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Chemical Structure| 73590-85-9
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Product Details of [ 73590-85-9 ]

CAS No. :73590-85-9 MDL No. :MFCD00869021
Formula : C17H19N3O2S Boiling Point : -
Linear Structure Formula :- InChI Key :XURCIPRUUASYLR-UHFFFAOYSA-N
M.W : 329.42 Pubchem ID :155794
Synonyms :
Ufiprazole;​OMEP sulfide;Pyrmetazole;OMZ sulfide;OMP sulfide

Calculated chemistry of [ 73590-85-9 ]

Physicochemical Properties

Num. heavy atoms : 23
Num. arom. heavy atoms : 15
Fraction Csp3 : 0.29
Num. rotatable bonds : 5
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 93.01
TPSA : 85.33 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -5.81 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.88
Log Po/w (XLOGP3) : 3.52
Log Po/w (WLOGP) : 3.73
Log Po/w (MLOGP) : 1.8
Log Po/w (SILICOS-IT) : 4.48
Consensus Log Po/w : 3.28

Druglikeness

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

Water Solubility

Log S (ESOL) : -4.25
Solubility : 0.0184 mg/ml ; 0.0000559 mol/l
Class : Moderately soluble
Log S (Ali) : -5.0
Solubility : 0.00333 mg/ml ; 0.0000101 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -6.58
Solubility : 0.0000876 mg/ml ; 0.000000266 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.93

Safety of [ 73590-85-9 ]

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

Application In Synthesis of [ 73590-85-9 ]

* 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 [ 73590-85-9 ]
  • Downstream synthetic route of [ 73590-85-9 ]

[ 73590-85-9 ] Synthesis Path-Upstream   1~15

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YieldReaction ConditionsOperation in experiment
100% With tetrabutylammomium bromide; edetate disodium; sodium hydroxide In dichloromethane; water Step S1: 80.0 g (0.36 mol) of 4-methoxy-3,5-dimethyl-2-chloromethylpyridine hydrochloride (Compound I) was added to 480 mL of dichloromethane.0.2 g of disodium edetate was dissolved in 80 mL of water and added to the reaction solution.Step S2: After stirring and dissolving, 64.0 g (0.356 mol) was added.2-mercapto-5-methoxybenzimidazole (formula II),2.0 g (0.006 mol, 2percent molar equivalent) of tetrabutylammonium bromide,Sodium hydroxide adjusts the pH to 10,Stir until the reaction is over,Liquid separation,extraction,washing,dry,concentrate,a compound of formula III,Calculated in 100percent yield.Sodium hydroxide adjusts the pH to 10,The specific adjustment method is:Adjust the pH value in sections,Fine-tuning with 10percent sodium hydroxide in the early stage of the reaction;In the middle of the reaction, it was adjusted by using 15percent sodium hydroxide.Let it reach a pH of 8,Add 15percent sodium hydroxide every 10 minutes.This kind of benefit is adjusted more fully,Can better observe the effect of the adjustment,Make its PH reach 9;In the later part of the reaction, it was adjusted by using 20percent hydrogen peroxide.Make it PH to 10,The way the adjustment is added when it is interrupted,Add sodium hydroxide every 20 minutes;By adjusting the pH value in sections,Thereby making the adjusted pH more precise,More saving on sodium hydroxide,Save the production costs of the enterprise.
95.2% With sodium hydroxide In methanol; waterReflux To a 1000 ml three-mouth flask is added 2-mercapto-5-methoxy benzimidazole 50.0g (0.28 µM), 500 ml of water and sodium hydroxide 22g (0.56 µM), after stirring dissolves clear slowly dropping 2-(chloromethyl)-4-methoxy-3,5-dimethyl pyridine hydrochloride 62g (0.28 µM) with methanol 300 ml of solution, stirring and heating to reflux the reaction, TLC monitoring raw material the reaction is complete. By reducing pressure methanol, water 200 ml, and dichloromethane is used for 300 ml * 3 extraction, the combined organic phase into the 2500 ml single-port in the bottle, the pressure off the solvent, adding petroleum ether to the residue in 1000 ml, lowering the temperature to 5 - 10 °C stirring crystallization, extraction, drying, to obtain white solid the ufiprazole 87g, yield 95.2percent.
94% With sodium hydroxide In ethanol; acetone at 40 - 45℃; for 3 h; Large scale The reactor was added anhydrous ethanol 12.0kg, stirring, adding sodium hydroxide 1.09kg (27.25mol, 2.05eq) After stirring for 30 min, the internal temperature was controlled at 20-25 ° C. 2.40 kg (13.32 mol, 1.00 eq) of EL2,EL3 3.10kg (13.96mol, 1.05eq), acetone 4.0kg, the reaction was heated to an internal temperature of 40 ~ 45 ,Reaction 3h, TLC monitoring EL2 disappeared, the reaction was complete. The reaction liquid temperature was lowered to 25 ~ 30 ,After stirring for 30 min, insoluble materials were removed by filtration, the filter cake was washed once with 1.5 kg of acetone,The filtrate was concentrated under reduced pressure (bath temperature 40 ~ 45 ), the residue was added ethyl acetate 13.2kg, cooled to 0 ~ 5 ,Stir 3h, filter. The filter cake was washed once with 1.5 kg of ethyl acetate at 0-10 ° C,40 ~ 45 vacuum drying 8 to 10 hours. 4.14 kg of Intermediate 1 (EL1) was obtained with a yield of 94percent and a purity of 95.5percent by HPLC.
94% With sodium hydroxide In ethanol; acetone at 20 - 45℃; for 3 h; Large scale The reactor was filled with 12.0 kg of absolute ethanol.Stir and add 1.09 kg of sodium hydroxide (27.25 mol, 2.05 eq). After stirring for 30 minutes, the internal temperature is controlled at 20 to 25°C.EL2 2.40 kg (13.32 mol, 1.00 eq) and EL3 3.10 kg (13.96 mol, 1.05 eq) were successively added.Acetone 4.0kg, the reaction solution was heated to an internal temperature of 40 to 45°C, and the reaction was conducted for 3 hours. TLC monitored EL2 disappeared. The reaction is complete. The internal temperature of the reaction solution is reduced to 25 to 30°C.After stirring for 30 minutes, the insoluble material was removed by filtration.The filter cake was washed once with acetone 1.5 kg, and the filtrate was concentrated under reduced pressure (bath temperature 40-45°C).The residue was added with 13.2 kg of ethyl acetate and cooled down to 0-5°C.Stir for 3h and filter. The filter cake was washed once with ethyl acetate of 0-10 °C 1.5 kg,40 ~ 45 °C vacuum drying 8 ~ 10 hours. Obtained 4.14 kg of Intermediate 1 (EL1) in 94percent yield.Purity was 95.5percent by HPLC.
90% With sodium carbonate In methanolReflux Methanol was stirred at 25-35 0C and cooled to 20-25 0C. To the cold solution, 2-chloromethyl-3,5-dimethyl-4-methoxy-pyridine hydrochloride (1 mol), 2-mercapto-5-methoxy-benzimidazole (1 mol) and sodium carbonate (2.2 mol) and heated to reflux temperature. After completion of the reaction, the by-product formed was removed by filtration. Methanol was removed by distillation from the filtrate until small amount of methanol remains. The residue was dissolved in toluene and washed with aqueous solution of sodium carbonate. The organic layer was distilled under vacuum and cooled. To the residue toluene was added and seeded with qualified compound of formula (II). The obtained solid was filtered, washed with toluene and dried to obtain title compound. Yield: 80-90 percent; Purity: 99percent.
130 g With sodium hydroxide In methanol; water at 30 - 35℃; 2-mercapto-5-methoxy benzimidazole (83.10 gm) was added at 30-35°C to a solution of NaOH (42 gm) in Methanol (200 ml) and Water (100 ml) to form a 1st reaction mass. A solution of 2-Chloromethyl-3,5-dimethyl-4-methoxy pyridine hydrochloride ( 100 gm) in methanol (50 ml) and water (150 ml) mixture was added to the 1st reaction mass in 90- 120 min at 30-35°C and the reaction mass stirred for 10-15 hrs and the reaction followed by TLC and HPLC.The reaction mass was worked up by addition of Water(900 ml), stirred for 2 hours, and filtered, washed with water(2x300 ml); suck dried, filtered and dried at 42-46C for 24-30 hrs in an oven to afford stage- 1 intermediate with M./C content < 0.5percent and a Dry Wt: - 130 gm

Reference: [1] Patent: CN108409714, 2018, A, . Location in patent: Paragraph 0049-0054; 0063-0067; 0076-0080; 0089-0093
[2] Patent: CN106632256, 2017, A, . Location in patent: Paragraph 0008
[3] Patent: CN107400117, 2017, A, . Location in patent: Paragraph 0058-0060
[4] Patent: CN107400118, 2017, A, . Location in patent: Paragraph 0046; 0047; 0048
[5] Patent: WO2011/12957, 2011, A1, . Location in patent: Page/Page column 16
[6] Patent: WO2008/102145, 2008, A2, . Location in patent: Page/Page column 18; 19
[7] Patent: WO2008/102145, 2008, A2, . Location in patent: Page/Page column 19-20
[8] Patent: WO2010/134099, 2010, A1, . Location in patent: Page/Page column 6; 7; 9; 10; 16-18
[9] Patent: WO2013/72934, 2013, A1, . Location in patent: Page/Page column 11
[10] Chemistry Letters, 2016, vol. 45, # 2, p. 110 - 112
[11] Patent: CN105218521, 2016, A, . Location in patent: Paragraph 0018
[12] Organic Process Research and Development, 2016, vol. 20, # 12, p. 2092 - 2099
[13] Patent: CN103694223, 2016, B, . Location in patent: Paragraph 0004; 0024; 0025
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YieldReaction ConditionsOperation in experiment
85% With sodium methylate In methanol; ethyl acetate Example 22
First, 277 mg (0.92 mmol) of 5-methoxy-2-[(4-chloro-3,5-dimethyl-2-pyridyl)methyl]thio}-1H-benzimidazole obtained in Example 21 and 1.00 g (5.20 mmol) of methanol 28percent solution of sodium methoxide were introduced to a 3-necked flask (30 ml volume) equipped with a thermometer, a magnetic stirrer and a condenser tube, and the mixture was agitated for 10 hours while being slowly refluxed.
Then the mixture was neutralized with dilute hydrochloric acid.
Ethyl acetate (10 ml) was added thereto and an organic layer was separated, and an aqueous layer was extracted twice with 10 ml of ethyl acetate.
The extracts and the above mentioned organic layer were combined and dried over anhydrous magnesium sulfate.
The solvent was removed under reduced pressure to give 232 mg of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio}-1H-benzimidazole (yield of 85percent) with revealing the properties.
1H-NMR spectrum (270 MHz, DMSO-d6, TMS, ppm), δ:2.26(s, 3H), 2.42(s, 3H), 3.59(s, 3H), 3.77(s, 3H), 4.62(s, 2H), 6.70(dd, 1H, J=3.0 Hz, 8.9 Hz), 6.90(bs, 1H), 7.27(d, 1H, J=8.9 Hz), 8.07(s, 1H), 12.30(bs, 1H)
Reference: [1] Patent: US6197962, 2001, B1,
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Reference: [1] Patent: US2007/82929, 2007, A1, . Location in patent: Page/Page column 42
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Reference: [1] Patent: WO2004/35565, 2004, A1, . Location in patent: Page 5; 8-9
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Reference: [1] Patent: CN107434802, 2017, A, . Location in patent: Paragraph 0018; 0020; 0022
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YieldReaction ConditionsOperation in experiment
75% With sodium methylate; magnesium chloride; potassium carbonate In methanol; water; ethyl acetate Example 3
Preparation of 5-methoxy-2-[((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)-thio)-1H benzimidazole.
To a solution of the product from Example 2 (100 g; 0.29 mole) in methanol (500 ml), was added potassium carbonate (138g; 1.0 mole) followed by 30percent sodium methoxide solution (330 ml; 2.0 moles) and anhydrous magnesium chloride (20 g).
The contents were refluxed for 2 hours after which the reaction mixture was cooled to ambient temperature, filtered to remove inorganics and concentrated under reduced pressure.
To the residue was added water (500 ml) and ethyl acetate (200 ml).
The organic layer was separated, dried and chilled to 0.°C and kept overnight to afford 65g (75percent) of the title compound as a crystalline powder.
Reference: [1] Patent: EP1085019, 2001, A1,
[2] Patent: US6245913, 2001, B1,
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Reference: [1] European Journal of Organic Chemistry, 2017, vol. 2017, # 24, p. 3427 - 3430[2] Khim. Prir. Soedin., 2017, vol. 53, # 2, p. 318 - 319,2
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Reference: [1] Patent: US6350876, 2002, B2, . Location in patent: Example 23
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Reference: [1] Patent: US6350876, 2002, B2, . Location in patent: Example 22
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Reference: [1] Synthetic Communications, 2002, vol. 32, # 8, p. 1211 - 1217
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Reference: [1] Heterocyclic Communications, 2016, vol. 22, # 1, p. 17 - 19
[2] Magnetic Resonance in Chemistry, 2017, vol. 55, # 4, p. 274 - 282
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Reference: [1] Synthetic Communications, 2002, vol. 32, # 8, p. 1211 - 1217
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YieldReaction ConditionsOperation in experiment
93.5% 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.
93 % ee With tert.-butylhydroperoxide In water; toluene at -20℃; for 12 h; Titanium tetraisopropoxide (4.5 mg, 0.016 mmol) was added to a solution of (S,S)-1,2-bis-(2-bromophenyl)ethane-1,2-diol (12 mg, 0.032 mmol) in toluene (2 ml) at 25° C. The solution was stirred for 10 minutes, water (5.7 mg, 0.32 mmol) was added, and the solution was stirred for another 10 minutes. 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole (105 mg, 0.32 mol) was then added to the solution, and the temperature was adjusted to -20° C. Thereafter, t-butyl hydroperoxide (70percent, 96 μl, 0.064 mmol) was slowly added. After 12 hours at -20° C., the solution was extracted three times with aqueous ammonium hydroxide (12.5percent NH3, 3.x.5 ml). Thereafter, the methyl isobutyl ketone (5 ml) was added to the combined aqueous extracts. After this, the pH of the aqueous phase was adjusted using acetic acid, the aqueous phase was separated and extracted with an additional amount of methyl isobutyl ketone (5 ml). The organic solution was cooled to -10° C. over night, and the neutral form of R-omeprazole was precipitated as a solid to obtain the title compound. The enantiomeric excess of R-omeprazole was 93percent.
100 % ee With oxygen; NADP In aq. phosphate buffer; isopropyl alcohol at 25℃; for 24 h; Enzymatic reaction General procedure: The Activity FIOP and enantioselectivity (percent ee) of the 53 exemplary non-naturally occurring monooxygenase polypeptides of Table 2B in carrying out the biocatalytic conversion of the substrate compound (1) (pyrmetazole) to the product compound (2) ((R)- or (S)-omeprazole) were determined that following general HTP assay conditions: 5 g/L pyrmetazole substrate, 10 μL of lysate of the engineered CHMO polypeptide, 1 g/L KRED of SEQ ID NO: 268, 0.5 g/L NADP, in a solution of 50 mM potassium phosphate buffer, 10percent (v/v) IPA, pH 9.0, 25° C. reaction temperature and 24 h reaction time (with 400 rpm stirring). Further details of the HTP assay methods are described in the Examples.
Reference: [1] Catalysis Today, 2017, vol. 279, p. 84 - 89
[2] Heterocyclic Communications, 2016, vol. 22, # 1, p. 17 - 19
[3] Patent: US2008/319195, 2008, A1, . Location in patent: Page/Page column 5
[4] Patent: US9228216, 2016, B2, . Location in patent: Page/Page column 50-52
[5] Journal of Organic Chemistry, 2018, vol. 83, # 14, p. 7453 - 7458
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YieldReaction ConditionsOperation in experiment
49 % ee With dihydrogen peroxide In water; acetonitrile at 20℃; for 5.5 h; 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-1 H- benzimidazole (4a) and the (salen)manganese complex 2a - e are dissolved in acetonitrile. The reaction temperature is adjusted, then 30percent aqueous H2O2 is added dropwise and the mixture is stirred for several hours. Then the reaction mixture is transferred portion-wise into a cold (0 0C) 10percent aqueous solution of Na2SO3 and stirred for additional 15 min. The obtained mixture is extracted with dichloromethane. The organic phase is dried over Na2SO4 and concentrated yielding an oily residue which is analyzed by chiral and achiral HPLC analytical method.Typically, runs were carried out on 0.5 - 6 mmol scale of the starting material 4a in acetonitrile (1 mmol 4a in 10 mL MeCN). The amounts of added reagents, temperature and reaction time in particular examples are indicated in Tables 1 to 3. Also the results are indicated in Tables 1-3.
80 % ee
Stage #1: at 50 - 55℃; for 1 h;
Stage #2: With N-ethyl-N,N-diisopropylamine In toluene at 25 - 30℃; for 0.0833333 h;
Stage #3: With Cumene hydroperoxide In toluene at 20℃; for 4 h;
0.495 g (1.5 mmol) of the compound of formula III, 5 ml of dried toluene and 1 mmol of a chiral ligand (166.1 mg of the methyl ester of (S)-mandelic acid (general formula IV: X = OMe, Y = H, rVc)) were placed in a 3 -neck 50-ml flask, which was equipped with a magnetic stirrer and a thermometer. The mixture in the flask was heated in an oil bath to a temperature in the range of 50 to 55 °C. Then, 0.15 ml of Ti(Oz-Pr)4 (general formula V: Z = Ti, R5 = i-Pr) were added to this mixture at once. The resulting mixture was stirred at a temperature in the range of 50 to 55 °C for 1 hour. Then, the temperature of the reaction mixture was maintained at 25 to 30 °C and 85 μ of diisopropylethylamine were added to the reaction mixture. The mixture was stirred for 5 minutes and 0.25 ml of 88percent cumene hydroperoxide were added to the solution. The resulting reaction mixture was stirred at the room temperature for 4 hours. The reaction was terminated by addition of 5 ml of a 5percent aqueous solution of Na2S203 and diluted with 5 ml of toluene. The resulting mixture was filtered through filtration paper. The two-phase filtrate was divided in a separating funnel and the toluene fraction was extracted with additional 5 ml of water. After drying with anhydrous magnesium sulfate the toluene solution was evaporated to dryness in a rotational vacuum evaporator. The resulting evaporation residue was chromatographed on silica gel. Chloroform : methanol : 25percent NH OH in the (10 : 1 : 0.1) proportion was used as the eluent. The fractions of the product were combined, evaporated in a rotational vacuum evaporator and analyzed in a HPLC system on a chiral phase (CHIRALPAK AD-H.(R).); mobile phase 50percent of hexane : 50percent of ethanol, detection 302 nm).Esomeprazole (formula I) with the enantiomeric excess of 80 percent was obtained.
67.7 % ee
Stage #1: at 50 - 55℃; for 1 h;
Stage #2: With N-ethyl-N,N-diisopropylamine In toluene at 25 - 30℃; for 0.0833333 h;
Stage #3: With Cumene hydroperoxide In toluene at 20℃; for 4 h;
(R)-omeprazole was prepared with the same procedure as described in example 1. 1 mmol (200 mg) of (jf?)-3-chloromandelic acid methyl ester (general formula ent-TV: X = OMe, Y = 3-Cl) was used as the chiral ligand.(/?)-omeprazole (formula ent-I) with the enantiomeric excess of 67.6 percent was obtained.
83.7 % ee With oxygen; NADP In aq. phosphate buffer; isopropyl alcohol at 25℃; for 24 h; Enzymatic reaction General procedure: The Activity FIOP and enantioselectivity (percent ee) of the 53 exemplary non-naturally occurring monooxygenase polypeptides of Table 2B in carrying out the biocatalytic conversion of the substrate compound (1) (pyrmetazole) to the product compound (2) ((R)- or (S)-omeprazole) were determined that following general HTP assay conditions: 5 g/L pyrmetazole substrate, 10 μL of lysate of the engineered CHMO polypeptide, 1 g/L KRED of SEQ ID NO: 268, 0.5 g/L NADP, in a solution of 50 mM potassium phosphate buffer, 10percent (v/v) IPA, pH 9.0, 25° C. reaction temperature and 24 h reaction time (with 400 rpm stirring). Further details of the HTP assay methods are described in the Examples.
82.5 % ee With C64H64N4O6Ti2; 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.
71.5 % 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.
68 % ee With dihydrogen peroxide; acetic acid In methanol; water at 0℃; for 12 h; General procedure: The appropriate catalyst 5 (10 molpercent) and sulfide (1.0 mmol) were dissolved in CH3OH/H2O (1:1) (5 mL) and this solution was cooled to 0 °C. Subsequently the additive HOAc (2.0 mmol) and the oxidant hydrogen peroxide (1.5 mmol, 30percent, w/w) were added. The mixture was stirred for 12 h and then was treated with 10 mL of saturated ammonium chloridesolution and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated to give pure sulfoxides through flash column chromatography on silica gel (hexane/ethyl acetate(10:1)). All the products in the paper are known compounds that exhibited spectroscopic data identical to those reported in the literature [34]. The ee was determined by HPLC on chiral column (Daicel,Chiralpak, OD-H). The configuration of sulfoxides product from these reactions was proven to be (S) by comparing the specific rotation with the literature values [35].

Reference: [1] Patent: WO2007/88559, 2007, A1, . Location in patent: Page/Page column 9-10
[2] Patent: WO2007/88559, 2007, A1, . Location in patent: Page/Page column 10
[3] Russian Journal of Organic Chemistry, 2008, vol. 44, # 1, p. 124 - 127
[4] Synthesis, 2008, # 16, p. 2513 - 2518
[5] European Journal of Organic Chemistry, 2009, # 7, p. 987 - 991
[6] Patent: WO2010/43601, 2010, A1, . Location in patent: Page/Page column 23; 25
[7] Patent: WO2010/91652, 2010, A1, . Location in patent: Page/Page column 14
[8] Patent: WO2011/120475, 2011, A1, . Location in patent: Page/Page column 13; 14
[9] Patent: WO2011/120475, 2011, A1, . Location in patent: Page/Page column 14
[10] Tetrahedron Asymmetry, 2012, vol. 23, # 6-7, p. 457 - 460
[11] RSC Advances, 2014, vol. 4, # 87, p. 46545 - 46554
[12] Patent: US9228216, 2016, B2, . Location in patent: Page/Page column 50-52
[13] Catalysis Today, 2017, vol. 279, p. 84 - 89
[14] Catalysis Today, 2017, vol. 279, p. 84 - 89
[15] Catalysis Communications, 2017, vol. 92, p. 114 - 118
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  • [ 119141-88-7 ]
YieldReaction ConditionsOperation in experiment
67 % ee With dihydrogen peroxide In water; acetonitrile at -10℃; for 5 h; 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-1 H-benzimidazole (4a) (0.987 g , 3 mmol) and manganese complex of (R,R)-1 ,2-bis(3,5-di-te/f-butyl-2-hydoxybenzyl- amino)cyclohexane (10c) (96 mg, 5 mol percent) are dissolved in acetonitrile (45 ml). The reaction mixture is cooled to -100C and 30percent aqueous H2O2 (13.8 ml, 45 mol equiv) is added dropwise over 3 hours period. The reaction mixture is stirred for additional 2 hours. HPLC analysis shows formation of 56percent of sulfoxide (1a) with 67percent ee (S-enriched) and 5percent of sulfone.
9 % ee With dihydrogen peroxide In water; acetonitrile at 0 - 20℃; for 3.5 h; 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-1 H- benzimidazole (4a) and a preformed salan (10b) - metal complex are dissolved in acetonitrile. The reaction temperature is adjusted and 30percent aqueous H2O2 is added dropwise. The mixture is stirred for several hours. Then, it is poured portionwise into a cold (0 0C) 10percent aqueous Na2SO3 and stirred for additional 15 min and extracted with dichloromethane. The organic phase is dried over Na2SO4 and concentrated yielding an oily residue which is analyzed by chiral and achiral HPLC.Typically, runs were carried out on 1 mmol scale of the starting material 4a in acetonitrile (1 mmol 4a in 10 mL MeCN). The amounts of added reagents, temperature and reaction time in particular examples are indicated in Table 4. Also the results are indicated in Table 4.
75.1 % ee
Stage #1: With titanium(IV) isopropylate; C69H72N6O3 In water; toluene at 50℃; for 1 h; Inert atmosphere
Stage #2: With p-cumenyl hydroperoxide; N-ethyl-N,N-diisopropylamine In water; toluene at 25℃; for 0.5 h;
Titanium tetraisopropoxide (66.7 mg, 0.235 mmol) and water (8.0 mg, the total amount of water is 8.47 mg, 0.47 mmol) were added to a solution of L1 (67.1 mg, 0.065 mmol) in toluene (20 mL) at 25 C. After stirring at that temperature for 1 h, pyrmetazol (165.0 mg, 0.5 mmol) was added. Then, the mixture was heated to 50 Cand maintained for 1 h. After the mixture was cooled to 25 C, N,N-diisopropylethylamine (16.8 mg, 0.13 mol) and cumene hydroperoxide (80percent in cumene, 110.5 mg,0.65 mmol) were added subsequently. After stirring at 25 C for 1 h, a small sample of reaction mixture was taken for HPLC analysis for conversion and selectivity, and the product was isolated by preparative thin-layer chromatography (TLC; eluent: CH2Cl2/MeOH 25/1) for determination of the enantiomeric purity.
Reference: [1] Patent: WO2009/66321, 2009, A2, . Location in patent: Page/Page column 19
[2] Patent: WO2009/66321, 2009, A2, . Location in patent: Page/Page column 19-20
[3] Patent: WO2010/43601, 2010, A1, . Location in patent: Page/Page column 31
[4] Patent: WO2010/43601, 2010, A1, . Location in patent: Page/Page column 30; 31
[5] Synthetic Communications, 2015, vol. 45, # 1, p. 70 - 77
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