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CAS No. :103577-40-8 MDL No. :MFCD00834357
Formula : C16H14F3N3OS Boiling Point : -
Linear Structure Formula :- InChI Key :CCHLMSUZHFPSFC-UHFFFAOYSA-N
M.W : 353.36 Pubchem ID :1094080
Synonyms :

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Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
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* 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.

  • Downstream synthetic route of [ 103577-40-8 ]

[ 103577-40-8 ] Synthesis Path-Downstream   1~13

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YieldReaction ConditionsOperation in experiment
67.3% Stage #1: lansoprazole sulfide With D-tartaric acid monophenyl ester benzylamine In water; toluene at 60℃; for 0.5h; Stage #2: With titanium(IV) isopropylate In water; toluene for 1h; Further stages; 2 example 2 The lansoprazole sit sulfide precursor 3. 53g And monobenzyl tartrate monobenzamide (2.0 g) were mixed,35 ml of toluene was added,Heated to 60 ° C,To be dissolved raw materials,Add H200. 03ml,Reaction 30min,0.18 g of titanium isopropoxide,Continue to react lh,Cooled to 20 ° C, 0.80 ml of diisopropylethylamine was added,Reaction 30min, the ice bath to 0 ° C, and temperature control at 0 ~ 5 ° C by adding 80% CHP 6. 0ml,The reaction was carried out at 0-5 ° C for 5 h.After completion of the reaction, 10 ml of 30% Na2S203 was added,(V = 1: 1), dropwise add 33ml heptane, precipitation of white solid, stirring lh, suction filtration. The filter cake was washed with 8 ml of toluene-methyl t-butyl ether (V = 1: 4) and dried to give 2.51 g of the desired product as a white solid. The yield was 68.1%, and the enantiomeric excess 99. 7%.
With hydroquinidine-2,5-diphenyl-4,6-pyrimidinediyl diether; dihydrogen peroxide; tungsten(VI) oxide In tetrahydrofuran at 0℃; for 50h; Title compound not separated from byproducts;
Stage #1: lansoprazole sulfide With 1,8-diazabicyclo[5.4.0]undec-7-ene In isopropyl alcohol at 10 - 15℃; Stage #2: With (1R)-(-)-(8,8-dichloro-10-camphorsulfonyl) oxaziridine In isopropyl alcohol at 25 - 30℃; 13 Example 13 (Lansoprazole: DBU as base)Lansoprazole sulfide (l .Ogm; 0.0028moles) was added to isopropyl alcohol (7ml) at 25- 3O0C with stirring. 1,8-Diazabicyclo [5.4.0] undec-7-ene (0.43gms; 0.0028moles) was then added to the mixture and stirred at 10-150C. (-) Dichlorooxaziridine [(-)-(8,8- dichlorocamphorylsulfonyl)oxaziridine (0.8gms; 0.0027moles) was then added and the reaction stirred at 25-3O0C, till completion of reaction. The reaction was quenched with dilute sodium hydroxide solution and extracted with dichloromethane. The organic layer was concentrated to obtain the product. Chemical Purity: 92.43% (S) isomer: 90.29% (R) isomer: 9.71%
With (1R)-(-)-(8,8-dichloro-10-camphorsulfonyl) oxaziridine In isopropyl alcohol at 10 - 30℃; for 15h; 14 Example 14 (Dichlorooxaziridine without base)Lansoprazole sulfide (l .Ogm; 0.0028moles) was added to isopropyl alcohol (7ml) at 25- 300C with stirring and cooled to 10-150C. [(-)-(8,8-dichlorocamphorylsυlfonyl)oxaziridine (0.8gms; 0.0027moles) was then added and the reaction stirred at 25-300C, for 15 hours. The reaction was quenched with dilute sodium hydroxide solution and extracted with dichloromethane. The organic layer was concentrated to obtain the product. Chemical Purity: 6.85% (S) isomer: 68.29% (R) isomer: 31.71%
71.7 % ee With oxygen; nicotinamide adenine dinucleotide phosphate In aq. phosphate buffer; isopropyl alcohol at 25℃; for 24h; Sealed tube; Enzymatic reaction; 7.D D. Preparation of S-Lansoprazole or R-Lansoprazole (“Dexlansoprazole”) D. Preparation of S-Lansoprazole or R-Lansoprazole (“Dexlansoprazole”) (0374) This example illustrates the use of engineered CHMO polypeptides of the present disclosure for carrying out the biocatalytic conversion of the sulfide precursor substrate (and pyrmetazole analog), 2-((3-methyl-4-(2,2,2-trifluoroethoxyl)pyridin-2-yl)methylthio)-1H-benzo[d]imidazole, to either of the prazole compounds (S)-lansoprazole or (R)-lansoprazole in enantiomeric excess, as shown in Scheme 7. (0375) (0376) Screening assays using the sulfide precursor substrate 2-((3-methyl-4-(2,2,2-trifluoroethoxyl)pyridin-2-yl)methylthio)-1H-benzo[d]imidazole were carried out with certain engineered CHMO polypeptides of the present disclosure. Assay conditions and results for % conversion and product enantioselectivity are provided below in Table 20. [table-us-00021-en] TABLE 20 Enantioselectivity SEQ ID NO: % Conversion (% ee) 5/6 1.21 R-selective (n.d.)4 21/22 1.12 S-selective (n.d.)4 71/72 273 S-selective (71.7% ee) 79/80 193 S-selective (91.6% ee) 11.5 g/L lansoprazole sulfide, 15 g/L enzyme, 0.5 g/L NADP+, 1 g/L KRED, 4% IPA, 25 mM phosphate buffer pH 8.5, 17 h reaction time. 22.0 g/L lansoprazole sulfide, 25 g/L enzyme, 0.5 g/L NADP+, 1 g/L KRED, 4% IPA, 25 mM phosphate buffer pH 8.5, 17 h reaction time. 31.5 g/L lansoprazole sulfide, 5 g/L enzyme, 0.5 g/L NADP+, 1 g/L KRED, 4% IPA, 25 mM phosphate buffer pH 8.5, 24 h reaction time. 4% ee could not be determined due to low % conversion of substrate to product. (0378) As shown in Table 20, the engineered CHMO polypeptides of SEQ ID NO: 22, 72, and 80, are capable of converting the lansoprazole sulfide precursor substrate to (S)-lansoprazole in enantiomeric excess. The polypeptides of SEQ ID NO: 72 and 80 are capable of 27% and 19% conversion with enantioselectivity of about 72% ee and 92% ee, respectively. Although the engineered CHMO polypeptide of SEQ ID NO: 6 showed only 1% conversion it was confirmed to be selective for the (R)-lansoprazole product. The polypeptide of SEQ ID NO: 6 was also found to convert pyrmetazole to favor the (R)-omeprazole product over the (S)-omeprazole product in 98.9% enantiomeric excess (see Table 2A). It is reasonable to expect that further directed evolution of the engineered polypeptide of SEQ ID NO: 6 will result in an engineered CHMO polypeptide capable of producing the (R)-lansoprazole product in high enantiomeric excess (e.g., 98% or greater) and much higher % conversion (e.g., 20% or greater). (0379) All publications, patents, patent applications and other documents cited in this application are hereby incorporated by reference in their entireties for all purposes to the same extent as if each individual publication, patent, patent application or other document were individually indicated to be incorporated by reference for all purposes. (0380) While various specific embodiments have been illustrated and described, it will be appreciated that various changes can be made without departing from the spirit and scope of the invention(s).
89.5 % ee With C64H64N4O6Ti2; dihydrogen peroxide In water; ethyl acetate at 0℃; for 6h; Overall yield = 87 %; enantioselective reaction; 2.2. Standard procedure for small-scale catalytic sulfoxidation General procedure: Sulfide (OMS or LPS, 100 mol) and the Ti-salalen catalyst(1.1 mol) were dissolved in the solvent (typically: EtOAc, 6.0 mL),the mixture was thermostatted at desired temperature (typically 0 °C, or -20 to +20 °C for variable-temperature measurements),and 30% aqueous hydrogen peroxide (0.105 mmol of H2O2) was then introduced in one portion. Stirring (500 rpm) was continued at that temperature (typically 24 h). For low-temperature experiments, the reaction times were about 30 h at -10 °C and up to 10 days at -20 °C. To analyze the reaction outcome, 20 L aliquots of the reaction mixture were taken to a vial and immediately carefully evaporated to dryness with a stream of compressed air during ca. 15-20 s. The remaining solid was dissolved in 0.20 mL of 1% Et3N solution in isopropyl alcohol, and the contents of residual sulfide, (R)- and(S)-sulfoxide, and sulfone, were analyzed by chiral HPLC as noted above.
88 % ee With C68H72N4O10Ti2; dihydrogen peroxide In water; ethyl acetate at 0℃; for 24h; Overall yield = 91 %; enantioselective reaction; 2.2. Standard procedure for small-scale catalytic sulfoxidation General procedure: Sulfide (OMS or LPS, 100 mol) and the Ti-salalen catalyst(1.1 mol) were dissolved in the solvent (typically: EtOAc, 6.0 mL),the mixture was thermostatted at desired temperature (typically 0 °C, or -20 to +20 °C for variable-temperature measurements),and 30% aqueous hydrogen peroxide (0.105 mmol of H2O2) was then introduced in one portion. Stirring (500 rpm) was continued at that temperature (typically 24 h). For low-temperature experiments, the reaction times were about 30 h at -10 °C and up to 10 days at -20 °C. To analyze the reaction outcome, 20 L aliquots of the reaction mixture were taken to a vial and immediately carefully evaporated to dryness with a stream of compressed air during ca. 15-20 s. The remaining solid was dissolved in 0.20 mL of 1% Et3N solution in isopropyl alcohol, and the contents of residual sulfide, (R)- and(S)-sulfoxide, and sulfone, were analyzed by chiral HPLC as noted above.
62.3 % ee Stage #1: lansoprazole sulfide With titanium(IV) isopropylate; (R,R)-tartaric acid ethyl ester In water; ethyl acetate at 50 - 55℃; Stage #2: With N-ethyl-N,N-diisopropylamine In water; ethyl acetate at 20 - 25℃; for 0.5h; Stage #3: With Cumene hydroperoxide In water; ethyl acetate at 10 - 15℃; for 18h; Overall yield = 96.5 percent; 4.2; 5.2 Step 2. In a 250ml three-necked flask, add 3.5g lansoprazole sulfide and 35ml ethyl acetate,4.8g hexadentate chiral ligand, 2.8g Ti(O-iPr)4, 0.2g purified water, after stirring at 5055 until it is clear, cool down to 2025,Add 1.2g of N,N-diisopropylethylamine, stir for 0.5h, and lower the temperature to 10-15,Ethyl acetate solution (3.0g, 20ml) of cumene hydroperoxide was slowly added dropwise. After the addition was completed, the temperature was maintained and the reaction continued for 8h.After the reaction, a sample was taken and analyzed by gas chromatography area normalization method. The yield of dexlansoprazole was 96.5%.After analysis by chiral liquid chromatography, the enantiomeric excess of dexlansoprazole was 62.3%.

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YieldReaction ConditionsOperation in experiment
90% The lansoprazole sulfide 2700 g and toluene 33750 ml are added to a reaction tank, stirring at room temperature for 10 minutes. Adding L(+)DET 3348 ml and water 40532 ml, stirring and heating. When the temperature to 56 - 60 C when, the beginning of the thermal insulation 15 minutes. Joined four tetraisopropoxide 2268 ml, continue to thermal insulation 1 hours. The start of the cooling. When the temperature to 10 C -15 C when, adding triethylamine to 1080 ml. Triethylamine canada finishes, starting to drop the cumene hydroperoxide 4698 ml. Hydrogen peroxide after cumin instillment, reacting the beginning of 2.5 hours. By adding 12.5% ammonia water 27000 ml, cyclohexane 27000 ml, and stir for 5 minutes. Liquid, the organic layer using 12.5% ammonia water (27000 ml 2) extraction 2 times. After extraction, the combined aqueous layer. Adding toluene/cyclohexane=1:1 (13500 ml), wash once, and layered extraction. The aqueous layer started to cool off when the temperature is 15 - 20 C when, starting to drop plus metering of the glacial acetic 17820 g, adjusting the pH to 7 - 8. When a kind of white solid when, by adding ethyl acetate 27000 ml extraction. The aqueous layer then adding ethyl acetate 13500 ml extraction. The combined ethyl acetate, saturated sodium chloride aqueous solution for 13500 ml wash once, and extraction. In the ethyl acetate reaction solution adding anhydrous sodium sulfate 5400 g. Filtering adding triethylamine to 135 ml, depressurized distillation (T<55 C). When the surplus fluid approximately is 5400 ml when, stop distilling, started to cool off. When the temperature is 25 - 30 C when, adding cyclohexane 75600 ml. Stirring 2 hours then adding ethyl acetate/cyclohexane=1:4 (about 405 ml) wash once, getting white solid, vacuum 40 C drying 4 h, about to 2000 g solid, yield by about: 75%, content about 99.5%, optical purity of about 83%, dry weight loss (%) ? 0.5%.
87.8% Dissolve 2.84g of tetraisopropyl titanate in 25mL of organic solvent to prepare a solution of tetraisopropyl titanate. Dissolve 8.02g of titanium catalyst ligand in 50mL of organic solvent to form titanium catalyst ligand solution, and 3.53 g of compound of formula I was dissolved into 25mL of organic solvent to form a compound of formula I; The organic solvent is a mixture of toluene and DMF with a volume ratio of 2: 5; At 25 C, the Tetra isopropyl titanate solution was added to the titanium catalyst ligand solution, heated to 75 C, incubated 5min, then cooled to 70 C, incubated for 10min, then cooled to 65 C. The solution of the compound of formula I was stirred for 5min, then cooled to 58 C, incubated 20min, then 2.322g N, N- diisopropylethylamine was added, cooled to 46 C, incubated 7min, then cooled 35 C, and then incubated for 5min; Then cooled to -10 C, after stirring for 5min, the 1.52g of cumene hydroperoxide and 0.036g of calcium peroxide were added. After the reaction reached the end point, 50mL of 15% Na2S2O3 aqueous solution was added to the reaction solution reached end point, then 23mL petroleum ether was added, stirred for 15min, then added 45mL concentration of 7.5% aqueous sodium chloride solution, and stirred for 30min. filtered, and allowed to stand for stratification; The lower layer was separated, and 80 mL of ammonia water having a concentration of 10% and cyclohexane (120 mL) were added to the lower layer. The mixture was stirred and the aqueous layer was separated. The pH of the separated aqueous layer was adjusted to 7.2, then 65 mL of n-butanol was added for extraction, the organic layer was separated and evaporated to dryness to give a concentrate; Each 1 g of the concentrate was dissolved in a mixture of 15 mL of n-butanol and 9 mL of petroleum ether, 8.5 mL of a aqueous sodium bicarbonate solution with a concentration of 0.05% was added, the mixture was stirred well, and the organic layer was separated. 35 mL of water and 5 mL of propylene glycol was added into the organic layer, The mixture was allowed to stand, filtered, and the filter cake was collected and dried to give 3.24 g of a solid, Yield 87.8%, mp 143-145 C, optical purity ee value of 99.9%.
87.8% With dihydrogen peroxide; triethylamine; In tetrahydrofuran; water; at 15 - 20℃; for 2h;Large scale; Process amplification test:In a 10L double-layer glass reactor, 1.0 kg of substrate 2-[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylthio-1H-benzimidazole was added, 100 g of the catalyst (prepared by the method of Example 1) and 6 L of the mixed solvent (VTHF/TEA = 20:1) were uniformly stirred.Temperature control to 15-20 C;25% by weight of an aqueous solution of hydrogen peroxide (2 eq, based on the substrate) was added dropwise, and the reaction solution was detected by HPLC after 2 hours (conversion rate: 99.84%, sulfone content: 0.62%, ee% value: 99.8%);The catalyst was removed by filtration using a microporous membrane having a pore diameter of 0.45 mum; the addition of sodium dithionite to the starch potassium iodide test paper did not show an oxidative neutral solution;The neutral solution was placed in a 30 L glass kettle and heated to 50-55 C. Then, purified water was added dropwise until the system became cloudy, and the dropwise addition was stopped. The amount of purified water added thereto was 1 V volume.Insulation stirring for crystal aging for 1-2h;Then continue to add 3V volume of purified water, after the end of the addition, cool down to room temperature at a temperature drop rate of 5 C / h for 30 min -60 min, filter, acetone wash, vacuum drying at 40-50 C to obtain a white solid with high optical purity R - Lansoprazole 960g(yield was 87.8%, purity was 99.85%, ee% was 99.9%, sulfone content was 0.02%),
68.1% The lansoprazole sit sulfide precursor 3. 53g And monobenzyl tartrate monobenzamide (2.0 g) were mixed,35 ml of toluene was added,Heated to 60 C,To be dissolved raw materials,Add H200. 03ml,Reaction 30min,0.18 g of titanium isopropoxide,Continue to react lh,Cooled to 20 C, 0.80 ml of diisopropylethylamine was added,Reaction 30min, the ice bath to 0 C, and temperature control at 0 ~ 5 C by adding 80% CHP 6. 0ml,The reaction was carried out at 0-5 C for 5 h.After completion of the reaction, 10 ml of 30% Na2S203 was added,(V = 1: 1), dropwise add 33ml heptane, precipitation of white solid, stirring lh, suction filtration. The filter cake was washed with 8 ml of toluene-methyl t-butyl ether (V = 1: 4) and dried to give 2.51 g of the desired product as a white solid. The yield was 68.1%, and the enantiomeric excess 99. 7%.
2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyhdinyl]methyl]thio]-1 H- benzimidazole (50.0 g) and toluene (1.25 L) were charged into a vessel and stirred for about 10 minutes. (+)-Diethyltartrate (62.0 mL) and water (0.61 mL) were added and heated to 58C. The mixture was maintained at 58C for 15 minutes. Titanium isopropoxide (42.0 mL) was added and stirred for 1 hour at 58C. The mixture was cooled to 15C and diisopropylethylamine (25.0 mL) was added. Cumene hydroperoxide (26.9 ml) was added at -2C over a period of 10 minutes and the mixture was maintained at -100C for 3 hours, 30 minutes. 30% sodium thiosulphate solution (180 mL) was added and the mixture was warmed to room temperature. The mixture was filtered through a Hyflow (flux-calcined diatomaceous earth) bed and the layers were separated. The solvent was <n="58"/>distilled completely from the organic layer under reduced pressure below 600C. The residue was cooled to 27C, n-heptane (500 ml_) was added, and the mixture was stirred for 4 hours. The formed solid was filtered, washed with n-heptane (50 ml) and suction dried, to afford 50.0 g of (R)-2-[[[3-methyl-4-(2,2,2-thfluoroethoxy)- 2-pyridinyl]methyl]sulfinyl]-1 H-benzimidazole.
Reference Example 1; [0091]Preparation of (R) -2- [ [ [3-methyl-4- (2, 2, 2-trifluoroethoxy) -2- pyridyl] methyl] sulfinyl]benzimidazole 1.5 hydrate [0092] Under a nitrogen atmosphere, 2- [ [ [3-methyl-4- (2,2,2- trifluoroethoxy) -2-pyridyl] methyl] thio]benzimidazole (100 g) , toluene (500 mL) , water (0.23 mL) and diethyl (+) -tartrate (10.6 mL) were mixed. Under a nitrogen atmosphere, titanium (IV) isopropoxide (8.3 mL) was added to the mixture at 500C to 6O0C, and the mixture was stirred at the same temperature for 30 min. Under a nitrogen atmosphere, diisopropylethylamine (16.3 mL) was added to the obtained mixture at 00C to 100C, cumene hydroperoxide (156.8 mL, content 82%) was added at -100C to 1O0C, and the mixture was stirred at -100C to 1O0C for 4 hr to give a reaction mixture. 25% Aqueous sodium thiosulfate solution (135 g) was added to 1/2 of the reaction mixture under a nitrogen atmosphere to decompose remaining cumene hydroperoxide. The mixture was concentrated to 230 mL, diisopropyl ether (900 mL) was added to the obtained concentrate at room temperature, and the mixture was stirred <n="23"/>at the same temperature to allow crystal precipitation. The crystals were separated and washed successively with diisopropyl ether/n-heptane (1/1) (100 iriL) and municipal water (100 mL X 2) (pale-yellowish white crystals, 101.6 g) . The total amount of the wet crystal was dissolved in acetone (200 mL) , and the mixture was stirred for 13 min. To a mixture of acetone (75 mL) and municipal water (375 mL) was added dropwise the acetone solution over 17 min, and municipal water (525 mL) was added dropwise over 15 min. After cooling to 100C or below, the mixture was stirred for about 2 hr. The crystals were collected by filtration, washed with cooled acetone/municipal water (1/5, 100 mL) , and then with municipal water (100 mL) to give pale-yellowish white crystals (103.2 g) of (R) -2- [ [ [3-methyl-4- (2, 2, 2-trifluoroethoxy) -2- pyridyl] methyl] sulfinyl]benzimidazole 1.5 hydrate; The wet crystals (6.9 g) obtained in Reference Example 1 were dried under reduced pressure at 900C for 1.5 hr to give (R) -2- [ [ [3-methyl-4- (2,2, 2-trifluoroethoxy) -2- pyridyl]methyl]sulfinyl]benzimidazole (brown crystals, 2.9 g) . 1H-NMR: 2.23 (3H,s), 4.37 (2H, q, J=7.8Hz) , 4.77 (IH, d, J=13.7Hz) , 4.87 (IH, d, J=13.7Hz) , 6.67 (IH, d, J=5.7Hz) , 7.26-7.33 (2H,m) , 7.45(lH,bs), 7.78(lH,bs), 8.34 (IH, d, J=5.6Hz) IR (vcirf1) : 3072, 2968, 1577, 1475, 1442, 1311, 1261, 1167 water content: 0.39% optical purity: 99.9%ee chemical purity: 97.9% (285 nm, HPLC area percent value) melting point (DSC) : 148.90C
Mixture of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methy l]thio]- 1 H- benzimidazole (50 grams) and toluene (400 ml) was heated to reflux temperature and water was removed by azeotropic distillation. The reaction mixture was cooled to room temperature under nitrogen atmosphere. Water (0.4 ml) and L(+)-diethyltatarate (22.4 grams) were added to the reaction mixture under nitrogen atmosphere. The reaction mixture was heated to 55-60C and stirred for 15 minutes. Titanium isopropoxide (14.4 grams) was added to the reaction mixture, stirred for 60 minutes at 55-60C and then cooled to 21-25C. Diisopropyl ethyl amine (11.8 grams) and cumene hydroperoxide (29.61 grams) were added to the reaction mixture and stirred for 2 hours at 20-250C. The reaction mixture was quenched with sodium thiosulphate solution and the layers were separated. The organic layer washed with sodium thiosulphate solution and water (100 ml) was added to it. Methyl tertiary butyl ether (200 ml) followed by cyclohexane (1 L) was added to the organic layer and stirred for 2 hours at 25-35C. The solid obtained was filtered and washed with methyl tertiary butyl ether. Acetone (250 ml) was added to the wet solid and stirred for 15 minutes at 25-35C. Water (750 m) was added to reaction mixture at 25-30C and stirred for 30 minutes. The solid obtained was filtered washed with water. Yield: 75 gramsChiral Purity by HPLC: 99.00 %; other isomer: 0.34%; sulfone: 0.49%; sulfide: 0.07%
Reference Example (1) Preparation of crude (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyll methyllsulfinyll-lH-benzimidazole (crude R-lansoprazole) of formula (I) 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridmyl]-methyl]thio]-lH- benzimidazole was dissolved in toluene. (+)-Diethyl tartrate was added and heated to 55-60C. To the solution was added titanium(IV)isopropoxide and stirred for 1 hour at 55-60C. Reaction mixture cooled to 25-30C and diisopropylethylamine was added over it. To the solution was added cumene hydroperoxide in toluene at 0 to-3C. Reaction mixture maintained for 3 hours. After completion of reaction, reaction mixture was quenched with 20% N,N dimethylamine solution followed by separation of aqueous layer. The separated aqueous was washed with dichloromethane. The pH of the aqueous layer was adjusted to 9.0-9.2 using acetic acid and extracted into toluene. Organic layer was concentrated to a residue. To the residue, dichloromethane was added over it to dissolve the gummy material followed by addition of isopropyl ether. After stirring for 2 hours, the product was filtered and dried under vacuum at 45C for 12 hours. (Alternatively the gummy material was dissolved in toluene/IPE followed to addition of diol reagent and optionally water to yield diol solvate of dexlansoprazole)HPLC purity: 99.00 %; Sulphone content: 0.84 %; Chiral purity: -97 % (e,e)
Example 1 : Preparation of Amorphous Form of Sodium Salt of Dexlansoprazole2-({ [3-Methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}sulfanyl)-lH- benzimidazole (900 g), L-diethyl tartarate (157.5 g), titanium isopropoxide (108.54 g) and toluene (9 L) were added together, heated to 45 C to 50C and stirred for 1.5 hours at 45 C to 50C, followed by cooling to 20C to 25C. Diisopropylethylamine (55.8 g) was added to the reaction mixture at 20C to 25C and stirred for 5 minutes to 10 minutes. Cumene hydroperoxide (508.32 g) was added drop-wise in 1.0 hours at 20C to 25C. Aqueous sodium thiosulphate solution (450 g in 450 mL deionized water) was added in 10 minutes to 15 minutes at 20C to 25 C. The mixture was stirred for 5 minutes to 10 minutes and filtered through a Celite bed and washed with toluene (900 mL). The reaction mixture was allowed to settle followed by separation of the toluene layer. The toluene layer was added drop-wise into pre-heated (65C to 70C) aqueous sodium hydroxide solution (203.4 g sodium hydroxide in 7.2 L de-ionized water) in 0.5 hours. The mixture was stirred for 2 hours at 65 C to 70C, cooled to 20C to 25C, stirred for 10 hours to 12 hours, filtered and washed with hot toluene (500 mL). The wet solid obtained was mixed with de-ionized water (4.5 L) and heated to 60C to 65C. Toluene (4.5 L) was added to the mixture and stirred at 60C to 65C for 1 hour. The mixture was cooled to 30C to 35C and the solid was filtered. The wet solid obtained was washed with toluene (500 mL) at 30C to 35 C. De-ionized water (4.5 L) was added to the wet filtered solid and heated to 60C to 65 C. Toluene (4.5 L) was added to the mixture, stirred at 60C to 65 C for 1 hour and cooled to 30 C to 35C. The wet solid was filtered and washed with toluene (500 mL) at 30C to 35C. The solid was dried under vacuum at 50C to 55C for 10 hours to 12 hours to obtain the title compound as amorphous solid.Yield: 51.8%Chiral purity: 99.02%Chromatographic purity: 98.58%Moisture content: 1.87%
With titanium(IV) isopropylate; diethyl (2R,3R)-tartrate; Cumene hydroperoxide; N-ethyl-N,N-diisopropylamine; In toluene; at -3 - 0℃; for 3h; 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyl]thio]-1H-benzimidazole was dissolved in toluene. (+)-Diethyl tartrate was added and heated to 55-60 C. To the solution was added titanium(IV)isopropoxide and stirred for 1 hour at 55-60 C. Reaction mixture cooled to 25-30 C. and diisopropylethylamine was added over it. To the solution was added cumene hydroperoxide in toluene at 0 to -3 C. Reaction mixture maintained for 3 hours. After completion of reaction, reaction mixture was quenched with 20% N,N dimethylamine solution followed by separation of aqueous layer. The separated aqueous was washed with dichloromethane. The pH of the aqueous layer was adjusted to 9.0-9.2 using acetic acid and extracted into toluene. Organic layer was concentrated to a residue. To the residue, dichloromethane was added over it to dissolve the gummy material followed by addition of isopropyl ether. After stirring for 2 hours, the product was filtered and dried under vacuum at 45 C. for 12 hours. (Alternatively the gummy material was dissolved in toluene/IPE followed to addition of diol reagent and optionally water to yield diol solvate of dexlansoprazole) [0074] HPLC purity: 99.00%; Sulphone content: 0.84%; Chiral purity: ?97% (e,e)
8 g With titanium(IV) isopropylate; diethyl (2R,3R)-tartrate; Cumene hydroperoxide; water; N-ethyl-N,N-diisopropylamine; In toluene; at -5 - 75℃; (+)-diethyI L-tartrate (3.619 g /0.0175 moles), titanium (IV) isopropoxide (2.415 g / 0.0084 moles) and water (0.06 g / 0.0033 moles) were added to toluene (75 ml) at 25C to 30C. The solution was stirred for 15 minutes and 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyI]- methyl]thio]-lH-benzimidazoIe (10 g / 0.02829 moles) was added. The reaction mass was heated to 70C to 75C, maintained for 5 minutes and cooled to 25C to 30Cover 30 minutes. Diisopropylethylamine (2.342 g / 0.0181 moles) was added, stirred for 30 minutes and then cooled to -5C to 0C. A solution of 80% cumene hydroperoxide (14.788 g/ 0.0971 moles) in toluene (10 ml) was added at -5C to 0C over 60 minutes. The reaction was stirred for 2 to2.5 hours at -5C to 0C and quenched with 5% aqueous KOH solution (50 ml) maintaining temperature at about -5C to 0C. The temperature of the reaction mass was raised to 25C - 30C and methanol was charged (25 ml). The reaction mass was basified to a pH of 12.5 to 13.0 with 20% aqueous KOH solution and stirred for 10 minutes at 30C to 35C. The aqueous layer was separated at 30C to 35C and the organic layer was extracted with a mixture of 5% aqueous KOH (30 ml) and methanol (15 ml) at 30C to 35C. The aqueous layers were combined and washed with DC (3 x 30 ml) at 30C to 35C. The pH of the aqueous solution was adjusted to 8.5 to 9.5 with 20% acetic acid at 30C to 35C. The solid was extracted in ethyl acetate (2 x 50 ml). The organic layers were combined together and dried over anhydrous sulphate. The solvent was distilled completely under vacuum at 45C and stripped off with ethyl acetate (2 x 100 ml). The residue was dissolved in ethyl acetate (37.5 ml). Glycerol (2.5 g) was added and reaction mass was diluted with ethyl acetate (75 ml). The reaction mass was heated to 43C to 45C and n-heptane (200 ml) was added slowly at 40C to 45C. The reaction mass was cooled to 25C to 30C, and stirred for 30 minutes. The solid was isolated by filtration, washed with n-heptane (20 ml) and dried under vacuum at 25C to 30C for 8 to 10 hours. Yield: 8.0 g HPLC purity: 98.17%
Reference Example 3 Production of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole (R(+)-lansoprazole) In a nitrogen atmosphere, 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]thio]benzimidazole (20.0 g, 0.057 mol), toluene (100 ml), water (55 mg, 0.0031 mol as based on total water content) and diethyl (+)-tartrate (2.12 ml, 0.012 mol) were mixed and stirred at 50 to 55 C. for 30 minutes. After titanium (IV) isopropoxide (1.66 ml, 0.0057 mol) was added to the mixture in a nitrogen atmosphere, the mixture was stirred at 50 to 55 C. for 1 hour. After diisopropylethylamine (3.25 ml, 0.019 mol) was added to the resulting mixed liquor under cooling in a nitrogen atmosphere, cumene hydroperoxide (30.6 ml, content 82%, 0.17 mol) was added at 0 to 5 C., followed by 3.5 hours of stirring at 0 to 5 C., to cause the reaction. Analysis of the reaction liquor by HPLC (column: CHIRALCEL OD (Daicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol=90/10, flow rate: 1.0 ml/min, detection wavelength: 285 nm) detected a sulfide at 1.32% and a sulfone at 1.81% as related substances in the reaction liquor, with no other related substances detected. The enantiomer excess rate of the title compound in said reaction liquor was 96.4% ee.
With titanium(IV) tetraethanolate; diethyl (2R,3R)-tartrate; dihydrogen peroxide; In water; toluene; at 60℃; for 1.16667h;Green chemistry; 1.2 mol 1-methylimidazole with 0.6 mol of 1,2-dibromoethane in 200 ml in chloroform at 80 C were stirred and reacted for 2h. Added to the above reaction solution was 0.4 mol phosphotungstic acid. Maintain the temperature, continue the reaction 1h, produce white turbid, filtration and separation, 60 C vacuum drying 6h to obtain white solid catalyst, phosphotungstic acid · 1,2-di(1-methylimidazol-3-yl)ethane. 0.1 mol lansoprazole sulfide and 0.05 mol of L-(+)-tartaric acid diethyl ester in 150 ml in toluene, 60 C under stirring, add dropwise 0.02 mol tetraethyl titanate. Maintain temperature and stir for 30min; then add 0.5g the above catalyst. After stirring 10 min, maintain at 60 C. Add dropwise 4g aqueous hydrogen peroxide. After adding dropwise, continue maintaining temeprature and reacting for 30min, by chromatographic detection reaction is complete.Filtering out the solid catalyst. Mother liquor by adding 50 ml of water, after stirring, the stirring by adding 100 ml petroleum ether, separating solid, using volume ratio 3:1 acetone - water system re-crystallization, to obtain dexlansoprazole; HPLC purity 99.9%, has been detected in the sulfones impurity, dexlansoprazole e.e. Value is 99.8%.
With titanium(IV) tetraethanolate; diethyl (2R,3R)-tartrate; dihydrogen peroxide; In water; toluene; at 60℃; for 1.16667h;Green chemistry; 1.2 mol 1-methylimidazole with 0.6 mol of 1,2-dibromoethane in 200 ml in chloroform at 80 C under stirring were reacted for 2h. Added to the above reaction solution was 0.4 mol of phosphomolybdic acid, maintain the temperature, continue the reaction for 1h, produce white turbid, filtration and separation, 60 C vacuum drying 6h to obtain white solid catalyst, phosphomolybdic acid · 1,2-di(1-methylimidazol-3-yl)ethane. 0.1 mol lansoprazole sulfide and 0.05 mol of L-(+)-tartaric acid diethyl ester in 150 ml toluene. Under 60 C stirring, add dropwise 0.02 mol tetraethyl titanate. Maintain temperature while stirring for 30min; then add 0.5g of above catalyst. After stirring 10min, maintain at 60 C. Add dropwise 4g aqueous hydrogen peroxide. After adding dropwise, continue maintaing temperature and react for 30min, by chromatographic detection reaction is complete.Filtering out the solid catalyst. Mother liquor by adding 50 ml of water, after stirring, the stirring by adding 100 ml petroleum ether, separating solid, using volume ratio 3:1 acetone - water system re-crystallization, to obtain dexlansoprazole; HPLC purity 99.2%, has been detected in the sulfones impurity, dexlansoprazole e.e. Value is 99.8%.
A 30g (85mmol) of 2 - [[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] thio] Benzimidazole and 6.28 g (22%mol)of N, N'-dibenzyl- (R, R) -tartaric acid diamide were mixed into 150ml toluene then heated to 70 C and stirred for 15 minutes. Then drop added 3.83 ml (15% mol) 0.09 ml of titanium tetraisopropoxide under the maintain temperature and insulation stirring for 1.5 hour, then add 229 mg of water , and insulation stirring for 1.5 hour. Then, 2.36 ml of diisopropylethylamine was added and the mixture was stirred for 30 minutes. Then, dropwise added 30.6 ml of phenyl isopropyl hydroperoxide. The reaction was carried out at 30 C for 2 hours. By HPLC detection, The enantiomeric excess was 98.6% and the sulfoxide content was 96.0% and contained 1.9% thioether and 2.0% sulfone. [0122] A 30%100 ml aqueous sodium thiosulfate solution into the above mentioned reaction solution added, and the mixture was stirred for 15 minutes. The toluene layer was separated and the aqueous layer was back-extracted twice with toluene. The combined toluene layer was added to a 1.2 liter 12.5% aqueous ammonia solution and stirred for about 2.5 hours the amino water layer was separated. The 12.5% ammonia water was stirred and washed three times with toluene. After mixing all the aqueous ammonia, adjust the pH of the solution to about 8.0, stir for 2 hours. Filtration, white solid washed with with ice water, suction dry and wet weight was about 68 grams. Then again it was Washed with distilled water, filtered, drained, wet weight of about 53 grams. [0123] The above white solid was dissolved in 400 ml of acetone, dried, concentrated to 280 ml, then it was added dropwise to mixture solvent of 140 ml of acetone and 700 ml of water, then 560 ml of water was added and insulation stirring was carried out for 2h. Filtered and dried in vacuo at 35 C to give 20.9 g of a white solid. HPLC analysis of enantiomeric excess of 100%, sulfoxide content of 99.8%, sulfone content of 0.2%.
0.1 moles of Lansoprazole Sulfide and 0.05 mol of L-(+)-tartaric acid diethyl ester were dissolved in 150 mL of toluene. At 60 C with stirring, 0.02 mol of tetraethyl titanate was added dropwise and incubated for 30 min. Followed by the addition of 0.5g of the above catalyst , and after stirring for 10min maintain the reaction temperature at 60 C. dropping addition of 4g hydrogen peroxide, then after the completion of addition, continuous incubation reaction for 30min, and through the chromatographic reaction is complete. The solid catalyst was filtered off. 50 mL of water was added to the mother liquor. After stirring, 100 mL of petroleum ether was added to the mixture. The solid was separated and recrystallized from an acetone-water system with a volume ratio of 3: 1 to give lansoprazole; HPLC purity 99.3%, sulfone impurity 0.1% lansoprazole e.e. value was 99.8%.
Example 2, Under nitrogen protection,2-methyl-4- (2,2,2-trifluoroethoxy) pyridyl) methyl] -thio] -1H-benzimidazole (4.5 kg, 12.7 mol) ,Toluene (22 L) and L - (+) - diethyl tartrate (958 mL, 5.6 mol) were mixed.Under nitrogen protection,Titanium tetraisopropoxide (7.47 L, 2.53 mol) was added at 50 C to 60 C,The mixture was stirred for 30 minutes.Diisopropylethylamine (0.733 L, 4.44 mol) was added at room temperature,(6.88 L, 37.5 mol) was added dropwise at -5 C to 5 C, and the mixture was stirred at room temperature for 1.5 hours.In the above reaction solution,Adding 30% aqueous sodium thiosulfate solution,Decomposition of excess cumene peroxide.Separation of organic phase,Add water (4.5 L) in turn,Petroleum ether (60 to 90 C) (13.5 L),Tert-butyl methyl ether (18 L) and petroleum ether (27 L),Stirring crystallization.filter,Washed with tert-butyl methyl ether-toluene (4: 1) (4 L)You have the R-lansoprazole.
3.4 kg 1) Under the nitrogen atmosphere, the 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]thio]benzo imidazole (4.5 kg, 12.7 muM, containing 1.89 g water), toluene (22 L), water (25 g, 1.39 muM, the total amount of water 1.49 muM) and (+) - tartaric acid diethyl (0.958 L, 5.6 muM) mixing, in the 50 to 60 C conditions, under the nitrogen atmosphere to the above is added in the mixture (IV) [...] (0.747 L, 2 . 53 muM), and at this temperature the mixture stirring 30 minutes. In under nitrogen, the same temperature will be diisopropyl ethylamine (0.733 L, 4 . 44 muM) is added to the mixture and, in the -5 to 5 C lower, the cumene hydrogen peroxide (6.88 L, content of 82%, 37.5 muM) adding, the mixture in the -5 to 5 C under stirring 1.5 hours, thereby obtaining a reaction mixture. (2) In the helium atmosphere, to the reaction mixture (1) is added in 30% aqueous solution of sodium thiosulfate (17 L), so to decompose the remaining cumene hydrogen peroxide, the mixture is dispensed, the obtained organic layer are added into water (4.5 L), heptane (13.5 L), tert-butyl methyl ether (18 L) and heptane (27 L). The mixture at 10 C under stirring to make its crystallization, separation of tertiary butyl methyl ether and the crystal and mixed solution of toluene (tert-butyl methyl ether: toluene=4:1) (4 L) washing, to obtain (R)- type wet crystal. (3) Stirring and the above-mentioned (2) wet crystal of acetone (20 L) suspension dropwise added to acetone (7 L) and water (34 L) in the mixed solution, then add water (47 L), in about 10 C under stirring compound, and separate the precipitated crystalline, water - acetone (acetone: water=1:3) (4 L) and water (12 L) washing, the obtained (R)- configuration wet crystal. (4) The above-mentioned (3) the obtained wet crystal is dissolved in ethyl acetate (45 L) and water (3 L) in, then distribution, filter the organic layer in a small amount of insolubles, then adding triethylamine (0.2 L), the pressure of the mixture, to obtain 7 L liquid, in 50 C lower, added to the concentrate in methanol (2.3 L), 12.5% ammonia (23 L), then the 50 C lower tertiary butyl methyl ether (22 L) to carry out the distribution. Then added to the organic layer in the 12.5% ammonia (11 L) distribution (this operation is repeated a plurality of times). The mixed layer, and add ethyl acetate (22 L), then adding acetic acid dropwise under cooling conditions, adjust the pH to 8. After the solution is distributed, ethyl acetate (11 L) extracting the aqueous layer, the combined organic layer, and 20% brine (11 L) wash. Add triethylamine (0.2 L), the organic layer and concentrated under reduced pressure. In the concentrate and then to the adding acetone (5 L), once again the pressure of the mixture, the concentrate is dissolved in acetone (9 L) in, and this solution dropwise added to acetone (4.5 L) and water (22.5 L) in the mixture, then dropwise adding water (18 L), in about 10 C lower and agitating the mixture. Separating the precipitated crystal, and sequentially for cold acetone - water (1:3) (3 L) and water (12 L) washing, shall be (R)- configuration wet crystal. (5) The above-mentioned (4) the obtained wet crystal is dissolved in ethyl acetate (32 L), then separating the aqueous phase, the organic layer is concentrated under reduced pressure to obtain the 14 L liquid, added to the residue in ethyl acetate (36 L) and active carbon (270 g), stirring compound, filter and remove the active carbon, the filtrate is concentrated under reduced pressure to obtain about 14 L liquid. In the about 40 C added dropwise to the residue under in heptane (90 L), at the same temperature under stirring for about 30 minutes, and in the separating crystal 40 C ethyl acetate - heptane (1:8, 6L) washing, drying to obtain light brown granular target compound (3.4 kg).

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  • 4
  • [ 103577-40-8 ]
  • [ 99464-83-2 ]
  • cyclohexyl 1-[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzimidazol-1-yl]ethyl carbonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In acetonitrile; at 69℃; for 34h; To a solution (50 mL) of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]benzimidazole (2.12 g) and 1-chloroethyl cyclohexylcarbonate (1.86 g) in acetonitrile were added sodium iodide (0.45 g) and potassium carbonate (1.66 g) and the mixture was stirred at 60C for 34 hrs. Acetonitrile was evaporated under reduced pressure and the residue was extracted with ethyl acetate (150 mL) and water (50 mL). The organic layer was separated and washed with 10% aqueous sodium sulfite solution (30 mL). It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with ethyl acetate:hexane=1:1) to give cyclohexyl 1-[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzimidazol-1-yl]ethyl carbonate (1.00 g) as an amorphous form.1H-NMR(CDCl3): 1.08-1.98 (10H,m) , 1.86 (3H,d,J=6.5Hz) , 2.35 (3H, s), 4.44(2H,q,J=7.5Hz), 4.54(1H,m), 4.86(2H,s), 6.65(1H,d,J=5.8Hz), 6.86(1H,q,J=6.5Hz), 7.17-7.29(2H,m), 7.56-7.72 (2H,m) , 8.36(1H, d, J=5.8Hz).
  • 5
  • [ 127337-60-4 ]
  • [ 583-39-1 ]
  • [ 103577-40-8 ]
YieldReaction ConditionsOperation in experiment
97% With sodium hydroxide In methanol; water at 10 - 35℃; for 4h; 1 Example 1 Synthesis of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-pyridinyl]methyl)hio]-1H-benzimidazole (Lansoprazole sulfide) To a stirred suspension of 100 g of 4- (2, 2, 2)-trifluoroethoxy-3-methyl-2-chloromethyl-pyridine hydrochloride and 54.4 g of 2-mercapto-benzimidazole at 10C in 500 ml of methanol, 125.6 g of a 30% by weight aqueous solution of NAOH are added at such a rate as to maintain the internal temperature within 35C. The temperature of the mixture is then brought to 20-25C and is kept for additional 4 hours in these conditions. Then 1000 ml of deionized water are added, causing the thickening of the precipitate. The pH of the suspension is adjusted to 9 with HC1 33% in water and the mixture is then cooled to 5C and maintained for 1 hour. The precipitate obtained is filtered and washed with water to obtain 235 g of a wet product which once dried weighs 124.5 g and has an HPLC purity > 99%. Yield 97%.
97.5% Stage #1: Benzimidazol-2-thiol With sodium hydroxide In water at 30 - 40℃; Large scale reaction; Stage #2: 3-methyl-4-(2,2,2-trifluoroethoxy)-2-chloromethylpyridine hydrochloride In water at 25 - 30℃; for 4 - 5h; Large scale reaction;
97% With sodium hydroxide In methanol at 70℃; for 2h; Large scale; In a 50L reactor was added 2-mercaptobenzimidazole 0.9kg,2-chloromethyl-3-methyl-4- (trifluoroethoxy) pyridine hydrochloride, 1.68 kg of methanol and 6 L of methanol,Heated to 70 ° C reflux,A solution of 0.8 kg of methanol (6.5 L) of sodium hydroxide was added dropwise under reflux, and the mixture was added dropwise over 2 h,TLC to test the end of the reaction, concentrated to remove methanol, add 7L water at room temperature for 1h,Filtered, washed with water to pH = 7 and dried to give a white solid (2) 1.74 kg, yield 97%;
96% With pyrographite; sodium hydroxide In water at 20℃; Large scale; 1.1 (1) Preparation of Compound III Put purified water (455L) at room temperature,Sodium hydroxide (22.4 kg) and Compound 1 (35 kg) were put into a reaction vessel,Then 1 to 1.5 hours after the addition of activated carbon compound 2,The reaction was then held at room temperature for 1.5 hours,Centrifuge, rinse with 35 L water, spin-dry for about 1 hour and dry.Then the dry material and toluene (315L) into the reactor, warmed to reflux, Maintain reflux for about 20 minutes and cool to room temperature for about 30 minutes. Centrifuge,Rinse with 35 L of water, spin-dry for about 1.5 hours and dry to give compound 3. Yield of about 96.0%;
95% With sodium hydroxide In ethanol at 20℃; for 2h; 1.1 (1) (IV) Preparation Sodium hydroxide (20.0 g, 0.5 mol) Into ethanol (95%, 0.5L)After stirring and dissolving, Compound II (34.1 g, 0.23 mol)Compound III (62.7 g, 0.23 mol),The reaction was stirred at room temperature for 2 h.Steamed about 400mL of ethanol,Water (0.46 L) was added to the residue,After stirring for 1h at room temperature,The filter cake was washed with water (300 mL x 3).The resulting solid was washed with ethyl acetate (300ml) washed for 1 h and filtered with suction.Cake at 45 drying,The resulting white powdery solid IV (76.32g), yield 95%.
88% With sodium carbonate In methanol Reflux; 10 Example 10 Preparation of anhydrous 2[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridinyllmethyllthiol-lH-benzimidazole of formula (II)(Π) To a stirred suspension of (2-chloromethyl)-3-methyl-4-(2,2,2- trifluoroethoxy)pyridine hydrochloride (250g) and sodium carbonate in methanol, 2-mercapto-benzimidazole (142g) was added and heated to reflux temperature. After completion of the reaction, reaction mass was cooled, DM water was added over to the reaction mixture under stirring. The obtained 2[[[3-methyl-4-(2,2,2- trifluoroethoxy)-2-pyridinyl]methyl]thio]-lH-benzimidazole was filtered out from the solution mixture under vacuum and washed with water. The obtained wet product was taken in toluene and heated to reflux under azeotropic condition to remove water. After complete removal of moisture, cooled to 0-5°C and the solid obtained was filtered and dried under vacuum at 85-90° C for 12 hours. The isolated product contains less than 0.15% moisture content.Dry weight: 255-280g; Yield: 80-88%; HPLC Purity: NLT 99%
88% With sodium carbonate In methanol Reflux; 10 Example 10 Preparation of anhydrous 2[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzimidazole of Formula (II) To a stirred suspension of (2-chloromethyl)-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine hydrochloride (250 g) and sodium carbonate in methanol, 2-mercapto-benzimidazole (142 g) was added and heated to reflux temperature. After completion of the reaction, reaction mass was cooled, DM water was added over to the reaction mixture under stirring. The obtained 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzimidazole was filtered out from the solution mixture under vacuum and washed with water. The obtained wet product was taken in toluene and heated to reflux under azeotropic condition to remove water. After complete removal of moisture, cooled to 0-5° C. and the solid obtained was filtered and dried under vacuum at 85-90° C. for 12 hours. The isolated product contains less than 0.15% moisture content. Dry weight: 255-280 g; Yield: 80-88%; HPLC Purity: NLT 99%
88% With sodium hydroxide In ethanol for 2h; Reflux; 16 Preparation of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]thio]-1H-benzimidazole In a 250 mL three-necked flask, 2-Chloromethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine hydrochloride (11 g,40 mmol), 2-mercaptobenzimidazole (9 g, 60 mmol) and sodium hydroxide (6 g, 150 mmol) were dissolved in ethanol (80 mL)The reaction was refluxed for 2 hours. Cooled to room temperature, filtered, and the filtrate evaporated 2/3 of the ethanol. Cooled to 0 ° C and filtered to give a white solid which was dried to give 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]thio]-1H-benzimidazole, product yield 88%.
85% With sodium carbonate for 0.0333333h; Microwave irradiation;
80% With sodium hydroxide In water; acetone for 0.75h;
With sodium hydroxide In dichloromethane; water at 40℃; for 2h; 1 EXAMPLE 1 2.68 g of 2-chloromethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine.HCl, 1.376 g of 2-mercaptobenzimidazole, and 0.134 g of benzyl triethyl ammonium chloride as an interphase transfer catalyst were mixed in 24 ml of dichloromethane. 0.9534 g of NaOH (40%)/12 ml water mixture solution was dripped into the above mixture while stirring. The temperature of the resulting solution was raised to 40° C. for about 2 hours. Then, dichloromethane was removed from the mixture under a reduced pressure. The solid obtained was stirred with 50 ml of water, and filtered to obtain 3.28 g of solid Lansoprazole precursor: 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylthio]-1H-benzimidazole. At room temperature, 3.28 g of the above precursor, 0.1625 g of polyethylene glycol-400 as an interphase transfer catalyst, and 0.3936 g of Mo(acac)2 as an oxidation catalyst were mixed in 45 ml of isopropanol (abbreviated as IPA). To the resulting mixture 3.06 g of 35% H2O2 aqueous solution was added in 5-10 minutes. The reaction was carried out for about one hour, and then 60 ml of water was added, and the reaction was continued for another one hour while stirring. Finally, the precipitate formed was filtered, water washed, and dried to obtain Lansoprazole with a yield of about 88% (HPLC purity >98%).
Stage #1: 3-methyl-4-(2,2,2-trifluoroethoxy)-2-chloromethylpyridine hydrochloride; Benzimidazol-2-thiol With sodium hydroxide In methanol; water for 0.5h; Industry scale; Stage #2: With hydrogenchloride In methanol; water 1 EXAMPLE 1 [Production Method of 2-(((3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl)methyl)thi o)benzimidazole monohydrate] 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyri dine (87.4 kg) was dissolved in methylene chloride (655 L), thionyl chloride (41.1 L) was added to the solution, and the mixture was heated under reflux for about 60 minutes. Water (183 kg) was added to the mixture, and the mixture was concentrated. To the residue were added methanol (656 L) and 2-benzimidazolethiol (59. 8 kg), then the pH was adjusted to 11.0 - 11.5 with a 30% aqueous solution of sodium hydroxide, and the mixture was reacted for 30 minutes. To the reaction solution was added water (524 kg) and the mixture was recrystallized. pH was adjusted to 8.5 - 10.0 with 35% hydrochloric acid, and then the precipitated crystals were filtered. The crystals were washed with an aqueous methanol solution (methanol:water = 5:5 (weight ratio)) and water, and then dried to obtain 141.6 kg of 2-(((3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl)methyl)thi o)benzimidazole monohydrate as white crystals (yield: 96.5%).
With potassium carbonate In water; acetone at 40 - 60℃; for 4 - 5h; 3 A saturated solution of potassium carbonate (800 gm) in water (1.0 Lit) was added drop-wise to a mixture of 2-chloromethyl-3-methyl-4-(2,2,2-trifluroethoxy) pyridine hydrochloride (1.0 Kg) and 2-mercaptobenzimidazole (560 gm) in aqueous acetone (9 Lit, 10%). The reaction mixture was heated for 4-5 hours at 40 - 600C and acetone (about 5 Lit) was distilled off under reduced pressure from the reaction mass. Water (8.0 Lit) was added to the resultant mass and the separated product was filtered, washed with water and dried to get the title compound. Yield: 1.3 Kg HPLC Purity: 99.8% Moisture content: 4.8%
With sodium hydroxide In water at 25 - 35℃; for 2h; 19 2-(chloromethyl)-3-methyl-4-(2,2,2-trifluoroethoxy)pyridinehydrochloride(96.49 grams) was dissolved in water (600 ml) and subjected to carbon treatment. The solution was filtered through high flow. The filtrate was added to a mixture of 2-mercarptobenzimidazole (50 grams), sodium hydroxide (32 grams) and water (600 ml) at 25-35°C. The reaction mixture stirred for 2 hours and the obtained solid was filtered, washed with water. The obtained wet solid was purified from toluene to get the title compound. Yield: 106 grams
With sodium hydroxide In methanol for 5h; Reflux;
With sodium iodide; sodium hydroxide In ethanol; acetone for 1.5h; Reflux;
With sodium hydroxide In methanol at 40 - 50℃; for 2h; Industrial scale; 8 (a) In the clean glass dad, add 9L anhydrous methanol, add 0.6kg under stirring(Raw material A) and 0.5kg sodium hydroxide solid, heated to 40 ~ 50 ° C, temperature control, stirring dissolved, then add lkg2-chloromethyl-3-methyl-4- (2,2,2, trifluoroethoxy) pyridine hydrochloride (raw material B) dissolved, reaction 2h, add appropriate amount of purified water, cool to room temperature, filter, washed with purified water, dried, 45 ° C Dried in vacuo to give intermediate C.
2800 g With sodium hydroxide In methanol at 60 - 70℃; for 2h; Autoclave; Large scale; 1.1 The preparation method of the right lansoprazole comprises the following steps: Step 1: Preparation of Lansoprazole Sulfide: To 50 L glass reactor by adding 16675 ml methanol, open stirring ice bath cooling. Slowly adding sodium hydroxide 1256 g, and stirring to dissolve completely. Temperature control 35 °C the following. Adding 2 - mercapto benzimidazole 1256 g, blue rope chloride hydrochloride 2300 g, and heating to reflux. 60 - 70 °C when, reacting at the beginning of the 2 hours. HPLC detection reaction finishes, started to cool off. The temperature is lower than 30 °C when, the filtration is started. Filtration is completed, the beginning of the filtrate is distilled under reduced pressure (50 - 60 °C). The evaporated methanol as the feeding volume of the 1/2 when, lowering the temperature to 25 - 30 °C. Adding 34500 ml water, precipitated white solid, stirring 30 minutes. Then adding washing a disk loading, vacuum 70 °C drying 5 h, shall be about 2800 g, yield by about 122%, content is about 80%, dry weight loss (%) ≤ 0.5%.
With sodium iodide; sodium hydroxide In ethanol; acetone for 1.5h; Reflux; Synthesis of Heterocyclic Sulfide (3) (0212) a N (0213) 2-Mercaptobenzimidazole (1.0 mmol), 2-(Chloromethyl)-3-methyl-4- (2,2,2- trifluoroethoxy)pyridine hydrochloride (1.0 mmol), NaOH (2.0 mmol) and Nal (0.033 mmol) were added to a ethanol and acetone mixed solvent (v:v, 3:1 ). After refluxing for 1.5 hours, cool down to the room temperature. Filtrate the reaction mixture and dry the residues on rotary evaporators, then directly load the residues onto a short silica gel column, followed by gradient elution with Hexane/EtOAc mixture (30/1-15/1 ratio). Removing the solvent in vacuo, afforded the desired products.
With sodium hydroxide In methanol at 20 - 35℃; 6 Example 2 General procedure: Dissolve 23.5 g of ilaprazole chloromethylpyridine hydrochloride in 70 ml of methanol for use.At room temperature, dissolve 20.5 g of ilaprazole 2-mercaptobenzimidazole and 8.5 g of sodium hydroxide in 110 ml of methanol. Stir to dissolve them. After the dissolution is complete, add the above-mentioned preparation at a controlled time of 10 minutes to 30 minutes. Methanol solution, heated to 35°C after addition, reacted for 3 h, TLC detected that the reaction was complete.After the reaction is complete, slowly add 150 ml of water preheated to 35°C for the first crystallization to the reaction solution for 20 minutes to 30 minutes, keep it warm and stir for 45 minutes; then slowly add it to the reaction solution for 10 minutes to 15 minutes. Use 45 ml of purified water preheated to 35°C for crystals. After the addition, cool to 10°C, stir for 45 min, and filter; wash the filter cake with purified water to neutrality and place it at 45°C to vacuum dry 18 h.The HPLC result of the obtained ilaprazole sulfide was similar to that in Example 1, and the moisture content was detected to be 1.3%

Reference: [1]Current Patent Assignee: ITALFARMACO SPA - WO2004/56803, 2004, A1 Location in patent: Page 7,8
[2]Location in patent: experimental part Gangula, Srinivas; Elati, Chandrasekhar R.; Neredla, Anitha; Baddam, Sudhakar R.; Neelam, Uday Kumar; Bandichhor, Rakeshwar; Dongamanti, Ashok [Organic Process Research and Development, 2010, vol. 14, # 1, p. 229 - 233]
[3]Current Patent Assignee: Zhang Defang; Zhang Yi - CN107056753, 2017, A Location in patent: Paragraph 0031; 0033
[4]Current Patent Assignee: SHANGHAI HUAYUAN MEDICINE TECH DEV - CN106866630, 2017, A Location in patent: Paragraph 0032; 0033; 0034; 0035; 0038
[5]Current Patent Assignee: CHANGSHA KANGPU LARGE PHARMACY - CN107141280, 2017, A Location in patent: Paragraph 0018; 0022; 0026
[6]Current Patent Assignee: ORCHID PHARMA LTD - WO2011/98938, 2011, A1 Location in patent: Page/Page column 17
[7]Current Patent Assignee: ORCHID PHARMA LTD - US2013/12714, 2013, A1 Location in patent: Paragraph 0072
[8]Current Patent Assignee: HAINAN WEIKANG PHARMACEUTICALS QIANSHAN; ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN107011252, 2017, A Location in patent: Paragraph 0115; 0116
[9]Location in patent: experimental part Sailu; Ramakrishna; Komaraiah; Reddy [Heterocyclic Communications, 2008, vol. 14, # 5, p. 363 - 366]
[10]Reddy, Ganta Madhusudhan; Mukkanti; Kumar, T. Laxmi; Babu, J. Moses; Reddy, Padi Pratap [Synthetic Communications, 2008, vol. 38, # 20, p. 3477 - 3489]
[11]Current Patent Assignee: SYN-TECH CHEM. &amp; PHARM. CO., LTD.; INDUSTRIAL TECHNOLOGY RESEARCH INSTITUTE - US2006/128964, 2006, A1 Location in patent: Page/Page column 3
[12]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1790647, 2007, A1 Location in patent: Page/Page column 14; 15
[13]Current Patent Assignee: WOCKHARDT LIMITED - WO2007/138468, 2007, A2 Location in patent: Page/Page column 12
[14]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2010/95144, 2010, A2 Location in patent: Page/Page column 27
[15]Zhou, Zhixu; Li, Linwei; Yan, Ning; Du, Lei; Sun, Changshan; Sun, Tiemin [Chemistry Letters, 2016, vol. 45, # 2, p. 110 - 112]
[16]Ye, Xinyi; Moeljadi, Adhitya Mangala Putra; Chin, Kek Foo; Hirao, Hajime; Zong, Lili; Tan, Choon-Hong [Angewandte Chemie - International Edition, 2016, vol. 55, # 25, p. 7101 - 7105][Angew. Chem., 2016, vol. 128, p. 7217 - 7221]
[17]Current Patent Assignee: YOUCARE PHARMACEUTICAL GROUP CO., LTD. - CN106928191, 2017, A Location in patent: Paragraph 0041
[18]Current Patent Assignee: LEPU MEDICAL TECHNOLOGY (BEIJING) COMPANY LIMITED - CN106946849, 2017, A Location in patent: Paragraph 0177-0181
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[20]Current Patent Assignee: LIVZON PHARMACEUTICAL GROUP INC. - CN113582973, 2021, A Location in patent: Paragraph 0053; 0058
  • 6
  • [ 1116-76-3 ]
  • [ 408332-88-7 ]
  • [ 103577-40-8 ]
  • [ 103577-45-3 ]
YieldReaction ConditionsOperation in experiment
With isopropylbenzene hydroperoxide;titanium(IV) isopropylate; In water; toluene; Example 17 Production of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole Under a nitrogen atmosphere, 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]thio]benzimidazole (5.00 g, 0.014 mol), toluene (35 mL), water (28 mg, 0.0016 mol, total water content 0.0017 mol) and diethyl (+)-tartrate (1.33 mL, 0.0078 mol) were mixed, and the mixture was stirred at 50 to 55 C. for 30 min. Under a nitrogen atmosphere, titanium(IV) isopropoxide (1.04 mL, 0.0035 mol) was added to the mixture, and the mixture was stirred at 50 to 55 C. for 1 hr. Under a nitrogen atmosphere and under cooling, to the obtained mixture was added <strong>[1116-76-3]trioctylamine</strong> (2.04 mL, 0.0047 mol) and then cumene hydroperoxide (3.78 mL, 0.021 mol) was added at 15 to 20 C. The mixture was reacted by stirring at 15 to 20 C. for 1.5 hr. The reaction mixture was analyzed by high performance liquid chromatography (conditions (A)). As a result, it was found that 5.4% of a sulfide form and 5.4% of a sulfone form were present as analogous substances in the reaction mixture, and other analogous substances were not present. The enantiomer excess of the title compound in the reaction mixture was 98.1% ee.
  • 7
  • [ 75-09-2 ]
  • [ 103577-66-8 ]
  • [ 134469-07-1 ]
  • lansoprazole sulphide hydrate [ No CAS ]
  • [ 103577-40-8 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; sodium hydroxide; thionyl chloride; In methanol; water; REFERENCE EXAMPLE 5 Production of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]-methyl]thio]benzimidazole monohydrate 49.9 g. of <strong>[103577-66-8]2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine</strong> was dissolved into 0.4 L. of methylene-chloride, followed by dropwise addition of 24 ml. of thionylchloride for about 30 minutes. The mixture was allowed to react at more than about 30° C. for about 1 hour. After completion of the reaction, 0.1 L. of water was added, and the methylenechloride was evaporated off under reduced pressure. The residue was dissolved into 0.4 L. of methanol, followed by addition of 34.2 g. of 2-benzimidazolethiol. To the mixture was added dropwise 60 ml. of a 30percent aqueous sodium hydroxide solution at about 25° C. for about 1 hour. The mixture was allowed to react at room temperature for about 0.5 hour. To the resultant mixture was added 0.3 L. of water, followed by stirring at below 10° C. for about 30 minutes. The resultant mixture was adjusted to a pH of about 9 with 35percent hydrochloric acid in order to precipitate crystals. The resultant crystals were collected by filtration and washed with, in turn, 0.1 L. of 50percent methanol and 0.2 L. of water. The obtained crystals were dried with hot air at below 50° C. to give 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]-methyl]thio]benzimidazole as white crystals. Yield:81.0 g. (96.7percent based on HYD).
  • 8
  • [ 3967-54-2 ]
  • [ 103577-40-8 ]
  • 4-[2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzimidazol-1-yl]-1,3-dioxolan-2-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: lansoprazole sulfide With sodium hydride In DMF (N,N-dimethyl-formamide) at 0℃; for 1h; Stage #2: 4-chloro-1,3-dioxolan-2-one for 1h; 27 Example 27; 4-[2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]-1,3-dioxolan-2-one Sodium hydride (736 mg, 60% in oil) was washed with hexane and added to a solution (20 mL) of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzimidazole (5.0 g) in N,N-dimethylformamide under ice-cooling. The mixture was stirred at 0°C for 1 hr. and chloroethylene carbonate (2.07 g) was added. The mixture was stirred for 1 hr. and extracted with ethyl acetate - water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 4-[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy}-2-pyridinyl]methyl]thio]-2H-benzimidazol-1-yl]-1,3-dioxolan-2-one as a colorless solid (3.0 g).
  • 9
  • [ 50893-36-2 ]
  • [ 103577-40-8 ]
  • ethyl 1-(2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzimidazol-1-yl]ethyl carbonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
A solution (50 mL) of 1-chloroethyl ethyl carbonate (1.52 g) and sodium iodide (4.48 g) in acetonitrile was stirred at 60°C for 1 hr. Acetonitrile was evaporated under reduced pressure and the residue was extracted with diethyl ether (60 mL). After filtration, the filtrate was concentrated under reduced pressure. To the residue were added 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]benzimidazole (1.57 g) and acetonitrile (30 mL) and the mixture was stirred at room temperature for 3 days. After concentration under reduced pressure, ethyl acetate (200 mL) and saturated aqueous sodium hydrogen carbonate (100 mL) were added to the residue to allow for extraction. The ethyl acetate layer was separated and washed with 10percent aqueous sodium sulfite solution (50 mL) and saturated brine (50 mL). It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with ethyl acetate:hexane=1:2) to give ethyl 1-(2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzimidazol-1-yl]ethyl carbonate (0.84 g) as a colorless solid.1H-NMR (CDCl3) : 1.25(3H,t,J=7.1Hz), 1.87(3H,d,J=6.3Hz), 2.35(3H,s), 4.05-4.25(2H,m), 4.40(2H,q,J=7.8Hz), 4.83(1H,d,J=13.5Hz), 4.88(1H,d,J=13.5Hz), 6.66(1H,d,J=5.4Hz), 7.19-7.28(2H,m), 7.60(1H,m), 7.70(1H,m), 8.36(1H,d,J=5.4Hz).
  • 10
  • [ 127337-60-4 ]
  • [ 103577-40-8 ]
  • [ 583-39-1 ]
  • [ 138530-94-6 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 3-methyl-4-(2,2,2-trifluoroethoxy)-2-chloromethylpyridine hydrochloride; Benzimidazol-2-thiol With sodium hydroxide In water at 25 - 35℃; Inert atmosphere; Stage #2: lansoprazole sulfide With water; (+)-Weinsaeure-diethylester In dichloromethane at 55 - 60℃; for 0.25h; Inert atmosphere; 20 2-(chloromethyl)-3-methyl-4-(2,2,2-trifluoroethoxy)pyridinehydrochloride (49 grams) was dissolved in water (300 ml) and subjected to carbon treatment. The solution was filtered through high flow. The filtrate was added to a mixture of 2-mercarptobenzimidazole (25 grams), sodium hydroxide (16 grams) and water (300 ml) at 25-35°C. The reaction mixture stirred and 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridinyl]methyl]thio]-lH-benzimidazole compound was extracted into methylene chloride. Water (0.4 ml) and L(+)-diethyltatarate (22.4 grams) were added to the methylene chloride layer under nitrogen atmosphere. The reaction mixture was heated to 55-60°C and stirred for 15 minutes. Titanium isopropoxide (14.4 grams) was added to the reaction mixture, stirred for 60 minutes at 55-60°C and then cooled to 21-25°C. Diisopropyl ethyl amine (11.8 grams) and cumene hydroperoxide (29.61 grams) were added to the reaction mixture and stirred for 2 hours at 20-250C. The reaction mixture was quenched with sodium thiosulphate solution and the layers were separated. The organic layer washed with sodium thiosulphate solution and water (100 ml) was added to it. Methyl tertiary butyl ether (200 ml) followed by cyclohexane (1 L) was added to the organic layer and stirred for 2 hours at 25-35°C. The solid obtained was filtered and washed with methyl tertiary butyl ether. Acetone (250 ml) was added to the wet solid and stirred for 15 minutes at 25-35°C. Water (750 m) was added to reaction mixture at 25- 300C and stirred for 30 minutes. The solid was filtered washed with water. Yield: 70 grams
  • 11
  • [ 103577-40-8 ]
  • [ 21286-54-4 ]
  • [ 1245448-54-7 ]
YieldReaction ConditionsOperation in experiment
To the solution of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl] sulfanyl]-lH-benzimidazole (100 g) present in methylenechloride (1500 ml) added potassium carbonate (58.5g) and heated the reaction mixture to reflux temperature. Added a solution of L-(-)-camphorsulfonyl chloride (106 g) in methylenechloride (500 ml) to the reaction mixture slowly at the same temperature. Stirred the reaction mixture for 6 hrs. Cooled the reaction mixture and added water to the reaction mixture. Separated the both aqueous and organic layers. Distilled off the solvent completely under reduced pressure from the organic layer. To the reaction mixture n-heptane (400 ml) was added and stirred for 45 min. Filtered the solid precipitated and washed with n-heptane. The title compound obtained as a crystalline solid. Yield: 220 grams
  • 12
  • [ 103577-66-8 ]
  • [ 103577-40-8 ]
  • 13
  • [ 4857-06-1 ]
  • [3-methyl-4-(2,2,2-trifluoroethoxy)pyridine-2-yl]methanethiol [ No CAS ]
  • [ 103577-40-8 ]
YieldReaction ConditionsOperation in experiment
88.1% Stage #1: [3-methyl-4-(2,2,2-trifluoroethoxy)pyridine-2-yl]methanethiol With potassium hydroxide In ethanol at 30℃; Stage #2: 2-Chloro-1H-1,3-benzimidazole In ethanol at 30℃; for 3h; 1-3 Example 2 Synthesis method of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridine] methylthio-1H-benzimidazole having structural formula (III): Ethanol 400mL was added to a reaction bottle of 1000mL, and then 3-methyl-4-(2,2,2-trifluoroethoxy)pyridine-2-yl] methanethiol 22.4 g (100 mmol) and potassium hydroxide 0.8 g (14 mmol), stirred at 30 °C, respectively, By constant pressure low liquid funnel drops add 19.8g 2-chlorobenzoimidazole (130mmol) and ethanol (100ml) of the mixed solution, add bicond 30 °C reaction for 3h, HPLC monitoring, after the reaction is completed to the reaction bottle dropwise add 0.1mol / L hydrochloric acid, process control temperature 10 °C, adjust pH to 6, add bicontrolled temperature 10 °C stirring crystallization for 3h. The above system is filtered through a Brinell funnel to obtain a filter cake, and the solid is washed with 67.2g of purified water to obtain wet products. Drying: temperature control 45 °C blast drying for 8h, product formula III 31.1g (88mmol), yield 88.1%, sampling detection.
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