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CAS No. : | 6313-33-3 | MDL No. : | MFCD00012865 |
Formula : | CH5ClN2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NMVVJCLUYUWBSZ-UHFFFAOYSA-N |
M.W : | 80.52 | Pubchem ID : | 10313058 |
Synonyms : |
|
Num. heavy atoms : | 4 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 20.18 |
TPSA : | 49.87 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.76 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 0.04 |
Log Po/w (WLOGP) : | 0.35 |
Log Po/w (MLOGP) : | -0.49 |
Log Po/w (SILICOS-IT) : | -0.34 |
Consensus Log Po/w : | -0.09 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.36 |
Solubility : | 34.8 mg/ml ; 0.432 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.64 |
Solubility : | 18.4 mg/ml ; 0.229 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | 0.62 |
Solubility : | 336.0 mg/ml ; 4.18 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.94 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302+H312+H332-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With copper 8-hydroxyquinolinate; sodium hydroxide In water at 100℃; for 0.5 h; Microwave irradiation | 1 mmol of 2-iodo-5-methylbenzoic acid, 1 mmol of formamidine hydrochloride, and 8-quinolinolato copper (B ) 0.05 mmol, 1 mmol of sodium hydroxide and 3 mL of water. Placed in the microwave reactor, the microwave reactor at 150 W power heating 100 ° C to 30 minutes, cooled to room temperature. The product was extracted with ethyl acetate and concentrated under reduced pressure. The product was purified by column chromatography to give a white solid in 92percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With copper 8-hydroxyquinolinate; sodium hydroxide In water at 100℃; for 0.5 h; Microwave irradiation | 1 mmol of 2-iodo-4-methylbenzoic acid was added to the reaction vessel, 1 mmol of formamidine hydrochloride, 0.05 mmol of 8-quinolinol copper (B), 1 mmol of sodium hydroxide and 3 mL of water. Into the microwave reaction The reactor was then heated in a microwave reactor at 150 W for 100 ° C to 30 minutes and cooled to room temperature. And extracted with ethyl acetate The product was removed and concentrated under reduced pressure. The product was purified by column chromatography to give a white solid in 82percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With 8-quinolinol; sodium hydroxide; copper dichloride In water at 20℃; for 0.333333 h; Sealed tube; Microwave irradiation | General procedure: In a 10 mL glass tube 2-iodobenzoic acid (1.0 mmol), acetamidine hydrochloride (1.2 mmol), CuCl2 (0.1 mmol), L2 (0.1 mmol), and NaOH (4.0 equiv.) and 3.0 mL water were placed. The vessel was then sealed with a septum and placed into the microwave cavity. Initial microwave irradiation of 120 W by using a CEM Discover microwave synthesizer was used at the room temperature for 20 min. The reaction mixture was stirred continuously during the reaction. After completion of the reaction, the solvent was removed in vacuo. The residue was purified by silica gel column chromatography to afford the corresponding product. All the products were confirmed by NMR and MS spectroscopic analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With 8-quinolinol; sodium hydroxide; copper dichloride In water at 20℃; for 0.333333 h; Sealed tube; Microwave irradiation | General procedure: In a 10 mL glass tube 2-iodobenzoic acid (1.0 mmol), acetamidine hydrochloride (1.2 mmol), CuCl2 (0.1 mmol), L2 (0.1 mmol), and NaOH (4.0 equiv.) and 3.0 mL water were placed. The vessel was then sealed with a septum and placed into the microwave cavity. Initial microwave irradiation of 120 W by using a CEM Discover microwave synthesizer was used at the room temperature for 20 min. The reaction mixture was stirred continuously during the reaction. After completion of the reaction, the solvent was removed in vacuo. The residue was purified by silica gel column chromatography to afford the corresponding product. All the products were confirmed by NMR and MS spectroscopic analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With 8-quinolinol; sodium hydroxide; copper dichloride In water at 20℃; for 0.333333 h; Sealed tube; Microwave irradiation | General procedure: In a 10 mL glass tube 2-iodobenzoic acid (1.0 mmol), acetamidine hydrochloride (1.2 mmol), CuCl2 (0.1 mmol), L2 (0.1 mmol), and NaOH (4.0 equiv.) and 3.0 mL water were placed. The vessel was then sealed with a septum and placed into the microwave cavity. Initial microwave irradiation of 120 W by using a CEM Discover microwave synthesizer was used at the room temperature for 20 min. The reaction mixture was stirred continuously during the reaction. After completion of the reaction, the solvent was removed in vacuo. The residue was purified by silica gel column chromatography to afford the corresponding product. All the products were confirmed by NMR and MS spectroscopic analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With 8-quinolinol; sodium hydroxide; copper dichloride In water at 20℃; for 0.333333 h; Sealed tube; Microwave irradiation | General procedure: In a 10 mL glass tube 2-iodobenzoic acid (1.0 mmol), acetamidine hydrochloride (1.2 mmol), CuCl2 (0.1 mmol), L2 (0.1 mmol), and NaOH (4.0 equiv.) and 3.0 mL water were placed. The vessel was then sealed with a septum and placed into the microwave cavity. Initial microwave irradiation of 120 W by using a CEM Discover microwave synthesizer was used at the room temperature for 20 min. The reaction mixture was stirred continuously during the reaction. After completion of the reaction, the solvent was removed in vacuo. The residue was purified by silica gel column chromatography to afford the corresponding product. All the products were confirmed by NMR and MS spectroscopic analysis. |
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 |
---|---|---|
37% | Stage #1: at 20℃; for 0.666667 h; Stage #2: With sodium hydroxide In water at 0℃; |
Preparation of -hydroxypyrimidine-^carboxylic acid:; To a suspension of 2.52 g (12.0 mmol) of diethyloxaloacetate sodium salt in 8 mL of water was added 1.9 mL of 6.25 M NaOH(α? ), dropwise over 1 min. The mixture was stirred at ambient temperature for 40 min to give an orange solution. Next, 2.1 g (26 mmol) of formamidine hydrochloride in 2 mL of water was added. The reaction was cooled with an ice bath, and with the aid of a pH meter, the pH was maintained between 1 1 and 1 1.5, by the addition of 6.25 M NaOH as the reaction progressed over 40 min. The pH was then adjusted to 1 by the addition of 12 M HCl, giving a white precipitate. This was filtered, washed with 0.1 M HCl (2 x 5 mL), then dried on the filter to give 618 mg (37percent) of a light tan solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.8% | With sodium methylate In methanol at 20℃; for 24 h; | Following the preparation protocol of Section 2.8, the reaction mixture offormimidamide hydrochloride 4b (739 mg, 7.1 mmol), sodium methoxide (1M inmethanol, 7.1 mL, 7.1 mmol) and compound 5 (1.34 g, 7.1 mmol) in methanol (50mL) was stirred at room temperature for 1 d to give compound 6b as a light yellowsolid (558 mg, 55.8percent); mp 154-156 °C; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.89(s, 1H), 8.53 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Stage #1: at 210℃; for 0.25 h; Heating / reflux Stage #2: With sodium hydroxide In water at 80℃; |
A solution of 9.85 g of compound 10 (5 mmol) and 6.8 g of formamidine hydrochloride (85 mmol) was heated under reflux for 15 min at 210° C. After cooling to 80° C., the solution was basified with saturated sodium hydroxide and washed with n-hexane and water to give 6.59 g of compound 11 (yield, 64percent). 1H-NMR (300 MHz, d6-DMSO): δ 7.98 (s, 1H), 7.42 (s, 1H), 7.11 (s, 1H), 3.89 (d, 6H). |
64% | Stage #1: at 210℃; for 0.5 h; Stage #2: With sodium hydroxide In water |
Example 1: Preparation of l-((3S)-3-(4-(3-chloro-2,4-difluorophenylamino)- 7-methoxyquinazolin-6-yloxy)pyrrolidin-l-yl)pro-2-pen-l-one; (1-1) 6,7-dimethoxyquinazolin-4(3H)-one; 36.9 g of 4,5-dimethoxyanthranilic acid was mixed with 25.0 g of formamidine hydrochloride, and the mixture was stirred at 210 °C for 30 minutes. After completion of the reaction, the solid thus obtained was cooled to room temperature, stirred with 200 mi (0.33 M) of aqueous sodium hydroxide and filtered under a reduced pressure. The solid thus obtained was washed with water and air-dried to obtain the title compound (24.6 g, 64percent). 1H-NMR (300MHz, DMSO-d6) δ 7.99 (s, IH), 7.44 (s, IH), 7.13 (s, IH),3.90 (5, 3H), 3.87 (5, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.19% | Stage #1: With sodium methylate In methanol at 5℃; Stage #2: at 20℃; Stage #3: With hydrogenchloride In water |
Example 1Preparation of Compound 17; K2OsO4, NaIO4 EtOHZNH4CI refluxAcetori e: water ( 1 : 1 ) 5tep 7 - Synthesis of compound IBA suspension of sodium methoxide (30percent solution in methanol) (32.4 g, 599.31 mmol) in methanol (-300 mL) was cooled to 5 0C and to the cooled solution was added formamtdine hydrochloride (IA, 10.05 g, 124.86 mmol). The reaction was allowed to stir for 10 minutes, then diethyl allylmalonate (25 g, 124.85 mmol) was added and the resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and the residue obtained was dissolved in ice water (-100 mL) and acidified to pH = 7 using HCl. The white precipitate formed was filtered, washed with water and dried in vacuo to provide compound IB (13.52 g, 71.19percent). |
71.19% | Stage #1: With sodium methylate In methanol at 5℃; for 0.166667 h; Stage #2: at 20℃; |
Step 1 - Synthesis of Compound IB; To a cold suspension of sodium methoxide (32.4 g, 599.31 mrnol) in methanol (about. 300 mL) at 5 C was added formamidine hydrochloride (10.05 g, 124.86 mmol) and the resulting solution was allowed to stir for 10 minutes. Diethyl allylmalonate (IA, 25 g, 124.85 mmol) was added and the resulting reaction was allowed to stir for about 15 hours at room temperature. The reaction mixture was concentrated in vacuo and the solid residue obtained was dissolved in ice cold water (about 100 mL) and acidified to pH = 7 using 2N HCl. The white precipitate obtained was filtered, washed with water and dried under vacuum to provide compound IB (13.52 g, 71.19percent). |
71.19% | Stage #1: With sodium methylate In methanol at 5℃; Stage #2: at 20℃; for 15 h; Stage #3: With hydrogenchloride In water |
Example 1Preparation of Compound 6 Step 1 - Synthesis of Compound 1B; To a cold suspension of sodium methoxide (30percent solution in methanol) (32.4 g, 599.31 mmol) in methanol (about 300 mL) at 5 °C was added formamidine hydrochloride (10.05 g, 124.86 mmol) and the resulting reacton was allowed to stir for 10 minutes. Diethyl allylmalonate (1A, 25 g, 124.85 mmol) was then added and the resulting reaction was allowed to stir for about 15 hours at room temperature. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in ice cold water (about 100 mL) and acidified to pH = 7 using 2N HCl. The white precipitate obtained was filtered, washed with water and dried under vacuum to provide compound IB (13.52 g, 71.19percent). |
71.19% | Stage #1: With sodium methylate In methanol at 5℃; for 0.166667 h; Stage #2: at 20℃; for 15 h; |
A solution of sodium methoxide (30percent solution in methanol) (32.4 g, 599.31 mmol) in methanol (~300 mL) was cooled to 5 °C and to the cooled solution was added formamidine hydrochloride (10.05 g, 124.86 mmol). The reacton was allowed to stir at 5 °C for 10 minutes, then diethyl aliylmaionate (25 g, 124.85 mmol) was added and the resulting reaction was allowed to stir at room temperature for about 15 hours. The reaction mixture was concentrated in vacuo and the residue obtained was dissolved in ice cold water (-100 mL) and acidified to pH = 7 using 1 N HCI. The white precipitate obtained was filtered, washed with water and dried under vacuum to provide Compound 1A (13.52 g, 71.19percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With sodium acetate In 2-methoxy-ethanol at 120℃; for 6 h; | A mixture of compound 5-amino-2-chloropyridine-4-carboxylic acid(1000 g, 5.8 mol) was dissolved in 5000 mlEthylene glycol monomethyl ether, AddedFormamidine hydrochloride(1867 g, 23.2 mol), sodium acetate (2360 g, 17.4 mol). The reaction was heated to 120 ° C for 6 hours. After the reaction was complete, the reaction was cooled to room temperature, poured into 4000 ml of water and extracted twice with ethyl acetate. The organic phase was combined, dried and concentrated to afford the crude product which was filtered to give 6-chloropyridine And [3,4-d] pyrimidin-4 (3H) ketone (924 g, 5-1 mol) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In ethanol at 70 - 80℃; | To a three-necked flask was added ethyl trifluoroacetoacetate (0.16 mL, 1.0 eq.),DBU (0.19 mL, 1.2 eq.),Add absolute ethanol (10 mL) to dissolve.A solution of formamidine hydrochloride in ethanol (0.09 g of formamidine hydrochloride in 2 mL of ethanol,The amount of formamidine hydrochloride1.05 eq.).Dropping the temperature to 70-80 ° C for 3 to 5 hours.TLC monitoring,The reaction was complete.The solvent was distilled off under reduced pressure,Diluted with water (20 mL)With 1mol / L hydrochloric acid adjusted pH = 6 ~ 7,Extraction with ethyl acetate (3 x 8 mL)The organic phase was combined with anhydrous sulfuric acidSodium drying, filtration, vacuum distillation of the solvent was light yellow solid, add petroleum ether (5mL) shock, filter, filter cake washed with petroleum ether,The oven was dried at 55 ° C for 2 hours to give a pale yellow flake solid in 96percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With sodium ethanolate In ethanol at 0 - 90℃; | To a stirred solution of NaOEt (2.7 g, 0.04 mol) in EtOH (40 mL) was added formamidine acetate (4.2 g, 0.04 mol), followed by addition of diethylfluoromalonate in ethanol (10 mL) at 0° C. The reaction mixture was stirred at 90° C. overnight. Ethanol was removed under reduced pressure and the reaction mixture was acidified with conc. HCl to pH 1. The resulting solid was filtered and dried under vacuum to afford 20.1 (crude, 750 mg, 52percent). 1H-NMR (DMSO-d6 200 MHz): δ 12.40 (bs, 2H), 7.89 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With sodium ethanolate In ethanolReflux; Inert atmosphere | Intermediate 1, Step a: tert-Butyl 4-hydroxy-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate To a solution of 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate (2.00 g, 7.39 mmol) in EtOH (37 mL) was added formamidine hydrochloride (910 mg, 11.08 mmol) followed by NaOEt (6.89 mL, 2.68 M in EtOH) dropwise. The mixture was then heated to reflux overnight. The mixture was concentrated in vacuo and then dissolved in a minimum amount of water. The pH was adjusted to pH 7 with 1 N HCl. The aqueous layer was then saturated with solid NaCl and extracted with a combination of EtOAc and DCM. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. Chromatography on SiO2 eluting with IPA/EtOAc afforded the desired product as a white solid (993 mg, 53percent). MS (ESI) mass calcd. C12H12N3O3, 251.13. m/z found 252.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.05 (s, 1H), 4.42 (s, 2H), 3.69-3.61 (m, 2H), 2.63 (s, 2H), 1.49 (s, 9H). |
42% | With sodium ethanolate In ethanol at 70℃; for 5 h; | STEP B: 3-Oxo-piperidine- l ,4-dicarboxylic acid 1 -te -butyl ester 4-ethyl ester (4.6 g, 16.8 mmol) was dissolved in EtOH (90 mL), and sodium ethoxide (2.3 g, 33.6 mmol) and formamidine hydrochloride (2.0 g, 25.2 mmol) were sequentially added. The resulting suspension was heated to 70°C and stirred for 5 hours, and then the reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in saturated ammonium chloride and extracted with ethyl acetate. The aqueous phase was adjusted to pH -5.5 using concentrated AcOH, and extracted several more times with ethyl acetate. The combined organic layers were sequentially washed with water and brine, dried, and concentrated to afford 4-hydroxy-5,8-dihydro-6H-pyrido[3,4- d]pyrimidine-7-carboxylic acid /er/-butyl ester as a brown solid (1.8 g, 42percent yield). MS (ESl) m/e (M+H+) = 251.28 |
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