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CAS No. : | 42908-86-1 | MDL No. : | MFCD00152348 |
Formula : | C8H6Cl2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | TXZFBHYDQGYOIT-UHFFFAOYSA-N |
M.W : | 189.04 | Pubchem ID : | 3016395 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 46.39 |
TPSA : | 17.07 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.45 cm/s |
Log Po/w (iLOGP) : | 1.88 |
Log Po/w (XLOGP3) : | 2.82 |
Log Po/w (WLOGP) : | 2.65 |
Log Po/w (MLOGP) : | 2.67 |
Log Po/w (SILICOS-IT) : | 3.3 |
Consensus Log Po/w : | 2.66 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.06 |
Solubility : | 0.165 mg/ml ; 0.00087 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.84 |
Solubility : | 0.276 mg/ml ; 0.00146 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.98 |
Solubility : | 0.0196 mg/ml ; 0.000104 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.09 |
Signal Word: | Danger | Class: | 6.1,8 |
Precautionary Statements: | P261-P280-P305+P351+P338-P310 | UN#: | 2927 |
Hazard Statements: | H302-H314-H331-H351 | Packing Group: | Ⅱ |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sulfuryl dichloride; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 4h;Reflux; | To a solution of o-toluoyl chloride (9.3 g, 60 mmol) in CCl4 (20 mL), sulfuryl chloride (9.7 g, 72 mmol) and diazoisobutyronitrile (0.25 g, 1.5 mmol) were added. The reaction mixture was refluxed for 4 h, cooled down, filtered, and concentrated in vacuo. Vacuum distillation of the residue afforded 9.8 g (87%) of chloride 13, b.p. 172-174 C (36 Torr) (cf. Ref. 17: b.p. 135 C (14 Torr)). |
87% | With sulfuryl dichloride; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 4h; | Sulfurylchloride (9.7 g, 72 mmol) and azobisisobutyronitrile (0.25 g,1.5 mmol) were added to a solution of 2-methylbenzoyl chloride 15(9.3 g, 60 mmol) in CCl4 (20 mL). The reaction mixture was refluxed for 4 h, cooled, and fi ltered. The solvent was evaporated in vacuo, and the residue was distilled. Acid chloride 16 was isolated in the yield of 9.8 g (87%), b.p. 172-174 C (36 Torr)(cf. Ref. 19: 135 C (14 Torr)). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate In acetone |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate In acetone |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate In acetone |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
· Step 2 The concentrated residue obtained in the above Step 1 was cooled on a water bath, and, while maintaining the internal temperature at not more than 60C, 80.1 g (2.5 mol) of methanol was added dropwise thereto over 1 hour. The mixture was further stirred at 50C for 1 hour, and then cooled to 25C. Next, 300 ml of toluene was added to the reaction mixture, and the mixture was added dropwise over 30 minutes to a solution of 70.0 g (0.51 mol) of potassium carbonate dissolved in 300 ml of water. The toluene layer was separated, washed with 130 g of 30% brine, and then concentrated under reduced pressure to obtain 189.2 g of methyl 2-chloromethylbenzoate. The apparent yield was 102.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; N-benzyl-N,N,N-triethylammonium chloride;boron trifluoride diethyl etherate; In xylene; at 100 - 132℃; for 3h; | To a 1-L four-necked flask, 643 ml of xylene, 134.1 g (1.0 mol) of phthalide, 18.2 g (0.08 mol) of benzyltriethylammonium chloride, and 9.9 g (0.07 mol) of BF3-etherate complex were added, and heated to 100C. Subsequently, 142.8 g (1.2 mol) of thionyl chloride was added dropwise thereto over 1 hour, and stirred at 125 to 132C for 2 hours. Xylene and excessive thionyl chloride (about 350 ml) were distilled off at normal pressure until the internal temperature became 135C, and xylene (about 350 ml) was further distilled off under reduced pressure. | |
With dichlorotriphenylphosphorane; at 180℃; for 4h; | Isososrbide-2-aspirinate-5-(2-nitrooxy-methyl)benzoate 31; Phthalide (m.w. 134.13g/mol, 5.03g = 37 mmol) and dichlorotri phenyl phosphorane (m.w. 333.19 g/mol, 12.3g = 38 mmol) were heated at 1800C for 4 hrs with stirring[3]. Colour change from green to brown was seen over the course of 4 hrs. TLC (hexane/ethyl acetate 2: 1) showed 3 spots and NMR determined that the top spot (Rf 0.77) was that of 2-chloromethylbenzoyl chloride, the second spot (Rf 0.57) was phthalide and the bottom spot (Rf 0.14) was triphenylphosphorous. A large amount of the phthalide was unreacted.2- chloromethylbenzoyl chloride (Figure 12) (m.w. 189.04 g/mol, 600mul) was dissolved in dichloromethane (10 ml). Triethylamine (m.w. 101.19 g/mol, d=0.726 g/ml, 600mul = 4.3 mmol) was added and the mixture was cooled to 00C. Compound 17 (m.w. 308.14 g/mol, 0.5298g = 1.7 mmol) was added and the mixture was stirred at room temperature overnight while protected from light. The mixture (green colour) was washed with HCI (2M, 10 ml), 5% NaHCO3 (10 ml) and distilled water (10 ml) and dried over sodium sulfate. Mixture was concentrated producing 769.5 mg of a brown/green oil. This was chromatographed using hexane/ethyl acetate (2:1) resulting in 419.4 mg of a brown solid (Rf 0.38). 1H NMR delta fCDChi 400MHz: 2.38 (3H, s, OCOCH3), 4.03 (4H, m, ISH-I, ISH-I', ISH-6 and ISH-6'), 4.66 (IH, d, ISH-3), 5.04 (2H, m, CH2CI), 5.10 (IH, ss, ISH-4), 5.42 (2H, m, ISH-2/H-5), 7.12 (IH, d, Ar-H), 7.28 (IH, m, Ar-H), 7.42 (IH, m, Ar-H), 7.6 (3H, m, Ar-H), 8.01 (2H, dd, Ar-H). 13C NMR ppm fCDChi 400MHz: 20.51 (OCOCH3), 43.95 (CH2CI), 70.15 (ISC-I), 72.78 (ISC-6), 74.33 (ISC-5), 78.11 (ISC-2), 80.52 (ISC-4), 85.58 (ISC-3), 122.21 (Ar2 C-2/C-6), 123.42, 125.65 (Ar2 C-4), 128.03 (Ar.C-6),128.07 (Ar1C^), 130.60 (Ar1C-S), 130.73 (ArIC-I), 131.43 (Ar1 C-4), 133.45 (Ar2 C-5), 133.92, 138.54, 150.25 (Ar2OCO), 163.12 (OCOArCH2ONO2), 165.47 (ArOCOCH3), 169.29 (ArC(O)OR). 400 mg was dissolved in CH3CN/THF (6 ml, 4/2 v/v) and treated with AgNO3 (m.w. 169.87 g/mol, 0.30 g = 1.7 mmol) and refluxed for 4 hours before stirring overnight at room temperature while protected from light. Mixture was filtered and concentrated. This was reconstituted in ethyl acetate (10 ml) and water (2 ml). The organic phase was washed with water (3 x 2 ml), brine (2 ml) and dried over sodium sulfate. Concentrated, producing an oil which was chromatographed using hexane/ethyl acetate (2:1) resulting in 95 mg of yellow wax-like material.^ NMR delta fCDChi 400MHz: 2.38 (3H, s, OCOCH3), 4.01 (4H, m, ISH-I, ISH-I', ISH-6 and ISH-6'), 4.65 (IH, d, ISH-3), 5.02 (IH, t, ISH-4), 5.41 (2H, m, CH2), 5.86 (2H, ss, ISH-2/H-5), 7.11 (IH, d, Ar-H), 7.28 (IH, t, Ar-H), 7.49 (2H, q, Ar-H), 7.61 (2H, q, Ar-H), 8.01 (IH, d, Ar-H), 8.10 (IH, d, Ar- H). 13C NMR ppm fCDChi 400MHz: 20.51 (OCOCH3), 70.37 (CH2ONO2), 72.78 (ISC-I), 73.46 (ISC-6), 74.30 (ISC-5), 78.01 (ISC-2), 80.61 (ISC-4), 85.64 (ISC-3), 122.19 (Ar2 C-2/C-6), 123.40, 125.66 (Ar2 C-4), 128.76 (Ar.C-6),129.77 (Ar1C^), 129.85 (Ar1C-S), 130.30 (ArIC-I), 131.41 (Ar1 C-4), 132.44 (Ar2 C-5), 133.25, 133.93, 150.23 (Ar2OCO), 163.12 (OCOArCH2ONO2), 164.71 (ArOCOCH3), 169.28 (ArC(O)OR). | |
With dichlorotriphenylphosphorane; at 180℃; for 4h; | [00528] A solution of crude 2-(chloromethyl)benzoyl chloride (prepared by heating a neat mixture of isobenzofuran-l(3H)-one (14.5 equiv) and PPh3C12 (15.1 equiv) at 180 C for 4 h) in dichloromethane was added portion- wise to a suspension of Compound 1-107 in dichloromethane and pyridine (2:1) until one-half of the crude material was added and the solution became homogeneous. The solution was partitioned between saturated aqueous ammonium chloride and dichloromethane. The layers were separated and the aqueous layer was extracted with dicliloromethane. The organics were dried over magnesium sulfate, filtered, the solvent was removed in vacuo, and purification by silica gel chromatography (0- 10% methanol in dicliloromethane) provided intermediate X-259 as a yellow film (12%). The benzyl chloride intermediate was stirred with l,8-diazabicyclo[5.4.0]undec-7-ene (28 equiv) in dicliloromethane for 1.5 h. The solution was partitioned between saturated aqueous ammonium chloride and dichloromethane. The layers were separated and the aqueous layer was extracted with dichloromethane. The organics were dried over magnesium sulfate, filtered, the solvent was removed in vacuo, and purification by silica gel chromatography (ethyl acetate in hexanes) provided the desired product as a white solid (52%).LRMS Calcd for C25H19FN702 [M+H]+ 468.16, observed 468.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With aluminium trichloride 1.) CH2Cl2, room temperature, 15 min, 2.) room temperature, 10 min; Yield given. Multistep reaction. Yields of byproduct given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With aluminium trichloride 1.) CH2Cl2, room temperature, 15 min, 2.) room temperature, 10 min; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With aluminium trichloride 1.) CH2Cl2, room temperature, 15 min, 2.) room temperature, 10 min; Yield given. Multistep reaction. Yields of byproduct given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With aluminium trichloride 1.) CH2Cl2, room temperature, 15 min, 2.) room temperature, 10 min; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In acetonitrile for 3h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 1.Synthesis of N-methyl[4-(1-methyl-2-{2-{4-[(4-methylpiperazinyl)-methylphenyl}-benzimidazol-5-yloxy)(2-pyridyl)]carboxamide To a solution of {4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1 eq) in tetrahydrofuran was added 4-(chloromethyl)benzoylchloride (1 eq) and triethylamine (2 eq). N-acylation is completed in 0.5 h.The reaction mixture was concentrated and partitioned between ethyl acetate and water.The organic layer was concentrated and to the crude product was added methylpiperazine (4 eq) and tetrahydrofuran and stir for 16 h at ambient temperature.The reaction mixture was concentrated and partitioned between ethyl acetate and water.The organic layer was concentrated and taken in acetic acid and heated to 60 C. for 3 h.Preparative chromatography yielded N-methyl[4-(1-methyl-2-{2-{4-[(4-methylpiperazinyl)methyl-phenyl}-benzimidazol-5-yloxy)(2-pyridyl)]carboxamide. MS: MH+=470. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.2% | With pyridine; phosphorus pentachloride; In dichloromethane; water; | Example 2 Synthesis of 2-chloromethyl-alpha-methoxyiminobenzyl chloride <strong>[42908-86-1]2-Chloromethylbenzoyl chloride</strong> (18.90 g, 0.1 mol) was dissolved in dichloromethane (50 ml). The solution was added to a mixture of methoxyamine hydrochloride (12.53 g, 0.15 mol), pyridine (19.78 g, 0.25 mol) and dry dichloromethane (150 ml) under ice-cooling over 1 hour, and then the resulting mixture was stirred at 0 C. for 2 hours. After completion of the reaction, water (300 ml) was added, adjusted to pH<2 with conc. hydrochloric acid, and extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dichloromethane (200 ml), and phosphorus pentachloride (20.82 g, 0.1 mol) was added under ice-cooling over 5 minutes. The mixture was stirred at 0 C. for 1 hour. After completion of the reaction, saturated aqueous sodium bicarbonate solution (400 ml) was added, and the mixture was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-chloromethyl-alpha-methoxyiminobenzyl chloride (18.15 g, 83.2%) as a colorless oil. 1 H-NMR(CDCl3) delta ppm: 4.12 (3H,s), 4.83(2H,s), 7.40-7.62(4H,m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In water; acetonitrile; | Example 2 Synthesis of 2-(2-chloromethylphenyl)-2-oxoacetonitrile--(2) A mixture of 98% cuprous cyanide (2.01 g), acetonitrile (40 ml) and <strong>[42908-86-1]2-chloromethylbenzoyl chloride</strong> (3.79 g) was heated under reflux with stirring for 4 hours. After the mixture was cooled by allowing it to stand, the mixture was diluted with ether, the precipitated insoluble materials were filtered off, and then the filtrate was washed successively with a saturated aqueous solution of sodium bicarbonate, water and saturated brine. The ether layer thus obtained was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain the crude product (3.49 g). The crude product was crystallized from ether-haxane to give the title compound (2.85 g, yield: 79.5%, white crystals). mp. 54.5-56.5 C. 1 H-NMR (CDCl3) delta ppm: 5.00(2H,s), 7.62-7.84(3H,m), 8.35(1H,dd,J=7.9,1.2 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(I) iodide; sodium hydrogencarbonate; In quinoline; water; acetonitrile; | Example 1 Synthesis of 2-(2-chloromethylphenyl)-2-oxoacetonitrile--(1) A mixture of acetonitrile (100 ml), 95% sodium cyanide (6.19 g), 95% cuprous iodide (2.00 g) and quinoline (0.13 g) was stirred at 60 C. A solution of <strong>[42908-86-1]2-chloromethylbenzoyl chloride</strong> (19.0 g) in acetonitrile (100 ml) was added dropwise to the reaction mixture over 3 hours. After completion of the addition, the mixture was stirred at 60 C. for 5 hours. After the reaction mixture was cooled by allowing it to stand, the reaction mixture was diluted with ether, and washed successively with water, a saturated aqueous solution of sodium bicarbonate and water. The ether layer thus obtained was dried over anhydrous sodium sulfate and at the same time decolorized with Norit SX-3. Evaporation of the solvent under reduced pressure gave the crude title compound (17.6 g, purity: about 72% determined by 1 H-NMR analysis). The 2-chloromethylbenzoyl cyanide was normally used in the next step as the crude product. If necessary, it was isolated as white crystals by crystallizing it from ether-hexane. | |
292.34 g (82%) | With tetrabutylammomium bromide; In water; toluene; | Example 1 Preparation of 2-chloromethylbenzoyl cyanide under phase-transfer conditions in water/toluene 1 g (3 mmol) of tetrabutylammonium bromide was added to a solution of 117.6g (2.4 mol) of sodium cyanide in 400 g of water. The mixture obtained was then adjusted to a pH of 10.5 using about 200 g of 1% strength by weight hydrochloric acid, after which 1000 g of toluene were added. A solution of378 g (2.0 mol) of <strong>[42908-86-1]2-chloromethylbenzoyl chloride</strong> in 1000 ml of toluene wasmetered into this 2-phase mixture in the course of 30 min. After stirring at 25-35 C. for about 2-3 hours, the phases were separated. The organic phase was washed once each with 200 ml of water and 200 ml of 1% strength by weight hydrochloric acid, then dried over magnesium sulfate and concentrated. The crude product was purified bymeans of fractional distillation (b.p.: 100 C., 0.3 mbar). Yield: 292.34 g (82%) |
345.8 g (97%) | With tin(IV) chloride; In toluene; acetonitrile; | Example 1 Preparation of 2-chloromethylbenzoyl cyanide in acetonitrile 7.8 g (3 mol %) of tin tetrachloride are added to a suspension of 196 g (4 mol) of sodium cyanide in 1000 ml of acetonitrile. The mixture was then heated to 60 C. and, over the course of 30 minutes, 378 g (2 mol) of <strong>[42908-86-1]2-chloromethylbenzoyl chloride</strong> were added dropwise. The mixture was stirred at about 60 C. for 6 hours and then cooled. The undissolved catalyst was then removed by filtration through silica gel. Alternatively, the catalyst can also be washed out of the reaction mixture after adding toluene using 200 ml of a dilute mineral acid three times. The clear solution remaining after removal of the catalyst was subjected to fractional distillation. Yield: 345.8 g (97%); boiling point (0.5)=105 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; | Example 3 Preparation of 2-chloromethylbenzoyl cyanide using CuCN A solution of 9.45 g (0.05 mol) of <strong>[42908-86-1]2-chloromethylbenzoyl chloride</strong> in 100 mlof acetonitrile was treated with 8.9 g (0.1 mol) of Cu(I) cyanide, after which the reaction mixture was stirred at about 0 C. for 24 hours.HPLC analysis showed 24% of phthalide, 62% of 2-chloromethylbenzoyl cyanideand about 10% of dimeric benzoyl cyanide. It was possible to separate the reaction mixture by chromatography on silica gel (eluent: hexane/toluene=1:1) or by fractional distillation as described in Example 1 (b.p. 0.5 =106 C.). Yield: 5.27 g (58%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
pyridine; In isopropyl alcohol; benzene; | Example 2 o-Chloromethylbenzoic acid phenyl ester The ester was prepared by Method C only, by dissolving 47 g (0.5 mole) of phenol in 60 ml of benzene in the apparatus used in the preparation of the para compound, adding 0.5 ml of absolute pyridine as catalyst, and then adding 95 g (0.5 mole) of undiluted o-chloromethylbenzoyl chloride drop by drop at 55 to 60 C. over a period of about 1 hour, the mixture being stirred for another 4 hours at the refluxing temperature to complete the reaction. The benzene was then distilled out of the clear, light red solution thus obtained. The viscous oily, clear, red residue obtained in a quantitative yield crystallized after standing for a while at -15 C. The crystal mass thus obtained was ground in a chilled mortar with about 100 ml of intensely cooled isopropanol; the undissolved portion was removed by suction filtering and washed with 100 ml of isopropanol chilled to -20 C. After drying, 87 g (70%) was obtained of a colorless crystallizate with a melting point of 39-41 C. For the analysis, 15 g was dissolved at 35 C. in 125 ml of isopropanol and set aside to crystallize at -20 C. 12.7 g of colorless needles was obtained with a melting point of 39-41 C. Elemental analysis: C14 H11 ClO2 (Mol. Wt.=246.7). Calculated: C 68.17%; H 4.49%; Cl 14.37%; O 12.97%. Found: C 67.89%; H 4.35%; Cl 14.11%; O 13.26%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
525 mg (64.5%) | With trifluorormethanesulfonic acid; sodium hydrogencarbonate; In dichloromethane; water; | Step 3 Preparation of Ethyl 5-[o-(chloromethyl)benzoyl]-3-ethoxycarbonyl-4-hydroxy-1-methylpyrrole-2-acetate Ethyl 3-ethoxycarbonyl-4-hydroxy-1-methylpyrrole-2-acetate (510 mg, 2.0 mmol) is mixed with o-(chloromethyl)benzoyl chloride (565 mul, 4.0 mmol) under nitrogen, and 2.0 ml anhydrous trifluoromethanesulfonic acid is added. The reaction mixture is stirred at room temperature for one hour followed by dilution with methylene chloride (50 ml), and then water (30 ml). Solid sodium bicarbonate is slowly added until the acid is neutralized. The organic layer is separated and the aqueous layer is washed with methylene chloride (50 ml). The combined organic layers are washed with water (20 ml) and saturated brine (50 ml). Subsequently, the washed layers are dried with sodium sulfate and the solvent is removed in vacuo to give a red solid which is recrystallized from ethanol to give 525 mg (64.5%) of ethyl 5-[o-(chloromethyl)benzoyl]-3-ethoxycarbonyl-4-hydroxy-1-methylpyrrole-2-acetate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In 1,4-dioxane; ethyl acetate; benzene; | EXAMPLE 20 Preparation of N-{5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrophenyl}amino-2,3-dihydroisoindolinone (compound No. 73) 2-Chloro-4-trifluoromethyl-3'-hydrazino-4'-nitrodiphenyl ether (3.5 g), triethylamine (2.2 g) and dioxane (100 ml) were introduced into a 200 ml four-neck flask, and after dissolution, <strong>[42908-86-1]2-chloromethylbenzoyl chloride</strong> (1.9 g) was added little by little at room temperature, followed by stirring at 95-100 C. for 3 hours. After cooling, the resulting material was discharged into water and extracted with benzene, followed by washing with an aqueous solution hydrogen sulfate and water and drying with anhydrous sodium sulfate. After drying, benzene was distilled off under reduced pressure, and the resulting material was purified by means of a silica gel column employing benzene/ethyl acetate (95:5) as a developing solvent to obtain 0.9 g of an objective product having a melting point of 207-208 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In 2-methoxy-ethanol; water; | (a) o-chloromethylbenzoic acid pentabromophenyl ester: In a 500-ml three-necked flask, 4 g (= 0.1 mole) of sodium hydroxide was dissolved at 60 C in 270 ml of methyl glycol, and 48.9 g of pentabromophenol was stirred in for the preparation of a phenolate solution, as in Example 8c. At 30 to 34 C, 18.9 g (- 0.1 mole) of o-chloromethylbenzoyl chloride was added drop by drop, with stirring, over a period of about 40 minutes, whereupon a white, crystalline preciptate settled out, which after 1 hour was suction filtered. After the product had been stirred up in water, suction filtered, washed and dried, 58 g (= 90.5%) of o-chloromethylbenzoic acid pentabromophenyl ester was obtained, which melted at 201-205 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In 2-methoxy-ethanol; | (b) By the "one-vessel method", directly from o-chloromethylbenzoyl chloride: In a 6-liter flask, 32 g of sodium hydroxide was dissolved at 60 C in 4 liters of methyl glycol, and then 391 g (= 0.8 mol) of pentabromophenol were dissolved whereupon this phenolate solution was cooled to 35 C. At this temperature 75.7 g of o-chloromethyl benzoyl chloride was added, drop by drop, with stirring, over a period of 50 minutes. The ester precipitated in crystal form. Then the mixture was heated for 5 hours at ebullition, and then cooled and worked up as in the preceding examples. Product: 353 g (= 80.7% yield) M.P. 259-263 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With sodium hydroxide; In 2-methoxy-ethanol; | (c) Preparation and isolation of o-chloromethylbenzoic acid-2,4,6-tribromophenyl)-ester: In a two-liter three-necked flask, 40 g of sodium hydroxide was dissolved in 950 ml of methyl glycol at 60 C, and then 331 g (= 1 mole) of tribromophenol was stirred in, and then 189 g (= 1 mole) of o-chloromethyl benzoyl chloride was added, drop by drop, with stirring, over a period of 13/4 hours, at a reaction mixture temperature not exceeding 40 C, into the clear phenolate solution, cooled to 30 to 40 C. Stirring was then continued for one hour at room temperature; the mixture was then cooled to 0 C, the crystallizate was suction filtered and washed free of sodium chloride with water, and dried at 80 C in a vacuum drying chamber. 397 g (= 82% yield) was obtained of o-chloromethylbenzoic acid tribromophenyl ester melting at 180-110 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Example 6 Synthesis of o-(chloromethyl)benzoic Acid 2-chloroethyl Ester 180 g of o-(chloromethyl)benzoic acid chloride was placed in a double-neck 500 ml flask equipped with a cooler, thermometer and dropping funnel. 50 ml of 2-chloroethanol was added dropwisely, while maintaining the internal temperature of reactor at 40~50 C. After all amounts of 2-chloroethanol were infused, the reacting solution was stirred for 10 hours, while maintaining the internal temperature of reactor at 40~50 C. The residue was subjected to fractional distillation under reduced pressure at the reactor equipped with a fractional distiller to afford 165 g of desired compound (yield 94%) as oil. Boiling point: 88~92 C.(1.1 mm Hg) 1H-NMR(CDCl3): delta 3.83(t, 2H, J=5.5 Hz), 4.59(t, 2H, J=5.5 Hz), 5.02(s, 2H), 7.36~7.58(m, 3H), 8.01(d, 1H, J=8 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With thionyl chloride; N-benzyl-N,N,N-triethylammonium chloride; | EXAMPLE 1 Synthesis of o-(chloromethyl)benzoyl Chloride A mixture of phthalide 134 g(1 mol), SOCl2 95 ml(1.3 mol), BF3Et2O 2.5 ml (0.02 mol) and benzyltriethylammonium chloride 4.5 g(0.02 mol) was placed in a double-neck 500 ml flask equipped with a thermometer and cooler. The mixture was stirred for 15 hours, while maintaining the interal temperature of reactor at 95~100 C. for reaction. After the reaction is completed, a fractional distillation under reduced pressure was made at the reactor equipped with a fractional distiller to afford 180 g of a desired compound (yield 95%). Boiling point: 75~80 C.(1 mm Hg) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In methanol; | Example 3 Synthesis of o-(chloromethyl)benzoic Acid Methyl Ester 180 g of o-(chloromethyl)benzoyl chloride was placed in a double-neck 500 ml flask equipped with a thermometer, cooler and dropping funnel. While maintaining the internal temperature of a reactor at 40~50 C., 50 ml of methanol was added dropwise. After all amounts of methanol were infused, the reacting mixture was stirred for 10 hours, while maintaining the internal temperature of a reactor at 40~50 C. After a distillator was equipped, a fractional distillation under reduced pressure was made to afford 165 g of desired compound (yield 94%) as oil. Boiling point: 77~80 C. (1 mm Hg) 1H-NMR(CDCl3): delta 3.9(s, 3H), 5.02(s, 2H), 7.31~7.56(m, 3H), 7.96(d, 1H, J=8 Hz) |
89% | With triethylamine; In methanol; dichloromethane; | Example 4 Synthesis of o-(chloromethyl)benzoic Acid Methyl Ester To a double-neck 500 ml flask equipped with a cooler, thermometer and dropping funnel was added 180 g of o-(chloromethyl)benzoic acid chloride dissolved in 1,000 ml of methylene chloride. The internal temperature was adjusted at 0 C., triethylamine(138 ml) was added and then 50 ml of methanol was added dropwise. After all amounts of methanol were infused, the reacting mixture was stirred for 10 hours, while maintaining the internal temperature of a reactor at 20~30 C. The reaction mixture was acidified with 5% HCl solution (300 ml). The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated. The residue, so formed, was subjected to fractional distillation under reduced pressure to afford 155 g of desired compound (yield 89%) as oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In ethanol; | Example 5 Synthesis of o-(chloromethyl)benzoic Acid Ethyl Ester To a double-neck 500 ml flask equipped with cooler, thermometer and dropping funnel was added 180 g of o-(chloromethyl)benzoic acid chloride, and then 60 ml of ethanol was further added dropwise, while maintaining the internal temperature of reactor at 40~50 C. After all amounts of methanol were infused, the reacting mixture was stirred for 10 hours, while maintaining the internal temperature of a reactor at 40~50 C. After a distiller was equipped immediately, the residue was subjected to fractional distillation under reduced pressure to afford 179 g of desired compound (yield 90%) as oil. Boiling point: 79~82 C.(1.1 mm Hg) 1H-NMR(CDCl3): delta 1.4(t, 3H, J=8 Hz), 4.38(q, 2H, J=8 Hz), 5.02(s, 2H), 7.32~7.55(m, 3H), 7.96(d, 1H, J=8 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; In chloroform; | A) Preparation of 2-(chloromethyl)-benzoylchloride To thionyl chloride (35 ml) cooled at 0 C. with ice bath, the <strong>[612-20-4]2-hydroxymethylbenzoic acid</strong> (4 g, 26.3 mmoles) is added. The temperature is let reach the room value and the mixture is left under stirring for 2 hours, then it is evaporated at reduced pressure and treated 3 times with chloroform for completely removing the thionyl chloride. The reaction raw product is used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0 - 20℃;Absence of light; | Isososrbide-2-aspirinate-5-(2-nitrooxy-methyl)benzoate 31; Phthalide (m.w. 134.13g/mol, 5.03g = 37 mmol) and dichlorotri phenyl phosphorane (m.w. 333.19 g/mol, 12.3g = 38 mmol) were heated at 1800C for 4 hrs with stirring[3]. Colour change from green to brown was seen over the course of 4 hrs. TLC (hexane/ethyl acetate 2: 1) showed 3 spots and NMR determined that the top spot (Rf 0.77) was that of <strong>[42908-86-1]2-chloromethylbenzoyl chloride</strong>, the second spot (Rf 0.57) was phthalide and the bottom spot (Rf 0.14) was triphenylphosphorous. A large amount of the phthalide was unreacted.2- chloromethylbenzoyl chloride (Figure 12) (m.w. 189.04 g/mol, 600mul) was dissolved in dichloromethane (10 ml). Triethylamine (m.w. 101.19 g/mol, d=0.726 g/ml, 600mul = 4.3 mmol) was added and the mixture was cooled to 00C. Compound 17 (m.w. 308.14 g/mol, 0.5298g = 1.7 mmol) was added and the mixture was stirred at room temperature overnight while protected from light. The mixture (green colour) was washed with HCI (2M, 10 ml), 5% NaHCO3 (10 ml) and distilled water (10 ml) and dried over sodium sulfate. Mixture was concentrated producing 769.5 mg of a brown/green oil. This was chromatographed using hexane/ethyl acetate (2:1) resulting in 419.4 mg of a brown solid (Rf 0.38). 1H NMR delta fCDChi 400MHz: 2.38 (3H, s, OCOCH3), 4.03 (4H, m, ISH-I, ISH-I', ISH-6 and ISH-6'), 4.66 (IH, d, ISH-3), 5.04 (2H, m, CH2CI), 5.10 (IH, ss, ISH-4), 5.42 (2H, m, ISH-2/H-5), 7.12 (IH, d, Ar-H), 7.28 (IH, m, Ar-H), 7.42 (IH, m, Ar-H), 7.6 (3H, m, Ar-H), 8.01 (2H, dd, Ar-H). 13C NMR ppm fCDChi 400MHz: 20.51 (OCOCH3), 43.95 (CH2CI), 70.15 (ISC-I), 72.78 (ISC-6), 74.33 (ISC-5), 78.11 (ISC-2), 80.52 (ISC-4), 85.58 (ISC-3), 122.21 (Ar2 C-2/C-6), 123.42, 125.65 (Ar2 C-4), 128.03 (Ar.C-6),128.07 (Ar1C^), 130.60 (Ar1C-S), 130.73 (ArIC-I), 131.43 (Ar1 C-4), 133.45 (Ar2 C-5), 133.92, 138.54, 150.25 (Ar2OCO), 163.12 (OCOArCH2ONO2), 165.47 (ArOCOCH3), 169.29 (ArC(O)OR). 400 mg was dissolved in CH3CN/THF (6 ml, 4/2 v/v) and treated with AgNO3 (m.w. 169.87 g/mol, 0.30 g = 1.7 mmol) and refluxed for 4 hours before stirring overnight at room temperature while protected from light. Mixture was filtered and concentrated. This was reconstituted in ethyl acetate (10 ml) and water (2 ml). The organic phase was washed with water (3 x 2 ml), brine (2 ml) and dried over sodium sulfate. Concentrated, producing an oil which was chromatographed using hexane/ethyl acetate (2:1) resulting in 95 mg of yellow wax-like material.^ NMR delta fCDChi 400MHz: 2.38 (3H, s, OCOCH3), 4.01 (4H, m, ISH-I, ISH-I', ISH-6 and ISH-6'), 4.65 (IH, d, ISH-3), 5.02 (IH, t, ISH-4), 5.41 (2H, m, CH2), 5.86 (2H, ss, ISH-2/H-5), 7.11 (IH, d, Ar-H), 7.28 (IH, t, Ar-H), 7.49 (2H, q, Ar-H), 7.61 (2H, q, Ar-H), 8.01 (IH, d, Ar-H), 8.10 (IH, d, Ar- H). 13C NMR ppm fCDChi 400MHz: 20.51 (OCOCH3), 70.37 (CH2ONO2), 72.78 (ISC-I), 73.46 (ISC-6), 74.30 (ISC-5), 78.01 (ISC-2), 80.61 (ISC-4), 85.64 (ISC-3), 122.19 (Ar2 C-2/C-6), 123.40, 125.66 (Ar2 C-4), 128.76 (Ar.C-6),129.77 (Ar1C^), 129.85 (Ar1C-S), 130.30 (ArIC-I), 131.41 (Ar1 C-4), 132.44 (Ar2 C-5), 133.25, 133.93, 150.23 (Ar2OCO), 163.12 (OCOArCH2ONO2), 164.71 (ArOCOCH3), 169.28 (ArC(O)OR). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12%; 61% | With triethylamine; In dichloromethane; at 0℃; for 1h; | Intermediate 1-1Preparation of 2-(3-bromo-2-methylphenyl)isoindolin-1-one A solution of 3-bromo-2-methylaniline (10 g, 53.7 mmol) in DCM (200 mL) at 0 C. was treated with TEA (14.98 mL, 107 mmol), followed by dropwise addition of 2-(chloromethyl)benzoyl chloride (10.16 g, 53.7 mmol) in DCM (50 mL) over 1 h. The mixture was diluted with DCM (ca. 1 L), washed with NaHCO3 (aq) and water, and concentrated to remove most of the solvent. The precipitate was collected by filtration and washed with DCM (2×10 mL) to provide N-(3-bromo-2-methylphenyl)-2-(chloromethyl)benzamide as a white solid (8.0 g). The filtrate was concentrated further, resulting in additional precipitate which was collected by filtration and washed with DCM (2×10 mL) to provide additional N-(3-bromo-2-methylphenyl)-2-(chloromethyl)benzamide as a white solid (3.06 g), for a combined yield of 61%. Mass spectrum 338, 340, 342 The filtrate was concentrated and purified by column chromatography (hexane-EtOAc) to provide 2-(3-bromo-2-methylphenyl)isoindolin-1-one as a yellow solid (2.0 g, 12%). A solution of the N-(3-bromo-2-methylphenyl)-2-(chloromethyl)benzamide (11.06 g, 32.7 mmol) in DMF (50 mL) was cooled to 0 C. and treated with a mixture of sodium hydride (60% oil dispersion, pre-washed with hexane, 1.70 g, 42.5 mmol) and DMF (10 mL). The mixture was stirred at 0 C. for 1.5 h, then was treated with water. The precipitate was collected by filtration, dried and combined with the material purified by column chromatography (see above) to provide 2-(3-bromo-2-methylphenyl)isoindolin-1-one as a yellow solid (9.41 g, 95%). 1H NMR (400 MHz, chloroform-d) delta 7.96 (1H, d, J=7.5 Hz), 7.58-7.67 (2H, m), 7.49-7.57 (2H, m), 7.20-7.25 (1H, m), 7.15 (1H, t, J=7.9 Hz), 4.72 (2H, s), 2.31 (3H, s). Mass spectrum m/z 302, 304 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In chloroform; at 0 - 5℃; for 0.5h; | General procedure: A solution of the corresponding amine17a-c (30 mmol) in CHCl3 (20 mL) was added dropwise at 0-5 C to a stirred solution of 2-(chloromethyl)benzoyl chloride16 (2.84 g, 15 mmol) in CHCl3 (20 mL). The reaction mixture was stirred at this temperature for 30 min, warmed to room temperature, and poured into H2O (60 mL). The organic layer was separated, washed with H2O (2×30 mL), and dried overMgSO4. The solvent was evaporated in vacuo. Compounds 18a,c were purifi ed by chromatography on silica gel using CHCl3-hexane mixture (3 : 1) and CHCl3 as the eluents, while compound18b was crystallized from MeOH. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In dichloromethane; | [00528] A solution of crude 2-(chloromethyl)benzoyl chloride (prepared by heating a neat mixture of isobenzofuran-l(3H)-one (14.5 equiv) and PPh3C12 (15.1 equiv) at 180 C for 4 h) in dichloromethane was added portion- wise to a suspension of Compound 1-107 in dichloromethane and pyridine (2:1) until one-half of the crude material was added and the solution became homogeneous. The solution was partitioned between saturated aqueous ammonium chloride and dichloromethane. The layers were separated and the aqueous layer was extracted with dicliloromethane. The organics were dried over magnesium sulfate, filtered, the solvent was removed in vacuo, and purification by silica gel chromatography (0- 10% methanol in dicliloromethane) provided intermediate X-259 as a yellow film (12%). The benzyl chloride intermediate was stirred with l,8-diazabicyclo[5.4.0]undec-7-ene (28 equiv) in dicliloromethane for 1.5 h. The solution was partitioned between saturated aqueous ammonium chloride and dichloromethane. The layers were separated and the aqueous layer was extracted with dichloromethane. The organics were dried over magnesium sulfate, filtered, the solvent was removed in vacuo, and purification by silica gel chromatography (ethyl acetate in hexanes) provided the desired product as a white solid (52%).LRMS Calcd for C25H19FN702 [M+H]+ 468.16, observed 468.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetra-(n-butyl)ammonium iodide; triethylamine; In tetrahydrofuran; N,N-dimethyl-formamide; | A) tert-butyl (cyclopropylmethyl){trans-2-[4-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]cyclopropyl}carbamate To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (126.8 mg) and triethylamine (70.1 muL) in THF (2.1 mL) was added 2-(chloromethyl)benzoyl chloride (95 mg). The mixture was stirred at room temperature overnight, and saturated aqueous ammonium chloride solution was added. The mixture was extracted with ethyl acetate, and the extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a mixture (260.5 mg) containing the title compound and tert-butyl [trans-2-(4-[2-(chloromethyl)benzoyl]amino}phenyl)cyclopropyl]-(cyclopropylmethyl)carbamate. To a solution of this mixture and tetrabutylammonium iodide (15.51 mg) in DMF (4.2 mL) was added sodium hydride (20.16 mg). The mixture was stirred at room temperature for 2 hr and poured into water. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (123.7 mg). 1H NMR (300 MHz, DMSO-d6) delta 0.07-0.17 (1H, m), 0.18-0.28 (1H, m), 0.33-0.53 (2H, m), 0.90-1.08 (1H, m), 1.14-1.27 (2H, m), 1.37 (9H, s), 2.07 (1H, ddd, J = 9.4, 6.5, 3.2 Hz), 2.65-2.78 (1H, m), 3.00 (1H, dd, J = 14.4, 6.8 Hz), 3.20 (1H, dd, J = 14.4, 6.8 Hz), 5.49 (2H, s), 7.09 (2H, d, J = 8.5 Hz), 7.17 (2H, d, J = 8.5 Hz), 7.50-7.73 (4H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44 mg | General procedure: Synthesized using Method C detailedabove and purified by preparative HPLC (tr = 12.9 min, pgr. F).Data for crude 3: Yellowish foam (44 mg, 47%, 60% purity (tr= 7.89 min, prg. A)). Data for purified 3: Colorless foamisolated as the corresponding TFA-salt (11 mg, 10%, 97%purity (tr = 3.68 min, prg. C)). 1H NMR (300 MHz,CDCl3/epsilonMeOD): = 8.02-7.74 and 7.66-6.96 (2×m, 17H), 4.80-2.60 (m, 20H, CF3COOH, COOH and18H), 1.56-1.36 (m, 18H) ppm. 13C NMR (75 MHz, CDCl3/epsilonMeOD): = 174.2, 172.4, 172.0, 171.5,171.0, 168.1, 167.9 (4Cq), 144.2, 144.1, 138.7, 137.9, 137.6, 131.9, 131.4, 131.3, 129.4 (7Cq), 130.2,130.1, 129.9, 129.3, 129.1, 128.7, 128.5, 128.4, 128.3, 128.2, 128.1, 127.3, 127.2, 127.0, 125.7, 125.6,125.5, 125.2 (17CH), 63.7, 63.5 (2CH2), 58.8, 58.6, 58.5 (2Cq), 53.7, 51.9, 51.1, 51.0, 50.8, 38.7S7(7CH2), 28.6 (6CH3, 2×CONtBu) ppm. LC-MS: 746.9 (100, [M+H]+). HRMS (TOF MS ES+) calcdfor C45H55N4O6 [M+H]+ m/z 747.4116, found 747.4113. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In water; acetonitrile; | Synthesis Example 1 Synthesis of Chloromethylbenzoylglycine Represented by the Following Formula Glycine (3 g) was dissolved in a mixture of water (20 g), acetonitrile (10 g), and sodium hydroxide (2 g), and the solution was cooled to 10 C., to thereby prepare a glycine solution. Separately, chloromethylbenzoyl chloride (8 g) was dissolved in acetonitrile (20 g), and the solution was cooled to 10 C. The liquid was added dropwise to the glycine solution over 2 hours. Simultaneously a solution of sodium hydroxide (2 g) in water (20 g) was added dropwise to the glycine solution over 2 hours. Five hours later, the solution was acidified with 5 weight % aqueous hydrochloric acid, to thereby precipitate chloromethylbenzoylglycine as a target product. The precipitated product was separated through filtration and dried, to thereby yield 7 g of chloromethylbenzoylglycine as a target product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With triethylamine; In dichloromethane; at 20℃; for 2h; | Compound 9 was dissolved in dichloromethane, chloromethyl benzoyl chloride, and a small amount of triethylamine were added, stirred at room temperature for 2 hours. After completion of the reaction, water was added, extracted with dichloromethane, and the organic layers were combined, spin-dried and purified by column chromatography to obtain yellow solid. Yield 75%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane;Cooling with ice; | General procedure: In a 50 mL flask add thioether diethylamine or other appropriate diamine compound,Dichloromethane and TEA were added, and 2-(chloromethyl)benzoyl chloride dissolved in dichloromethane or other benzene ring-substituted 2-(chloromethyl)benzoyl chloride was added while stirring on ice. After the addition was complete, the ice bath was removed and stirred overnight. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | In chloroform; at 0 - 25℃; for 0.5h; | To a stirred solution of 2-(chloromethyl)benzoyl chloride 13 (2.84 g, 15 mmol) in CHCl3 (20 mL), a solution of morpholine (2.78 g, 32 mmol) in CHCl3 (20 mL) was added dropwise at 0-5 C. The reaction mixture was stirred at this temperature for 30 min and after warming up to room temperature was poured into water (60 mL). The organic layer was separated, washed with water (2.30 mL), dried with MgSO4, and the solvent was removed in vacuo. Purification of the residue by silica gel column chromatography afforded 2.95 g (82%) of compound 12, viscous oil. Found (%): C, 60.32; H, 5.97; N, 5.73; Cl, 14.71. C12H14ClNO2. Calculated (%): C, 60.13; H, 5.89; N, 5.84; Cl, 14.79. IR, nu/cm-1: 3479, 3255, 3060, 2967, 2920, 2856, 1633 (C=O), 1456, 1279, 1259, 1114, 1019, 846, 775, 741, 680. 1H NMR, delta: 3.16 (t, 2 H, CH2N, J = 4.4 Hz); 3.53 (t, 2 H, CH2N, J = 4.4 Hz); 3.66 (t, 4 H, CH2OCH2, J = 4.4 Hz); 4.66-4.86 (m, 2 H, CH2Cl); 7.32 (t, 1 H, H(5)Bza, J = 6.6 Hz); 7.34-7.42 (m, 2 H, H(3,4)Bza); 7.47 (d, 1 H, H(6)Bza, J = 6.6 Hz). |
82% | In chloroform; at 0 - 5℃; for 0.5h; | General procedure: A solution of the corresponding amine17a-c (30 mmol) in CHCl3 (20 mL) was added dropwise at 0-5 C to a stirred solution of 2-(chloromethyl)benzoyl chloride16 (2.84 g, 15 mmol) in CHCl3 (20 mL). The reaction mixture was stirred at this temperature for 30 min, warmed to room temperature, and poured into H2O (60 mL). The organic layer was separated, washed with H2O (2×30 mL), and dried overMgSO4. The solvent was evaporated in vacuo. Compounds 18a,c were purifi ed by chromatography on silica gel using CHCl3-hexane mixture (3 : 1) and CHCl3 as the eluents, while compound18b was crystallized from MeOH. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In chloroform; at 0 - 5℃; for 0.5h; | General procedure: A solution of the corresponding amine17a-c (30 mmol) in CHCl3 (20 mL) was added dropwise at 0-5 C to a stirred solution of 2-(chloromethyl)benzoyl chloride16 (2.84 g, 15 mmol) in CHCl3 (20 mL). The reaction mixture was stirred at this temperature for 30 min, warmed to room temperature, and poured into H2O (60 mL). The organic layer was separated, washed with H2O (2×30 mL), and dried overMgSO4. The solvent was evaporated in vacuo. Compounds 18a,c were purifi ed by chromatography on silica gel using CHCl3-hexane mixture (3 : 1) and CHCl3 as the eluents, while compound18b was crystallized from MeOH. 2-Chloromethyl-N,N-diethylbenzamide (18a). The yield was2.7 g (80%), oil. Found (%): C, 63.64; H, 7.01; N, 6.28; Cl, 15.53.C12H16ClNO. Calculated (%): C, 63.85; H, 7.14; N, 6.21;Cl, 15.71. IR, nu/cm-1: 2973, 2935, 2875, 1631 (C=O), 1459, 1431,1290, 1082, 771, 679. 1H NMR (DMSO-d6), delta: 1.04 (t, 3 H,CH3CH2N, J = 7.0 Hz); 1.18 (t, 3 H, CH3CH2N, J = 7.0 Hz);3.08 (q, 2 H, CH3CH2N, J = 6.6 Hz); 3.51 (q, 2 H, CH3CH2N,J = 6.6 Hz); 4.71 (s, 2 H, CH2Cl); 7.31 (t, 1 H, HBza(5),J = 8.1 Hz)*; 7.40-7.48 (m, 2 H, HBza(3), HBza(4)); 7.58 (d, 1 H,HBza(6), J = 8.1 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole (500 mg, 0.80 mmol) in THF (8 mL) at -78 C. was added a 0.5 M solution of KHMDS in THF (2.6 mL, 1.3 mmol). After stirring at -78 C. for 30 min, 2-(chloromethyl)benzoyl chloride (0.28 mL, 1.9 mmol) was added to the mixture. After stirring at room temperature for 16 h, the reaction was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution. The aqueous and organic layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried with sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to yield (4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indol-1-yl)(2-(chloromethyl)phenyl)methanone. MS: (ES) m/z calculated for C42H36ClF7N40 [M+H]+ 781.3, found 781.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-1H-indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine (500 mg, 0.9 mmol) in THF (8.8 mL) at -78 C. was added a 1 M solution of LHMDS in THF (0.98 mL, 0.98 mmol). After stirring at -78 C. for 30 min, 2-(chloromethyl)benzoyl chloride (0.25 mL, 1.78 mmol) was added to the mixture. After stirring at room temperature for 16 h, the reaction was quenched with H2O. The aqueous and organic layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried with sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to yield (2-(chloromethyl)phenyl)(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indol-1-yl)methanone. MS: (ES) m/z calculated for C38H33ClF4N6O2 [M+H]+717.2, found 717.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.71 g | In acetonitrile; at 20℃; for 5h; | Under ice bath, weigh 3- (2, 2, 2-trifluoroethylthio) -4-methyl-6-fluoroaniline (Intermediate III-1, refer to WO2010100189, US2012053052, JP2012519662, EP2403837 or CN102341376, etc. Prepared by the reported method) 3.20 g (13.39 mmol) was placed in a 100 ml three-necked flask, 30 ml of acetonitrile was added, and stirring was started; to this solution, 2- (chloromethyl) benzoyl chloride (intermediate IV-1, It can be prepared according to the methods reported in WO2008023810, CN101139308, WO2001042185, WO2001042182, WO2001042183, WO9916743, etc.) 2.76g (14.68mmol) of 20ml acetonitrile solution; after the dropwise addition, warm to room temperature and continue the reaction for 5 hours; after the reaction is monitored by TLC The solvent was removed under reduced pressure, and the residue was subjected to column chromatography (eluent: ethyl acetate and petroleum ether, with a volume ratio of 1:30) to obtain 4.71 g of a white solid, that is, intermediate compound II.1. |
Tags: 42908-86-1 synthesis path| 42908-86-1 SDS| 42908-86-1 COA| 42908-86-1 purity| 42908-86-1 application| 42908-86-1 NMR| 42908-86-1 COA| 42908-86-1 structure
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P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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