5 g, 2.68 mmol) in THF (2 ml) and the reaction mixture is allowed to warm to room temperature over 30 minutes. After standing at room temperature overnight, the reaction mixture is diluted with EtOAc (30 ml) and washed with water (2×5 ml), brine, dried (MgSO4) and concentrated in vacuo. The resulting oil is dissolved in MeOH (5 ml) is treated dropwise with 6M HCl (1.15 ml). After standing at room temperature for 4 days, the reaction mixture is concentrated in vacuo and co-evaporated with MeOH/EtOAc. The crude residue is triturated with EtOAc to afford the title compound. [MH+ 196]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Reference Example 47 methyl { (3S)-6-[{ (3S) -7- [6-fluoro-2- (5-methylisoxazol-3-yl) - lH-benzimidazol-1-yl] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}acetate; [0355]A solution of methyl { (3S) -6- [ { (3S) -7- [ (2-amino-5- fluorophenyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}acetate (150 mg, 0.275 mmol) in N,N-dimethylacetamide (1.4 mL) was ice-cooled, and <strong>[39499-34-8]5-methylisoxazole-3-carbonyl chloride</strong>(48.0 mg, 0.330 mmol) was added dropwise. The reaction mixture was stirred at 00C for 20 min, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A solution of the obtained residue in acetic acid (1 mL) was stirred overnight at 1200C. The reaction mixture was cooled to room temperature, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 50:50) to give the title compound (104 mg, yield 60%) as a white solid. MS m/z 637 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With triethylamine; In 1,2-dichloro-ethane; at 20℃; | Example 4 : Preparation of 5-cvclopropyl-8-methoxy-1 -(5-methylisoxazole-3-carbonyl)- 2,3,5,6-tetrahvdrobenzorbin ,51diazocin-4i1 H)-one5-cyclopropyl-8-methoxy-1 -(5-methylisoxazole-3-carbonyl)-2, 3,5,6- tetrahydrobenzo[b][1 ,5]diazocin-4(1 H)-oneTo a solution of 5-cyclopropyl-8-methoxy-2,3,5,6-tetrahydrobenzo[b][1 ,5]diazocin-4(1 H)-one (50.0mg, 0.203mmol) from Example 1 in dichloroethane (2.0ml) was added triethylamine (0.057ml, 0.406mmol) and <strong>[39499-34-8]5-methylisoxazole-3-carbonyl chloride</strong> (32.5mg, 0.223mmol). The reaction mixture was stirred at room temperature overnight and then quenched with saturated aqueous sodium bicarbonate, followed by extraction with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Preparative thin layer chromatography (ethyl acetate/methanol: 98/2) of the crude residue gave the desired compound (53mg, 74%).1H NMR (300MHz, CDCI3), δ 6.99 (d, J=8.6, 1 H), 6.93 (d, J=2.8, 1 H), 6.72 (dd, J=2.8, 8.6, 1 H), 6.02 (s, 1 H), 5.07 (dd, J=6.6, 13.6, 1 H), 4.74 (d, J=14.9, 1 H), 4.06 (d, J= 14.9, 1 H), 3.79 (s, 3H), 3.02 (m, 2H), 2.71 (dd, J=6.6, 13.6, 1 H), 2.47 (m, 1 H), 2.31 (s, 3H), 1 .07 (m, 1 H), 0.82 (m, 2H), 0.60 (m, 1 H).MS(ES+): [M+H]+=356.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With triethylamine; In dichloromethane; at 20℃; for 0.5h; | Example B26Preparation of Compound 108; A mixture of intermediate 8 (0.000285 mol) and 5-methyl-3-isoxazolecarbonyl chloride (0.000285 mol) in Et3N (0.00057 mol) and CH2Cl2 (5 ml) was stirred at room temperature for 30 minutes. Then an aqueous solution of Na2CO3 (1 ml) was added to the reaction mixture and the reaction mixture was filtered through an extrelute filter. Then the filtrate's solvent was evaporated and the residue was purified by high-performance liquid chromatography (standard gradient elution with NH4HCO3). The product fractions were collected and the solvent was evaporated. The residue was dried, yielding 0.044 g (34%; MP: 222.5 C. to 223.4 C.) of compound 108. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With polymer-supported morpholine; In dichloromethane; N,N-dimethyl-formamide; at 20℃; | 5-methyl-3-isoxazolecarbonyl chloride (0.029 g, 0.200 mmol) in DCM (1 mL) and DMF (0.5 mL) was added to a solution of l-(7H-pyrrolo[2,3-J]pyrimidin-4-yl)-4-piperidinamine D2 (0.043 g) in DMF (1.5 mL) in the presence of polymer-supported morpholine (0.279 g, 0.600 mmol, loading 2.15 mmol/g). The reaction mixture was shaken overnight at room temperature. The morpholine resin was filtered off and washed with a DCM:DMF (1 : 1) mixture. The unreacted acid chloride was removed by filtration on a Si-NH2 cartridge [Biotage] eluting with a DCM:DMF 1 : 1 mixture, and then the solvents were removed in vacuo. The crude mixture was purified by MDAP using a formic acid method to afford E16 (23.4 mg); ¾ NMR (d6- DMSO) δ 11.70 (IH, brs), 8.64 (IH, d), 8.14 (IH, s), 7.18 (IH, d), 6.59 (IH, d), 6.52 (IH, s), 4.71 (2H, dt), 4.12 (IH, m), 3.15 (2H, dt), 2.44 (3H, s), 1.85 (2H, m), 1.60 (2H, m), MS(ES+) 326 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With triethylamine; In dichloromethane; at 20℃; for 16h; | Example 4; N-(2-(4-(4-Fluorobenzyl)-lH-imidazol-2-yl)-3-hydroxy-4-oxo-6, 7,8,9- tetrahydro-7,10-ethanopyrimido[l,2-a]azepin-10(4H)-yl)-5-methyl-l,2-oxazole-3- carboxamide.; To a solution of 10-amino-2-(4-(4-fluorobenzyl)-lH-imidazol-2-yl)-3- hydroxy-7,8,9,10-tetrahydro-7,10-ethanopyrimido[l,2-a]azepin-4(6H)-one, Example 1 (30 mg, 0.076 mmol) in CH2C12 (3 mL) was added triethylamine (0.063 mL, 0.455 mmol) followed by <strong>[39499-34-8]5-methylisoxazole-3-carbonyl chloride</strong> (55.2 mg, 0.379 mmol) and the resulting mixture stirred at room temperature. After 16 h the reaction mixture was concentrated to give the crude product which was treated with 2Mdimethylamine/MeOH (0.5 mL) in MeOH (2 mL) at 60C for 2 h. The mixture was then cooled and purified by preparative HPLC to afford the title compound (15 mg, 39 %) as a white solid. XH NMR (500 MHz, DMSO-i¾) δ ppm 13.4 (1 H, br. s.), 9.0 (1 H, s), 7.4 (1 H, br. s.), 7.4 (2 H, dd, J=8.24, 5.80 Hz), 7.2 (2 H, t, J=8.85 Hz), 6.6 (1 H, s), 4.1 (2 H, d, J=3.36 Hz), 4.1 (2 H, s), 2.7 - 2.8 (2 H, m), 2.5 (1 H, br. s.), 2.0 - 2.0 (2 H, m), 1.9 - 1.9 (2 H, m), 1.7 - 1.8 (2 H, m). LCMS (M+H) = 505.49. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | To a 250 mL single neck flask equipped with a ST "Y" tube, condenser and a pressure equalizing dropping funnel containing 85 mL of anhydrous THF, was cautiously added NaH (0.84 g, 35.0 mmol) with constant stirring, maintaining the temperature below 20 C with external cooling. After the reaction, 14b (1.9 g, 15.0 mmol) was added over 30 min through the "Y" tube, and after the addition, a further 10 mL of THF washed the "Y" tube. The reaction mixture was heated to reflux for 20 min, cooled to room temperature and 5-methylisoxazolyl carbonylchloride [7] (2.30 g, 16.0 mmol) in anhydrous THF (25 mL) was added dropwise over 5 min. After stirring at room temperature for a further 10 min, the mixture was quenched with water and transferred to a 250 mL Erlenmeyer flask, neutralized with concentrated HCl (∼10 mL), diluted with dichloromethane (55 mL) and transferred to a separatory funnel. The aqueous layer was discarded and the organic layer was washed successively with water (55 mL), 10% NaHCO3 (2 × 55 mL), and water (55 mL). The organic layer was dried over sodium sulfate, evaporated in vacuo and the residue triturated with anhydrous Et2O (110 mL). The crude solid was recrystallized from EtOAc, to give 15b (0.75 g 21%) as cream colored crystals, mp 132-134 C 1H NMR (CDCl3) δ 1.0 (3H, J = 6.4 Hz, CH3), 2.0-2.7 (8H, m, cyclohexene ring 5H, and the isoxazole ring CH3), 6.4 (1H, s, CH), 6.8 (1H, s (split), CH on isoxazole ring), 8.3 (1H, br s, N-H). 13C NMR (CDCl3) δ 12.63, 20.94, 29.11, 36.68, 44.95, 101.46, 112.97, 152.95, 154.03, 157.31, 172.28 and199.72. IR (KBr) 3397.41 cm-1 (NH stretch), 3143.68 cm-1 (5-methylisoxazole stretch), 1685.35 cm-1 and 1618.99 cm-1 (two CO stretches). Anal. (C, H, N). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | General procedure; To a 250 mL single neck flask equipped with a ST "Y" tube, condenser and a pressure equalizing dropping funnel containing 85 mL of anhydrous THF, was cautiously added NaH (0.84 g, 35.0 mmol) with constant stirring, maintaining the temperature below 20 C with external cooling. After the reaction, 14b (1.9 g, 15.0 mmol) was added over 30 min through the "Y" tube, and after the addition, a further 10 mL of THF washed the "Y" tube. The reaction mixture was heated to reflux for 20 min, cooled to room temperature and 5-methylisoxazolyl carbonylchloride [7] (2.30 g, 16.0 mmol) in anhydrous THF (25 mL) was added dropwise over 5 min. After stirring at room temperature for a further 10 min, the mixture was quenched with water and transferred to a 250 mL Erlenmeyer flask, neutralized with concentrated HCl (∼10 mL), diluted with dichloromethane (55 mL) and transferred to a separatory funnel. The aqueous layer was discarded and the organic layer was washed successively with water (55 mL), 10% NaHCO3 (2 × 55 mL), and water (55 mL). The organic layer was dried over sodium sulfate, evaporated in vacuo and the residue triturated with anhydrous Et2O (110 mL). The crude solid was recrystallized from EtOAc, to give 15b (0.75 g 21%) as cream colored crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | General procedure; To a 250 mL single neck flask equipped with a ST "Y" tube, condenser and a pressure equalizing dropping funnel containing 85 mL of anhydrous THF, was cautiously added NaH (0.84 g, 35.0 mmol) with constant stirring, maintaining the temperature below 20 C with external cooling. After the reaction, 14b (1.9 g, 15.0 mmol) was added over 30 min through the "Y" tube, and after the addition, a further 10 mL of THF washed the "Y" tube. The reaction mixture was heated to reflux for 20 min, cooled to room temperature and 5-methylisoxazolyl carbonylchloride [7] (2.30 g, 16.0 mmol) in anhydrous THF (25 mL) was added dropwise over 5 min. After stirring at room temperature for a further 10 min, the mixture was quenched with water and transferred to a 250 mL Erlenmeyer flask, neutralized with concentrated HCl (∼10 mL), diluted with dichloromethane (55 mL) and transferred to a separatory funnel. The aqueous layer was discarded and the organic layer was washed successively with water (55 mL), 10% NaHCO3 (2 × 55 mL), and water (55 mL). The organic layer was dried over sodium sulfate, evaporated in vacuo and the residue triturated with anhydrous Et2O (110 mL). The crude solid was recrystallized from EtOAc, to give 15b (0.75 g 21%) as cream colored crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In dichloromethane; at 25℃; for 2h; | General procedure: Example 6B (0.2 g, 0.556 mmol) was dissolved in dichloromethane (2.7 ml) and pyridine (0.3 ml) and was treated dropwise with a solution of 3-methylbutanoyl chloride (0.102 ml, 0.835 mmol) in dichloromethane (0.5 ml). The reaction mixture was stirred at 25 C for 2 hours, concentrated, and purified using reverse phase HPLC (Phenomenex Luna C8(2) 5 um ΙΟθΑ AXIA column (30mm x 75mm) run with a gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B), at a flow rate of 50mL/min (0-0.5 min 10% A, 0.5-7.0 min linear gradient 10-95% A, 7.0- 10.0 min 95% A, 10.0-12.0 min linear gradient 95- 10% A) to afford the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.4% | ER-898912To a mixture of ER-888840 (50 mg, 0.188 mmol) and pyridine (0.046 mL, .563 mmol) in DCM (2 mL) was added <strong>[39499-34-8]5-methylisoxazole-3-carbonyl chloride</strong> (27.3 mg, .188 mmol). The mixture was stirred 18 h at rt, followed by the addition of DMAP (23 mg, 0.188 mmol) and allowed reaction mixture to stir 6 h at rt. HATU (85.8 mg, 0.226 mmol) was added and the reaction was stirred for 18 h at room temp. The completed reaction was diluted with DCM (10 mL) and then washed with 0.5 M citric acid (3 mL), water (3 mL) and sat. NaHC03 (3 mL). The organic layer was dried over MgS04, filtered and concentrated followed by purification over silica gel (10 g, eluting with 0 - 10% MeOH in DCM). The desired fractions were combined, concentrated and dried in vacuo to provide ER-898912 (51 mg, 0.136 mmol, 72.4 % yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
350 mg | With triethylamine; In dichloromethane; at 0℃; for 0.166667h; | Step A - Preparation of Int Int 49-1 To a solution of tert-butyl 3-phenylpiperazine-l-carboxylate (300 mg, 1.14 mmol) and Et3 (230 mg, 2.28 mmol) in CH2CI2 (5 mL) was added 5-methylisoxazole-3-carbonyl chloride (182 mg, 1.26 mmol). The reaction mixture was stirred 0C for 10 min. Water was added and the mixture was extracted with 2x CH2CI2. The organic layers were dried over a2S04 and concentrated. The reside was purified by prep-TLC to afford 350 mg as yellow solid. H NMR (CD3OD) delta 7.29-7.21 (m, 5H), 5.74 (m, 1H), 4.59-4.56 (m, 1H), 4.10-4.02 (m, 1H), 3.89-3.83 (m, 1H), 3.38-3.29 (m, 2H), 3.03-2.91 (m, 2H), 2.40-2.32 (m, 3H), 1.32 (s, 9H). MS (ESI) m/z(M+l): 372. |
350 mg | With triethylamine; In dichloromethane; at 0℃; for 0.166667h; | To a solution of tert-butyl 3 -phenylpiperazine- 1 -carboxylate (300 mg, 1.14 mmol) and NEt3 (230 mg, 2.28 mmol) in CH2C12 (5 mL) was added 5-methylisoxazole-3-carbonyl chloride (182 mg, 1.26 mmol). The reaction mixture was stirred 0C for 10 mm. Water was added and the mixturewas extracted with 2x CH2C12. The organic layers were dried over Na2504 and concentrated.The reside was purified by prep-TLC to afford 350 mg as yellow solid. ?H NMR (CD3OD) oe7.297.21 (m, 5H), 5.74 (m, 1H), 4.594.56 (m, 1H), 4.104.02 (m, 1H), 3.893.83 (m, 1H),3.383.29 (m, 2H), 3.032.91 (m, 2H), 2.402.32 (m, 3H), 1.32 (s, 9H). MS (ESI) mlz(M+1):372. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With pyridine; at 20℃; for 3h; | Into a 100-mL round-bottom flask were added tert-butyl 5-[[5-(3-aminophenyl)- 1,3,4-thiadiazol-2-yl][(tert-butoxy)carbonyl]amino]-1H-indazole-1-carboxylate (200 mg, 0.39 mmol, 1.00 equiv) and 5-methyl-1,2-oxazole-3-carbonyl chloride (200 mg, 1.37 mmol, 4.00 equiv) in pyridine (20 mL). The resulting solution was stirred for 3 h at room temperature, and then it was concentrated under vacuum to provide a residue,which then purified by silica gel column with DCM/methanol (10:1) as eluent to furnish 180 mg (74%) of tert-butyl 5-[[(tert- butoxy)carbonyl]([5-[3-(5-methyl-1,2-oxazole-3-amido)phenyl]-1,3,4-thiadiazol-2-yl])amino]- 1H-indazole-1-carboxylate as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | -Methylisoxazole-3-carbonyl chloride (1 .0 eq) (prepared using general method B1 ) was dissolved in anhydrous THF (4 mL/mmol) and treated with triethylamine (1.0 eq). After stirring for 5 minutes 4-(2- aminoethyl)benzenesulfonamide (1 .0 eq) was added to the acid chloride solution. The reaction was stirred at room temperature, under an argon atmosphere overnight. The solvent was removed in vacuo, and the residue purified by reverse phase column chromatography using acetonitrile/10 mM ammonium bicarbonate (aq) as mobile phase to give the titled compound as a white solid (205 mg, 48%). 1H NMR (600 MHz, DMSO-afe) δ = 8.79 (t, J = 5.8 Hz, 1 H), 7.74 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 8.3 Hz, 2H), 7.30 (s, 2H), 6.50 (q, J = 0.6 Hz, 1 H), 3.52 - 3.46 (m, 2H), 2.91 (t, J = 7.2 Hz, 2H), 2.45 (d, J = 0.6 Hz, 3H). HRMS calculated for Ci3H14N304Si [M-H]" 308.071 1 , found 308.0708. | |
205 mg | With triethylamine; In tetrahydrofuran; at 20℃; for 15h;Inert atmosphere; | 5-Methylisoxazole-3-carboxylic acid (150 mg, 1.18 mmol) dissolved in toluene (2 mL) was treated with DMF (1 drop) and thionyl chloride (1.42 mmol, 103 Ι then heated to reflux for 5 h. The solvent was removed in vacuo to afford crude 5-methylisoxazole-3- carbonyl chloride (155 mg, 1.06 mmol) as a brown oil. The crude acid chloride without purification was dissolved in THF (4 mL), treated with Et3N (155 μ, i.o6 mmol) and stirred for 5 min, before adding 4-(2-aminoethyl)benzenesulfonamide (220 mg, 1.10 mmol) and stirring at room temperature for 15 h under N2 atmosphere. The reaction mixture was concentrated in vacuo and purified by MPLC, affording the titled compound as an amorphous white solid (205 mg, 62%): NMR (600 MHz, DMSO- d6) δ 8.79 (t, J = 5-8 Hz, lH), 7-74 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 8.3 Hz, 2H), 7.30 (s, 2H), 6.50 (q, J= 0.8 Hz, lH), 3.49 (m, 2H), 2.91 (t, J = 7.2 Hz, 2H), 2.45 (d, J= 0.8 Hz, 3H); ^C NMR (151 MHz, DMSO-d6) δ 171.0, 158.8, 158.5, 143-3, 142.0, 129.0, 125. 6, 101.1, 39-8, 34-3, H-7; HRMS (ESI-TOF) m/z calcd for C13H14N304S [M-H]- 308.0711, found 308.0708; LC-MS m/z 308.0 [M+H]+, purity >99% (ELSD). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 20h; | N-ethyl-N-isopropylpropan-2-amine (0.1 ml,0.573 mmol) was added to a solution of the product of Example 10A (0.07 1 g, 0.21 mmol) and <strong>[39499-34-8]5-methylisoxazole-3-carbonyl chloride</strong> (Maybridge, mt., 0.044 g, 0.30 mmol) in CH2Cl2 (1.0 ml). The reaction mixture was stirred at ambient temperature for 20h and then was diluted with CH2Cl2 (5.0 ml). The mixture was transferred to an addition funnel and was washed with water (2 x 5 ml) and brine (1 x 5 ml). The organic phase was concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, 50% heptanes/ethyl acetate to 100% ethyl acetate) to give the title compound (0.066 g, 0.15 mmol, 70% yield). H1 NMR (500 MHz, DMSO-d6) δ ppm 8.28(dd, J=13.9,0.8 Hz, 1H), 7.69(td, J=7.9,1.5Hz, 1H), 7.64-7.53(m, 2H), 7.52-7.41(m, 2H), 7.30(d, J=7.4 Hz, 1H), 7.27(dd, J=8.3,2.2 Hz, 1H), 6.53(d, J=0.8 Hz, 1H), 4.41-4.29(m, 1H), 4.28-4.19(m, 1H), 4.10-3.80(m, 3H), 3.70-3.55(m, 1H), 3.55-3.47(m, 1H), 3.30-3.19(m, 1H), 2.47(dd, J=14.8,0.5 Hz, 3H); MS (ESI+) m/z 446 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; triethylamine; In dichloromethane; at 20℃; for 16h; | To a solution of 11a (0.08 g, 0.15 mmol) in CH2Cl2 (5 mL/mmol) was added acetyl chloride (0.012 mL, 0.17 mmol), Et3N (0.063 mL, 0.45 mmol) and DMAP (2 mg, 0.015 mmol). The mixture was stirred for 16 hours at room temperature. A solution of sat. NaHCO3 (sat., aq.) was added and the mixture was extracted with EtOAc (3x). The combined organic layers were dried over MgSO4, the solids were removed by filtration and the solvent of the filtrate was concentrated under reduced pressure. The crude was purified via silica gel column chromatography using a heptane/EtOAc gradient (from 10:0 to 0:10). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With triethylamine; In dichloromethane; for 0.5h; | To a suspension of 5-methylisoxazole-3-carboxylic acid (130 mg, 0.89 mmol, CAS: 3405-77-4) in DCM (5 mL) was added oxalyl chloride (0.5 mL) and THF (0.1 mL). After 30 min, to the reaction mixture was added oxalyl chloride (0.5 mL) and DMF (0.05 mL). After a further 30 min the reaction mixture was concentrated in vacuo, azeotroping twice with toluene to give <strong>[39499-34-8]5-methylisoxazole-3-carbonyl chloride</strong> (150 mg, 100%). To a stirred solution of benzyl (1 S,2R)-2-((S)-1 -((1 ,3-dioxoisoindolin-2-yl)methyl)- 8-(((S)-pyrrolidin-3-yl)oxy)-1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1- carboxylate (92 mg, 0.14 mmol) and triethylamine (0.10 mL, 0.70 mmol) in DCM (1 mL) was added portionwise a solution of <strong>[39499-34-8]5-methylisoxazole-3-carbonyl chloride</strong> (150 mg, 0.91 mmol) in DCM (2 mL). After 30 min saturated aqueous NaHCC>3 (2 mL) was added and the organic layer separated and dried over MgSCL,filtered and concentrated in vacuo. The residue was passed through an SCX-2 cartridge (1 g, methanolic ammonia) and concentrated in vacuo to give (1 S,2R)-benzyl 2-((S)-1-((1 ,3-dioxoisoindolin-2-yI)methyl)- 8-(((S)-1-(5-methylisoxazole-3-carbonyl)pyrrolidin-3-yl)oxy)-1 ,2,3,4-tetrahydroiso- quinoline-2-carbonyl)cyclohexanecarboxylate (34 mg, 33%), used without further purification. LCMS (Method 4a): 3.07 min, 748.6 [M+NH4f. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.4% | With pyridine; at 20℃; | Example 6 N-{4-[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]phenyl}pyridine-4-carboxamide N-{4-[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]phenyl}pyridine-4-carboxamide (Scheme I, Step 4-1a): 4-[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]aniline (Example 1, Step 3a) (0.20 g, 0.75 mmol, 1.0 eq) was dissolved in 3 ml of pyridine. Isonicotinoyl chloride, hydrochloride (0.17 g, 0.98 mmol, 1.3 eq) was added in one portion. After stirring overnight in rt reaction mixture was poured into 50 ml of water. Precipitated solid was filtered, washed with water and dried. Crude product was purified by maceration in MeOH to yield product as a white solid (0.26 g, 92.9%). LCMS (method B) RT = 3.03 min, MS (m/z ESI+) 373.4. 1H NMR (300 MHz, DMSO-d6): 10.76 (s br. 1H), 8.79 (m, 2H), 8.09 (m, 4H), 8.00 (m, 2H), 7,87 (m, 1H), 7.17 (m, 2H), 3,86 (s, 3H). 13C NMR (300 MHz, DMSO-d6): 175.6, 168.2, 164.8, 163.5, 150.8, 142.1, 141.9, 130.4, 128.3, 122.1, 122.1, 120.9, 116.2, 115.4, 56.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.3% | With pyridine; at 20℃; | Example 6 N-{4-[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]phenyl}pyridine-4-carboxamide N-{4-[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]phenyl}pyridine-4-carboxamide (Scheme I, Step 4-1a): 4-[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]aniline (Example 1, Step 3a) (0.20 g, 0.75 mmol, 1.0 eq) was dissolved in 3 ml of pyridine. Isonicotinoyl chloride, hydrochloride (0.17 g, 0.98 mmol, 1.3 eq) was added in one portion. After stirring overnight in rt reaction mixture was poured into 50 ml of water. Precipitated solid was filtered, washed with water and dried. Crude product was purified by maceration in MeOH to yield product as a white solid (0.26 g, 92.9%). LCMS (method B) RT = 3.03 min, MS (m/z ESI+) 373.4. 1H NMR (300 MHz, DMSO-d6): 10.76 (s br. 1H), 8.79 (m, 2H), 8.09 (m, 4H), 8.00 (m, 2H), 7,87 (m, 1H), 7.17 (m, 2H), 3,86 (s, 3H). 13C NMR (300 MHz, DMSO-d6): 175.6, 168.2, 164.8, 163.5, 150.8, 142.1, 141.9, 130.4, 128.3, 122.1, 122.1, 120.9, 116.2, 115.4, 56.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23.4% | With dmap; In dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; for 12h; | At 0, dissolve 1.5mmol of methyl 2-(6-amino-4oxo-3(4H)-quinazolinyl)acetate in 21ml of anhydrous dichloromethane, add 7ml of anhydrous DMF and 2 equivalents of DMAP ,After the temperature stabilizes, the acid chloride prepared in one step (dissolved in 3 ml of anhydrous dichloromethane) is slowly added dropwise. After the acid chloride was added dropwise, most of the ice was removed, and the reaction system was allowed to slowly rise to room temperature to continue the reaction for 12 hours, then the reaction was quenched with 50ml of 10% ammonia water, and the aqueous phase was extracted with dichloromethane (3×50ml).Combine the organic phases and remove 2/3 of the dichloromethane by rotary evaporation,The remaining organic phase is then washed with saturated brine until it is neutral.The organic phase was dried over anhydrous magnesium sulfate overnight, and the dichloromethane was removed by rotary evaporation.The residue was added to ice water, the precipitated solid was filtered and dried to obtain 120 mg of light yellow product (I1) with a yield of 23.4% |
Tags: 39499-34-8 synthesis path| 39499-34-8 SDS| 39499-34-8 COA| 39499-34-8 purity| 39499-34-8 application| 39499-34-8 NMR| 39499-34-8 COA| 39499-34-8 structure
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