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CAS No. : | 6092-54-2 | MDL No. : | MFCD00000651 |
Formula : | C7H13ClO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | KIWBRXCOTCXSSZ-UHFFFAOYSA-N |
M.W : | 164.63 | Pubchem ID : | 22466 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.86 |
Num. rotatable bonds : | 6 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 42.23 |
TPSA : | 26.3 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) : | -4.83 cm/s |
Log Po/w (iLOGP) : | 2.62 |
Log Po/w (XLOGP3) : | 3.48 |
Log Po/w (WLOGP) : | 2.94 |
Log Po/w (MLOGP) : | 1.96 |
Log Po/w (SILICOS-IT) : | 2.1 |
Consensus Log Po/w : | 2.62 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.66 |
Solubility : | 0.363 mg/ml ; 0.0022 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.71 |
Solubility : | 0.0318 mg/ml ; 0.000193 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.59 |
Solubility : | 0.426 mg/ml ; 0.00259 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.81 |
Signal Word: | Danger | Class: | 6.1,8 |
Precautionary Statements: | P261-P270-P280-P303+P361+P353-P304+P340+P310-P305+P351+P338 | UN#: | 3277 |
Hazard Statements: | H301+H311+H331-H314 | Packing Group: | Ⅱ |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.3% | Stage #1: With potassium carbonate In tetrahydrofuran; water at 20℃; for 0.333333 h; Stage #2: at 20℃; for 5 h; |
General procedure: Compound 1 (2 g, 3.7 mmol) was dissolved in 60 mL of THF and 12 mL of water. Potassium carbonate (1.55 g, 11.2 mmol) was added, and the mixture was stirred at room temperature for 20 min. Then, n-hexyl chloroformate (0.74 g, 4.5 mmol) was added drop-wise and stirring was continued for another 5 h. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated in vacuum. The residue was chromatographed (silica gel, dichloromethane/methanol 25:1) to afford the title compound 1.47 g as colorless crystals: yield 63.3percent, m.p. [4] 130-132 °C, 1H NMR (300 MHz DMSO-d6) δ (ppm): 0.87 (3H, t, J = 6.9 Hz, -CH2CH2CH3), 1.12 (3H, t, J = 7.2 Hz, -CH2CH3), 1.27-1.29 (6H, m, -CH2CH2CH2CH2CH3), 1.57 (2H, q, J = 6.6 Hz, -OCH2CH2CH2-), 2.68 (2H, t, J = 6.9 Hz, >NCH2CH2-), 3.77 (3H, s, >NCH3), 3.94-4.00 (4H, m, -OCH2CH3, -OCH2CH2CH2-), 4.22, (2H, t, J = 6.9 Hz, >NCH2CH2-), 4.59 (2H, d, J = 5.4 Hz, -CH2NH-), 6.76 (2H, d, J = 8.7 Hz, ArH), 6.88 (1H, d, J = 8.1 Hz, ArH), 6.98 (1H, m, NH), 7.10-7.17 (2H, m, ArH), 7.39 (1H, d, J = 8.4 Hz, ArH), 7.47 (1H, s, ArH), 7.54 (1H, t, J = 7.7 Hz, ArH), 7.79 (2H, d, J = 8.7 Hz, ArH), 8.39 (1H, d, J = 4.8 Hz, ArH), 8.60-9.30 (2H, brs, -NH2); ESI-MS(m/z): 628.4[M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.4 g | Stage #1: With potassium carbonate In water; acetonitrile at 27℃; for 0.5 h; Stage #2: at 12 - 20℃; for 2 h; |
Reference Example-2: Preparation of Dabigatran etexilate free base To a stirred suspension of p-TSA salt of l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]- benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide(20g) in acetonitrile (80 mL), at 27°C, was charged a solution of potassium carbonate (24.7 g) in DM water (50 mL).The reaction mass was stirred for 30 min, and then cooled to 12-15°C. n-Hexyl chloroformate (4.9g) was added and stirred for 30 min. The temperature of the reaction mass was raised 17°C and stirred for 30 min. Second lot of n-hexylchloroformate (1.49 g) was charged and the reaction mass stirred for another hour at 16-20°C, when analytical HPLC revealed completion of the reaction. DM water (50mL) was added and the reaction mass slurred for 15 min at 30°C. The precipitate was filtered, washed with water, dried under vacuum, at 50°C, to afford Dabigatran Etexilate as off-white solid material ( 16.4g, >96percent hplc pure). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35.1 g | Stage #1: With potassium carbonate In water; acetone at 5℃; for 1 h; Stage #2: at 0 - 20℃; for 1 h; |
By embodiments 2 - 4 prepared in the target product is 40g adding 3000 ml glass reaction in the bottle, sequentially adding potassium carbonate 33.0g, water 220 ml, acetone 350 ml, stirring the temperature to 5 °C, continuing to stir 10 minutes, slowly instillment chlorine formic acid oneself ester 16.0g, after finishing dropping to continue to 5 °C stirring 1 hours, to the reaction solution is added in dichloromethane 1600 ml, up to 28 °C extracting the organic layer, the saturated salt water for 1600 ml washing, the organic layer is dried with anhydrous sodium sulfate, vacuum concentrated solvent to obtain yellowish liquid. Dichloromethane is used for 80 ml dissolved concentrated residual liquid, adding 1000 ml in the reaction flask, lowering the temperature to 0 °C, in 0 °C slow the instillment uses acetone 640 ml of dissolved methanesulfonic acid 7.7g mixed solution, after the completion of the dropping the temperature to room temperature stirring 1 hour, filtering, dichloromethane 320 ml washing, in 40 °C vacuum drying 5 hours, to obtain 35.1g white compound A, HPLC analysis for 99.789percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In tetrahydrofuran; water; at 20℃; for 2h; | Reference Example 1 : Preparation of Dabigatran etexilate free base 1.1 g of l-memyl-2-[N-(4-amidino-pheny)-aminomethyl]-benzirnidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-[2-(ethoxycarbonylethyl)-amide-hydrochloride was dissolved in a mixture of 40 ml of tetrahydrofuran and 10 ml of water, then 570 mg (4.12 mMol) of potassium carbonate and 362 mg (2.2 mMol) of <strong>[6092-54-2]n-hexyl chloroformate</strong> were added and stirred for two hours at room temperature. The solvent was then distilled off, the residue was mixed with about 50 ml of saturated saline solution and the resulting solution was extracted three times with 20 ml of dichloromethane. The extracts were dried over sodium sulphate and evaporated down. The crude product thus obtained was purified by column chromatography (100 g silica gel; dichloromethane+5% ethanol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In dichloromethane; at 0 - 20℃; for 2h; | To a stirred solution of an alcohol (1.0 mmol), with the general formula IV, in CH2Cl2 (3.0 ml) were added BTC (0.40 mmol) and pyridine (1.0 mmol) in CH2Cl2 (3.0 ml) at 0 C. The reaction mixture was warmed to room temperature and stirred for 2 h. The solvent was removed in vacuo at 30 C and the residue dissolved in EtOAc (10 ml) and stirred for 30 min. The precipitate was filtered off and the solvent removed in vacuo at 30 C to give the crude chloroformate, with the general formula III. CH2Cl2 (5.0 ml) was added and the solution cooled to 0 C. An amine (0.50 mmol), with the general formula II, and K2CO3 (2.0 mmol) were added and the reaction mixture was stirred for 24 h at room temperature. The reaction mixture was poured into water and extracted with CH2Cl2 or Et2O. The organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the crude product. The crude product was purified by chromatography to give the title compound. Starting compound II: 4-(2-Aminophenylamino)-2-chloro-2'-methylbenzophenone Starting compound VI: 1-Hexanol Purification: Chromatography using CH2Cl2 as eluent13C NMR (CDCl3): delta 196.9, 154.5, 149.4, 139.3, 138.0, 135.2, 133.7, 133.5, 131.4, 131.0, 130.7, 129.8, 129.0, 126.9, 126.0, 125.5, 125.0, 121.9, 116.3, 112.5, 66.1, 31.6, 29.0, 25.6, 22.7, 20.6, 14.2 | |
With triethylamine; In dichloromethane; at 0 - 10℃; for 2h; | To 50-mL3 neck round-bottom flask methyl bis(trichloromethyl) carbonate(2.9g, 9 . 77mmol, 1 . 00 equivalent) in dichloromethane (20 ml) solution in the, triethylamine (2g, 19.76mmol, 2.02 equivalent), then in 0-10 C and dropwise under stirring hexyl-1-ol(1g, 9.79mmol, 1.00 equiv). In 0-10 C stirring the solution obtained under 2 hours, then concentrated under vacuum, is 2g crude chloro(hexyloxy)methanone, is the yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With triethylamine; In tetrahydrofuran; at 40℃; for 3h; | 5.15 f2-(2,6-DIOXO-PIPERrom-3lambdaXyi3-DIOXO-23-DIHYDRO-lH- ISOINDOL-5-YLMETHYL1-CARBAMIC ACID HEXYL ESTER <n="55"/>A mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-l,3-dione hydrochloride (1.0 g, 3.1 mmol), hexyl chloroformate (0.51 g, 3.1 mmol), and triethylamine (0.63 g, 6.2 mmol) in THF (35 mL) was stirred at 40 0C under nitrogen for 3 hours. The mixture was cooled and diluted with ethyl acetate (100 mL), washed with water (3 x 100 mL), and evaporated. The residue was chromatographed in methylene chloride-methanol gradient, eluting the product at 19: 1 methylene chloride-methanol. This material was further purified by preparative HPLC, using a 50- 50 acetonitrile-water isocrat, and providing 0.40 g as a white solid, in 31% yield; mp 111-113 C; HPLC, Waters Symmetry C- 18, 3.9 x 150 mm, 5 mum, 1 mL/min, 240 nm, 50/50 CH3CN/0.1 % H3PO4, 5.08 (99.1 1%); 1H NMR (DMSO-rf6) delta 1.11-1.57 (m, 1 IH), 2.02-2.07 (m, IH), 2.46-2.63 (m, 2H), 2.84-2.96 (m, IH), 3.97 (t, J = 8.3 Hz, 2H), 4.35 (d, J = 6.0 Hz, 2H), 5.15 (dd, J = 12.9 Hz, J = 5.4 Hz, IH), 7.72-7.77 (m, 2H), 7.84-7.90 (m, 2H), 11.13 (s, IH); 13C NMR (DMSO-^6) delta 13,8, 22.0, 25.0, 28.6, 30.8, 30.9, 43.5, 49.0, 64.0, 121.6, 123.5, 129.8, 131.6, 133.2, 147.9, 156.6, 167.0, 167.1, 169.8, 172.7; Anal. Calcd for C2IH15N3O6: C, 60.71; H, 6.07; N, 10.1 1. Found: C, 60.49; H, 6.13; N, 9.91. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 1h; | 5.19 (2-lf3,y)-3-METHYL-2.6-DIOXO-PTPERIDIN-3-YLl-l,3-DIOXO-2,3- DIHYDRO-IH-ISOINDOL-S-YLMETHYL)-CARBAMIC ACID HEXYL ESTERA mixture of 5-aminomethyl-2-[(3S)-3-methyl-2,6-dioxo-piperidin-3-yl]-isoindole- 1,3-dione hydrochloride (0.40 g, 1.18 tnmol), hexyl chloroformate (0.19 mL, 1.18 mmol) and diisopropylethyl amine (0.41 mL, 2.37 mmol) in acetonitrile (20 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate (100 mL), washed with dilute aqueous HCI (2 x 150 mL) and water (2 x 150 mL), dried (MgSO4), and evaporated under vacuum, providing 0.45 g of the product, in 88% yield; mp 95-97 0C; HPLC, Waters Symmetry C-18, 3.9 x 150 mm, 5 mum, 1 mL/min, 240 ntn, 50/50 CH3CN/0.1 % H3PO4, 6.94 (97.26 %); 1H NMR (DMSO-afe) delta 0.78-0.86 (m, 3H), 1.09-1.26 (m, 6H), 1.52-1.54 (m, 2H), 1.89 (s, 3H), 1.99-2.08 (m, IH), 2.54-2.59 (m, 2H), 2.64-2.72 (m, IH), 3.96 (t, J = 6.6 Hz, 2H), 4.33 (d, J = 6.0 Hz, 2H), 7.70-7.87 (m, 4H), 1 1.02 (s, IH); 13C NMR (DMSO-^6) delta 13.8, 21.0, 22.0, 25.0, 28.6, 29.1, 30.9, 43.5, 58.7, 64.0, 121.3, 123.1, 129.6, 131.4, 133.1 , 147.7, 156.6, 167.7, 167.8, 172.1, 172.2; Anal. Calcd KJr C22H27N3O6: C, 61.53; H, 6.34; N, 9.78. Found: C, 61.73; H5 6.33; N, 9.58. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In dichloromethane; at 0 - 20℃; for 24h; | To a stirred solution of an alcohol (1.0 mmol), with the general formula IV, in CH2Cl2 (3.0 ml) were added BTC (0.40 mmol) and pyridine (1.0 mmol) in CH2Cl2 (3.0 ml) at 0 C. The reaction mixture was warmed to room temperature and stirred for 2 h. The solvent was removed in vacuo at 30 C and the residue dissolved in EtOAc (10 ml) and stirred for 30 min. The precipitate was filtered off and the solvent removed in vacuo at 30 C to give the crude chloroformate, with the general formula III. CH2Cl2 (5.0 ml) was added and the solution cooled to 0 C. An amine (0.50 mmol), with the general formula II, and K2CO3 (2.0 mmol) were added and the reaction mixture was stirred for 24 h at room temperature. The reaction mixture was poured into water and extracted with CH2Cl2 or Et2O. The organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the crude product. The crude product was purified by chromatography to give the title compound. Starting compound II: 4-(2-Aminophenylamino)-2-chloro-2'-methylbenzophenone Starting compound VI: 1-Hexanol Purification: Chromatography using CH2Cl2 as eluent13C NMR (CDCl3): delta 196.9, 154.5, 149.4, 139.3, 138.0, 135.2, 133.7, 133.5, 131.4, 131.0, 130.7, 129.8, 129.0, 126.9, 126.0, 125.5, 125.0, 121.9, 116.3, 112.5, 66.1, 31.6, 29.0, 25.6, 22.7, 20.6, 14.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In tetrahydrofuran; at 20℃; for 4h; | Example H. 3 (E)-4- (5, 6-dimethoxy-2-oxo-1, 2-dihydro-indol-3- ylidenemethyl) phenyl, n-hexyl carbonate.; A solution of (E)-3-(4-hfydroxybenzylidene)-5,6-dimethoxy-1, 3- dihydro-indol-2-one (0.2 g, 0.686 mmole) in THF (10 ml) was dropwise added with a solution of <strong>[6092-54-2]n-hexyl chloroformate</strong> (0.112 ml, 0.686 mmole) in THF (10 ml). The mixture was stirred for 4 h at room temperature. The precipitated TEA*HCl was filtered off and filtration waters were concentrated. The resulting residue was purified by silica gel column chromatography, eluting with a AcOEt/n-hexane (9/1) mixture, to afford the product as an orange solid (0.110 g, yield 75%). M. p. : 139-141C. 1H NMR (DMSO-d6+AcOH-d4) : lH NMR (DMSO- d6+AcOH-d4): No. 0. 88 (3H, t), 5 1.28-1. 38 (6H, m), 8 1.68 (2H, quint.), 8 3.58 (3H, s), 8 3.78 (3H, s), No. 4.22 (2H, t), 8 6.51 (1H, s), 8 7. 08 (1H, s), 8 7.39 (2H, d, J=9 Hz), 8 7.43 (1H, s), 8 7.76 (2H, d, J=9 Hz), 8 10.35 (1H, s). HPLC purity: 98.34%. Elemental analysis: found C (66.57%), H (6.4%), N (3.24%)- calculated C (67.78%), H (6.40%), N (3. 29%). (C24H27NO6). |
75% | In tetrahydrofuran; at 20℃; for 4h; | Example H.3 (E)-4-(5,6-dimethoxy-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)phenyl, n-hexyl Carbonate A solution of (E)-3-(4-hydroxybenzylidene)-5,6-dimethoxy-1,3-dihydro-indol-2-one (0.2 g, 0.686 mmole) in THF (10 ml) was dropwise added with a solution of <strong>[6092-54-2]n-hexyl chloroformate</strong> (0.112 ml, 0.686 mmole) in THF (10 ml). The mixture was stirred for 4 h at room temperature. The precipitated TEA*HCl was filtered off and filtration waters were concentrated. The resulting residue was purified by silica gel column chromatography, eluding with a AcOEt/n-hexane (9/1) mixture, to afford the product as an orange solid (0.110 g, yield 75%). M.p.: 139-141 C. 1H NMR (DMSO-d6+AcOH-d4): 1H NMR (DMSO-d6+AcOH-d4): delta 0.88 (3H, t), delta 1.28-1.38 (6H, m), delta 1.68 (2H, quint.), delta 3.58 (3H, s), delta 3.78 (3H, s), delta 4.22 (2H, t), delta 6.51 (1H, s), delta 7.08 (1H, s), delta 7.39 (2H, d, J=9 Hz), delta 7.43 (1H, s), delta 7.76 (2H, d, J=9 Hz), delta 10.35 (1H, s). HPLC purity: 98.34%. Elemental analysis: found C (66.57%), H, (6.4%), N, (3.24%)-calculated C (67.78%), H, (6.40%), N, (3.29%).(C24H27NO6). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.4 g | Reference Example-2: Preparation of Dabigatran etexilate free base To a stirred suspension of p-TSA salt of l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]- benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide(20g) in acetonitrile (80 mL), at 27C, was charged a solution of potassium carbonate (24.7 g) in DM water (50 mL).The reaction mass was stirred for 30 min, and then cooled to 12-15C. n-Hexyl chloroformate (4.9g) was added and stirred for 30 min. The temperature of the reaction mass was raised 17C and stirred for 30 min. Second lot of n-hexylchloroformate (1.49 g) was charged and the reaction mass stirred for another hour at 16-20C, when analytical HPLC revealed completion of the reaction. DM water (50mL) was added and the reaction mass slurred for 15 min at 30C. The precipitate was filtered, washed with water, dried under vacuum, at 50C, to afford Dabigatran Etexilate as off-white solid material ( 16.4g, >96% hplc pure). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium carbonate; In tetrahydrofuran; water; | EXAMPLE 90 1-Methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide 1.1 g (2.06 mMol) of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride was dissolved in a mixture of 40 ml of tetrahydrofuran and 10 ml of water, then 570 mg (4.12 mMol) of potassium carbonate and 362 mg (2.2 mMol) of <strong>[6092-54-2]n-hexyl chloroformate</strong> were added and stirred for two hours at room temperature. The solvent was then distilled off, the residue was mixed with about 50 ml of saturated saline solution and the resulting solution was extracted three times with 20 ml of dichloromethane. The extracts were dried over sodium sulphate and evaporated down. The crude product thus obtained was purified by column chromatography (100 g silica gel; dichloromethane+5% ethanol). Yield: 78% of theory, C35 H42 N6 O5 (626.8) Rf value: 0.49 (silica gel; dichloromethane/ethanol=19:1) EQU61 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; | EXAMPLE H Hexyl N-[2,3-dihydro-3,3-dimethyl-2-oxo-(1H)-indol-6-yl]-carbamate 5.27 g. (0.032 mole) Hexyl chloroformate are added dropwise, while cooling with ice and within the course of 15 minutes, to a suspension of 5.28 g. (0.03 mole) 6-amino-2,3-dihydro-3,3-dimethyl-(1H)-indolin-2-one and 4.6 ml. triethylamine in 50 ml. anhydrous dichloromethane. The solution is then stirred for 3 hours at ambient temperature, the solvent is removed in a vacuum and the residue is purified by flash column chromatography with heptane/butan-2-one (2:1 v/v) as elution agent. Yield 5.2 g. (60% of theory); m.p. 180-183 C. after recrystallisation from ethyl acetate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With pyridine; In ISOPROPYLAMIDE; water; | EXAMPLE 4 To a solution of 4.0 g of arabinofuranosylcytosine dissolved in 50 ml of dimethylacetamide, there are added 3.0 g of pyridine and 4.06 g of n-hexylchloroformate. The reaction is carried out by stirring the mixture at room temperature for 3 hours. After the reaction is over, dimethylacetamide is evaporated under reduced pressure. The residue is diluted with 100 ml of cold water and the mixture is stirred under ice-cooling for one hour. The precipitated solids are filtrated and dried. The resultant white powders are washed with ethyl ether to obtain 2.9 g of N4 -hexyloxycarbonyl-1-beta-D-arabinofuranosylcytosine (Yield:47%). Elemental analysis for C16 H25 N3 O7: Calcd. (%): C 51.75; H 6.79; N 11.31; Found (%): C 51.53; H 6.88; N 11.26. NMR(DMSO-d6) delta value: --CH3 0.88, --(CH2)3 -- 1.1-1.9, H2 '-H5 ' 3.3-4.3, --OCH2 -- 4.12, H1 ' 6.10, H5 7.04, H6 8.08 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 19 n-Hexyl-p-Iodophenethyl Carbonate (m of Table I) p-Iodophenethyl alcohol was reacted with n-hexyl-chloroformate according to the carbonate synthesis of Procedure B. The isolated material gave an ir and nmr spectra in agreement with the proposed structure. The oil had a refractive index of ND25 = 1.5295. The mass spectrum (70 ev) parent ion was measured at m/e 376.0508, and calculated for C15 H21 IO3 at 376.0538. Analysis: calculated C15 H21 IO3: C, 47.91; H, 5.63; found C, 48.07; H, 5.66. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In tetrahydrofuran; water | II 4-(hexyloxycarbonylamidino)-nitrobenzene EXAMPLE II 4-(hexyloxycarbonylamidino)-nitrobenzene 2.8 ml of hexyl chloroformate in 80 ml of tetrahydrofuran are added dropwise to 3.5 g of 4-nitrobenzamidine-hydrochloride and 7.2 g of potassium carbonate in a mixture of 350 ml tetrahydrofuran and 70 ml water, whilst cooling with ice. After 1 hour's stiring in an ice bath the mixture is left to stand overnight at ambient temperature. The organic phase is separated off, washed twice with saturated saline solution, dried and concentrated by evaporation. Yield: 5.1 g (100% of theory), Rf value: 0.72 (silica gel; cyclohexane/ethyl acetate=1:1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With pyridine; at 20℃; | n-Hexyl chloroformate (980 mul) was added to a pyridine (3.0 ml) solution of 4-N-acetyl-3'-O-triisopropylsilyl-2'-cyano-2'-deoxy-1-beta-D-arabinofuranosylcytosine (hereinafter referred to as 4-N-acetyl-3'-O-TIPS-CNDAC) (450 mg) under a nitrogen atmosphere, and the mixture was stirred at room temperature overnight. The reaction mixture was separated with ethyl acetate and water. The organic layer was washed with brine, and then dried over anhydrous sodium sulfate. Solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (33% ethyl acetate/hexane) to give Compound 8a (462 mg, 80%) as a white foam. 1H-NMR(DMSO-d6)delta 11.0 (1H, s), 8.09 (1H, d, J = 7.3 Hz), 7.27 (1H, d, J = 7.3 Hz), 6.21 (1H, d, J = 7.3 Hz), 4.80 (1H, m), 4.42 (2H, m), 4.07 (4H, m), 2.11 (3H, s), 1.57 (2H, m), 1.25 (6H, m), 1.12-1.05 (21H, m), 0.83 (3H, m); FAB-LRMS m/z (negative) 577 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
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Preparation of dabigatran mesylate. 9 g of compound VII-HCl (0.017 mol) were dissolved in 300 ml of chloroform. 6, ml of triethylamine were added to this solution and then a solution of 3.4 ml (0.02 mol) of hexyl chloroformate in chloroform was added dropwise. After one hour the reaction mixture is shaken with brine, the organic layer is separated, which is dried with sodium sulfate and concentrated. The obtained evaporation residue is crystallized from ethyl acetate. Yield: 9.6 g (90%)This product is dissolved in acetone and an equimolar amount of methanesulfonic acid is added dropwise. The separated evaporation residue is aspirated and dried at the laboratory temperature. Yield: 73%; content according to HPLC: 99.5%. |
Yield | Reaction Conditions | Operation in experiment |
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Preparation of dabigatran mesylate. To 9.1 g of compound VII-2HC1 (0.016 mol) 270 ml of chloroform and 9 ml (0.064 mol) of triethylamine are added. Then, a solution of 3.1 ml (0.018 mol) of hexyl chloroformate in chloroform is added dropwise at the laboratory temperature. After one hour the reaction mixture is shaken with brine and the organic layer is separated, which is dried with sodium sulfate and concentrated. The obtained evaporation residue is crystallized from ethyl acetate. Yield: 8.6 g (86%)This product is dissolved in acetone and an equimolar amount of methanesulfonic acid is added dropwise. The separated precipitate is aspirated and dried at the laboratory temperature. Yield: 75%; content according to HPLC: 99.5%. 27 |
Yield | Reaction Conditions | Operation in experiment |
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89% | Example 9; Preparation of l-methyl-2-[lambdaL[4-(lambdaLn-hexyloxycarbonylamidino)phenyl]-amino- methyl]-benzimidazol-5-yl-carboxylic acid-lambdaL(2-pyridyl)-lambdaL(2-ethoxycarbonylethyl)- amide mesylate (7) from l-methyl-2-[iV-[4-amidinophenyl]-amino-methyl]- benzimidazol-5-yl-carboxylic acid-lambdaL(2-pyridyl)-lambdaL(2-ethoxycarbonylethyl)-amide (5A); In the reaction vessel 50.0 g (74.4 mmol) 5A and 63.0 g (446.6 mmol) potassium carbonate are suspended in 380 ml acetone and 248 ml of water and at 200C 13.48 g (81.9 mmol) of n-hexylchloroformate are metered in within 1 h. After 30 min further reaction the suspension is heated to approx. 500C. A clear two-phase mixture is formed, into which another 0.12 g (0.7 mmol) n-hexylchloroformate are metered after the conversion level has been checked, so that all the starting material is reacted. The aqueous phase is separated off, the organic phase is filtered clear and the filter is washed with 50 ml acetone. Under a slight vacuum 300 ml acetone are distilled off and replaced by 250 ml MIBK. The aqueous phase that settles out is separated off and the organic phase is extracted at 50-600C with 50 ml of water. Then 300 ml solvent are distilled off and replaced by 500 ml acetone. The reaction solution is cooled to 30-360C, 7 seed crystals are added (obtained for example <n="30"/>from an earlier reaction according to Example 7 or according to the method described inExample 3 of WO 03/074056) and a previously prepared solution of 6.44 g (67 mmol) methanesulphonic acid in 50 ml acetone is added dropwise. The suspension is stirred for20 min, the product is isolated by filtration and washed with 300 ml acetone. The isolated substance is dried at 450C in vacuo.Yield: 48.0 g (89 %) purity: > 99% HPLC peak area | |
Step (1): Dissolving the mixing operation: specific dosage aspects, 3-[2-[(4-amidinophenyl)aminomethyl]-1-methyl-1H-benzimidazole-5-carbonyl](pyridin-2-yl)amino}propionic acid ethyl ester tosylate in an amount of 40g, potassium carbonate in an amount of 56g; Preparation of 3-[2-[(4-amidinophenyl)aminomethyl]-1-methyl-1H-benzimidazole-5-carbonyl](pyridin-2-yl)amino}propionic acid ethyl ester p-toluenesulfonate: Step A: 3-[2-[(4-amidinophenyl)aminomethyl]-1-methyl-1H-benzimidazole-5-carbonyl](pyridin-2-yl)amino}propionic acid ethyl ester in an amount of 50g was added to methanol in an amount of 300g. Step C, after evaporation under reduced pressure, 320 g of methanol is added to dissolve; Step D, the p-toluenesulfonic acid in an amount of 31g; Finally, 3-[2-[(4-amidinophenyl)aminomethyl]-1-methyl-1H-benzimidazole-5-carbonyl](pyridin-2-yl)amino}propionic acid ethyl ester p-toluenesulfonate was obtained 41.5g. Step (2): N-hexyl chloroformate ester in an amount of 12g; Step (3): Dabigatran etexilate 25.6g. Step (4): The resulting 20.0g of dabigatran etexilate was dissolved in approximately 200ml of acetone 42C, methanesulfonic acid 3.5g was added dropwise, After complete addition, the reaction solution was sufficiently cooled to about 4C for crystallization, After filtration, the filtered cake was dried 7 ~ 8h, resulting product namely dabigatran etexilate methanesulfonate were obtained 21.5g. Further the obtained finished products for testing, and test results showed that the final calculation: 3-[[[2-[[(4-amidinophenyl)amino]methyl]-1H-benzimidazole-1-methyl-5-carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester p-toluenesulfonate, weight yield of 68.8%; and high performance liquid chromatography (HPLC) purity: 99.5%, largest single miscellaneous 0.1%. |
Yield | Reaction Conditions | Operation in experiment |
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94% | Example 7; Preparation of l-methyl-2-[lambdaL[4-(lambdaLn-hexyloxycarbonylamidino)phenyl]-amino- methyl]-benzimidazol-5-yl-carboxylic acid-lambdaL(2-pyridyl)-lambdaL(2-ethoxycarbonylethyl)- amide (6B) from l-methyl-2-[lambdaL[4-(l,2,4-oxadiazol-5-on-3-yl)phenyl]-amino-methyl]- benzimidazol-5-yl-carboxylic acid-lambdaL(2-pyridyl)-lambdaL(2-ethoxycarbonylethyl)-amide (4); 60 g (91 mmol) l-methyl-2-[lambda/-[4-(l,2,4-oxadiazol-5-on-3-yl)phenyl]-amino-methyl]- benzimidazol-5-yl-carboxylic acid-lambda/-(2-pyridyl)-lambda/-(2-ethoxycarbonylethyl)-amide (4) are hydrogenated with 3.0 g 10% palladium on charcoal (moistened with water) in 126 ml THF and 54 ml of water at 400C under 4 bar excess hydrogen pressure for 25 min. The hydrogenation solution is filtered and the filter is washed with 75 g THF/water (7:3). The filtrate is combined successively with 56 ml THF, 260 ml of water and batchwise with 75.2 g (544 mmol) potassium carbonate at ambient temperature. Then 14.2 g (86 mmol) of n-hexylchloroformate are metered in over 40 min. After the conversion level has been checked a further 1.2 g (7.3 mmol) n-hexylchloroformate are metered in, so that all the starting material is reacted. The suspension is heated to approx. 45C. A clear two-phase mixture is formed. The aqueous phase is discarded and the THF is largely distilled off. 150 ml acetone are added to the suspension, it is heated to 500C and filtered clear. The filter is rinsed with 100 ml acetone. The filtrate is cooled to ambient temperature and the product is precipitated by the slow addition of 100 ml of water. The moist product is washed with 150 ml acetone/water (1:1) and 150 ml of water and dried in vacuo. <n="29"/>Yield: 56.9 g (94 %) HPLC-purity: > 98.8 % |
Yield | Reaction Conditions | Operation in experiment |
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> 90% | With potassium carbonate; In tetrahydrofuran; water; at 20℃; for 1h; | 30 mg of 1-benzyl-N-[(4-carbamimidoylphenyl)methyl]pyrazole-4-carboxamide hydrochloride and 35 mg of potassium carbonate were dissolved in 0.4 ml of water and 2 ml of tetrahydrofuran. The mixture was stirred at room temperature, and 0.013 ml of <strong>[6092-54-2]n-hexyl chloroformate</strong> (Sigma-Aldrich) added. Stirring was continued for 1 h, following which the organic layer was removed, and dried in vacuo to obtain the synthetic target (>90% yield). The mass of the compound was verified using LC/MS/MS.Calculated mass: 461.6; Experimental mass (m+1): 462.5 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 90% | With potassium carbonate; In tetrahydrofuran; water; at 20℃; for 1h; | 48 mg of N-[(4-carbamimidoylphenyl)methyl]-1-(4-fluorophenyl)-2,5-dimethyl-pyrrole-3-carboxamide hydrochloride and 50 mg of potassium carbonate were dissolved in 0.6 ml of water and 3 ml of tetrahydrofuran. The mixture was stirred at room temperature, and 0.019 ml of <strong>[6092-54-2]n-hexyl chloroformate</strong> (Sigma-Aldrich) added. Stirring was continued for 1 h, following which the organic layer is removed, and dried in vacuo to obtain the synthetic target (>90% yield). The mass of the compound was verified using LC/MS/MS.Calculated mass: 492.6; Experimental mass (m+1): 493.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.2% | EXAMPLES Step 1A: Synthesis of 4-aminobenzamidine-N-hexylcarbamate Aminobenzamidine*2HCl (21.2 g) is dissolved in acetone (150 ml), regulated to a temperature of 20 C. and sodium hydroxide solution (80 ml, 4M) is added dropwise. At 20 C. n-hexylchloroformate (16.5 g) is metered in. After rinsing with acetone (20 mL) the mixture is stirred for a further 15 min at 5-10 C. Then the phases are separated. The organic phase is evaporated down in vacuo, diluted with butyl acetate (150 mL) and the phases are separated again. The mixture is once more extracted with water (40 mL) and combined with hydrochloric acid (9, 84 mL, 32%). The residual water is distilled off using the water separator and then evaporated down. The suspension is mixed at 45 C. with acetone (150 mL), cooled to 20 C. and suction filtered. It is washed with a mixture of butyl acetate and acetone (100 mL). The filter cake is dried in vacuo and 29.2 g of product 3 are obtained (97.2% of theoretical). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: aripiprazole With n-butyllithium; diisopropylamine In 2-methyltetrahydrofuran; hexanes at -78℃; for 0.166667h; Stage #2: n-hexyl chloroformate In 2-methyltetrahydrofuran; hexanes at -78 - 20℃; | 1 To a solution of diisopropylamine (1.11 mL, 7.87 mmol) in 2-methyltetrahydrofuran (37 mL) at -5° C. was added n-BuLi (3.0 mL, 2.5 M in hexanes, 7.49 mmol) slowly. After 20 minutes, the reaction was cooled to -78° C. and Aripiprazole (1.68 g, 3.74 mmol) was added. After a further 10 minutes, hexylchloroformate (1.53 mL, 9.37 mmol) was added. The reaction was held at -78° C. for 2 hours before allowing to warm to room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (2×30 mL). The organics were combined, washed with saturated aqueous sodium hydrogen carbonate solution (30 mL), brine (30 mL), dried over MgSO4 and concentrated. The crude product was purified by column chromatography on silica eluting with 0 to 3% tetrahydrofuran in ethyl acetate. The product was triturated in heptane to remove aliphatic impurities and then filtered and dried to afford Compound 59 (0.487 g) as a colorless solid. 1H-NMR (300 MHz, CDCl3) δ 7.14 (2H, m), 7.07 (1H, d), 6.95 (1H, m), 6.62 (1H, dd), 6.54 (1H, d), 4.38 (2H, t), 3.95 (2H, t), 3.06 (4H, m), 2.89 (2H, t), 2.66 (6H, m), 2.47 (2H, t), 1.90-1.65 (6H, m), 1.49-1.30 (6H, m), 0.88 (3H, t). [M+H]+=576.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; In 2-methyltetrahydrofuran; at 0 - 20℃; | To a mixture of <strong>[129722-25-4]dehydro-aripiprazole</strong> (1.5 g, 3.4 mmol), potassium tert-butoxide (0.75 g, 6.7 mmol) and 2-methyltetrahydrofuran (30 mL) at 0 C. was added hexyl chloroformate (1.32 mL, 8.1 mmol). The reaction mixture was stirred for 2 h, allowed to self warm to room temperature and stirred for a further 4 h. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and evaporated. The residue was further purified on silica eluting with ethyl acetate/tetrahydrofuran and the major product containing fractions evaporated to give a yellow solid. This was triturated in heptane (30 mL) for 2.5 h, filtered and dried to give Compound 328 (1.55 g) as a white solid.1H-NMR (300 MHz, CDCl3) delta 8.15 (d, 1H), 7.71 (d, 1H), 7.32 (d, 1H), 7.21-7.12 (m, 3H), 7.09 (d, 1H), 6.97-6.91 (m, 1H), 4.29 (t, 1H), 4.13 (t, 1H), 3.12-3.01 (m, 4H), 2.73-2.55 (m, 4H), 2.50 (t, 2H), 1.95-1.85 (m, 2H), 1.82-1.70 (m, 4H), 1.50-1.28 (m, 6H), 0.94-0.86 (m, 3H). [M+H]+=574.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With triethylamine; In tetrahydrofuran; at -10 - 20℃; for 2h; | General procedure: Ethyl chloroformate (0.19 mL, 2 mmol) was added to a suspension containing <strong>[63-45-6]primaquine diphosphate</strong> (0.911 g, 2 mmol) and triethylamine (3 mol equiv) in tetrahydrofuran (5 mL) at -10 C. The mixture was stirred at -10 C for 30 min and then left at room temperature for 90 min. The reaction mixture was filtered and the filtrate evaporated. The residue was re-dissolved in dichloromethane and the organic layers were washed (satd NaHCO3, water), dried (anhydrous MgSO4) and evaporated to dryness to yield an oily residue that was subjected to column chromatography on silica gel (ether/light petroleum, 7:3) to give 4a as a brown oil in 53% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With triethylamine; In acetone; at 0 - 20℃; for 1.5h;Inert atmosphere;Product distribution / selectivity; | b) Reaction using acetone as solventUnder Ar atmosphere, the amidino compound hydrochloride (ll-HCI) (1 .50 g, 2.80 mmol, 100% a/a purity according to HPLC/MS) was stirred in acetone (38 mL), cooled down to 0 C and Et3N (1 .17 mL, 8.40 mmol) and <strong>[6092-54-2]n-hexyl chloroformate</strong> (0.50 mL, 3.06 mmol) were added, and stirred at r.t. for 30 min. After verifying the progress of the reaction by t.l.c, more <strong>[6092-54-2]n-hexyl chloroformate</strong> (0.30 mL, 1 .84 mmol) was added and stirred at r.t. for 1 h. The solvent was evaporated under low pressure and the residue was dissolved in EtOAc (30 mL), and the organic phase was washed with NaOH 1 N (15 mL). The aqueous phase was extracted with EtOAc (30 mL), the organic phases were mixed, and washed with NaCI (sat) (15 mL). The organic phase was dried over anhydrous MgSO4, the solvent was evaporated to dryness and the residue obtained was dried under vacuum, obtaining the crude product of interest (1 .56 g, 89% yield, 97% a/a purity according to HPLC/MS). 1H RMN (400 MHz, CD3OD) : delta (ppm) = 8.39 (dd, J = 4.8, 1 .2, 1 H), 7.70 (d, J = 8.8, 2H), 7.57 (d, J = 0.8, 1 H), 7.51 (ddd, J = 8.0, 8.0, 1 .6, 1 H), 7.37 (d, J = 8.4, 1 H), 7.29 (dd, J = 8.4, 1 .6, 1 H), 7.14 (m, 1 H), 6.92 (d, J = 8.0, 2H), 6.76 (d, J = 8.8, 2H), 4.65 (s, 2H), 4.36 (t, J = 7.2, 2H), 4.09 (t, J = 6.8, 2H), 4.05 (q, J = 7.2, 2H), 3.82 (s, 3H), 2.76 (t, J = 7.2, 2H), 1 .68 (m, 2H), 1 .46-1 .30 (m, 6H), 1 .20 (m, J = 7.2, 3H), 0.92 (t, J = 6.8, 3H). |
83% | Step a: Preparation of Dabigatran etexilate, tetrahydrateEthyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2- yl)-lH-benzo[d]imidazole-5-carboxamido)propanoate hydrochloride salt (74.0 g, 0.14 mol) was dissolved in a mixture of water (1.17 L) and 2-methyl tetrahydrofuran ("2- MeTHF") (2.31 L) at 25 C. The resulting solution was acidified to pH 3.5 using HCl (30 ml, 1.5 M). An aqueous solution of K2C03 (52.7 g, 0.41 mol in 340 ml water) was added drop wise during half an hour. The resulting reaction mixture was stirred for 30 min at 25 C. Hexilchloroformate ("HCF") (24.9 ml, 0.15 mol) was added dropwise during 10-15 min and the reaction mixture was stirred for 2 h at 25 C (precipitation started approximately after 20 min and a suspension was formed). The resulting suspension is cooled to 0-5 C and stirred for 1 h. The precipitate was filtered off, washed with water (200 mL) and ice cooled 2-MeTHF (200 mL). The obtained cake is dried at 40 C/10 mbar /4hYield: 80.6 g (83%) Dabigatran etexilate tetrahydrate (HPLC: 99.63%; KF:9.66%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.94% | With triethylamine; In dichloromethane; at 10 - 20℃;Large scale; | The above obtained 17 kg of 3-[[[2-[[(4-amidinophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]pyridin-2-ylamino]propionic acid ethyl ester p-toluenesulfonate (3) , 221kg dichloromethane and 12.75kg triethylamine (molar equivalent of 5.0 eq) was added to the kettle, stirred, n-hexylchloroformate (11.22 kg) (molar equivalent: 2.7 eq) and dichloromethane (17 kg) are slowly added at 10-20C, After the reaction was completed, it was washed successively with 170kg water and stirred for 15min , the organic phase was separated with 170kg of 1.1% dilute hydrochloric acid and stirred for 30min, again organic phase was seperated with saturated sodium bicarbonate solution (85kg) and stirred for 15 min, finally, the organic phase was separated and concentrated under reduced pressure to dryness, 90kg of ethyl acetate was added, heated to 50-55C for 1h, slowly cooled to 0-10C, stirred for 1h, after centrifugation, the filter cake was washed once with 30 kg of ethyl acetate, centrifuged to dryness, and the filter cake was rinsed with ethyl acetate, incubated at 40-50C, alowly cooled to 0-10C after stirring for 1h, stirred for 1h, discharge centrifugation, the filter cake was rinsed once with 30 kg of ethyl acetate, centrifuged to dryness, and vacuum dried at 40-50 C to give 9.5 kg of 3-[[[[2-[[[4-[[[(hexyloxy)carbonyl]amino]formimino]phenyl]amino]methyl]-1-methyl-1H-benzimidazole-5 -yl] carbonyl](pyridin-2-yl) ethyl propionate(2), yield 88.94 %, purity 99.42 %, |
With potassium carbonate; In water; acetone; at 15℃;Product distribution / selectivity; | a) Preparation of Dabigatran etexilate:55 g of l-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide tosylate was dissolved in 437 ml of acetone and 273 ml of water. 16.4 g of hexyl chloroformate and 34 g of potassium carbonate was added to it at a temperature of about 15 C. After the end of the reaction, the precipitated product is filtered off and washed with acetone/water. Dissolved the obtained solid in 270 ml of acetone under heating and then filtered. The title product was crystallized by the addition of 220 ml of water. The isolated substance is dried under reduced pressure at 45 C.Yield: 44 g |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With triethylamine; In dichloromethane; at 20℃; for 24h; | General procedure: 6-Trifluoromethoxybenzothiazol-2-ylamine (1, 100 mg, 0.42 mmol), chloroformate (0.74 mmol), and triethylamine (64 mg, 0.64 mmol) were combined in methylene chloride (3 mL) and stirred 24 h at ambient temperature. The reaction was concentrated. The residue was treated with methanol/water (1:1, 5 mL) and the solid collected by filtration and dried under vacuum to afford product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium carbonate; In water; acetone; at 15 - 20℃; for 1.5h; | Example 4. Preparation of DAB etexilate of Formula (I) 120 ml acetone, 60 ml water, 16.6 g (0.120 mol) potassium carbonate and 20g (0.040 mol) of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-IH-benzo[d]imidazole-5- carboxamido) propanoate of Formula (II) were stirred at 20-25C. A solution of 9.88 g (0.060 mol) of hexyl chloroformate of Formula (IX) in 50 ml acetone was added to the reaction mass at 15- 20C in 1 .5 hours. The reaction mass was further stirred for 2 hours at 15-20C. The precipitated solid was filtered and washed with 40 ml water. The wet cake was dissolved in 160 ml acetone at 20-25C. The insoluble were removed by filtration. Added 160 ml water to the clear filtrate at 20-25C in 2 hours and the reaction mass was further stirred for 2 hours. The solid was isolated by filtration, washed with mixture of acetone : water (1 : 1), and dried under vacuum below 45C to obtain dabigatran etexilate. Yield: 18.85 g Efficiency: 75% |
74.6% | With potassium carbonate; In tetrahydrofuran; water; at 5℃; for 2h; | In a 250 ml reaction flask,5.0 g (10.0 mmol) of compound 4 was added,50 ml of tetrahydrofuran,25 ml water,(30.0 mmol) of potassium carbonate.Cooled to 5 C,(12 mmol) of <strong>[6092-54-2]n-hexyl chloroformate</strong> in tetrahydrofuran (20 ml) was added dropwise,Stirring was continued for 2 h.The organic layer was separated and concentrated under reduced pressure at 40 C,50 ml of acetone was added to the solution,Slowly cool to 5 C.filter,Drying afforded 4.7 g of an off-white solid (1),Yield 74.6%. |
73% | With sodium hydroxide; In acetone; at 20℃; for 3h; | Add to the reactor sequentially at room temperature3-({2-[(4-Mercapto-phenylimino)-methylene]-1-methylene-1H-benzimidazole-5-carbonyl}-pyridin-2-imine)-propionic acid Ethyl ester 20.3g, 60ml acetone, stirred and dissolved,Slowly drip 12 ml of 5% sodium hydroxide solution.Then, 6.8 ml of a mixture of <strong>[6092-54-2]n-hexyl chloroformate</strong> and 20 ml of acetone was slowly added dropwise to the reactor.The mixture was added dropwise for about 1 hour, and the mixture was stirred at room temperature for 2 hours until the reaction was completed.Evaporate the solvent under reduced pressure.The residue was taken up in 50 ml of ethyl acetate.Wash each time with 20 ml of saturated brine and wash a total of three times.The combined aqueous layers were back-extracted with 20 mL of ethyl acetate.Dry and distill off the solvent under reduced pressure. The residue was recrystallized from ethyl acetate.Weighed 18.6 g of dabigatran etexilate, the yield was 73%, and the purity by HPLC was 99.2%. |
59.7% | 3-({2-[(4-Carbamimidoyl-phenylamino)methyl]-1-methyl-1H-benzoimidazole-5-carbonyl}pyridin-2-yl-amino)propionic acid ethyl ester (1.0 g, 1.86 mmol)was dissolved in 50 mL of THF and 10 mL of water. Potassium carbonate(0.83 g, 6.0 mmol) was added, and the mixture was stirred at roomtemperature for 15 min. Then, hexyl chloroformate (0.31 g, 1.86 mmol)was added and stirring was continued for another hour. The organic phasewas separated, dried over anhydrous sodium sulfate, and concentrated invacuo. The residue was left in 10 mL mixtured solution (acetone:water= 1:1) at room temperature for slow evaporation in air. Colourless needlecrystals of the target compound formed after approximately three days,yield 59.7%, m.p. 127~129 C, IR (KBr), sigma/cm-1: 3459.30, 1730.50,1629.95, 1473.34, 1384.60, 1265.05, 1132.09, 670.95. ESI-MS(m/z) : 628[M + H] +, 650 [M + Na]+. 1H NMR (CDCl3, 400 MHz): delta 0.84 (t, 3H), 1.17(t, 3H), 1.19 (m, 6H), 1.39-2.14 (bs, 8H), 1.65 (m, 2H), 2.76 (t, 2H), 3.66 (s,3H), 4.02 (m, 4H), 4.37 (t, 2H), 4.41 (d, 2H), 6.61 (d, 2H), 6.67 (d, 1H), 6.96(t, 1H), 7.04 (m, 2H), 7.23 (d, 1H), 7.28 (d, 1H), 7.66 (s, 1H), 7.70 (d, 2H),8.39 (dd, 1H). | |
43.2% | f) Dabigatran etexilate 14.0 g (28 mmol) of ethyl 3-[(2-[(4-{carbamimidoyl}phenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate as obtained in step (e) and 12.4 g of potassium carbonate were suspended in a mixture of 140 mL of water and 700 mL of tetrahydrofuran. After stirring at room temperature for 15 minutes, 4.6 g (28 mmol) of hexyl chloroformate were added dropwise. The resulting mixture was stirred at room temperature for 1 hour. The organic phase was extracted, washed with 200 mL of brine and dried with anhydrous sodium sulfate. The solvent was removed under vacuum, and the resulting solid was suspended in 100 mL of ethyl acetate at 10C. The solid was isolated by filtration and purified by column chromatography eluting with ethyl acetate, to yield 7.6 g of dabigatran etexilate as an off-white solid. Yield: 43.2 %. Purity (HPLC, method 1): 98.3 %. | |
43.2% | With potassium carbonate; In tetrahydrofuran; water; at 20℃; for 1.25h;Product distribution / selectivity; | f) Dabigatran etexilate14.0 g (28 mmol) of ethyl 3-[(2-[(4-{carbamimidoyl}phenyl)amino]methyl}-l- methyl-lH-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate as obtained in step (e) and 12.4 g of potassium carbonate were suspended in a mixture of 140 mL of water and 700 mL of tetrahydrofuran. After stirring at room temperature for 15 minutes, 4.6 g (28 mmol) of hexyl chloro formate were added drop wise. The resulting mixture was stirred at room temperature for 1 hour. The organic phase was extracted, washed with 200 mL of brine and dried with anhydrous sodium sulfate. The solvent was removed under vacuum, and the resulting solid was suspended in 100 mL of ethyl acetate at 10C . The solid was isolated by filtration and purified by column chromatography eluting with ethyl acetate, to yield 7.6 g of dabigatran etexilate as an off-white solid. Yield: 43.2 %. Purity (HPLC, method 1): 98.3 %. |
17.6 g | Example 6: Preparation of Dabigatran etexilate 1 -Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide (20 g), acetone (220 mL) and water (180 mL) were charged into a round bottom flask and maintained until a clear solution was observed. The reaction mixture was cooled to 5-10C, followed by addition of potassium carbonate (27.6 g) and maintained for about 30 minutes at the same temperature. n-Hexyl chloroformate (1 1 .2 g) in acetone (20 mL) was added slowly to the reaction mixture over a period of 60-90 minutes at 5-10C and maintained for 1 -2 hours at the same temperature. After completion of reaction, confirmed by using TLC, ammonium chloride (10 g) was added at 5-10C and mixture was maintained for 30-60 minutes at 5-10C. The reaction mixture was allowed to attain 25-35 C and maintained for 1 -2 hours at the same temperature. Then the reaction mixture was heated to 50-55 C and maintained for 15-30 minutes. The layers were separated and the acetone layer was cooled to 25-35 C and maintained for 15-30 minutes. Water (240 mL) was added to the separated acetone layer and maintained for 2-3 hours. The obtained reaction mixture was cooled to 5- 10 C and maintained for 1 -2 hours. The solid obtained was filtered and washed with a (1 :1 ) mixture of pre-cooled acetone and water (20 mL). The resultant solid compound and isopropanol (240 mL) were charged into another round bottom flask and heated to 50-55 C until a clear solution was obtained. The reaction mixture was cooled to 25-35 C, followed by addition of seed (0.2 g) and maintained the reaction mixture for 2-3 hours at 25-35 C and further maintained for 1 -2 hours at 0-5^. The solid obtained was collected by filtration, washed with isopropanol (20 mL) and dried at 50-55 C under vacuum to afford the title compound. Yield: 17.6 g; Purity by HPLC: 99.75% | |
at 10 - 15℃; | Acetone (437 ml) and water (273 ml) were taken into a reaction flask, followed by the addition of Dabigatran hydrochloride (55 g) at 25-30C and then stirring for 15-20 minutes to form a clear solution. Potassium carbonate (34 g) was added to the above solution at 25-30C and the resulting mass was cooled to 10-15C, followed by the addition of n-hexyl chioroformate (16.5 g) at the same temperature. The reaction mass was stirred for 12-14 hours at 10-15C and then filtered the solid. The resulting solid was dissolved in dichloromethane (1000 ml) and the resulting organic layer was washed two times with 10% potassium carbonate solution (500 ml x 2). The resulting organic layer was thenwashed with 20% sodium chloride solution, followed by distillation under vacuum to produce 55.5 g of Dabigatran Etexilate as solid. | |
With potassium carbonate; In tetrahydrofuran; water; at 38℃; | The reaction mixture was charged with PR-II and mixed system materials, and dissolved at 38 C with stirring.The <strong>[6092-54-2]n-hexyl chloroformate</strong> was added in portions to the end of the reaction, and the organic phase was recovered under reduced pressure at 40 C. To the residue was added acetone, dissolved at 40 C, added with water, stirred at 22 C for 3 hours, and filtered. The filter cake was washed with acetone and water, and the filter cake was dried under reduced pressure at 45 C for 6 hours to obtain a crude product of dabigatran etexilate PR-III;Among them, the mixed system material is tetrahydrofuran / potassium carbonate / water system, tetrahydrofuran, potassium carbonate, water mass ratioFor 18:1:7.2, the mass ratio of the mixed system to the PR-II is 20:1.Among them, the mass ratio of <strong>[6092-54-2]n-hexyl chloroformate</strong> and PR-II added for the first time is 1:1, and subsequent addition of 3 times of chloroformic acid in batchesN-hexyl ester, the added mass ratio of <strong>[6092-54-2]n-hexyl chloroformate</strong> to PR-II is 0.1:1, and the time interval of batch addition is 1 h;Wherein, the mass ratio of acetone to PR-II added in the residue is 10:1, and acetone is added to the residue and dissolved.The mass ratio of incoming water is 2:1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate; In ethanol; water; acetone; at 28 - 32℃; for 0.333333h; | Example 12Preparation of ethyl-3-[(2-[(4-{N'-[(hexyloxycarbonyl]-carbamimidoyl}- phenyl)amino]methyl}-l-methyl-lH-benzimidazoIe-5-yl)carbonyl]-(2- pyridinyl)amino}propanoate (1) from the 1:2 p-toluenesulfonic acid salt of ethyl-N-[(2-[(4-carbamimidoylphenyl)amino]methyl}-l-methyl-lH- benzimidazole-5-yl)carbonyl] -N-py ridine-2-yl- beta-alanianateInto a 2000 ml round-bottomed flask equipped with a mechanical stirrer 175 ml of water, 105 ml of acetone and 105 ml of ethanol are weighed in, whereupon 42.6 g (0.308 mole) of potassium carbonate are dissolved in the mixture. 35.0 g (0.041 mole) of the 1 :2 p-toluene sulfonic acid salt of l-methyl-2-[N-(4- amidino-phenyl)-aminomethyl]-5-benzimidazole-carboxylic acid -N-[2- methoxycarbonyl)-ethyl] -amide are added and the mixture is warmed to 28- 32C. A solution of 8.5 ml of chloro hexyl formiate in 30 ml of acetone is added whereupon the reaction mixture is stirred at 28-32 C for 20 minutes. After the addition of 700 ml of ethyl acetate the two-phase system obtained is separated, the organic layer is washed with water (three times 350 ml each) pre-warmed to 60-65 C and the solution is concentrated. To the solution a further amount (350 ml) of ethyl acetate is added and the solution is concentrated again. To the solution 630 ml of a 4: 1 solvent mixture of cyclohexane and ethyl acetate are added. The mixture is allowed to cool to room temperature and stirred at this temperature for 30-60 minutes. The product is filtered, washed with a 3:2 solvent mixture of cyclohexane and ethyl acetate (twice 90 ml each) and dried. Thus 22.0 g (85 %) of the title compound are obtained. The analytical sample of the product is obtained after recrystallization. Mp.: 125-128C.IR (KBr): 3408, 3381, 1730, 1611, 1471, 1258, 1143 cm-1.1H-NMR (DMSO-£¾, 500 MHz): 8,50-9,30 (bs, 2H), 8,39 (dd, IH), 7,80 (d, 2H), 7,53 (dt, IH), 7,47 (d, IH), 7,40 (d, IH), 7,12 (m, 2H), 6,95 (t, IH), 6,68 (d, IH), 6,75 (d, 2H), 4,60 (d, 2H), 4,22 (t, 2H), 3,97 (m, 4H), 3,77 (s, 3H), 2,68 (t, 2H), 1,58 (m, 2H), 1,29 (m, 6H), 1,12 (t, 3H), 0,86 (t, 3H) ppm. |
85% | With potassium carbonate; In ethanol; water; acetone; at 28 - 32℃; for 0.333333h; | Into a 2000 ml round-bottomed flask equipped with a mechanical stirrer 175 ml of water, 105 ml of acetone and 105 ml of ethanol are weighed in, whereupon 42.6 g (0.308 mole) of potassium carbonate are dissolved in the mixture. 35.0 g (0.041 mole) of the 1:2 p-toluene sulfonic acid salt of 1-methyl-2-[N-(4-amidino-phenyl)-aminomethyl]-5-benzimidazole-carboxylic acid-N-[2-methoxycarbonyl)-ethyl]-amide are added and the mixture is warmed to 28-32 C. A solution of 8.5 ml of chloro hexyl formiate in 30 ml of acetone is added whereupon the reaction mixture is stirred at 28-32 C. for 20 minutes. After the addition of 700 ml of ethyl acetate the two-phase system obtained is separated, the organic layer is washed with water (three times 350 ml each) pre-warmed to 60-65 C. and the solution is concentrated. To the solution a further amount (350 ml) of ethyl acetate is added and the solution is concentrated again. To the solution 630 ml of a 4:1 solvent mixture of cyclohexane and ethyl acetate are added. The mixture is allowed to cool to room temperature and stirred at this temperature for 30-60 minutes. The product is filtered, washed with a 3:2 solvent mixture of cyclohexane and ethyl acetate (twice 90 ml each) and dried. Thus 22.0 g (85%) of the title compound are obtained. The analytical sample of the product is obtained after recrystallization. Mp.: 125-128 C. IR (KBr): 3408, 3381, 1730, 1611, 1471, 1258, 1143 cm-1. 1H-NMR (DMSO-d6, 500 MHz): 8.50-9.30 (bs, 2H), 8.39 (dd, 1H), 7.80 (d, 2H), 7.53 (dt, 1H), 7.47 (d, 1H), 7.40 (d, 1H), 7.12 (m, 2H), 6.95 (t, 1H), 6.68 (d, 1H), 6.75 (d, 2H), 4.60 (d, 2H), 4.22 (t, 2H), 3.97 (m, 4H), 3.77 (s, 3H), 2.68 (t, 2H), 1.58 (m, 2H), 1.29 (m, 6H), 1.12 (t, 3H), 0.86 (t, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.3% | General procedure: Compound 1 (2 g, 3.7 mmol) was dissolved in 60 mL of THF and 12 mL of water. Potassium carbonate (1.55 g, 11.2 mmol) was added, and the mixture was stirred at room temperature for 20 min. Then, <strong>[6092-54-2]n-hexyl chloroformate</strong> (0.74 g, 4.5 mmol) was added drop-wise and stirring was continued for another 5 h. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated in vacuum. The residue was chromatographed (silica gel, dichloromethane/methanol 25:1) to afford the title compound 1.47 g as colorless crystals: yield 63.3%, m.p. [4] 130-132 C, 1H NMR (300 MHz DMSO-d6) delta (ppm): 0.87 (3H, t, J = 6.9 Hz, -CH2CH2CH3), 1.12 (3H, t, J = 7.2 Hz, -CH2CH3), 1.27-1.29 (6H, m, -CH2CH2CH2CH2CH3), 1.57 (2H, q, J = 6.6 Hz, -OCH2CH2CH2-), 2.68 (2H, t, J = 6.9 Hz, >NCH2CH2-), 3.77 (3H, s, >NCH3), 3.94-4.00 (4H, m, -OCH2CH3, -OCH2CH2CH2-), 4.22, (2H, t, J = 6.9 Hz, >NCH2CH2-), 4.59 (2H, d, J = 5.4 Hz, -CH2NH-), 6.76 (2H, d, J = 8.7 Hz, ArH), 6.88 (1H, d, J = 8.1 Hz, ArH), 6.98 (1H, m, NH), 7.10-7.17 (2H, m, ArH), 7.39 (1H, d, J = 8.4 Hz, ArH), 7.47 (1H, s, ArH), 7.54 (1H, t, J = 7.7 Hz, ArH), 7.79 (2H, d, J = 8.7 Hz, ArH), 8.39 (1H, d, J = 4.8 Hz, ArH), 8.60-9.30 (2H, brs, -NH2); ESI-MS(m/z): 628.4[M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.09 g | With triethylamine; In dichloromethane; at 20℃;Cooling with ether-dry ice; | To a solution of 7- [4- (4-benzo [b] thiophen-4-yl-piperazin- 1-yl) -butoxy] -lH-quinolin-2-one (800 mg) synthesized in the same manner as in WO2006/112464 (Example 1) in dichloromethane (20 ml) was added triethylamine (0.65 ml), with stirring under ice-cooling, hexylchloroformate (0.6 g) was added at room temperature overnight. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate :n- hexane=l:2) to give 7- [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) -butoxy] -quinolin-2-yl hexyl carbonate (1.09 g) .oil: colorless1H-NMR (CDCI3) delta ppm : 0.91 (3H, t, J=7.0 Hz), 1.30-1.50 (6H, m) , 1.70-1.84 (4H, m) , 1.88-1.98 (2H, m) , 2.54 (2H, t, J=7.5 Hz), 2.72 (4H, br) , 3.20 (4H, br) , 4.15 (2H, t, J=6.4 Hz),4.30 (2H, t, J=6.7 Hz), 6.90 (1H, dd, J=0.4, 7.6 Hz), 7.08 (1H, dr J=8.6 Hz), 7.20 (1H, dd, J=2.4, 8.9 Hz), 7.27 (1H, t, J=7.8 Hz), 7.33 (1H, d, J=2.4 Hz), 7.36-7.44 (2H, m) , 7.54 (1H, d, J=8.0 Hz), 7.72 (1H, d, J=9.0 Hz), 8.15 (1H, d, J=8.6 Hz) |
1.09 g | With triethylamine; In dichloromethane; at 20℃;Cooling with ice; | WO 2006/112464 (Example 1)Was synthesized in the same manner as7- [4- (4-benzo [b] thiophene-4-yl-piperazin-l-yl) -butoxy]-1 H-quinolin-2-one (800 mg)In dichloromethane (20 ml) was added triethylamine(0.65 ml), and the mixture was stirred under ice cooling,Hexyl chloroformate (0.6 g) was added,The mixture was stirred at room temperature overnight.Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.The organic layer was dried over sodium sulfate,The solvent was distilled off under reduced pressure.The residue was purified by silica gel column chromatography(Ethyl acetate: n-hexane = 1: 2)7- [4- (4-benzo [b] thiophene-4-yl-piperazin-l-yl) butoxy]-Quinolin-2-yl hexyl carbonate(1.09 g). Oily matter: colorless |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.4% | With sodium hydroxide; In water; acetone; at 20℃; for 1h; | Take the above compound of formula 3 added to 53.6g reaction flask was added 300mL of acetone at room temperature was added dropwise a solution of 87g of 14% sodium hydroxide and then added dropwise N-hexyl chloroformate16.5g, room temperature for 1 hour, allowed to stand for a certain time, minutes lower aqueous phase, the organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to a solid separated mother liquor, cooling to 0 crystallization was stirred for 2 hours and filtered to give crude compound of formula 4, and recrystallized from acetone, and dried in vacuo dabigatran etexilate, 54.2 g, yield 86.4%, purity (HPLCMethod): 99.79%. |
72.7% | The intermediate (S5) 0.27 kg (0.5mol) added to the 4L volume ratio of 1:1 and the water mixed solvent such as tetrahydrofuran, to stir and dissolve, cooling to 0-5C, adding 0.21 kg (1.5mol) potassium carbonate, stirring 0.5 hours. Subsequently oneself ester chloroformate 0.10 kg (0.6mol) in dropping Go, maintain 0-5 C reaction 1-2 hours. Filtering, produced intermediate S6 crude product. The crude product into the 1.5L in tetrahydrofuran, heating to 40-45C, stirring to dissolve. The 4.5L preheating to 38-40 C the purified water, in dropping Go, stirring, then slow cooling to 0-5C, stirring crystallization 2 hours. Filtration, dried under vacuum to get the intermediate (S6) 0.23 kg, yield 72.7%, the largest single impurity 0.10%, purity 99.70%. | |
With potassium carbonate; In water; acetone; at 10℃; for 1h; | Example-6: 350 mL acetone, 250 mL water and 32.2 g potassium carbonate were stirred in round bottom flask at 25C. The reaction mixture was cooled to 10C and 100 g of 1- methyl-2-[N-(4-amidinophenyl) aminomethyl]benzimidazol-5-yl-carboxylic acid-N- phenyl-N-(2-ethoxy carbonylethyl)amide hydrochloride of Formula (E) was added. 15 mL acetone and 16.8 mL n-hexyl chloro formate were added to the reaction mixture and stirred for 1 hour. The precipitated product was filtered and' washed with mixture of acetone and water. The wet-cake was dissolved in acetone and stirred for 30 min. The product was obtained by addition of water followed by filtration. The wet-cake thus obtained was washed with acetone and dried to obtain dabigatran etexilate of Formula (E). 50 g dabigatran etexilate and 500 mL ethyl acetate were stirred at 25C. The reaction mixture was charcoalized and filtered. The filtrate was heated 75C to 80C and stirred for 30 minutes and cooled to 25C to 35C. The reaction mixture was filtered and washed with ethyl acetate to obtain pure dabigatran etexilate of Formula (F). |
0.9 g | Example 2: Preparation of dabigatran etexilate 1 -Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride (10 g) and tetrahydrofuran (400 mL) were charged into a round bottom flask. Water (80 mL was charged followed by potassium carbonate (9.3 g) and stirred for 10-15 minutes, n- Hexyl chloroformate (3.4 g) was added slowly to the reaction mixture at 25-30QC and maintained for 2 hours at 25-30QC. The layers were separated and the organic layer was distilled under reduced pressure at below 30QC to obtain the crude compound. To the crude, dichloromethane (500 mL) was charged and the organic layer was washed twice with 10% sodium chloride (2 x 100 mL). The organic layer was concentrated under reduced pressure at below 40QC to obtain the crude. The above obtained crude (2 g) and a mixture of ethyl acetate (20 mL) and ethanol (4 ml) were charged into another round bottom flask and maintained at 25-30QC for 20-30 minutes. The reaction mixture was cooled to 10QC and the solid was collected by filtration, washed with ethyl acetate (4 mL) and ethanol (4 ml). The wet compound was suction dried and later dried in an oven at 50QC for 3 hours to afford the title compound. Yield: 0.9 g; Purity by HPLC: 98.99%. | |
With potassium carbonate; In water; acetone; for 1h; | 350 mL acetone, 250 mL water and 32.2 g potassium carbonate were stirred in round bottom flask at 25 C. The reaction mixture was cooled to 10 C. and 100 g of 1-methyl-2-[N-(4-amidinophenyl) aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxy carbonylethyl)amide hydrochloride of Formula (E) was added. 15 mL acetone and 16.8 mL <strong>[6092-54-2]n-hexyl chloroformate</strong> were added to the reaction mixture and stirred for 1 hour. The precipitated product was filtered and washed with mixture of acetone and water. The wet-cake was dissolved in acetone and stirred for 30 min. The product was obtained by addition of water followed by filtration. The wet-cake thus obtained was washed with acetone and dried to obtain dabigatran etexilate of Formula (F). | |
17.45 g | With potassium carbonate; In water; acetone; at 15 - 20℃; for 0.5h; | 17.5 g of the compound of formula (III) is added to a mixture of 105 mL of acetone and 70 mL of purified water. After adding 18.08 g of K2C03, 8.02 mL of hexyl chloroformate is added dropwise for 30 minutes while keeping 15 ~ 20 ", and the mixture is stirred at room temperature until the reaction is completed. The TLC Lobanung termination is confirmed, the solids are filtered off, 175 mL of EE and 175 mL of purified water are added. Separate the organic layer, add MgS04 and CA-1, stir for 30 minutes, and filter. The resulting filtrate was concentrated, recrystallized and filtered using Myou Sho, and the resulting solid was vacuum-dried at 40 C to obtain 17.45 g of the target compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.3 g | Example 1 : Preparation of beta-Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino] iminomethyl] phenyl]amino]methyl]-1 -methyl-1 H-benzimidazol-5-yl]carbonyl]-N-2- pyridinyl-, ethyl ester (dabigatran etexilate) in one pot 1 -Methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide (10 g) and ethanol (100 mL) were charged into a round bottom flask and cooled to about 5C, dry HCI gas was passed for about 8-10 hours at around 5-10C. The clear solution obtained was maintained for 14-16 hours at 25-30QC for the completion of the reaction and the solution was distilled under reduced pressure at below 40 C. To the crude compound obtained, ethanol (250 mL) and ammonium carbonate (20 g) were charged and the mixture was maintained for 14-16 hours at 25-30QC. To the above obtained reaction mass, water (100 mL) and tetrahydrofuran (200 mL) were charged and the resulting mixture was concentrated under reduced pressure at below 48QC. To the crude obtained, tetrahydrofuran (400 mL), potassium carbonate (18.7 g) were charged followed by slow addition of n-hexyl chloroformate (1 1 .75 g) at 25-30QC and maintained the reaction mass at 25-30QC for around 3 hours. After completion of the reaction, the organic layer was separated and distilled off under reduced pressure. The crude obtained was dissolved in dichloromethane (400 mL) and washed twice with water (2x100 mL) followed by washing twice with 10% sodium chloride solution (2x100 mL) and the layers were separated. The organic layer was concentrated under reduced pressure at below 40QC. To the crude obtained, ethyl acetate (80 mL) was charged and the solid was collected by filtration and washed with ethyl acetate (10 mL). The compound was dried in an oven at 50C for 5 hours to afford the title compound. Yield: 5.3 g; Purity by HPLC: 97.90%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.6% | The acetate salt of ethyl N-[(2- [(4-carbamimidoylphenyl)amino]methyl}-l- methyl-3a,7a-dihydro- lH-benzimidazol-5-yl)carbonyl]-N-pyridin-2-yl- -alaninate (50 g) was added to tetrahydrofuran (750 mL) and deionized water (250 mL) and the mixture was stirred for 20 minutes. Potassium carbonate (37.08 g) was added to the reaction mixture and the mixture was stirred for 30 minutes. A solution of <strong>[6092-54-2]n-hexyl chloroformate</strong> (16.19 g) in tetrahydrofuran (250 mL) was added to the reaction mixture at 18C to 20C. The reaction mixture was stirred for 2 hours at 20C to 22C. The reaction mixture was taken in a separating funnel and the tetrahydrofuran layer was collected. Potassium carbonate (40 g) was added to the reaction mixture and the mixture was stirred for 30 minutes. The layers obtained were separated and the tetrahydrofuran layer was taken. Carbon (5 g) was added to the tetrahydrofuran layer and it was stirred for 20 minutes. The reaction mixture was filtered through celite. The tetrahydrofuran layer was collected and butylated hydroxytoluene (0.5 g) was added to the reaction mixture. The solvents were recovered under vacuum. Acetone (150 mL) was added to the reaction mixture and the mixture was stirred for 20 minutes. The acetone (130 mL) was recovered under vacuum. The solid obtained was dissolved in acetone (392 mL). A solution of methane sulfonic acid (8.14 g) in acetone (56 mL) was added to the reaction mixture at 18C to 20C. The reaction mixture was stirred at 20C to 22C for 2 hours, filtered, and dried under suction. The reaction mixture was further dried under vacuum at 55C for 15 hours to get the title compound having an XRPD pattern as depicted in Figure 1. Yield: 52 g Percentage Yield: 80.6% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With pyridine; In chloroform; at 20℃; | General procedure: A solution of the corresponding chloroformate (8.08 mmol) in dry chloroform (25 mL) was slowly added dropwise to a stirred solution of Se-methylselenourea (3.94 mmol) in dry chloroform (25 mL) and pyridine (2.5 mL). The mixture was stirred for 24-72 h at room temperature. Water was added to the reaction and the mixture was extracted with dichloromethane (3×20 mL). The organic layer was washed with water (3×20 mL), dried with Na2SO4 and the solvents were removed under vacuum by rotatory evaporation and the residue was treated with ethyl ether (100mL). |
Yield | Reaction Conditions | Operation in experiment |
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In a 1 litre RB flask equipped with a mechanical stirrer and addition funnel, water(125 ml) and potassium carbonate (23 gm) were charged at 25-28C. Acetone (75. ml)and ethanol (75ml) were charged at the same temperature. The mixture was cooled to10-15C and to this was charged l-methyl-2- [N- [4-amidinophenyl] aminomethyl]benzimidazol-5-yl- carboxylic acid-N-(2-pyridyl)- N-(2-ethoxycarbonylethyl)amide mesylate (25g) at the same temperature. The reaction mixture was stirred at same temperature for 15-20 mm and to this n-hexylchloroformate (8.9 gm) dissolved in acetone (10 ml) was added over a period of 10-15 mm at the same temperature. The mixture was stirred at 15-20C for 1 hour. The completion of reaction was monitored by TLC. After the completion of reaction, the reaction mixture was diluted with water(125 ml) and the slurry was stirred for 1 hour at 15 to 20C. The slurry was filtered and the solid was washed with water (2 x 50 ml) and dried at 40-45C to obtain Dabigatran etexilate tetrahydrate. Yield: 20 g (77%); Purity: greater than 97 % | ||
With triethylamine; In acetone; at 20 - 25℃; | Mixing 5.0 g (8.4 mmol) of hydrazine methanesulfonate (III-2) with 100 mL of acetone,4.24 g (42 mmol) of triethylamine was added.Control temperature is 20 ~ 25 C,2.10 g (12.8 mmol) of <strong>[6092-54-2]n-hexyl chloroformate</strong> was added dropwise with stirring.Continue to stir after the addition is complete.After the reaction, suction filtration,The filtrate was concentrated under reduced pressure to about 15 mL.Cool down to 0~10 C,Filter the precipitated solids,The dabigatran etexilate (I) is dried under vacuum at 45 to 55 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.1% | In tetrahydrofuran; water; at 15 - 20℃; for 2h; | (4-amidinophenyl)glycine ethyl ester (50 gm) was added in THF (600 ml) to obtain a mixture. To this mixture, water (200 ml) was added followed by addition of a base(62.4 gm) and the mass was cooled to 15-20C. To this mixture, n-hexylchloroformate (40.5 gm) was added dropwise. The temperature of the reaction mass was raised to room temperature and was maintained under stirring at the same temperature forhours. The completion of the reaction was monitored by TLC. The layers were separated and the aqueous layer was extracted with THF (250 ml). The organic layer was concentrated under vacuum. The oil obtained was treated with dichloromethaneand water. The organic layer was washed with water and distilled at 40C to obtainresidue. To this residue, hexane (500 ml) was added and the mixture was stirredroom temperature. The solid separated was filtered, washed with hexane (250 ml) and dried at 50-55C to obtain 50 gm of [(4-[(hexyloxy)carbonyl] carbamimidoyl} phenyl)amino]acetic acid ethyl ester. Yield: 63.1 % |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.4% | With potassium carbonate; In acetonitrile; at 0℃; | In a three-necked bottle, 3-(((((4-(phenylphenyl)amino)methyl)-1-methyl-1H-benzimidazol-5-yl)carbonyl) (pyridine-2-) 200% (0.30 mol) of p-toluenesulfonate of ethylamino)propionate,4000 mL of acetonitrile was added, and 207 g (1.5 mol) of potassium carbonate was slowly added dropwise at -0 C.194 g (1.2 mol) of <strong>[6092-54-2]n-hexyl chloroformate</strong> was slowly added dropwise, and the reaction was monitored by HPLC.Dichloromethane was distilled off under reduced pressure to give crude crude yd., and recrystallized from 2000 mL of isopropyl alcohol to afford 181 g of a white solid, dabigabite, with a yield of 98.4% and a liquid phase purity of 99.7%. |
17.5 g | With potassium carbonate; In water; acetone; at 12 - 25℃; for 1.5h; | To a stirred suspension of p-TSA salt of compound of formula 5 (25g) in acetone (200mL), at 25-35C, was charged a solution of potassium carbonate (32.2 g) in DM water(125 mL).The reaction mass was cooled to 12-1 8C. n-Hexyl chioroformate (6.4g) wasadded slowly to the reaction mass. The temperature of the reaction mass was raised 19-25C and stirred for 30 mm. Second lot of n-hexylchloroformate (1.9 g) was chargedand the reaction mass stirred for another hour at 19-25C, when analytical HPLC revealed completion of the reaction. Raised the temperature of reaction mass to 50-56C and stirred for 10 mm. Separated the layers and stored the organic layer at 50-56C. Back extracted the aqueous layer with toluene (75 mL). Carbon PS-133 was added to the combined organic layer and stirred for 15 mm. Filtered the reaction mass and washedwith hot toluene (75 mL).Washed the organic layer with DM water at 50-56C.Concentrated the organic layer under vacuum and charged isopropyl acetate (25 mL). Distilled off the solvent, completely, under vacuum. Charged isopropyl acetate (250 mL) to the residue, heated up to 60-65C till a clear solution is obtained. Then cooled to 20-25C and stirred for 9hr, at 20-25C. The precipitated product was filtered,washed with isopropyl acetate and dried under vacuum, at 50C, to afford pure Dabigatran Etexilate as off-white solid material (17.5 g, >99.5% HPLC pure). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | In chloroform; at 20℃; for 24h; | General procedure: Appropriate chloroformates (6 mmol) dissolved in dry chloroform (25 mL) were added dropwise while stirring to 4,4-diaminodiphenyl diselenide (3 mmol) dissolved in dry chloroform (25 mL). The mixture was kept with stirring at room temperature for another 24 h and during stirring a solid precipitate formed. The resulting solid was collected by filtration and solvent was evaporated under vacuum. The residue was treated with ethyl ether (3 x 25 mL) to obtain the desired compounds. Compounds 2j and 2m were additionally washed with hexane (20 mL) for purification. 4.1.2.4 Dihexyl (diselanediyldibenzene-4,1-diyl)biscarbamate (2d) From hexyl chloroformate. Yellow solid; mp: 84 C. Yield: 63%. IR (KBr) cm-1: 3359 (N-H), 2954 (C-H), 1704 (C=O), 814 (Se-Se). 1H NMR (400 MHz, CDCl3) delta: 0.86-0.87 (m, 6H, 2CH3); 1.25-1.28 (m, 8H, 2delta+2epsilonCH2); 1.58-1.60 (m, 4H, 2gammaCH2) 3.35-3.37 (m, 4H, 2betaCH2); 4.05-4.07 (m, 4H, 2betaCH2 + 2alphaCH2); 7.43 (d, 4H, A+A', H3+H5, J3-2 = J5-6 = 8.7 Hz); 7.50 (d, 4H, A+A', H2+H6, J2-3 = J6-5 = 8.7 Hz); 9.79 (s, 2H, 2NH). 13C NMR (100 MHz, CDCl3) delta: 14.8 (2C, 2CH3); 22.9 (2C, 2epsilonCH2); 25.9 (2C, 2deltaCH2); 31.8 (2C, 2gammaCH2); 33.6 (2C, 2betaCH2); 61.6 (2C, 2 alphaCH2); 119.7 (4C, A+A', C3, C5); 123.5 (2C, A+A', C1); 134.3 (4C, A+A', C2, C6); 140.6 (2C, A+A', C4); 154.4 (2C, 2C=O). MS (m/z% abundance): 600 (M+?, 16), 498 (36), 300 (78), 198 (66), 172 (78), 43 (100). Elemental Analysis for C26H36N2O4Se2, Calcd/Found (%): C: 52.18/52.10; H: 6.06/5.85; N: 4.68/4.98. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.6% | The acetate salt of ethyl N-[(2-[(4-carbamimidoylphenyl)amino]methyl}-1-methyl-3a,7a-dihydro-1H-benzimidazol-5-yl)carbonyl]-N-pyridin-2-yl-beta-alaninate (50 g) was added to tetrahydrofuran (750 mL) and deionized water (250 mL) and the mixture was stirred for 20 minutes. Potassium carbonate (37.08 g) was added to the reaction mixture and the mixture was stirred for 30 minutes. A solution of <strong>[6092-54-2]n-hexyl chloroformate</strong> (16.19 g) in tetrahydrofuran (250 mL) was added to the reaction mixture at 18 C. to 20 C. The reaction mixture was stirred for 2 hours at 20 C. to 22 C. The reaction mixture was taken in a separating funnel and the tetrahydrofuran layer was collected. Potassium carbonate (40 g) was added to the reaction mixture and the mixture was stirred for 30 minutes. The layers obtained were separated and the tetrahydrofuran layer was taken. Carbon (5 g) was added to the tetrahydrofuran layer and it was stirred for 20 minutes. The reaction mixture was filtered through celite. The tetrahydrofuran layer was collected and butylated hydroxytoluene (0.5 g) was added to the reaction mixture. The solvents were recovered under vacuum. Acetone (150 mL) was added to the reaction mixture and the mixture was stirred for 20 minutes. The acetone (130 mL) was recovered under vacuum. The solid obtained was dissolved in acetone (392 mL). A solution of methane sulfonic acid (8.14 g) in acetone (56 mL) was added to the reaction mixture at 18 C. to 20 C. The reaction mixture was stirred at 20 C. to 22 C. for 2 hours, filtered, and dried under suction. The reaction mixture was further dried under vacuum at 55 C. for 15 hours to get the title compound having an XRPD pattern as depicted in FIG. 1. Yield: 52 g Percentage Yield: 80.6% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With pyridine; In dichloromethane; at 0 - 25℃; for 3.5h;Inert atmosphere; | Step 2. Preparation of Ethyl(2S,3R)-3-[(2-[((hexyloxy)carbonyl]amino}pyridin-4-yl)methyl]-4-oxo-1-[(1R)-1-phenylethyl]carbamoyl}azetidine-2-carboxylate A stirred solution of ethyl(2S,3R)-3-[(2-aminopyridin-4-yl)methyl]-4-oxo-1-[(1R)-1-phenylethyl]carbamoyl}azetidine-2-carboxylate (50.0 mg, 0.126 mmol) in dry methylene chloride (0.50 mL) under nitrogen was cooled in an ice water bath and treated with pyridine (22 muL, 0.28 mmol) followed by hexyl chloroformate (23 muL, 0.14 mmol) dropwise. The reaction mixture was stirred at 0-5 C. for 1 h followed by slow warming (over 2.5 h) to room temperature. The reaction mixture was diluted with 10 mL H2O and extracted with two 15 mL portions of CH2Cl2. The organic phase was washed with 15 mL portions of H2O and brine and was dried over Na2SO4. The solution was concentrated to nearly colorless viscous oil. The crude material was purified by flash chromatography (25 g silica gel, 30-50% EtOAc/hex) to yield the title compound (43 mg, 66%) as a colorless glass: HPLC retention time: 4.27 min (Method A); MS (ESI+) for C28H36N4O6 m/z 525.3 (M+H)+; MS (ESI-) for C28H36N4O6 m/z 523.4 (M-H)-; 1H NMR (400 MHz, CDCl3) delta 8.21 (1H, d, J=5.1 Hz) 7.93 (1H, s) 7.73 (1H, br. s.) 7.35 (4H, m) 7.28 (1H, m) 6.89 (1H, dd, J=5.1, 1.5 Hz) 6.67 (1H, d, J=8.1 Hz) 5.03 (1H, m) 4.16 (5H, m) 3.54 (1H, ddd, J=8.3, 6.8, 2.7 Hz) 3.20 (1H, m) 3.09 (1H, m) 1.70 (2H, m) 1.55 (3H, d, J=7.1 Hz) 1.37 (6H, m) 1.16 (3H, t, J=7.2 Hz) 0.91 (3H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With pyridine; In dichloromethane; at 0 - 25℃; for 3.5h;Inert atmosphere; | Step 2. Preparation of Benzyl(2S,3R)-3-[(2-[(hexyloxy)carbonyl]amino}pyridin-4-yl)methyl]-4-oxo-1-[(1R)-1-phenylethyl]carbamoyl}azetidine-2-carboxylate A stirred solution of benzyl(2S,3R)-3-[(2-aminopyridin-4-yl)methyl]-4-oxo-1-[(1R)-1-phenylethyl]carbamoyl}azetidine-2-carboxylate (206 mg, 0.449 mmol) in dry methylene chloride (3.0 mL) under nitrogen was cooled in an ice water bath and treated with pyridine (95 muL, 1.2 mmol) followed by hexyl chloroformate (110 muL, 0.67 mmol) dropwise. The reaction mixture was stirred at 0-5 C. for 1 h at which point the cooling bath was allowed to slowly warm to room temperature over 2.5 h. At this time, HPLC indicated the starting material had been consumed. The reaction mixture was diluted with 20 mL H2O and extracted with two 20 mL portions of CH2Cl2. The organic phase was washed with 15 mL H2O and brine and was dried over Na2SO4. The solution was concentrated to a light yellow glass. The crude material was purified by flash chromatography (30 g silica gel, 30-50% EtOAc/hex) to yield the title compound (242 mg, 92%) as a colorless glass: HPLC retention time: 4.51 min (Method A); MS (ESI+) for C33H38N4O6 m/z 587.4 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.71% | With triethylamine; In dichloromethane; at 0 - 5℃; | 100 gm (0.718 mol) para nitro phenol was dissolved in 1000 ml dichioromethane. To the obtained clear solution was added 80 gm (0.790 mol) triethylamine. Reaction mixture was then cooled to 0-5C. To the reaction mixture was added pure 165 gm (1.0 mol) n-hexyl chloroforrnate at 0-5C. Reaction was then stirred at 0-5C for 5-6 hr. the completion of reaction was monitored by TLC. Upon completion of reaction, reaction mixture was quenched with 1000 ml water. Organic layer was separated and aqueous layer was extracted with 500 ml dichioromethane. Combined dichloromethane layer was washed two times with 1 000ml 0.5N NaOH solution. Finally dichloromethane layer was washed two times with 1000 ml purified water. Dichioromethane was removed under vacuum to obtain title compound.Yield: 132 g (68.71%); Purity by HPLC:99.73%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | (phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)- 1 H-pyrazole-5-carboxamide (227d)(150 mg, 0.27 mmol) in anhydrous acetonitrile (10 mL) was added triethylamine (88 mg,0.87 rnmol) followed by a solution of hexyl chloroformate (45 mg, 0.27 rnmol) inanhydrous acetonitrile (3.0 mL). The reaction mixture was stirred for II h at roomtemperature, diluted with EtOAc (40 mL) and washed with water (20 rnL). The aqueouslayer was extracted again with EtOAc (20 mL) and combined organic layers were dried over MgSO4, filtered and concentrated in vacuum. The residue obtained was purified by flash column chromatography [silica gel I 2g, eluting with 0-50 % (ethyl acetate/MeOH (9:1, v/v) in hexanes) to obtain free base of 233b as a free base. The free base was dissolvedMeOH added 3 N HC1 in MeOH (5.0 mL), stirred for 4h at room temperature and concentrated in vacuum to furnish (-)-Hexyl (3 -(5-(5-((cyclopropylmethylamino)- (phenyl)methyl)-2-fluorophenylcarbamoyl)-3-Ori fluoromethyl)- 1 H-pyrazol- I - yl)phenyl)(imino)methylcarbarnate (233b) (126 mg, 59 % yield) hydrochloride as a white solid. ?H NMR (300 MHz, DMSO-d6) 8 10.85 (s, IH), 10.23 (d,J= 23.1 Hz, 2H), 8.05 (t,.J= 2.0 Hz, IH), 7.98- 7.69 (m, 7H), 7.53 - 7.27 (m, 4H), 5.65 (s, 1H), 4.23 (s, 2H), 2.69 (s,2H), 1.66 (s, 2H), 1.46 - 1.22 (m, 6H), 0.93 - 0.79 (m, 3H), 0.62 -0.47 (m, 2H), 0.30 (d, J = 5.1 Hz, 2H), 0.00(s, 2H); MS (ES+) 304.9 (M/2-2H20), 340.4 (M12+l), 679.5 (M+l);C36H38F4N6O.2HC1.2H2O: C, 54.89; H, 5.63; Cl, 9.00; N, 10.67; Found: C, 54.92, H, 5.51.CI, 8.80;N, 10.60. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With potassium carbonate; In tetrahydrofuran; water; | General procedure: The mixture of 10 (0.50 g, 0.952 mmol), K2CO3 (0.74 g,5.4 mmol), ethyl chloroformate (0.11 g, 1.00 mmol), 25 ml THFand 5 ml H2O was stirred at 0-5 C for 1 h. After removing theTHF under reduced pressure, the residue was extracted by 30 mlCH2Cl2. The organic phase was washed with brine, dried overanhydrous sodium sulfate and concentrated in vacuo. The resultingresidue was purified by silica gel chromatography (CH2Cl2/MeOH = 50:1) to give I-2a (0.26 g) as white solids in 52% yields |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With potassium carbonate; In tetrahydrofuran; water; | General procedure: The mixture of 10 (0.50 g, 0.952 mmol), K2CO3 (0.74 g,5.4 mmol), ethyl chloroformate (0.11 g, 1.00 mmol), 25 ml THFand 5 ml H2O was stirred at 0-5 C for 1 h. After removing theTHF under reduced pressure, the residue was extracted by 30 mlCH2Cl2. The organic phase was washed with brine, dried overanhydrous sodium sulfate and concentrated in vacuo. The resultingresidue was purified by silica gel chromatography (CH2Cl2/MeOH = 50:1) to give I-2a (0.26 g) as white solids in 52% yields |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With potassium carbonate; In tetrahydrofuran; water; | General procedure: The mixture of 10 (0.50 g, 0.952 mmol), K2CO3 (0.74 g,5.4 mmol), ethyl chloroformate (0.11 g, 1.00 mmol), 25 ml THFand 5 ml H2O was stirred at 0-5 C for 1 h. After removing theTHF under reduced pressure, the residue was extracted by 30 mlCH2Cl2. The organic phase was washed with brine, dried overanhydrous sodium sulfate and concentrated in vacuo. The resultingresidue was purified by silica gel chromatography (CH2Cl2/MeOH = 50:1) to give I-2a (0.26 g) as white solids in 52% yields, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With potassium carbonate; In tetrahydrofuran; water; | General procedure: The mixture of 10 (0.50 g, 0.952 mmol), K2CO3 (0.74 g,5.4 mmol), ethyl chloroformate (0.11 g, 1.00 mmol), 25 ml THFand 5 ml H2O was stirred at 0-5 C for 1 h. After removing theTHF under reduced pressure, the residue was extracted by 30 mlCH2Cl2. The organic phase was washed with brine, dried overanhydrous sodium sulfate and concentrated in vacuo. The resultingresidue was purified by silica gel chromatography (CH2Cl2/MeOH = 50:1) to give I-2a (0.26 g) as white solids in 52% yields, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With triethylamine; In dichloromethane; at 20℃; for 12h;Inert atmosphere; | 1H-Pyrazole 14b (0.07 g, 1.03 mmol) was dissolved in dry DCM (9 mL). The solution was cooled to 0C and triethylamine (0.21 mL, 1.54 mmol) was added followed by hexyl chloroformate (0.25 g, 1.54 mmol) in DCM (1.3 mL). The reaction was allowed to warm to rt and stirred under nitrogen atmosphere for 12 h. The reaction was quenched with sat. aq. NH4Cl and the aqueous phase was extracted with DCM (3 × 10 mL); the combined organic layer was washed with sat. aq. NaHCO3 and brine, dried over Na2SO4 and the solvent was evaporated under reduced pressure. The crude was purified by silica gel column chromatography (cyclohexane/EtOAc 85:15) to afford 28 (0.12 g, 57%) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The 16.4g (0.1mol), n-hexyl chloroformate (III), 100ml of dichloromethane, 8.0g of sodium hydroxide (0.2mol), 32ml water was added to reacted flask, reacted for 20 min at 20 C then added 10.5g (0.05mol) p-aminobenzamidine dihydrochloride (IV), 1 hour addition was completed, after addition was completed reacted for 4 hours. After reaction was completed added 100ml water, after stirring for a few minutes standing, the layer of water, washed once with water 100ml and then, the organic layer was evaporated dichloromethane give a sticky solid (II). Sticky solid was added to 50ml of acetone, dissolved by heating, added 6.30g (0.05mol) of oxalic acid dihydrate, cooling crystallization, filtered, washed with acetone, and dried to give oxalate impurity condensates (IIa) HPLC content 98.92%, a yield of 47.89%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.4% | Example 4-1 and 4-2 was prepared compound (p-bromophenyl formamidine, 0.35mol) was dissolved V (tetrahydrofuran) :V (water) = 5:1 of a mixed solvent (1500mL), and white turbid liquid, stir anhydrous potassium carbonate 55.3g (0.4mol), stirred at room temperature 15min, the reaction liquid gradually turns yellow-green to clarify. Then slowly dropwise n-hexyl acrylate 69.1g (0.42mol), the reaction solution was gradually added dropwise during clarification white to yellow, the reaction was stirred 12h. Was allowed to stand, the organic layer was separated, the aqueous phase was extracted with ethyl acetate (300mL × 3), combined organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to a large amount of white solid was precipitated, filtered to give a crude product Compound , at 65 dissolved in an appropriate amount of ethyl acetate to clarify, room temperature for 3h, then allowed to stand at 4 crystallization, filtration, and dried in vacuo to afford 104.3g compound as white crystals (bromo substituent), HPLC purity 99.6% detection, yield 90.4 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.6% | After the compound prepared in Example 4-3 was (p-chlorophenyl formamidine, 0.18mol) was dissolved in V (tetrahydrofuran) :V (water) = 5 :1 800mL of a mixed solvent of a white turbid solution, stir triethylamine 103.7g (0.75mol), stirred at room temperature 15min, the reaction liquid gradually turns yellow-green to clarify. Then slowly dropwise n-hexyl ester 33g (0.2mol), was added dropwise during the reaction was gradually clarified white to yellow, the reaction was stirred 12h. Was allowed to stand, the organic layer was separated, the aqueous phase was extracted with ethyl acetate (100mL × 4), organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to a large amount of white solid was precipitated, filtered to give a crude product Compound , at 65 dissolved in an appropriate amount of ethyl acetate to clarify, room temperature for 3h, then allowed to stand at 4 crystallization, filtration, and dried in vacuo to give 49.2g of white crystalline compound (chloro substituted), HPLC purity 99.3% detection, yield 89.6 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In dichloromethane; at 20℃; for 4h; | To the reaction flask, add 21.2 g (0.10 mol) of p-aminobenzamidine dihydrochloride (II), 150 ml of dichloromethane. Add 80 ml of 15% (0.12 mol) solution of sodium hydroxide at a controlled temperature of 20 deg.C. Add dropwise 16.5g (0.1 mol) n-hexyl chloroformate (III). React for 4h. The aqueous layer was separated and the dichloromethane was distilled off to obtain 26.4 g of an oily product of the condensate (I). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium carbonate; In acetone; at 20℃; for 3h; | To 100-mL3 neck round bottom flask was added (3R,4R,5S)-5-[[[(1Z)-amino]([[(tert-butoxy)carbonyl]imino])methyl]amino]-4-acetylamino-3-(pentan-3-yloxy)cyclohexyl 1-en-1-carboxylate (300mg, 0.66mmol, 1.00 equiv) in acetone (50 mL) was added potassium carbonate (240mg, 1.74 mol, 2631.13 equiv), hexyl chloroformate (163mg, 0.99mmol, 1.50 eq). in room temperature The resulting solution was stirred for 3 hours, 100mL H 2 O and washed with, and then extracted with 2x100mL ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, combined and concentrated under vacuum. The residue was purified on a silica gel column , Extracted with ethyl acetate: petroleum ether (1:5-1:1) to give 300mg (78%) (3R,4R,5S)-5-[[(1E)-[[(tert-butoxy)carbonyl]imino]([[(hexyloxy)carbonyl]amino])methyl]amino]-4-acetylamino-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylic acid ethyl esteras a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.9% | With sodium hydroxide; In acetone; at 0 - 10℃; | Take dabigatran etexilate intermediates (3)10g, add acetone 50ml, 4N sodium hydroxide solution 20ml, stir well after the insulation 0 ~ 10 dropping 12g of <strong>[6092-54-2]n-hexyl chloroformate</strong> dissolved in 15ml acetone solution, after adding insulation reaction 20 ~ 30min, TLC (developer: Ethyl acetate: petroleum ether = 4: 1) to determine the end point of the reaction. After completion of the reaction, the organic layer was separated and concentrated in vacuo at 30 C under reduced pressure to dryness. Ethyl acetate (40 ml) was dissolved, adjusted to pH 2 with concentrated hydrochloric acid, filtered in an ice-water bath, washed with 15 ml of ethyl acetate, And dried under reduced pressure to obtain the target compound in a yield of 85.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With potassium carbonate; In tetrahydrofuran; water; at 0 - 5℃; for 1h; | The mixture of II-7 (0.30 g, 0.552 mmol), K2CO3 (0.46 g,3.31 mmol), hexyl chloroformate (0.11 g, 0.662 mmol), 15 ml THFand 5 ml H2O was stirred at 0-5 C for 1 h. After removing theTHF under reduced pressure, the residue was extracted by 20 mlCH2Cl2. The organic phase was washed with brine, dried over anhydroussodium sulfate and concentrated in vacuo. The resulting residuewas purified by silica gel chromatography (CH2Cl2:MeOH = 40:1) to give II-9a (0.13 g) as white solids in 40% yields,m.p. 114-116 C. 1H NMR (300 MHz, DMSO) d 9.15 (brs, 2H),7.92 (d, J = 8.3 Hz, 2H), 7.68-7.34 (m, 4H), 7.02 (d, J = 9.1 Hz, 1H),4.42-4.24 (m, 1H), 4.19-4.04 (m, 1H), 4.01 (t, J = 6.5 Hz, 2H),3.97-3.88 (m, 1H), 3.75-3.47 (m, 2H), 3.48-3.38 (m, 2H), 3.13-2.91 (m, 2H), 2.80 (t, J = 5.9 Hz, 2H), 2.40-2.24 (m, 2H), 2.08-1.90(m, 2H), 1.76-1.40 (m, 10H), 1.33-1.22 (m, 6H), 0.87 (t,J = 5.7 Hz, 3H). 13C NMR (75 MHz, CDCl3) d (ppm) 174.41, 167.09,164.31, 151.44, 141.85(2C), 139.22, 132.90, 132.28, 129.28(2C),127.26(2C), 120.61, 115.25, 108.74, 65.20, 58.75, 55.67, 46.69,46.17, 42.63, 41.41, 39.25, 37.31, 37.01, 31.03, 28.32, 25.83,25.13, 24.36, 24.26, 22.91, 22.05, 13.50. HRMS (ESI): m/z [M+H]+.calc. for C35H47N6O3 599.3704; found 599.3710. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With potassium carbonate; In tetrahydrofuran; water; at 0 - 5℃; for 1h; | The mixture of II-7 (0.30 g, 0.552 mmol), K2CO3 (0.61 g,4.42 mmol), hexyl chloroformate (0.22 g, 1.32 mmol), 15 ml THFand 5 ml H2O was stirred at 0-5 C for 1 h. After removing theTHF under reduced pressure, the residue was extracted by 20 mlCH2Cl2. The organic phase was washed with brine, dried over anhydroussodium sulfate and concentrated in vacuo. The resulting residuewas purified by silica gel chromatography (CH2Cl2:MeOH = 60:1) to give II-9b (0.17 g) as white solids in 43% yields,m.p. 79-81 C. 1H NMR (300 MHz, DMSO-d6) d (ppm) 9.16 (brs,2H), 8.04-7.77 (m, 2H), 7.46 (d, J = 9.2 Hz, 2H), 7.33 (d, J = 6.7 Hz,2H), 7.06 (d, J = 9.1 Hz, 1H), 5.70-5.42 (m, 1H), 4.53-4.33 (m,1H), 4.33-4.16 (m, 1H), 4.13-3.78 (m, 4H), 3.74-3.62 (m, 1H),3.62-3.47 (m, 2H), 3.43-3.35 (m, 2H), 3.12-2.96 (m, 1H), 2.91-2.67 (m, 2H), 2.42-2.23 (m, 2H), 2.06-1.91 (m, 2H), 1.75-1.62(m, 4H), 1.62-1.49 (m, 4H), 1.48-1.40 (m, 2H), 1.40-0.95 (m,14H), 0.95-0.67 (m, 6H). 13C NMR (75 MHz, CDCl3) d (ppm)174.34, 166.97, 164.55, 154.30, 149.23, 142.19, 141.10, 139.69,132.72, 131.78, 129.43(2C), 126.93(2C), 120.84, 115.39, 108.90,65.91, 65.19, 58.74, 53.71, 46.70, 46.19, 41.41, 39.21, 38.22,37.27, 37.10, 31.05, 30.90, 28.31, 28.18, 25.85, 25.14, 25.00,24.38, 24.36, 22.93, 22.07, 22.02, 13.54, 13.51. HRMS (ESI): m/z[M+H]+. calc. for C42H59N6O5 727.4541; found 727.4556. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.7% | With potassium carbonate; In ethyl acetate; at 0℃; for 1.5h; | A solution of 15 g (0.091 mol) of p-nitrobenzamidine in 80 mL of ethyl acetate was added dropwise to the reaction vessel at 0 C. 15 g (0.091 mol) of potassium carbonate was added dropwise at 0 C. N-hexyl chloroformate. After stirring for 1.5 hours, the mixture was separated and the organic layer was washed with saturated brine, and ethyl acetate was evaporated to dryness to give p-nitrobenzamidine imine24.3 g, yield 96.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium hydride; In tetrahydrofuran; for 2h; | 10 g of p-nitrobenzamide (4) was weighed and dissolved in anhydrous tetrahydrofuran (100 ml), and 3 g of sodium hydride was added thereto. After the temperature was stabilized, <strong>[6092-54-2]n-hexyl chloroformate</strong> was added dropwise. 9. 9 g was added dropwise. 2h ice bath cooling, filter to the head The standard product was obtained as a white solid (15 g, yield 85%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium carbonate; In water; acetone; at 10 - 25℃; | Into a 500mL reaction flask was added intermediate DG2 (21.7g, 43mmol, 1.0eq), potassium carbonate (12g, 86mmol, 2.0eq),200mL water and 100mL acetone, stir to dissolve,N-Hexyl chloroformate (7.8 g, 47 mmol, 1.1 eq) was slowly added dropwise at 10-15 C. After dropping, react at 20-25 ,TLC monitors the reaction. After the reaction is completed, cool to 10 C, filter with suction, wash the filter cake with acetone / water, and dry to obtain crude solid DG. The crude product was recrystallized with 150 mL of acetone and water (2: 1) to obtain 23.8 g of white solid product DG. Yield: 88%. |
78% | A solution of IV (10.0 g, 18.6 mol) in THF (tetrahydrofuran) (75 ml) and water (15 ml) was added, potassium carbonate (9.4 g, 65.0 mmol) was added and stirred at room temperature for 0.5 h, Cooled to below 10 C, <strong>[6092-54-2]n-hexyl chloroformate</strong> (4.30 g, 26.1 mmol) was added and stirred for 2 h. Concentrated solvent, add ethanol 100ml, stirring lh, filter, concentrated under reduced pressure. The residue was recrystallized twice from ethyl acetate to give 8.62 g of solid dabigatran group with a yield of 78% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With N-ethyl-N,N-diisopropylamine; trifluoroacetic anhydride; In dichloromethane; at 0 - 20℃; for 4h; | A solution of 25 mg (0.027 mmol) of a cyclic depsipeptide according to formula (II) in 2 mL of dichloromethane(MC) was cooled to 0 C. Then 24 mL of DIPEA and 14 mL of hexyl chloroformate was slowly added. The reaction mixturewas allowed to warm up to rt and stirred for additional 4 hours. For workup the reaction mixture was diluted with dichloromethaneand washed with hydrochloric acid and sat. bicarbonate solution, and brine. After drying over sodium sulfatethe solvent was removed and the residue obtained purified by chromatography on silica gel (cHex/EtOAc (1:1) + 10%MeOH). Yield: 20 mg (70%) of a derivative of the cyclic depsipeptide according to formula (II) wherein the phenol moietyof A6 has been transformed into the corresponding carbonic acid hexyl ester. ESI MS: 1079.41 [M+Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35.1 g | By embodiments 2 - 4 prepared in the target product is 40g adding 3000 ml glass reaction in the bottle, sequentially adding potassium carbonate 33.0g, water 220 ml, acetone 350 ml, stirring the temperature to 5 C, continuing to stir 10 minutes, slowly instillment chlorine formic acid oneself ester 16.0g, after finishing dropping to continue to 5 C stirring 1 hours, to the reaction solution is added in dichloromethane 1600 ml, up to 28 C extracting the organic layer, the saturated salt water for 1600 ml washing, the organic layer is dried with anhydrous sodium sulfate, vacuum concentrated solvent to obtain yellowish liquid. Dichloromethane is used for 80 ml dissolved concentrated residual liquid, adding 1000 ml in the reaction flask, lowering the temperature to 0 C, in 0 C slow the instillment uses acetone 640 ml of dissolved methanesulfonic acid 7.7g mixed solution, after the completion of the dropping the temperature to room temperature stirring 1 hour, filtering, dichloromethane 320 ml washing, in 40 C vacuum drying 5 hours, to obtain 35.1g white compound A, HPLC analysis for 99.789% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 2h; | Triethylamine of Example 1 (0 · lg, 0.2 mmol), 2 eq was dissolved in lmlDMF,Adding hexyl chloroformate (0.05g, 0.3mmol), adding, room temperature reaction 2h, the reaction is completed into the water,The residue was purified by column chromatography to give 80 mg of product, 65% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With 1-methyl-1H-imidazole; In dichloromethane; at 0 - 20℃;Inert atmosphere; | A solution of (9 - [(R) -2 - [[(R) - [[(R) -1 (isopropoxy) ethyl] amino] phenoxyphosphoryl] methoxyYl] propyl] adenine) I-1-a1 (120 mg, 0.25 mmol),N-methylimidazole (41 ul, 0.5 mmol) andDichloromethane (5 ml),Under nitrogen and at 0 C,Hexyl chloroformate (135 mg, 0.75 mmol) was added dropwise,After the addition, stirring was continued at room temperatureOvernight, the reaction was concentrated under reduced pressure and the residue was chromatographed on a silica gel column (ethyl acetate / hexane, 0-50%) to give the product III-1-a1(96 mg, 62%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | A solution of 3-d-methyl-2- (4-amidino-phenylaminomethyl) -benzoimidazol-5-yl- carboxylic acid) - (N-phenyl) L-octadecylcarbonyloxy) glycerophosphorylcholine-3-yl ester (9.8 g, 10 mmol) was dissolved in 250 ml of THF and 50 ml of H20 and potassium hydroxide (2.1 g, 15 mmol) was added and the mixture was stirred at room temperature 15min. Slowly add <strong>[6092-54-2]n-hexyl chloroformate</strong> (1.8lg, 1 lmmo 1) and continue stirring for 2h. Concentrated and extracted three times with ethyl acetate (20 ml X 3), dried over Na 2 SO 4 and concentrated. The crude product was purified by silica gel column chromatography to give 3- {1-methyl-2- [N- (N-n-Hexanoyloxycarbonyl) amidinophenyl) -aminomethyl] -benzoimidazol-5-yl- carboxylic acid} - (N-phenyl) Octadecylcarbonyloxy) glycerophosphorylcholine-2-yl-ester (compound 2, 8.2 g, yield 73%). Mass spectrum (ESI-MS): 1118.7 (M + H) +, 1140.6 (M + Na) +; C6QH92N7oII P (1117). High-resolution mass spectrum (HR-ESI-MS): 1140.6530 (M + Na) +, calculated: 1140.6572) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.3% | 2) nitrogen protection,17.18mL of absolute ethanol was added to the reaction solution prepared in step while stirring, the temperature was lowered to 0 to 10 C,410.6 g of ammonium carbonate are added portionwise at this temperature,Plus warming to 20 ~ 25 , incubated for 12h.After the reaction, suction filtration, about 1718mL absolute ethanol rinse cake, filtration,The filtrate was concentrated under reduced pressure to ethanol-free,Add about 859mL water, 20 ~ 30 beating 2h,Suction filtration, the filter cake was added to acetonitrile 859mL,20 ~ 30 beating 2h, suction filtration,After the filter cake was dried, 153.0 g of compound 4 was obtained,The yield was 86.0%Impurity compound 6 content was 5.8% (HPLC area normalization method).3) nitrogen protection, To the reaction flask was added with stirring 765 mL of tetrahydrofuran and 765 mL of water, then 153.0 g of compound 4 obtained in step was added, Stir at 20-30 clear, then cooled to 10-20, In two batches of 58.9g of potassium carbonate was added, stirred and dissolved, finally, 51.7g of <strong>[6092-54-2]n-hexyl chloroformate</strong> was added dropwise, added to 20 ~ 25, incubated for 1h.4)after the reaction,Concentrated under reduced pressure to remove tetrahydrofuran, suction filtered,The filter cake was added to 2800 mL of ethyl acetate,Heat a clear, cool to 0 ~ 10 ,After suction filtration, the filter cake was dried to give 142.8 g of dabigatran etexilate as a white solid,The yield was 74.3%, the purity was 98.7%The by-product compound 7 content was 0.2% (HPLC area normalization method). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | (C) Preparation of intermediate five: In a reaction flask were added 200mL of water, 30g of potassium carbonate, 200mL of tetrahydrofuran and 21g of Intermediate four (4), Stirring and dissolving, stirring for 15min at 25 C; slowly adding dropwise 26.7g of <strong>[6092-54-2]n-hexyl chloroformate</strong> at 25 C, dropping off and reacting at 25 C,The reaction was monitored by TLC. After the reaction was completed, the mixture was slightly cold and suction filtered. The filter cake was washed with water and dried to give 29.7 g of Intermediate (5) of 95.8% purity with a yield of 85% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6% | With pyridine; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 10h; | To a solution of 2-morpholinoethyl 3-(2-((4-carbamimidoylphenyl)carbamoyl)-5-methoxy-4- vinylphenyl)-6-((cyclopropylmethyl)carbamoyl)picolinate hydrochloride(2d) (1 g, 1.51 mmol) in Acetonitrile (10 mL) and DMF (4 mL) was added DIPEA (3.95 mL, 22.62 mmol), hexyl chloroformate (2.47 mL, 15.08 mmol) and stirred at room temperature for 10 h. The reaction mixture was triturated twice with MTBE (50 mL) and decanted. The residue obtained was dissolved in acetonitrile (3 mL) and purified by reverse phase flash column chromatography (30 g, C18 column) eluting with 0.1 % HC1 in water and acetonitrile. The desired fractions were combined and lyophilized to afford 2-morpholinoethyl 6- ((cyclopropylmethyl)carbamoyl)-3-(2-((4-(N- (0392) ((hexyloxy)carbonyl)carbamimidoyl)phenyl)carbamoyl)-5-methoxy-4-vinylphenyl)picolinate hydrochloride (6a) (97 mg, 8 % yield) as a white solid; MR (300 MHz, OMSO-de, D20) delta 8.25 (d, J= 8.1 Hz, 1H), 8.08 (d, J= 8.0 Hz, 1H), 7.97 (s, 1H), 7.88 - 7.71 (m, 4H), 7.12 - 6.96 (m, 2H), 6.07 (dd, J= 17.7, 1.4 Hz, 1H), 5.48 (dd, J= 11.3, 1.4 Hz, 1H), 4.55 - 4.32 (m, 2H), 4.25 (t, J= 6.6 Hz, 2H), 3.91 (s, 3H), 3.83 - 3.64 (m, 4H), 3.23 (s, 4H), 3.09 (s, 4H), 1.74 - 1.57 (m, 2H), 1.43 - 1.23 (m, 6H), 1.16 - 1.00 (m, 1H), 0.94 - 0.80 (m, 3H), 0.51 - 0.41 (m, 2H), 0.32 - 0.22 (m, 2H); MS (ES+) 755.7 (M+l), (E S-) 789.8 (M+Cl); Analysis calculated for C4iH5oN608.3HC1.2H20: C, 54.70; H, 6.38; N, 9.33. Found: C, 54.79; H, 6.30; N, 9.27. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 10h; | To a solution of 2-morpholinoethyl 3-(2-((4-carbamimidoylphenyl)carbamoyl)-5-methoxy-4- vinylphenyl)-6-((cyclopropylmethyl)carbamoyl)picolinate hydrochloride(2d) (1 g, 1.51 mmol) in Acetonitrile (10 mL) and DMF (4 mL) was added DIPEA (3.95 mL, 22.62 mmol), hexyl chloroformate (2.47 mL, 15.08 mmol) and stirred at room temperature for 10 h. The reaction mixture was triturated twice with MTBE (50 mL) and decanted. The residue obtained was dissolved in acetonitrile (3 mL) and purified by reverse phase flash column chromatography (30 g, C18 column) eluting with 0.1 % HC1 in water and acetonitrile. The desired fractions were combined and lyophilized to afford 2-morpholinoethyl 6- ((cyclopropylmethyl)carbamoyl)-3-(2-((4-(N- (0392) ((hexyloxy)carbonyl)carbamimidoyl)phenyl)carbamoyl)-5-methoxy-4-vinylphenyl)picolinate hydrochloride (6a) (97 mg, 8 % yield) as a white solid; MR (300 MHz, OMSO-de, D20) delta 8.25 (d, J= 8.1 Hz, 1H), 8.08 (d, J= 8.0 Hz, 1H), 7.97 (s, 1H), 7.88 - 7.71 (m, 4H), 7.12 - 6.96 (m, 2H), 6.07 (dd, J= 17.7, 1.4 Hz, 1H), 5.48 (dd, J= 11.3, 1.4 Hz, 1H), 4.55 - 4.32 (m, 2H), 4.25 (t, J= 6.6 Hz, 2H), 3.91 (s, 3H), 3.83 - 3.64 (m, 4H), 3.23 (s, 4H), 3.09 (s, 4H), 1.74 - 1.57 (m, 2H), 1.43 - 1.23 (m, 6H), 1.16 - 1.00 (m, 1H), 0.94 - 0.80 (m, 3H), 0.51 - 0.41 (m, 2H), 0.32 - 0.22 (m, 2H); MS (ES+) 755.7 (M+l), (E S-) 789.8 (M+Cl); Analysis calculated for C4iH5oN608.3HC1.2H20: C, 54.70; H, 6.38; N, 9.33. Found: C, 54.79; H, 6.30; N, 9.27. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8% | To a solution of 2-morpholinoethyl 3-(2-((4-carbamimidoylphenyl)carbamoyl)-5-methoxy-4- vinylphenyl)-6-((cyclopropylmethyl)carbamoyl)picolinate hydrochloride(2d) (1 g, 1.51 mmol) in Acetonitrile (10 mL) and DMF (4 mL) was added DIPEA (3.95 mL, 22.62 mmol), hexyl chloroformate (2.47 mL, 15.08 mmol) and stirred at room temperature for 10 h. The reaction mixture was triturated twice with MTBE (50 mL) and decanted. The residue obtained was dissolved in acetonitrile (3 mL) and purified by reverse phase flash column chromatography (30 g, C18 column) eluting with 0.1 % HC1 in water and acetonitrile. The desired fractions were combined and lyophilized to afford 2-morpholinoethyl 6- ((cyclopropylmethyl)carbamoyl)-3-(2-((4-(N- (0392) ((hexyloxy)carbonyl)carbamimidoyl)phenyl)carbamoyl)-5-methoxy-4-vinylphenyl)picolinate hydrochloride (6a) (97 mg, 8 % yield) as a white solid; MR (300 MHz, OMSO-de, D20) delta 8.25 (d, J= 8.1 Hz, 1H), 8.08 (d, J= 8.0 Hz, 1H), 7.97 (s, 1H), 7.88 - 7.71 (m, 4H), 7.12 - 6.96 (m, 2H), 6.07 (dd, J= 17.7, 1.4 Hz, 1H), 5.48 (dd, J= 11.3, 1.4 Hz, 1H), 4.55 - 4.32 (m, 2H), 4.25 (t, J= 6.6 Hz, 2H), 3.91 (s, 3H), 3.83 - 3.64 (m, 4H), 3.23 (s, 4H), 3.09 (s, 4H), 1.74 - 1.57 (m, 2H), 1.43 - 1.23 (m, 6H), 1.16 - 1.00 (m, 1H), 0.94 - 0.80 (m, 3H), 0.51 - 0.41 (m, 2H), 0.32 - 0.22 (m, 2H); MS (ES+) 755.7 (M+l), (E S-) 789.8 (M+Cl); Analysis calculated for C4iH5oN608.3HC1.2H20: C, 54.70; H, 6.38; N, 9.33. Found: C, 54.79; H, 6.30; N, 9.27. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | With triethylamine; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 10h; | To a solution of 2-morpholinoethyl 3-(2-((4-carbamimidoylphenyl)carbamoyl)-5-methoxy-4- vinylphenyl)-6-((cyclopropylmethyl)carbamoyl)picolinate hydrochloride(2d) (1 g, 1.51 mmol) in Acetonitrile (10 mL) and DMF (4 mL) was added DIPEA (3.95 mL, 22.62 mmol), hexyl chloroformate (2.47 mL, 15.08 mmol) and stirred at room temperature for 10 h. The reaction mixture was triturated twice with MTBE (50 mL) and decanted. The residue obtained was dissolved in acetonitrile (3 mL) and purified by reverse phase flash column chromatography (30 g, C18 column) eluting with 0.1 % HC1 in water and acetonitrile. The desired fractions were combined and lyophilized to afford 2-morpholinoethyl 6- ((cyclopropylmethyl)carbamoyl)-3-(2-((4-(N- (0392) ((hexyloxy)carbonyl)carbamimidoyl)phenyl)carbamoyl)-5-methoxy-4-vinylphenyl)picolinate hydrochloride (6a) (97 mg, 8 % yield) as a white solid; MR (300 MHz, OMSO-de, D20) delta 8.25 (d, J= 8.1 Hz, 1H), 8.08 (d, J= 8.0 Hz, 1H), 7.97 (s, 1H), 7.88 - 7.71 (m, 4H), 7.12 - 6.96 (m, 2H), 6.07 (dd, J= 17.7, 1.4 Hz, 1H), 5.48 (dd, J= 11.3, 1.4 Hz, 1H), 4.55 - 4.32 (m, 2H), 4.25 (t, J= 6.6 Hz, 2H), 3.91 (s, 3H), 3.83 - 3.64 (m, 4H), 3.23 (s, 4H), 3.09 (s, 4H), 1.74 - 1.57 (m, 2H), 1.43 - 1.23 (m, 6H), 1.16 - 1.00 (m, 1H), 0.94 - 0.80 (m, 3H), 0.51 - 0.41 (m, 2H), 0.32 - 0.22 (m, 2H); MS (ES+) 755.7 (M+l), (E S-) 789.8 (M+Cl); Analysis calculated for C4iH5oN608.3HC1.2H20: C, 54.70; H, 6.38; N, 9.33. Found: C, 54.79; H, 6.30; N, 9.27. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | General procedure: (4-phenoxyphenyl)hydrazine hydrochloride[66] 2 (8.2 g, 34.6 mmol, 1 equiv.) and 1-methyl pyrrolidone (2.41 mL,31.1 mmol, 0.9 equiv.) were dissolved in dry pyridine (700 mL). Thesolution was cooled in an ice bath to 0 C. Then, 2-benzyloxyethyl chloroformate 4a (6.87 mL, 38.6 mmol, 1.1 equiv.) was added dropwiseover a period of 30 min at 0-5 C and allowed to stir for 1 h at 0 C and1 h at room temperature. The reaction mixture was diluted by additionof methylene chloride (300 mL) and dry pyridine (70 mL) and themixture was cooled at -10 C using an ice-salt bath. A solution ofdiphosgene (6.26 mL, 51.8 mmol, 1.5 equiv.) in methylene chloride(30 mL) was added dropwise using a syringe pump over a period of 1 hwhile maintaining -10 C with an ice-salt bath. After the addition iscomplete the reaction mixture stirred 1 h at -10 C and 2 h at roomtemperature. The reaction mixture was diluted with water (1 L) andextracted with diethyl ether (3×250 mL). The combined organiclayers were washed with water (2×250 mL) and brine (3×100 mL),dried over MgSO4, and filtered. Purification by column chromatographyusing cyclohexane/ethyl acetate (98/2 to 95/5, v/v) as eluent gave thetitle compound 6a (BepPPOX) as a yellow oil (9.94 g, 71%). 4.1.1.3 5-Hexyloxy-3-(4-phenoxyphenyl)-1,3,4-oxadiazol-2(3H)-one (6e=HpPPOX) Prepared using Hexyl chloroformate 4e applying similar method as described above for 6a. Analytical data for HpPPOX: yellow oil (85%). Rf (AcOEt/Cyclohexane 1:3, v/v) 0.95. HRMS (ESI) m/z [M+H]+ calcd. for C20H23N2O4: 355.1652Da ; found : 355.1652Da. 1H NMR delta 7.72 (dd, J=9.0Hz, J=2.0Hz, 2H), 7.30 (m, 2H), 6.97-7.12 (m, 5H), 4.37 (t, J=6.6Hz, 2H), 1.80 (m, 2H), 1.30-1.58 (m, 6H), 0.90 (t, J=6.8Hz, 3H). 13C NMR delta 157.16 (s), 155.33 (s), 154.67 (s), 148.38 (s), 131.65 (s), 129.83 (2*d), 123.42 (d), 119.78 (2*d), 119.49 (2*d), 118.68 (2*d), 71.79 (t), 31.36 (t), 28.35 (t), 25.17 (t), 22.50 (t), 13.99 (q). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | General procedure: <strong>[60481-02-9](4-phenoxyphenyl)hydrazine hydrochloride</strong>[66] 2 (8.2 g, 34.6 mmol, 1 equiv.) and 1-methyl pyrrolidone (2.41 mL,31.1 mmol, 0.9 equiv.) were dissolved in dry pyridine (700 mL). Thesolution was cooled in an ice bath to 0 C. Then, 2-benzyloxyethyl chloroformate 4a (6.87 mL, 38.6 mmol, 1.1 equiv.) was added dropwiseover a period of 30 min at 0-5 C and allowed to stir for 1 h at 0 C and1 h at room temperature. The reaction mixture was diluted by additionof methylene chloride (300 mL) and dry pyridine (70 mL) and themixture was cooled at -10 C using an ice-salt bath. A solution ofdiphosgene (6.26 mL, 51.8 mmol, 1.5 equiv.) in methylene chloride(30 mL) was added dropwise using a syringe pump over a period of 1 hwhile maintaining -10 C with an ice-salt bath. After the addition iscomplete the reaction mixture stirred 1 h at -10 C and 2 h at roomtemperature. The reaction mixture was diluted with water (1 L) andextracted with diethyl ether (3×250 mL). The combined organiclayers were washed with water (2×250 mL) and brine (3×100 mL),dried over MgSO4, and filtered. Purification by column chromatographyusing cyclohexane/ethyl acetate (98/2 to 95/5, v/v) as eluent gave thetitle compound 6a (BepPPOX) as a yellow oil (9.94 g, 71%). 4.1.1.3 5-Hexyloxy-3-(4-phenoxyphenyl)-1,3,4-oxadiazol-2(3H)-one (6e=HpPPOX) Prepared using Hexyl chloroformate 4e applying similar method as described above for 6a. Analytical data for HpPPOX: yellow oil (85%). Rf (AcOEt/Cyclohexane 1:3, v/v) 0.95. HRMS (ESI) m/z [M+H]+ calcd. for C20H23N2O4: 355.1652Da ; found : 355.1652Da. 1H NMR delta 7.72 (dd, J=9.0Hz, J=2.0Hz, 2H), 7.30 (m, 2H), 6.97-7.12 (m, 5H), 4.37 (t, J=6.6Hz, 2H), 1.80 (m, 2H), 1.30-1.58 (m, 6H), 0.90 (t, J=6.8Hz, 3H). 13C NMR delta 157.16 (s), 155.33 (s), 154.67 (s), 148.38 (s), 131.65 (s), 129.83 (2*d), 123.42 (d), 119.78 (2*d), 119.49 (2*d), 118.68 (2*d), 71.79 (t), 31.36 (t), 28.35 (t), 25.17 (t), 22.50 (t), 13.99 (q). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Add 100 ml of tetrahydrofuran and 20 ml of water to a 250 ml three-necked flask. After adding 3.5 g (0.01 mol) of myristic hydrochloride and 1.7 g (0.02 mol) of sodium hydrogencarbonate, and stirring at room temperature for 10 minutes, 0.1 g of N,N-dimethyl-4-aminopyridin was added. Acridine, 1.7 g (0.01 mol) of <strong>[6092-54-2]n-hexyl chloroformate</strong> was dissolved in 5 ml of tetrahydrofuran, and the resulting solution was slowly dropped into the reaction flask at room temperature. After the completion of the dropwise addition, stirring was continued for 2 hours until the end of the reaction, and tetrahydrofuran was distilled off under reduced pressure. Add 50ml of saturated brine Extracted with 20 ml of ethyl acetate, the aqueous layer was extracted twice with 10 ml of ethyl acetate. The organic layer was combined and washed twice with dilute citric acid, and the organic layer was separated. After getting 3.2g of compound, The yield is 73% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In acetonitrile; | The prodrug three hexyloxycarbonyl-<strong>[83150-76-9]octreotide</strong> (Octreotide-P) was synthesized from <strong>[83150-76-9]octreotide</strong> using the synthetic pathway shown in Scheme 1 : |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | Step 1 To a 0 C. solution of tert-butyl (4-carbamimidoylbenzyl)carbamate acetate salt (200 mg, 0.65 mmol) in CH2Cl2 (8 mL, 0.08 M) was added DIEA (0.23 mL, 1.3 mmol). After stirring for 15 min at the same temperature, hexyl chloroformate (0.13 mL, 0.78 mmol) was added dropwise. After stirring for 1 h at the same temperature, the reaction was quenched by addition of H2O. The resulting mixture was extracted with CH2Cl2, dried over anhyd Na2SO4, and conc under vacuum. The residue was purified by chromatography (0-100% EtOAc-hexanes) to give tert-butyl (4-(N-((hexyloxy)carbonyl)carbamimidoyl)benzyl)carbamate (151 mg, 62% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sodium hydroxide; In water; acetone; at 10 - 25℃; | Add Intermediate D-3 (12.7g, 36mmol, 1.0eq), sodium hydroxide (2.2g, 54mmol, 1.5eq), 200mL water and 100mL acetone to the 500mL reaction flask, dissolve with stirring, slowly at 10-15 N-Hexyl chloroformate (7.1 g, 43 mmol, 1.2 eq) was added dropwise. After the drop, the reaction was performed at 20-25 C, and the reaction was monitored by TLC. After the reaction is completed, cool to 10 C, filter with suction, wash the filter cake with acetone / water, and dry to obtain the crude solid DG-D4. The crude product was recrystallized with 150 mL of acetone and water (4: 1) to obtain 15.1 g of white solid product DG-D4. Yield: 87%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With water; potassium carbonate; In acetone; at 10 - 20℃; | In a 500 mL reaction flask, add 200 mL of acetone, 100 mL of water, and add intermediate DG2 (15 g, 30 mmol, 1.0 eq), potassium carbonate (8.3 g, 30 mmol, 2.0 eq) with stirring, control the temperature at 10-20 C Add <strong>[6092-54-2]n-hexyl chloroformate</strong> (10.4 g, 63 mmol, 2.1 eq) and stir at 10-20 C for 1-2 hours. The reaction solution was concentrated, extracted with dichloromethane (100 mL × 3), dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude solid. The crude product was recrystallized with 150 mL of ethyl acetate / petroleum ether (2: 1) to obtain 18.1 g of DG-D2 solid product. The yield is 78%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.7% | With potassium carbonate; In water; acetone; at 10 - 20℃; | Add 20g of benzenesulfonate shown in Formula 7 to the reaction bottle, add 150mL of acetone and 90mL of purified water to the reaction bottle,9.5 g of potassium carbonate was added, 5.6 g of <strong>[6092-54-2]n-hexyl chloroformate</strong> was added dropwise at a temperature of 10 to 20C, and the mixture was stirred at 10 to 20C for 1 to 2 hours.After filtering and drying, it is rinsed with acetone/purified water (volume ratio)=5/3 and dried.The filter cake was beaten with water, recrystallized with acetone and water, and mixed with ethyl acetate and tetrahydrofuran to obtain 14 g of finished product of dabigatran etexilate free base 4, yield: 73.7%. |
Tags: 6092-54-2 synthesis path| 6092-54-2 SDS| 6092-54-2 COA| 6092-54-2 purity| 6092-54-2 application| 6092-54-2 NMR| 6092-54-2 COA| 6092-54-2 structure
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P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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