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Structure of 2-Amino-6-chlorobenzoic acid
CAS No.: 2148-56-3
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
4.5
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Selective and Cell-Active PBRM1 Bromodomain Inhibitors Discovered through NMR Fragment Screening
Shifali Shishodia ; Raymundo Nuñez ; Brayden P. Strohmier ; Karina L. Bursch ; Christopher J. Goetz ; Michael D. Olp , et al.
Abstract: PBRM1 is a subunit of the PBAF chromatin remodeling complex that uniquely contains six bromodomains. PBRM1 can operate as a tumor suppressor or tumor promoter. PBRM1 is a tumor promoter in prostate cancer, contributing to migratory and immunosuppressive phenotypes. Selective chemical probes targeting PBRM1 bromodomains are desired to elucidate the association between aberrant PBRM1 chromatin binding and cancer pathogenesis and the contributions of PBRM1 to immunotherapy. Previous PBRM1 inhibitors unselectively bind SMARCA2 and SMARCA4 bromodomains with nanomolar potency. We used our protein-detected NMR screening pipeline to screen 1968 fragments against the second PBRM1 bromodomain, identifying 17 hits with Kd values from 45 μM to >2 mM. Structure–activity relationship studies on the tightest-binding hit resulted in nanomolar inhibitors with selectivity for PBRM1 over SMARCA2 and SMARCA4. These chemical probes inhibit the association of full-length PBRM1 to acetylated histone peptides and selectively inhibit growth of a PBRM1-dependent prostate cancer cell line.
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Purchased from AmBeed: 77326-36-4 ; 104-87-0 ; 2148-56-3 ; 1591-37-3 ; 387-45-1 ; 936-08-3 ; 1123-56-4 ; 2819989-75-6 ; 703-80-0 ; 1885-29-6 ; 115643-59-9 ; 15764-16-6 ; 487-68-3 ; 145737-61-7 ; 5779-95-3 ; 88-68-6 ; 6575-11-7 ; 77326-62-6 ; 88-65-3 ; 73096-42-1 ; 2835-78-1 ; 4635-59-0 ; 5779-94-2 ; 56043-01-7 ; 5779-93-1 ; 1591-38-4 ; 446-52-6 ; 1108790-90-4 ; 62803-47-8 ; 620-23-5 ; 54166-95-9 ; 22179-72-2 ; 529-20-4 ; 63329-53-3 ; 100-52-7 ; 123-11-5 ; 1711-06-4 ; 454-89-7 ; 170875-01-1 ; 883032-29-9 ; 2819989-61-0 ; 1915012-21-3 ; 2819989-58-5 ; 2819989-60-9 ; 2819989-57-4 ; 2819989-68-7 ; 2819989-67-6 ; 111478-13-8 ; 118-92-3 ; 22458-07-7 ; 80258-99-7 ; 24782-64-7 ; 175204-03-2 ; 97-96-1 ; 1885-31-0 ; 780802-33-7 ; 89-98-5
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| CAS No. : | 2148-56-3 |
| Formula : | C7H6ClNO2 |
| M.W : | 171.58 |
| SMILES Code : | NC1=C(C(O)=O)C(Cl)=CC=C1 |
| English Name : | 2-Amino-6-chlorobenzoic acid |
| MDL No. : | MFCD00051530 |
| InChI Key : | SZCPTRGBOVXVCA-UHFFFAOYSA-N |
| Pubchem ID : | 75071 |
| GHS Pictogram: | |
| Signal Word: | |
| Hazard Statements: | |
| Precautionary Statements: | |
| Class: | |
| UN#: | |
| Packing Group: |
| Num. heavy atoms | 11 |
| Num. arom. heavy atoms | 6 |
| Fraction Csp3 | 0.0 |
| Num. rotatable bonds | 1 |
| Num. H-bond acceptors | 2.0 |
| Num. H-bond donors | 2.0 |
| Molar Refractivity | 42.82 |
| TPSA ? Topological Polar Surface Area: Calculated from |
63.32 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.94 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.47 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.63 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.48 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.14 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.13 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-2.17 |
| Solubility | 1.17 mg/ml ; 0.0068 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-2.41 |
| Solubility | 0.673 mg/ml ; 0.00392 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.02 |
| Solubility | 1.63 mg/ml ; 0.00948 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
| BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
| P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
| CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
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 |
-6.3 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 |
1.0 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) |
1.13 |
* 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 |
|---|---|---|
| 99% | In 1,4-dioxane at 12 - 20℃; | |
| 93% | In 1,4-dioxane at 0 - 23℃; for 24h; | 3 In a 250 mL round-bottom flask under N2 was dissolved 2-amino-6-chlorobenzoic acid (11.69 g, 68 mmol) in 100 mL of 1,4-dioxane. The solution was cooled to 0° C. and to this solution was added phosgene (36 ml, 68 mmol) via a dropping funnel. The reaction mixture was stirred for 24 hours allowing to warm to 23° C. (rt). The resulting white solid was filtered off and washed with 1,4-dioxane and Et2O. Yield=12.5 g, 93% |
| 91% | With potassium hydroxide In water; toluene | 101.A 5-chloro-2H-3,1-benzoxazine-2,4(1H)-dione Example 101A 5-chloro-2H-3,1-benzoxazine-2,4(1H)-dione A solution of potassium hydroxide (1.68 g, 30 mmol) and 2-amino-6-chlorobenzoic acid (3.43 g, 20 mmol) in water (25 mL) at 0° C. was treated dropwise with 20% phosgene in toluene (16.8 mL, 32 mmol) resulting in a precipitate. The mixture was stirred for 1 hour and the solid was collected by filtration, washed with water and dried to give the title compound (3.6 g, 91%). 1H NMR (300 MHz, DMSO-d6) δ 7.11 (d, J=7.35 Hz, 1H), 7.31 (d, J=6.99 Hz, 1H), 7.66 (t, J=8.09 Hz, 1H), 11.83 (s, 1H). |
| 91% | With potassium hydroxide In water; toluene at 0℃; for 1h; | 101A EXAMPLE 101 5-chloro-3-(1,1-dioxido-4H-pyrido[3,2-e][1,2,4]thiadiazin-3-yl)-4-hydroxy-1-(3-methylbutyl)-2(1H)-quinolinone EXAMPLE 101A 5-chloro-2H-3,1-benzoxazine-2,4(1H)-dione A solution of potassium hydroxide (1.68 g, 30 mmol) and 2-amino-6-chlorobenzoic acid (3.43 g, 20 mmol) in water (25 ML) at 0° C. was treated dropwise with 20% phosgene in toluene (16.8 ML, 32 mmol) resulting in a precipitate.The mixture was stirred for 1 hour and the solid was collected by filtration, washed with water and dried to give the title compound (3.6 g, 91%).1H NMR (300 MHz, DMSO-d6) δ 7.11 (d, J=7.35 Hz, 1H), 7.31 (d, J=6.99 Hz, 1H), 7.66 (t, J=8.09 Hz, 1H), 11.83 (s, 1H). |
| 91% | With potassium hydroxide In water; toluene at 0℃; for 1h; | 101.A 5-chloro-2H-3,1-benzoxazine-2,4(1H)-dione 5-chloro-2H-3,1-benzoxazine-2,4(1H)-dione A solution of potassium hydroxide (1.68 g, 30 mmol) and 2-amino-6-chlorobenzoic acid (3.43 g, 20 mmol) in water (25 ML) at 0° C. was treated dropwise with 20% phosgene in toluene (16.8 ML, 32 mmol) resulting in a precipitate.The mixture was stirred for 1 hour and the solid was collected by filtration, washed with water and dried to give the title compound (3.6 g, 91%).1H NMR (300 MHz, DMSO-d6) δ 7.11 (d, J=7.35 Hz, 1H), 7.31 (d, J=6.99 Hz, 1H), 7.66 (t, J=8.09 Hz, 1H), 11.83 (s, 1H). |
| 90% | With sodium hydroxide In water | |
| In 1,4-dioxane at 20℃; for 1h; | ||
| With sodium hydrogencarbonate In 1,4-dioxane at 50℃; for 1h; | 2 Phosgene (51 g, 0.52 mol) dissolved in 150 ml of dioxane was added in portions to a mechanically stirred slurry of 2-amino-6-chloro-benzoic acid (30 g, 0.175 mol) and sodium bicarbonate (44 g, 0.52 mol) in 300 ml of dioxane. Violent reaction with gas evolution occurred and the reaction mixture was cooled to keep the temperature below 50°C. Then stirring was continued at 50°C for 1 hour. The reaction mixture was cooled to 15°C, the resulting precipitate was collected, washed with water and dried to give the isatoic anhydride. |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 92% | at 180℃; for 6h; | Synthesis of hydroxybenzimidoyl chloride (2) [21]. A mixture of 2-amino-6-chlorobenzoic acid (30 mmol)with formamide (40 mL) was heated at 180°C for 6 h, thenwater (100 mL) was added to the reaction mixture. Theprecipitated solid was filtered out and washed repeatedlywith water, then dissolved in ethyl acetate (100 mL),and the solution was washed three times with water. Theethyl acetate layer was concentrated, and the solvent wasevaporated to give the intermediate 2, yield 92%. |
| 82% | at 130℃; | |
| 78% | With acetic acid at 150℃; Sealed tube; | 5-Chloroquinazolin-4(3H)-one (12e) This compound was synthesizedfollowing GP A starting from 6-chloro anthranilic acid (200.0mg, 1.17 mmol), formamide (9.8 mL), and acetic acid (1.0 mL). Since nosolid was formed by pouring the reaction mixture into ice water, thesame work-up as for 12c was performed giving beige solid 12e (163.2mg, 0.90 mmol, 78 %). LC-MS m/z ([M+H]+) = 181.03, tr = 2.45 min,purity: 92 %. 1H NMR (DMSO-d6, 500 MHz) δ = 12.33 (br s, 1H), 8.09 (s,1H), 7.73 (t, 1H, J = 8.0 Hz), 7.61 (d, 1H, J = 8.0 Hz), 7.53 (dd, 1H, J =1.0, 8.0 Hz) [56]. 1H NMR (500 MHz, DMSO-d6) δ = 12.32 (br s, 1H),8.08 (s, 1H), 7.72 (t, J = 7.9 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.52 (dd,J = 1.0, 7.9 Hz, 1H). Contains 14 mol% formamide according to 1H NMRspectrum. 13C NMR (126 MHz, DMSO-d6) δ = 158.9, 151.3, 146.3,134.2, 132.4, 129.2, 126.9, 119.6. |
| 76% | at 140℃; | 4.2. Preparation of quinazolin-4(3H)-one derivatives 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. |
| 76% | at 145℃; for 5h; | 1 Example 1: Preparation of 5-chloroquinazoline-4(3H)-one 6-Chloro-2-aminobenzoic acid (87.0 mmol) was placed in a 100 mL round bottom flask, 30 mL of formamide was added thereto, stirred, heated to 145 ° C for 5 h, the reaction was stopped, cooled to room temperature, suction filtered, and washed to give an off-white Solid, the yield after drying was 76.0%. |
| 76% | at 145℃; for 5h; | 1 Example 1: Preparation of 5-chloroquinazoline-4 (3H) -one 6-chloro-2-aminobenzoic acid (87.0 mmol) was placed in a 100 mL round-bottomed flask, 30 mL of formamide was added thereto, stirred, and heated to 145 ° C for 5 hours to stop the reaction.Cool to room temperature, suction filter and wash with water to obtain an off-white solid. The yield after drying is 76.0%. |
| 67.8% | at 140℃; for 6h; | 1.1 Synthesis of 5-chloroquinazolin-4(3H)-one o a 25 mL three-necked flask, 0.86 g (0.005 mol) of 2-amino-6-chlorobenzoic acid was added,3 mL (0.020 mol) of formamide was added,The mixture was heated to reflux (140 ° C) for 6 h, then 10 mL of water was added and the mixture was stirred until the temperature reached 60 ° C. The reaction mixture was cooled to room temperature and filtered through suction to give 0.61 g of a light brown powder.Yield 67.8%, m.p. 212-214 ° C (literature value 210 ° C); |
| at 180℃; | ||
| at 130 - 135℃; for 4h; | General Procedure for the Preparation of 4(3H)-Quinazolinones (18). 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℃; Inert atmosphere; | ||
| at 140℃; Inert atmosphere; | Experimental procedure: General procedure: A round-bottom flask was charged with o-aminobenzoic acids (10 mmol, 1.0 equiv) and formamide (0.10 mol, 10 equiv), the reaction mixture was stirred at 140 oC for 5-6 hours. After the reaction was completed, the reaction was allowed to cool to room temperature, ice water was added, and the solid precipitates were formed. The precipitates were filtered and washed with water (3 40 mL) and then dried to give quinazoline-4(3H)-ones. These intermediates were used for the next step without further purification. To a solution of quinazolin-4(3H)-one (10 mmol, 1.0 equiv) in DMF (15 mL) was added potassium carbonate (20 mmol, 2.0 equiv). The resulting mixture was heated at 80 °C with stirring for 30 min. KI (1.0 mmol, 0.10 equiv) was added and after stirring for further 15 min, brominated olefins (12 mmol, 1.2 equiv) was dropwise added into the mixture. The reaction mixture was further stirred at 80 °C in an oil bath for 3 h. The reaction was cooled to room temperature, quenched with water, and then extracted with ethyl acetate (3 15 mL). The combined organic fractions were dried over anhydrous Na2SO4. The residue was recrystallized with dichloromethane and petroleum ether to give the target products with the yields of 60-90%. | |
| Heating; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 76% | at 210℃; for 0.25h; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 99% | In 1,4-dioxane for 2h; Reflux; | 4.1 Step 1: Preparation of 5-chloro-2H-benzo[d][1,3] oxazin-2,4(1H)-dione Triphosgene (570 mg, 1.9 mmol) was added to a 2-amino-6-chlorobenzoic acid (1 g, 5.8 mmol) solution dissolved in 1,4-dioxane (10 mL), and the solution was refluxed for 2 hours. Thereafter, the reaction was cooled on ice. The solid was washed with hexane and dried in vacuo to yield 1.1 g (99%) of pure compound as a brown solid. |
| 99% | In 1,4-dioxane Reflux; | 3.3-1 [3-1] Synthesis of 5-chloro-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (Compound <3-2>) To the solution of 2-amino-6-chlorobenzoic acid (1 g, 5.8 mmol) dissolved in 1,4-dioxane (10 ml), triphosgene (570 mg, 1.9 mmol) was added, and the solution was refluxed for 2 hours. Then, the reactant was cooled on ice. The solid was washed with hexane and was under vacuum drying to obtain a 1.1 g (99%) of pure compound as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ 1H NMR (300 MHz, Methanol-d4) δ 7.63 (t, J=8.1 Hz, 1H), 7.40-7.24 (m, 1H), 7.10 (d, J=8.2 Hz, 1H); MS found (M+H)+ (m/z), 198.09; calcd for C8H4ClNO3 m/z, 198.10. |
| 97% | With pyridine In dichloromethane; acetonitrile at 50℃; for 2h; | 1 Intermediate D: 5-chloro-1H-benzo[d][1,3]oxazine-2,4-dione Intermediate D: 5-chloro-1H-benzo[d][1,3]oxazine-2,4-dioneTo a stirred solution of 2-amino-6-chloro benzoic acid (10 g, 0.0583 mmol) in acetonitrile (60 mL, 1 M), was added pyridine (9.4 mL, 0.117 mmol, 2 equiv), and triphosgene (17.3 g, 0.058 mmol, 1 equiv) in dichloromethane (85 mL, 0.7 M). The orange reaction solution was heated at 50° C. for two hours then cooled to room temperature. The solution was diluted with water (50 mL), and the organic and aqueous layers were separated. The aqueous layer was washed with dichloromethane (3×50 mL), the combined organic layers were washed once with brine (50 mL), and dried over magnesium sulfate. The solvent was removed in vacuo leaving a light brown solid. The solid was titrated with hexanes to yield 5-chloro-1H-benzo[d][1,3]oxazine-2,4-dione (11.3 g, 97%) as a white solid. 1H NMR (Acetone, 500 MHz): δ (ppm) 7.09-7.11 (1H, d, J=8.3 Hz), 7.29-7.31 (1H, d, J=8.2 Hz), 7.63-7.66 (1H, t, J=8.0 Hz), 11.83 (1H, bs). |
| 97% | In tetrahydrofuran at 20℃; for 3h; | |
| 94% | In tetrahydrofuran at 50℃; | |
| 87% | In tetrahydrofuran | 3.a a. a. 5-Chloro-2H-3,1-benzoxazine-2,4(1H)-dione To a stirred warm (50° C.) solution of 2-amino-6-chlorobenzoic acid (2.00 g, 11.7 mM) in tetrahydrofuran (20 mL) was added bis(trichloromethyl)carbonate (1.20 g, 4.10 mM). A vigorous gas evolution ensued along with the formation of a precipitate. The reaction mixture was allowed to cool to room temperature and the precipitate was collected by filtration and washed with ether. Air drying gave the title compound as a tan solid (2.0 g, 87%); MS(CI): 198 (M+H). |
| 87% | With triethylamine In tetrahydrofuran at 0 - 20℃; for 18h; | General procedure for isatoic anhydride synthesis General procedure: Toa solution of amino-benzoic acid (2.90 mmol, 1 eq) in anhydrous THF (25 mL), triethylamine (2.90 mmol, 1 eq) was added and the mixture was cooled down to 0°C. Then triphosgene (0.97 mmol, 1 eq) was added portion wise and the reaction allowed to reach room temperature and left stirring for 18 hours. 1mL of H2O was carefully added to the mixture and the solvent was removed under reduced pressure. The residue was precipitated from H2O, affording pure product. |
| 87% | With potassium carbonate In ethyl acetate at 20℃; for 24h; | |
| 83% | In 1,4-dioxane for 3h; Reflux; | 64.1 Step 1) 5-Chloro 1H-benzo [d] [1,3] oxazine-2,4-dione The compound 2-amino-6-chlorobenzoic acid (1.00 g, 5.83 mmol) was suspended in 1,4-dioxane (20 mL)The bis (trichloromethyl) carbonate (605 mg, 2.04 mmol) was then added to the reaction and the reaction mixture was heated to reflux and stirred for 3 hours. It was then cooled to room temperature and filtered with suction. The filter cake was washed with petroleum ether (50 mL) Washed and then dried under vacuum to give the title compound as a light brown solid (954 mg, 83%). |
| 82% | In 1,4-dioxane at 20℃; for 3h; | 4.2. 5-Chloroisatoic anhydride (2c) 2-Amino-6-chlorobenzoic acid (1 g, 6 mmol, 1 eq) was suspended in 1,4-dioxane (60 mL) under 0 °C. Triphosgene (1.4 g, 5 mmol, 0.8 eq) was added and the solution stirred for 3 h at a temperature under 20 °C. The solid was collected by filtration and washed with water to give product 2c (0.95 g, 82%): mp > 260 °C; IR (KBr) υ 3436, 1774, 1701 cm-1; 1H NMR (DMSO-d6, 300 MHz) δ 11.85 (s, 1H), 7.66 (t, J = 8.3 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H). Anal. Calcd. for C8H4ClNO3: C,48.63; H, 2.04; Cl, 17.94; N, 7.09. Found: C, 48.67; H, 2.06; Cl, 17.85; N, 7.18. |
| 78% | In tetrahydrofuran at 0℃; for 6h; Inert atmosphere; Large scale; | 3 Under electromagnetic stirring and ice-water bath cooling, 1c (2000mg, 11.6mmol) and tetrahydrofuran (35mL) were added to a 150mL round bottom flask respectively. After the reaction system was cooled, triphosgene (1172mg, 3.9mmol) was added slowly. Under N2 protection, the reaction was stirred for 6h. After the reaction, the solvent was removed under reduced pressure, an appropriate amount of petroleum ether was added and ultrasonicated, the precipitated solid was fully suspended in the petroleum ether, filtered, and dried.White solid of compound 2c1790 mg (78%). |
| 62% | With pyridine In dichloromethane; acetonitrile at 20 - 55℃; Inert atmosphere; | 32 Example 32. Preparation of 5-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethyIphenyl)quinazolin-4(3H)-one [0266] A mixture of 2-amino-6-chlorobenzoic acid (5.00 g, 29.1 mmol) in acetonitrile (50.0 ml_) was stirred at room temperature under nitrogen. Pyridine (4.72 mL, 58.3 mmol) was added, followed by drop-wise addition of triphosgene (2.85 g, 9.60 mmol) in CH2CI2 (20.0 mL). After the addition, the mixture was heated at 55°C for 2 hours, then cooled to 25°C and stirred overnight. Water (100 mL) was added to quench, the mixture was filtered, and washed with cold CH2CI2, to provide 5-chloro-1/-/-benzo[d][1 ,3]oxazine-2,4-dione (3.54 g, 62%) as a white solid.[0267] A mixture of 5-chloro-1H-benzo[d][1,3]oxazine-2,4-dione (3.50 g, 17.7 mmol) and 2 M NH3 in EtOH (11.5 mL, 23.0 mmol) and EtOH (10.0 mL) was stirred at room temperature for 2 hours. The volatiles were removed under reduced pressure, the residue was triturated with water (50 mL), and the solid was filtered, to provide 2-amino-6-chlorobenzamide (1.60 g, 49%) as a tan solid.[0268] A mixture of 2-amino-6-chlorobenzamide (0.490 g, 3.00 mmol), 4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylbenzaldehyde (0.925 g, 3.00 mmol), NaHSO3 (94%, 0.468 g, 4.50 mmol), and p-TsOH«H2O (0.171 g, 0.900 mmol) in DMA (10.0 mL) was heated at 1400C for 16 hours. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was diluted with EtOAc (50 mL), washed with water (50 mL), then brine (50 mL), dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure, to provide 2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)-5-chloroquinazolin-4(3H)-one as an off-white solid. The crude material was used directly in the next step without characterization.[0269] Following the method described for desilylation using TBAF in Example 33 below, the title compound was made from 2-(4-(2-(tert- butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)-5-chloroquinazolin-4(3H)-one in 21% yield and was isolated as a white solid. 1H NMR (300 MHz, DMSO-Cf6): δ 12.32 (s, 1 H), 7.90 (s, 2H), 7.82-7.55 (m, 2H), 7.48 (dd, J = 7.54, 1.35 Hz, 1 H), 4.90 (t, J = 5.51 Hz, 1 H), 3.86 (t, J = 4.90 Hz, 2H), 3.77-3.68 (m, 2H), 2.32 (s, 6H). MS (APCI) m/z 345 [Ci8Hi7CIN2O3+H]+. |
| 62% | With pyridine In dichloromethane; acetonitrile Inert atmosphere; | 27 A mixture of 2-amino-6-chlorobenzoic acid (5.00 g, 29.1 mmol) in acetonitrile (50.0 mL) was stirred at room temperature under nitrogen. Pyridine (4.72 mL, 58.3 mmol) was added, followed by drop-wise addition of triphosgene (2.85 g, 9.60 mmol) in CH2Cl2 (20.0 mL). After the addition, the mixture was heated at 55° C. for 2 hours, then cooled to 25° C. and stirred overnight. Water (100 mL) was added to quench, the mixture was filtered, and washed with cold CH2Cl2, to provide 5-chloro-1H-benzo[d][1,3]oxazine-2,4-dione (3.54 g, 62%) as a white solid |
| With pyridine In dichloromethane; acetonitrile at 50℃; for 2h; | 1 Preparation of 5-chloro-2H-3,l-benzoxazine-2,4(lH)-dione (2) 2-amino-6-chlorobenzoic acid (1) (10 g, 1 equiv) was dissolved in acetonitrile (58.1 mL, 19.1 equiv) at 50°C, and added with pyridine (9.4 mL, 2 equiv). Then, triphosgene (5.7 g, 0.33 equiv) in methylene chloride (30 mL, 9 equiv) was added dropwise with stirring. The reaction mixture was stirred for 2 hours at 50°C. The solvent was removed by rotary evaporation. The residue was then dispersed in 50 mL water and filtered. The tan solid was washed with a minimal amount of acetonitrile to remove color, and dried to produce an off-white solid powder. HPLC RT was 4.41 minutes. All compounds were characterized using high performance liquid chromatograph (HPLC), with elution from the Zorbax Cg column using a gradient of 0-100% acetonitrile in water containing 0.07% trifluoroacetic acid (TFA) and detection using absorbance at 210 nm and 254 nm. | |
| With pyridine In dichloromethane; acetonitrile at 50℃; for 2h; | 1 Preparation of 5-chloro-2H-3,1-benzoxazine-2,4(1H)-dione (2) 2-amino-6-chlorobenzoic acid (1) (10 g, 1 equiv) was dissolved in acetonitrile (58.1 mL, 19.1 equiv) at 50° C., and added with pyridine (9.4 mL, 2 equiv). Then, triphosgene (5.7 g, 0.33 equiv) in methylene chloride (30 mL, 9 equiv) was added dropwise with stiffing. The reaction mixture was stirred for 2 hours at 50° C. The solvent was removed by rotary evaporation. The residue was then dispersed in 50 ml water and filtered. The tan solid was washed with a minimal amount of acetonitrile to remove color, and dried to produce an off-white solid powder. HPLC RT was 4.41 minutes. All compounds were characterized using high performance liquid chromatograph (HPLC), with elution from the Zorbax C8 column using a gradient of 0-100% acetonitrile in water containing 0.07% trifluoroacetic acid (TFA) and detection using absorbance at 210 nm and 254 nm. | |
| In tetrahydrofuran; dichloromethane at 20℃; | ||
| With pyridine In acetonitrile at 50 - 60℃; for 2h; Inert atmosphere; | FF In Method FF, 2-Amino-6-chlorobenzoic acid (63 mmol, 1.0 equiv) is dissolved in acetonitrile (60 mL) in a 250 mL round bottomed-flask, placed under an atmosphere of Ar and heated to 50 °C. Pyridine (2.0 equiv) is added followed by dropwise the addition of a solution of triphosgene (0.34 equiv in 30 mL acetonitrile) while maintaining the internal temperature below 60 °C. The mixture is then stirred at 50 °C for 2h after which the solvent is removed under vacuum. The remaining residue is dispersed in 50 mL of water and filtered. The resulting solid is washed with a minimal amount of acetonitrile to remove discoloration and then dried to provide desired anhydride X-l. | |
| In tetrahydrofuran at 45 - 50℃; for 3h; | 13.a A) 5-Chloro-lH-benzo [d] [l, 3] oxazin-2,4-dione (Compound 13a) 2-Amino-6-chlorobenzoic acid (500.0 mg, 2.91 mmol)Triphosgene (288.3 mg, 0.97 mmol)In the 25 mL single-necked round bottom flask,And then slowly added to 14mL tetrahydrofuran solution, heated to 45-50 , reaction 3h.After completion of the reaction, the solvent was concentrated, n-hexane was added, the solid was precipitated and dried to obtain a crude product,Directly for the next step. | |
| Stage #1: 2-chloro-6-aminobenzoic acid In tetrahydrofuran at -10℃; for 0.5h; Stage #2: bis(trichloromethyl) carbonate In tetrahydrofuran at -10 - 25℃; | General Procedure for the Preparation of IsatoicAnhydride (12). General procedure: Compound 12 was prepared according tothe procedure previously reported.36 A mixture of anthranilicacid 11 (50 mmol) and tetrahydrofuran (THF, 100 mL) wasstirred at -10 °C for 30 min. Then, a solution of triphosgene(BTC, 50 mmol) in THF (30 mL) was added dropwise to themixture described above. After that, the mixture was stirred for1 h at -10 °C, followed by 18-24 h at 20-25 °C. The solventwas removed under reduced pressure, and anhydrous ether(150 mL) was added to the obtained residue while the mixturewas being vigorously stirred. The precipitate was collected byfiltration, washed with anhydrous ether, and dried to givecompound 12 in yields of 80-90%. | |
| In tetrahydrofuran at -5 - 20℃; for 15h; | Synthesis of Isatoic Anhydrides (2) General procedure: A mixture of anthranilic acid (40 mmol) and tetrahydrofuran (THF, 100 mL) was stirred at -5 °C for 30 min. Then, triphosgene (40 mmol) was dissolved in THF (20 mL) and added dropwise to the above mixture. After that, the mixture was stirred for 5 h at -5°C, followed by 10 h at room temperature. The solvent was removed under reduced pressure, and the residue was washed with ether, and dried to afford compound 2 in yield of 85-95%. | |
| In tetrahydrofuran at -5℃; for 5h; | ||
| In tetrahydrofuran at 20℃; for 6h; | 4.1.1. Synthetic procedure for 2 General procedure: To a solution of different 2-aminobenzoic acid (5.0 mmol) in 20 mLanhydrous tetrahydrofuran (THF) was added triphosgene (BTC, 0.445 g,1.67 mmol) in batches. The reaction mixture was stirred at room temperaturefor 6 h and then poured into ice water. The resulting solid werefiltrated to obtain compounds 1, which were dissolved in 10 mL ofanhydrous N,N-dimethyl formamide (DMF), and then sodium hydride(NaH, 0.096 g, 4.0 mmol) was added in batches at 0. The reactionmixture was stirred at 0 for 30 min, and then methyl iodide (CH3I,0.469 g, 3.3 mmol) was added dropwise. The reaction was detected byTLC. After completion, the reaction mixture was poured into the icewater. The resulting solid were filtrated to obtain compounds 2. | |
| In tetrahydrofuran at 20℃; for 6h; | ||
| In 1,4-dioxane |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: dioxane / 1 h / 20 °C 2: NaH / dimethylformamide / 5 h / 20 °C | ||
| Multi-step reaction with 2 steps 1.1: 1,4-dioxane / 12 - 20 °C 2.1: sodium hydride / mineral oil; N,N-dimethyl acetamide / 45 °C / Inert atmosphere 2.2: 2 h / 20 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: 1,4-dioxane / 12 - 20 °C 2: potassium carbonate / N,N-dimethyl-formamide / 72 h / 20 °C / Inert atmosphere; Large scale |
| Multi-step reaction with 3 steps 1.1: 1,4-dioxane / 1 h / Inert atmosphere; Reflux; Large scale 2.1: acetyl chloride / 1,4-dioxane / 10 h / 45 °C / Inert atmosphere; Large scale 3.1: sodium hydride / mineral oil; N,N-dimethyl acetamide / 45 °C / Inert atmosphere 3.2: 2 h / 20 °C / Inert atmosphere | ||
| Multi-step reaction with 3 steps 1: 1,4-dioxane / 1 h / Inert atmosphere; Reflux; Large scale 2: acetyl chloride / 1,4-dioxane / 10 h / 45 °C / Inert atmosphere; Large scale 3: potassium carbonate / N,N-dimethyl-formamide / 72 h / 20 °C / Inert atmosphere; Large scale | ||
| Multi-step reaction with 2 steps 1: tetrahydrofuran; dichloromethane / 20 °C 2: potassium carbonate / N,N-dimethyl-formamide / 20 °C | ||
| Multi-step reaction with 2 steps 1: tetrahydrofuran / 3 h / 20 °C 2: potassium carbonate / N,N-dimethyl-formamide / 5 h / 20 °C | ||
| Multi-step reaction with 2 steps 1.1: tetrahydrofuran / 6 h / 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C 2.2: 0 °C |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1: dioxane / 1 h / 20 °C 2: NaH / dimethylformamide / 5 h / 20 °C 3: NaH / dimethylformamide / 5 h / 85 °C | ||
| Multi-step reaction with 2 steps 1.1: sodium hydrogencarbonate / 1,4-dioxane / 1 h / 50 °C 2.1: sodium hydride / Isobutyramide / 5 h / 0 - 20 °C 2.2: 5 h / 85 °C 2.3: 20 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 72% | With sodium hydroxide; acetic acid In water | 1 Synthesis of 2-(2,6-Dichlorophenylamino)-1H-imidazo[4,5-f]quinazoline-7,9(6H,8H)-dione Example 1 Synthesis of 2-(2,6-Dichlorophenylamino)-1H-imidazo[4,5-f]quinazoline-7,9(6H,8H)-dione To a solution of 6-chloroanthranilic acid (1.72 g, 10 mmol) and NaOH (0.40 g, 10 mmol) in water (15 mL) was added sodium cyanate (0.72 g, 11 mmol), followed by acetic acid (0.66 g, 11 mmol). The solution was stirred for 9 h, and then acidified with conc. HCl. The precipitate was filtered off and washed with water. The wet solid was added to a solution of NaOH (8.0 g, 200 mmol) in water (60 mL) and stirred for 20 h. The precipitate was filtered off and suspended in water (80 mL), then heated to boiling and acidified with 50% H2SO4. The cooled mixture was filtered, the solid washed well with water and dried to give 5-chloroquinazolin-2,4-dione (1.42 g, 72%). |
| Multi-step reaction with 2 steps 1: 65 percent / NaOH, acetic acid / H2O / 10 h 2: 35 percent / TFA / 24 h / Heating | ||
| With urea In methanol | 5.a 10-Chloro-2,3,5,6-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione a) A mixture of 2.0 g (11 mmol) of 2-amino-6-chlorobenzoic acid and 1.4 g (23 mmol) 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. 1.2 g (53%) of 5-chloro-1,2,3,4-tetrahydroquinazoline-2,4-dione were obtained as white crystals; MS: me/e=196 (M+). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 97% | With chloroformic acid ethyl ester In 1,4-dioxane at 50℃; for 11h; Heating / reflux; | 1 Example [1] [1 2-DIHVDRO-4-HYDROXY-5-CHLORO-L-METHVL-2-OXO-QUINOLINE-3-CARBOXYLIC] acid methyl ester 2-Amino-6-chlorobenzoic acid (30 g) was suspended in 1,4-dioxane (225 ml) and ethyl chloroformate (75 ml) was added. The mixture was heated at reflux for 1 hour, then cooled to [50°C,] and acetyl chloride (75 ml) was added. The mixture was stirred for 10 hours, after which the precipitated product was filtered off and washed with toluene. Drying in vacuum yields 5-chloroisatoic anhydride (33 g, 97% yield). 5-Chloroisatoic anhydride [(30] gram) was dissolved in dimethylacetamide (300 ml), and cooled to [5°C] over a nitrogen atmosphere. Sodium hydride (5.8 g, 70 %) was added portionwise, followed by addition of methyl iodide (11.5 ml). The reaction mixture was stirred at room temperature for 18 hours and the evacuated (40 mbar) for 1 hour in order to remove excess methyl iodide. Sodium hydride (5. [8] g, 70 %) was added followed by addition of dimethyl malonate (20 ml), and the mixture was heated to [85°C.] After 3 hours at [85°C,] the mixture was cooled and diluted with cold water (2.4 litre). The product was precipitated by addition [OF 5 M HCL] (aq) until pH=1.5-2. Filtration of the precipitated product and recrystallisation from methanol gave the title compound (29 g, 70 % yield). In essentially the same manner the ethyl ester is obtained from the corresponding starting materials. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Stage #1: 2-phenoxynicotinic acid With 1,1'-carbonyldiimidazole In acetonitrile at 20℃; for 2h; Stage #2: 2-chloro-6-aminobenzoic acid In acetonitrile |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 63% | With pyridine at 20℃; for 24h; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 64% | Stage #1: chloroacetonitrile With sodium In methanol at 25℃; for 0.666667h; Inert atmosphere; Stage #2: 2-chloro-6-aminobenzoic acid In methanol at 25℃; for 2h; Inert atmosphere; | |
| 62% | Stage #1: chloroacetonitrile With sodium methylate In methanol at 20℃; for 0.5h; Inert atmosphere; Stage #2: 2-chloro-6-aminobenzoic acid In methanol at 20℃; for 2h; | 26.1 Step 1: 5-Chloro-2-(chloromethyl)quinazolin-4(3H)-one To a solution of sodium methoxide in methanol (5.4 M, 540 μ, 2.91 mmol) were added MeOH (10 ml) and 2-chloroacetonitrile (1.01 g, 848 μ, 13.4 mmol) at r.t. under an argon atmosphere. The mixture was stirred at r.t. for 30 min. A solution of 2-amino-6-chlorobenzoic acid (2 g, 11.7 mmol) in methanol (50.0 ml) was then added dropwise at r.t.. The clear brown solution was stirred at r.t. for 2 firs. A solid started to precipitate out after ca. 90 min. The flask was placed in an oil bath preheated to 80°C and the mixture was stirred at 80°C for 2 firs, turning back to a clear light brown solution after a few minutes. The mixture was cooled to r.t., and a solid started to precipitate out. The suspension was stirred at r.t. overnight. The solid was collected by filtration, washed with MeOH (15 ml), 0 (15 ml) and dried to provide a first crop of the title com- pound (840 mg). Grey powder. The filtrate was concentrated to leave a brown sticky solid. The crude product was purified by silica gel chromatography using a Cf^C^/MeOH gradient as eluent. The product-containing fractions were combined and concentration. The residue was triturated in CH2CI2, filtered and dried to provide a second crop of the title compound (800 mg). Off-white solid. Total yield: 1.64 g (62%). MS: M = 228.9 (M+H)+ |
| 62% | Stage #1: chloroacetonitrile With sodium methylate In methanol at 20℃; for 0.5h; Inert atmosphere; Stage #2: 2-chloro-6-aminobenzoic acid In methanol at 20 - 80℃; | 26.1 Step 1: 5-Chloro-2-(chloromethyl)quinazolin-4(3H)-one To a solution of sodium methoxide in methanol (5.4 M, 540 μl, 2.91 mmol) were added MeOH (10 ml) and 2-chloroacetonitrile (1.01 g, 848 μl, 13.4 mmol) at r.t. under an argon atmosphere. The mixture was stirred at r.t. for 30 min. A solution of 2-amino-6-chlorobenzoic acid (2 g, 11.7 mmol) in methanol (50.0 ml) was then added dropwise at r.t. The clear brown solution was stirred at r.t. for 2 hrs. A solid started to precipitate out after ca. 90 min. The flask was placed in an oil bath preheated to 80° C. and the mixture was stirred at 80° C. for 2 hrs, turning back to a clear light brown solution after a few minutes. The mixture was cooled to r.t., and a solid started to precipitate out. The suspension was stirred at r.t. overnight. The solid was collected by filtration, washed with MeOH (15 ml), H2O (15 ml) and dried to provide a first crop of the title compound (840 mg). Grey powder. The filtrate was concentrated to leave a brown sticky solid. The crude product was purified by silica gel chromatography using a CH2Cl2/MeOH gradient as eluent. The product-containing fractions were combined and concentration. The residue was triturated in CH2Cl2, filtered and dried to provide a second crop of the title compound (800 mg). Off-white solid. Total yield: 1.64 g (62%). MS: M=228.9 (M+H)+ |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: 1,4-dioxane / 1 h / Inert atmosphere; Reflux; Large scale 2: acetyl chloride / 1,4-dioxane / 10 h / 45 °C / Inert atmosphere; Large scale | ||
| With pyridine; bis(trichloromethyl) carbonate In acetonitrile at 50 - 60℃; for 2h; Inert atmosphere; | [00603] In Method FF, 2-Amino-6-chlorobenzoic acid (63 mmol, 1.0 equiv) is dissolved in acetonitrile (60 mL) in a 250 mL round bottomed-flask, placed under an atmosphere of Ar and heated to 50 °C. Pyridine (2.0 equiv) is added followed by dropwise the addition of a solution of triphosgene (0.34 equiv in 30 mL acetonitrile) while maintaining the internal temperature below 60 °C. The mixture is then stirred at 50 °C for 2h after which the solvent is removed under vacuum. The remaining residue is dispersed in 50 mL of water and filtered. The resulting solid is washed with a minimal amount of acetonitrile to remove discoloration and then dried to provide desired anhydride X-1. | |
| Multi-step reaction with 2 steps 1: triethylamine; dmap / acetonitrile / 2 h / 20 °C 2: 2-chloro-1-methyl-pyridinium iodide / acetonitrile / 0.17 h / 20 °C |
| Multi-step reaction with 2 steps 1: acetonitrile / 3 h / 25 °C 2: water / 17 h / 25 - 70 °C |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1.1: 1,4-dioxane / 12 - 20 °C 2.1: sodium hydride / mineral oil; N,N-dimethyl acetamide / 45 °C / Inert atmosphere 2.2: 2 h / 20 °C / Inert atmosphere 3.1: mineral oil; N,N-dimethyl acetamide / 5 h / 85 °C / Inert atmosphere | ||
| Multi-step reaction with 3 steps 1: 1,4-dioxane / 12 - 20 °C 2: potassium carbonate / N,N-dimethyl-formamide / 72 h / 20 °C / Inert atmosphere; Large scale 3: mineral oil; N,N-dimethyl acetamide / 5 h / 85 °C / Inert atmosphere | ||
| Multi-step reaction with 4 steps 1.1: 1,4-dioxane / 1 h / Inert atmosphere; Reflux; Large scale 2.1: acetyl chloride / 1,4-dioxane / 10 h / 45 °C / Inert atmosphere; Large scale 3.1: sodium hydride / mineral oil; N,N-dimethyl acetamide / 45 °C / Inert atmosphere 3.2: 2 h / 20 °C / Inert atmosphere 4.1: mineral oil; N,N-dimethyl acetamide / 5 h / 85 °C / Inert atmosphere |
| Multi-step reaction with 4 steps 1: 1,4-dioxane / 1 h / Inert atmosphere; Reflux; Large scale 2: acetyl chloride / 1,4-dioxane / 10 h / 45 °C / Inert atmosphere; Large scale 3: potassium carbonate / N,N-dimethyl-formamide / 72 h / 20 °C / Inert atmosphere; Large scale 4: mineral oil; N,N-dimethyl acetamide / 5 h / 85 °C / Inert atmosphere | ||
| Multi-step reaction with 3 steps 1.1: tetrahydrofuran / 3 h / 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 5 h / Reflux; Inert atmosphere 3.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 20 °C / Inert atmosphere 3.2: 5 h / 80 °C | ||
| Multi-step reaction with 3 steps 1.1: tetrahydrofuran / 3 h / 20 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 5 h / 20 °C 3.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 20 °C / Inert atmosphere 3.2: 5 h / 80 °C |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: toluene; diethyl ether; methanol / 0.5 h / 20 °C 2: hydrogenchloride / 1,4-dioxane / 50 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: tetrahydrofuran / 3 h / 20 °C 2: sodium hydride / N,N-dimethyl-formamide; mineral oil / 5 h / Reflux; Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 79% | With acetic acid In water at 80 - 90℃; | 2 Preparation of 5-chloro-2,4-quinazolinedione The flask was charged with 12 mmol of 2-amino-6-chlorobenzoic acid, 65 mL of water and 1.5 mL of glacial acetic acid, and the mixture became a suspension.A solution of 2.36 g (28 mmol) of potassium cyanate in 10 mL of water was added dropwise to the above mixture and refluxed at 80-90 ° C for 1-2 h.Cooled to room temperature, 2.0 g (50 mmol) of sodium hydroxide was added to the suspension and reacted at 80-90 ° C for 3-5 h.The precipitate was formed, filtered, washed with water and dried to give a yellow solid in 79% yield. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 86% | With triethylamine In dichloromethane at 0 - 20℃; for 2.5h; | General procedure for benzoxazinone synthesis usingacid chlorides General procedure: 1 eq. anthranilic acid analog was dissolved in dichloromethane with 2.5eq. triethylamine, followed by addition of 1.5 eq. acid chloride. Then thereaction was stirred at 0 oC during the first 30 min, and was then allowedto warm up to room temperature. After 2 h, the solvent was removed undervacuum. Silica column chromatography (5-30% ethyl acetate in petroleum ether)gave the final compound. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1.1: sodium carbonate / N,N-dimethyl-formamide / 0.5 h / 20 °C 2.1: hydrogenchloride; sodium nitrite / water / 1.5 h / 0 °C 2.2: 1.5 h / 60 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With ammonium formate In ethanol Reflux; | 4.1.5 General procedure for the preparation of compounds 10a-10i General procedure: To a solution of intermediates 7a-7i (1 equiv.) and ammonium formate (3 equiv.) in EtOH was added trimethyl orthoformate (3 equiv.). The mixture was heated under reflux for 5-8h. After the addition was completed, TLC analysis indicated the reaction was complete. After cooled to room temperature, the mixture was filtered, and the solid was collected and dried to give a crude intermediates 8a-8i for the next step. A solution of the corresponding intermediates 8a-8i (1 equiv.) in POCl3 (10 equiv.) was stirred at 100°C for 2h. After the addition was completed, TLC analysis indicated the reaction was complete. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure to give a crude intermediates 9a-9i for the next step. Then, a solution of corresponding intermediates 9a-9i (1 equiv.), methyl 4-(aminomethyl)-benzoate hydrochloride (1 equiv.) and DIPEA (4 equiv.) in IAP was stirred at 90°C for 6-8h, at which time TLC analysis indicated the reaction was completed. After cooled to room temperature, the mixture was filtered, and the solid was collected to give intermediates 10a-10i, which was used directly in the next step without purification. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 78 % | In ethanol Reflux; | 1.1 Step 1): Synthesis of 5-chloroquinazolin-4(3H)-one 2-amino-6-chlorobenzoic acid (17.2g, 100mmol)and formamidine acetate (15.6g, 150mmol) were added to ethanol (150mL) solution,Heated to reflux and stirred for 24 hours,After cooling and filtering, 14 g of white solid was obtained, with a yield of 78%; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 85 % | In ethanol Reflux; | 2.1Synthesis of 5-chloroquinazolin-4(3H)-one (2) A mixture of2-Amino-6-chlorobenzoic acid (15 g, 87.4 mmol) and formamidine acetate (13.7 g,131.1 mmol) in ethanol (150 mL) was heated under reflux for 24 h and then thesolution was concentrated. The residue was diluted with water, and thesuspension was filtered, washed with water, and dried to give pure product(yield 85%). 1H NMR (400 MHz, DMSO-d6) δ 12.28(s, 1H), 8.07 (s, 1H), 7.72 (t, J =8.0 Hz, 1H), 7.60 (d, J = 8.1 Hz,1H), 7.51 (d, J = 7.8 Hz, 1H). |
| 85 % | In ethanol Reflux; | 2.1Synthesis of 5-chloroquinazolin-4(3H)-one (2) A mixture of2-Amino-6-chlorobenzoic acid (15 g, 87.4 mmol) and formamidine acetate (13.7 g,131.1 mmol) in ethanol (150 mL) was heated under reflux for 24 h and then thesolution was concentrated. The residue was diluted with water, and thesuspension was filtered, washed with water, and dried to give pure product(yield 85%). 1H NMR (400 MHz, DMSO-d6) δ 12.28(s, 1H), 8.07 (s, 1H), 7.72 (t, J =8.0 Hz, 1H), 7.60 (d, J = 8.1 Hz,1H), 7.51 (d, J = 7.8 Hz, 1H). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With potassium carbonate In acetone at 100℃; Inert atmosphere; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 99.7 % | Stage #1: L-N-Boc-Ala; 2-chloro-6-aminobenzoic acid With pyridine; triphenyl phosphite at 20℃; Stage #2: 3-aminocyclobutanol hydrochloride With potassium hydroxide In N,N-dimethyl-formamide at 60℃; | 1.1 The first step Synthesis of tert-butyl ester (S) - (1-(5-chloro-3-(3-hydroxycyclobutyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate Add 2-amino-6-chlorobenzoic acid (0.69g, 4.0mmol), (S)-2-((tert-butoxycarbonyl)amino)propionic acid (0.76g, 4.0mmol), pyridine (10mL) to the reaction flask ) and triphenyl phosphite (2.44g, 7.86mmol).The reaction system was reacted at room temperature for 14 h, and then 3-aminocyclobutanol hydrochloride (0.49 g, 4.0 mmol), DMF (2 mL) and KOH (0.44 g, 7.9 mmol) were added to the system.After the addition, the reaction system was heated to 60° C. for 10 h.After the reaction was complete, cool to room temperature, add 3M hydrochloric acid (40 mL), and extract with ethyl acetate (50 mL×2).The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.The residuewas purified by silica gel column chromatography (CH2Cl2 /MeOH (v/v)=50/1) to obtain the title compound as a colorless liquid (1.57 g, yield 99.7%). |
| 99.7 % | Stage #1: L-N-Boc-Ala; 2-chloro-6-aminobenzoic acid With pyridine; triphenyl phosphite at 20℃; Stage #2: 3-aminocyclobutanol hydrochloride With potassium hydroxide In N,N-dimethyl-formamide at 60℃; | 1.1 The first step Synthesis of tert-butyl ester (S) - (1-(5-chloro-3-(3-hydroxycyclobutyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate Add 2-amino-6-chlorobenzoic acid (0.69g, 4.0mmol), (S)-2-((tert-butoxycarbonyl)amino)propionic acid (0.76g, 4.0mmol), pyridine (10mL) to the reaction flask ) and triphenyl phosphite (2.44g, 7.86mmol).The reaction system was reacted at room temperature for 14 h, and then 3-aminocyclobutanol hydrochloride (0.49 g, 4.0 mmol), DMF (2 mL) and KOH (0.44 g, 7.9 mmol) were added to the system.After the addition, the reaction system was heated to 60° C. for 10 h.After the reaction was complete, cool to room temperature, add 3M hydrochloric acid (40 mL), and extract with ethyl acetate (50 mL×2).The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.The residuewas purified by silica gel column chromatography (CH2Cl2 /MeOH (v/v)=50/1) to obtain the title compound as a colorless liquid (1.57 g, yield 99.7%). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 31 % | Stage #1: L-N-Boc-Ala; 2-chloro-6-aminobenzoic acid With pyridine; triphenyl phosphite at 20℃; Stage #2: 2-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropylamine at 60℃; | 3.1 The first step Synthesis of tert-butyl ((1S)-1-(5-chloro-4-oxo-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)-3,4 -dihydroquinazolin-2-yl)ethyl)carbamate Add 2-amino-6-chlorobenzoic acid (0.20 g, 1.16 mmol), (S)-2-((tert-butoxycarbonyl) amino) propionic acid (0.18 g, 1.15 mmol), pyridine (8.0 mL) and triphenyl phosphite (0.85g, 2.74mmol).The reaction system was reacted at room temperature for 18 h, and then 2-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropylamine (0.24 g, 1.27 mmol) was added to the system.After the addition, the reaction system was heated to 60°C for 6 hours.After the reaction was complete, it was cooled to room temperature and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (CH2Cl2/MeOH (v/v)=40/1) to obtain the title compound as a colorless liquid (0.17 g, yield 31%). |
| 31 % | Stage #1: L-N-Boc-Ala; 2-chloro-6-aminobenzoic acid With pyridine; triphenyl phosphite at 20℃; Stage #2: 2-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropylamine at 60℃; | 3.1 The first step Synthesis of tert-butyl ((1S)-1-(5-chloro-4-oxo-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)-3,4 -dihydroquinazolin-2-yl)ethyl)carbamate Add 2-amino-6-chlorobenzoic acid (0.20 g, 1.16 mmol), (S)-2-((tert-butoxycarbonyl) amino) propionic acid (0.18 g, 1.15 mmol), pyridine (8.0 mL) and triphenyl phosphite (0.85g, 2.74mmol).The reaction system was reacted at room temperature for 18 h, and then 2-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropylamine (0.24 g, 1.27 mmol) was added to the system.After the addition, the reaction system was heated to 60°C for 6 hours.After the reaction was complete, it was cooled to room temperature and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (CH2Cl2/MeOH (v/v)=40/1) to obtain the title compound as a colorless liquid (0.17 g, yield 31%). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 87 % | Stage #1: 2-chloro-6-aminobenzoic acid; (R)-2-((tert-butoxycarbonyl)amino)pentanoic acid With pyridine; diphenyl phosphite at 20℃; Stage #2: aniline at 55℃; | 8.1 Step 1: Preparation of (R)-tert-butyl(1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)butyl)carbamate 2-amino-6-chlorobenzoic acid (1.0 eq) and Diphenyl phosphite (6eq) was added while stirring a solution of (R) -2-((tert-butoxycarbonyl)amino)pentanoic acid (1.4eq) in a pyridine solvent at room temperature. The resulting mixture was stirred at 55°C for 4.5 hours, added with aniline (1.2eq), and reacted at 55°C for 1.5 hours. Then, the reaction mixture was cooled to room temperature and extracted with ethyl acetate and water. The organic layer was dehydrated with anhydrous magnesium sulfate (MgSO4) and concentrated under reduced pressure. After purifying the residue by column chromatography, the obtained solid was dried to (R)-tert-butyl(1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazoline-2- yl)butyl)carbamate was obtained in 87% yield. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 81 % | Stage #1: 2-chloro-6-aminobenzoic acid; (R)-2-(N-t-butoxycarbonylamino)hexanoic acid With pyridine; diphenyl phosphite at 55℃; Stage #2: aniline at 55℃; | 11.1 Step 1: Preparation of (R)-tert-butyl(1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)pentyl)carbamate A solution of 2-amino-6-chlorobenzoic acid (1.0eq) and (R) -2-((tert-butoxycarbonyl)amino)hexanoic acid (1.4eq) mixed together in a pyridine solvent was prepared at room temperature. While stirring, diphenyl phosphite (6 eq) was added. The resulting mixture was stirred at 55°C for 4.5 hours, added with aniline (1.2eq), and reacted at 55°C for 1.5 hours. Then, the reaction mixture was cooled to room temperature and extracted with ethyl acetate and water. The organic layer was dehydrated with anhydrous magnesium sulfate (MgSO4) and concentrated under reduced pressure. After the residue was purified by column chromatography, the obtained solid was dried to (R)-tert-butyl(1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazoline-2- Il) pentyl) carbamate was obtained in 81% yield. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 99 % | Stage #1: 2-chloro-6-aminobenzoic acid; (R)-2-((tert-butoxycarbonyl)amino)pentanoic acid With pyridine; diphenyl phosphite at 60℃; Stage #2: 3-Fluoroaniline at 60℃; | 9.1 Step 1:(R)-tert-butyl(1-(5-chloro-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)butyl)carbamatemanufacturing A solution of 2-amino-6-chlorobenzoic acid (1.0eq) and (R) -2-((tert-butoxycarbonyl)amino)pentanoic acid (1.4eq) in a pyridine solvent was mixed at room temperature. While stirring, diphenyl phosphite (6 eq) was added. The resulting mixture was stirred at 60°C for 7.5 hours, added with 3-fluoroaniline (1.2eq), and reacted at 60°C for 2 hours. Then, the reaction mixture was cooled to room temperature and extracted with ethyl acetate and water. The organic layer was dehydrated with anhydrous magnesium sulfate (MgSO4) and concentrated under reduced pressure. After the residue was purified by column chromatography, the obtained solid was dried to (R) -tert-butyl (1- (5-chloroRho-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)butyl)carbamate was obtained in 99% yield. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 54% | With water In formamide at 150℃; for 1h; Microwave irradiation; | 4.2.3.General procedure C (synthesis of quinazolin-4(3H)-one derivatives) General procedure: The quinazolin-4(3H)-one derivatives 11a-s were synthesized according to the published procedure [38]. Appropriate anthranilic acid (purchased or 10a-j) (25.0 mmol) was dissolved in formamide (25 mL) and heated at 150 C for 1 h in a microwave reactor. The solvent was evaporated and water (10 mL) was added to the residue. The precipitated solid was filtered off and dried overnight at room temperature. If the precipitation did not occur, the water phase was extracted with EtOAc (2 ×50 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude products 11a-s were used in the next reaction without further purification.6-Methylquinazolin-4(3H)-one, 7-methylquinazolin-4(3H)-one and 8-methylquinazolin-4(3H)-one were purchased from Apollo Scientific. |
Tags: 2148-56-3 | 2-Amino-6-chlorobenzoic acid | Fluorinated Building Blocks | Aryls | Chlorides | Amines | Carboxylic Acids | Benzene Compounds | Organic Building Blocks

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