Structure of 619-17-0
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CAS No. : | 619-17-0 |
Formula : | C7H6N2O4 |
M.W : | 182.13 |
SMILES Code : | O=C(O)C1=CC=C([N+]([O-])=O)C=C1N |
MDL No. : | MFCD00007262 |
InChI Key : | UEALKTCRMBVTFN-UHFFFAOYSA-N |
Pubchem ID : | 12076 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 46.63 |
TPSA ? Topological Polar Surface Area: Calculated from |
109.14 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
-0.15 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.91 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.88 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-1.15 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-1.62 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
-0.02 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.38 |
Solubility | 0.756 mg/ml ; 0.00415 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.83 |
Solubility | 0.0272 mg/ml ; 0.00015 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.79 |
Solubility | 29.3 mg/ml ; 0.161 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.05 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.56 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
3.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.75 |
* 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 |
---|---|---|
86.6% | at 150℃; for 16 h; | 2-amino-4-nitrobenzoic acid (7.28g, 40.0mmol) and ammonium formate (3.78g, 60.0mmol) were added to 1OmL of formamide, heated to 150 ° C, incubated 16h, cooled to room temperature, Precipitation of solid,Filtered, washed with isopropanol and dried to give 6.62 g of 86 mg as a brown needles of 7-nitro-3H-quinazolin-4-one in 86.6percent yield. |
83% | at 140℃; | General procedure: To a three necked flask, substituted anthranilic acid (1 meq.) was added in excess of formamide (6 meq). The reaction mixture was then heated at 140 °C for 4-6 h. The reaction was monitored with thin layer chromatography and upon completion; ice was added to the reaction mixture. The resultant solid was filtered, washed with water, dissolved in ethyl acetate, dried over MgSO4 and concentrated to obtain the pure desired product. Where product did not precipitate on addition of ice, the reaction mixture was extracted with ethyl acetate, dried over MgSO4 and concentrated to obtain the desired quinazolin-4(3H)-one derivatives 1-9, 11-15, 17-21 and 23-25.The amino derivatives 10, 16 and 22 were prepared using the following general procedure:To a reaction flask, substituted nitroquinazolin-4(3H)-one derivative (0.3 g, 1.56 mmol) was added followed by addition of 6 mL ethyl acetate and SnCl2*2H2O (2.12 g, 9.42 mmol), then reaction mixture was refluxed for 8 h. The reaction mixture was cooled to room temperature and quenched with saturated sodium bicarbonate solution, followed by repeated extraction with ethyl acetate (3 .x. 50 mL). The organic layers were combined, dried over anhydrous MgSO4 and concentrated to obtain the desired amino substituted quinazolin-4(3H)-one derivatives 10, 16 and 22.The substituted anthranilic acid (1 g) was dissolved in excess acetic anhydride (10 mL) and the resulting reaction mixture was stirred at room temperature for 4-7 h. The reaction was monitored for completion using thin layer chromatography. The solvent was evaporated under vacuum and the resultant residue was stirred with ammonia solution for 7 h. Upon completion, the reaction mixture was extracted with ethyl acetate (3 .x. 10 mL), the organic extracts were combined, dried over MgSO4 and evaporated to obtain compounds 26-30, 31a and 32. The 2-methyl-8-nitroquinazolin-4(3H)-one intermediate (31a) was reduced to compound 31 using the same procedure as reported in Scheme 1 for the synthesis of compounds 10, 16 and 22. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | at 130℃; for 18 h; | A mixture of 2-amino-4-nitrobenzoic acid (10.0 g, 54.93 mmol) was refluxed at 130° C. for 18 h in methoxyethanol (50 mL) and formamidine acetate (11.43 g, 109.81 mmol). The clear reaction mixture was cooled to room-temperature to form a yellowish precipitant. The solvent was removed under vacuum, and the precipitant was washed several times with aqueous ammonia (0.01 M). The solid was dried in vacuo to yield 8.9 g (84percent) of a light yellow powder. 1H NMR Data: dmso-d6-ppm (δ); 12.68 (1H), 8.37 (d, 1H), 8.33 (d, 1H), 8.26 (1H) and 8.23 (dd, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | at 200℃; for 0.5 h; | Example 8Synthesis of 7-aminoquinazolin-4-one 4-Nitroanthranilic acid (10.0 g, 54.9 mmol) and formamidine hydrochloride (6.63 g, 82.4 mmol) were ground together in a mortar and pestle to produce a fine, intimate mixture. The mixture was placed in a 250 mL round-bottom flask, and spread evenly over the surface. The flask was placed in an oilbath at 200° C. The solid underwent a color change, and a distillate was seen on the side of flask, but did not really melt. After 30 min the flask was removed from the heating bath. 0.3M sodium hydroxide solution (150 mL) was added to the cooled flask, the black solid mass was broken up with a spatula, and stirred for 1 h. The solid was filtered off and washed with water. The filtrate was discarded. The black solid was suspended in dichloromethane/methanol (10:1) and filtered through a plug of silica, eluting with the same solvent until no more product came off. The material was one spot by TLC, plus black baseline material, but was poorly soluble, so a large volume of solvent was needed.The filtrate was evaporated to dryness and the solid residue triturated with a little methanol and filtered to give 7-nitroquinazoline-4-one (4.65 g, 44percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.6% | With ammonium formate; at 150℃; for 16h; | 2-amino-4-nitrobenzoic acid (7.28g, 40.0mmol) and ammonium formate (3.78g, 60.0mmol) were added to 1OmL of formamide, heated to 150 C, incubated 16h, cooled to room temperature, Precipitation of solid,Filtered, washed with isopropanol and dried to give 6.62 g of 86 mg as a brown needles of 7-nitro-3H-quinazolin-4-one in 86.6% yield. |
83% | at 140℃; | General procedure: To a three necked flask, substituted anthranilic acid (1 meq.) was added in excess of formamide (6 meq). The reaction mixture was then heated at 140 C for 4-6 h. The reaction was monitored with thin layer chromatography and upon completion; ice was added to the reaction mixture. The resultant solid was filtered, washed with water, dissolved in ethyl acetate, dried over MgSO4 and concentrated to obtain the pure desired product. Where product did not precipitate on addition of ice, the reaction mixture was extracted with ethyl acetate, dried over MgSO4 and concentrated to obtain the desired quinazolin-4(3H)-one derivatives 1-9, 11-15, 17-21 and 23-25.The amino derivatives 10, 16 and 22 were prepared using the following general procedure:To a reaction flask, substituted nitroquinazolin-4(3H)-one derivative (0.3 g, 1.56 mmol) was added followed by addition of 6 mL ethyl acetate and SnCl2·2H2O (2.12 g, 9.42 mmol), then reaction mixture was refluxed for 8 h. The reaction mixture was cooled to room temperature and quenched with saturated sodium bicarbonate solution, followed by repeated extraction with ethyl acetate (3 × 50 mL). The organic layers were combined, dried over anhydrous MgSO4 and concentrated to obtain the desired amino substituted quinazolin-4(3H)-one derivatives 10, 16 and 22.The substituted anthranilic acid (1 g) was dissolved in excess acetic anhydride (10 mL) and the resulting reaction mixture was stirred at room temperature for 4-7 h. The reaction was monitored for completion using thin layer chromatography. The solvent was evaporated under vacuum and the resultant residue was stirred with ammonia solution for 7 h. Upon completion, the reaction mixture was extracted with ethyl acetate (3 × 10 mL), the organic extracts were combined, dried over MgSO4 and evaporated to obtain compounds 26-30, 31a and 32. The 2-methyl-8-nitroquinazolin-4(3H)-one intermediate (31a) was reduced to compound 31 using the same procedure as reported in Scheme 1 for the synthesis of compounds 10, 16 and 22. |
at 150℃; for 1h;Microwave irradiation; | Step A: 7-nitroquinazolin-4(3H)-one A mixture of 2-amino-4-nitrobenzoic acid (5.0 g, 82 mmol) and formamide (8 mL, 201.5 mmol) in a microwave reaction vessel was heated in a microwave reactor at 150 C for 1 h. The resulting slurry was cooled to room temperature, stirred with aqueous NaHC03, filtered and the solid was washed with water and Et20 then vacuum dried to provide 7-nitroquinazolin-4(3H)-one as a dark brown solid. LCMS calc. = 192.03; found = 192.16 (M+H)+. |
at 130 - 135℃; for 4h; | General procedure: Compound 18 was prepared accordingto the procedure previously reported.39 A mixture of anthranilicacid 11 (0.1 mol) and formamide (18 g, 0.4 mol) was heated at130-135 C. After the mixture had been stirred for 4 h, water(40 mL) was added. The reaction mixture was cooled to 60 C,and water (20 mL) was added to the mixture. After the mixturehad been stirred for 30 min, the precipitated product wasfiltered off with suction. The crude products were recrystallizedwith ethanol to give compound 18 in yields of 80-95%. | |
at 120℃; | General procedure: The mixtures of anthranilic acid or respective 5-substituted-2-aminobenzoicacid (1) (1 mmol) and an excess of formamide (10 mmol) in around-bottom flask were heated at 120 C with stirring for 3-5 h. Thereaction was checked by TLC. After the starting materials completelydisappeared, the resulting mixtures were cooled to room temperatureand then poured into ice-cold water. The light or dark brown precipitateswere formed. The precipitates were filtered and washed threetimes with water (20 mL each) and dried to give quinazoline-4(3H)-onederivatives (2). These intermediates were used for the next step withoutfurther purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | at 160℃; for 6h; | A mixture of 2-amino-4-nitrobenzoic acid (10.0 g, 55.0 mmol) and urea (33.0 g, 55.0 mmol) was heated to 160 C for 6h. Then the reaction mixture was cooled to 100C and water (60 mL) was added. The solution was stirred for 5 min. The formed precipitate was fdtered off, washed with cold water and further suspended in 0.5N NaOH (50 mL). The mixture was refluxed for 5 min. Then the reaction mixture was cooled to RT and fdtered. The fdtrate was adjusted to pH=2 with cone. HC1. The crude product was fdtered off, washed with MeOFWLO = 1 : 1 (100 mL) and dried in vacuo to give 7-nitroquinazoline-2,4(lH,3H)-dione (10.4 g, 91%) as a yellow solid. Calc’d for C8H5N3O4, 208.0; Found, 208.0 |
90% | at 160℃; for 6h; | 2-Amino-4-nitrobenzoic acid 1a (2.21 g, 10 mmol) and urea (6.0 g, 100 mmol) were stirred at 160 C for 6 h, then cooled to 100 C and water (60 mL) was added. The solution was stirred for 5 min, the formed precipitate was filtered off, washed with cold water and further suspended in 0.5 N NaOH. The mixture was refluxed for 5 min, then cooled to rt. The pH was adjusted to 2 with conc. HCl. Crude 2a was filtered off, washed with MeOH/H2O (1:1), dried in vacuo to give 2a (1.85 g, 90% yield) as light-brown powder. MS (ESI + APCI) m/z: 206.0 [M-H]-. |
at 150℃; for 20h; | General procedure: Anthranilic acids (3, 29.1 mmol, 1 eq) and urea (582.8 mmol, 20 eq) were poured into 100 mL round bottom flask. Then, the reaction mixture was heated at 150 oC for 20 h. The reaction was monitored by TLC. After the reaction was completed, it cooled down to room temperature. Then, 60 mL water was poured and the reaction mixture was heated at 100 oC for 1 h. The reaction mixture was cooled in ice bath and the white solid was precipitated. The white solid was filtered and washed with water and hexane. The residue (4, 28.3 mmol, 97%) was dried in vacuo and used next step without further purification. The chemical yield of first reaction was usually around 90%. The compound 4 (28.3 mmol, 1 eq) was dissolved in triethylamine (56.6 mmol, 2 eq). Then, POCl3 (254.5 mmol, 9 eq) was slowly added to the reaction mixture. The reaction mixture was heated at 115 oC for 17 h. The reaction was monitored by TLC. After the completion of the reaction, the reaction solvents were evaporated with toluene several times. The residue was diluted with water and extracted with ethyl acetate several times. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude 5 (25.2 mmol) was used in next step without further purification. The crude 5 (25.2 mmol) was dissolved in 2 N NaOH solution (75.6 mmol, 38 mL, 3 eq) and was stirred at room temperature for 20 h. The reaction mixture was cooled to room temperature. Acetic acid (75.6 mmol, 3 eq) was added to the reaction mixture. The aqueous phase was extracted with ethyl acetate and the combined organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford crude 6 (19.4 mmol), which was used in next step without further purification. To a 25 mL round bottom flask were added crude 6 (0.93 mmol), anilines (7, 2.8 mmol, 3 eq), and DMF (3.1 mL). The reaction mixture was stirred at 85 oC for 16 h. The reaction mixture was cooled to room temperature and precipitates were formed. The precipitates were washed with water and hexane thoroughly. The residue (8, 0.88 mmol, 94%) was dried in vacuo. If the precipitates were not formed, the reaction mixture was purified by prep HPLC (Shim-pack PREP-ODS, H2O:CH3CN:CH3OH=40:30:30 to H2O:CH3CN:CH3OH=1:49.5:49.5, flow rate=12 mL/min, 40 oC, λ=254 nm, retention time : 30 min). The chemical yields for each final products are described below. |
at 150℃; for 16h; | A mixture of 2-amino-4-nitrobenzoic acid (10 g, 54.94 mmol) and urea (32.96 g, 549.45 mmol) was heated to 150 C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-water and stirred for 10 min. The resulting solids were collected and triturated with glacial acetic acid to give the desired product. LCMS(m/z) 208.14 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium sulfate; In ethanol; at 100℃; for 1.08333h;Microwave irradiation; | First, 80 g of phthalic anhydride was added to a 500 mL four-necked flask, and 180 mL of concentrated sulfuric acid was slowly added thereto. After stirring for 10 minutes, the mixture was placed in a water bath and 60 g of fuming nitric acid was added dropwise at 70 C. After the completion of the dropwise addition, the reaction was stirred at 70 C for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature with an ice bath and filtered. The residue was washed three times with water and then dissolved in 100 mL of distilled water. Keeping at 55 C for 1 h, filtering, drying the residue to obtain 4-nitrophthalic acid; 100g of 4-nitro phthalic acid added to four-necked flask, to which was added 30mL of acetic anhydride, stirred until solid was completely dissolved at 90 deg.] C, temperature was raised to 120 deg.] C and dissolved,Stirring at 90 C until all the solid dissolved, dissolved and heated to 120 C and maintained at this temperature for 2h, and side reaction while stirring, after cooling the reaction to room temperature, filtration, take the filter cake washed with ether 2, Dried at 40 C for 4 hours to obtain 4-nitrophthalic anhydride; 20 g of urea was added to a 500-mL three-necked flask, placed in a water bath, and the 4-nitrophthalic anhydride was added to the flask in 3 portions at a controlled temperature of 5 C, And the temperature was gradually raised to 70 C after the completion of the addition, so that 4-nitrophthalic anhydride was completely dissolved, and the temperature was lowered to 45 C. The flask was evacuated and 10 mL of the solid was precipitated when no more solid precipitated And then the mixture was stirred for 20 min at 400 rpm. After stirring, the mixture was cooled to room temperature, filtered, washed with distilled water and dried at 50 C. Giving 4-nitro-2-carbamoylbenzoic acid; To a 500 mL four-necked flask, 40 mL of a 10% aqueous solution of sodium hypochlorite was placed in an ice bath, and 100 g of the 4-nitro-2-carbamoylbenzoic acid obtained above was added thereto at 0 C. The temperature was increased to 30 C, After the reaction, the reaction was cooled to -5 C, and immediately after cooling, the mixture was suction filtered and the residue was dried at 60 C to obtain 2-amino-4-nitrobenzoic acid. To a 250 mL three-necked flask, 15 g of the 2-amino-4-nitrobenzoic acid obtained above was added, and 90 mL of absolute ethanol was added thereto. The mixture was refluxed at 100 C for 1 hour. After refluxing, 50 mL of 9% Ammonium sulfate solution, in the 800W microwave heating continue to return under 5min, hot filter, wash the residue to pH 7, the combined filtrate, pour 50g ice water and stir quickly, standing 5min after the crude product precipitation, with the quality The crude product was dissolved in 30% hydrochloric acid and filtered. The filtrate with 30% ammonia water quality adjusted to pH 3, solid precipitation after the filter, the residue placed 60 drying, can be 2,4-diaminobenzoic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | at 200℃; for 0.5h; | Example 8Synthesis of 7-aminoquinazolin-4-one 4-Nitroanthranilic acid (10.0 g, 54.9 mmol) and formamidine hydrochloride (6.63 g, 82.4 mmol) were ground together in a mortar and pestle to produce a fine, intimate mixture. The mixture was placed in a 250 mL round-bottom flask, and spread evenly over the surface. The flask was placed in an oilbath at 200 C. The solid underwent a color change, and a distillate was seen on the side of flask, but did not really melt. After 30 min the flask was removed from the heating bath. 0.3M sodium hydroxide solution (150 mL) was added to the cooled flask, the black solid mass was broken up with a spatula, and stirred for 1 h. The solid was filtered off and washed with water. The filtrate was discarded. The black solid was suspended in dichloromethane/methanol (10:1) and filtered through a plug of silica, eluting with the same solvent until no more product came off. The material was one spot by TLC, plus black baseline material, but was poorly soluble, so a large volume of solvent was needed.The filtrate was evaporated to dryness and the solid residue triturated with a little methanol and filtered to give 7-nitroquinazoline-4-one (4.65 g, 44%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonia; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In methanol; dichloromethane; at 20℃; | To a solution of 2-amino-4-nitro-benzoic acid (9.1 g, 50mmol) in CH2C12 (500 mL) was added EDC (12 gram, 60 mmol) ,HOBt (6.8 g, 50 ramol) , DIEA (12 mL) , and NH3 in MeOH (2M, 40mL). The reaction was stirred at RT for overnight, and aprecipitation formed. The solid was isolated via vacuumfiltration. | |
With ammonia; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In methanol; dichloromethane; at 20℃; | To a solution of 2-amino-4-nitro-benzoic acid (9.1 g, 50 mmol) in CH2Cl2 (500 mL) was added EDC (12 gram, 60 mmol), HOBt (6.8 g, 50 mmol), DIEA (12 mL), and NH3 in MeOH (2M, 40 mL). The reaction was stirred at RT for overnight, and a precipitation formed. The solid was isolated via vacuum filtration. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With urea; In methanol; | a) A mixture of 5 g (0.027 mol) of 2-amino-4-nitrobenzoic acid and 16.5 g (0.27 mol) of urea was heated to 160 C. for 2 hrs. and at 180 C. for a further 2 hrs. The resulting brown mass was triturated with 200 ml of methanol, filtered off and dried in a vacuum. 4.8 g (80%) of 7-nitro-1,2,3,4-tetrahydro-quinazoline-2,4-dione were obtained as a white solid; MS: me/e=207 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
SynthesisPeptidomimetics 37-44 were synthesized via solid phase peptide synthesis, using Suzuki couplings employing various boronic acids and aryl bromides. Intermediates display hydrophobic substituents from the aromatic spacer (Abz). The simple quinazoline scaffolds derived from commercially available starting materials. The synthesis of the quinazolines cores 45a-b was accomplished by the cyclization of 4-nitroanthranilic acid by the reaction with sodium isocyanate or cyclization employing a carbon dioxide atmosphere with catalytic DBU (1 ,8-diazabicyclo[5.4.0]undec-7-ene) from 4- and 5-nitro precursors respectively Figure 10. Alkylation was followed by reduction of the nitro group followed by coupling with A- nitrobenzoyl chloride via anilide formation to provide 48a-b. Reduction to the aniline, coupling with AcArg(Pmc)-OH, and deprotection of the guanidine protecting group afforded 50a-b.A convergent synthesis using methyl-4-amino-2-bromobenzoate or methyl-4-aminobenzoate and 4-nitroaniline created non-peptidic inhibitors 56aa-ci, as seen in Figure 13. Suzuki coupling of the bromoaniline with the corresponding boronic acid, employing PdCI2(dppf) as a catalyst, created compounds 51a followed by reductive amination utilizing N-Boc- aminoacetaldehyde produced compounds 52a-c. A series of deprotections followed by guanidinylation of the resulting amine afforded the N-terminal portions of the inhibitor 53a-c. The C-terminal hydrophobic portion of the molecule was synthesized via alkylation of A- nitroaniline with the corresponding bromide and subsequent reduction of the nitro group utilizing tin (II) chloride, producing compounds 55a-i. Coupling of compounds 53a-c and 55a- i followed by Boc deprotection under acidic conditions produced inhibitors 56aa-ci. Inhibitors64a-b were derived from a similar synthesis, but in place of the reductive amination step, 48c was reacted with Boc-Gly-OH to provide the amide intermediate compound 62 which was manipulated in a similar manner to provide inhibitors 64a-b, seen in Figure 16.The synthesis of inhibitors 57aa-fa was designed to employ a late stage Suzuki coupling to provide faster access to a number of derivatives at the R1 position, while keeping R2 as a <n="13"/>benzyl substituent, see Figure 15. Commercially available methyl-4-amino-3-bromobenzoate was saponified under basic conditions followed by amide bond formation with compound 55a to provide compound 59a. This intermediate was then reacted with different boronic acid derivatives PdCI2(dppf) as a catalyst to provide 60aa-fa. A series of functional group transformations provided inhibitors 57aa-fa. The indole scaffold was readily derived from commercially available 4-iodoaniline and Boc- GIy-OH, which were reacted to form iodo-amide compound 65, seen in Figure 17. Sonagashira cross-coupling of compound 65 and ethynyl-trimethyl-silane (TMS-acetylene) followed by removal of the silyl protecting group afforded terminal alkyne compound 66. A consecutive Sonagashira cross-coupling with 2-iodo-4-nitroaniline followed by cycloisomerization employing catalytic copper (II) acetate41 afforded indole scaffold compound 68. Reduction of the nitro to the amine followed by alkylation with the cooresponding bromide provided compound 70a-b. A series of functional group transformations, similar to the reactions depicted in Figures 10 and 13, provided inhibitors 71a-b. It is also to be understood that the following claims are intended to cover all of the generic and specific features of the invention herein described, and all statements of the scope of the invention which, as a matter of language, might be said to fall therebetween. Now that the invention has been described, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | In 2-methoxy-ethanol; at 130℃; for 18h; | A mixture of 2-amino-4-nitrobenzoic acid (10.0 g, 54.93 mmol) was refluxed at 130 C. for 18 h in methoxyethanol (50 mL) and formamidine acetate (11.43 g, 109.81 mmol). The clear reaction mixture was cooled to room-temperature to form a yellowish precipitant. The solvent was removed under vacuum, and the precipitant was washed several times with aqueous ammonia (0.01 M). The solid was dried in vacuo to yield 8.9 g (84%) of a light yellow powder. 1H NMR Data: dmso-d6-ppm (delta); 12.68 (1H), 8.37 (d, 1H), 8.33 (d, 1H), 8.26 (1H) and 8.23 (dd, 1H). |
In ethanol;Reflux; | The 46g (0 · 25mol) 2- amino-4-nitrobenzoic acid and 52g (0 · 5mol) was added formamidine acetate 500mL single-necked round bottom flask was added 200mL ethanol, refluxed 4~6h,The system will have a lot of yellow precipitate. At this point heating was stopped and the system was cooled to about 50 C, part of the ethanol was removed in vacuo to approximately system 50mL, added to the system 30mL, stirred for several minutes after the refrigeration system LH, filtered, the filter cake was washed successively with chilled ethanol (3 X 1o mL) washed with water (2 X 10 mL) and dried under vacuum to obtain the 7-nitro - -quinazolinone 2, khaki-colored crystalline solid 39.6g, yield: 82.8%, m.rho: 282~284 C, IR (KBr) v: 3174,3064,2960,1683,1613,1528,803; this compound was used without further purification was used directly in the next step chlorine substitution reactions. |
Tags: 619-17-0 synthesis path| 619-17-0 SDS| 619-17-0 COA| 619-17-0 purity| 619-17-0 application| 619-17-0 NMR| 619-17-0 COA| 619-17-0 structure
A526900 [84228-45-5]
Methyl 4-amino-2-nitrobenzoate
Similarity: 0.92
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