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[ CAS No. 138530-94-6 ] {[proInfo.proName]}

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Chemical Structure| 138530-94-6
Chemical Structure| 138530-94-6
Structure of 138530-94-6 * Storage: {[proInfo.prStorage]}
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Product Details of [ 138530-94-6 ]

CAS No. :138530-94-6 MDL No. :MFCD13196699
Formula : C16H14F3N3O2S Boiling Point : -
Linear Structure Formula :- InChI Key :MJIHNNLFOKEZEW-RUZDIDTESA-N
M.W : 369.36 Pubchem ID :9578005
Synonyms :
Dexlansoprazole;T-168390;TAK-390;(+)-Lansoprazole
Chemical Name :(R)-2-(((3-Methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole

Calculated chemistry of [ 138530-94-6 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 25
Num. arom. heavy atoms : 15
Fraction Csp3 : 0.25
Num. rotatable bonds : 6
Num. H-bond acceptors : 7.0
Num. H-bond donors : 1.0
Molar Refractivity : 87.24
TPSA : 87.08 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) : -6.42 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.04
Log Po/w (XLOGP3) : 3.01
Log Po/w (WLOGP) : 5.49
Log Po/w (MLOGP) : 1.57
Log Po/w (SILICOS-IT) : 3.54
Consensus Log Po/w : 3.13

Druglikeness

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

Water Solubility

Log S (ESOL) : -4.07
Solubility : 0.0311 mg/ml ; 0.0000843 mol/l
Class : Moderately soluble
Log S (Ali) : -4.5
Solubility : 0.0116 mg/ml ; 0.0000314 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -6.84
Solubility : 0.0000529 mg/ml ; 0.000000143 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 3.4

Safety of [ 138530-94-6 ]

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 [ 138530-94-6 ]

* 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 [ 138530-94-6 ]
  • Downstream synthetic route of [ 138530-94-6 ]

[ 138530-94-6 ] Synthesis Path-Upstream   1~10

  • 1
  • [ 103577-40-8 ]
  • [ 138530-94-6 ]
YieldReaction ConditionsOperation in experiment
90%
Stage #1: With diethyl (2R,3R)-tartrate In water; toluene at 56 - 60℃; for 0.25 h; Large scale
Stage #2: With titanium(IV) isopropylate In water; toluene for 1 h; Large scale
Stage #3: With Cumene hydroperoxide; triethylamine In water; toluene at 10 - 15℃; for 2.5 h; Large scale
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 12.5percent ammonia water 27000 ml, cyclohexane 27000 ml, and stir for 5 minutes. Liquid, the organic layer using 12.5percent 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: 75percent, content about 99.5percent, optical purity of about 83percent, dry weight loss (percent) ≤ 0.5percent.
87.8%
Stage #1: With titanium(IV) isopropylate; C48H50N8O4 In N,N-dimethyl-formamide; toluene at 25 - 75℃; for 0.25 h;
Stage #2: With calcium peroxide; Cumene hydroperoxide; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide; toluene at -10 - 58℃; for 0.533333 h;
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 15percent 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 7.5percent 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 10percent 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 0.05percent 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 87.8percent, mp 143-145 ° C, optical purity ee value of 99.9percent.
87.8% With dihydrogen peroxide; triethylamine In tetrahydrofuran; water at 15 - 20℃; for 2 h; 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;25percent 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: 99.84percent, sulfone content: 0.62percent, eepercent value: 99.8percent);The catalyst was removed by filtration using a microporous membrane having a pore diameter of 0.45 μm; 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 87.8percent, purity was 99.85percent, eepercent was 99.9percent, sulfone content was 0.02percent),
68.1%
Stage #1: With D-tartaric acid monobenzyl ester benzylamine In water; toluene at 60℃; for 0.5 h;
Stage #2: With titanium(IV) isopropylate In water; toluene for 1 h;
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 80percent CHP 6. 0ml,The reaction was carried out at 0-5 ° C for 5 h.After completion of the reaction, 10 ml of 30percent 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 68.1percent, and the enantiomeric excess 99. 7percent.
99.9 % ee
Stage #1: With titanium(IV) isopropylate; diethyl (2R,3R)-tartrate In water; toluene at 50 - 60℃; for 0.5 h; Inert atmosphere
Stage #2: With Cumene hydroperoxide; N-ethyl-N,N-diisopropylamine In water; toluene at -10 - 10℃; for 4 h; Inert atmosphere
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 82percent) was added at -100C to 1O0C, and the mixture was stirred at -100C to 1O0C for 4 hr to give a reaction mixture. 25percent 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: 0.39percent optical purity: 99.9percent ee chemical purity: 97.9percent (285 nm, HPLC area percent value) melting point (DSC) : 148.90C
~ 97 % ee
Stage #1: With titanium(IV) isopropylate; diethyl (2R,3R)-tartrate In toluene at 55 - 60℃;
Stage #2: With Cumene hydroperoxide; N-ethyl-N,N-diisopropylamine In toluene at -3 - 30℃;
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 55-60°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 20percent 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)HPLC purity: 99.00 percent; Sulphone content: 0.84 percent; Chiral purity: -97 percent (e,e)
~97% ee With titanium(IV) isopropylate; diethyl (2R,3R)-tartrate; Cumene hydroperoxide; N-ethyl-N,N-diisopropylamine In toluene at -3 - 0℃; for 3 h; 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 20percent   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: 99.00percent; Sulphone content: 0.84percent; Chiral purity: ˜97percent (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 25°C to 30°C. 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 70°C to 75°C, maintained for 5 minutes and cooled to 25°C to 30°Cover 30 minutes. Diisopropylethylamine (2.342 g / 0.0181 moles) was added, stirred for 30 minutes and then cooled to -5°C to 0°C. A solution of 80percent cumene hydroperoxide (14.788 g/ 0.0971 moles) in toluene (10 ml) was added at -5°C to 0°C over 60 minutes. The reaction was stirred for 2 to2.5 hours at -5°C to 0°C and quenched with 5percent aqueous KOH solution (50 ml) maintaining temperature at about -5°C to 0°C. The temperature of the reaction mass was raised to 25°C - 30°C and methanol was charged (25 ml). The reaction mass was basified to a pH of 12.5 to 13.0 with 20percent aqueous KOH solution and stirred for 10 minutes at 30°C to 35°C. The aqueous layer was separated at 30°C to 35°C and the organic layer was extracted with a mixture of 5percent aqueous KOH (30 ml) and methanol (15 ml) at 30°C to 35°C. The aqueous layers were combined and washed with DC (3 x 30 ml) at 30°C to 35°C. The pH of the aqueous solution was adjusted to 8.5 to 9.5 with 20percent acetic acid at 30°C to 35°C. 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 45°C 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 43°C to 45°C and n-heptane (200 ml) was added slowly at 40°C to 45°C. The reaction mass was cooled to 25°C to 30°C, and stirred for 30 minutes. The solid was isolated by filtration, washed with n-heptane (20 ml) and dried under vacuum at 25°C to 30°C for 8 to 10 hours. Yield: 8.0 g HPLC purity: 98.17percent
99.8 % ee With titanium(IV) tetraethanolate; diethyl (2R,3R)-tartrate; dihydrogen peroxide In water; toluene at 60℃; for 1.16667 h; 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 99.9percent, has been detected in the sulfones impurity, dexlansoprazole e.e. Value is 99.8percent.
99.8 % ee With titanium(IV) tetraethanolate; diethyl (2R,3R)-tartrate; dihydrogen peroxide In water; toluene at 60℃; for 1.16667 h; 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 99.2percent, has been detected in the sulfones impurity, dexlansoprazole e.e. Value is 99.8percent.
100 % ee
Stage #1: With (2R,3R)-N,N′-dibenzyl-2,3-dihydroxybutanediamide In toluene at 70℃; for 0.25 h;
Stage #2: With titanium(IV) isopropylate In water; toluene at 70℃; for 1.5 h;
A 30g (85mmol) of 2 - [[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] thio] Benzimidazole and 6.28 g (22percentmol)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 (15percent 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 98.6percent and the sulfoxide content was 96.0percent and contained 1.9percent thioether and 2.0percent sulfone. [0122] A 30percent100 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 12.5percent aqueous ammonia solution and stirred for about 2.5 hours the amino water layer was separated. The 12.5percent 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 100percent, sulfoxide content of 99.8percent, sulfone content of 0.2percent.
99.8 % ee
Stage #1: With tetramethoxytitanium; diethyl (2R,3R)-tartrate In toluene at 60℃; for 0.5 h;
Stage #2: With phosphomolybdovanadic acid 1,2-bis(1-methylimidazol-3-yl)ethane; dihydrogen peroxide In toluene at 60℃; for 0.666667 h;
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 99.3percent, sulfone impurity 0.1percent lansoprazole e.e. value was 99.8percent.
3.4 kg
Stage #1: With titanium(IV) isopropylate; diethyl (2R,3R)-tartrate In water; toluene at 50 - 60℃; for 0.5 h; Inert atmosphere; Large scale
Stage #2: With Cumene hydroperoxide; N-ethyl-N,N-diisopropylamine In water; toluene at -5 - 5℃; for 1.5 h; Inert atmosphere; Large scale
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 µM, containing 1.89 g water), toluene (22 L), water (25 g, 1.39 µM, the total amount of water 1.49 µM) and (+) - tartaric acid diethyl (0.958 L, 5.6 µM) 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 µM), and at this temperature the mixture stirring 30 minutes. In under nitrogen, the same temperature will be diisopropyl ethylamine (0.733 L, 4 . 44 µM) is added to the mixture and, in the -5 to 5 °C lower, the cumene hydrogen peroxide (6.88 L, content of 82percent, 37.5 µM) 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 30percent 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), 12.5percent 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 12.5percent 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 20percent 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).

Reference: [1] Patent: CN106946849, 2017, A, . Location in patent: Paragraph 0182-0188; 0189-0303
[2] Patent: CN107400119, 2017, A, . Location in patent: Paragraph 0026; 0027; 0032; 0034; 0044; 0048; 0052
[3] Patent: CN108314675, 2018, A, . Location in patent: Paragraph 0052-0057
[4] Chemistry Letters, 2016, vol. 45, # 2, p. 110 - 112
[5] Patent: CN105218391, 2016, A, . Location in patent: Paragraph 0177-0181
[6] Organic Letters, 2007, vol. 9, # 12, p. 2265 - 2268
[7] Patent: WO2009/117489, 2009, A1, . Location in patent: Page/Page column 57-58
[8] Patent: WO2009/113696, 2009, A1, . Location in patent: Page/Page column 21-22; 26
[9] Patent: WO2010/95144, 2010, A2, . Location in patent: Page/Page column 24-25
[10] Patent: WO2011/98938, 2011, A1, . Location in patent: Page/Page column 18
[11] Patent: WO2011/121546, 2011, A1, . Location in patent: Page/Page column 4-5
[12] Patent: US2013/12714, 2013, A1, . Location in patent: Paragraph 0073
[13] Patent: WO2013/140120, 2013, A1, . Location in patent: Page/Page column 46-47
[14] Patent: US9145389, 2015, B2, . Location in patent: Page/Page column 8
[15] Patent: CN106565677, 2017, A, . Location in patent: Paragraph 0014; 0015; 0016; 0017; 0018; 0019; 0020
[16] Patent: CN106565676, 2017, A, . Location in patent: Paragraph 0014; 0015; 0016; 0017; 0018; 0019; 0020
[17] Patent: CN103880819, 2017, B, . Location in patent: Paragraph 0020-0123
[18] Patent: CN106518847, 2017, A, . Location in patent: Paragraph 0015-0017
[19] Patent: CN106543146, 2017, A, . Location in patent: Paragraph 0025; 0033; 0034; 0035; 0036; 0037; 0038
[20] Patent: CN108164507, 2018, A, . Location in patent: Paragraph 0018-0023
  • 2
  • [ 103577-40-8 ]
  • [ 138530-94-6 ]
  • [ 138530-95-7 ]
YieldReaction ConditionsOperation in experiment
67.3%
Stage #1: With D-tartaric acid monophenyl ester benzylamine In water; toluene at 60℃; for 0.5 h;
Stage #2: With titanium(IV) isopropylate In water; toluene for 1 h;
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 80percent CHP 6. 0ml,The reaction was carried out at 0-5 ° C for 5 h.After completion of the reaction, 10 ml of 30percent 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 68.1percent, and the enantiomeric excess 99. 7percent.
71.7 % ee With oxygen; nicotinamide adenine dinucleotide phosphate In aq. phosphate buffer; isopropyl alcohol at 25℃; for 24 h; Sealed tube; Enzymatic reaction 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 percent conversion and product enantioselectivity are provided below in Table 20. [table-us-00021-en] TABLE 20 Enantioselectivity SEQ ID NO: percent Conversion (percent ee) 5/6 1.21 R-selective (n.d.)4 21/22 1.12 S-selective (n.d.)4 71/72 273 S-selective (71.7percent ee) 79/80 193 S-selective (91.6percent ee) 11.5 g/L lansoprazole sulfide, 15 g/L enzyme, 0.5 g/L NADP+, 1 g/L KRED, 4percent 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, 4percent 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, 4percent IPA, 25 mM phosphate buffer pH 8.5, 24 h reaction time. 4percent ee could not be determined due to low percent 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 27percent and 19percent conversion with enantioselectivity of about 72percent ee and 92percent ee, respectively. Although the engineered CHMO polypeptide of SEQ ID NO: 6 showed only 1percent 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 98.9percent 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., 98percent or greater) and much higher percent conversion (e.g., 20percent 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 6 h; 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 30percent 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 1percent 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 24 h; 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 30percent 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 1percent 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.

Reference: [1] Patent: CN105218391, 2016, A, . Location in patent: Paragraph 0177-0184
[2] Tetrahedron Asymmetry, 2003, vol. 14, # 4, p. 407 - 410
[3] Patent: WO2008/152462, 2008, A1, . Location in patent: Page/Page column 18
[4] Patent: WO2008/152462, 2008, A1, . Location in patent: Page/Page column 19
[5] Patent: US9228216, 2016, B2, . Location in patent: Page/Page column 94-96
[6] Catalysis Today, 2017, vol. 279, p. 84 - 89
[7] Catalysis Today, 2017, vol. 279, p. 84 - 89
  • 3
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  • [ 138530-94-6 ]
Reference: [1] Patent: WO2010/95144, 2010, A2, . Location in patent: Page/Page column 22
  • 4
  • [ 75-89-8 ]
  • [ 138530-94-6 ]
YieldReaction ConditionsOperation in experiment
59.4%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 50 - 55℃; Large scale reaction
Stage #2: at 25 - 95℃; Large scale reaction
A mixture of (R)-(+)-4 (12 kg, 38 mol) and acetone (264 L) were heated to 45-50 °C till clear solution is obtained. The resulting clear solution was cooled to -5 to 0 °C and stirred at -5 to 0 °C for 1.0-1.5 h. The precipitated (RS)-(+/-)-4 was filtered and the filtrate was evaporated under vacuum at below 45 °C to obtain thick residue of (R)-(+)-4. DMF (65 L) was charged in another clean and reactor at 25-35 °C, cooled to 15-20 °C and then added 2,2,2-trifluoroethanol (23.9 kg, 239 mol) at below 20 °C under stirring. Potassium carbonate (33 kg, 239 mol) was charged to the resulting reaction mass at below 20 °C and heated to 50-55 °C for 30-45 min to form potassium salt of 2,2,2-trifluoroethanol. Reaction mass was cooled to 25-35 °C, added solution of (R)-(+)-4 in DMF (43 L) at 25-35 °C and then heated to 85-95 °C for 4-6 h. The resulting reaction mass was cooled to 25-35 °C, filtered to remove all the inorganic byproducts present in the reaction mass and wet cake was washed with acetonitrile (43 L). To the combined filtrate, Demineralized water (216 L) and carbon (3.1 kg) was charged and stirred at 60-70 °C for 20-30 min. Again, reaction mass was filtered over Hyflow bed, and washed the bed with Demineralized Water (24 L). The resulting filtrate was cooled to 5-10 °C and then adjusted the pH of the solution to 8.0-8.7 using 10percent Acetic acid solution. The resulting heterogeneous mass was stirred at 5-10 °C for 2-3 h to ensure the total solid precipitation. Subsequently, the solid was filtered, washed with Demineralized Water (55 L) and re-slurried the wet cake in DM Water (160 L) to ensure removal of all the inorganic byproducts. Finally, the wet cake was dried at 45-50 °C under vacuum for 10-12 h to afford (R)-(+)-2-[3-Methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-1H-benzimidazole ((R)-(+)-1). Yield 8.32 kg (59.4percent); Purity by HPLC 99.64percent; Chiral purity by HPLC 99.98percent; 1HNMR (400 MHz, DMSO-d6): 13.54 (br, 1H), 8.28 (d, 1H, J = 8.8 Hz), 7.64 (s, 2H), 7.3 (m, 2H), 7.09 (d, 1H, J = 6 Hz), 4.9 (q, 2H, J = 8.8 Hz), 4.78 (q, 2H, J = 13.6 Hz); 2.17 (s, 3H); 13CNMR (400 MHz, DMSO-d6) 161.3, 154.1, 150.9, 148.1, 139.0, 123.7, 123.2, 122.3, 115.8, 107.0, 64.6, 60.0, 34.4, 10.5; IR (cm-1) 3369, 3070, 2975, 2896, 1583, 1474, 1441, 1265, 1166, 1043, 743; MS (m/z) 370 (M++H).
Reference: [1] Tetrahedron Letters, 2011, vol. 52, # 42, p. 5464 - 5466
[2] Patent: WO2009/117489, 2009, A1, . Location in patent: Page/Page column 62-63
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  • [ 134469-07-1 ]
  • [ 138530-94-6 ]
Reference: [1] Patent: WO2010/95144, 2010, A2, . Location in patent: Page/Page column 27
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  • [ 103577-45-3 ]
  • [ 138530-94-6 ]
YieldReaction ConditionsOperation in experiment
> 97 % ee
Stage #1: With (R)-1,1'-Bi-2-naphthol In dichloromethane at 20 - 40℃;
Stage #2: With ammonia In methanol; methyl tert-butyl ether (MTBE) at 25 - 35℃;
EXAMPLES; EXAMPLE 1; Resolution of (R)-2-[[[3-methyl-4-(2,2,2-trifiuoroethoxy)-2-pridinyI-l] methyl] suIfinyl]-lH-benzimidazole (R-(+)-LansoprazoIe) from racemic Lansoprazole.2-[[[3-methyl-4-(2,2,2-trifiuoroethoxy)-2-pridinyl-l]methyl]sulfinyl]-lH- benzimidazole (racemic Lansoprazole) (200 gm, 0.542 moles) and R-(+)-BINOL (232.52 gm, 0.813 moles) was dissolved in methylene di chloride (7 L) at room temperature in a <n="8"/>10 L flask and heated to 35-40° C, under stirring, to get a clear solution. The reaction mixture was concentrated under vacuum below 35° C until the volume of the reaction mixture was approximately 5-6 times with respect to lansoprazole. Toluene (5760 ml) was charged to the reaction mixture, which was cooled to about 20-25° C. n-Hexane (1440 ml) was then added and the temperature was maintained between 20° C and 25° C. The reaction mixture was then cooled to 0-5° C and stirred at this temperature for 12 hours. The crystallized product was filtered and washed with n-hexane and suck-dried to obtain 230 gm of crude R-(+)-lansoprazole - R-(+)-BINOL inclusion complex.Purification of crude complexThe crude R-(+)-lansoprazole - R-(+)-BINOL inclusion complex was dissolved in 3000 ml methylene dichloride and concentrated under vacuum maintaining the temperature below 35° C until the volume of the reaction mixture was about 5-6 times with respect to lansoprazole. Toluene (5760 ml) was charged to reaction mixture and the reaction mixture was cooled to about 20-25° C. n-Hexane (1440 ml) was added maintaining the temperature between 20° C and 25° C. The reaction mixture was then cooled to 0-5° C and stirred at this temperature for 12 hours. The crystallized product was filtered and washed with n-hexane. The wet product was dried at 40° C under vacuum to get 185 gm of pure R-(+)-lansoprazole - R-(+)-BINOL inclusion complexChiral purity by HPLC > 97percent eeYield: 92.55 percent w/wEXAMPLE 2Preparation of (R)-2-[[[3-methyl-4-(2,2,2-trifiuoroethoxy)-2-pridinyl-l] methyl] sulfinyl]-lH-benzimidazole (R-(+)-Lansoprazole) <n="9"/>185 gm of the pure R-(+)-lansoprazole - R-(+)-BINOL inclusion complex obtained in Example 1 was dissolved in methanol (92.5 ml) and liquor ammonia (925 ml) at 25-35° C. Methyl tertbutyl ether (MTBE) (925 ml) was added to the reaction mixture at 25-35° C and stirred for 10 min to get a clear solution. The organic layer was separated and extracted with liquor ammonia twice (462.5ml x 2 times) at 25-35° C and the organic layer was again separated. All of the aqueous layers were collected and washed twice with MTBE (462.5 ml X 2) at 25-35° C. The aqueous layer was separated and cooled to 10° C. The pH of the aqueous layer was adjusted to 9-9.3 using 50percent aqueous acetic acid solution. The reaction mass was cooled to 5° C and stirred for 60 minutes maintaining the temperature between 5° C and 10° C. The product obtained was filtered and washed with a mixture of 1 ml liquor ammonia solution in 200 ml chilled water and then with 100 ml chilled water. The wet product was dried at 40° C under vacuum to get 59 gm of R-(+)- LansoprazoleChiral Purity by HPLO 97 percent e.e.Yield: 32 percent w/w
94 % ee With ammonium hydroxide In ethanol Example 6: Preparation of form XIII[00207] R-(+)-lansoprazole (2.0 g, 73percent ee) was dissolved by stirring in absolute EtOH (8 mL, 4 VoI) at room temperature and ammonium hydroxide 25percent (0.5 mL) was added to the solution. This led to the formation of a precipitate, which was filtered and the filtrate was evaporated to dryness to give (1.67 g, 76percent ee). The above described procedure was repeated with 4 vol EtOH and ammonium hydroxide 25percent (0.5 mL) and the resulting precipitate was removed from the mother liquor, which was concentrated in vacuum to give (1.65 g, 80percent ee). To this material was added EtOH (6 mL) but no dissolution was observed. Subsequently, ammonium hydroxide 25percent (1 mL) was added and the mixture was heated to 35-400C to allow dissolution. The resulting solution was cooled to room temperature and diisopropyl ether (50 mL) was added dropwise. Cooling to 0 - (+5)°C led to precipitation. The solids were separated from their mother liquors by filtration. HPLC analysis of both solid and filtrate suggested an optical purity level of 17percent ee in the solid and 93.6percent ee in the filtrate. The filtrate was evaporated under reduced pressure and dried in a vacuum oven at 25°C for 16 h to give a solid (1.3 g, 94percent ee) of Form XIII. Example 7 - Preparation of form XIII of dexLansoprazole
9.31 g With triethylamine In hexane; isopropyl alcohol at 30℃; Reference Example 2Isolation of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroet- hoxy)-2-pyridinyl]methyl]sulfinyl] -1 H-benzimidazole (R(+)-lansoprazole) stance.Lansoprazole (racemate) (34.2 g) was dissolved in 2-pro- panol (1.710 ml) and hexane (1.140 ml) containing triethylamine (0.2percent) and fractionated by HPLC (column: CHIRALCEL OD 50 mm dia.x500 mm, temperature: room temperature, mobile phase: hexane/2-propanol=85/1 5, flowrate: 60 ml/min, detection wavelength: 285 nm, 1 shot: about300 mg) to isolate the individual optical isomers. Fractions of an optical isomer of shorter retention time were combined and concentrated; the individual lots were combined and dissolved in ethanol (250 ml); after triethylamine (3 ml) wasadded, the solution was filtered through a 0.45 tm filtet After the filtrate was concentrated, hexane was added, and the filtrate was again evaporated to dryness to yield R(+)-lansoprazole (9.31 g, optical purity 98.3percent cc) as an amorphous sub-
Reference: [1] Patent: WO2009/87672, 2009, A1, . Location in patent: Page/Page column 6-8
[2] Patent: WO2010/39885, 2010, A2, . Location in patent: Page/Page column 27
[3] Patent: WO2011/42910, 2011, A2,
[4] Patent: US9145389, 2015, B2, . Location in patent: Page/Page column 8
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Reference: [1] Chirality, 2010, vol. 22, # 1, p. 35 - 41
[2] Chemical Communications, 2017, vol. 53, # 3, p. 509 - 512
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  • [ 138530-94-6 ]
Reference: [1] Tetrahedron Letters, 2011, vol. 52, # 42, p. 5464 - 5466
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  • [ 138530-94-6 ]
Reference: [1] Chemistry Letters, 2016, vol. 45, # 2, p. 110 - 112
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Reference: [1] Patent: CN106543146, 2017, A,
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