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[ CAS No. 117976-89-3 ] {[proInfo.proName]}

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Chemical Structure| 117976-89-3
Chemical Structure| 117976-89-3
Structure of 117976-89-3 * Storage: {[proInfo.prStorage]}
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Product Details of [ 117976-89-3 ]

CAS No. :117976-89-3 MDL No. :MFCD00868879
Formula : C18H21N3O3S Boiling Point : -
Linear Structure Formula :- InChI Key :YREYEVIYCVEVJK-UHFFFAOYSA-N
M.W : 359.44 Pubchem ID :5029
Synonyms :
LY307640

Calculated chemistry of [ 117976-89-3 ]

Physicochemical Properties

Num. heavy atoms : 25
Num. arom. heavy atoms : 15
Fraction Csp3 : 0.33
Num. rotatable bonds : 8
Num. H-bond acceptors : 5.0
Num. H-bond donors : 1.0
Molar Refractivity : 97.75
TPSA : 96.31 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -7.0 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.16
Log Po/w (XLOGP3) : 2.1
Log Po/w (WLOGP) : 3.7
Log Po/w (MLOGP) : 0.88
Log Po/w (SILICOS-IT) : 3.29
Consensus Log Po/w : 2.43

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.31
Solubility : 0.177 mg/ml ; 0.000493 mol/l
Class : Soluble
Log S (Ali) : -3.75
Solubility : 0.0635 mg/ml ; 0.000177 mol/l
Class : Soluble
Log S (SILICOS-IT) : -6.9
Solubility : 0.000045 mg/ml ; 0.000000125 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 3.7

Safety of [ 117976-89-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 117976-89-3 ]

* 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.

  • Upstream synthesis route of [ 117976-89-3 ]
  • Downstream synthetic route of [ 117976-89-3 ]

[ 117976-89-3 ] Synthesis Path-Upstream   1~17

  • 1
  • [ 117976-89-3 ]
  • [ 117976-90-6 ]
YieldReaction ConditionsOperation in experiment
100% With sodium hydroxide In ethanol Example 2 Ethanol (30 ml) was added to sodium hydroxide (2.25 g (55.1 mmol)), and dissolution was carried out. 2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (20.0 g (55.6 mmol)) was then put into the ethanol solution, and after dissolution had been confirmed, diisopropyl ether (2000 ml) was added slowly, whereby 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole sodium salt (22.8 g) was obtained through precipitation (yield 100percent).; Example 3 Ethanol (22.5 ml) was added to sodium hydroxide (1.65 g (41.3 mmol)), and dissolution was carried out. 2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (15.0 g (41.7 mmol)) was then put into the ethanol solution, and after dissolution had been confirmed, tert-butyl methyl ether (160 ml) was added slowly, whereby 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole sodium salt (15.9 g) was obtained through precipitation (yield 100percent).
100% With sodium hydroxide In water Reference Example 17; Sodium hydroxide (0.557 g) was dissolved in ion exchange water (5 ml). 2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (4.96 g) was then put into the solution, and after dissolution had been confirmed, freeze drying was carried out for 22 hours using a bottle-type freeze dryer, thus obtaining 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]1H-benzimidazole sodium salt quantitatively.; Reference Example 18; Sodium hydroxide (0.560 g) was dissolved in ion exchange water (10 ml). 2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (4.98 g) was then put into solution, and after dissolution had been confirmed, freeze drying was carried out for 22 hours using a bottle-type freeze dryer, thus obtaining 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole sodium salt quantitatively.; Reference Example 19; Sodium hydroxide (0.507 g) was dissolved in ion exchange water (15 ml). 2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (4.50 g) was then put into the solution, and after dissolution had been confirmed, freeze drying was carried out for 22 hours using a bottle-type freeze dryer, thus obtaining 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole sodium salt quantitatively.; Reference Example 20; Sodium hydroxide (0.506 g) was dissolved in ion exchange water (25 ml). 2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (4.50 g) was then put into the solution, and after dissolution had been confirmed, freeze drying was carried out for 22 hours using a bottle-type freeze dryer, thus obtaining 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole sodium salt quantitatively.; Reference Example 21; Sodium hydroxide (0.556 g) was dissolved in ion exchange water (10 ml). 2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (5.00 g) was then put into the solution, and after dissolution had been confirmed, the solution was put into a Tray-type freeze dryer and freeze drying was carried out, thus obtaining 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole sodium salt quantitatively. Here, the Tray temperature was raised to 25° C.
98% With sodium carbonate; 2-fluoro-3-chloro-5-(trifluoromethyl)pyridine In ethanol at 35 - 40℃; for 2 h; Example 2:
500ml 2- fluoro-3-chloro-5-trifluoromethylpyridine in ethanol (2-fluoro-3-chloro-5-trifluoromethylpyridine:ethanol 1:1) was added with 30g rabeprazole, regulation temperature 36°C; to the reaction mixture was added 2g anhydrous sodium carbonate, dried over 1g anhydrous sodium sulfate, the reaction solution was measured at pH 9.0, maintaining the temperature at 35°C-40°C, the reaction was stirred for 2 hours. 1g of activated carbon was added, 0.5 hours decolorization, suction filtered, 400ml of n-hexane was added, the reaction was stirred for 2 hours at 36°C, suction filtered, the filter cake was washed with an appropriate amount of n-hexane, and dried, giving 32.3g white powder, yield 98.00percent, purity 99.9 percent.
97% With sodium hydroxide In water at 4 - 5℃; Sodium hydroxide (5.62 g) was dissolved in DM water (200 ml) and cooled to [4-5°C.] Rabeprazole (50 g) was added and mixture stirred to obtain a clear solution. The solution was treated with 2 g of carbon DC-enoanticromos for 30 min at [5-10°C.] Carbon was removed by filtration and residue washed with DM water (2x25 ml). The contents were [LYOPHILIZED] using standard method. Rabeprazole sodium was obtained as a white powder.
94.9% With sodium hydroxide In methanol at 25 - 35℃; 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl]sulfinyl]-1H-benzimidazole (obtained as per reference example 1) (50.0 grams, 0.139 moles) was dissolved in a mixture of sodium hydroxide (7.5 grams, 0.187 moles) and methanol (100.0 ml), and the solution was stirred at ambient temperature 25-35 °C. The reaction solution is filtered through hi-flow and washed with methanol (50.0 ml). Then, the solvent of the filtrate was distilled off under reduced pressure. The reaction mass was cooled to ambient temperature, and petroleum ether (400.0 ml) was then added to the residual mass, which was then stirred at 25-30 °C for about 1-2 hours. The precipitated solid was filtered and washed with petroleum ether (100.0 ml) and dried at 50-60°C for 12 hours to afford the desired amorphous form of rabeprazole sodium (Weight: 50.4 grams, 94.9percent).
94.9% With sodium hydroxide In methanol at 25 - 35℃; for 1 h; 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl]sulfinyl]-1H-benzimidazole (obtained by reference example 1) (50.0 grams, 0.139 moles) was dissolved in a mixture of sodium hydroxide (7.5 grams, 0.187 moles) and methanol (100.0 ml), and the resulted solution was stirred at ambient temperature 25-35°C for about one hour. The reaction solution was filtered through hi-flow and washed with methanol (50.0 ml). Then the solvent of the filtrate was distilled off under reduced pressure. The reaction mass is cooled to ambient temperature, to which toluene (200.0 ml) was added. The residual mass was then refluxed for about 2-6 hours. After cooling the reaction solution, the precipitated solid was filtered, washed with toluene (100.0 ml) and dried at 90-100°C for 12 hours to afford the desired form Z ofrabeprazole sodium (Weight: 50.4 grams, 94.9percent).
94.9% With sodium hydroxide In methanol at 25 - 35℃; 2-[[[4-(3-methoxypropoxy)-3-melhyl-2-pyridinyl]-methyl] sulfinyl]-1H-benzimidazole (obtained by reference example 1) (50.0 grams, 0.139 moles) was dissolved in a mixture of sodium hydroxide (7.5 grams, 0.187 moles) and methanol (100.0 ml) and stirred at ambient temperature 25-35°C. The reaction solution was filtered through hi-flow and washed with methanol (50-0 ml). Then the solvent of the filtrate was distilled off under reduced pressure. The reaction mass was cooled to ambient temperature. Dichloromethane (100.0 ml) was added to the reaction mixture, which was then distilled to remove traces of methanol. Dichloromethane (50.0 ml) and petroleum ether (100.0 ml) was then added to the residual mass, which was then stirred at 25-30 °C for about 6-8 hours. Additional petroleum ether (150 ml) was added to the reaction mixture, which was stirred at 25-30 °C for 1-2 hours. The precipitated solid was filtered and washed with petroleum ether (100.0 ml) and dried at 50-60°C for 12 hours to afford the desired form X of rabeprazole sodium (Weight: 50.4 grams, 94.9percent).
94.9% With sodium hydroxide In methanol at 25 - 35℃; for 1 h; 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl]sulfinyl]-1H-benzimidazole (obtained by reference example 1) (50.0 grams, 0.139 moles) was dissolved in a mixture of sodium hydroxide (7.5 grams, 0.187 moles) and methanol (100.0 ml), and the resulted solution was stirred at ambient temperature 25-35° C. for about one hour. The reaction solution was filtered through hi-flow and washed with methanol (50.0 ml). Then the solvent of the filtrate was distilled off under reduced pressure. The reaction mass is cooled to ambient temperature, to which toluene (200.0 ml) was added. The residual mass was then refluxed for about 2-6 hours. After cooling the reaction solution, the precipitated solid was filtered, washed with toluene (100.0 ml) and dried at 90-100° C. for 12 hours to afford the desired form Z of rabeprazole sodium (Weight: 50.4 grams, 94.9percent).
94.9%
Stage #1: With sodium hydroxide In methanol at 20℃;
Stage #2: at 25 - 30℃; for 6 - 8 h;
Example 1; Preparation Of Crystalline Form-X Of Rabeprazole Sodium 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl] sulfinyl]-lH- benzimidazole (obtained as per reference example) (50.0 grams, 0.139 moles) is dissolved in a mixture of sodium hydroxide (7.5 grams, 0.187 moles) and methanol (100.0 ml) and stirred at ambient temperature. The reaction solution is filtered through hi-flow and washed with methanol (50.0 ml). Methanol from the filtrate is distilled off under high vacuum. The reaction mass is cooled to ambient temperature followed by addition of dichloromethane (100.0 ml) accompanied by distillation to remove traces of methanol. Dichloromethane (50.0 ml) and petroleum ether (100.0 ml) is then added to the residual mass, which is then stirred at 25-30°C for about 6-8 hours. The solid that is obtained further diluted with petroleum ether (150 ml) and stirred at 25-30°C for about 6-8 hours. The precipitated solid is filtered and washed with petroleum ether (100.0 ml) and dried at 50-60°C for 12 hours to afford the desired Form X of Rabeprazole sodium (Weight: 50.4 grams, 94.9percent). The X-ray Diffraction Pattern, Differential Scanning Calorimetry thermogram of Form X of Rabeprazole sodium obtained in above example is in accordance with Figure 1 and 2 respectively.
94% at 20 - 30℃; Inert atmosphere 1.73 g (0.075 mol) of sodium metal was dissolved in 120 ml of methanol at room temperature under nitrogen atmosphere. 27 g (0.075 mol) of 2-[[[4-(3-methoxy propoxy)- 3 -methyl-2-pyridinyl)] methyl] sulfinyl]-lH-benzimidazole was added to the solution at room temperature. The obtained mixture was stirred for 15 minutes to get clear solution. The clear reaction mass was stirred at 300C for one hour. 2.7 g of activated charcoal was added stirred for one hour (30+/-2 0C). Filtered the reaction mixture, the clear filtrate was concentrated under reduced pressure to obtain 29 g of crude title compound. The above crude solid was crystallized from a mixture of 87 ml methylene dichloride and 290 ml of t-butyl methyl ether in a nitrogen atmosphere to obtain 27 g (94percent) of title compound
93% With sodium hydroxide In methanol at 20℃; for 1 h; 1L of three-necked flask, was added 4g (0.1mol) in 100ml of methanol solution of sodium hydroxide, followed by addition of 36g of rabeprazole (0.1 mol), the reaction was stirred for 1h at room temperature to give a clear solution.Filtered and the filtrate rotary crude done.Room temperature using 150ml The crude product was dissolved in dichloromethane, and then 400ml of n-heptane was slowly added dropwise, the solution gradually became cloudy, and then stirred at room temperature after the addition was complete 1h.Filtered off with suction, the filter cake was rinsed with n-heptane alkoxy filter cake in a vacuum oven, 40-45 blast drying 12h, weighed to obtain rabeprazole sodium finished 35.62g (0.093mol), 93percent yield.
91.1% With sodium hydroxide In methanol at 25 - 35℃; 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl]sulfinyl]-1H-benzimidazole (obtained as per reference example 1) (750.0 grams, 2.089 moles) was dissolved in a mixture of sodium hydroxide (112.5 grams, 2.8125 moles) and methanol (1500.0 ml), and the resulting solution was stirred at ambient temperature 25-35°C. The reaction solution was filtered through hi-flow and washed with methanol (750.0 ml). The solvent of the filtrate was distilled off completely under reduced pressure. The reaction mass was cooled to ambient temperature, and dichloromethane (1500.0 ml) was added to the reaction mass. The solvent was distilled again to remove traces of methanol. The reaction mass was cooled to ambient temperature, and n-butanol (375.0 ml) and tertiary butyl methyl ether (6.0 L) was added to the residual mass which is stirred at 25-30°C for 6-8 hours. The reaction mixture was further cooled to 5-15 °C and then stirred for another 3-5 hours. The solid then precipitated was filtered and washed with tertiary butyl methyl ether (1500.0 ml) and dried at 50-60°C for 7 hours to afford the desired crystalline Form Y of rabeprazole sodium (Weight: 725.0 grams, 91.1percent).
91.1% With sodium hydroxide In methanol at 25 - 35℃; for 1 h; 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl]sulfinyl]-1H-benzimidazole (obtained as per reference example 1) (50.0 grams, 0.139 moles) was dissolved in a mixture of sodium hydroxide (7.5 grams, 0.187 moles) and methanol (100.0 ml), and the solution was stirred at ambient temperature 25-35° C. The reaction solution is filtered through hi-flow and washed with methanol (50.0 ml). Then, the solvent of the filtrate was distilled off under reduced pressure. The reaction mass was cooled to ambient temperature, and petroleum ether (400.0 ml) was then added to the residual mass, which was then stirred at 25-30° C. for about 1-2 hours. The precipitated solid was filtered and washed with petroleum ether (100.0 ml) and dried at 50-60° C. for 12 hours to afford the desired amorphous form of rabeprazole sodium (Weight: 50.4 grams, 94.9percent). REFERENCE EXAMPLE 3 [0052] Preparation of Crystalline form X of 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl]sulfinyl]-1H-benzimidazole sodium (Rabeprazole Sodium) [0053] 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl]sulfinyl]-1H-benzimidazole (obtained by reference example 1) (50.0 grams, 0.139 moles) was dissolved in a mixture of sodium hydroxide (7.5 grams, 0.187 moles) and methanol (100.0 ml) and stirred at ambient temperature 25-35° C. The reaction solution was filtered through hi-flow and washed with methanol (50.0 ml). Then the solvent of the filtrate was distilled off under reduced pressure. The reaction mass was cooled to ambient temperature. Dichloromethane (100.0 ml) was added to the reaction mixture, which was then distilled to remove traces of methanol. Dichloromethane (50.0 ml) and petroleum ether (100.0 ml) was then added to the residual mass, which was then stirred at 25-30° C. for about 6-8 hours. Additional petroleum ether (150 ml) was added to the reaction mixture, which was stirred at 25-30° C. for 1-2 hours. The precipitated solid was filtered and washed with petroleum ether (100.0 ml) and dried at 50-60° C. for 12 hours to afford the desired form X of rabeprazole sodium (Weight: 50.4 grams, 94.9percent). REFERENCE EXAMPLE 4 [0054] Preparation of Crystalline form-Y of 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl]sulfinyl]-1H-benzimidazole sodium (Rabeprazole Sodium) [0055] 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl]sulfinyl]-1H-benzimidazole (obtained as per reference example 1) (750.0 grams, 2.089 moles) was dissolved in a mixture of sodium hydroxide (112.5 grams, 2.8125 moles) and methanol (1500.0 ml), and the resulting solution was stirred at ambient temperature 25-35° C. The reaction solution was filtered through hi-flow and washed with methanol (750.0 ml). The solvent of the filtrate was distilled off completely under reduced pressure. The reaction mass was cooled to ambient temperature, and dichloromethane (1500.0 ml) was added to the reaction mass. The solvent was distilled again to remove traces of methanol. The reaction mass was cooled to ambient temperature, and n-butanol (375.0 ml) and tertiary butyl methyl ether (6.0 L) was added to the residual mass which is stirred at 25-30° C. for 6-8 hours. The reaction mixture was further cooled to 5-15° C. and then stirred for another 3-5 hours. The solid then precipitated was filtered and washed with tertiary butyl methyl ether (1500.0 ml) and dried at 50-60° C. for 7 hours to afford the desired crystalline Form Y of rabeprazole sodium (Weight: 725.0 grams, 91.1percent).
91.1%
Stage #1: With sodium hydroxide In methanol at 20℃;
Stage #2: at 5 - 30℃; for 9 - 13 h;
Example 2; Preparation Of Crystalline Form-Y Of Rabeprazole Sodium 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl] sulfinyl]-1H- benzimidazole (obtained as per reference example) (750.0 grams, 2.089 moles) is dissolved in a mixture of sodium hydroxide (112.5 grams, 2. 8125 moles) and methanol (1500.0 ml) and stirred at ambient temperature. The reaction solution is filtered through hi-flow and washed with methanol (750.0 ml). Methanol from the filtrate is distilled off under high vacuum. The reaction mass is cooled to ambient temperature followed by addition of dichloromethane (1500.0 ml) accompanied by distillation to remove traces of methanol. The reaction mass is cooled to ambient temperature and n-butanol (375.0 ml) and tertiary butyl methyl ether (6.0 lit) is added to the residual mass which is stirred at 25- 30°C for 6-8 hours. The reaction mixture is further cooled to 5-15°C and then stirred for another 3-5 hours. The solid is thus obtained is filtered and washed with tertiary butyl methyl ether (1500.0 ml) and dried at 50-60°C for 7 hours to afford the desired crystalline Form Y of Rabeprazole sodium (Weight: 725.0 grams 91. 1percent). The X-ray Diffraction Pattern, Differential Scanning Calorimetry thermogram of Form Y of Rabeprazole sodium obtained in the example is in accordance with Figure 3 and 4 respectively.
90.3% With sodium hydroxide In methanol Example 1 2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (4.97 g (13.8 mmol)) was dissolved in methanol (5 ml). Sodium hydroxide (0.559 g (13.7 mmol)) was then put into the methanol solution, and after dissolution had been confirmed, dipropyl ether (500 ml) was added slowly, whereby 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole sodium salt (4.77 g) was obtained through precipitation (yield 90.3percent).
90%
Stage #1: Heating / reflux
Stage #2: at 30℃; for 1 h;
Example- 1 Preparation of amorphous Rabeprazole sodium3.03 gm of freshly cut clean sodium metal was dissolved in 500 ml of tert. butyl alcohol under nitrogen atmosphere by refluxing to give a clear solution which was cooled to about 25-300C. Rabeprazole (50 gm) was added to it at about 300C and stirred for about one hour to give an orange brown solution. The <n="7"/>reaction mass was treated with about 2.5 gm of activated charcoal and stirred at 27-300C for about one hour. The reaction mass was filtered using hyio bed and λvashed with about 50 ml of tert. butyl alcohol. The filtered solution was distilled under vacuum at 40-500C to remove lert.butyl alcohol, high vacuum was applied for about 30 min to remove traces of lert. butyl alcohol. 750 ml of diisopropyl ether were added to the viscous mass, and stirred under nitrogen at 27-300C for about one hour. Off-white, amorphous powder of rabeprazole-Na salt was obtained, which was filtered under nitrogen and washed with 50 ml of diisopropyl ether. The product was dried under vacuum at 65-700C for about 48 hours to give amorphous rabeprazole sodium. Wt. of rabeprazole sodium = 47 gms percent yield = 90 percent purity > 99 percent percent water by ICF. < 4 percent
90%
Stage #1: Heating / reflux
Stage #2: at 30℃; for 1 h;
Example- 1 Preparation of amorphous Rabeprazole sodium3.03 gm of freshly cut clean sodium metal was dissolved in 500 ml of tert. butyl alcohol under nitrogen atmosphere by refluxing to give a clear solution which was cooled to about 25-300C. Rabeprazole (50 gm) was added to it at about 300C and stirred for about one hour to give an orange brown solution. The <n="7"/>reaction mass was treated with about 2.5 gm of activated charcoal and stirred at 27-300C for about one hour. The reaction mass was filtered using hyio bed and λvashed with about 50 ml of tert. butyl alcohol. The filtered solution was distilled under vacuum at 40-500C to remove lert.butyl alcohol, high vacuum was applied for about 30 min to remove traces of lert. butyl alcohol. 750 ml of diisopropyl ether were added to the viscous mass, and stirred under nitrogen at 27-300C for about one hour. Off-white, amorphous powder of rabeprazole-Na salt was obtained, which was filtered under nitrogen and washed with 50 ml of diisopropyl ether. The product was dried under vacuum at 65-700C for about 48 hours to give amorphous rabeprazole sodium. Wt. of rabeprazole sodium = 47 gms percent yield = 90 percent purity > 99 percent percent water by ICF. < 4 percent
83% With sodium hydroxide In water Example 1:Isolation of Rabeprazole sodium using ethyl acetate as solvent:Rabeprazole (50 gm) was dissolved in solution of sodium hydroxide (5.39 gm ) in demineralized water (162.5 ml). The solution was extracted with dichloromethane (100 ml) twice. The aqueous layer was then treated with neutral activated charcoal (1 gm) for 30 minutes at 28 to 35°C. Carbon was removed by filtration and the residue washed with demineralized water (12.5 ml). Ethyl alcohol (50 ml) was added to the clear filtrate. The solution was concentrated to thick mass under vacuum at 40 - 45°C. The thick mass was dissolved in ethyl alcohol (100 ml) and was again concentrated to a thick mass under vacuum at 40 - 45°C. The residue was then dissolved in ethyl acetate (100 ml) and the solution was concentrated to a thick oily mass under vacuum. The residue thus obtained was dissolved in ethyl acetate (100 ml) and the solution was added slowly over a period of 20 to 30 minutes to diisopropyl ether (500 ml). The slurry thus obtained was stirred for 60 minutes at 28 to 35°.. The solid was filtered and washed with diisopropyl ether. Then the solid was dried at 45 - 50° to get Rabeprazole sodium as a white amorphous solid (powder X-ray diffraction of the product does not show any sharp peak, shows only the base line), with mean particle diameter ranging between 10 to 50μm. Yield: 45 gm (85 percent), Assay: 99.5 percent (by HPLC). IR Spectra (KBr, cm'1): 3382, 2927, 1583, 1462, 1384, 1298, 1269, 1190, 1157, 1093, 1018, 745. H NMR Spectra [200 M Hz, CD3OD] δ (ppm): 8.23 - 8.25 (IH, d, ArH); 7.57 - 7.62 (2H, m, ArH); 7.0 - 7.09 (2H, m, ArH); 6.87 - 6.90 (IH, d, ArH); 4.57 - 4.63 (2H, d, O=S-CH2-Ar); 4.0 - 4.1 (2H, t, -O-CH2-CH2-); 3.49 - 3.55 (2H, t, -CH2-O-CH3); 3.31 (3H, s, -OCH3); 2.1 (3H, s, Ar-CH3); 1.96 - 2.0 (2H, t, -CH2-CH2-CH2-).; Example 2:Isolation of Rabeprazole sodium using dichloromethane as solvent:Rabeprazole (50 gm) was dissolved in solution of sodium hydroxide (5.4 gm) in demineralized water (150 ml). The solution was extracted with dichloromethane (100 ml) twice. The aqueous layer was then treated with neutral activated charcoal (1 gm) for 30 minutes at 28 to 35°C. Carbon was removed by filtration and the residue washed with EPO <DP n="7"/>demineralized water (12.5 ml). Ethyl alcohol (50 ml) was added to the clear filtrate. The solution was concentrated to thick mass under vacuum at 40 - 450C. The thick mass was dissolved in ethyl alcohol (100 ml) and was again concentrated to a thick mass under vacuum at 40 - 45°C. The residue was then dissolved in dichloromethane (150 ml) and the solution was filtered through 0.5-micron filter pad. The clear solution thus obtained was added slowly over a period of 20 to 30 minutes to diisopropyl ether (500 ml). The slurry thus obtained was stirred for 30 minutes at 28 to 35°. The solid was filtered and washed with diisopropyl ether. Then the solid was dried at 45 - 50° to get Rabeprazole sodium as a white amorphous solid (as evident from powder X-ray diffraction of the product), with mean particle diameter ranging between 15 to 55μm. Yield: 44 gm (83 percent), Assay: 99.5 percent (by HPLC)
72% With sodium hydroxide In hexane; dichloromethane at 10 - 20℃; for 4 h; A solution of 10 - ((0.029mol) 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]-methyl]thio]-1H-benzimidazole (condensate) Add 100ml toluene, 0.2 g of purified water, 8. lg (+) - L-diethyl tartrate, 4.5 g of titanium tetraisopropoxide, 52-55 ° C for lh; cooled to 25 ° C, 3.4 g of N, N-diisopropylethylamine, 4.5 g hydrogen peroxide cumene, 25-30 ° C reaction 2 h. After the oxidation reaction, with 2.5percent sodium hydroxide solution extraction 2 times, each 60ml, combined with sodium hydroxide solution, Add lg algae and lg activated carbon decolorization, the filtrate with saturated ammonium chloride solution to ρΗ = 9.7, the control temperature of 10-20 ° C, precipitation of white solid, crystallization lh after filtration. A 16 g dextroride dexeprazole was obtained (dry 8 g (0.022 mol 1)). 120 ml of dichloromethane and 300 ml of n-hexane were mixed and 0.88 g (0.022 mol) of sodium hydroxide solid was added with stirring. The control temperature is 10-20 ° C, Add dextrorolidazole wet to the above mixture, add finished, continue to control temperature 10-20 ° C 4h. The reaction was completed, filtered, washed, vacuum dried at 60 ° C, and dexamethasone was dissolved in sodium 7.2 g, yield: 72percent Purity: 99.81percent, sulfone:0.01percent.
64.94% With sodium hydroxide In methanolCooling with ice 39.76 g of rabeprazole was dissolved in 80 ml of methanol and added dropwise with sodium hydroxide in 80 ml of methanol under ice-cooling. After the addition was completed, the mixture was stirred at room temperature for 2 hours.Dried methanol, weighed 41.59 grams.Recrystallization from methyl tert-butyl ether and n-butanol, crystallization at room temperature, ice bath, filtration.Sampling measured content, sulfoxide content of 99.89percent, sulfone content of 0.07percent.The mixture was dried in vacuo and weighed 27.42 g in 64.94percent yield.Rabeprazole sodium salt NMR spectrum shown in Figure 1, thermogravimetric analysis showed that the product contains 1.0 crystal water (Figure 2).

Reference: [1] Patent: US2007/225502, 2007, A1, . Location in patent: Page/Page column 5
[2] Patent: US2007/225502, 2007, A1, . Location in patent: Page/Page column 8-9
[3] Patent: CN104119315, 2016, B, . Location in patent: Paragraph 0021; 0022
[4] Patent: WO2003/101452, 2003, A1, . Location in patent: Page 2
[5] Organic Process Research and Development, 2009, vol. 13, # 5, p. 896 - 899
[6] Patent: EP1452533, 2004, A1, . Location in patent: Page 8
[7] Patent: EP1452533, 2004, A1, . Location in patent: Page 9
[8] Patent: EP1452533, 2004, A1, . Location in patent: Page 8-9
[9] Patent: US2004/180935, 2004, A1, . Location in patent: Page/Page column 7
[10] Patent: WO2003/82858, 2003, A1, . Location in patent: Page/Page column 12-13
[11] Patent: WO2009/116072, 2009, A2, . Location in patent: Page/Page column 15-16
[12] Patent: CN106674198, 2017, A, . Location in patent: Paragraph 0026-0027
[13] Patent: EP1452533, 2004, A1, . Location in patent: Page 9
[14] Patent: US2004/180935, 2004, A1, . Location in patent: Page/Page column 6-7
[15] Patent: WO2003/82858, 2003, A1, . Location in patent: Page/Page column 13
[16] Patent: US2007/225502, 2007, A1, . Location in patent: Page/Page column 4-5
[17] Patent: WO2008/35192, 2008, A2, . Location in patent: Page/Page column 5
[18] Patent: WO2008/35192, 2008, A2, . Location in patent: Page/Page column 5
[19] Patent: WO2006/120701, 2006, A1, . Location in patent: Page/Page column 5; 6
[20] Patent: CN104311540, 2016, B, . Location in patent: Paragraph 0039-0040
[21] Patent: CN106317019, 2017, A, . Location in patent: Paragraph 0077; 0078; 0079; 0080
[22] Patent: EP1818331, 2007, A1, . Location in patent: Page/Page column 6
[23] Patent: WO2008/17020, 2008, A2, . Location in patent: Page/Page column 23-24
[24] Synthetic Communications, 2009, vol. 39, # 2, p. 278 - 290
[25] Patent: WO2009/133572, 2009, A2, . Location in patent: Page/Page column 7
[26] Patent: WO2010/6904, 2010, A2, . Location in patent: Page/Page column 19
[27] Patent: WO2010/4571, 2010, A2, . Location in patent: Page/Page column 3-4
[28] Patent: EP1921075, 2008, A2, . Location in patent: Page/Page column 8
[29] Patent: WO2011/4281, 2011, A1, . Location in patent: Page/Page column 4; 5
[30] Patent: WO2012/146643, 2012, A1, . Location in patent: Page/Page column 14; 15
[31] Patent: WO2014/91450, 2014, A1, . Location in patent: Page/Page column 16-17
[32] Patent: WO2008/155780, 2008, A2, . Location in patent: Page/Page column 11
[33] Patent: WO2008/155780, 2008, A2, . Location in patent: Page/Page column 12
  • 2
  • [ 117976-89-3 ]
  • [ 117976-47-3 ]
  • [ 117976-90-6 ]
YieldReaction ConditionsOperation in experiment
95% With sodium hydroxide In methanol at 0 - 50℃; for 4 - 5 h; Dissolve sodium hydroxide in methanol, stir to celerity. Add rabeprazole obtained in example 3 to it and stir at 45° - 5O0C for 4 to 5 h. Cool the reaction mixture to ca 250C, charge activated charcoal, stir and filter through celite bed. Collect the filtrate, distill under vacuum to remove methanol to obtain residue containing traces of methanol. Dissolve the residue in dichloromethane, add the solution with stirring to an alkane or ether solvent in an inert atmosphere to obtain amorphous powder of rabeproazole sodium which is dried under vacuum between 40°-45°C Yield: 95percent Purity: 99.5percent Sulphone impurity: 0.2percent (highest single impurity) Example 5: Sodium hydroxide is dissolved in methanol at 250C to 350C for an hour. To this solution, rabeprazole obtained in example 3 is added at a temperature between 0° to 50C and stirred for 3 to 4 hours to dissolve it completely. Then activated charcoal is added, stirred and filtered through c elite b ed. The filtrate thus obtained is distilled under vacuum at 40°-45°C to remove methanol to obtain a thick residue. To this residue, alkane or ether solvent is added with stirring to obtain amorphous powder of rabeprazole sodium, which is dried under vacuum between 40° to 450C. Yield: 95percent Purity: 99.5percent Sulphone impurity: 0.2percent (highest single impurity) Main advantages of the invention: 1) Provides process for obtaining rabeprazole in good yield and purity. 2) Provides process for preparing rabeprazole sodium exclusively in non-aqueous medium. 3) Provides simple and economical process for preparing rabeprazole sodium.
Reference: [1] Patent: WO2006/24890, 2006, A1, . Location in patent: Page/Page column 7
  • 3
  • [ 1310-73-2 ]
  • [ 117976-89-3 ]
  • [ 117976-90-6 ]
Reference: [1] Patent: WO2008/146297, 2008, A2, . Location in patent: Page/Page column 6
  • 4
  • [ 117977-21-6 ]
  • [ 117976-89-3 ]
YieldReaction ConditionsOperation in experiment
88% With sodium hydroxide; dihydrogen peroxide In methanol; water at 20℃; for 0.666667 h; EXAMPLE 6; 2 g of 2-[[[4-(3-methoxy-propoxy)-3-methyl-2-pyridinyl]methyl]thio]-1H-benzimidazole was suspended in 36 ml of methanol at room temperature, to which 1.93 g of45percent NaOH in 14 ml water was added while stirring. 0.09 g of Na2WO4*2H2O oxidation catalyst was dissolved in 0.66 g H2O2 (50percent aqueous solution), and further diluted with 10 ml of water. The oxidant/catalyst solution was added to the reactant/base solution dropwise so that the addition was completed in about 30 minutes while stirring at room temperature. The reaction was continued for additional 10 minutes while stirring. 10 ml of 10percent Na2S2O3 aqueous solution was then added, and the resulting mixture was subjected to a reduced pressure to remove methanol therefrom. Finally, a precipitate was formed after adding a diluted acetic acid aqueous solution to a pH value of about 8, which was filtered, water washed, and dried in vacuo to obtain Rabeprazole with a yield of about 88percent (LC purity>95percent).
86.8% With dihydrogen peroxide; sodium carbonate In methanol; water at 20℃; for 0.666667 h; EXAMPLE 7; The procedures in Example 6 were repeated except that the 1.93 g of 45percent NaOH was replaced by 4.7 g of Na2CO3. Rabeprazole yield: 86.8percent (LC purity>95percent).
80.6%
Stage #1: With N-ethyl-N,N-diisopropylamine In methanol at 15℃; for 0.166667 h;
Stage #2: With dihydrogen peroxide In methanol for 6 h;
Rabeprazole sulfide 6.86g (0.02mol)Soluble in 100ml anhydrous methanol,Adjust to pH=8-9 with N,N-diisopropylethylamine.Add 350 mg of graphene oxide containing 3.0percent Cu2+, and stir at 15 ° C for 10 min.Slowly add 4.53g (0.04mol) of 30percent hydrogen peroxide.After the dropwise addition, the reaction was stirred for 6 h.Filter out the catalyst,And washed three times,Collect the filtrate,The rabeprazole crude product is obtained by rotary evaporation and concentration.Add 30 ml of isopropyl alcohol,10percent KOH aqueous solution 20ml,Stir for 5 minutes,Rotary evaporation,The residue is added to 50 ml of water.Stir for 10 minutes, suction filtration,The filtrate was adjusted to pH=7-8 with 10percent glacial acetic acid.Filtered, washed, dried,Rabeprazole boutique 5.8g,The yield was 80.6percent.
79% With tert.-butylhydroperoxide In ethanol; water at 16 - 17℃; for 3.08333 h; 1.5 mg (0.6percent molar) VO(acac)2) is dissolved in 12 ml ethanol at room temperature. The solution is stirred and 3 grams of 2-[[[4-(3-methoxy-propxy)-3-methyl-2-pyidinyl]methyl]thio]-1H-benzimidazole are added. 1.5 ml aqueous tert-butyl hydroperoxide (TBHP) (70percent) is added over a 5-minute period at 16-17° C. and the solution is then stirred for 3 hours. After completion of the reaction, the product mixture is cooled to about 15° C. and treated with aqueous sodium metabisulphate. The resultant solid is filtered off, washed with cooled ethyl acetate to afford the end product as an almost white solid (2.5 grams, yield 79percent).
78.25%
Stage #1: With sodium hypochlorite In acetonitrile at 0 - 5℃; Inert atmosphere
Stage #2: With acetic acid In water; acetonitrile
50 g of 2-[4-(3-methoxy propoxy-3-methylpyridine-2-yl) methyl thio]- lH-benzimidazole was taken in 100 ml acetonitrile. To this mixture 185.2 g (0.95mol) sodium hypochlorite was added drop wise between 0-50C in a nitrogen atmosphere and the obtained mixture was stirred at 0-50C for 30 minutes. After completion of reaction, the pH of reaction mixture was adjusted to 9.0 by using 5 percent acetic acid. The mixture was extracted with methylene dichloride, and the extract was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and dried under vacuum. The obtained residue was dissolved in 20 ml of methylene dichloride followed by t-butyl methyl ether to get the clear solution. Stir the mass for one hour at room temperature to get the precipitate. Filtered the precipitated product and washed with 100 ml of t-butyl methyl ether. Dry the product at 600C under vacuum to obtain title compound 41 g (78.25percent) as off white solid
74.94% With sodium hypochlorite; sodium hydroxide In water; acetonitrile at 0 - 5℃; for 2 h; Take 50g of rabeprazole sulfide composition (145.59mmol) was added to a 1L three-necked flask, followed by addition of 500ml of acetonitrile / water mixture (V / V = 2/1), stirred and solid sodium hydroxide was added 11.65g (291.18 mmol).Then cooled to 0-5 , start added dropwise 140.89g 10percent NaClO solution (189.27mmol), after the completion of the dropwise addition the reaction was stirred incubated 2h.The reaction gusset fully monitored, 0-5 slowly added dropwise 11.51gNa2S2O3(72.80mmol) in 100ml of water quench unreacted sodium hypochlorite, then with 5percent acetic acid adjusted to PH 8-8.5, to precipitate a solid, heat stirred for 2h.Filtered off with suction, the solid in a vacuum oven, 40-45 blast drying 12h.Sample of rabeprazole was weighed 39.22g (109.11mmol), a yield of 74.94percent.
70% With sodium hydroxide; sodium hypochlorite; tetrabutylammomium bromide In dichloromethane; water at 10 - 25℃; for 1.75 h; Example 1 - Synthesis of 24f4-(3-Methoxypropoxy)3-methylpyridine-2- yllmethylthiol-lH-benzimidazole (Rabeprazole)Example Ia 100 g of Rabeprazole sulphide was dissolved in 500 ml of methylene dichloride at RT and 2.0 g of tetrabutylammonium bromide was added under stirring at RT. The reaction mass was cooled to 10-150C and 418 ml aqueous 5.5 wtpercent sodium hypochlorite solution was charged slowly for 45 min, and the reaction mixture was stirred for one hour. pH was monitored and kept between 11 and 12 using diluted caustic solution (5percent NaOH). The reaction mixture was warmed to 20-250C and stirred for 1-2 hrs.The pH was adjusted to 7.5 to 8.0 with 50percent acetic acid. The methylene dichloride layer was separated and the aqueous layer was extracted with 300 ml of methylene dichloride. The solvent was evaporated under vacuum at 35°C and 300 ml of acetonitrile was added at room temperature. The resultant mass was heated to 50-550C to dissolve the residue completely, then cooled to 0-50C and maintained at this temperature for 1.0 hour. The compound was filtered and washed with 2 x 25 ml of acetonitrile. Finally, the compound was dried at 40 - 450C under vacuum for 2-3 hrs.The dry product thus obtained weighed 70 - 75 g (70percent yield), purity as determined by HPLC was 98.5 - 99 percent.
67.2% With sodium hydroxide; sodium hypochlorite In water; acetonitrile at 0 - 5℃; for 0.166667 - 0.333333 h; EXAMPLE 8: PREPARATION OF RABEPRAZOLE USING 1.0 EQUIVALENT OF SODIUM HYPOCHLORITE AND 2.25 EQUIVALENTS OF SODIUM HYDROXIDE:RAB-1 (20Og) and acetonitrile (600 ml) was taken into a round bottom flask and cooled to 0 to 5 0C. A mixture of a solution of 52.47 g of sodium hydroxide in 240 ml of water and 11.2percent aqueous sodium hypochlorite solution (400 ml) and was added to it at the same temperature, and maintained for about 10 minutes. Reaction completion was checked using thin layer chromatography. After the reaction was completed, a solution of sodium thiosulfate (80 g) in water (400 ml) was added to it, and stirred for about 10 minutes. Another water (1000 ml) was added to the reaction mass and the reaction mass was allowed to reach 30 0C. Carbon (20 g) was added to it and stirred for about <n="32"/>15 minutes. Then the reaction mass was filtered and the filtered bed was washed with water (200 ml). The filtrate was washed with toluene (400 ml) in two equal lots and then dichloromethane (400 ml) was added to it. pH of the reaction mass was adjusted to about 8.3 and the organic layer was separated. The aqueous layer was extracted into dichloromethane (60 ml). The combined organic layer was added to methyl tertiary butyl ether (1320 ml) and cooled to about 5 0C. 4 g of seeding material was added to the reaction mass and stirred at about 5 0C for about 3 hours. The separated solid was filtered and washed with methyl tertiary butyl ether (200 ml). The wet material was dried at about 45 to 50 0C for about 4 hours to yield 140.7 g of the title compound (percent yield:67.2).Purity by HPLC: 99.7.Impurity 1 (Rabeprazole sulfide): 0.07percent.Impurity 2 (Rabeprazole sulfone): 0.04percent.EXAMPLE 9: PREPARATION OF RABEPRAZOLE USING 1.0 EQUIVALENT OF SODIUM HYPOCHLORITE AND 2.0 EQUIVALENTS OF SODIUM HYDROXIDE:RAB-1 (25 g) and acetonitrile (75 ml) were taken into a round bottom flask and cooled to 0 to 5 0C. A mixture of a solution of 5.8 g of sodium hydroxide in 30 ml of water and 11.2percent aqueous sodium hypochlorite solution (50 ml) and was added to it at the same temperature, and maintained for about 20 minutes. Reaction completion was checked using thin layer chromatography. After the reaction was completed, a solution of sodium thiosulfate (10 g) in water (50 ml) was added to it, and stirred for about 10 minutes. Another lot of water (125 ml) was added to the reaction mass and the reaction mass was allowed to reach 30 0C. Carbon (0.25 g) was added to it and stirred for about 15 minutes. Then the reaction mass was filtered and the filtered bed was washed with water (25 ml). The filtrate was washed with toluene (50 ml) in two equal lots and then dichloromethane (50 ml) was added to it. pH of the reaction mass was adjusted to about 8.4 with acetic acid and the organic layer was separated. The aqueous layer was extracted into dichloromethane (7.5 ml). The combined organic layer was added to methyl tertiary butyl ether (165 ml) and cooled to about 5 0C. 0.5 g of seeding material was added to the reaction mass and stirred at about 5 0C for about 3 hours. The <n="33"/>separated solid was filtered and washed with methyl tertiary butyl ether (25 ml). The wet material was dried at about 45 to 50 0C for about 4 hours to yield 17.6 g of the title compound (percent yield: 67.4).Purity By HPLC: 99.6percentImpurity 1 (Rabeprazole sulfide): Less than 0.002percent.Impurity 2 (Rabeprazole sulfone): 0.02percent.
23.5%
Stage #1: With 3-chloro-benzenecarboperoxoic acid In dichloromethane at -15℃;
Stage #2: With sodium hydroxide In dichloromethane; water
Synthesis of 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole
(Reference Example 7)
2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (25.0 g (72.8 mmol)) was dissolved in dichloromethane and cooled.
Then, mcpba (70.2percent purity; 5.37 g (21.8 mmol)) was added gradually so that the internal temperature did not exceed -15°C. 10percent Aqueous sodium hydroxide solution (70.8 ml) was then added, and after stirring and still standing the water layer was separated.
The separated water layer was washed with dichloromethane (48 ml) twice.
After addition of a 2N-ammoriium acetate aqueous solution, the water layer was extracted with dichloromethane (48 ml) twice.
The dichloromethane layer was washed with water (48 ml) twice, concentrated under a reduced pressure, crystallized with dichloromethane (14 ml) and acetonitrile (92 ml), and filtered to obtain 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (6.26 g) (HPLC purity 99.7percent, yield 23.9percent).
(Reference Example 8) 2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (25.0 g (72.8 mmol)) was dissolved in dichloromethane and cooled. Then, mcpba (70.2percent purity; 5.37 g (21.8 mmol)) was added gradually so that the internal temperature did not exceed -15°C. 10percent Aqueous sodium hydroxide solution (70.8 ml) was then added, and after stirring and still standing the water layer was separated. The separated water layer was washed with dichloromethane (48 ml) twice. After addition of a 2N-ammonium acetate aqueous solution, the water layer was extracted with dichloromethane (48 ml) twice. The dichloromethane layer was washed with water (48 ml) twice, concentrated under a reduced pressure, crystallized with ethyl acetate (66 ml) and filtered to obtain 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (6.15 g) (HPLC purity 99.8percent, yield 23.5percent).(Reference Example 9) 2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (25.0 g (72.8 mmol)) was dissolved in dichloromethane and cooled. Then, mcpba (70.2percent purity; 7.16 g (29.1 mmol)) was added gradually so that the internal temperature did not exceed -15°C. 10percent Aqueous sodium hydroxide solution (70.8 ml) was then added, and after stirring and still standing the water layer was separated. The separated water layer was washed with dichloromethane (48 ml) twice. After addition of a 2N-ammonium acetate aqueous solution, the water layer was extracted with dichloromethane (48 ml) twice. The dichloromethane layer was washed twice with water (48 ml), concentrated under a reduced pressure, crystallized with dichloromethane (18 ml) and acetone (120 ml), and filtered to obtain 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (8.56 g) (HPLC purity 99.7percent, yield 32.7percent).(Reference Example 10) 2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (25.0 g (72.8 mmol)) was dissolved in dichloromethane and cooled. Then, mcpba (70.2percent purity; 7.16 g (29.1 mmol)) was added gradually so that the internal temperature did not exceed -15°C. 10percent Aqueous sodium hydroxide solution (70.8 ml) was then added, and after stirring and still standing the water layer was separated. The separated water layer was washed with dichloromethane (48 ml) twice. After addition of a 2N-ammonium acetate aqueous solution, the water layer was extracted with dichloromethane (48 ml) twice. The dichloromethane layer was washed with water (48 ml) twice, concentrated under a reduced pressure, crystallized with isopropyl alcohol (88 ml), and filtered to obtain 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (8.29 g) (HPLC purity 99.7percent, yield 31.7percent).(Reference Example 11) 2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1 H-benzimidazole (25.0 g (72.8 mmol)) was dissolved in dichloromethane and cooled. Then, mcpba (70.2percent purity; 7.16 g (29.1 mmol)) was added gradually so that the internal temperature did not exceed -15°C. 10percent Aqueous sodium hydroxide solution (70.8 ml) was then added, and after stirring and still standing the water layer was separated. The separated water layer was washed with dichloromethane (48 ml) twice. After addition of a 2N-ammonium acetate aqueous solution, the water layer was extracted with dichloromethane (48 ml) twice. The dichloromethane layer was washed with water (48 ml) twice, concentrated under a reduced pressure, crystallized with acetonitrile (132 ml), and filtered to obtain 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (8.25 g) (HPLC purity 99.7percent, yield 31.5percent).(Reference Example 12) 2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (25.0 g (72.8 mmol)) was dissolved in dichloromethane and cooled. Then, mcpba (70.2percent purity; 8.95 g (36.4 mmol)) was added gradually so that the internal temperature did not exceed -15°C. 10percent Aqueous sodium hydroxide solution (70.8 ml) was then added, and after stirring and still standing the water layer was separated. The separated water layer was washed with dichloromethane (48 ml) twice. After addition of a 2N-ammonium acetate aqueous solution, the water layer was extracted with dichloromethane (48 ml) twice. The dichloromethane layer was washed with water (48 ml) twice, concentrated under a reduced pressure, crystallized with acetone (165 ml), and filtered to obtain 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (10.8 g) (HPLC purity 99.6percent, yield 41.4percent).(Reference Example 13) 2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (25.0 g (72.8 mmol)) was.dissolved in dichloromethane and cooled. Then, mcpba (70.2percent purity; 8.95 g (36.4 mmol)) was added gradually so that the internal temperature did not exceed -15°C. 10percent Aqueous sodium hydroxide solution (70.8 ml) was then added, and after stirring and still standing the water layer was separated. The separated water layer was washed with dichloromethane (48 ml) twice. After addition of a 2N-ammonium acetate aqueous solution, the water layer was extracted with dichloromethane (48 ml) twice. The dichloromethane layer was washed with water (48 ml) twice, concentrated under a reduced pressure, crystallized with toluene (110 ml), and filtered to obtain 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (10.6 g) (HPLC purity 99.6percent, yield 40.4percent).(Reference Example 14) 2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (25.0 g (72.8 mmol)) was dissolved in dichloromethane and cooled. Then, mcpba (70.2percent purity; 8.95 g (36.4 mmol)) was added gradually so that the internal temperature did not exceed -15°C. 10percent Aqueous sodium hydroxide solution (70.8 ml) was then added, and after stirring and still standing the water layer was separated. The separated water layer was washed with dichloromethane (48 ml) twice. After addition of a 2N-ammonium acetate aqueous solution, the water layer was extracted with dichloromethane (48 ml) twice. The dichloromethane layer was washed with water (48 ml) twice, concentrated under a reduced pressure, crystallized with dichloromethane (28 ml) and ethyl acetate (184 ml), and filtered to obtain 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1 H-benzimidazole (10.9 g) (HPLC purity 99.7percent, yield 41.7percent).(Reference Example 15) 2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1 H-benzimidazole (25.0 g (72.8 mmol)) was dissolved in dichloromethane and cooled. Then, mcpba (70.2percent purity; 10.7 g (43.7 mmol)) was added gradually so that the internal temperature did not exceed -15°C. 10percent Aqueous sodium hydroxide solution (70.8 ml) was then added, and after stirring and still standing the water layer was separated. The separated water layer was washed with dichloromethane (48 ml) twice. After addition of a 2N-ammonium acetate aqueous solution, the water layer was extracted with dichloromethane (48 ml) twice. The dichloromethane layer was washed with water (48 ml) twice, concentrated under a reduced pressure, crystallized with acetone (198 ml), and filtered to obtain 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (12.6 g) (HPLC purity 99.3percent, yield 48.3percent).(Reference Example 16) 2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1 H-benzimidazole (25.0 g (72.8 mmol)) was dissolved in dichloromethane and cooled. Then, mcpba (70.2percent purity; 10.7 g (43.7 mmol)) was added gradually so that the internal temperature did not exceed -15°C. 10percent Aqueous sodium hydroxide solution (70.8 ml) was then added, and after stirring and still standing the water layer was separated. The separated water layer was washed with dichloromethane (48 ml) twice. After addition of a 2N-ammonium acetate aqueous solution, the water layer was extracted with dichloromethane (48 ml) twice. The dichloromethane layer was washed with water (48 ml) twice, concentrated under a reduced pressure, crystallized with dichloromethane (27 ml) and ether (220 ml), and filtered to obtain 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (14.5 g) (HPLC purity 99.1 percent, yield 55.4percent).
23.5%
Stage #1: With 3-chloro-benzenecarboperoxoic acid In dichloromethane at -15℃;
Stage #2: With sodium hydroxide In dichloromethane; water
Reference Example 7; 2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (25.0 g (72.8 mmol)) was dissolved in dichloromethane, and then the solution was cooled, and mcpba (70.2percent purity; 5.37 g (21.8 mmol)) was added little by little such that the internal temperature did not exceed -15° C. After the addition, a 10percent sodium hydroxide aqueous solution (70.8 ml) was added, the mixture was stirred and then left to stand, and then the aqueous layer was separated off. The separated aqueous layer was washed twice with dichloromethane (48 ml). A 2N ammonium acetate aqueous solution was then put into the solution, and then extraction was carried out twice with dichloromethane (48 ml). The dichloromethane layers were washed twice with water (48 ml), vacuum concentration was carried out, crystallization was carried out using dichloromethane (14 ml) and acetonitrile (92 ml), and then filtration was carried out, thus obtaining 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (6.26 g) (HPLC purity 99.7percent, yield 23.9percent).; Reference Example 8; 2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (25.0 g (72.8 mmol)) was dissolved in dichloromethane, and then the solution was cooled, and mcpba (70.2percent purity; 5.37 g (21.8 mmol)) was added little by little such that the internal temperature did not exceed -15° C. After the addition, a 10percent sodium hydroxide aqueous solution (70.8 ml) was added, the mixture was stirred and then left to stand, and then the aqueous layer was separated off. The separated aqueous layer was washed twice with dichloromethane (48 ml). A 2N ammonium acetate aqueous solution was then put into the solution, and then extraction was carried out twice with dichloromethane (48 ml). The dichloromethane layers were washed twice with water (48 ml), vacuum concentration was carried out, crystallization was carried out using ethyl acetate (66 ml), and then filtration was carried out, thus obtaining 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (6.15 g) (HPLC purity 99.8percent, yield 23.5percent).; Reference Example 9; 2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (25.0 g (72.8 mmol)) was dissolved in dichloromethane, and then the solution was cooled, and mcpba (70.2percent purity; 7.16 g (29.1 mmol)) was added little by little such that the internal temperature did not exceed -15° C. After the addition, a 10percent sodium hydroxide aqueous solution (70.8 ml) was added, the mixture was stirred and then left to stand, and then the aqueous layer was separated off. The separated aqueous layer was washed twice with dichloromethane (48 ml). A 2N ammonium acetate aqueous solution was then put into the solution, and then extraction was carried out twice with dichloromethane (48 ml). The dichloromethane layers were washed twice with water (48 ml), vacuum concentration was carried out, crystallization was carried out using dichloromethane (18 ml) and acetone (120 ml), and then filtration was carried out, thus obtaining 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (8.56 g) (HPLC purity 99.7percent, yield 32.7percent).; Reference Example 10; 2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (25.0 g (72.8 mmol)) was dissolved in dichloromethane, and then the solution was cooled, and mcpba (70.2percent purity; 7.16 g (29.1 mmol)) was added little by little such that the internal temperature did not exceed -15° C. After the addition, a 10percent sodium hydroxide aqueous solution (70.8 ml) was added, the mixture was stirred and then left to stand, and then the aqueous layer was separated off. The separated aqueous layer was washed twice with dichloromethane (48 ml). A 2N ammonium acetate aqueous solution was then put into the solution, and then extraction was carried out twice with dichloromethane (48 ml). The dichloromethane layers were washed twice with water (48 m), vacuum concentration was carried out, crystallization was carried out using isopropyl alcohol (88 ml), and then filtration was carried out, thus obtaining 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (8.29 g) (HPLC purity 99.7percent, yield 31.7percent).; Reference Example 11; 2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (25.0 g (72.8 mmol)) was dissolved in dichloromethane, and then the solution was cooled, and mcpba (70.2percent purity; 7.16 g (29.1 mmol)) was added little by little such that the internal temperature did not exceed -15° C. After the addition, a 10percent sodium hydroxide aqueous solution (70.8 ml) was added, the mixture was stirred and then left to stand, and then the aqueous layer was separated off. The separated aqueous layer was washed twice with dichloromethane (48 ml). A 2N ammonium acetate aqueous solution was then put into the solution, and then extraction was carried out twice with dichloromethane (48 ml). The dichloromethane layers were washed twice with water (48 ml), vacuum concentration was carried out, crystallization was carried out using acetonitrile (132 ml), and then filtration was carried out, thus obtaining 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (8.25 g) (HPLC purity 99.7percent, yield 31.5percent). Reference Example 12 2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (25.0 g (72.8 mmol)) was dissolved in dichloromethane, and then the solution was cooled, and mcpba (70.2percent purity; 8.95 g (36.4 mmol)) was added little by little such that the internal temperature did not exceed -15° C. After the addition, a 10percent sodium hydroxide aqueous solution (70.8 ml) was added, the mixture was stirred and then left to stand, and then the aqueous layer was separated off. The separated aqueous layer was washed twice with dichloromethane (48 ml). A 2N ammonium acetate aqueous solution was then put into the solution, and then extraction was carried out twice with dichloromethane (48 ml). The dichloromethane layers were washed twice with water (48 ml), vacuum concentration was carried out, crystallization was carried out using acetone (165 ml), and then filtration was carried out, thus obtaining 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (10.8 g) (HPLC purity 99.6percent, yield 41.4percent). Reference Example 13 2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (25.0 g (72.8 mmol)) was dissolved in dichloromethane, and then the solution was cooled, and mcpba (70.2percent purity; 8.95 g (36.4 mmol)) was added little by little such that the internal temperature did not exceed -15° C. After the addition, a 10percent sodium hydroxide aqueous solution (70.8 ml) was added, the mixture was stirred and then left to stand, and then the aqueous layer was separated off. The separated aqueous layer was washed twice with dichloromethane (48 ml). A 2N ammonium acetate aqueous solution was then put into, and then extraction was carried out twice with dichloromethane (48 ml). The dichloromethane layers were washed twice with water (48 ml), vacuum concentration was carried out, crystallization was carried out using toluene (110 ml), and then filtration was carried out, thus obtaining 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (10.6 g) (HPLC purity 99.6percent, yield 40.4percent). Reference Example 14 2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (25.0 g (72.8 mmol)) was dissolved in dichloromethane, and then the solution was cooled, and mcpba (70.2percent purity; 8.95 g (36.4 mmol)) was added little by little such that the internal temperature did not exceed -15° C. After the addition, a 10percent sodium hydroxide aqueous solution (70.8 ml) was added, the mixture was stirred and then left to stand, and then the aqueous layer was separated off. The separated aqueous layer was washed twice with dichloromethane (48 ml). A 2N ammonium acetate aqueous solution was then put into the solution, and then extraction was carried out twice with dichloromethane (48 ml). The dichloromethane layers were washed twice with water (48 ml), vacuum concentration was carried out, crystallization was carried out using dichloromethane (28 ml) and ethyl acetate (184 ml), and then filtration was carried out, thus obtaining 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (10.9 g) (HPLC purity 99.7percent, yield 41.7percent). Reference Example 15 2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (25.0 g (72.8 mmol)) was dissolved in dichloromethane, and then the solution was cooled, and mcpba (70.2percent purity; 10.7 g (43.7 mmol)) was added little by little such that the internal temperature did not exceed -15° C. After the addition, a 10percent sodium hydroxide aqueous solution (70.8 ml) was added, the mixture was stirred and then left to stand, and then the aqueous layer was separated off. The separated aqueous layer was washed twice with dichloromethane (48 ml). A 2N ammonium acetate aqueous solution was then put into the solution, and then extraction was carried out twice with dichloromethane (48 ml). The dichloromethane layers were washed twice with water (48 ml), vacuum concentration was carried out, crystallization was carried out using acetone (198 ml), and then filtration was carried out, thus obtaining 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (12.6 g) (HPLC purity 99.3percent, yield 48.3percent). Reference Example 16 2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (25.0 g (72.8 mmol)) was dissolved in dichloromethane, and then the solution was cooled, and mcpba (70.2percent purity; 10.7 g (43.7 mmol)) was added little by little such that the internal temperature did not exceed -15° C. After the addition, a 10percent sodium hydroxide aqueous solution (70.8 ml) was added, the mixture was stirred and then left to stand, and then the aqueous layer was separated off. The separated aqueous layer was washed twice with dichloromethane (48 ml). A 2N ammonium acetate aqueous solution was then put into the solution, and then extraction was carried out twice with dichloromethane (48 ml). The dichloromethane layers were washed twice with water (48 ml), vacuum concentration was carried out, crystallization was carried out using dichloromethane (27 ml) and ether (220 ml), and then filtration was carried out, thus obtaining 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (14.5 g) (HPLC purity 99.1percent, yield 55.4percent). HPLC Conditions Column: Nucleosil 5c18 (made by Chemco) Mobile phase: methanol: phosphate buffer (pH 7)=3:2 Flow speed: 1.0 ml/min Detector: 290 nm

Reference: [1] Patent: US2009/5570, 2009, A1, . Location in patent: Page/Page column 3-4
[2] Patent: US2009/5570, 2009, A1, . Location in patent: Page/Page column 4
[3] Organic Process Research and Development, 2013, vol. 17, # 10, p. 1272 - 1276
[4] Patent: CN108395425, 2018, A, . Location in patent: Paragraph 0042; 0043; 0044; 0046; 0047; 0048; 0078; 0079
[5] Patent: US2004/138466, 2004, A1, . Location in patent: Page 5
[6] Patent: JP2004/524303, 2004, A, . Location in patent: Page/Page column 11
[7] Patent: WO2009/116072, 2009, A2, . Location in patent: Page/Page column 14-15
[8] Patent: CN106674198, 2017, A, . Location in patent: Paragraph 0024-0025
[9] Patent: WO2006/49486, 2006, A1, . Location in patent: Page/Page column 11
[10] Patent: WO2008/45777, 2008, A2, . Location in patent: Page/Page column 30-32
[11] Patent: EP1775292, 2007, A1, . Location in patent: Page/Page column 15 -17
[12] Patent: US2007/225502, 2007, A1, . Location in patent: Page/Page column 3; 7-8
[13] Patent: EP1452533, 2004, A1, . Location in patent: Page 8
[14] Patent: US2004/138466, 2004, A1, . Location in patent: Page 6
[15] Patent: US2004/180935, 2004, A1, . Location in patent: Page/Page column 6
[16] Patent: JP2004/524303, 2004, A, . Location in patent: Page/Page column 14
[17] Patent: US6313303, 2001, B1,
[18] Patent: US5045552, 1991, A,
[19] Patent: EP1775292, 2007, A1, . Location in patent: Page/Page column 17
[20] Patent: WO2007/66202, 2007, A1, . Location in patent: Page/Page column 9
[21] Patent: WO2003/82858, 2003, A1, . Location in patent: Page/Page column 11-12
[22] Patent: WO2008/17020, 2008, A2, . Location in patent: Page/Page column 19-21
[23] Patent: WO2008/17020, 2008, A2, . Location in patent: Page/Page column 22-23
[24] Synthetic Communications, 2009, vol. 39, # 2, p. 278 - 290
[25] Patent: WO2009/14431, 2009, A1, . Location in patent: Page/Page column 12
[26] Patent: WO2009/14431, 2009, A1, . Location in patent: Page/Page column 13
[27] Organic Process Research and Development, 2009, vol. 13, # 5, p. 896 - 899
[28] Patent: WO2010/6904, 2010, A2, . Location in patent: Page/Page column 26-27
[29] Patent: WO2010/4571, 2010, A2, . Location in patent: Page/Page column 3-4
[30] Patent: WO2010/146428, 2010, A1, . Location in patent: Page/Page column 8
[31] Patent: WO2014/91450, 2014, A1, . Location in patent: Page/Page column 15-16
[32] Patent: CN104311540, 2016, B, . Location in patent: Paragraph 0039-0040
[33] Patent: CN106317019, 2017, A, . Location in patent: Paragraph 0070; 0071; 0072; 0073; 0074
[34] Patent: WO2018/57989, 2018, A1, . Location in patent: Page/Page column 123
[35] Patent: WO2008/155780, 2008, A2, . Location in patent: Page/Page column 10
  • 5
  • [ 1080503-70-3 ]
  • [ 1080503-68-9 ]
  • [ 117976-89-3 ]
YieldReaction ConditionsOperation in experiment
90%
Stage #1: With n-butyllithium In tetrahydrofuran at -90 - -80℃;
Stage #2: at -80 - -20℃;
Example 10.- Preparation of rabeprazole, compound of general formula (11) wherein R2 is hydrogen, R4 is hydrogen, R5 is methyloxypropyloxy, and R6 is methyl; [Show Image] 4.26 g (21.8 mmol) of 2,3-dimethyl-4-(3-methoxy-propoxy)piridine were dissolved in 42 ml of anhydrous tetrahydrofuran at room temperature under inert atmosphere, and the solution was then cooled below - 90° C. 8.72 ml of a 2.5M solution of n-butyl lithium (21.8 mmol) were added dropwise and the temperature was maintained below -80° C. 2,3-dimethyl-4-(3-methoxy-propoxy)pyridine may be prepared in accordance with the process described in EP-A-0268956. After 30 minutes at this temperature, the mixture was slowly added to a solution of 2.0 g (6.24 mmol) of (-)-menthyl 2-benzimidazolylsulphinate, as obtained in Example 7, in 36 ml of tetrahydrofuran cooled below -80°C as well. Once the addition was completed, the resulting mixture was allowed to stand up to -20° C, then 100 ml of water were slowly added and it was allowed to reach room temperature. The reaction mixture was analyzed by HPLC, and conversion and yield were found to be 95percent and 90percent respectively.
Reference: [1] Patent: EP1992619, 2008, A1, . Location in patent: Page/Page column 16
  • 6
  • [ 924663-40-1 ]
  • [ 117976-89-3 ]
YieldReaction ConditionsOperation in experiment
5 %Chromat. With lithium carbonate In acetonitrile for 2 h; Heating / reflux EXAMPLE 5
2-[3-Methyl-4-(3-methoxypropoxy)-2-pyridinyl)metyl]sulfanyl}-1H-benzimidazole(I) (Rabeprazole)
A 25 ml three-necked round-bottom flask equipped with magnetic stirring, reflux condenser and under nitrogen atmosphere, is loaded with 2-[3-methyl-4-(3-methoxypropoxy)-1-oxy-2-pyridinyl)metyl]sulfanyl}-1H-benzimidazole (0.4 g 1.1 mmoles), acetonitrile (10 ml), Lithium carbonate (75 mg), RuCl3 (18 mg, 0.1 mmoles) and NaVO3 (15 mg, 0.12 mmoles).
The mixture is heated to reflux 2 hours and analyzed by HPLC, showing a 5percent of 2-[3-Methyl-4-(3-methoxypropoxy)-2-pyridinyl)metyl]sulfinyl}-1H-benzimidazole.
Reference: [1] Patent: US2007/249662, 2007, A1, . Location in patent: Page/Page column 5
[2] Patent: EP1847538, 2007, A1, . Location in patent: Page/Page column 7
  • 7
  • [ 117977-21-6 ]
  • [ 117976-89-3 ]
  • [ 117976-47-3 ]
YieldReaction ConditionsOperation in experiment
75% With sodium hydroxide; N-chloro-succinimide; water In acetonitrile at 0 - 5℃; for 2 h; Rabeprazole sulphide is added to aqueous sodium hydroxide solution at room temperature. Acetonitrile is added, stirred to obtain a solution. Cooled the solution to 0° to 50C and N-chlorosuccinimide is added slowly over a period of around 2 hr maintaining the temperature between 0° to 50C. After completion of the reaction, aqueous sodiumthiosulphate is added, adjusted the pH to 12.50 to 13.50 with sodium hydroxide, if needed. Added charcoal, stirred and filtered. Filtrate is extracted with dichloromethane to separate organic and aqueous layers. Aqueous layer is adjusted to pH 9.0 with ammonium acetate and extracted with dichloromethane. Combined dichloromethane layer is washed with 10percent aqueous brine. Washed dichloromethane layer is treated with triethylamine and n-hexane. Mixture stirred at 20° to 250C. Solid obtained filtered, washed with a mixture of dichloromethane-n-hexane, dried to obtain sulphoxide compound Rabeprazole. Yield: 75-79percent Purity: 99.64percent Over oxidation Impurity: 0.1 to 0.2percent
57% With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 1 h; To a solution of rabeprazole sulphide in dichloromethane is added a solution of m-chloroperbenzoic acid in dichloromethane maintaining the temperature at about - 2O0C and stirred for an hour. Water is added and pH adjusted to around 10.4 with 10percent aqueous sodium hydroxide aqueous and organic layers are separated. Add water again, to organic layer, adjust the pH to 13.0 with aqueous 10percent sodium hydroxide. Separate organic layer. Adjust the ph of aqueous layer to 9.5-10 with ammonium acetate solution and extract with dichloromethane. Distilling the organic layer under vacuum to obtain a residue, this is crystallized with acetone/ethyl acetate to get Rabeprazole. Yield: 57percent Purity: 98.5 to 99percent Over oxidation impurity: 0.5 to 0.8percent
52% With sodium hypochlorite; water In dichloromethane at 0 - 5℃; for 3 - 6 h; Dichloromethane solvent is cooled to 0° to 50C and add rabeprazole sulphide and stirred to dissolve completely. Sodium hypochlorite solution (5percent w/w) is added over a period of 1-2 h. The reaction mixture is further stirred between 0° to 50C for 2 to 4 h. Slowly the mixture is brought to room temperature. Adjusted the pH to 10.0 to 10.5 with ammonium sulphate. Separated the dichloromethane layer and extracted with 2.5percent aqueous sodium hydroxide. Separated the aqueous layer and adjusted the pH to 8.7 to 9.2 with ammonium acetate solution. Extracted the pH adjusted aqueous layer with dichloromethane. Evaporated dichloromethane layer under vacuum at 20- 250C to obtain a residue. Dissolved the residue in ethyl-acetate and cooled to obtain sulphoxide compound (Rabeprazole). Yield: 52-57percent; Purity: 98.5 to 99percent; Over oxidation Impurity: 0.5 to 0.8percent
Reference: [1] Patent: WO2006/24890, 2006, A1, . Location in patent: Page/Page column 6-7
[2] Patent: WO2006/24890, 2006, A1, . Location in patent: Page/Page column 6
[3] Patent: WO2006/24890, 2006, A1, . Location in patent: Page/Page column 5-6
  • 8
  • [ 408332-88-7 ]
  • [ 117977-21-6 ]
  • [ 117976-89-3 ]
YieldReaction ConditionsOperation in experiment
49% With N-ethyl-N,N-diisopropylamine; isopropylbenzene hydroperoxide In water; toluene Example 26
Asymmetric synthesis of (+)-2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulphinyl]-1H-benzimidazole, (+)-(If).
2.1 g (6.3 mmol) of 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]thio]-1H-benzimidazole was dissolved in 50 ml of toluene.
To the solution was added 40 μl (2.2 mmol) of water, 1.6 ml (9.4 mmol) of (+)-diethyl L-tartrate and 1.1 ml (3.8 mmol) of titanium(IV) isopropoxide.
The mixture was stirred for 60 minutes at 50° C. and then cooled to room temperature. 0.44 ml (2.6 mmol) of N,N-diisopropylethylamine and 1.1 ml (6.0 mmol) of cumene hydroperoxide (80percent) were added to the solution.
After stirring for 2 h at room temperature the mixture consisted of 9percent sulphide, 4percent sulphone and 85percent sulphoxide according to HPLC.
To the mixture toluene (50 ml) was added and the resultant solution was extracted three times with an aqueous ammonia (12percent) solution with a total volume of 150 ml.
The combined aqueous layers were neutralized by the addition of concentrated acetic acid (30 ml).
Thereafter, the workup procedure employed extraction, evaporation and flash chromatography yielding 1.63 g of the title compound with a purity of 99.9percent (achiral analysis) and with an enantiomeric excess (e.e.) of 91percent (chiral analysis).
After treating the material with acetonitrile, there was a precipitate that could be removed by filtration.
Concentrating the filtrate afforded 1.1 g (49percent) of the title compound as an oil with an optical purity of 96.0percent e.e.
Reference: [1] Patent: US5948789, 1999, A,
  • 9
  • [ 13811-71-7 ]
  • [ 117977-21-6 ]
  • [ 117976-89-3 ]
YieldReaction ConditionsOperation in experiment
60% With N-ethyl-N,N-diisopropylamine; isopropylbenzene hydroperoxide In water; toluene Example 25
Asymmetric synthesis of (-)-2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulphinyl]-1H-benzimidazole, (-)-(If).
2.1 g (6.3 mmol) of 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]thio]-1H-benzimidazole was dissolved in 50 ml of toluene.
To the solution was added 40 μl (2.2 mmol) of water, 1.6 ml (9.4 mmol) of (-)-diethyl D-tartrate and 1.1 ml (3.8 mmol) of titanium(IV) isopropoxide.
The mixture was stirred for 60 minutes at 50° C. and then cooled to room temperature. 0.44 ml (2.6 mmol) of N,N-diisopropylethylamine and 1.1 ml (6.0 mmol) of cumene hydroperoxide (80percent) were added.
After stirring for 2 h at room temperature the mixture consisted of 9percent sulphide, 4percent sulphone and 86percent sulphoxide according to achiral HPLC.
To the mixture toluene (50 ml) was added and the resultant solution was extracted three times with an aqueous ammonia (12percent) solution with a total volume of 150 ml.
The combined aqueous layers were neutralized by the addition of concentrated acetic acid (30 ml).
Thereafter, the workup procedure employed extraction, evaporation and flash chromatography yielding 1.62 g of the title compound with a purity of 99.9percent (achiral analysis) and with an enantiomeric excess (e.e.) of 90percent (chiral analysis).
After treating the material with acetonitrile there was a precipitate that could be removed by filtration.
Concentrating the filtrate afforded 1.36 g (60percent) of the title compound as an oil with an optical purity of 91.5percent e.e.
Reference: [1] Patent: US5948789, 1999, A,
  • 10
  • [ 937-14-4 ]
  • [ 117977-21-6 ]
  • [ 117976-89-3 ]
Reference: [1] Patent: EP1818331, 2007, A1, . Location in patent: Page/Page column 6
  • 11
  • [ 924663-38-7 ]
  • [ 117976-89-3 ]
Reference: [1] Patent: EP1921075, 2008, A2, . Location in patent: Page/Page column 8
  • 12
  • [ 5038-11-9 ]
  • [ 117976-89-3 ]
YieldReaction ConditionsOperation in experiment
79% With ammonium acetate; sodium hydroxide; chloro-trimethyl-silane; sodium hydrogencarbonate In methanol; ethanol; dichloromethane; water Example 11
Preparation of 2-[[[4-[3-methoxypropoxy]-3-methyl-2-pyridinyl]-methyl]sulfinyl]-1H-benzimidazole (compound of formula (I), rabeprazole)
To a suspension of 0.45 g (1.20 mmol) of 2-[[[4-[3-methoxypropoxy]-3-methyl-2-pyridinyl]-methyl]sulfinyl]-1H-benzimidazole N-oxide and 0.32 g (1.57 mmol) of 4,4'-thiobismorpholine (synthesised as described by) in 8.5 mL of methanol was added dropwise a solution of 0.27 g (2.49 mmol) of chlorotrimethylsilane in 0.9 mL of ethanol.
After stirring the reaction over 1.5 h at 0°C, a solution of 0.10 g (2.50 mmol) of NaOH in 2.2 mL of water was added.
The alcohol solvents were removed by distillation at reduced pressure and the residue was dissolved with 12 mL of water and adjusted to pH 13 with 50percent NaOH.
The resultant aqueous phase was washed with 8 mL of CH2Cl2 three times, the pH was adjusted to pH 9-10 with aqueous solution of ammonium acetate and extracted three times with 10 mL of CH2Cl2.
The combined organic phases were washed twice with aqueous solution of NaHCO3 at pH 9, dried with anhydrous Na2SO4 and evaporated to dryness to obtain 0.34 g (79percent) of 2-[[[4-[3-methoxypropoxy]-3-methyl-2-pyridinyl]-methyl]sulfinyl]-1H-benzimidazole.
This solid could be further purified by crystallizing from CH2Cl2/triethylamine/heptane.
Reference: [1] Patent: EP2022789, 2009, A1,
  • 13
  • [ 117977-20-5 ]
  • [ 117976-89-3 ]
Reference: [1] Patent: WO2014/91450, 2014, A1,
  • 14
  • [ 675198-19-3 ]
  • [ 117976-89-3 ]
Reference: [1] Patent: WO2014/91450, 2014, A1,
  • 15
  • [ 118175-10-3 ]
  • [ 117976-89-3 ]
Reference: [1] Patent: CN106674198, 2017, A,
  • 16
  • [ 134469-07-1 ]
  • [ 117976-89-3 ]
Reference: [1] Patent: CN106674198, 2017, A,
  • 17
  • [ 37699-43-7 ]
  • [ 1589-49-7 ]
  • [ 134469-07-1 ]
  • [ 924663-38-7 ]
  • [ 102804-77-3 ]
  • [ 117976-89-3 ]
Reference: [1] Pharmazie, 2005, vol. 60, # 11, p. 814 - 818
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