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CAS No. : | 74974-54-2 | MDL No. : | MFCD00216629 |
Formula : | C5H11ClO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NPEIUNVTLXEOLT-UHFFFAOYSA-N |
M.W : | 154.59 | Pubchem ID : | 144702 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 34.24 |
TPSA : | 27.69 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.92 cm/s |
Log Po/w (iLOGP) : | 2.1 |
Log Po/w (XLOGP3) : | 0.45 |
Log Po/w (WLOGP) : | 0.82 |
Log Po/w (MLOGP) : | 0.54 |
Log Po/w (SILICOS-IT) : | 0.64 |
Consensus Log Po/w : | 0.91 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.82 |
Solubility : | 23.5 mg/ml ; 0.152 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.6 |
Solubility : | 38.9 mg/ml ; 0.251 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.32 |
Solubility : | 7.45 mg/ml ; 0.0482 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.56 |
Signal Word: | Danger | Class: | 3 |
Precautionary Statements: | P210-P403+P235 | UN#: | 1993 |
Hazard Statements: | H225 | Packing Group: | Ⅲ |
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 |
---|---|---|
62% | at 20℃; | 4.0 g Semicarbazide hydrochloride, 9.67 mL 2-chloro-1,1,1-trimethoxyethane and 40 mL methanol were combined and stirred at ambient temperature for 3 d. After this time additional 3.5 mL 2-chloro-1,1,1-trimethoxyethane was added to complete the reaction. The mixture was then concentrated under reduced pressure and the crude product was partitioned between ethyl acetate and 1N hydrochloric acid. The organic phase separated and it was washed with additional 1N hydrochloric acid (.x.2). The combined aqueous extracts were extracted with ethyl acetate (.x.5) and all of the organic fraction were then combined, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The solid that remained was triturated with ethyl acetate to give the title compound which was used without further purification.Yield: 2.97g (62percent of theory)Analysis: 1H NMR (500 MHz, dimethyl sulfoxide-d6) in ppm 4.49 (2H, s), 11.55 (1H, br. s.), 11.70 (1H, br. s.) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With sodium methylate; chlorine at 15℃; for 4h; | 1 Beispiel 1 In einen 500 ml Kolben mit Rührer und Gaseinleitungsrohr wurde bei 10 °C eine Mischung von 240 g (2 mol) 1,1,1-Trimethoxyethan und 1 % NaOCH3 (30 %ig) vorgelegt. Innerhalb von 4 Stunden wurden 110 g Chlor gasförmig eingeleitet, wobei die Innentemperatur nicht über 15 °C steigt. Nachdem die gesamte Chlormenge eingeleitet worden war, wurde die Mischung destillativ aufgearbeitet. Über eine Destillationsapparatur mit ca. 5 theoretischen Trennstufen wurden im Vorlauf Leichtsieder wie Methanol und Methylacetat bei einem Rücklaufverhältnis von 5 : 1 abgetrennt. Im Hauptlauf wurden bei einem Rücklaufverhältnis von 2 : 1 234 g 2-Chloro-1,1,1-trimethoxyethan mit einem Gehalt > 99,0 % erhalten. Dies entspricht einer Ausbeute von ca. 76 %. |
69% | With methanol; chlorine at 15℃; for 4h; | 2 Beispiel 2 In einen 1000 ml Kolben mit Rührer und Gaseinleitungsrohr wurde bei 10 °C eine Mischung von 480 g (4 mol) 1,1,1-Trimethoxyethan und 48 g (10 Gew %) Methanol vorgelegt. Innerhalb von 4 Stunden wurden 220 g (3,14 mol) Chlor gasförmig eingeleitet, wobei die Innentemperatur nicht über 15 °C steigt. Nach dem die gesamte Chlormenge eingeleitet worden ist, wurde die Mischung destillativ aufgearbeitet. Über eine Destillationsapparatur mit ca. 5 theoretischen Trennstufen wurden im Vorlauf Leichtsieder wie Methanol und Methylacetat bei einem Rücklaufverhältnis von 5 : 1 abgetrennt. Im Hauptlauf wurden bei einem Rücklaufverhältnis von 2 : 1 425 g 2-Chloro-1,1,1-trimethoxyethan mit einem Gehalt > 99,0 % erhalten. Dies entspricht einer Ausbeute von ca. 69 %. |
67% | With chlorine at 15℃; for 4h; | 3 Beispiel 3 In einen 1000 ml Kolben mit Rührer und Gaseinleitungsrohr wurden bei 10 °C 480 g (4 mol) 1,1,1-Trimethoxyethan vorgelegt. Innerhalb von 4 Stunden wurden 220 g (3,14 mol) Chlor gasförmig eingeleitet, wobei die Innentemperatur nicht über 15 °C stieg. Nachdem die gesamte Chlormenge eingeleitet worden war, wurde die Mischung destillativ aufgearbeitet. Über eine Destillationsapparatur mit ca. 5 theoretischen Trennstufen wurden im Vorlauf Leichtsieder wie Methanol und Methylacetat bei einem Rücklaufverhältnis von 5 : 1 abgetrennt. Im Hauptlauf wurden bei einem Rücklaufverhältnis von 2 : 1 413 g 2-Chloro-1,1,1-trimethoxyethan mit einem Gehalt > 99,0 % erhalten. Dies entspricht einer Ausbeute von ca. 67 %. |
57% | With tert-butylhypochlorite In tetrachloromethane at 50 - 60℃; for 0.25h; | |
32% | With hydrogenchloride; N-chloro-succinimide In methanol at 70 - 80℃; for 3.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With toluene-4-sulfonic acid In ethanol at 65℃; for 22h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | In methanol; at 20℃; | 4.0 g Semicarbazide hydrochloride, 9.67 mL 2-chloro-1,1,1-trimethoxyethane and 40 mL methanol were combined and stirred at ambient temperature for 3 d. After this time additional 3.5 mL 2-chloro-1,1,1-trimethoxyethane was added to complete the reaction. The mixture was then concentrated under reduced pressure and the crude product was partitioned between ethyl acetate and 1N hydrochloric acid. The organic phase separated and it was washed with additional 1N hydrochloric acid (.x.2). The combined aqueous extracts were extracted with ethyl acetate (.x.5) and all of the organic fraction were then combined, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The solid that remained was triturated with ethyl acetate to give the title compound which was used without further purification.Yield: 2.97g (62percent of theory)Analysis: 1H NMR (500 MHz, dimethyl sulfoxide-d6) in ppm 4.49 (2H, s), 11.55 (1H, br. s.), 11.70 (1H, br. s.) |
In methanol; at 20℃; for 72h; | Step 14.0 g Semicarbazide hydrochloride, 9.67 mL 2-chloro-1 ,1 ,1 -trimethoxyethane and 40 mL methanol were combined and stirred at ambient temperature for 3 d. After this time additional 3.5 mL 2-chloro-1 ,1 ,1 -trimethoxyethane was added to complete the reaction. The mixture was then concentrated under reduced pressure and the crude product was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic phase separated and it was washed with additional 1 N hydrochloric acid (x2). The combined aqueous extracts were extracted with ethyl acetate (x5) and all of the organic fraction were then combined, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The solid that remained was triturated with ethyl acetate to give the title compound which was used without further purification.Yield: 2.97g (62percent of theory)Analysis: 1H NMR (500 MHz, dimethyl sulfoxide-d6) in ppm 4.49 (2 H, s), 1 1.55 (1 H, br. s.), 1 1.70 (1 H, br. s.) | |
In methanol; at 20℃; for 144h; | A mixture of semicarbazide hydrochloride (5 g, 44.8 mmol) and 2-chloro- 1, 1, 1- trimethoxyethane (13.29 ml, 99 mmol) in methanol (50 ml) was stirred at room temperature for 3 days at which time the reaction became a homogenous solution. Additional 2-chloro- 1, 1,1- trimethoxyethane (4.3 ml, 32.3 mmol) was added and the reaction was stirred for 3 days longer. The reaction mixture was concentrated and the residue was partitioned in ethyl acetate (500 mL) and IN aqueous HC1 (75 mL). The organic layer was washed with additional IN aqueous HC1 (2 x 75 mL). The combined aqueous layers were back-extracted with additional ethyl acetate (5 x 100 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound. MS (DCI+) m/z 150.9 (M+NH4)+. |
In methanol; at 20℃; for 3h; | Example 325-chloromethyl-2,4-dihydro-l ,2,4-triazol~3-one (74); [0718] Semicarbazide.HCl (5 g, 89 mmol), 2-chloro-l,l,l-trimethoxyethane (12.07 mL, 179 mmol) and methanol (50 mL) were combined and stirred at room temperature for 3 days, with the reaction monitored by 1H NMR. Additional 2-chloro- 1,1,1 -trimethoxyethane (8.77 mL) was added to complete the reaction. Methanol was then removed under vacuum. The resulting residue was extracted with ethyl acetate (500 mL) and washed with IN HCl (2 x 100 mL). The aqueous phase was back extracted with ethyl acetate (5 X 100 mL). The organic layers were then combined, dried over anhydrous sodium sulfate, and solvent was removed under reduced pressure to give 3.1 g of 5-chloromethyl-2,4-dihydro-l,2,4-triazol-3- one (74) as a white powder. 1H NMR (DMSO-d6): delta 11.65 (s, 1H), 11.50 (s, 1H), 4.48 (s, 2H); LCMS (m/z): 133.90 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With propionic acid In xylene at 145℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | at 60℃; for 2h; | 4-Chloro-2-amino-benzothiol (4.05 g, 25.4 mmol, 1 equiv.) and 2-chloro-1 ,1 ,1- trimethoxy ethane (5.0 ml, 37 mmol, 1.45 equiv.) were heated with stirring at 60C for 2 h. The reaction mixture was cooled at r.t. and triturated with diethyl ether (10 ml). The undissolved solid was filtered and rinsed with Et2O and pentane, to give 1.54 g (28% yield) of the desired product. The mother liquors were evaporated to dryness, the orange solid residue was dissolved in Et2O (50 ml) and washed consecutively <n="90"/>with 1 N HCI (25 ml), water (25 ml), 5% NaHCO3 solution (25 ml) and brine (25 ml). The organic layer was dried (MgSO4) and evaporated to smaller volume, under reduced pressure. The precipitant solid was filtered and washed with Et2O and pentane, to give a second fraction of the desired product 1.88 g (34% yield). Total yield 62%, mp 102-1040C, HPLC-MS (method 1): m/z 260 [M+H+CH3CN]+, Rt = 4.52 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With acetic acid at 160℃; for 0.5h; Microwave; | 1.C C. Preparation of a Compound of Formula (4a) in which R is 4-Fluorophenyl 4-Fluorobenzenecarbohydrazide (0.3 g, 2mmol) was suspended in chloro-1,1,1-trimethoxyethane (2 ml). To the suspension was added acetic acid (1 ml), and the solution was heated in a microwave for 30minutes at 160° C. The solvent was removed under reduced pressure, and the residue purified using Biotage, eluding with 20% ethyl acetate/hexanes, to provide 5-(chloromethyl)-3-(4-fluorophenyl)-1,2,4-oxadiazole in 89% yield. |
89% | With acetic acid at 160℃; for 0.5h; Microwave irradiation; | 1.C C. Preparation of a Compound of Formula (4a) in which R is 4-Fluorophenyl[0157] 4-Fluorobenzenecarbohydrazide (0.3 g, 2mmol) was suspended in chloro- 1,1,1 - trimethoxyethane (2 ml). To the suspension was added acetic acid (1 ml), and the solution was heated in a microwave for 30inutes at 1600C. The solvent was removed under reduced pressure, and the residue purified using Biotage, eluting with 20% ethyl acetate/hexanes, to provide 5-(chloromethyl)-3-(4-fluorophenyl)-l,2,4-oxadiazole in 89% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | In methanol at 150℃; for 1h; Microwave irradiation; | D 8-(Chloromethyl)-9-((R)-chroman-4-yl)-2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-9H-purine. The titled compound was obtained in low yield (15%) from the microwave reaction (60 min at 150° C.) of N4-((R)-chroman-4-yl)-2-(6-fluoro-1H-benzo[d]imidazol-1-yl)pyrimidine-4,5-diamine (36 mg), 2-chloro-1,1,1-trimethoxyethane (1 mL), a catalytic amount of para-toluene sulfonic acid monohydrate and MeOH (1 mL). The resulting reaction mixture was concentrated in vacuo, and purified via RP-HPLC. 1H-NMR (300 MHz, CDCl3) δ 9.2 (br s, 1H), 9.1 (s, 1H), 8.0 (br s, 1H), 7.8 (m, 2H), 7.2-7.1 (m, 3H), 6.8 (m, 2H), 6.1 (dd, 1H), 4.9 (q, 2H), 4.6 (m, 1H), 4.4 (td, 1H), 3.1 (m, 1H), 2.5 (s, 1H) ppm; 19F δ-76, -115 ppm; MH+=435/437. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: N-(3-chlorophenyl)-6-hydrazinylpyridazin-3-amine With hydrogenchloride In diethyl ether for 0.166667h; Stage #2: 2-chloro-1,1,1-trimethoxyethane In N,N-dimethyl-formamide for 4h; | 3.i (Step 3-i) N-(3-chlorophenyl)-6-hydrazinylpyridazin-3 -amine (4.0 g, 17 mmol)) was taken up in HClZEt2O (20 mL) and stirred for 10 min. The reaction mixture was concentrated, taken up in DMF (20 mL), and 2-chloro-l,l,l-trimethoxyethane (5.2 g, 34 mmol) was added. After stirring for 3 hours, a precipitate began to form. After one hour additional stirring, the reaction mixture was filtered to give the product, 3- (chloromethyl)-N-(3-chlorophenyl)-[l,2,4]triazolo[4,3-£]pyridazin-6-amine, as a white solid. (4 g, 13.6 mmol, 80% yield): 1H-NMR (500 MHz, DMSO-d6) 10.40 (s, IH), 8.19 (d, J = 9.8 Hz, IH), 8.13 (t, J = 1.8 Hz, IH), 7.68 (dd, J = 1.7, 8.2 Hz, IH), 7.40 (t, J = 8.1 Hz, IH), 7.28 (d, J = 9.9 Hz, IH), 7.1 1 - 7.09 (m, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-amino-3-hydroxypyridine; 2-chloro-1,1,1-trimethoxyethane In diethylene glycol dimethyl ether at 80℃; for 6h; Stage #2: With toluene-4-sulfonic acid In diethylene glycol dimethyl ether at 80℃; for 48h; | 36A 2-Amino-3-pyridinol (1.1 g, Chemical Abstracts #16867-03-1) and chloromethyltrimethylorthoformate (2.27 g) were combined in diglyme (in 21 mL) and heated at 80° C. for 6 hours. The mixture was treated with p-toluenesulfonic acid hydrate (4 mg) and heated at 80° C. for an additional 48 hours. The mixture was allowed to cool to room temperature and diluted with chloroform (40 mL) and ethanol (10 mL). The mixture was filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in methanol and filtered again. The resulting filtrate was concentrated under reduced pressure to provide the title compound and then dissolved in acetonitrile (35 mL) and used as a solution in the next step. 1H NMR (CDCl3, 300 MHz) δ 4.82 (2H, s), 7.38 (dd, 1H, J=8.7, 5.4 Hz), 7.89 (dd, 1H, J=8.7, 1.5 Hz), 8.62 (dd, 1H, J=5.4, 1.5 Hz). MS (DCI/NH3) m/z 169 (M+H)+. | |
With toluene-4-sulfonic acid In diethylene glycol dimethyl ether at 80℃; for 48h; | 36.36A Example 36 2-f [4-(2-methoxyphenyl)-1-piperazinyl]methyl}[1,3]oxazolo[4,5-b]pyridine Example 36A 2-(chloromethyl)[1,3]oxazolo[4,5-b]pyridine 2-Amino-3-pyridinol (1.1 g, Chemical Abstracts No.16867-03-1) and chloromethyltrimethylorthoformate (2.27 g) were combined in diglyme (in 21 mL) and heated at [80 °C] for 6 hours. The mixture was treated with [P-TOLUENESULFONIC] acid hydrate (4 mg) and heated at [80 °C] for an additional 48 hours. The mixture was allowed to cool to room temperature and diluted with chloroform (40 [ML)] and ethanol (10 mL). The mixture was filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in methanol and filtered again. The resulting filtrate was concentrated under reduced pressure to provide the title compound and then dissolved in acetonitrile (35 mL) and used as a solution in the next [STEP. 1H] NMR [(CDC13,] 300 MHz) [8] 4.82 (2H, s), 7. 38 (dd, 1H, J=8.7, 5.4Hz), 7.89 (dd, 1H, J=8.7, [1.] [5HZ),] 8.62 (dd, [1H,] J=5.4, [1.] [5HZ).] MS [(DCI/NH3)] m/z 169 (M+H) +. | |
With acetic acid In toluene for 3h; Reflux; | 15.a Example 15: (R)-l-Oxazolo[4,5-b]pyridin-2-ylmethyl-3-(l-phenyl- cycloheptanecarbonyloxy)-l-azonia-bicyclo[2.2.2]octane chloridea) 2-Chloromethyl-oxazolo[4,5-]pyridine 2-Amino-pyridin-3-ol (1 g) in a mixture of toluene (10 mL) and acetic acid (10 mL) was treated with 2-chloro-l,l,l-trimethoxy-ethane (1.685 g) and the mixture stirred and heated under reflux for 3 h. The solvent was removed under reduced pressure and the residue purified on silica gel using diethyl ether / z'søhexane (1 : 1). The sub-titled compound was isolated as an off-white solid (1.12 g).1H NMR (399.826 MHz, CDCl3) δ 8.63 (dd, IH), 7.88 (dd, IH), 7.37 (dt, IH), 4.81 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
for 0.5h;Heating / reflux; | Reflux a solution of <strong>[112253-70-0]2-amino-4-bromobenzamide</strong> (27 g, 0.13 mol; see Joshi and Chaudhari (1987) Indian J. CHEM., Sect. B, 26B (6) : 602-4) in 2-CHLORO-1, 1, 1-TRIMETHOXYETHANE (50 mL) for 30 minutes, during which time a large precipitate appears. Evaporate the mixture fully and triturate with ether to collect 7-BROMO-2-CHLOROMETHYL-3H-QUINAZOLIN-4-ONE as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 135℃; for 5h; | Heat a solution of <strong>[713-41-7]2-amino-4-trifluoromethyl-benzamide</strong> (800 mg, 3.9 mmol) in 2- chloro-l, 1, 1-trimethoxyethane (5 mL) at 135C for 5 hours. Concentrate the mixture under reduced pressure, dilute with 50 mL of ether, and collect the precipitate to give 2- chloromethyl-7-trifluoromethyl-quinazolin-4-one. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | at 120℃; for 1h; | 57 5-Chloro-2-fluoro-benzoic acid hydrazide (188 mg, 1.0 mmol) and 2-chloro-1, [1,] [1-] trimethoxy-ethane (1.0 mL) were heated in a sealed vial at [120°C] for 1 hour. The reaction mixture was place directly onto a flash column (silica gel) and purified using 0-7% ethyl acetate in hexanes to afford [2- (5-CHLORO-2-FLUORO-PHENYL)-5-CHLOROMETHYL- [1,] 3,4] oxadiazole [(180 MG, 73%). IHNMR (CDC13) 6 (PPM)] : 8.09 (m, 1H), 7.55 (1H), 7.26 (m, [1H),] 4.82 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In ethanol at 80℃; for 3h; | |
86% | In ethanol at 80℃; for 3h; | VIII.1.a A reaction mixture of 12.0 g (77.9 mmol) of 2-amino-4-nitrophenol and 10.5 mL (77.9 mmol) of 2-chloro-1.1.1-trimethoxyethane in 110 mL of ethanol is stirred for 3 hours at 80° C. After this time, the mixture is poured onto water and the precipitate formed is filtered off. The filtrate is washed with water and dried at 80° C. Yield: 14.2 g (86% of theory); C8H5ClN2O3; EII mass spectrum: m/z=213/215 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; toluene; | EXAMPLE 1 3-Chloromethyl-1,2,4-triazolin-5-one A mixture of semicarbzide hydrochloride (5.69 Kg, 51.0 mol), 2-chloro-1,1,1-trimethoxy ethane (94.0 mol) and methanol (54 L) was stirred at room temperature for 4 days. The solvent was then removed under reduced pressure and toluene (25 L) was added. The resulting slurry was cooled to 0° C. and filtered to afford 3-chloromethyl-1,2,4-triazolin-5-one (6.69 Kg, 98percent) as a white solid (mp 197-199° C.); 1H NMR (d6 DMSO) delta=4.43 (2H, s, CH2), 11.48 (1H, s, NH) and 11.64 (1H, s NH); 13C NMR (d6 DMSO) delta=36.9 (ClCH2), 144.6 (CH2C=N) and 156.9 (NHCONH). The difficulty in following the reaction of such water soluble compounds has been overcome using the following HPLC conditions: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In dichloromethane at 20℃; for 18h; | 62 A solution of 1,1-dimethylethyl (3fl)-3-[(2-aminophenyl)amino]methyl}-1- piperidinecarboxylate (4.20 g, 13.8 mmol), 2-chloro-1,1 ,1-trimethoxyethane (6.40 g, 41.4 mmol, Aldrich), and p-toluenesulfonic acid (0.26 g, 1.4 mmol) in 70 mL of dichloromethane was stirred at RT. After 18 hours the solution was diluted with 100 mL of dichloromethane, washed twice with saturated aqueous NaHCO3, dried overNa2SO4, and concentrated to dryness at reduced pressure. The crude product was purified by flash chromatography (silica gel, gradient elution of hexane to 6:4 hexane/EtOAc) to afford 4.71 g (94%) of 1 ,1-dimethylethyl (3fl)-3-[2-(chloromethyl)- 1 /-/-benzimidazol-1-yl]methyl}-1-piperidinecarboxylate as a light tan foam. 1H NMR (DMSO-αfe): δ 7.67-7.58 (m, 2H), 7.28 (t, 1H), 7.23 (t, 1H), 5.06 (s, 2H), 4.28-4.13 (m,2H), 3.79 (d, 1H)T 3.72-3.38 (m, 1H), 2.80-2.58 (m, 2H), 2.05 (m, 1 H), 1.72-1.54 (m, 2H), 1.50-0.97 (m, 11H). MS m/z364 (M+H). |
94% | Stage #1: 1,1-dimethylethyl (3R)-3-[(2-aminophenyl)amino]methyl}-1-piperidinecarboxylate; 2-chloro-1,1,1-trimethoxyethane With toluene-4-sulfonic acid In dichloromethane at 20℃; for 18h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water | 39.c A solution of 1,1-dimethylethyl (3R)-3-[(2-aminophenyl)amino]methyl}-1-piperidinecarboxylate (4.20 g, 13.8 mmol), 2-chloro-1,1,1-trimethoxyethane (6.40 g, 41.4 mmol, Aldrich), and p-toluenesulfonic acid (0.26 g, 1.4 mmol) in 70 mL of dichloromethane was stirred at RT. After 18 hours the solution was diluted with 100 mL of dichloromethane, washed twice with saturated aqueous NaHC03, dried over Na2S04, and concentrated to dryness at reduced pressure. The crude product was purified by flash chromatography (silica gel, gradient elution of hexane to 6:4 hexane/EtOAc) to afford 4.71 g (94%) of 1,1-dimethylethyl (3R)-3-[2-(chloromethyl)-1H-benzimidazol-1-yl]methyl}-1-piperidinecarboxylate as a light tan foam. 1H NMR (DMSO-d6): 8 7.67-7.58 (m, 2H), 7.28 (t, 1H), 7.23 (t, 1H), 5.06 (s, 2H), 4.28-4.13 (m, 2H), 3.79 (d, 1H), 3.72-3.38 (m, 1H), 2.80-2.58 (m, 2H), 2.05 (m, 1H), 1.72-1.54 (m, 2H), 1.50-0.97 (m, 11H). MS m/z 364 (M+H). |
85% | With toluene-4-sulfonic acid In dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Stage #1: 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline-8-amine; 2-chloro-1,1,1-trimethoxyethane With hydrogenchloride In water Stage #2: With sodium hydrogencarbonate In dichloromethane; water | 14.1 EXAMPLE 14.1 2-(chloromethyl)-8-fluoro-4-methyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline To a suspension of 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline-8-amine (3.7 g, 20.6 mmol) in 2-chloro-1,1,1-trimethoxyethane (25 ml), conc. HCl (3 ml) was added. The resulting solution was stirred over night. The reaction mixture was diluted with dichloromethane and basified with saturated sodium bicarbonate solution. The aqueous layer was back-extracted with dichloromethane, and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient elution with 60% ethyl acetate/hexanes to 5% 2M NH3 in methanol/(60% ethyl acetate/hexanes)) provided a yellow solid (2.8 g, 56%). 1H NMR (300 MHz, CDCl3): δ 7.17(dxd, 1H), 6.78(d, 1H), 4.73-4.78 (m, 3H), 2.81-2.99 (m, 2H), 2.07-2.13 (m, 2H), 1.42 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
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87% | In acetonitrile for 48h; Heating / reflux; | 16.a.D Ytterbium triflate (1.16 g, 1.8 mmol) and 2-chloro-1,1,1-trimethoxyethane (7.56 mL, 56.0 mmol) was added to a solution of 3-amino-4-ethylamino-6-(3-trifluoromethylphenyl)-pyridine-2-carbonitrile (5.73 g, 18.7 mmol) in acetonitrile (150 mL). The mixture was refluxed for 48 hours, then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with diethyl ether, filtered off to afford the title compound (5.92 g, 87%) as a solid. 1H NMR (DMSO-d6) δ: 8.85 (s, 1H); 8.50-8.00 (m, 2H); 7.90-7.70 (m, 2H); 5.26 (s, 2H); 4,55-4.45 (m, 2H); 1.48 (t, J=7 Hz, 3H). MS m/z: 365 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
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51% | In <i>N</i>-methyl-acetamide | 357 3-[8-(chloromethyl)-1,1-dioxido-4H-[1,3]oxazolo[5,4-h][1,2,4]benzothiadiazin-3-yl]-4-hydroxy-1-(isobutylamino)quinolin-2(1H)-one EXAMPLE 357 3-[8-(chloromethyl)-1,1-dioxido-4H-[1,3]oxazolo[5,4-h][1,2,4]benzothiadiazin-3-yl]-4-hydroxy-1-(isobutylamino)quinolin-2(1H)-one A solution of Example 354 (0.030 g, 0.067 mmol) in dimethylformamide (3 mL) was treated with 2-chloro-1,1,1-trimethoxyethane (0.50 mL) and a catalytic amount of para-toluenesulfonic acid at 60° C. for 4 hours. The solvent was removed under a stream of warm nitrogen and the resulting residue was triturated with water and filtered, then triturated with methanol and filtered to yield the title compound (22 mg, 51%). The sodium salt was made by the procedure of Example 1D. MS (ESI-) m/z 500 (M-H)-. 1H NMR (300 MHz, DMSO-d6) δ 1.04 (d, J=6.62 Hz, 6H) 1.87 (m, J=20.04, 13.42, 6.99 Hz, 1H) 2.63 (m, 2H) 5.13 (s, 2H) 5.95 (t, J=6.99 Hz, 1H) 7.08 (t, J=7.54 Hz, 1H) 7.36 (d, J=9.19 Hz, 1H) 7.57 (m, 2H) 7.99 (d, J=8.82 Hz, 1H) 8.09 (dd, J=7.91, 1.29 Hz, 1H) 16.59 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With toluene-4-sulfonic acid In toluene for 0.75h; Heating / reflux; | 1 1.4 grams (5.6 mmol) of 2-aminobenzo[b]thiophene-3-carboxamide was dissolved in 100 ml of toluene, and the solution was heated to reflux. 1.5 grams (10 mmol) of 2-chloro-l,l,l-trimethoxyethane was added, and the mixture was then heated for 45 minutes, while 10 mg of para-toluene sulfonic acid was added. Within a few minutes, a white powder separated. The powder was filtered and dried by vacuum, giving 1.0 grams (72 % yield) of Product I(b). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | In ethanol; for 6h;Heating / reflux; | Step B: A mixture of <strong>[17672-21-8]methyl 2-amino-3-hydroxybenzoate</strong> (3.5 g, 20.70 mmol) and 2-chloro-1,1,1-trimethoxyethane (3.0 mL, 22.06 mmol) in ethanol (30 mL) was stirred under reflux for 6 h. The reaction mixture was cooled to ambient temperature and the solvent volume was reduced under reduced pressure approximately to 2/3 of initial volume. The precipitate formed was filtered, washed with ether (3*10 mL), and dried under vacuum to afford methyl 2-(chloromethyl)benzoxazole-4-carboxylate (3.1 g, 66%) as a yellow solid: 1H NMR (500 MHz, CDCl3) delta 8.05 (dd, J=8.0, 1.0 Hz, 1H), 7.78 (dd, J=9.0, 1.0 Hz 1H), 7.47 (t, J=5.0 Hz, 1H), 4.84 (s, 2H), 4.04 (s, 3H); (APCI+) m/z 226 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | at 160℃; for 0.0833333h; Microwave irradiation; | |
75% | at 160℃; for 0.0833333h; Microwave irradiation; Sealed vial; | 27 A mixture of 2,3-dihydro-1-benzofuran-5-carbohydrazide (2.02 g, 11.3 mmol) and 2-chloro-1,1,1-trimethoxyethane (7.92 ml, 56.7 mmol) was tightly sealed in a vial, and microwave was irradiated thereon at 160° C. for 5 min. The reaction mixture was recrystallized from hexane to give the title compound (2.01 g, yield 75%) as colorless crystals.NMR (CDCl3) δ 3.29 (2H, t, J=8.9 Hz), 4.68 (2H, t, J=8.9 Hz), 4.75 (2H, s), 6.89 (1H, d, J=8.7 Hz), 7.81-7.88 (1H, m), 7.90-7.94 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5- (chloromethyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (21 mg, 0.156 mmol, 1.03 eq; prepared from semicarbazide and 2-chloro-l,l,l-trimethoxyethane as described by Cameron J. Cowden, Robert D. Wilson, Brian C. Bishop, Ian F. Cottrell, Antony J. Davies and Ulf-eta. Dolling; Tetrahedron Letters, 2000, 41, 8661-8664). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.9% | Example 11.1; 5-Chloro-2-chloromethyl-1-methyl-1H-benzoimidazole; 4-Chloro-N-1-methyl-benzene-1,2-diamine (100 mg, 0.64 mmol) was dissolved in 5 mL of 2-chloro-1,1,1-trimethoxy-ethane, and 80 uL of 12N HCl was added to the reaction. The reaction was allowed to stir at room temperature for overnight. The reaction was poured onto saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The crude products were purified by column chromatography using acetone:dichloromethane 10%:90% to give white solid (129.9 mg, 93.9%).1HNMR (300 MHz, CDCl3): (ppm) 3.80 (s, 3H, N-CH3), 4.80 (s, 2H, C-CH2-Cl, 7.21-7.28 (m, 1H, H-Ar), 7.70 (s, 1H H-Ar). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With acetic acid at 118℃; for 12h; | 1 A solution 4-(benzyloxycarbonylamino)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1A, 2.0 g, 1.0 equivalent) in DME (0.5 M) was treated with NMM (1.0 equivalent) and IBCF (1.0 equivalent) at -15° C. After 10 min, aqueous ammonia (1.5 equivalents) was added. The reaction mixture was stirred at room temperature for 1.5 hr. The reaction was complete as determined by LCMS analysis and then partitioned between ethyl acetate and water. The organics were subsequently washed with brine, then dried over Na2SO4, filter, and the volatiles removed under reduced pressure. The residue was purified by crystallization from diethyl ether to afford the tert-butyl 4-(benzyloxycarbonylamino)-4-carbamoylpiperidine-1-carboxylate (1B, 70%).1B (1.0 equivalent) and a catalytic amount of acetic acid in MeOH (0.05M) was passed through H-cube hydrogenator equipped with Pd/C cartridge at 50° C. The methanol in the reaction mixture was then removed under reduced pressure, and the product was washed with cold ether twice to afford the tert-butyl 4-amino-4-carbamoylpiperidine-1-carboxylate (1C, 90%).1C (0.3M) was added 2-chloro-1,1,1-trimethoxyethane (4.0 equivalents) and acetic acid (2.0 equivalents). The mixture was stirred for 12 hr at 118° C. Solvent was removed under reduced pressure and the residue was purified by crystallization from cold diethyl ether to afford tert-butyl 2-(chloromethyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate (1D, 67%).1D in a seal tube was added 2.0 M ammonia in 2-propanol (0.04M). Excess ammonia gas was bubbled in and the mixture was heated at 60° C. for 12 hr. The reaction was complete as determined by LCMS analysis. After removal of solvent; the residue tert-butyl 2-(aminomethyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate (1E) was used without further purification. ESI-MS: m/z 283.1 (M+H)+.For deprotection, 1E (1.0 equivalent) was dissolved in CH2Cl2 at 0° C., and slowly treated with a 1.6:1 solution of CH2Cl2/TFA (2:1 final ratio, 0.15 M). The reaction was completed in 30 minutes at 0° C. as determined by LCMS analysis. The volatiles were removed under reduced pressure to yield the respective 2-(aminomethyl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one (1G) as TFA salts which were used without further purification. ESI-MS: m/z 183.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With acetic acid at 60℃; for 1h; | 8 Example 8Preparation of 1-(3-(2-(chloromethyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-enecarbonyl)benzo[b]thiophen-2-yl)-3-ethylurea (8); To 4-Amino-1-(2-(3-ethylureido)benzo[b]thiophene-3-carbonyl)piperidine-4-carboxamide TFA salt (7 (Example 7), 300 mg, 1.0 equivalent), 2-chloro-1,1,1-trimethoxyethane (4.0 equivalents) and acetic acid (0.07 M) was added, and then the mixture was heated to 60° C. for 1 hr. The volatiles was removed under reduced pressure and the residue was purified by SiO2 chromatography (5%-10% MeOH/CH2Cl2 gradient) to afford 1-(3-(2-(chloromethyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-enecarbonyl)benzo[b]thiophen-2-yl)-3-ethylurea (8, 65%). Two rotamers observed (ratio 3:2).First rotamer: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm, 1.10 (dt, J=11.18, 7.29 Hz, 3H), 1.56 (br. s., 2H), 1.98 (br. s., 2H), 3.27 (dd, J=19.45, 5.56 Hz, 2H), 3.64 (t, J=1.37 Hz, 2H), 4.07 (br. s., 2H), 4.34 (s, 2H), 6.40 (t, J=5.18 Hz, 1H), 7.21 (m, 1H), 7.29-7.50 (m, 2H), 7.68-7.77 (m, 1H) 9.47 (br. s., 1H); ESI-MS: m/z 447.1 (M+H)+.Second rotamer: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm, 1.10 (dt, J=11.18, 7.29 Hz, 3H), 1.69 (br. s., 2H), 1.90 (br. s., 2H), 3.27 (dd, J=19.45, 5.56 Hz, 2H), 3.64 (t, J=11.37 Hz, 2H), 4.07 (br. s., 2H), 4.30 (s, 2H), 6.35 (t, J=5.31 Hz, 1H), 7.17-7.25 (m, 1H), 7.29-7.50 (m, 2H), 7.68-7.77 (m, 1H), 9.35 (br. s., 1H); ESI-MS: m/z 447.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-Hydroxy-4-methylanilin; 2-chloro-1,1,1-trimethoxyethane With acetic acid for 24h; Reflux; Stage #2: With sulfuric acid at 100℃; for 2h; Stage #3: With potassium carbonate In water | 3.a To 2-amino-5-methyl-phenol (2 g) in acetic acid (20 niL) and was added 2-chloro- 1,1,1 - trimethoxy-ethane (3.01 g) and the mixture heated under reflux for 24h. The solvent was removed under reduced pressure and the residue treated with cone, sulfuric acid (5 mL). The brown solution was heated a 1000C for 2h, cooled to room temperature and quenched into water (200 mL). The mixture was made basic by the addition of solid potassium carbonate and the products extracted into diethyl ether (2 x 150 mL). The dried extracts were concentrated to an oil and the oil purified by flash column chromatography using diethyl ether / rsøhexane (3 : 7) to afford the sub-titled compound as an oil (0.170 g).1H NMR (400 MHz, DMSO) Î' 7.60 (IH, d), 7.35 (IH, q), 7.18 (IH, dt), 4.74 (2H, s), 2.50 (3H, s). | |
Stage #1: 2-Hydroxy-4-methylanilin; 2-chloro-1,1,1-trimethoxyethane With acetic acid for 24h; Reflux; Stage #2: With sulfuric acid at 100℃; for 2h; Stage #3: With potassium carbonate In water | 26.a Example 26: (R)-l-(6-Methyl-benzooxazol-2-ylmethyl)-3-(l-phenyl- cycloheptanecarbonyloxy)-l-azonia-bicyclo[2.2.2]octane chloridea) 2-Chloromethyl-6-methyl-benzooxazole To 2-amino-5 -methyl-phenol (2 g) in acetic acid (20 mL) and was added 2-chloro- 1,1,1 - trimethoxy-ethane (3.01 g) and the mixture heated under reflux for 24h. The solvent was removed under reduced pressure and the residue treated with cone, sulfuric acid (5 mL). The brown solution was heated a 1000C for 2h, cooled to room temperature and quenched into water (200 mL). The mixture was made basic by the addition of solid potassium carbonate and the products extracted into diethyl ether (2 x 150 mL). The dried extracts were concentrated to an oil and the oil purified by flash column chromatography using diethyl ether / z'søhexane (3 : 7) to afford the sub-titled compound as an oil (0.170 g).1H NMR (400 MHz, DMSO) δ 7.60 (IH, d), 7.35 (IH, q), 7.18 (IH, dt), 4.74 (2H, s), 2.50 (3H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-chloro-1,1,1-trimethoxyethane; 3-amino-4-hydroxytoluene With acetic acid for 24h; Reflux; Stage #2: With sulfuric acid at 100℃; for 2h; Stage #3: With potassium carbonate In water | 8.a A mixture of 2-amino-4-methyl~phenol (2 g) and 2-chloro-l,l,l-trimethoxy-ethane (3.01 g) in acetic acid (20 mL) was heated under reflux for 24h. The solvent was removed under reduced pressure and the residue treated with cone, sulfuric acid (5 mL). The brown solution was heated at 1000C for 2h, cooled , and quenched into water (200 mL). The mixture was made basic by the addition of solid potassium carbonate and the products extracted into diethyl ether (2 x 150 mL). The dried extracts were concentrated to an oil and the oil purified by chromatography on silica eluting with diethyl ether / wÏhexane (3 : 7) to afford the titled compound as an oil (0.360 g).1H NMR (400 MHz, CDCl3) Î' 7.52 (IH, dd), 7.42 (IH, d), 7.20 (IH, dd), 4.74 (2H, d), 2.48 (3H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | at 60℃; for 1h; | 4-chloro-2-amino-benzothiol (5 g, 31.3 mmol, 1 equiv.) was mixed with 2-chloro-1,1,1-trimethoxyethane (50.6 ml, 37.56 mmol, 1.2 equiv.) and heated at 60° C. with stirring for 1 hour (After 2 min the reaction mixture turned solid so more 2-chloro-1,1,1-trimethoxyethane (1.5 ml) was added). Et2O and pentane were added, however no precipitation occurred so the mixture was evaporated to dryness to give an orange solid. This was triturated by stirring with Et2O at room temperature The undissolved solid was filtered, rinsed with Et2O and pentane to give 1.5 g (22%) of light brown solid. The mother liquor was evaporated to dryness, dissolved in Et2O, washed with 1 N HCl, H2O, 10% NaHCO3, H2O and brine. This was then dried (MgSO4) and evaporated to a smaller volume when solid precipitated it was filtered and washed with pentane to give 2.18 g (32%) of light brown solid. The new mother liquor was treated as above to give a further 550 mg (8%) of product. Total yield 40%. |
28% | at 60℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-amino-3-(methylamino)benzonitrile; 2-chloro-1,1,1-trimethoxyethane In water at 20℃; for 72h; Stage #2: With sodium hydrogencarbonate In water | 66 2-Amino-3-(methylamino)benzonitrile (441 mg; may be prepared as described in intermediate 65) was dissolved in 2-chloro-1 ,1 ,1-trimethoxyethane (3 ml_, Aldrich). Concentrated hydrochloric acid (0.6 ml.) was added dropwise and the mixture was stirred at RT for 3 days. It was basified with aqueous sodium bicarbonate solution and then extracted with DCM (3 x 100 ml_). The combined organic layers were dried over soldium sulphate, filtered and evaporated to obtain a light red solid. This was purified by chromatography on silica gel (eluent petroleum ether / EtOAc 1 :1 ) to give the title compound (300 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With toluene-4-sulfonic acid In dichloromethane at 30℃; for 1h; | 44 PREPARATION 44 6-Bromo-2-(chloromethyl)-3-phenyl-3H-imidazo[4,5-b]pyridine To a solution of 5-bromo-N2-phenylpyridine-2,3-diamine (0.85 g, 3.21 mmol, Preparation 43) in dichloromethane (16 mL) was added 2-chloro-1,1,1-trimethoxyethane (1.32 mL, 9.64 mmol) and p-toluenesulfonic acid monohydrate (62 mg, 0.32 mmol). The reaction mixture was stirred in a closed system (Radley tube) at 30 °C for 1 h. The reaction mixture was cooled to room temperature followed by the addition of water. After phase separation the organic phase was dried (Na2SO4), filtered and evaporated to dryness under reduced pressure to afford the product as a dark solid. Purification by flash chromatography (silica gel, heptane/Ethyl acetate, 5:1) afforded 6-bromo-2-(chloromethyl)-3-phenyl-3H-imidazo[4,5-b]pyridine (0.92 g, 2.86 mmol, 89 % yield) as an off-white solid. LRMS (m/z): 323 (M+1)+. |
89% | With toluene-4-sulfonic acid In dichloromethane at 30℃; for 1h; | To a solution of 5-bromo-N2-phenylpyridine-2,3-diamine (0.85 g, 3.21 mmol, Preparation 43) in dichloromethane (16 mL) was added 2-chloro-1 ,1 ,1 - trimethoxyethane (1 .32 mL, 9.64 mmol) and p-toluenesulfonic acid monohydrate (62 mg, 0.32 mmol). The reaction mixture was stirred in a closed system (Radley tube) at 30 °C for 1 h. The reaction mixture was cooled to room temperature followed by the addition of water. After phase separation the organic phase was dried (Na2S04), filtered and evaporated to dryness under reduced pressure to afford the product as a dark solid. Purification by flash chromatography (silica gel, heptane/Ethyl acetate, 5:1 ) afforded 6-bromo-2-(chloromethyl)-3-phenyl-3H-imidazo[4,5-b]pyridine (0.92 g, 2.86 mmol, 89 % yield) as an off-white solid.LRMS (m/z): 323 (M+1 )+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With toluene-4-sulfonic acid In dichloromethane at 20℃; | 68 PREPARATION 68 2-(Chloromethyl)-1-phenyl-1H-imidazo[4,5-b]pyridine To a solution of N3-phenylpyridine-2,3-diamine (33 mg, 0.18 mmol, Preparation 67) in dichloromethane (3 mL) was added 2-chloro-1,1,1-trimethoxyethane (74 μl, 0.54 mmol) and p-toluenesulfonic acid monohydrate (3 mg, 0.02 mmol). The reaction mixture was stirred overrnight at room temperature. The reaction mixture was evaporated to dryness under reduced pressure. Dichloromethane and water were added and the organic phase was separated using a phase separator, washed with aqueous 1M NaOH and dried over magnesium sulphate. Subsequent evaporation of the solvent afforded the title compound (39 mg, 0.16 mmol, 89 % yield) as a dark oil. LRMS (m/z): 244 (M+1)+. |
89% | Stage #1: 3-N-phenylpyridine-2,3-diamine; 2-chloro-1,1,1-trimethoxyethane With toluene-4-sulfonic acid In dichloromethane at 20℃; Stage #2: With sodium hydroxide In dichloromethane; water | To a solution of N3-phenylpyridine-2,3-diamine (33 mg, 0.18 mmol, Preparation 67) in dichloromethane (3 mL) was added 2-chloro-1 ,1 ,1-trimethoxyethane (74 μΙ, 0.54 mmol) and p-toluenesulfonic acid monohydrate (3 mg, 0.02 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness under reduced pressure. Dichloromethane and water were added and the organic phase was separated using a phase separator, washed with aqueous 1 M NaOH and dried over magnesium sulphate. Subsequent evaporation of the solvent afforded the title compound (39 mg, 0.16 mmol, 89 % yield) as a dark oil.LRMS (m/z): 244 (M+1 )+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With toluene-4-sulfonic acid In dichloromethane at 20℃; for 72h; Sealed vessel; | 50 PREPARATION 50 tert-Butyl 2-(chloromethyl)-3-phenyl-3H-imidazo[4,5-b]pyridin-5-ylcarbamate tert-Butyl 5-amino-6-(phenylamino)pyridin-2-ylcarbamate (260 mg, 0.87 mmol, Preparation 49) was dissolved in dichloromethane (10 mL). 2-chloro-1,1,1-trimethoxyethane (0.35 mL, 2.60 mmol) was added and the mixture was divided into 2 batches. para-Toluenesulfonic acid (pTsOH, 8 mg) was added to each batch. The reaction mixtures were stirred at room temperature for 72h in a closed vial. The reaction mixture was washed with water and dried over a phase separator. The organic layer was evaporated to dryness and purified by column chromatography (silica gel, Heptane/Ethyl acetate 3-30%) to isolate the final compound (250 mg, 80%). LRMS (m/z): 360 (M+1)+ |
80% | With toluene-4-sulfonic acid In dichloromethane at 20℃; for 72h; | ferf-Butyl 5-amino-6-(phenylamino)pyridin-2-ylcarbamate (260 mg, 0.87 mmol, Preparation 49) was dissolved in dichloromethane (10 mL). 2-chloro-1 ,1 ,1 - trimethoxyethane (0.35 mL, 2.60 mmol) was added and the mixture was divided into 2 batches. p-Toluenesulfonic acid (pTsOH, 8 mg) was added to each batch. The reaction mixtures were stirred at room temperature for 72h in a closed vial. The reaction mixture was washed with water and dried over a phase separator. The organic layer was evaporated to dryness and purified by column chromatography (silica gel, Heptane/Ethyl acetate 3-30%) to isolate the final compound (250 mg, 80%).LRMS (m/z): 360 (M+1 )+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: anthranilic acid amide; 2-chloro-1,1,1-trimethoxyethane With toluene-4-sulfonic acid In toluene at 80℃; for 0.5h; Stage #2: 2-hydroxyphenylpiperazine With triethylamine In N,N-dimethyl-formamide at 20℃; for 24h; | 6.44 grams (47 mmol) of anthranilamide and 10.9 grams (67.5 mmol) of 2-chloro- 1,1,1-trimethoxy ethane were dissolved in 50 ml of toluene and stirred at a temperature of 80 °C. A catalytic amount of p-toluene sulfonic acid was added, and the temperature was maintained at 80 °C for an additional 30 minutes. A precipitate formed, which was filtered and dried to yield 9.3 grams of an intermediate. 10 grams (56.1 mmol) of l-(2- hydroxyphenyl)piperazine, 100 ml of dimethylformamide, and 10 ml of triethylamine were then added, and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure, and the residue was purified on silica gel (100 % ethyl acetate), yielding 4.15 grams of L-238. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11.1 grams (81.6 mmol) of anthranilamide and 18 grams (122.4 mmol) of 2-chloro- 1,1,1-trimethoxy ethane were dissolved in 100 ml of toluene and stirred at a temperature of 80 C. A catalytic amount of p-toluene sulfonic acid was added, and the temperature was maintained at 80 C for an additional 30 minutes. A precipitate formed, which was filtered and dried to yield 15.5 grams of an intermediate. 21.7 grams (1 18 mmol) of l-(3- hydroxyphenyl)piperazine, 150 ml of dimethylformamide, and 12.5 ml of triethylamine were then added, and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure, and the residue was purified on silica gel (100 % ethyl acetate), yielding 15 grams of R-55. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With pyridinium p-toluenesulfonate at 100℃; for 5h; | 34 PREPARATION 342-(Chloromethyl)-3-phenylimidazo[1 ,2-f [1 ,2,4]triazin-4(3H)-one62 mg (0.25 mmol) of pyridinium p-toluenesulfonate were added to a suspension of 500 mg ( 2.47 mmol) of 1 -amino-A/-phenyl-1 H-imidazole-2-carboxamide in 3.3 mL of 2- chloro-1 ,1 ,1 -trimethoxyethane. The mixture was stirred at 100 °C for 5 hours and the solvent was evaporated. The crude product was purified by flash chromatography (1% to 3% MeOH/DCM) to yield 0.227 g (35%) of the title compound as a beige solid.LRMS (m/z): 261 (M+1 )+. |
35% | With pyridinium p-toluenesulfonate at 100℃; for 5h; | 34 PREPARATION 34 2-(chloromethyl)-3-phenylimidazo[1,2-f][1,2,4]triazin-4(3H)-one 62 mg (0.25 mmol) of pyridinium p-toluenesulfonate were added to a suspension of 500 mg (2.47 mmol) of 1-amino-N-phenyl-1H-imidazole-2-carboxamide in 3.3 mL of 2-chloro-1,1,1-trimethoxyethane. The mixture was stirred at 100 ºC for 5 hours and the solvent was evaporated. The crude product was purified by flash chromatography (1% to 3% MeOH/DCM) to yield 0.227 g (35%) of the title compound as a beige solid. LRMS (m/z): 261 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With pyridinium p-toluenesulfonate at 100℃; for 5h; | 36 PREPARATION 362-(Chloromethyl)-3-o-tolylimidazo[1,2-f [1 ,2,4]triazin-4(3H)-onePyridinium p-toluenesulfonate (0.067 g, 0.27 mmol) was added to a suspension of 1 - amino-N-o-tolyl-1 H-imidazole-2-carboxamide (0.58 g, 2.68 mmol) in 2-chloro-1 ,1 ,1 - trimethoxyethane (3.62 mL). The mixture was stirred at 100 °C for 5 hours. The solvent was evaporated to dryness and the residue was purified by flash chromatography (10% to 50% AcOEt/hexanes) to yield 0.360 g (49% yield) of the title compound.LRMS (m/z): 275 (M+1 )+. |
49% | With pyridinium p-toluenesulfonate at 100℃; for 5h; | 36 2-(chloromethyl)-3-o-tolylimidazo[1,2-f][1,2,4]triazin-4(3H)-one PREPARATION 36 2-(chloromethyl)-3-o-tolylimidazo[1,2-f][1,2,4]triazin-4(3H)-one Pyridinium p-toluenesulfonate (0.067 g, 0.27 mmol) was added to a suspension of 1-amino-N-o-tolyl-1H-imidazole-2-carboxamide (0.58 g, 2.68 mmol) in 2-chloro-1,1,1-trimethoxyethane (3.62 mL). The mixture was stirred at 100 ºC for 5 hours. The solvent was evaporated to dryness and the residue was purified by flash chromatography (10% to 50% AcOEt/hexanes) to yield 0.360 g (49% yield) of the title compound. LRMS (m/z): 275 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: trans-[4-(3-amino-[1,5]naphthyridin-4-ylamino)-cyclohexyl]-acetonitrile; 2-chloro-1,1,1-trimethoxyethane With acetic acid at 125℃; for 0.5h; Stage #2: With sodium hydrogencarbonate In water; ethyl acetate | 12 Example 12 Trans [4-(2-Aminomethyl-imidazo[4,5-c]quinolin-l-yl)-cyclohexyl]-acetonitrile Trans [4-(2-Chloromethyl-imidazo[4,5-c]quinolin-l-yl)-cyclohexyl]-acetonitrileA solution of trans [4-(3-amino-quinolin-4-ylamino)-cyclohexyl]-acetonitrile (500 mg, 1.80 mmol) in acetic acid (1.5 mL) was treated with 2-chloro-l,l,-trimethyoxyethane (0.48 mL, 3.60 mmol). The mixture was heated to 125 °C for 30 minutes. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and saturated sodium hydrogencarbonate solution. The aqueous phase was extracted with ethyl acetate (2x) and the combined organic phases washed (saturated sodium hydrogencarbonate solution and brine), dried (sodium sulfate) and concentrated. Crude trans [4-(2-chloromethyl-imidazo[4,5-c]quinolin-l-yl)-cyclohexyl]- acetonitrile was isolated as a dark green foam solid and was used without further purification. LCMS (Method B, ESI): RT = 2.61 min, m+H = 339 and 341. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | In toluene; at 200℃; for 16h;Inert atmosphere; | General procedure: The synthesis of 3c is representative, with the exception of vinyl ethers 2a and 2b where 5.0 equivalents are required to solely obtain the protected alcohols 3a and 3b, respectively. To a sealable 25-mL pressure vessel was successively added 1 (0.154 g, 1.0 mmol), toluene (2 mL), and 2c (0.33 mL, 3.0 mmol) under argon. The solution was heated to 200 oC and stirred for 16 h. Upon completion of the reaction, the sealable pressure vessel was cooled to room temperature. The solution was transferred to another flask, while rinsing with ethyl acetate, after which the solution was concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, EtOAc:hexanes 1:20) to afford 3c (0.18 g, 77% yield aspale yellow needles |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.1% | With sulfuric acid In methanol at -10 - 45℃; for 2h; | 1 Example 1 1L reaction flask by adding 250mL of methanol and methyl chloroacetate 100g (0.92mol), stirring dissolved, cooled to -10 ~ 0 , and then added trimethyl orthoformate 127g (1.20mol), continue to stir, keep the temperature slowly drop And adding 36.5g of concentrated sulfuric acid with a mass concentration of 98%. After the addition, the temperature was raised to 35 to 45C for 2 hours, and the raw material methyl chloroacetate was not monitored by gas chromatography to stop the reaction. The reaction mixture was concentrated at 45 to 55 ° C under reduced pressure, the solvent was removed, the mixture was cooled to room temperature, added to 500 mL of potassium hydroxide aqueous solution (0.05 M), extracted with ethyl acetate (250 mL × 2), and ethyl acetate , And the mixture was washed with 300 mL of saturated brine. The ethyl acetate phase was added to 30 g of anhydrous sodium sulfate and stirred for 2 hours. Anhydrous sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure at 45 to 55 ° C until no distillate was distilled off to obtain a product And the purity was 98.6% and the yield was 95.1% by gas chromatography. |
With sulfuric acid In methanol at 20℃; | General Procedure for the Generation of Ketals General procedure: The synthesis of 4b is representative. To a solution of acetophenone (5.0 mL, 42.86 mmol) in methanol (12 mL) at room temperature was added trimethyl orthoformate (6.1 mL, 55.72 mmol) and sulfuric acid (0.93 mL of a 0.40M solution in methanol). The solution was refluxed for 12 hours, after which the solution was concentrated in vacuo and cooled in an ice bath. The cold solution was poured into an aqueous KOH solution (0.05M, 0.119 g, 2.13 mmol) and extracted with ethyl acetate (2 x 50 mL) and washed with brine (50 mL). The solution was concentrated in vacuo to afford 4b (6.77 g) as an orange crude liquid, which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,2-dimethoxyethane; at 95℃;Sealed tube; | 3,4-Diaminothiophene (0.29 g, 2.54 mmol) and 2-chloro-l,l,l-trimethoxy-ethane (0.5 g, 3.38 mmol) were combined in DME (5 mL) in a sealed tube and heated at 95 C for overnight and concentrated to give a crude product to go to the next step without purification. LC-MS: m/z 173 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With toluene-4-sulfonic acid at 100℃; for 1h; | 9.1 Step 1 : (2-Chloromethyl-l -isopropyl-lH-imidazo[4.5-clpyridin-6-yl -r2-f4-methoxypiperidin-l - yl pyrimidin-4-yl1 amine N4-Isopropyl-N2-[2-(4-methoxypiperidin-l-yl)pyrimidin-4-yl]pyridine-2,4,5-triamine (Example 3, step 4) (50 mg, 0.14 mmol) was dissolved in 2-chloro-l,l,l-trimethoxy ethane (1 mL) and a catalytic amount of p-toluensulfonic acid was added. The reaction mixture was heated at 100 °C for 1 h and then the volatiles were removed in vacuo. The resulting residue was purified by chromatography (Si-PCC, gradient 0-10% MeOH in DCM) to afford the title compound (50 mg, 86%). LCMS (ESI): [M+H]+ 416.3. |
86% | With toluene-4-sulfonic acid at 100℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid at 70℃; Inert atmosphere; | 44.2 Step 2 - Synthesis of 5-(6-(chloromethyl)-1 1-fluoropyrido[3 ‘, 2 ‘:4,5/pyrimido [1 , 6-a/indol-2-yl)-2- (2, 4-difluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide Step 2 - Synthesis of 5-(6-(chloromethyl)-1 1-fluoropyrido[3 ‘, 2 ‘:4,5/pyrimido [1 , 6-a/indol-2-yl)-2- (2, 4-difluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide To a solution of 5-(5 -amino-6-(4-fluoro- 1 H-indol-2-yl)pyridin-2-yl)-2-(2,4- difluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3 -carboxamide (500 mg,0.80 mmol) in HOAc (9 mL) was added 2-chloro-1,1,1-trimethoxyethane (2.5 mL) at RT under nitrogen. The mixture was stirred at 70°C overnight and then it was filtered. The insoluble solid was washed with water and collected to obtained crude 5-(6-(chloromethyl)-1 1- fluoropyrido[3 ‘,2’ :4,5 ]pyrimido[ 1,6-a] indol-2-yl)-2-(2,4-difluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (450 mg, yield: 82.5%) without furtherpurification. ‘H-NMR (CDC13, 400 MHz) 8.138.20 (m, 2H), 8.14 (d, J= 8.4 Hz, 1H),7.70-7.94 (m, 4H), 7.457.46 (m, 1H), 7.19-7.21 (m, 1H), 7.01-7.07 (m, 2H), 5.76 (s, 1H), 5.18(s, 2H), 3.42 (s, 3H), 2.96 (d, J= 4.4 Hz, 3H), 2.68 (s, 3H). MS (M+H): 678 / 680. | |
With acetic acid at 70℃; Inert atmosphere; | 44.2 Step 2 - Synthesis of 5-(6-(chloromethyl)-l l-fluoropyrido[3',2 ':4,5]pyrimido[l , 6-a]indol-2-yl)-2- (2A-difluorophenyl)-N-methyl-6-{N-methylmethylsulfonamido)benzofuran-3-carboxamide To a solution of 5-(5-amino-6-(4-fluoro-lH-indol-2-yl)pyridin-2-yl)-2-(2,4- difluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (500 mg, 0.80 mmol) in HO Ac (9 mL) was added 2-chloro-l, l, l-trimethoxy ethane (2.5 mL) at RT under nitrogen. The mixture was stirred at 70 °C overnight and then it was filtered. The insoluble solid was washed with water and collected to obtained crude 5-(6-(chloromethyl)-l 1- fluoropyrido[3',2':4,5]pyrimido[l,6-a]indol-2-yl)-2-(2,4-difluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (450 mg, yield: 82.5%) without further purification. 1H- MR (CDC13, 400 MHz) δ 8.13-8.20 (m, 2H), 8.14 (d, J= 8.4 Hz, 1H),7.70-7.94 (m, 4H), 7.45-7.46 (m, 1H), 7.19-7.21 (m, 1H), 7.01-7.07 (m, 2H), 5.76 (s, 1H), 5.18 (s, 2H), 3.42 (s, 3H), 2.96 (d, J= 4.4 Hz, 3H), 2.68 (s, 3H). MS (M+H)+: 678 / 680. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With trifluoroacetic acid In 1,4-dioxane at 85℃; for 3h; | 76.1 Step 1 - 5-(6-(chloromethyl) -1 1-fluoropyrido[3 ‘,2 ‘:4, 5/pyrimido[1 , 6-a/indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide Step 1 - 5-(6-(chloromethyl) -1 1-fluoropyrido[3 ‘,2 ‘:4, 5/pyrimido[1 , 6-a/indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide To a solution of 5-(5 -amino-6-(4-fluoro- 1 H-indol-2-yl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (900 mg, 1.496 mmol) and 2-chloro-1,1,1-trimethoxyethane (1850 mg, 11.97 mmol) in 1,4-Dioxane (15ml) was added TFA (lml, 12.98 mmol). The mixture was heated to 85 °C and stirred for 3 h. The mixture was concentrated in vacuo, then dissolved in 15 ml DCM. 5 ml Et3N was added and then the mixture evaporated in vacuo. The resulting mixture was purified using column chromatography (eluted with 0-20% ethyl acetate / DCM) to provide 5-(6-(chloromethyl) -11- fluoropyrido[3 ‘,2’ :4,5 ]pyrimido[ 1,6-a] indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (500mg, yield: 51%). MS (M+H): 661. |
51% | With trifluoroacetic acid In 1,4-dioxane at 85℃; for 3h; | 76.1 Step 1 - 5-(6-(chloromethyl) -11-fluoropyrido [3',2' : 4,5]pyrimido [ 1 , 6-a]indol-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide To a solution of 5-(5-amino-6-(4-fluoro-lH-indol-2-yl)pyridin-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (900 mg, 1.496 mmol) and 2-chloro-l, l, l-trimethoxy ethane (1850 mg, 11.97 mmol) in 1,4-Dioxane (15ml) was added TFA (lml, 12.98 mmol). The mixture was heated to 85 °C and stirred for 3 h. The mixture was concentrated in vacuo, then dissolved in 15 ml DCM. 5 ml Et3N was added and then the mixture evaporated in vacuo. The resulting mixture was purified using column chromatography (eluted with 0-20% ethyl acetate / DCM) to provide 5-(6-(chloromethyl) -11- fluoropyrido[3',2':4,5]pyrimido[l,6-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (500mg, yield: 51%). MS (M+H)+: 661. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With hydrogenchloride In 1,4-dioxane at 60℃; for 4h; Sealed tube; | 23.1 Step 1 - Synthesis of2-chloro-6-(chloromethyl)-1 1-fluoropyrido[3 ‘,2 ‘:4, 5Jpyrimido[1 , 6-ajindole Step 1 - Synthesis of2-chloro-6-(chloromethyl)-1 1-fluoropyrido[3 ‘,2 ‘:4, 5Jpyrimido[1 , 6-ajindole To a screw cap vial was added the reactant 6-chloro-2-(4-fluoro-1H-indol-2- yl)pyridin-3-amine (1 g, 3.8 mmol) and 2-chloro-1,1,1-trimethoxyethane (3 mg, 19 mmol), then 1,4-dioxane (10 mL) and 4.0 M HC1 / 1,4-dioxane (0.5 mL). The vial was capped and heated to60 °C and stirred for 4 hours. The reaction mixture was evaporated in vacuo to remove the volatiles. The resulting residue in DCM : PE = (1: 1) was stirred and filtered, the cake was driedto provide the yellow solid 2-chloro-6-(chloromethyl)- 11 -fluoropyrido [3 ‘,2’:4,5 ]pyrimido[ 1,6-a]indole (1 g, yield: 8 1%). ‘H-NMR (DMSO-d6, 400 MHz) ö 8.18 (d, J = 8.4 Hz, 1H), 8.05 (d, J= 8.8 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.61 (s, 1H), 7.50-7.56 (m, 1H), 7.33 (t, J = 8.4 Hz,1H), 5.39 (s, 2H). MS (M+H): 320. |
81% | With hydrogenchloride In 1,4-dioxane at 60℃; for 4h; | 23.1; 28.1 Step 1 To a screw cap vial was added the reactant 6-chloro-2-(4-fluoro-lH-indol-2- yl)pyridin-3 -amine (1 g, 3.8 mmol) and 2-chloro-l, l, l-trimethoxy ethane (3 mg, 19 mmol), then 1,4-dioxane (10 mL) and 4.0 M HCl / 1,4-dioxane (0.5 mL). The vial was capped and heated to 60 °C and stirred for 4 hours. The reaction mixture was evaporated in vacuo to remove the volatiles. The resulting residue in DCM : PE = (1 : 1) was stirred and filtered, the cake was dried to provide the yellow solid 2-chloro-6-(chloromethyl)-l l-fluoropyrido[3',2':4,5]pyrimido[l,6- a]indole (1 g, yield: 81%). 1H- MR (DMSO- 6, 400 MHz) δ 8.18 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.61 (s, 1H), 7.50-7.56 (m, 1H), 7.33 (t, J = 8.4 Hz, 1H), 5.39 (s, 2H). MS (M+H)+: 320. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.18 g | With boron trifluoride diethyl etherate In dichloromethane at 0 - 20℃; for 4h; | 1 Synthesis of 5-bromo-7-chloro-2-(chIoromethyl)benzo[i ]oxazole (11): Synthesis of 5-bromo-7-chloro-2-(chIoromethyl)benzo[i ]oxazole (11): 2- Chloro-l,l,l-trimethoxy ethane (0.3 mL, 2.04 mmol) was dissolved in dichloromethane (20 mL) at room temperature and cooled to 0 °C. Borontrifluoride etherate (0.5 mL, 4.09 mmol) was added dropwise followed by 2-amino-4-bromo-6-chlorophenol (10) (0.5 g, 2.25 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 4 h. The reaction mixture was transferred into saturated NaHC03 solution and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous a2S04 and concentrated under reduced pressure to give crude compound, which was purified by silica gel chromatography (0-20% ethyl acetate/n-hexane) to obtain 5- bromo-7-chloro-2-(chloromethyl)benzo[ii]oxazole (11). (Yield: 0.18 g, 19%). 1H MR (400 MHz, CDC13) δ 7.82 (s, 1H), 7.58 (s, 1H), 4.78 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.6% | In ethanol for 2h; Reflux; | 1.5 Step 5: Preparation of 5- [5-chloro-2-(chloromethyl)- 1H-benzimidazol- 1-yl]pyridine-2- carbonitrile A mixture of 5- [(2-amino-4-chlorophenyl)amino]pyridine-2-carbonitrile (190 mg, 0.78 mmol) and 2-chloro-1,1,1-trimethoxyethane (602 mg, 3.89 mmol, CAS No.: 74974-54-2) in ethanol (10 mL) was heated under reflux for 2 hours. The resulting reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC (50% ethyl acetate in petroleum ether) to afford 200 mg of 5-[5-chloro-2-(chloromethyl)-1H-benzimidazol-1- yl]pyridine-2-carbonitrile (yield was 84.6%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.5% | In ethanol for 2h; Reflux; | 11.3 Step 3: Preparation of tert-butyl (3R)-3- [5-chloro-2-(chloromethyl)- 1H-benzimidazol- 1-ylipyrrolidine- 1-carboxylate A mixture of tert-butyl (3R)-3- [(2-amino-4-chlorophenyl)amino]pyrrolidine- 1 -carboxylate(1.00 g, 3.21 mmol) and 2-chloro-1,1,1-trimethoxyethane (2.50 g, 16.2 mmol) in ethanol (30 mL)was heated under reflux for 2 hours. The resulting mixture was concentrated in vacuo and theresidue was purified by column (eluting with 50% ethyl acetate in petroleum ether) to afford 1.10g of tert-butyl (3R)-3- [5-chloro-2-(chloromethyl)- 1 H-benzimidazol- 1 -yl]pyrrolidine- 1-carboxylate as a white powder (yield was 92.5%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52.8% | With toluene-4-sulfonic acid at 60℃; for 0.75h; Microwave irradiation; | 13.8 Step 8: Preparation of 5-chloro-2-(chloromethyl)-1- [(3R)-2,2-dimethyl- 1,1- dioxidotetrahydrothiophen-3-yl] -1H-benzimidazole A mixture of 4-chloro-N’ - [(3R)-2,2-dimethyl- 1,1 -dioxidotetrahydrothiophen-3-yl]benzene- 1,2-diamine (300 mg, 1.01 mmol), 2-chloro-1,1,1-trimethoxyethane (1.95 g, 12.6 mmol) and 4- methylbenzenesulfonic acid (480 mg, 2.18 mmol) was heated at 60 °C for 45 minutes under microwave irradiation. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC to afford 185 mg of 5-chloro-2-(chloromethyl)-1-[(3R)-2,2- dimethyl- 1,1 -dioxidotetrahydrothiophen-3-yl] -1 H-benzimidazole (yield was 52.8%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With boron trifluoride diethyl etherate In dichloromethane at 0℃; for 0.583333h; Inert atmosphere; | 98.a (a) 7-bromo-2-(chloromethyl)-5-cyclopropyl-6-methyl-oxazolo[4, 5-c]qui fbi in-4-one (a) 7-bromo-2-(chloromethyl)-5-cyclopropyl-6-methyl-oxazolo[4, 5-c]qui fbi in-4-one To a stirred suspension of 3-amino-7-bromo-1-cyclopropyl-4-hydroxy-8-methyl-quinolin-2- one (prepared as described in Exampie 4 step (a)) (5.46 g, 17.66 mmol) in DCM (60 mL) under N2 at 0 00 was added 2-chloro-1,1,1-trimethoxyethane (3.33 mL, 24.73 mmol) followed by boron trifluoride diethyl etherate (2.4 mL, 19.43 mmol) drop-wise. After 35 mm the reaction mixture was allowed to warm to room temperature, followed by the sequential addition of H20 (30 mL) and DCM (60 mL). After separation of the layers the aqueous was extracted with DCM (2 x 60 mL). The organic phases were combined and solvent removed in vacuo to give a residue which was purified by flash chromatography using a slow gradient of 0-50% EtOAc in DCM as eluent to give 7-bromo-2-(chloromethyl)-5-cyclopropyl- 6-methyl-oxazolo[4,5-c]quinolin-4-one (2.84 g, 44 %) as a pale pink solid.LC-MS (Method D) 367.2 [M+H] RT 3.15 mm. |
44% | With boron trifluoride diethyl etherate In dichloromethane at 0℃; for 0.583333h; Inert atmosphere; | a Intermediate 2 - 7-bromo-2-(chloromethyl)-5-cyclopropyl-6-methyl-oxazolol4,5- clguinolin-4-one To a stirred suspension of 3-amino-7-bromo-1-cyclopropyl-4-hydroxy-8-methyl-quinolin-2- one (Intermediate 1) (5.46 g, 17.66 mmol) in DCM (60 mL) under N2 at 000 was added 2- chloro-1,1,1-trimethoxyethane (3.33 mL, 24.73 mmol) followed by BF3.OEt2 (2.4 mL, 19.43 mmol) dropwise. After 35 mm the reaction mixture was allowed to warm to room temperature, followed by the sequential addition of H20 (30 mL) and DCM (60 mL). After separation of the layers the aq. was extracted with DCM (2 x 60 mL). The organic phases were combined and solvent removed in vacuo to give a residue which was purified by flash chromatography using a slow gradient of 0-50% EtOAc in DCM as eluent to give 7-bromo- 2-(chloromethyl)-5-cyclopropyl-6-methyl-oxazolo[4, 5-c]qui nol in-4-one (2.84 g, 44 %) as a pale pink solid.LC-MS (Method D) 367.2 [M+H] RT 3.15 mm |
44% | With boron trifluoride diethyl etherate In dichloromethane at 0℃; for 0.583333h; Inert atmosphere; | 98.a (a) 7-bromo-2-(chloromethyl)-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one To a stirred suspension of 3-amino-7-bromo-1-cyclopropyl-4-hydroxy-8-methyl-quinolin-2- one (prepared as described in Example 4 step (a)) (5.46 g, 17.66 mmol) in DCM (60 mL) under N2 at 0°C was added 2-chloro-1 , 1 , 1-trimethoxyethane (3.33 mL, 24.73 mmol) followed by boron trifluoride diethyl etherate (2.4 mL, 19.43 mmol) drop-wise. After 35 min the reaction mixture was allowed to warm to room temperature, followed by the sequential addition of H2O (30 mL) and DCM (60 mL). After separation of the layers the aqueous was extracted with DCM (2 χ 60 mL). The organic phases were combined and solvent removed in vacuo to give a residue which was purified by flash chromatography using a slow gradient of 0-50% EtOAc in DCM as eluent to give 7-bromo-2-(chloromethyl)-5-cyclopropyl- 6-methyl-oxazolo[4,5-c]quinolin-4-one (2.84 g, 44 %) as a pale pink solid. LC-MS (Method D) 367.2 [M+H]+; RT 3.15 min. |
44% | With boron trifluoride diethyl etherate In dichloromethane at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In ethanol for 1h; Reflux; | 1.11A 3-(Chloromethyl)-6-nitro[1,2,4]triazolo[4,3-a]pyridine 10.0 g (64.9 mmol) of 2-hydrazino-5-nitropyridine were initially charged in 125 ml of ethanol, and 17.5 ml (130 mmol, 2 eq.) of 2-chloro- 1,1,1 -trimethoxyethane were added. The mixture was heated at reflux for 1 h. The reaction mixture was then concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel 50, cyclohexane/ethyl acetate mixtures, then ethyl acetate/2-propanol mixtures). Yield: 13.1 g (95% of theory) 10572] LC/MS [Method 1]: R=0.52 mm; MS (ESIpos):mlz=2 13 (M+H), j0573] ‘H-NMR (400 MHz, DMSO-d5): ö [ppm]=9.84(dd, 1H), 8.12 (dd, 1H), 8.03 (dd, 1H), 5.57 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In dichloromethane at 20℃; | 34.3 Step-3: Synthesis of methyl 3-(2-(chloromethyl)-1H-benzoldlimidazol-6-yl)propanoate Into a 100-mL round-bottom flask, was placed a solution of methyl 3-(3,4-diaminophenyl)propanoate (460 mg, 2.37 mmol, 1.00 equiv), DCM (10 mL), p-toluenesulfonic acid (40.8 mg, 0.24 mmol, 0.10 equiv) and 2-chloro-1,1,1-trimethoxyethane (1095 mg, 7.08 mmol, 3.00 equiv). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 20 mL of H2O. The resulting solution was extracted with 3×20 mL of DCM, dried over anhydrous Na2SO4, and concentrated under vacuum. The crude product was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether. The collected fraction was concentrated to give methyl 3-(2-(chloromethyl)-1H-benzo[d]imidazol-6-yl)propanoate (650 mg, 109%) as a yellow solid. MS: (ES, m/z): 253[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In dichloromethane at 20℃; for 4h; | 41.1 Step-1: Synthesis of 2-(chloromethyl)-1H-1,3-benzodiazole-6-carbonitrile Into a 50-mL round-bottom flask, was placed 3,4-diaminobenzonitrile (500 mg, 3.76 mmol, 1.00 equiv), dichloromethane (10 mL), p-toluenesulfonic acid (64.75 mg, 0.38 mmol, 0.10 equiv), 2-chloro-1,1,1-trimethoxyethane (1.74 g, 11.26 mmol, 3.00 equiv). The resulting solution was stirred for 4 h at room temperature. The reaction was then quenched by the addition of 5 mL of water. The solids were collected by filtration to give 2-(chloromethyl)-1H-1,3-benzodiazole-6-carbonitrile (910 mg, crude) as a brown solid. MS: (ES, m/z): 192 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: allyl β-L-arabinopyranoside; 2-chloro-1,1,1-trimethoxyethane With toluene-4-sulfonic acid In acetonitrile for 1.16667h; Inert atmosphere; Stage #2: With trifluoroacetic acid In acetonitrile at 22℃; for 1h; Inert atmosphere; | Allyl 4-O-chloroacetyl-β-L-arabinopyranoside (12) Allyl β-L-arabinopyranoside 11 (691 mg, 3.60 mmol) was dissolved inCH3CN (20.0 mL) at 35 C. p-TsOH (19.1 mg, 0.12 mmol) and Trimethylchloro-orthoacetate (876 mg, 6.5 mmol) were added slowly to the reactionmixture, which was stirred at room temperature (20 C) for 10 min. TLC(MeOH:CH2Cl2, 1:10, v/v) showed complete consumption of starting material(1 h). The reaction mixture was concentrated in vacuo and re-solubilized inthe same amount of CH3CN. Then TFA (676 μL) was added and the reaction mixture was stirred for1h at room temperature. The reaction mixture was then concentrated in vacuo, and the resulting crudewas purified by flash column chromatography (MeOH:CH2Cl2, 1:10, v/v) to give compound 12 as apale yellow wax (640 mg, 2.40 mmol, 66%). Rf = 0.46 (acetone:toluene, 4:6, v/v). = +91.3 (c 1.0, CHCl3). IR (neat, cm-1): 3600-3100, 2927.5, 2344.0, 1675.3, 1453.0, 1200.7,1130.6. 1H NMR (400 MHz, CDCl3) δ: 5.91 (ddd, J = 17.2, 10.4, 5.3 Hz, 1H, Allyl CH=CH2), 5.30(ddd, J = 17.2, 3.0, 1.5 Hz, 1H, Allyl CH=CH2), 5.21 (dd, J = 10.4, 1.3 Hz, 1H, Allyl CH=CH2), 4.94(d, J = 3.5 Hz, 1H, H-1), 4.21 (ddt, J = 12.8, 5.3, 1.3 Hz, 1H, Allyl O-CH2), 4.10 - 3.69 (m, 8H, AllylO-CH2, H-2, H-3, H-4, H5, ChloroAc CH2), 2.47 (bs, 2H, OH). 13C NMR (100 MHz, CDCl3) δ:167.7, 133.4, 118.1, 97.7, 73.5, 69.3, 68.8, 68.4, 60.5, 41.0. HRMS (ESI-TOF) m/z: [M + Na]+ Calcdfor C24H23ClO8: 289.0449; Found 289.0450. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In 1,4-dioxane for 18h; Reflux; | 4.1.2. 2-Benzylthio-4-chloro-5-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]benzenesulfonamide (3) A mixture of 2-benzylthio-4-chloro-5-(carbazoyl)benzenesulfonamide (2) (5.56 g, 15 mmol) and 2-chloro-1,1,1-trimethoxyethane (3.48 g, 22.5 mmol) in 1,4-dioxane (40 mL) was refluxed for 18 h. Next, solvent was evaporated under reduced pressure, acetonitrile (15 mL) was added and suspension was stirred vigorously at room temperature for 1 h. The precipitate was filtered off washed with cold acetonitrile and dried, next crystallization from acetonitrile was performed. Yield 4.52 g (70%); mp 180-181 °C; IR (KBr) νmax 3380, 3321, 3278 (NH), 3078, 3030 (CAr-H), 2926, 2852 (C-H),1585, 1524, 1454, (CC, CN), 1340, 1173 (SO2)cm-1; 1H-NMR (DMSO-d6, 500 MHz) δ 4.53 (s, 2H, SCH2), 5.17 (s, 2H,CH2Cl), 7.29 (t, 1H, Ar), 7.36 (t, 2H, Ar), 7.46 (d, 2H, Ar), 7.79 (s, 2H,SO2NH2), 7.82 (s, 1H, H-3), 8.40 (s, 1H, H-6) ppm; 13C-NMR (DMSO-d6, 125 MHz) δ 33.8, 36.7, 118.7, 128.3, 139.3, 129.4, 129.9, 130.2,134.5, 136.0, 137.8, 145.9, 163.1 (C-50), 163.5 (C-20) ppm. Anal. C16H13Cl2N3O3S2 (C, H, N). |
In 1,4-dioxane for 18h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In ethanol; for 5h;Inert atmosphere; Reflux; | A mixture of <strong>[14543-43-2]3-amino-4-hydroxybenzonitrile</strong> (2.98 mmol) and 2-chloro-1,1,1-trimethoxyethane (3.28 mmol) in ethanol (15 mL) was stirred and refluxed for 5 h. The reaction mixture was cooled to room temperature then evaporated. Cold diethyl ether was poured to the crude residue and the generating insoluble solid was filtered off. The resulting filtrate was concentrated and the crude residue was purified by flash column chromatography (n-hexane:EtOAc = 5:1 ratio) to give compound 26 (86%, white solid).1H NMR (400MHz, CDCl3) delta 4.77 (s, 2H), 7.66-7.71 (m, 2H), 8.08-8.01 (m, 1H); LCMS (ESI) m/z 193 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With toluene-4-sulfonic acid In acetonitrile at 60℃; for 3h; | 7A-01.3 Step 3 To a stirred solution of tert-butyl 4-amino-3-((oxazol-2-ylmethyl)amino)benzoate (13 g, 45 mmol) in MeCN (100 mL) was added 2-chloro-1,1,1-trimethoxy ethane (9.0 ml, 65 mmol) and pTSA.H2O (400 mg, 2.1 mmol) and the mixture was heated at 60° C. for 3 h. The reaction was then cooled to RT and concentrated under reduced pressure. The crude product was purified by flash chromatography (120 g silica gel, 0-100% EtOAc/heptane gradient) to yield tert-butyl 2-(chloromethyl)-1-(oxazol-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (11.6 g, 74%) as a light yellow solid. 1H NMR (CDCl3) δ 8.19 (d, 1H), 7.98 (dd, 1H), 7.77 (d, 1H), 7.64 (d, 1H), 7.12 (d, 1H), 5.64 (s, 2H), 5.00 (s, 2H), 1.62-1.66 (m, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With toluene-4-sulfonic acid In tetrahydrofuran at 40 - 45℃; for 5.41667h; Large scale; | THF (150 kg) was added to this solution, followed by 2-chloro-1 ,1 ,1 -trimethoxyethane (35.1 kg, 227 mol) and p-toluenesulfonic acid monohydrate (1 .8 kg, 9.5 mol). After the reaction mixture had been stirred for 25 minutes, it was heated at 40 °C to 45 °C for 5 hours, whereupon it was concentrated under reduced pressure to a volume of 135 to 181 L. 2-Propanol (142 kg) was added, and the mixture was again concentrated to a volume of 135 to 181 L, whereupon 2- propanol (36.5 kg) and purified water (90 kg) were added, and stirring was continued until a solution was obtained. This was filtered with an in-line liquid filter, and then treated with purified water (447 kg) at a reference rate of 150 to 400 kg/hour at 20 °C to 40 °C. After the mixture had been cooled to 20 °C to 30 °C, it was stirred for 2 hours, and the solid was collected via filtration with a centrifuge. The filter cake was rinsed with a solution of 2-propanol (20.5 kg) and purified water (154 kg); after drying, P17 was obtained as a white solid (32.1 kg, 109 mol, 57%). 1H NMR (400 MHz, Chloroform-cf) 5 8.14 - 8.1 1 (m, 1 H), 8.01 (dd, 1 H), 7.79 (br d, 1 H), 5.26 - 5.18 (m, 1 H), 5.04 (s, 2H), 4.66 - 4.58 (m, 2H), 4.53 (dd, 1 H), 4.34 (dt, 1 H), 3.96 (s, 3H), 2.82 - 2.71 (m, 1 H), 2 |
57% | With toluene-4-sulfonic acid at 40 - 45℃; for 5.41667h; Large scale; | 7 Tetrahydrofuran (150 kg) was added to this solution, followed by 2-chloro-1 ,1 ,1- trimethoxyethane (35.1 kg, 227 mol) and p-toluenesulfonic acid monohydrate (1 .8 kg, 9.5 mol). After the reaction mixture had been stirred for 25 minutes, it was heated at 40 °C to 45 °C for 5 hours, whereupon it was concentrated under reduced pressure to a volume of 135 to 181 L. 2- Propanol (142 kg) was added, and the mixture was again concentrated to a volume of 135 to 181 L, whereupon 2-propanol (36.5 kg) and purified water (90 kg) were added, and stirring was continued until a solution was obtained. This was filtered with an in-line liquid filter, and then treated with purified water (447 kg) at a reference rate of 150 to 400 kg/hour at 20 °C to 40 °C. After the mixture had been cooled to 20 °C to 30 °C, it was stirred for 2 hours, and the solid was collected via filtration with a centrifuge. The filter cake was rinsed with a solution of 2-propanol (20.5 kg) and purified water (154 kg); after drying, P15 was obtained as a white solid (32.1 kg, 109 mol, 57%). 1H NMR (400 MHz, chloroform-d) d 8.14 - 8.11 (m, 1 H), 8.01 (dd, J = 8.5, 1.1 Hz, 1 H), 7.79 (br d, J = 8.6 Hz, 1 H), 5.26 - 5.18 (m, 1 H), 5.04 (s, 2H), 4.66 - 4.58 (m, 2H), 4.53 (dd, component of ABX pattern, J = 15.7, 2.7 Hz, 1 H), 4.34 (dt, J = 9.1 , 6.0 Hz, 1 H), 3.96 (s, (0230) 3H), 2.82 - 2.71 (m, 1 H), 2.48 - 2.37 (m, 1 H). |
With toluene-4-sulfonic acid In acetonitrile at 60℃; for 1h; | Methyl (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate To a solution of Intermediate 22 (127 g, 0.54 mol) in MeCN (500 mL) was added 2-chloro-1,1,1-trimethoxy ethane (76.2 ml, 0.57 mol) and pTSA.H2O (5.12 g, 26.9 mmol). The mixture was heated to 60° C. for 1 h. The reaction was cooled to RT and concentrated under reduced pressure. The resultant crude product was triturated in 50% EtOAc/heptane. The solids were collected by filtration to deliver Intermediate 23 (79 g, 50%) as a tan solid. 1H NMR (600 MHz, CDCl3) δ 8.12 (s, 1H), 8.00 (d, 1H), 7.79 (d, 1H), 5.16-5.26 (m, 1H), 5.03 (s, 2H), 4.57-4.66 (m, 2H), 4.48-4.56 (m, 1H), 4.33 (m, 1H), 3.95 (s, 3H), 2.71-2.81 (m, 1H), 2.36-2.47 (m, 1H). |
With toluene-4-sulfonic acid In tetrahydrofuran at 40 - 45℃; for 5h; Large scale; | 7 Tetrahydrofuran (150 kg) was added to this solution, followed by 2-chloro-1,1,1-trimethoxyethane (35.1 kg, 227 mol) and p-toluenesulfonic acid monohydrate (1.8 kg, 9.5 mol). After the reaction mixture had been stirred for 25 minutes, it was heated at 40° C. to 45° C. for 5 hours, whereupon it was concentrated under reduced pressure to a volume of 135 to 181 L. 2-Propanol (142 kg) was added, and the mixture was again concentrated to a volume of 135 to 181 L, whereupon 2-propanol (36.5 kg) and purified water (90 kg) were added, and stirring was continued until a solution was obtained. This was filtered with an in-line liquid filter, and then treated with purified water (447 kg) at a reference rate of 150 to 400 kg/hour at 20° C. to 40° C. After the mixture had been cooled to 20° C. to 30° C., it was stirred for 2 hours, and the solid was collected via filtration with a centrifuge. The filter cake was rinsed with a solution of 2-propanol (20.5 kg) and purified water (154 kg); after drying, P15 was obtained as a white solid (32.1 kg, 109 mol, 57%). 1H NMR (400 MHz, chloroform-d) δ 8.14-8.11 (m, 1H), 8.01 (dd, J=8.5, 1.1 Hz, 1H), 7.79 (br d, J=8.6 Hz, 1H), 5.26-5.18 (m, 1H), 5.04 (s, 2H), 4.66-4.58 (m, 2H), 4.53 (dd, component of ABX pattern, J=15.7, 2.7 Hz, 1H), 4.34 (dt, J=9.1, 6.0 Hz, 1H), 3.96 (s, 3H), 2.82-2.71 (m, 1H), 2.48-2.37 (m, 1H). | |
32.1 kg | With toluene-4-sulfonic acid In tetrahydrofuran at 40 - 45℃; for 5h; | P15.7 Tetrahydrofuran (150 kg) was added to this solution, followed by 2-chloro-1 ,1 ,1- trimethoxyethane (35.1 kg, 227 mol) and p-toluenesulfonic acid monohydrate (1.8 kg, 9.5 mol). After the reaction mixture had been stirred for 25 minutes, it was heated at 40 °C to 45 °C for 5 hours, whereupon it was concentrated under reduced pressure to a volume of 135 to 181 L. 2- Propanol (142 kg) was added, and the mixture was again concentrated to a volume of 135 to 181 L, whereupon 2-propanol (36.5 kg) and purified water (90 kg) were added, and stirring was continued until a solution was obtained. This was filtered with an in-line liquid filter, and then treated with purified water (447 kg) at a reference rate of 150 to 400 kg/hour at 20 °C to 40 °C. After the mixture had been cooled to 20 °C to 30 °C, it was stirred for 2 hours, and the solid was collected via filtration with a centrifuge. The filter cake was rinsed with a solution of 2-propanol (20.5 kg) and purified water (154 kg); after drying, P15 was obtained as a white solid (32.1 kg, (1489) 109 mol, 57%). 1H NMR (400 MHz, chloroform-d) d 8.14 - 8.11 (m, 1H), 8.01 (dd, J = 8.5, 1.1 Hz, 1H), 7.79 (br d, J = 8.6 Hz, 1H), 5.26 - 5.18 (m, 1H), 5.04 (s, 2H), 4.66 - 4.58 (m, 2H), 4.53 (dd, component of ABX pattern, J = 15.7, 2.7 Hz, 1 H), 4.34 (dt, J = 9.1 , 6.0 Hz, 1 H), 3.96 (s, (1490) 3H), 2.82 - 2.71 (m, 1 H), 2.48 - 2.37 (m, 1 H). |
1.6 g | With toluene-4-sulfonic acid In acetonitrile at 60℃; for 3h; | 1.3 3. Preparation of (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl este Methyl (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoate (2.9g crude product from the previous step),2-Chloro-1,1,1-trimethoxyethane (2.3g, 15mmol), p-toluenesulfonic acid (1.1g, 6.1mmol), acetonitrile (20mL), react at 60 for 3h, after the reaction is complete, add water ( 15mL), DCM was extracted three times (3*30mL), the organic phases were combined, dried with anhydrous sodium sulfate, filtered, spin-dried, and separated by normal phase preparative chromatography (PE:EA=1:1) to obtain 1.6g of product.The two-step yield was 46.6% |
With toluene-4-sulfonic acid In acetonitrile at 60℃; for 2h; | 1 (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6- carboxylate (1k). To a solution of (S)-methyl 4-amino-3-((oxetan-2-ylmethyl)amino)benzoate (1j, 880 mg, 3.72 mmol, 1 eq) and 2-chloro-1,1,1-trimethoxy- ethane (604.58 mg, 3.91 mmol, 525.72 uL, 1.05 eq) in MeCN (20 mL) was added PTSA (64.14 mg, 372.46 umol, 0.1 eq). The mixture was stirred at 60°C for 2 hours. LCMS showed one major peak with desired mass. The reaction mixture was concentrated. The crude product was purified by silica gel column chromatography (Petroleum ether: Ethyl acetate = 1:1~0:1) to give 1k as a yellow solid.1H NMR (400MHz, CDCl3-d) 8.13 (s, 1H), 8.02 (dd, J = 1.4, 8.6 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 5.22 (dq, J = 2.8, 7.0 Hz, 1H), 5.04 (s, 2H), 4.68-4.60 (m, 2H), 4.57-4.51 (m, 1H), 4.35 (td, J = 6.0, 9.2 Hz, 1H), 3.97 (s, 3H), 2.82-2.71 (m, 1H), 2.49-2.38 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: methyl 4-amino-3-[(2S)-oxetan-2-ylmethyl]amino}benzoate; 2-chloro-1,1,1-trimethoxyethane With toluene-4-sulfonic acid In acetonitrile at 60℃; for 1h; Stage #2: 2-((4-chloro-2-fluorobenzyl)oxy)-6-(piperidin-4-yl)pyridine bis(4-methylbenzenesulfonate) With potassium carbonate In acetonitrile for 2h; | 3A-01.1 Step 1 To a stirred solution of Intermediate 22 (49.8 g, 211 mmol) in MeCN (300 mL) was added 2-chloro-1,1,1-trimethoxyethane (30.0 mL, 223 mmol) followed by pTSA.H2O (2.0 g, 10 mmol). After 1 h at 60° C., MeCN (400 mL), K2CO3 (116 g, 841 mmol) and Intermediate 3 (52.4 g, 90.2 mmol) were added. After 2 h, the solution was treated with water (1.6 L), allowed to cool to RT and stirred for 2 h. The resulting solid precipitate was collected by filtration, washed with water (2*300 mL) and dried under reduced pressure to provide methyl (S)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate as a solid (102 g, 84%). 1H NMR (DMSO-d6) δ 8.30 (s, 1H), 7.82 (d, 1H), 7.67 (d, 1H), 7.62 (t, 1H), 7.55 (t, 1H), 7.45 (d, 1H), 7.29 (d, 1H), 6.87 (d, 1H), 6.67 (d, 1H), 5.37 (s, 2H), 5.04-5.16 (m, 1H), 4.82 (dd, 1H), 4.62-4.73 (m, 1H), 4.44-4.52 (m, 1H), 4.37 (dt, 1H), 3.96 (d, 1H), 3.87 (s, 3H), 3.78 (d, 1H), 3.00 (d, 1H), 2.85 (d, 1H), 2.66-2.76 (m, 1H), 2.54-2.64 (m, 1H), 2.38-2.49 (m, 1H), 2.24 (t, 2.11-2.21 (m, 1H), 1.60-1.88 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: methyl 4-amino-3-[(2S)-oxetan-2-ylmethyl]amino}benzoate; 2-chloro-1,1,1-trimethoxyethane With toluene-4-sulfonic acid In acetonitrile at 50℃; for 2h; Stage #2: 3-fluoro-4-(((6-(piperidin-4-yl)pyridiny-2-yl)oxy)methyl)nemzonitrile bis(4-methylbenzenesulfonate) With potassium carbonate In acetonitrile for 2h; | 4A-01.1 Step 1 To a stirred solution of Intermediate 22 (33.6 g, 142 mmol) in MeCN (285 mL) was added 2-chloro-1,1,1-trimethoxyethane (20.1 mL, 149 mmol) followed by pTSA.H2O (1.35 g, 7.1 mmol). After 2 h at 50° C., MeCN (280 mL), K2CO3 (79 g, 570 mmol) and Intermediate 4 (93.2 g, 142 mmol) were added. After 2 h, the solution was treated with water (800 mL), allowed to cool to RT and stirred for 2 h. The resulting precipitate was collected by filtration, washed with 10% MeCN in water (150 mL), water (2*200 mL) and then dried under reduced pressure to provide methyl (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate as a colorless solid (77 g, 95%). 1H NMR (600 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.87 (d, 1H), 7.80 (d, 1H), 7.55-7.73 (m, 4H), 6.87 (d, 1H), 6.70 (d, 1H), 5.45 (s, 2H), 5.04-5.19 (m, 1H), 4.81 (dd, 1H), 4.66 (dd, 1H), 4.41-4.54 (m, 1H), 4.36 (dt, 1H), 3.94 (d, 1H), 3.86 (s, 3H), 3.76 (d, 1H), 2.97 (d, 1H), 2.82 (d, 1H), 2.63-2.77 (m, 1H), 2.49-2.63 (m, 1H), 2.37-2.46 (m, 1H), 2.18-2.29 (m, 1H), 2.05-2.18 (m, 1H), 1.47-1.82 (m, 4H). |
95% | Stage #1: methyl 4-amino-3-[(2S)-oxetan-2-ylmethyl]amino}benzoate; 2-chloro-1,1,1-trimethoxyethane With toluene-4-sulfonic acid In acetonitrile at 50℃; for 2h; Stage #2: 3-fluoro-4-(((6-(piperidin-4-yl)pyridiny-2-yl)oxy)methyl)nemzonitrile bis(4-methylbenzenesulfonate) With potassium carbonate In acetonitrile at 50℃; for 2h; | 103.1 Step 1 To a stirred solution of Intermediate 103-3 (33.6 g, 142 mmol) in MeCN (285 mL) was added 2-chloro-1 ,1 ,1-trimethoxyethane (20.1 mL, 149 mmol) followed by pTSA•H20 (1.35 g, 7.1 mmol). After 2 h at 50 °C, MeCN (280 mL), K2CO3 (79 g, 570 mmol) and Intermediate 103-0 (93.2 g, 142 mmol) were added. After 2 h, the solution was treated with water (800 mL), allowed to cool to RT and stirred for 2 h. The resulting precipitate was collected by filtration, washed with 10% MeCN in water (150 mL), water (2 x 200 mL) and then dried under reduced pressure to provide methyl (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1 -yl)methyl)-1 - (oxetan-2-ylmethyl)-1 H-benzo[d]imkjazole-6-carboxylate as a colorless solid (77 g, 95%). 1H NMR (600 MHz, DMSO-d6) d 8.28 (s, 1 H), 7.87 (d, 1 H), 7.80 (d, 1 H), 7.55-7.73 (m, 4H), 6.87 (d, 1 H), 6.70 (d, 1 H), 5.45 (s, 2H), 5.04-5.19 (m, 1 H), 4.81 (dd, 1 H), 4.68 (dd, 1 H), 4.41-4.54 (m, 1 H), 4.36 (dt, 1 H), 3.94 (d, 1 H), 3.88 (s, 3H), 3.76 (d, 1 H), 2.97 (d, 1 H), 2.82 (d, 1 H), 2.63-2.77 (m, 1 H), 2.49-2.63 (m, 1 H), 2.37-2.48 (m, 1 H), 2.18-2.29 (m, 1 H), 2.05-2.18 (m, 1 H), 1.47-1.82 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With toluene-4-sulfonic acid at 100℃; for 1h; | 301.3 3. Step- Synthesis of 6-chloro-2-(chloromethyl)-1-isopropyl-imidazo [4,5- c]pyridine To a solution of 6-chloro-N4-isopropyl-pyridine-3,4-diamine (1.3 g, 7.00 mmol, 1 eq) in 2-chloro-1,1,1-trimethoxy-ethane (4.60 g, 29.76 mmol, 4.0 mL, 4.25 eq) was added p- toluenesulfonic acid monohydrate (133 mg, 0.70 mmol, 0.1 eq), the mixture was stirred at 100 °C for 1 hour. Thin layer chromatography (petroleum ether/ethyl acetate = 3/1) showed one major new spot with lower polarity was detected. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 3/1) to afford 6-chloro-2-(chloromethyl)-1-isopropyl-imidazo[4,5-c] pyridine (0.82 g, 3.36 mmol, 48% yield) as a light yellow solid.1H NMR: (400MHz, CDCl3) δ: 8.76 (s, 1H), 7.98 (s, 1H), 5.14 (s, 2H), 4.85-4.93 (m, 1H), 1.58 (d, J = 6.8 Hz, 6H). Chemical Formula: C10H11Cl2N3, Molecular Weight: 244.12 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.1% | With sodium hydrogencarbonate; potassium iodide In N,N-dimethyl-formamide at 60℃; | 1.1 First step: preparation of compound 3 Compound 1 (5.0 g, 18.99 mmol) was dissolved in DMF (50 mL).3.23 g, 20.89 mmol), potassium iodide (320 mg, 1.93 mmol), sodium hydrogencarbonate (3.19 g, 37.97 mmol). After the feeding is completed,The reaction system was gradually warmed to 60 ° C, stirred for 11 to 12 hours; the solvent was concentrated under reduced pressure and ethyl acetate (EtOAc)The mixture was dissolved, and purified water (50 mL) was added; the organic phase was washed with purified water (50 mL) and brine (50 mL);The organic phase is dried over anhydrous sodium sulfate, filtered and evaporatedEtOAc.1) Compound 3 (5.8 g, yield: 80.1%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In dichloromethane at 20 - 25℃; | 1 Example 1 As shown in FIG. 3, a preparation method of a dabigatran etexilate intermediate, the specific process steps are as follows:Compound 8 (5.0 g, 14.60 mmol) was dissolved in dichloromethane (50 mL).Compound 5 (trimethyl 2-chloro orthoacetate, 6.77 g, 43.81 mmol),P-toluenesulfonic acid (251 mg, 1.46 mmol); after the addition, the reaction system is between 20 and 25The reaction was carried out at °C for 11 to 12 hours; after the reaction was completed, purified water (30 mL) was added, and the mixture was separated and extracted with water, and then extracted with dichloromethane.(20 mL of X 2); EtOAc (EtOAc)EtOAc.Concentrated to a crude product by column chromatography (eluent:Methylene chloride:methanol = 15:1) Compound 9 (4.7 g, yield: 80.3%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In acetonitrile at 20℃; for 1h; | 1 Allyl 2-O-chIoroacetyl-4-0-(2-naphtylmethyl)-a-L-rhamnopyranoside (13) Diol 1 (2.0 g, 6.0 mmol) was solubilized in anhydrous MeCN (5.0 mL). To the solution was added trimethylchloroorthoacetate (2.35 mL, 3.0 equiv) and PTSA (90 mg, 0.08 equiv). The solution was stirred at room temperature for 1 hour (reaction followed by TLC Toluene/EtOAc 7:3). To the reaction medium cooled to 0 °C was added a 90% aqueous TFA (3.0 mL) and the reaction mixture was stirred at room temperature for 15 min. Water (20 mL) was added. The product was extracted with DCM (2 x 40 mL). The organic phase was washed with saturated aqueous NaHC03 (2 x 25 mL) and brine (25 mL). The aqueous phase was extracted with DCM (2 x 25 mL). The combined organic phases were dried over Na2S04, filtered, evaporated and finally co-evaporated with toluene to yield the crude alcohol 13 as a 92:8 mixture of regioisomers. | |
With toluene-4-sulfonic acid In acetonitrile at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In acetonitrile at 20℃; for 1h; | 1 Allyl 2-para-methoxybenzyl-a-L-rhamnopyranoside (28) Diol 27 (1.0 g, 3.0 mmol) was solubilized in anhydrous acetonitrile (MeCN, 5 mL). To the solution was added trimethylchloroorthoacetate (1.39 mL, 3.0 equiv) and APTS (59 mg, 0.1 equiv). The solution was stirred at room temperature for 1 hour (reaction followed by TLC toluene/EtOAc 7:3). To the reaction medium cooled to 0 °C was added a 90% aqueous TFA (2.0 mL) and the reaction mixture was stirred at room temperature for 10 min. Water was added until the mixture became completely cloudy. The product was extracted with DCM (2 x 25 mL). The organic phase was washed with saturated aqueous NaHC( (2 x 25 mL) and brine (25 mL). The aqueous phase was extracted with DCM (2 x 12.5 mL). The combined organic phases were dried over Na2S0 , filtered, evaporated and finally co-evaporated with toluene to yield alcohol 28 as a mixture of regioisomers. The crade material is used as such in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With p-toluenesulfonyl chloride In dichloromethane at 20℃; for 4h; Inert atmosphere; | 1 4-[5-Bromo-2-(chloromethyl)benzimidazole-1-1]butanenitrile (NP-RSV-007) General procedure: A solution of the N-alkylated 4-bromobenzene-l,2-diamine (1.0 eq.), 2-chloro-1,1,1- trimethoxy-ethane (3.0 eq.) and p-toluenesulfonyl chloride monohydrate (0.1 eq.) in DCM was stirred vigorously at room temperature, under an atmosphere of argon for approximately 4 hours, until TLC confirmed full consumption of the starting material. The reaction was then concentrated in vacuo and the resulting crude product was dry-loaded onto silica gel. Purification was undertaken with column chromatography. NP-RSV-007 was synthesized according to general procedure C as described above. The following quantities were employed: NP-RSV-5 (200 mg, 0.787 mmol), 2-chl oro- 1, 1,1- trimethoxyethane (0.32 mL, 2.36 mmol) and p-TsOH H20 (15 mg, 0.079 mmol) in DCM (4 mL). This procedure yielded NP-RSV-007 (215 mg, 0.688 mmol, 87%) as a pale-yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 1.7 Hz, 1H), 7.44 (dd, J = 8.6, 1.8 Hz, 1H), 7.30 - 7.23 (m, 1H), 4.83 (s, 2H), 4.38 (t, J = 7.4 Hz, 2H), 2.45 (t, J = 6.9 Hz, 2H), 2.31 - 2.23 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 149.8, 143.6, 134.2, 127.4, 123.6, 118.4, 116.2, 110.9, 42.8, 36.6, 25.5, 15.0. HRMS calc. for Ci2Hi2BrClN3, 311.98976 found, 311.99105. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 120℃; for 3h;Inert atmosphere; | A solution of <strong>[64321-24-0]2-amino-6-chloro-pyridine-3-carboxamide</strong> (500 mg, 2.91 mmol, 1.0 eq) in 2-chloro-1,1,1-trimethoxy-ethane (5 mL) was heated at 120 C. under a N2 atmosphere for 3 h. The mixture was then filtered and the filter cake was washed with EtOAc/petroleum ether (1:3, 20 mL) then dried under reduced pressure to afford the title compound (450 mg, ?50% purity, 33%) as a brown solid, which was used without further purification. LCMS: [M+H]+ 230.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With p-toluenesulfonic acid monohydrate In tetrahydrofuran at 45℃; | 17.17c Step 17c: Methyl 2-(chloromethyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate(Compound 0120-23) preparation: To methyl 4-amino-3-((2-methoxyethyl)amino)benzoate (0119-23) (1.03 g, 4.60 mmol, 1.0 equivalent)And p-toluenesulfonic acid monohydrate (17.5 mg, 0.09 mmol, 0.02 equivalent)In tetrahydrofuran (20ml)Add to the mixture2-Chloro-1,1,1-trimethoxyethane (0.78 g, 5.06 mmol, 1.1 equivalents).The mixture was heated to 45°C and reacted overnight. reduceRemove the solvent by pressure. The residue was subjected to column chromatography on silica gel (petroleum ether: ethyl acetate 5:1) to obtain 2-(chloromethyl)-1-(2-methoxyethyl)-1H-benzo[d ] Methyl imidazole-6-carboxylate (1.25 g, yield: 93%). |
91% | With toluene-4-sulfonic acid In tetrahydrofuran at 45℃; for 5h; | 3 Step 3. Synthesis of methyl 2-(chloromethyl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate (P11) To a solution of C16 (5.00 g, 22.3 mmol) in tetrahydrofuran (100 mL) was added 2-chloro-1,1,1-trimethoxyethane (3.31 mL, 24.6 mmol), followed by p-toluenesulfonic acid monohydrate (84.8 mg, 0.446 mmol). The reaction mixture was heated at 45° C. for 5 hours, whereupon it was concentrated in vacuo; the residual oil was dissolved in ethyl acetate (10 mL) and heated until a solution formed. This was slowly stirred while cooling to room temperature overnight. The precipitate was collected via filtration and washed with heptane to afford P11 as a gray solid. Yield: 5.73 g, 20.3 mmol, 91%. 1H NMR (600 MHz, chloroform-d) δ 8.12 (br s, 1H), 8.01 (br d, J=8.6 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 4.96 (s, 2H), 4.52 (t, J=5.1 Hz, 2H), 3.96 (s, 3H), 3.74 (t, J=5.1 Hz, 2H), 3.28 (s, 3H). |
91% | With toluene-4-sulfonic acid In tetrahydrofuran at 45℃; for 5h; | 1 Step 1. Synthesis of methyl 2-(chloromethyl)-1-(2-methoxyethyl)-1H-benzimidazole-6- carboxylate (P20). To a solution of C50 (5.00 g, 22.3 mmol) in THF (100 ml_) was added 2-chloro-1 ,1 ,1 - trimethoxyethane (3.31 ml_, 24.6 mmol), followed by p-toluenesulfonic acid monohydrate (84.8 mg, 0.446 mmol). The reaction mixture was heated at 45 °C for 5 hours, whereupon it was concentrated in vacuo] the residual oil was dissolved in EtOAc (10 ml_) and heated until a solution formed. This was slowly stirred while cooling to room temperature overnight. The precipitate was collected via filtration and washed with heptane to afford P20 as a gray solid. Yield: 5.73 g, 20.3 mmol, 91 %. 1H NMR (600 MHz, Chloroform-d) d 8.12 (br s, 1 H), 8.01 (br d, 1 H), 7.79 (d, 1 H), 4.96 (s, 2H), 4.52 (t, 2H), 3.96 (s, 3H), 3.74 (t, 2H), 3.28 (s, 3H). |
91% | With toluene-4-sulfonic acid In tetrahydrofuran at 45℃; for 5h; | P11.3 Step 3. Synthesis of methyl 2-(chloromethyl)- 1 -(2-methoxyethyl)-1H-benzimidazole-6- carboxylate (P11). To a solution of C16 (5.00 g, 22.3 mmol) in tetrahydrofuran (100 mL) was added 2- chloro-1 ,1 ,1-trimethoxyethane (3.31 mL, 24.6 mmol), followed by p-toluenesulfonic acid monohydrate (84.8 mg, 0.446 mmol). The reaction mixture was heated at 45 °C for 5 hours, whereupon it was concentrated in vacuo; the residual oil was dissolved in ethyl acetate (10 mL) and heated until a solution formed. This was slowly stirred while cooling to room temperature overnight. The precipitate was collected via filtration and washed with heptane to afford P11 as a gray solid. Yield: 5.73 g, 20.3 mmol, 91%. 1H NMR (600 MHz, chloroform-d) d 8.12 (br s, 1 H), 8.01 (br d, J = 8.6 Hz, 1 H), 7.79 (d, J = 8.4 Hz, 1 H), 4.96 (s, 2H), 4.52 (t, J = 5.1 Hz, 2H), 3.96 (s, 3H), 3.74 (t, J = 5.1 Hz, 2H), 3.28 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: C18H17NO5S; acetic acid; 2-chloro-1,1,1-trimethoxyethane With triethylamine at 120℃; for 4h; Stage #2: With potassium acetate In methanol; isopropyl alcohol at 25 - 60℃; for 0.5h; | 2 Example 2 (Synthesis of Compound No. 8 of Specific Example Compound) 1.7 parts of acetic acid, 0.7 parts of triethylamine, 1.1 parts of a compound represented by the following formula (A) and 3 parts of trimethyl orthochloroacetate are added to a reaction vessel, and the mixture is reacted at 120 ° C. for 4 hours. After cooling, the precipitated solid was filtered and washed with 20 parts of isopropanol. After adding 10 parts of methanol to the obtained solid and stirring at 50 ° C., 1 part of potassium acetate was added and heated at 60 ° C. for 30 minutes. The precipitated solid was filtered, washed with 10 parts of methanol, and dried to obtain No. 1 of the specific example. 0.3 part of the compound represented by 8 was obtained. The compound had a maximum absorption wavelength λmax of 536 nm (DMF). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: C18H17NO5S; 2-chloro-1,1,1-trimethoxyethane With acetic acid; triethylamine at 80℃; for 2h; Stage #2: With potassium acetate In methanol at 25 - 60℃; for 0.5h; | 1 Example 1 (Synthesis of Compound No. 2 of Specific Example Compound) 1.1 parts of acetic acid in a reaction vessel,0.5 parts of triethylamine,Formula (A) aboveCompound 0.7 represented byDepartmentAndTrimethyl orthochloroacetate2Part,After reacting at 80 ° C for 2 hours,Cool to 25 ° C,The obtained reaction solution was concentrated. After adding 40 parts of methanol to the obtained solid and stirring at 50 ° C, 1 part of potassium acetate was added, and the mixture was heated at 60 ° C for 30 minutes. The precipitated solid was filtered, washed with 10 parts of methanol, and dried to obtain No. 1 of the specific example. 0.4 part of the compound represented by 2 was obtained. The compound had a maximum absorption wavelength λmax of 556 nm (DMF). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With acetic acid at 70℃; for 1h; | 42.g Step g. To a solution of the product from step f in acetic acid (5 ml) was added 2-chloro-1,1,1- trimethoxyethane (197 mg, 1.28 mmol). The reaction was stirred at 70 °C for 1 hour. The solution was cooled, concentrated and purified by RPLC (5% to 50% acetonitrile and water, using 0.1% TFA as modifier). Yield 38 mg, 32 %. Ion found by LCMS: [M + H]+ = 555.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With acetic acid at 70℃; for 2h; | 44.c Step c 2-Chloromethyl-1,1,1-trimethoxy ethane (1.08 g, 7.02 mmol) was added to the diamine intermediate, described in step-b of this example, (650 mg, 1.40 mmol) dissolved in glacial acetic acid (15 mL) and the reaction was stirred at 70°C for 2 hours. The mixture was concentrated on the rotary evaporator and purified by silica gel chromatography (Isco Combi Flash, 0 to 4 % methanol/DCM, 25 minute gradient). The pure fractions were pooled and concentrated to afford the product as a brown oil. Yield 71%. LC/MS [M+H]+ = 521.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With acetic acid In toluene at 130℃; for 24h; | Synthesis of Dimethyl 2-chloro-4-methylenepentanedioate (9): Methyl 2-(hydroxymethyl)acrylate (5.0 g, 43.06 mmol), d = 1.13 g/mL) and 2-Chloro-1,1,1-ethoxyethane (8.0 mL, 51.67 mmol, d = 1.15 g/mL)were added together in 200 mL round bottom flask with 100 mL tolueneand catalytic amount acetic acid (1 mL, 4.31 mmol). The reactionmixture was refluxed for 24 h at 130 C. The completion of reaction wasmonitored by TLC. The reaction mixture was subjected to azeotropicdistillation with toluene under reduced pressure (3x50 mL) to providethe desired compound obtained as a yellow oil and used as such withoutfurther purification, yield 85%. 1H NMR (500 MHz, Chloroform-d) δ6.32 (s, 1H), 5.74 (s, 1H), 4.54 (dd, J = 8.2, 6.4 Hz, 1H), 3.76 (s, 6H),3.06 (dd, J = 14.3, 6.3 Hz, 1H), 2.82 (dd, J = 14.2, 8.3 Hz, 1H). 13C NMR(126 MHz, CDCl3) δ 169.7, 166.6, 134.7, 130.1, 54.9, 53.0, 52.2, 37.9.HRMS (ESI-): m/z 207.0414 [M + H]+; calculated for C8H11ClO4 [M +H]+ 207.0419 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With boron trifluoride diethyl etherate In dichloromethane at 0 - 20℃; | 4.4.8 General method for the preparation of compounds 14a-14c General procedure: To a 0°C solution of 2-chloro-1,1,1-trimethoxyethane (1.5 equiv.) in anhydrous DCM, BF3·Et2O (1.1-2 equiv.) was added dropwise followed by the addition of the diamines 13a-13c (1 equiv.). The reaction mixture was stirred at room temperature overnight. The reaction was then quenched by the addition of a saturated aqueous solution of NaHCO3. The product was extracted by DCM 3 times, and the combined organic phases were washed with brine, dried over anhydrous Na2SO4, and the solvent was evaporated in vacuo to afford the desired product which was used without further purification.4.4.8.1 Methyl 2-(chloromethyl)-3-methyl-benzimidazole-5-carboxylate (14a) (0053) Following the general procedure, the reaction was performed with 2-chloro-1,1,1-trimethoxyethane (516mg, 3.34mmol, 1.5 equiv.), 12mL anhydrous DCM, 13a (400.2mg, 2.22mmol, 1 equiv.) and BF3·Et2O (727.4mg, 2.46mmol, 1.1 equiv.). Compound 14a was obtained as a pale-yellow solid in 94% yield (496.4mg). The reported 1H NMR matches the literature [44]. 1H NMR (400MHz, CD3OD) δ 8.19 (dd, J=1.7, 0.7Hz, 1H, ArH), 7.94 (dd, J=8.5, 1.6Hz, 1H, ArH), 7.67 (dd, J=8.5, 0.8Hz, 1H, ArH), 4.98 (s, 2H), 3.95 (d, J=0.6Hz, 6H). 13C NMR (101MHz, CD3OD) δ 167.18, 152.82, 144.50, 135.48, 125.29, 123.67, 118.43, 112.18, 51.33, 35.37, 29.45. HRMS calcd for C11H11N2O2Cl+H+ (M+H)+: 239.0587, found: 239.0589. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With boron trifluoride diethyl etherate In dichloromethane at 0 - 20℃; | 4.4.8 General method for the preparation of compounds 14a-14c General procedure: To a 0°C solution of 2-chloro-1,1,1-trimethoxyethane (1.5 equiv.) in anhydrous DCM, BF3·Et2O (1.1-2 equiv.) was added dropwise followed by the addition of the diamines 13a-13c (1 equiv.). The reaction mixture was stirred at room temperature overnight. The reaction was then quenched by the addition of a saturated aqueous solution of NaHCO3. The product was extracted by DCM 3 times, and the combined organic phases were washed with brine, dried over anhydrous Na2SO4, and the solvent was evaporated in vacuo to afford the desired product which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With boron trifluoride diethyl etherate In dichloromethane at 0 - 20℃; | 4.4.8 General method for the preparation of compounds 14a-14c General procedure: To a 0°C solution of 2-chloro-1,1,1-trimethoxyethane (1.5 equiv.) in anhydrous DCM, BF3·Et2O (1.1-2 equiv.) was added dropwise followed by the addition of the diamines 13a-13c (1 equiv.). The reaction mixture was stirred at room temperature overnight. The reaction was then quenched by the addition of a saturated aqueous solution of NaHCO3. The product was extracted by DCM 3 times, and the combined organic phases were washed with brine, dried over anhydrous Na2SO4, and the solvent was evaporated in vacuo to afford the desired product which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45.44% | With p-toluenesulfonic acid monohydrate In tetrahydrofuran at 45℃; | 18.18c Step 18c: ((S)-2-(chloromethyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (Compound 0120-24 Preparation of ): (S)-4-amino-3-(((tetrahydrofuran-2-yl)methyl)amino)methyl)benzoate (0119-24) (1090 mg, 4.35 mmol, 1.0 Equivalent), 2-chloro-1,1,1-trimethoxyethane (807 mg, 5.55 mmol, 1.2 unit) and p-toluenesulfonic acid monohydrate (89.889 mg, 0.522 mmol, 0.12 unit) The tetrahydrofuran (10 mL) solution was heated to 45°C and stirred overnight. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure To obtain (S)-2-(chloromethyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (609.5 mg, yield: 45.44%) is a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | at 130℃; for 2h; | 1 Synthesis of 2-(chloromethyl)-4-(trifluoromethyl)benzo[d]oxazole [00215] A mixture of 2-amino-3-(trifluoromethyl)phenol (1.00 g, 5.65 mmol) and 2-chloro-1,1,1-trimethoxyethane (4.36 g,28.20 mmol) was stirred for 2 h at 130°C under a nitrogen atmosphere. The resulting mixture was cooled to room temperature and concentrated onto silica gel. The resulting residue was purified by flash column chromatography, eluting with 17% ethyl acetate in petroleum ether to afford 2-(chloromethyl)-4-(trifluoromethyl)-1,3-benzoxazole as a yellow oil. [00216] Yield 1.00 g (75%). 1H NMR (400 MHz, DMSO) d 8.16 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.67 (dd, J = 7.6, 8.4 Hz, 1H), 5.18 (s,2H). m/z: [ESI+] 236,238 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With toluene-4-sulfonic acid In dichloromethane at 25℃; for 16h; Inert atmosphere; | 43 4-bromo-2-(chloromethyl)-6-nitro-1H-benzo[d]imidazolee (43A) To a solution of 3-Bromo-5-nitro-1,2-diaminobenzene (5A) (5.0 g, 22 mmol) in DCM (100 mL) under N2 was added 2-chloro-1,1,1-trimethoxyethane (6.65 g, 108 mmol) and p-TsOH.1-120 (0.41 g, 2.2 mmol). The mixture was stirred 25° C. for 16 h at which time, it was diluted with water (50 mL) and extracted with DCM (50 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (PE:EA=10:1˜6:1) to give (43A) (5.1 g, yield: 80%) as a yellow solid. LCMS: (ES+): m/z 290.0 [M+1]+. |
80% | With toluene-4-sulfonic acid In dichloromethane at 25℃; for 16h; Inert atmosphere; | 43 4-bromo-2-(chloromethyl)-6-nitro-1H-benzo[d]imidazolee (43A) To a solution of 3-Bromo-5-nitro-1,2-diaminobenzene (5A) (5.0 g, 22 mmol) in DCM (100 mL) under N2 was added 2-chloro-1,1,1-trimethoxyethane (6.65 g, 108 mmol) and p-TsOH.1-120 (0.41 g, 2.2 mmol). The mixture was stirred 25° C. for 16 h at which time, it was diluted with water (50 mL) and extracted with DCM (50 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (PE:EA=10:1˜6:1) to give (43A) (5.1 g, yield: 80%) as a yellow solid. LCMS: (ES+): m/z 290.0 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In acetonitrile at 60℃; for 16h; | 125 Methyl 2-(chloromethyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H- benzo[d]imidazole-6-carboxylate (125h). To the solution of methyl 4-amino-3-(((1-ethyl-1H- imidazol-5-yl)methyl)amino)benzoate (125g, 20 mg, 72.91 umol) in ACN (2 mL) was added 2-chloro-1,1,1-trimethoxy-ethane (22.54 mg, 145.82 umol, 19.60 uL) and TsOH (1.26 mg, 7.29 umol). The mixture was stirred at 60°C for 16 hours. LCMS showed 125g was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to give 125h as a yellow solid. The product was used directly in next step. MS mass calculated for [M+H]+ (C16H17ClN4O2) requires m/z 333.1, LCMS found m/z 333.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In acetonitrile at 60℃; for 6.5h; Inert atmosphere; | 140 Methyl 2-(chloromethyl)-1-((1,1-dioxidothietan-2-yl)methyl)-1H- benzo[d]imidazole-6-carboxylate (140h). To a mixture of methyl 4-amino-3-(((1,1- dioxidothietan-2-yl)methyl)amino)benzoate (140g, 120 mg, 422.04 umol) and 2-chloro-1,1,1- trimethoxy-ethane (94.60 mg, 611.96 umol, 82.26 uL) in CH3CN (5 mL) under N2. The mixture was added PTSA (7.27 mg, 42.20 umol). The reaction mixture was stirred at 60°C for 6 hours. LCMS showed the starting material was consumed and desired mass was detected. The reaction mixture was poured into water (15 mL) and extracted with ethyl acetate (30 mL*2). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep- TLC (SiO2, Petroleum ether: Ethyl acetate= 0: 1) to give 140h as a light yellow solid.1H NMR (400 MHz, MeOD-d4) 8.45 (s, 1H), 8.03 (dd, J = 1.4, 8.6 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H), 5.26 (d, J = 12.8 Hz, 1H), 5.12-4.93 (m, 3H), 4.87-4.74 (m, 1H), 4.22-3.99 (m, 2H), 3.96 (s, 3H), 2.12-1.92 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In ethyl acetate at 70℃; for 3h; | 6 3-fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzonitrile (6f). To a solution of tert-butyl 4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidine-1- carboxylate (6m, 9.5 g, 23.09 mmol, 1 eq) in EtOAc (500 mL) was added PTSA (11.93 g, 69.26 mmol, 3 eq). The resulted reaction mixture was stirred at 70 °C for 3 hours. LCMS showed 6m was consumed, and desired mass was detected. Saturated NaHCO3 (500 mL) was added to the reaction mixture and the organic layer was separated and concentrated to give crude 6f (TsOH salt) as a white solid. The crude product was used in the next step without purification |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.3% | With toluene-4-sulfonic acid In tetrahydrofuran at 70℃; for 12h; | 35.5 (5) Preparation of compound 35-6 TsOH.H. was added to THF (20 mL) solutions of 35-5a (0.5 g, 1.83 mmol, 1.0 eq) and 2-chloro-1,1,1-trimethoxyethane (0.562 g, 3.65 mmol, 2.0 eq). 2 O(35mg0183mmol0.1eq) The mixture was stirred at 70 °C for 12 hours. LCMS monitored, concentrated mixture, to obtain residues, which were purified by silica gel column chromatography, elution with (MeOH/DCM = 0-10%) to give 2-(chloromethyl)-1-((1-ethyl-1H-imidazole-4-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate, 35-6 (0.3g, 49.3% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With toluene-4-sulfonic acid In tetrahydrofuran at 50℃; for 16h; | 47.1 At 50 °C, to 4-amino-3- (((1-(hydroxymethyl)cyclopropyl)amine)) methyl benzoate (1.7g, 6.8mmol) in 30 mL THF solution, stirring while adding 2-chloro-1,1,1-trimethoxyethane (3.142 g, 20.4 mmol)) and TsOH (129.2 mg, 0.68 mmol) for 16 hours. LCMS detection. By adding saturated NaHCO3aqueous solution (50mL) quenching reaction mixture, extracted with EtOAc (30mL×3), washed with brine and dried, concentrated to give a crude product, which was further purified (EA/PE = 10 ~ 51%) to give 2-(chloromethyl)-1-((1-(hydroxymethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (1.5g, 71% yield). |
Tags: 74974-54-2 synthesis path| 74974-54-2 SDS| 74974-54-2 COA| 74974-54-2 purity| 74974-54-2 application| 74974-54-2 NMR| 74974-54-2 COA| 74974-54-2 structure
[ 51076-95-0 ]
2-Chloro-1,1,1-triethoxyethane
Similarity: 0.91
[ 51076-95-0 ]
2-Chloro-1,1,1-triethoxyethane
Similarity: 0.91
[ 51076-95-0 ]
2-Chloro-1,1,1-triethoxyethane
Similarity: 0.91
[ 51076-95-0 ]
2-Chloro-1,1,1-triethoxyethane
Similarity: 0.91
[ 51076-95-0 ]
2-Chloro-1,1,1-triethoxyethane
Similarity: 0.91
[ 51076-95-0 ]
2-Chloro-1,1,1-triethoxyethane
Similarity: 0.91
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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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