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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
Omeprazole sulfide is an inhibitor of proton pump, it is the metabolite of omeprazole.
Synonyms: Ufiprazole; Pyrmetazole; OMZ sulfide
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CAS No. : | 73590-85-9 |
Formula : | C17H19N3O2S |
M.W : | 329.42 |
SMILES Code : | CC1=CN=C(CSC2=NC3=CC(OC)=CC=C3N2)C(C)=C1OC |
Synonyms : |
Ufiprazole; Pyrmetazole; OMZ sulfide
|
MDL No. : | MFCD00869021 |
InChI Key : | XURCIPRUUASYLR-UHFFFAOYSA-N |
Pubchem ID : | 155794 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
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. |
Yield | Reaction Conditions | Operation 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]. |
Yield | Reaction Conditions | Operation 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 1; Preparation of 5-methoxy-2-["[Y4-methoxy-3 ,5-dimethyl-2-pyridinylVmethvn sulfinyl]-lH-benzimidazole potassium salt; Titanium isopropoxide (60.4.g) and D- (-) diethyl tartarate (87.6 g) was taken and stirred at room temperature under an inert atmosphere. Temperature was " increased up to 55-6O0C and 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2- pyridinyl)-methyl]thio]-lH-benzimidazole (100 g) was added at the above temperature. The resulting mixture was stirred for 30 minutes at the same temperature. Water (1.4 ml) was added and was stirred for another one hour. The resulting reaction mass was cooled to 5-1O0C and cumene hydroperoxide (78 g) was added. The resulting mixture was stirred for 3-4 hours at 5-1O0C. After completion of the reaction, toluene, triethylamine and water was added to the resulting reaction mixture. The organic layer was separated and washed with water. The organic layer was then cooled to 10-150C and methanolic potassium hydroxide (17.9 g dissolved in 145 ml methanol) was added. The resulting mixture was stirred for 30 minutes, seeded with pure potassium S-omeprazole and further stirred for 3-4 hours at room temperature. The resulting solid was filtered off, washed with toluene and methanol and dried under vacuum for 2-3 hours at 45-5O0C. The resulting solid was dissolved in water (350 ml) at room temperature. The pH was adjusted to 7.5-8.0 with acetic acid and dichloromethane (500 ml) was added. The organic layer was seperated, washed with brine and distilled off. The resulting oily mass was dissolved in methyl ethyl ketone (350 ml) at room temperature under stirring. The resulting reaction mass was then cooled to 10-150C and methanolic potassium hydroxide (7.2 g potassium hydroxide in 36 ml methanol) was added. The resuting mixture was stirred for 4-5 hours at room temperature, first and then cooled to 10-150C under stirring. Solid was filtered off, washed with methyl ethyl ketone and dried under vacuum at 40-450C for 6-8 hours.Yield: = 45-50 gSulfone = 0.15percent <n="11"/>HPLC Purity = 99.7percentChiral purity =99.9percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Water (157.6 mul) was added to a solution of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole in toluene (370 ml; 211.5 g/l) with a water content 25 of 0.031percent (w/w), followed by addition of D-(-)-diethyl tartrate (8.55 ml). The solution was heated to 50° C. and stirred at this temperature for 20 minutes. Titanium (IV) isopropoxide (7.15 ml) was added and reaction was left at 50° C. for 45 minutes. The temperature was lowered to 30° C. and diisopropylethylamine (6.2 ml) was added. Cumene hydroperoxide was added at an appropriate speed to maintain the temperature from 28° C. to 34° C. The temperature was raised to 35° C. after 2 hours and potassium methoxide (24.55 g) in methanol (222 ml) was added. The mixture was filtered after 14 hours and the crystals were washed with methanol:toluene (240 ml; 1:1) and methanol (120 ml) and dried. Yield: 79 g (74percent), ee>99.9percent. [00044] [alpha]D20=+28.7° (c=1percent, water); Assay: 89percent is S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole potassium salt (11percent is methanol). [00045] 1H-NMR (200 MHz, DMSO-d6, delta ppm): 2.23 (s, 3H), 2.24 (s, 3H), 3.71 (s, 3H), 3.75 (s, 3H), 4.40 (d, 1H), 4.78 (d, 1H), 6.58 (dd, 1H), 7.00 (d, 1H), 7.35 (d, 1H), 8.25 (s, 1H). | |
54% | Example 2 S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfnyl]-1H-benzimidazole Potassium Salt A solution of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole (15.4 g, 46.8 mmol) in toluene (70 ml) was heated to 50° C. and water (0.05 ml, 2.8 mmol) and D-(-)-diethyl tartrate (2.02 g, 9.82 mmol) were added.. The reaction mixture was stirred for 20 minutes.. titanium (IV) isopropoxide (1.34 g, 4.68 mmol) was added and the reaction mixture was stirred for 45 minutes.. The mixture was cooled to 30° C. and diisopropylethylamine (0.91 g, 7.01 mmol) was added followed by cumene hydroperoxide (9.52 g, 51.89 mmol).. The resultant mixture was stirred at 30° C. for 3 hours.. methanol (40 ml) was added followed by potassium hydroxide (3.05 g, 46.8 mmol) in methanol (30 ml).. Seed crystals were added and the reaction mixture was stirred at 35° C. overnight.. The precipitated product was filtered off, washed with methanol and toluene and dried in vacuo. Yield: 9.74 g (54percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91 - 92% | With dihydrogen peroxide;molybdenyl acetylacetonate; In methanol; water; at 0 - 5℃; for 3h; | EXAMPLE 3; 3 g of Omeprazole precursor: 2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylthio]-5-methoxy-1H-benzimidazole, 0.09 g of Mo(acac)2 oxidation catalyst were dissolved in 20 ml of methanol by stirring. The temperature of the resulting solution was reduced to 0-5° C., followed by adding 1.17 g of 35percent H2O2 aqueous solution. The reaction was carried out for about two hours, 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 Omeprazole with a yield of about 91-92percent (HPLC purity >98percent). |
91% | With dihydrogen peroxide; sodium carbonate;sodium tungstate; In methanol; water; at 20℃; for 0.666667h;Product distribution / selectivity; | EXAMPLE 2; The procedures in Example 1 were repeated except that the 1.88 g of 45percent NaOH was replaced by 1.93 g of Na2CO3. Omeprazole yield: 91percent (LC purity>95percent). |
~ 88% | With sodium hydroxide; dihydrogen peroxide;sodium tungstate; In methanol; water; at 20℃; for 0.666667h;Product distribution / selectivity; | EXAMPLE 1; 2 g of 2-[[(3,5-dimethyl-4-methoxy-2-pyridinyl)methyl]thio]-5-methoxy-1H-benzimidazole was suspended in 36 ml of methanol at room temperature, to which 1.88 g of 45percent NaOH in 14 ml water was added while stirring. 0.09 g of Na2WO4*2H2O oxidation catalyst was dissolved in 0.74 g H2O2 (50percent aqueous solution), and further diluted with 10 ml. of water. The oxidant/catalyst solution was added to the reactant/base solution dropwise so that the addition was completed in about 30 minutes while stirring at room temperature. The reaction was continued for additional 10 minutes while stirring. 10 ml of 10percent Na2S2O3 aqueous solution was then added, and the resulting mixture was subjected to a reduced pressure to remove methanol therefrom. Finally, a precipitate was formed after adding a diluted acetic acid aqueous solution to a pH value of about 8, which was filtered, water washed, and dried in vacuo to obtain Omeprazole with a yield of about 88percent (LC purity>95percent). |
88% | 10 g of <strong>[73590-85-9]omeprazole sulfide</strong>,8.6gTetraisopropyl titanate50 ml of toluene,Stirring at 30 ° C to dissolve and clarify.Cooling to 25 ,Insulated drop of 9.2gHydrogen peroxide cumene,60 minutes drop finished,After the drop,25 holding temperature 4h.The organic solvent was distilled off under reduced pressure,The residue was washed with acetone,filter,dry,To give 9.2 g of a white solid,The molar yield was 88percentChromatography purity 99.35percentThe content of peroxide impurity in formula III is 0.52percent. | |
88.4% | Omeprazole sulfide 6.58g (0.02mol)Soluble in 100ml of absolute ethanol,Adjust to pH=8-9 with triethylamine.240 mg of graphene oxide containing Ti4 + mass 4.0percent was added.Stir at 40 ° C for 10 min,3.4 g (0.03 mol) of 30percent hydrogen peroxide was slowly added dropwise.After the dropwise addition, the reaction was carried out for 3 h. The catalyst was filtered off.And washed three times,The collected filtrate was concentrated to give a crude omeprazole.Then beat with ethyl acetate and filter by suction.Drying to get omeprazole 6.1g,The yield was 88.4percent. | |
79.1% | With m-chloroperoxybenzoic acid; In ethyl acetate; | EXAMPLE 1 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]benzimidazole (10 g; 0.0304 mole) was suspended in ethyl acetate (100 ml) and cooled below 0° C. 3-chloroperoxybenzoic acid (5.25 g; 0.0304 mole) was added in such a manner that the temperature did not exceed 5° C. After completed addition it was left to crystallize for another half an hour at a temperature below 5° C. The product formed was filtered off, washed with ethyl acetate and dried in vacuo. Crude omeprazole (8.3 g; 79.1percent) was obtained. |
76.2% | With m-chloroperoxybenzoic acid; sodium carbonate; In ethyl acetate; | EXAMPLE 2 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]benzimidazole (10 g; 0.0304 mole) was suspended in ethyl acetate (100 ml) and cooled below 0° C. 3-chloroperoxybenzoic acid (5.25 g; 0.0304 mole) was added in such a manner that the temperature did not exceed 5° C. After the completed addition it was stirred for half an hour, the cooling was removed, a 4percent sodium carbonate solution (40 ml) was added and it was stirred for another half an hour. The product was filtered off and washed with water. After drying in vacuo crude omeprazole (8.0 g; 76.2percent) was obtained and it was purified according to the process disclosed in Example 1. |
75% | With titanium(IV) isopropylate; D-tartaric acid; Cumene hydroperoxide; N-ethyl-N,N-diisopropylamine; In toluene; at 20 - 65℃; for 1h; | In a 500 mL three-necked flask,A solution of 5-methoxy-2- (4-methoxy-3,5-dimethyl-2-pyridyl) methylthio-1H-benzimidazole(14.8 g, 45 mmol) was added to 75 mL of toluene, the temperature was raised to 65 ° C,Dissolved after addingD-tartrate(5.7 g, 27.5 mmol)And tetraisopropyl titanate(3.9 g, 13.8 mmol),While adding a small amount of purified water,After stirring for 1 hour,Down to 10 ° C. N, N-diisopropylethylamine (1.6 g, 12 mmol)And toluene-diluted cumene hydroperoxide (8 g, 45 mmol) were added and the reaction was continued at 20 ° C for 1 hour. After completion of the reaction, ammonia (60 mL) and purified water were added and stirred for 20 minliquid. The aqueous layer was added to dichloromethane (150 mL) and stirred for 20 min. The dichloromethane layer was added anhydrous sodium sulfate (15 g)Dried and dried for 1 hour, then filtered, and the dichloromethane was removed by steaming under reduced pressure at 50 ° C,The oil is an esomeprazole, Product yield 75percent. |
~ 69% | With dihydrogen peroxide;sodium tungstate; In ethanol; water; at 20℃; for 6.5h;Product distribution / selectivity; | CONTROL EXAMPLE 2; 0.35 g of 2-[[(3,5-dimethyl-4-methoxy-2-pyridinyl)methyl]thio]-5-methoxy-1H-benzimidazole was suspended in 5 ml of ethanol at room temperature. 0.035 g of Na2WO4*2H2O oxidation catalyst was dissolved in 0.099 g H2O2 (35percent aqueous solution), and further diluted with 2 ml of water. The oxidant/catalyst solution was added to the reactant suspension dropwise so that the addition was completed in about 30 minutes while stirring at room temperature. The reaction was continued for additional 6 hours while stirring. 2 ml of 10percent Na2S2O3 aqueous solution was then, added, and the resulting mixture was subjected to a reduced pressure to remove ethanol therefrom. Finally, a precipitate was formed after adding a diluted acetic acid aqueous solution to a pH value of about 8, which was filtered, water washed, and dried in vacuo to obtain Omeprazole with a yield of about 69percent (LC purity>80percent). |
63 - 79% | With tert.-butylhydroperoxide;bis(acetylacetonate)oxovanadium; In ethanol; water; at 16 - 17℃; for 3.08333h; | 1.5 mg (0.6percent molar) VO(acac)2) was dissolved in 12 ml ethanol at room temperature. The solution was stirred and 3 grams of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]benzimidazole (MPB) were added. 1.5 ml aqueous tert-butyl hydroperoxide (TBHP) (70percent) was added over a 5-minute period at 16-17° C. and the solution was then stirred for 3 hours. After completion of the reaction, the product mixture was cooled to about 15° C. and treated with aqueous sodium metabisulphate. The resultant solid was filtered off, washed with cooled ethyl acetate to afford the end product as an almost white solid (2.5 grams, yield 79percent). |
32% | With dihydrogen peroxide;bis(acetylacetonate)oxovanadium; In ethanol; water; at 20℃; for 12h; | 4 mg (0.06percent molar) VO (acac)2 were added to suspension of 9 grams of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-1H-benzimidazole (MPB) in 66 ml ethanol at room temperature. 35 ml of 35percent aqueous hydrogen peroxide (150percent mol) was added at room temperature with no visible exotherm, the mixture was then stirred. After 12 hours the reaction mixture still contained 65percent of untreated MPB and only 32percent omeprazole. Prolongation of the reaction time did not lead to further production of omeprazole. |
With sodium hydroxide; sodium hypochlorite; In dichloromethane; water; at -5 - 0℃; for 3h; | ((5-METHOXY-2-[[(4-METHOXY-3, 5-DIMETHYL-2-PYIRDYL) METHYL]-THIO]-LH-BENZIMIDAZOLE, (20g) was suspended in 200ML of dichloromethane. 140g of sodium hypochlorite solution (chlorine content: 3.6-4. 2percent ; sodium hydroxide content: 2.8-3. 0 percent) was added over a period of 3 hours maintaining a temperature OF-5°C to 0°C. The organic layer was separated and extracted with 200ml of 5percent sodium hydroxide solution. The pH of the aqueous layer was adjusted to between 8-8.5 using dilute acetic acid. The solids were filtered, washed with chilled water and dried in an oven to give 17g of the title compound. | |
With peracetic acid; In ethyl acetate; | Example 4 Preparation of Omeprazole To a solution of 100 g of the product from Example 3 in ethyl acetate (500 ml) was added peracetic acid (125 g) slowly at a temperature of -25°C. The contents were further stirred for 30 minutes and the pH of the mixture was adjusted to 8 with 10percent aqueous sodium hydroxide. The product thus precipitated was filtered and washed with water. The crude product was purified from methanol to afford 85g of pure omeprazole. | |
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 5℃; for 0.333333 - 0.416667h; | EXAMPLE 3; Preparation of 5/6-methoxy-1benzyloxycarbonyl-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleTo a solution of 5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylthio]-1H-benzimidazole (30 g) in dichloromethane (165 mL) at 0-5° C., under an inert atmosphere, was added meta-chloroperbenzoic acid (0.95 eq) over 10 minutes. The mixture was stirred for 10-15 minutes. To the reaction was added 12percent ammonium hydroxide (180 mL). The layers were separated. The organic layer was extracted with 12percent ammonium hydroxide (2.x.180 mL). The combined aqueous layers were washed with toluene (90 mL). To the aqueous layer was added dichloromethane (120 mL) and the mixture was cooled to 0-5° C. The pH was adjusted to pH=8.5-9.5 using 50percent aqueous acetic acid. The layers were separated. The aqueous layer was extracted with dichloromethane (2.x.90 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered through celite and vacuum distilled to 150 mL to give a solution of 5-methoxy-2-[[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulphinyl]1H-benzimidazole in dichloromethane. | |
With trans-stilbene ozonide; In methanol; for 3.5h;Heating / reflux;Product distribution / selectivity; | Trans-stilbene ozonide was prepared following the recipe of example 1, in an amount of 0.031 mol.The thus-prepared ozonide was added drop-wise over 0.5h to a boiling solution of sulfide (0.031 mol) in 100 ml of methanol. The reaction solution is boiled for 3 hours under reflux conditions. The experiment was performed for a number of sulfides, generally represented by formula III. After 3 hours, the reaction mixtures were analyzed for conversion rate. The results are shown in table 1. In all cases, sulfoxide selectivity was 100percent. | |
With 1-hexen-ozonide; In methanol; for 3.5h;Heating / reflux;Product distribution / selectivity; | 21 g 1-Hexene (0.20 mol) in 500 ml of methanol at -15°C was converted with 1.2 molar equivalents of ozone, thus producing 1-hexen-ozonide. The ozonide was present as a clear solution in methanol.The solution was used directly for the oxidation of the sulfides represented by formula III. Thereto, the ozonide was added dropwise over 0.5h to the boiling solution of the sulfide (0.20 mol) in 200 ml methanol. The reaction solution was refluxed for 3 hours. After 3 hours, the reaction mixtures were analyzed for conversion rate. The results are shown in table 2. In all cases, sulfoxide selectivity was 100percent. | |
With dihydrogen peroxide;sodium molybdate; In water; acetic acid; ethyl acetate; at 5 - 12℃; for 6.75h;pH 6 - 6.5; | 2-(chloromethyl)-3,5-dimethyl-4-methoxy pyridine hydrochloride (IV) (100.0 g) and 2-mercapto-5-methoxy benzimidazole (III) (81.0 g) were taken in RBF. Ethyl Acetate (400 mL) was added to RBF at 25°C to 350C. Sodium hydroxide (50.0 g) solution in water (200 mL) was added to the reaction mass within 30 mins. The reaction0 mass was stirred for 1 hr and heated to 500C to 55°C for 1 hr. After completion of the reaction on TLC, reaction mass was cooled to 250C to 300C. Water (200 mL) was added and stirred to separate the organic and aqueous layers. Aqueous layer was extracted with ethyl acetate (150 mL) and separated. The combined ethyl acetate layer was charcaolised (5.0 g) and stirred for 30 mins. The reaction mass was filtered through hyflow bed and washed with ethyl acetate (50 mL). The pH of the organic layer was adjusted to about 6.0 to 6.5 with acetic acid (0.5 mL) and cooled to 5°C to 100C.Sodium molybdate (1.33 g) solution in water (13.2 mL) was added to the reaction mass and stirred for 15 mins. 50percent hydrogen peroxide (37.0 g) was added into the reaction mass within 1.5 hrs at 5°C to 12°C. The reaction mass was stirred for 5 hrs.After completion of the reaction on TLC, the reaction mass is treated with sodium thiosulphate (11.0 g) solution in water (11.0 mL). Sodium hydroxide (6.0 g) solution in water (6 mL) was added into the reaction mass to adjust the pH of about 7.0 to 7.5. The reaction mass was further cooled to 00C to 5°C and stirred for 60 mins. The product was filtered and washed with mixture of methanol (50 mL) and water (50 mL) followed by washing with chilled ethyl acetate (75 mL).Crude omeprazole (120.0 g) wet-cake as obtained above and methanol (160 mL) were taken in another RBF at 25°C to 35°C. Sodium hydroxide (15.8 g) solution in water (176 mL) was added into the reaction mass. Charcaol (2.6 g) was added and stirred for 30 mins. The reaction mass was filtered on hyflow bed and washed with mixture of methanol (10 mL) and water (10 mL). The filtrate was treated with sodium hydrosulphite (2.0 g). The reaction mass was slowly treated with acetic acid (22.5 mL) to adjust the pH of about 7.5 to 7.9. The product was filtered and washed with water(244 mL) and dried at 400C to 45°C to obtain 100.0 g crystalline omeprazole Form B. Yield 68percent based on input 2-(chloromethyl)-3,5-dimethyl-4-methoxy pyridine hydrochloride (IV).HPLC purity: 99.87percentIndividual Impurities are as under:Im purity- A at RRT 0.44 : 0.01percent Impurity-B at RRT 0.46 : Not detectedImpuriry-C at RRT 0.80 : 0.02percentImpurity-D at RRT 0.90 : Not detectedImpurity-E at RRT 3.26 : Not detectedUnk Impurity: 0.03percent Total Impurities : 0.13percentImpurity-A: 5-methoxy- 1 H-benzimidazole-2-thiolImpurity-B: 2-[(R,S)]-[(3,5-dimethylpyridine-2-yl)methyl]sulphinyl]-5-methoxy-lH- benzimidazole Impurity-C: 5-methoxy-2[[4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulphanyl]- lH-benzimidazole [Omeprazole Sulfide]Impurity-D: 5-methoxy-2[[4-methoxy-3,5-dimethylpyridin-2-yl)methyl]suIphonyl]- lH-benzimidazole [Omeprazole Sulfone] Impurity-E: 4-methoxy-2-[[(R,S)-(5-methoxy- 1 H-benzimidazole-2-yl)- sulphinyl]methyl)-3,5-dimethylpyridine- 1 -oxide [Omeprazole N-Oxide] | |
With dihydrogen peroxide;bis(acetylacetonate)oxovanadium; In water; acetone; at 10 - 15℃; for 3.5h; | Preparation of omeprazoleVanadyl acetylacetonate (4.8 gm) was added to water (210 ml) and then cooled to 0 to 10°C. To the reaction mixture was added hydrogen peroxide (50 percent, 120 ml) at 0 to 10°C and stirred for 20 minutes. 5-Methyoxy-2-[[(4-methoxy-3,5-dimethylpyridin-2- yl)methyl]thio]-l H-benzimidazole (480 gm) and acetone (1950 ml) were added to the reaction mixture. The reaction mixture was maintained for 3 hours 30 minutes at 10 to 15°C and then added sodium hydroxide (46 percent, 16 ml) and water (1600 ml). The reaction mass was then cooled to 0 to 5°C and pH of the reaction mass was adjusted to 7.5 to 8.5 with acetic acid (1 1 gm) at 0 to 10°C. The reaction mass was stirred for 2 hours and filtered to obtain a wet solid. To the wet solid was added water (700 ml) and then added liquor ammonia (38 gm) and methanol (700 ml) at room temperature. The reaction mass was then cooled to 0 to 10°C, stirred for 45 minutes and filtered. The solid obtained was dried to give 405 gm of omeprazole. |
Yield | Reaction Conditions | Operation in experiment |
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84% | With oxone; sodium hydrogencarbonate;bis(acetylacetonate)oxovanadium; In methanol; water; at -2 - 0℃; for 5.5h; | A mixture of 3 grams 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl] thio]benzimidazole (MPB), 3 grams NaHCO3 and 20 ml aqueous methanol was cooled to -2° C. and 3.5 ml (5.69 mmol) Oxone.(R). was added. The mixture was stirred for 4 hours at 0° C. and a further 1 gram (mmol) Oxone.(R). was added and stirring continued for 1.5 hours. A solution of 0.8 gram sodium metabisulfite in 20 ml water was added dropwise over 5-10 minutes. After further stirring the resultant precipitate was filtered, washed successively with water and 50percent aqueous methanol and dried. [0064] Yield 2.7 grams, 84percent (purity 98.1percent), SOMP 0.15percent. |
83.5% | With tert.-butylhydroperoxide;bis(acetylacetonate)oxovanadium; In water; isopropyl alcohol; | The above described processes of Example 1 and Example 2 were repeated while using the conditions given in Table I below, to give the following results: |
74.6% | With tert.-butylhydroperoxide;bis(acetylacetonate)oxovanadium; In water; toluene; | The above described processes of Example 1 and Example 2 were repeated while using the conditions given in Table I below, to give the following results: |
68.5 - 80.7% | With tert.-butylhydroperoxide;bis(acetylacetonate)oxovanadium; In toluene; at 5 - 22℃; for 3h; | 15 mg (0.6percent molar) VO(acac)2) in 5 ml toluene were added to a suspension of 3 grams of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]benzimidazole (MPB) in 30 ml toluene at a temperature of about 5° C. 3.5 ml of tert-butyl hydroperoxide (TBHP) in toluene (3M, 115percent) were added dropwise, while the temperature was maintained between 5 and 7° C. Upon completing the addition of the TBHP, the temperature rose to 22° C. The reaction was allowed to proceed to completion (about 3 hours), after which the cooled product mixture was treated with aqueous sodium metabisulphite. The solid product was filtered off, washed with cooled ethyl acetate and dried in an oven (yield 80.7percent) |
60% | With sodium hydrogencarbonate;bis(acetylacetonate)oxovanadium; In water; acetone; for 30.75h; | The above described reaction of Example 8 was repeated while using the conditions given in Table II below, to give the following results: |
> 50% | With tert.-butylhydroperoxide;vanadium(V) oxide; SiO2; In methanol; water; | The above described processes of Example 1 and Example 2 were repeated while using the conditions given in Table I below, to give the following results: |
> 50% | With tert.-butylhydroperoxide;sodium vanadate; In methanol; water; | The above described processes of Example 1 and Example 2 were repeated while using the conditions given in Table I below, to give the following results: |
> 50% | With tert.-butylhydroperoxide;bis(acetylacetonate)oxovanadium; In methanol; water; | The above described processes of Example 1 and Example 2 were repeated while using the conditions given in Table I below, to give the following results: |
50.7% | With tetrabutylammomium bromide; sodium hydrogencarbonate;bis(acetylacetonate)oxovanadium; In water; ethyl acetate; for 30.75h; | The above described reaction of Example 8 was repeated while using the conditions given in Table II below, to give the following results: |
Yield | Reaction Conditions | Operation in experiment |
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Example; 1 5-Methoxy-2- [(3,5-dimethyl-4-methoxy-2-pyridyl)methylthio]-1H- benzimidazole (15 gm) was dissolved in methylene chloride (150 ml) and N,N- diisopropylethylamine (9.0 gm) was added to the solution. The solution was cooled to 0°C - 5°C. (R) -Camphor sulfonyl chloride (14.0 gm) dissolved in 25 ml of methylene chloride was added slowly for one hour at 0°C - 5°C. The reaction mixture was maintained at 0°C - 5°C for 3 hours. The pH was adjusted to 6.0- 6.5 with acetic acid, then ice-cooled water (60 ml) was added. The layers were separated. The organic layer was washed with 10percent aqueous sodium chloride. The organic layer was distilled under reduced pressure to obtain a residue containing the mixture of 1-(R)-camphor sulfonyl-5-methoxy-2-[(3,5-dimethyl-4- methoxy-2-pyridyl) methylthio]-1H-benzimidazole and 1-(R)-camphor sulfonyl-6- methoxy-2- [(3,5-dimethyl-4-methoxy-2-pyridyl)methylthio]-1H-benzimidazole (19.8 gm). |
Yield | Reaction Conditions | Operation in experiment |
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79% | In ethanol; | Example 1 Selective Oxidation of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl]thio]-1H-benzimidazole to form 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl]sulfinyl]-1H- benzimidazole (Omeprazole) 1.5 mg (0.6percent molar) VO (acac)2) was dissolved in 12 ml ethanol at room temperature. The solution was stirred and 3 grams of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]benzimidazole (MPB) were added. 1.5 ml aqueous tert-butyl hydroperoxide (TBHP) (70percent) was added over a 5-minute period at 16-17° C. and the solution was then stirred for 3 hours. After completion of the reaction, the product mixture was cooled to about 15° C. and treated with aqueous sodium metabisulphate. The resultant solid was filtered off, washed with cooled ethyl acetate to afford the end product as an almost white solid (2.5 grams, yield 79percent). |
Yield | Reaction Conditions | Operation in experiment |
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With tert.-butylhydroperoxide;VO(acac)2; In toluene; | Example 2 Selective Oxidation of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-1H-benzimidazole to form 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl]sulfinyl]-1H-benzimidazole (Omeprazole) 15 mg (0.6percent molar) VO(acac)2) in 5 ml toluene were added to a suspension of 3 grams of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]benzimidazole (MPB) in 30 ml toluene at a temperature of about 5° C. 3.5 ml of tert-butyl hydroperoxide (TBHP) in toluene (3M, 115percent) were added dropwise, while the temperature was maintained between 5 and 7° C. Upon completing the addition of the TBHP, the temperature rose to 22° C. The reaction was allowed to proceed to completion (about 3 hours), after which the cooled product mixture was treated with aqueous sodium metabisulphite. The solid product was filtered off, washed with cooled ethyl acetate and dried in an oven (yield 80.7percent) |
Yield | Reaction Conditions | Operation in experiment |
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With N-ethyl-N,N-diisopropylamine; isopropylbenzene hydroperoxide;titanium(IV) isopropylate; In 2,2,4-trimethylpentane; water; ethyl acetate; acetone; | Example 9 Asymmetric synthesis followed by optical purification of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulphinyl]-1H-benzimidazole, (+)-(Ia) 1.6 kg (5.0 mol) of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole was dissolved in 7.51 of ethyl acetate. To the solution was added 31 ml (1.7 mol) water. To the mixture was added 856 ml (5.0 mol) of (+)-diethyl L-tartrate, 744 ml (2.5 mol) of titanium(IV) isopropoxide and 436 ml (2.5 mol) diisopropylethylamine at room temperature. The addition of 830 ml (4.5 mol) cumene hydroperoxide was then performed at 30° C. After stirring for one hour at 30° C. the reaction was complete. Chiral and achiral chromatographic analyses showed that the mixture consited of 75percent sulphoxide with an enantiomeric excess (e.e.) of 80percent. The mixture was cooled to 10° C. and after addition of 1.5 l of isooctane and ethyl acetate (0.5 l), the product was extracted three times with an aqueous ammonia (12percent) solution with a total volume of 14 l. The combined aqueous phases were neutralised by addition of 1.5 l of concentrated acetic acid in the presence of ethyl acetate (4 l). The phases were separated and the aqueous phase was extracted with ethyl acetate (4 l). The solvent of the combined organic solutions was removed. Acetone (3.0 l) was added to precipitate the racemate of omeprazole which was filtered off. HPLC--analyses (achiral and chiral columns) of the filtrate showed that this solution consisted of 90percent sulphoxide with an optical purity of 95percent e.e. and thus the optical purity has been improved from 80percent e.e. to 95percent e.e. simply by one precipitation of racemic omeprazole. Further, a content analysis (HPLC) of the filtrate showed that the yield was 1.0 kg (58percent). |
Yield | Reaction Conditions | Operation in experiment |
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With N-ethyl-N,N-diisopropylamine; isopropylbenzene hydroperoxide;titanium(IV) isopropylate; In 2,2,4-trimethylpentane; water; ethyl acetate; acetone; acetonitrile; | Example 8 Asymmetric synthesis followed by optical purification of (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulphinl]-1H-benzimidazole, (-)-(Ia) 1.6 kg (5.0 mol) of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole was dissolved in 5.01 of ethyl acetate. To the solution was added 31 ml (1.7 mol) of water. To the mixture was added 856 ml (5.0 mol) of (-)-diethyl D-tartrate, 744 ml (2.5 mol) of titanium(IV) isopropoxide and 435 ml (2.5 mol) of diisopropylethylamine at room temperature. The addition of 830 ml (4.5 mol) cumene hydroperoxide was then performed at 30° C. After stirring for one hour at 30° C. the reaction was complete. Chiral and achiral chromatographic analyses showed that the mixture consisted of 71.4percent sulphoxide with an enantiomeric excess (e.e.) of 72.9percent. The mixture was cooled to 10° C. and after addition of 1.7 l of isooctane, the product was extracted three times with an aqueous ammonia (12percent) solution with a total volume of 10 l. The combined aqueous phases were neutralised by addition of 1.5 l of concentrated acetic acid in the presence of ethyl acetate (3 l). The phases were separated and the aqueous phase was extracted with ethyl acetate (3 l). The solvent of the combined organic solutions was removed and at the end of the evaporation acetonitrile (1.5 l) was added to facilitate the removal of solvent. Acetone (2.5 l) was added to precipitate the racemate of omeprazole which was filtered off (254 g). HPLC-analyses (achiral and chiral columns) of the filtrate showed that this solution consited of 88percent sulphoxide with an optical purity of 96.3percent e.e. and thus the optical purity has been improved from 72.9percent e.e. to 96.3percent e.e. simply by one precipitation of racemic omeprazole. Further, a content analysis (HPLC) of the filtrate showed that the yield was 0.8 kg (46percent). |
Yield | Reaction Conditions | Operation in experiment |
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With isopropylbenzene hydroperoxide;titanium(IV) isopropylate; In water; toluene; | Example 2 Asymmetric synthesis of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulphinyl]-1H-benzimidazole, (+)-(Ia) Titanium(IV) isopropoxide (1.3 ml, 4.5 mmol) and water (41 mul, 2.3 mmol) were added with stirring to a solution of (+)-diethyl L-tartrate (1.5 ml, 9.0 mmol) dissolved in toluene (10 ml). The mixture was stirred for 20 minutes at room temperature and then 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole (3.0 g, 9 mmol) and diisopropylethyl amine (0.45 ml, 2.6 mmol) were introduced. At 30 C. cumene hydroperoxide (tech, 80%, 1.8 ml, 9.9 mmol) was added. After 3 h at 30 C. the mixture consisted of 2.1% sulphide, 8.8% sulphone and 86.8% sulphoxide with an enantiomeric excess of 74%. |
Yield | Reaction Conditions | Operation in experiment |
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With potassium hydrogencarbonate; isopropylbenzene hydroperoxide;titanium(IV) isopropylate; In water; ethyl acetate; | Example 3 Asymmetric synthesis of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulphinyl]-1H-benzimidazole, (+)-(Ia). To a mixture of (+)-diethyl L-tartrate (4.2 g, 20 mmol), titanium(IV) isopropoxide (2.9 g, 10 mmol) and ethyl acetate was added water (0.18 ml, 10 mmol). The solution was stirred for 20 minutes whereupon 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole (3,4 g, 10 mmol) was added together with KHCO3 (0.31 g, 3.1 mmol) and cumene hydroperoxide (1.8 ml, 10 mmol). The addition was performed at room temperature. HPLC analysis was performed after 1.5 hours which showed 63.3percent sulphoxide with an enantiomeric excess of 38.9percent. | |
With isopropylbenzene hydroperoxide;titanium(IV) isopropylate; In dichloromethane; water; | Example 6 Asymmetric synthesis of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulphinyl]-1H-benzimidazole, (+)-(Ia). (+)-Diethyl L-tartrate (1.71 ml, 10 mmol) and titanium(IV) isopropoxide (1.5 ml, 5 mmol) were dissolved in methylene chloride (50 ml). Water (90 mul, 5 mmol) was added with stirring and the resultant mixture was heated to reflux for one hour. The mixture was cooled to room temperature. Thereafter, 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole (1.65 g, 5 mmol) and cumene hydroperoxide (80percent, 1.05 g, 5.5 mmol) were added at room temperature. The solution was stirred at room temperature for 90 minutes. The crude mixture was shown to consist of 42.8percent sulphide, 4.1percent sulphone and 48.3percent sulphoxide with an optical purity of 43percent e.e. The product was not isolated. | |
With isopropylbenzene hydroperoxide;titanium(IV) isopropylate; In dichloromethane; water; | Example 7 Asymmetric synthesis of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulphinyl]-1H-benzimidazole, (+)-(Ia). 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole (1.65 g, 5 mmol) was dissolved in methylene chloride (50 ml). (+)-Diethyl L-tartrate (1.71 ml, 10 mmol), titanium(IV) isopropoxide (1.5 ml, 5 mmol) and water (90 mul, 5 mmol) were added with stirring. The resultant mixture was stirred at room temperature for 20 minutes. Thereafter, cumene hydroperoxide (80percent, 1.05 g, 5.5 mmol) were added at room temperature and the solution was stirred at room temperature for 90 minutes. The crude mixture was shown to consist of 38.9percent sulphide, 8.4percent sulphone and 47.6percent sulphoxide with an optical purity of 32percent e.e. The product was not isolated. |
With isopropylbenzene hydroperoxide;titanium(IV) isopropylate; In water; toluene; | Example 8 Asymmetric synthesis of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulphinyl]-1H-benzimidazole, (+)-(Ia). 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole (0.5 g, 1.5 mmol) was suspended in toluene (2.5 ml). Water 9.2 mul (0.5 mmol), (+)-Diethyl L-tartrate (0.39 ml, 2.3 mmol) and titanium(IV) isopropoxide (0.27 ml, 0.91 mmol) were added at 50° C. The mixture was warmed at 50° C. for 90 minutes whereupon 0.25 ml of the solution was transferred to a test-tube. To this tube was then added 25 mul of cumene hydroperoxide (80percent) and almost immediately thereafter this mixture consisted of 41percent desired sulphoxide with an optical purity of 69.5percent ee. The product was not isolated. |
Yield | Reaction Conditions | Operation in experiment |
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With N-ethyl-N,N-diisopropylamine; isopropylbenzene hydroperoxide;titanium(IV) isopropylate; In toluene; | Example 5 Asymmetric synthesis of (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulphinyl]-1H-benzimidazole, (-)-(Ia). 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-thio]-1H-benzimidazole (4.0 g, 12.1 mmol) was suspended in toluene (12 ml) (-)-Diethyl D-tartrate (0.17 ml, 1.0 mmol) and titanium(IV) isopropoxide (0.15 ml, 0.50 mmol) were added with stirring at 50° C. The mixture was stirred at 50° C. for 50 minutes and then N,N-diisopropylethylamine (0.085 ml, 0.50 mmol) was added at ca. 30° C. Then, cumene hydroperoxide (83percent, 2.1 ml, 11.9 mmol) was added and the mixture was stirred for 15 minutes at 30° C. The crude mixture was shown to consist of 3.6percent sulphide, 2.7percent sulphone and 93percent sulphoxide with an optical purity of 91percent e.e. The product was not isolated. |
Yield | Reaction Conditions | Operation in experiment |
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With acetic anhydride; In methanol; water; toluene; | Example 10 Synthesis of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole (Omeprazole) Sodium perborate 4H2O (11.2 g, 73.0 mmol) was suspended in water (50 ml), followed by the dropwise addition of a solution of acetic anhydride (6.87 ml, 73.0 mmol)/methanol (5.75 ml) at 15.4° C. over 6 minutes and then, the mixture was stirred for about 13 min to prepare a homogenous solution (bulk temperature; 15.4° C. to 19.4° C.). The resulting solution was added dropwise to a solution (220 ml) of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio]-1H-benzimidazole (20.0 g, 60.8 mmol) in toluene/methanol (10:1) at -20° C. over 2 hr. The resulting mixture was further stirred at the same temperature for 1hr. The resulting crystals were collected by filtration, washed for three times with water (20 ml) and washed twice with tert-butyl methyl ether (20 ml). The resulting crystals were dried, to give the title compound (17.8 g, yield; 85.0percent) as a white solid. 1H-NMR (400 MHz, CDCl3); delta ppm) 2.20(s, 3H), 2.25(s, 3H), 3.68(s, 3H), 3.86(s, 3H), 4.70(Abq, 2H, J=13.7 Hz), 6.98-7.00(m, 2H), 7.65(br-d, 1H, J=8.29 Hz), 8.24(s, 1H), 1.19(br-s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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69% | Example 4 -; Toluene (125 m.), D-(-)-diethyl tartrate (4.7 q) and titanium (IV) isopropoxide (3.2 g) were charged in reaction vessel and stirred for 15 minutes. To this up to 0.4percent water based on the moisture content was added and stirring continued for 30 minutes at 25 - 3O0C to form a chiral titanium complex. Further, 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl]thio]-1H-benzimidazole (25 g) was added to the mass and contents were heated to 7O0C over a period of 1 hour and maintained at 70 - 750C for 30 minutes. After cooling the reaction mass to 10 - 150C, cumene hydroperoxide (28.5 g) was slowly added at 10 - 150C over a period of 3 hours.After reaction completion, an ethanolic solution of potassium hydroxide (5 g of potassium hydroxide dissolved in 50 ml of ethanol) was added to the reaction mass at 10 - 150C, content was stirred at 25 - 3O0C for 2 hours and chilled to 1O0C. The precipitated product was filtered and dissolved in 125 ml acetone at 50 - 550C, clarified, and the solvent was distilled off completely under vacuum. To this 25 ml of ethanol was added and solution was stirred at 25 - 3O0C for 1 hour. The solution was cooled to 0 - 50C, filtered and then dried under vacuum at 40 - 450C to obtain esomeprazole potassium Form C (18.2 g).Yield = 69percent Purity = 99.7percent Residual ethanol content - 10 - 20percent (determined by gas chromatography) Water content - Not more than 3.0percent Tap and Bulk density - 0.39 g/mL | |
46% | Step S3: 117.0 g (0.356 mol) of Compound III was dissolved in 500 mL of toluene,Heating to 50 ° C,0.8 g water (0.046 mol, 13percent molar equivalent) was added,44.0 g of D-diethyl tartrate (0.213 mol, 60percent molar equivalent),11.2 g of isopropyl titanate (0.107 mol, 30percent molar equivalent),Stir at 50 ° C for 50 minutes. Cool down to 25 ° C,10.8 g of triethylamine (0.107 mol, 30percent molar equivalent) was added.62.3 g of 85percent cumene hydroperoxide (CHP) (0.349 mol, 98percent molar equivalent) were added dropwise.The temperature is controlled at 25 °C.After the completion of the dropwise addition, the mixture was stirred for 1 hour.600mL 12.5percent ammonia water quenched the reaction,After stirring for 20 minutes, the solution was allowed to stand for separation.The organic phase was washed with 600 mL of 12.5percent aqueous ammonia.Combine the ammonia phase,Hydrochloric acid adjusts the pH to 8,Extracted with 500 mL of dichloromethane,The aqueous phase was extracted once more with 300 mL of dichloromethane.Organic phase merger,The mixture was washed with a 0.25percent aqueous solution of disodium edetate and saturated brine, and dried over anhydrous sodium sulfate for 15 hours or more.100 g of a solution of the compound IV in methylene chloride was obtained by filtration; the moisture content was 0.20percent; the yield was 90percent, the purity was ?98.9percent, and the chiral purity was ?98.9percent.Preparation of Esomeprazole Potassium Salt by Compound IV in Dichloromethane Solution60 g of compound IV in dichloromethane was added to 10.0 g of 50percent aqueous potassium hydroxide solution (70percent by mole).Equivalent) stirring to precipitate a solid,The reaction was stirred for 15 hours and filtered.The solid was recrystallized from 400 mL of ethanol.filter,Drying to obtain 28.0 g of esomeprazole potassium salt,The yield was 46percent, the purity was ?99.1percent, and the chiral purity was ?99.1percent. | |
Example 1Preparation of the potassium salt of 5-methoxy-2-[(S)-(4-methoxy-3,5-dimethyl-2- pyridinylmethyl)sulphinyl] -lH-benzimidazole (esomeprazole potassium); A solution of titanium isopropoxide (2.08 g, 0.0073 mol) and L (+) Diethyl tartrate(3.12 g, 0.015 mol) was heated to 45 to 500C and stirred for 90 minutes. The above mass was cooled to 25 to 3O0C and a mixture of <strong>[73590-85-9]omeprazole sulfide</strong> (10 g, 0.03 mol), cumene hydroperoxide (70percent solution, 8.6 g, 0.0315 mol), L (+) diethyl tartrate (4 g, 0.019 mol) and diisopropyl ethylamine (3.92 g, 0.03 mol) was added to this complex. The reaction mixture was stirred at 25 to 350C for eight hours. Toluene (100 ml) and water (100 ml) was then added to the reaction mixture and stirred for 10 minutes. The toluene layer was separated and methanolic potassium hydroxide solution (4.26 g in 30 ml methanol) was added to the toluene layer. The mixture was stirred for 15 to 16 hours at 25 to 35°C. The product was filtered under nitrogen atmosphere and washed with a mixture of toluene and methanol followed by hexane. The product was dried under reduced pressure at 50 to 55°C.Yield = 6.5gEnantiomeric excess = 99 percentSulfone content = 2.67 percent, HPLC Purity = 96.83 percent; A solution of titanium isopropoxide (5.2 g 0.018 mol) and L (+) Diethyl tartrate (17.8 g, 0.086 mol) was heated to 45 to 5O0C and the reaction mixture stirred for 90 minutes. The solution was cooled to 25 to 300C and a mixture of <strong>[73590-85-9]omeprazole sulfide</strong> (25 g, 0.0759 mol) and diisopropyl ethylamine (9.8 g, 0.0797 mol) was added to the above complex. Cumene hydro peroxide (70percent solution, 17.32 g, 0.0797 mol) was then added slowly over a period of one hour. The reaction mixture was stirred at 25 to 350C for 3 hours. Toluene (250 ml) and water (250 ml) was then added to the reaction mixture and the reaction mixture stirred for 10 minutes. The toluene layer was separated and methanolic potassium hydroxide solution (10.32 g in 75 ml methanol) was added to the toluene layer. The mixture was stirred for 15 to 16 hours at 25 to 35°C. The product was filtered under nitrogen atmosphere and washed with a mixture of toluene and methanol followed by hexane. The product was dried under reduced pressure at 50 to 55°C.Yield = 17.3 gEnantiomeric excess = 90 percentSulfone content = 2.39 percent,HPLC Purity = 97 percent ; A solution of titanium isopropoxide (5.2g, 0.018 mol) and L (+) Diethyl tartrate (7.8 g, 0.037 mol) was heated to 45 to 5O0C and the reaction mixture stirred for 90 minutes. The solution was cooled to 25 to 3O0C. A mixture of <strong>[73590-85-9]omeprazole sulfide</strong> (25 g, 0.0759 mol), cumene hydroperoxide (70percent solution, 17.32 g, 0.0797 mol), L (+) diethyl tartrate (8.5g, 0.0412 mol) and diisopropyl ethylamine (9.8 g, 0.0797 mol) was prepared separately. The above-prepared complex was added slowly to this slurry of <strong>[73590-85-9]omeprazole sulfide</strong> at 25-300C. The reaction mixture was stirred at 25 to 350C for 3 hours. Toluene (250 ml) and water (250 ml) was then added to the reaction mixture and the reaction EPO <DP n="13"/>mixture was stirred for 10 minutes. The toluene layer was separated and methanolic potassium hydroxide solution (10.32 g in 75 ml methanol) was added to the toluene layer. The mixture was stirred for 15 to 16 hours at 25 to 35°C. The product was filtered under , nitrogen atmosphere and washed with a mixture of toluene and methanol followed by hexane. The product was dried under reduced pressure at 50 to 55°C.Yield = 17.0 gEnantiomeric excess = 99percentSulfone content = 2.36 percent,HPLC Purity = 97.41percent; A solution of titanium isopropoxide (2.08 g, 0.0073 mol) and L (+) Diethyl tartrate (3.12 g, 0.015 mol) was heated to 45 to 500C and the reaction mixture stirred for 90 minutes. The above mass was cooled to 25 to 30°C and a mixture of <strong>[73590-85-9]omeprazole sulfide</strong> (10 g, 0.03 mol), cumene hydro peroxide (83percent solution, 8.6 g, 0.0355 mol), L (+) diethyl tartrate (4 g, 0.019 mol) and diisopropyl ethylamine (3.92 g, 0.03 mol) was added to this complex. The reaction mixture was stirred at 25 to 35°C for eight hours. Toluene (100 ml) and water (100 ml) was then added to the reaction mixture and stirred for 10 minutes. The toluene layer was separated and methanolic potassium hydroxide solution (4.26 g in 30 ml methanol) was added to the toluene layer. The mixture was stirred for 15 to 16 hours at 25 to 350C. The product was filtered under nitrogen atmosphere and washed with mixture of toluene and methanol followed by hexane. The product was dried under reduced pressure at 50 to 550C. Yield = 6.5gEnantiomeric excess = 99 percentSulfone content = 2.67 percent,HPLC Purity = 96.83 percent |
Yield | Reaction Conditions | Operation in experiment |
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Example 2Preparation of the potassium salt of 5-methoxy-2-[(R)-(4-methoxy-3,5-dimethyl-2- pyridinylmethyl)sulphinyl]-lH-benzimidazole (R-omeprazole potassium); A solution of titanium isopropoxide (2.08 g, 0.0073 mol) and D (-) Diethyl tartrate (3.12 g, 0.015 mol) was heated to 45 to 500C and stirred for 90 minutes. The above mass was cooled to 25 to 3O0C and a mixture of <strong>[73590-85-9]omeprazole sulfide</strong> (10 g, 0.03 mol), cumene hydroperoxide (70percent solution, 8.6 g, 0.0315 mol), D (-) diethyl tartrate (4 g, 0.019 mol) and diisopropyl ethylamine (3.92 g, 0.03 mol) was added to this complex. The reaction mixture was stirred at 25 to 350C for eight hours. Toluene (100 ml) and water (100 ml) was then added to the reaction mixture and stirred for 10 minutes. The toluene layer was EPO <DP n="11"/>separated and a methanolic potassium hydroxide solution (4.26 g in 30 ml methanol) was added to the toluene layer. The mixture was stirred for 15 to 16 hours at 25 to 350C. The product was filtered under nitrogen atmosphere and washed with a mixture of toluene and methanol followed by hexane. The product was dried under reduced pressure at 50 to 55°C.Yield = 6.5gEnantiomeric excess = 98 percentHPLC Purity = 98.0 percent |
Yield | Reaction Conditions | Operation in experiment |
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Example 3 Preparation of the barium salt of 5-methoxy-2- [(S)-(4-methoxy-3,5-dimethyl-2- pyridinylmethyl)sulphinyl]-lH-benzimidazole (esomeprazole barium); A solution of titanium isopropoxide (5.2 g 0.018 mol) and L (+) Diethyl tartrate (7.8 g, 0.037 mol) was heated to 45 to 500C and the reaction mixture stirred for 90 minutes. The solution was cooled to 25 to 300C and a mixture of <strong>[73590-85-9]omeprazole sulfide</strong> (25 g, 0.0759 mol), cumene hydro peroxide (70percent solution, 17.32 g, 0.0797 mol), L (+) diethyl tartrate (1Og, 0.0485 mol) and diisopropyl ethylamine (9.8 g, 0.0797 mol) was added to the above complex. The reaction mixture was stirred at 25 to 35°C for eight hours. Toluene (250 ml) and water (250 ml) was then added to the reaction mixture and the reaction mixture was stirred for 10 minutes. The toluene layer was separated and a methanolic barium hydroxide solution (14.36 g in 200 ml methanol) was added to the toluene layer. The solvent was evaporated under reduced pressure and methanol (250 ml) was added to the residue. The mixture was stirred for 15 to 16 hours at 25 to 35°C. The product was filtered and washed with methanol. The product was dried under reduced pressure at 50 to 550C.Yield = ll gEnantiomeric excess = 99percentHPLC Purity = 98 percent | ||
Example 7Preparation of the barium salt of 5-methoxy-2-[(S)-(4-methoxy-3,5-dimethyl-2- pyridinylmethyl)sulphinyl]-lH-benzimidazole (esomeprazole barium); Titanium isopropoxide (1.96 kg, 6.89 mol) and L (+) Diethyl tartrate (2.52 kg, 12.22 mol) were heated to 50 to 550C and the reaction mixture stirred for 90 minutes. The solution was cooled to 10 to 150C, the complex so prepared was added to a suspension containing cumene hydro peroxide (82percent solution, 5.04 kg, 27.15 mol), and diisopropyl ethylamine (2.744 kg, 21.23 mol) and <strong>[73590-85-9]omeprazole sulfide</strong> (7.0 kg, 21.25 mol) at 10 to 15°C over a period of 5-10 minutes. The reaction mixture was stirred at 10 to 35°C for 3-4 hours. Water (70 L) was then added to the reaction mixture under stirring followed by toluene (70 L) and the reaction mixture was stirred for 15-20 minutes. The toluene layer was separated and added to the solution containing potassium hydroxide (2.38 kg, 42.5 mol) and water (70 L) and stirred for 30 minutes. The aqueous layer was separated and dichloromethane (35 L) was added. The solution was acidified to pH 6.0-7.0 with dilute hydrochloric acid. The organic layer was then separated and solvent was recovered under reduced pressure in the presence of diisopropyl ethyl amine (70 ml). Methanol (14 L) was added to the residue and filtered to remove any suspended solid. The filtrate so obtained was added to the methanolic barium hydroxide solution (39.2 kg in 56 L methanol) and stirred for 10-12 hours at 25 to 350C. The product was filtered and washed with methanol. The product was dried under reduced pressure at 50 to 55°C. Yield = 2.70 kgEnantiomeric excess = 99percentHPLC Purity = 98 percent; Titanium isopropoxide (14 g, 0.049 mol) and L (+) Diethyl tartrate (36 g, 0.175 mol) were heated to 50 to 55°C and the reaction mixture stirred for 90 minutes. The solution was cooled to 10 to 15°C and the complex so prepared was added to a suspension containing cumene hydro peroxide (82percent solution, 72 g, 0.387 mol), diisopropyl ethylamine (39.2 g, 0.303 mol) and <strong>[73590-85-9]omeprazole sulfide</strong> (100 g, 0.303 mol) at 10 to 15°C over a period of 5-10 minutes. The reaction mixture was stirred at 10 to 350C for 3-4 hours. Water (1000 ml) was then added to the reaction mixture under stirring followed by EPO <DP n="15"/>toluene (1000 ml) and the reaction mixture was stirred for 15-20 minutes. The toluene layer was separated and added in to the solution containing potassium hydroxide (34 g, 0.607 mol) and water (1000 ml) and stirred for 30 minutes. The aqueous layer was separated and dichloromethane (500 ml) was added. The resulting solution was acidified to pH 6.0-7.0 with dilute hydrochloric acid. The organic layer was then separated and solvent recovered under reduced pressure in the presence of diisopropyl ethyl amine (1.0 g). Methanol (200 ml) was added to the residue and filtered to remove any suspended solid. The filtrate so obtained was added to a methanolic barium hydroxide solution (56 g in 400 ml methanol) and stirred for 10-12 hours at 25 to 35°C. The product was filtered and washed with methanol. The product was dried under reduced pressure at 50 to 55°C. Yield = 37 gEnantiomeric excess = 99percentHPLC Purity = 98 percent |
Yield | Reaction Conditions | Operation in experiment |
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65g (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. |
With hydrogenchloride; sodium methylate; In methanol; water; | Example 7 5-Methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridinyl)methylthio]-1H-benzimidazole (II) 5-Methoxy-2-[(3,5-dimethyl-4-nitro-2-pyridinyl)methylthio]-1H-benzimidazole (IX) (50 gm, 0.145 mole) was dissolved in methanol and heated to 45° C. A solution of sodium methoxide (50 gm, 0.925 mole) in methanol (150 ml) was added dropwise over a period of 3 hours at 45-60° C. Stirring was continued for another 2 hours and then methanol was distilled off under reduced pressure. To the cooled residue was added water (200 ml) followed by concentrated HCl (65 ml) until the pH of the mixture was 7.5. The reaction mixture was extracted with dichloromethane and the dichloromethane layer was washed with water (2*100 ml). The dichloromethane layer was dried over sodium sulfate and concentrated to yield the product as an amber color syrup. Yield was 40.1 gm, about 83.8percent of theoretical. A solid sample was obtained by trituration of the syrup several times with petroleum ether. Melting point was 87-90° C. |
Yield | Reaction Conditions | Operation in experiment |
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62% | EXAMPLE 11 5-METHOXY-2((3,5-DIMETHYL-4-METHOXY-2-PYRIDINYL)-METHYLTHIO)-1H-BENZIMIDAZOLE 2 g (5.80.10min 3 mole) of 5-methoxy-2((3,5-dimethyl-4-methoxy-2-pyridinyl-N-oxide)-methylthio)-1 H -benzimidazole were dissolved in 4 ml of chloroform. 0.58 ml (6.27.10min3 mole) of PBr3 was added over 2 minutes to the opalescent deep orange solution cooled to 0°C. The reaction was very exothermic and the temperature was held between 0 and 8°C during the addition. The system was held between 0 and 10°C for 1 hour. At the end of this time, 4 ml of chloroform and 10 ml of H2O were added at 0°C; the latter was added very slowly since the addition is very exothermic and the temperature is held between 0-10°C, acid pH. NaHCO3 was added to pH = 5. During the neutralization the temperature was held at 0°C. H2O and chloroform were added, followed by extraction and decantation. The aqueous phase was extracted with chloroform and the organic phase was washed several times with H2O. The organic phases were anhydrified with anhydrous Na2SO4. The system was filtered and evaporated under vacuum. 1.17 g of a browny orange solid were obtained, representing a 62percent yield. |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine; | EXAMPLE 29 OMEPRAZOL A solution of 25 ml ethyl acetate and 1.7 ml (0.0103 mole) of 2-ethylhexanoic acid was prepared, to which there were added 4 g (0.0117 mole) of 96percent pure 5-methoxy-2-((3,5-dimethyl-4-methoxy-2-pyridinyl)methylthio)-1 H -benzimidazole, 3.06 g (0.01214 mole) of metachloroperbenzoic acid were added to the resulting solution over 23 minutes at temperatures of -35 and -40°C. When the addition was completed, the system was held -35°C for 1 hour. Thereafter, 1.8 ml of triethylamine (0.013 mole) was added at that temperature after which the temperature was held at-35°C for 20 minutes. The mixture was filtered at that temperature and washed with cold ethyl acetate at a temperature of -20°C. It was allowed to dry under flowing air at room temperature. A white solid (3.7 g) was obtained, representing a 94percent yield. The melting point of the product was 147-150°C. |
Yield | Reaction Conditions | Operation in experiment |
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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), delta: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) |
Yield | Reaction Conditions | Operation in experiment |
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N-benzyl-N,N,N-triethylammonium chloride; In methanol; at 20℃; for 24h;Heating / reflux; | Prepared according to example 9, by substituting CD3ONa-CD3OH with CH3ONa-CH3OH. |
Yield | Reaction Conditions | Operation in experiment |
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85.1% | The preparation method of esomeprazole sodium includes the following steps:1) A mixture of 630 g (2 mol) of <strong>[73590-85-9]omeprazole sulfide</strong> and a compound represented by the formula M,The inorganic metal salt was mixed in 5 L of acetone,The mixing conditions are:Temperature 50 ,Stirred for 0.5 hour,Wherein the molar ratio of the <strong>[73590-85-9]omeprazole sulfide</strong> to the compound represented by the formula M, the inorganic metal salt is 1: 0.55: 0.1, and the inorganic metal salt is CoSO4.2) At a temperature of 45 ° C,30percent H2O2 was added dropwise to the mixture A of step 1) to carry out an oxidation reaction,After completion of the reaction, a solution of sodium hydroxide in methanol was added,The molar ratio of 30percent H2O2 to <strong>[73590-85-9]omeprazole sulfide</strong> is 1.8; the amount of the solution of sodium hydroxide in methanol is added, in terms of sodium hydroxide, to the amount of <strong>[73590-85-9]omeprazole sulfide</strong> Was 1.6.3) a process of purifying the obtained esomeprazole sodium,Refining process includes:First esomeprazole sodium dissolved in 65 ° C in 1.5L acetonitrile,Then 6L of petroleum ether was added dropwise,The temperature was lowered to 40 ° C at a rate of 0.02 ° C / s, and then cooled to 10 ° C at a rate of 0.15 ° C / s, allowed to stand for 1 hour, centrifuged and filtered to obtain 601.4 g of purified esomeprazole sodium,Yield: 85.1percentThe purity was 99.97percent by HPLC, no isomer and excessive oxidation to sulfone impurities. | |
The procedure is carried out as described in Cotton et al, Tetrahedron: Asymmetry 2000, 11(18), 3819-3825, which is hereby incorporated by reference in its entirety. Water (2.4 mmol), (R,R)-diethyl tartrate (11.4 mmol) and titanium tetraisopropoxide (5.6 mmol) were added to a suspension of 5-methoxy-2-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethylsulfanyl)-1H-benzoimidazole (18.8 mmol) in toluene (25 mL) at 54° C. The mixture was stirred for 50 minutes at 54° C., cooled to 30° C. and N,N-diisopropylethyl-amine (5.6 mmol) and cumene hydroperoxide (84percent in cumene, 18.2 mmol) were added. The mixture was stirred for 1 hour, and extracted three times with aqueous ammonium hydroxide. Methyl isobutyl ketone (9 mL) was added to the combined aqueous extracts, and the pH was adjusted with acetic acid. The organic layer was treated with 50percent aqueous sodium hydroxide (13.2 mmol) and acetonitrile (70 mL). The solution was concentrated during which the product gradually precipitated to give (R)-omeprazole sodium as a white solid. 1H NMR (DMSO-d6) delta 6 2.15 (s, 3H), 2.20 (s, 3H), 3.68 (s, 3H), 3.71 (s, 3H), 4.5 (m, 2H), 6.56 (m, 1H), 7.00 (d, 1H), 7.34 (d, 1H), 8.30 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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With 1,2:4,5-di-O-cyclohexylidene-D-fructopyranose; Cumene hydroperoxide; vanadium(V) oxytripropoxide; N-ethyl-N,N-diisopropylamine; In water; ethyl acetate; at 20 - 55℃; for 20.1667 - 20.25h;Product distribution / selectivity; | Example 2; Preparation of 5-methoxy-2-|'[('4-methoxy-3,5-dimethyl-2-pyridinvDmethyll sulfinyl] -lH-benzimidazole; To a suspension of vanadium oxytripropoxide (1.2 g) in ethyl acetate (200 ml), l,2:4,5-Dz-O-cyclohexylidene-/>fructopyranose (1.0 g) was added and the mixture was stirred for 10-15 minutes at room temperature under nitrogen atmosphere. 5- Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-7/-rbenzimidazole <n="11"/>(10 g) was added to the resulting mixture and the temperature was raised up to 50- 550C. Water (0.02 ml) was added to the said mixture and stirred for one hour. The reaction mass was cooled between 25-3O0C and added lambdazetaiV-diisopropylethylamine (0.7 g) followed by addition of cumene hydroperoxide (2.6 g) dropwise over a period of one hour. The reaction mass was further stirred for 18 hours at said temperature. Triethylamine (20 ml) was added to the resulting mixture and was extracted with water. The organic layer was separated and the aqueous layer was further extracted from dichloromethane at pH 8.0 to 8.5. The organic layer was combined and distilled under vacuum to obtain the product as oily mass. Yield = 4.0 gEnantiomeric excess = 67percent. | |
With Oxone; ethylenediaminetetraacetic acid; sodium hydrogencarbonate; 1,2:4,5-di-O-cyclohexylidene-beta-D-erythro-hexo-2,3-diulopyranose; In acetonitrile; at -10 - 20℃; for 3.16667 - 3.25h;Product distribution / selectivity; | Example 3; Preparation of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinvDmethvpi sulfinyl] -l//-benzimidazole; 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-7J/ benzimidazole (10 g) was taken in acetonitrile (150 ml) and to this add l,2:4,5-/J)/-O-cyclohexylidene- beta-D-erythro hexo-2,3-diulopyranose (10.2 g) was added under an nitrogen atmosphere. The reaction mixture was stirred at 15-2O0C for 10-15 minutes. Ethylenediaminetetracetic acid solution (10 ml) was added at the same temperature and the reaction mixture was cooled to -15 to -1O0C. Oxone (22.8 g) and sodium bicarbonate (2.1 g) was added to the reaction mixture over a period of one hour. After the addition, the resulting mixture was stirred for additional two hours. To the resulting reaction mixture, water (100 ml) and dichloromethane (200 ml) was added and stirred for few minutes. The organic layer was separated off, distilled under reduced pressure to obtain the oily residue. Yield = 3.5 gEnantiomeric excess = 77percent. | |
With dihydrogen peroxide;[MnCl((1R,2R)-N,N'-bis(3,5-di-tert-butylsalicylidene)diphenylethanediamine(-2H))]; In water; acetonitrile; at 20℃; for 5.5h;Product distribution / selectivity; | 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. |
0.495 g (1.5 mmol) of the compound of formula III, 5 ml of dried toluene and 104.1 mg (1.0 mmol) of (<;S)-lactic acid methyl ester (general formula IV: X = OMe, IVc) were placed in a 3- neck 50ml flask, which was equipped with a magnetic stirrer and a thermometer. The mixture in the flask was heated up in an oil bath to a temperature in the range of 50 to 55 0C. Then, 0.15 ml OfTi(OPr)4 were added to this mixture at a time. The resulting mixture was stirred at a temperature in the range of 50 to 55 0C for 1 hour. Then, the reaction mixture was maintained at a temperature of 25 to 30 0C and 85 mul 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 Na2S2O3 and diluted with 5 ml of toluene. The resulting mixture was filtered through filtration paper. The two-phase filtrate was separated in a separating funnel and the toluene fraction was extracted with anther 5 ml of water. After drying with anhydrous magnesium sulfate the toluene solution was evaporated in a rotary vacuum evaporator until dry. The resulting evaporation residue (0.55g) was subjected to chromatography on 16.0 g of silica gel. Chloroform : methanol : 25percent NH4OH in the ratio of (10 : 1 : 0,1) were used as the eluent. The fractions containing the compound of formula Ia were combined, evaporated in a rotary vacuum evaporator and analyzed with HPLC on the chiral phase (CHIRALPAK AD-H.(R)., mobile phase 50percent hexane : 50percent ethanol, detection 302 nm): (.^-omeprazole has the enantomeric excess of 56.0 percent. | ||
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 mu 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. | ||
(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. | ||
General procedure: In a typical experiment, Ti(Oi-Pr)4 (0.9 mL, 3 mmol) was added to a solution of (S,S)-DBzTA 5i (1.969 g, 6 mmol) and pyrmetazol (3.29 g, 10 mmol) in toluene (20 mL) at 80 °C. The solution was stirred for 60 min., after which water (54 mg, 3 mmol) was added to the mixture, and the solution was stirred for another 60 min. Next, the temperature was adjusted to 30 °C, after which cumene hydroperoxide (80 percent, 3.6 mL, 20 mmol) was slowly added. After 1 h at 30 °C, the solution was added to aqueous sodium hydroxide (1.2 g NaOH in 20 mL water), stirred for 1 h, and extracted with water (20 mL .x. 3). The aqueous phase was adjusted to pH 8 with acetic acid, separated, and extracted with dichloromethane (20 mL .x. 3). The combined organic solutions were dried over anhydrous Na2SO4, filtered, and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel with ethyl acetate/petroleum ether (2:1) as the eluent to afford the sulfoxide. | ||
With oxygen; NADP; In aq. phosphate buffer; isopropyl alcohol; at 25℃; for 24h;pH 9.0;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 muL 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. | |
With C64H64N4O6Ti2; dihydrogen peroxide; In water; ethyl acetate; at 0℃; for 24h; | 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. | |
With C68H72N4O10Ti2; dihydrogen peroxide; In water; ethyl acetate; at 0℃; for 24h; | 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. | |
With dihydrogen peroxide; acetic acid; In methanol; water; at 0℃; for 12h; | 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]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 1; Preparation of 5-methoxy-2- IT (4-methoxy-3 ,5-dimethyl-2-p widinyl)methyl] sulfmyl] -IH-benzimidazole sodium salt; To a suspension of vanadium oxytripropoxide (7.4 g) in toluene (200 ml), 1,2:4,5- Z)/-O-cyclohexylidene-/>fructopyranose (27.9 g) was added and the mixture was stirred for 10-15 minutes at room temperature under nitrogen atmosphere. 5- Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-/H'benzimidazole (10 g) was added to the resulting mixture and the temperature was raised up to 50- 55°C. Water(l ml) was added to the said mixture and stirred for one hour. The reaction mass was cooled to 25-3O0C and added AzetaiV-diisopropylethylamine (1.4 g) followed by addition of cumene hydroperoxide (5.2 g) dropwise over a period of an hour. The reaction mass was further stirred for 45 minutes at said temperature. Triethylamine (20 ml) was added to the resulting mass and extracted with water. The organic layer was separated and the aqueous layer was further extracted from methyl isobutyl ketone at pH 7.5 to 8.0. Aqueous sodium hydroxide (50percent) was added to the organic layer under stirring. Initially the solution was cooled at 10- 150C, for half an hour under stirring and then at 20-25°C for 2 hrs. The resulting solid was filtered off, washed with solvent and dried under vacuum at 40-450C. Yield = 5.8 gEnantiomeric excess = 75percent. | ||
5-methoxy-2-[(S)-[(4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl] thio] Benzimidazole (100 gm, 0.3 mole) was charged in Toluene (300 ml), reaction mass was heated to 55°C, (-) diethyl-D-tartarate (12.52 gm, 0.2 mole) was added, and then titanium (IV) isopropropoxide (8.63 gm, 0. 1 mole), followed by addition of triethyl amine 6.4 gm (0.21 mole) at 30°C. Cumene hydroperoxide (55gm, 1.2 mol) at 25-30°C.was slowly added after stirring for 2 hrs, HPLC analysis of the reaction mixture at this stage revealed (94percent) of chiral enantiomer. Methanol(50 ml) was charged in the reaction mass, the reaction mass quenched in 50percent sodium hydroxide solution (400ml),the product extracted in aq. layer and the aq. layer neutralized by acetic acid (25 ml), the product extracted in methylene chloride (400 ml) and solvent distilled out under vacuum. To the residue was added 2-butanone (200 ml) and toluene (400 ml) and 17percent methanolic sodium hydroxide solution (75ml) and the reaction mass seeded with R-isomer of Esomeprazole (sodium salt). Unwanted sodium salt of R- isomer was precipitated out with a "chiral purity of 79percent, which was filtered out. HPLC of the filtrate revealed a chiral purity of 99percent. The filtrate was charged in water (700 ml) and the product extracted in aq. Layer.An aq. solution of magnesium chloride (28 gm in 400ml of water) was added to the aq. Layer containing Esomeprazole sodium salt and the precipitated product was filtered . The product dissolved in methanol (800 ml) and the solvent distilled out under vacuum followed by removal of insoluble material to afford a residue. Acetone (250 ml) was charged, the precipitated product was filtered as Esomeprazole magnesium salt (58gm) with a chiral HPLC purity of 99.90percent. |
Yield | Reaction Conditions | Operation in experiment |
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Example 5:Preparation of Potassium salt of EsomeprazoleToluene (500 ml) was charged followed by D-(-)-diethyl tartrate (19.0 g), titanium (IV) isopropoxide (13.0 g), stirred for 15 minutes. To this water was charged up to 0.4percent based 5 on the moisture content of the reaction mass. The reaction mass was stirred for 30 minutes at 25-30° C to form a chiral titanium complex. Further, 5-methoxy-2-[[(4-methoxy- 3,5-dimethyl-2-pyridinyl)methyl] thio]-1 H-benzimidazole form Il (100 g) was charged to the complex and the contents were heated to 7O0C over a period of 1 hour and maintained at 70-750C for Yz hour. The reaction mass was then cooled to 10 - 15° C, cumene 0 hydroperoxide (115 g) was slowly added at 10 - 15° C over a period of 3 hours. After <n="23"/>reaction completion methanolic potassium hydroxide solution (20 g of potassium hydroxide dissolved in 200 ml of methanol) was added to the reaction mass at 10 - 15° C1 the contents were stirred at 25 - 30° C for 2 hours and chilled to 10° C. The precipitated product was filtered under nitrogen atmosphere, washed with toluene (150 ml). | ||
Example 6: Preparation of Potassium salt of EsomeprazoleToluene (180 ml) was charged followed by D-(-)-diethyl tartrate (11.4 g), titanium (IV) isopropoxide (7.8 g), stirred for 15 minutes. To this water was charged up to 0.4percent based on the moisture content of the reaction mass. The reaction mass was stirred for 30 minutes at 25-30° C to form a chiral titanium complex. Further, 5-methoxy-2-[[(4-methoxy- 3,5-dimethyl-2-pyridinyl)methyl] thio]-1H-benzimidazole form I (60.0 g) was charged to the complex and the contents were heated to 7O0C over a period of 1 hour and maintained at 70-750C for .4 hour. The reaction mass was then cooled to 10 - 15° C, cumene hydroperoxide (69.0 g) was slowly added at 10 - 15° C over a period of 3 hours. After reaction completion methanolic potassium hydroxide solution (12.0 g of potassium hydroxide dissolved in 120.0 ml of methanol) was added to the reaction mass at 10 - 15° C, the contents were stirred at 25 - 30° C for 2 hours and chilled to 10° C. The precipitated product was filtered under nitrogen atmosphere, washed with toluene (90 ml). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With tetrabutylammomium bromide; edetate disodium; sodium hydroxide; In dichloromethane; water;pH 10; | 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, 2% 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 100% yield.Sodium hydroxide adjusts the pH to 10,The specific adjustment method is:Adjust the pH value in sections,Fine-tuning with 10% sodium hydroxide in the early stage of the reaction;In the middle of the reaction, it was adjusted by using 15% sodium hydroxide.Let it reach a pH of 8,Add 15% 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 20% 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; water;Reflux; | To a 1000 ml three-mouth flask is added 2-mercapto-5-methoxy benzimidazole 50.0g (0.28 muM), 500 ml of water and sodium hydroxide 22g (0.56 muM), after stirring dissolves clear slowly dropping 2-(chloromethyl)-4-methoxy-3,5-dimethyl pyridine hydrochloride 62g (0.28 muM) 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 95.2%. |
94% | With sodium hydroxide; In ethanol; acetone; at 40 - 45℃; for 3h;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 94% and a purity of 95.5% by HPLC. |
94% | With sodium hydroxide; In ethanol; acetone; at 20 - 45℃; for 3h;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 25C.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 45C, 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 30C.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 40-45C).The residue was added with 13.2 kg of ethyl acetate and cooled down to 0-5C.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 94% yield.Purity was 95.5% by HPLC. |
90% | With sodium carbonate; In methanol;Reflux; | 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 %; Purity: 99%. |
With sodium hydroxide; In ethanol; water; for 2h;Heating / reflux;Product distribution / selectivity; | Reference Example 1; (according to EP5129):Preparation of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)thio]-1 H- benzimidazole Form I2-chloromethyl-3,5-dimethyl-4-methoxy pyridine hydrochloride (25 g) and 2-mercapto-5- methoxy benzimidazole (20 g) were dissolved in 95% ethanol (200 ml). To this sodium hydroxide solution (8 g of sodium hydroxide dissolved in 20 ml of water) was added and refluxed for 2 hours. The sodium chloride formed was filtered off and the solution was concentrated to residue. The residue was then recrystallised from 70% of ethanol (30 ml) to yield 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)thio]-1 H-benzimidazole Form I (7 g). Example 2: <n="21"/>Preparation of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)thio]-1 H- benzimidazole Form I2-chloromethyl-3,5-dimethyl-4-methoxy pyridine hydrochloride (50 g) and 2-mercapto-5- methoxy benzimidazole (40 g) were dissolved in 95% ethanol (400 ml). To this sodium hydroxide solution (16 g of sodium hydroxide dissolved in 40 ml of water) was added and refluxed for 2 hours. The sodium chloride formed was filtered off and the solution was concentrated to residue. The residue was then recrystallised from 70% methanol (60 ml) at50-550C, chilled to -5 to O0C and maintained for 2 hours. The solid was filtered and dried at 40-450C under vacuum to yield 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridinyl)methyl)thio]-1 H-benzimidazole Form I (21.0 g). Example 3:Preparation of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)thio]-1 H- benzimidazole Form I2-chloromethyl-3,5-dimethyl-4-methoxy pyridine hydrochloride (100 g) and 2-mercapto-5- methoxy benzimidazole (80 g) were dissolved in 95% ethanol (800 ml). To this sodium hydroxide solution (32 g of sodium hydroxide dissolved in 80 ml of water) was added and refluxed for 2 hours. The sodium chloride formed was filtered off and the solution was concentrated to residue. The residue was then dissolved in methylene chloride (120 ml) and stripped off methylene chloride with ethyl acetate (40 ml). Further ethyl acetate (160 ml) was added and heated to dissolve at 50-550C1 cooled to room temperature, chilled to - 5 to O0C, maintained for 1 hour. The solid was filtered and dried at 40-450C under vacuum to yield 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)thio]-1 H-benzimidazole Form I (47.0 g). | |
With sodium hydroxide; tetrabutylammomium bromide; In dichloromethane; water; at 5 - 20℃; for 2h;pH 10.0 - 10.5; | Example 4:Preparation of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)thio]-1 H- benzimidazole Form Il <n="22"/>2-hydroxymethyl-3,5-dimethyl-4-methoxy pyridine hydrochloride (300 g) was charged to dichloromethane (1770 ml) and cooled to 15 - 20 C. Thionyl chloride (240 g) was added slowly at 15 to 20 C and the contents were stirred at 25 to 30 C for 1 hour. After reaction 5 completion, water (300 ml) was added at 15 to 20 C and allowed to attain 25 to 3O0C. To this reaction mass 2-mercapto-5-methoxy benzimidazole (252 g) and tetrabutyl ammonium bromide (6 g) was added, and the pH of the reaction mass was adjusted to 10.0 to 10.5 at 5 to 15C using 30% sodium hydroxide solution and stirred for 2 hours at 15 to 2O0C maintaining pH 10.0 -to 10.5. After reaction completion the dichloromethane10 layer was separated and the aqueous layer was extracted with dichloromethane (370 ml x 2). The dichloromethane layer was then washed with water until the pH of the aqueous layer was 7.0 to 7.5, dried over sodium sulphate and partially concentrated at temperature below 50 C under vacuum. Ethyl acetate (240 ml) was added and stripped off to remove traces of dichloromethane, further ethyl acetate (800 ml) was added and heated to 50 to15 60 C, cooled to room temperature, chilled to 10 to -5 C and maintained for 1 hour. The product was then filtered, washed with chilled ethyl acetate (200 ml). The product was then dried at 30 to 35 C to yield 5-methoxy-2-[[(4-methoxy-3,5-dimethyl~2- pyridinyl)methyl)thio]-1 H benzimidazole form II (392 g, 80.6% yield). | |
With sodium hydroxide; In water; ethyl acetate; at 25 - 55℃; for 2.5h; | 2-(chloromethyl)-3,5-dimethyl-4-methoxy pyridine hydrochloride (IV) (100.0 g) and 2-mercapto-5-methoxy benzimidazole (III) (81.0 g) were taken in RBF. Ethyl Acetate (400 mL) was added to RBF at 25C to 350C. Sodium hydroxide (50.0 g) solution in water (200 mL) was added to the reaction mass within 30 mins. The reaction0 mass was stirred for 1 hr and heated to 500C to 55C for 1 hr. After completion of the reaction on TLC, reaction mass was cooled to 250C to 300C. Water (200 mL) was added and stirred to separate the organic and aqueous layers. Aqueous layer was extracted with ethyl acetate (150 mL) and separated. The combined ethyl acetate layer was charcaolised (5.0 g) and stirred for 30 mins. The reaction mass was filtered through hyflow bed and washed with ethyl acetate (50 mL). The pH of the organic layer was adjusted to about 6.0 to 6.5 with acetic acid (0.5 mL) and cooled to 5C to 100C.Sodium molybdate (1.33 g) solution in water (13.2 mL) was added to the reaction mass and stirred for 15 mins. 50% hydrogen peroxide (37.0 g) was added into the reaction mass within 1.5 hrs at 5C to 12C. The reaction mass was stirred for 5 hrs.After completion of the reaction on TLC, the reaction mass is treated with sodium thiosulphate (11.0 g) solution in water (11.0 mL). Sodium hydroxide (6.0 g) solution in water (6 mL) was added into the reaction mass to adjust the pH of about 7.0 to 7.5. The reaction mass was further cooled to 00C to 5C and stirred for 60 mins. The product was filtered and washed with mixture of methanol (50 mL) and water (50 mL) followed by washing with chilled ethyl acetate (75 mL).Crude omeprazole (120.0 g) wet-cake as obtained above and methanol (160 mL) were taken in another RBF at 25C to 35C. Sodium hydroxide (15.8 g) solution in water (176 mL) was added into the reaction mass. Charcaol (2.6 g) was added and stirred for 30 mins. The reaction mass was filtered on hyflow bed and washed with mixture of methanol (10 mL) and water (10 mL). The filtrate was treated with sodium hydrosulphite (2.0 g). The reaction mass was slowly treated with acetic acid (22.5 mL) to adjust the pH of about 7.5 to 7.9. The product was filtered and washed with water(244 mL) and dried at 400C to 45C to obtain 100.0 g crystalline omeprazole Form B. Yield 68% based on input 2-(chloromethyl)-3,5-dimethyl-4-methoxy pyridine hydrochloride (IV).HPLC purity: 99.87%Individual Impurities are as under:Im purity- A at RRT 0.44 : 0.01% Impurity-B at RRT 0.46 : Not detectedImpuriry-C at RRT 0.80 : 0.02%Impurity-D at RRT 0.90 : Not detectedImpurity-E at RRT 3.26 : Not detectedUnk Impurity: 0.03% Total Impurities : 0.13%Impurity-A: 5-methoxy- 1 H-benzimidazole-2-thiolImpurity-B: 2-[(R,S)]-[(3,5-dimethylpyridine-2-yl)methyl]sulphinyl]-5-methoxy-lH- benzimidazole Impurity-C: 5-methoxy-2[[4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulphanyl]- lH-benzimidazole [Omeprazole Sulfide]Impurity-D: 5-methoxy-2[[4-methoxy-3,5-dimethylpyridin-2-yl)methyl]suIphonyl]- lH-benzimidazole [Omeprazole Sulfone] Impurity-E: 4-methoxy-2-[[(R,S)-(5-methoxy- 1 H-benzimidazole-2-yl)- sulphinyl]methyl)-3,5-dimethylpyridine- 1 -oxide [Omeprazole N-Oxide] | |
130 g | With sodium hydroxide; In methanol; water; at 30 - 35℃; | 2-mercapto-5-methoxy benzimidazole (83.10 gm) was added at 30-35C 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 30-35C 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 < 0.5% and a Dry Wt: - 130 gm |
With sodium hydroxide; In methanol; at 86℃; for 2.5h; | Solubility in methanol is added to 70% sodium hydroxide solution, after mixing, adding stirring 2-mercapto-5-methoxy-benzimidazole, and then continue adding 2-chloromethyl -3, 5-dimethyl-4-methoxy pyridine hydrochloride, the mixed temperature of the solution rises to 86 C, thermal insulation 2.5h, wait for the temperature to drop to 22 C time, concentrated under reduced pressure, by adding dichloromethane, extraction, water washing, the recovered methylene chloride, by adding ethyl acetate, the 18 C conditions, and stirring crystallization 4.5h, centrifugal, 47 C drying under the conditions, obtain amazingel sulfide; | |
With sodium hydroxide; In dichloromethane; water; at 55℃; for 2h; | A solution of 11.1 g of 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride And 2-mercapto-5-methoxybenzimidazole 9.8 g was added to a 500 ml three-necked flask,Add 150 ml of methylene chloride, the reaction solution is white turbid liquid,The water bath was heated to 55 C. At this temperature,Dropping the concentration of 17% aqueous sodium hydroxide solution, drop finished, the reaction solution gradually white turbid liquid into a light yellow transparent liquid, 55 C under the time reaction 2 hours, Samples were taken as 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride Content below 0.5%The reaction was stopped and the reaction solution was allowed to cool to room temperature and washed three times with 150 ml of purified water to separate the organic phase. | |
With sodium hydroxide; In dichloromethane; water; at 0 - 5℃; for 2h;Reflux; | 1) will5-methoxy-2-mercaptobenzimidazole 100g dispersed in 500mlIn dichloromethane,Cool down to 0 ~ 5 ° C,To the above system, 44 ml of an aqueous solution of 15 wtpercent sodium hydroxide was added dropwise, and after the addition was completed,Temperature control 0 ~ 5 ° C,Continue to drop by 125g2-Chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride and 125 mla solution made of water,After the addition is completed,Warming up to reflux for 2 h,Then cool down to 15 ° C,Let stand for liquid separation,200 ml of water was added to the dichloromethane phase.Stir for 15min,The liquid phase was separated to give a dichloromethane phase. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.57% | In 3000mL neck round bottom flask was added 2-chloro-3,5-dimethyl-4-methoxypyridine hydrochloride 123.3g (0.555mol) and methanol 1500ml, with stirring, was added 2-mercapto-5-methoxy-benzimidazole 100.0g (0.555mol), was added dropwise a solution of sodium hydroxide (NaOH 44.4g/150ml purified water), heated at reflux dropwise IH water bath, the reaction was complete, the material was transferred into rotation evaporator, temperature 50-55 °C rotation about 1/2 of the solvent was distilled off, 1000ml purified water was added to the remaining feed solution, 250ml of ethyl acetate, stirred for 20min, extracted liquid separation, the aqueous layer was re-extracted with ethyl acetate 250ml was extracted once with ethyl acetate layers were combined, heated in a water bath to 50-60 °C, was added D-(-)-diethyl tartrate 68.7g (0.333mol), tetraisopropyl titanate 47.2 g (0.166 mol), stirred insulation 1h, after cooling to 30-40 °C, was added diisopropylethyl amine 21.4g (0.166mol), cumyl hydroperoxide was added dropwise 84.5g (0.555mol), reaction was complete insulation dropwise 1.5h, the reaction completion, 12.5percent aqueous ammonia 500ml was added to the reaction mixture, stirred for 20min, extract liquid separation, the organic layer was extracted twice with 12.5percent aqueous ammonia 500ml × 2, ammonia layers were combined, washed once with 400ml ethyl acetate, aqueous ammonia layer is taken, ethyl acetate was added 1000ml, cooled to ice bath at 5-15 °C was added dropwise glacial acetic acid pH adjusted to 7.5-8.5, dropwise liquid separation, the aqueous layer was extracted a second 600ml ethyl acetate was added, combined ethyl acetate acetate layer was washed with saturated brine 2 times 500ml × 2, ethyl acetate layer was taken, dried over anhydrous sodium sulfate, the drying agent was filtered off, the filtrate was rotary evaporator temperature 50-55 °C to afford dark purple oil was 176.3 g, was added acetone 1000ml, the whole was stirred to dissolve the oil, the material was transferred into 2000ml three neck round bottom flask, was added sodium hydroxide solution (sodium hydroxide 20.4g / 20.4 g of purified water), heated at reflux for 30min, decreased to 5-10 crystallization was stirred 6h, filtered off with suction, washed with 50ml of acetone filter cake 35-45 / -0.095MPa dried in vacuo 12h, to give esomeprazole sodium 145.9 g, yield 71.57percent. HPLC: 95.3percent, largest single hetero 4.1percent, eepercent: 97.3percent. | |
46.8% | Example 12 A. (Reaction for Preparation of Esomeprazole)Omeprazole sulfide (50gms; 0.152 moles) was added to isopropyl alcohol (350ml). 1,8- Diazabicyclo [5.4.0] undec-7-ene (23.1 gms; 0.152 moles) was added to the mixture at 10- 150C. l(R)-(-)-(Camphorylsulfonyl)oxaziridine (34.8gms; 0.151moles) was added to the mixture and allowed to stir for 20 hours till completion of reaction as monitored on TLC. The reaction was filtered and the filtrate concentrated at reduced pressure. Water (250ml) was added to the residue and the pH adjusted around 8.5 with acetic acid. Ethyl acetate was added and the organic layer separated, which was then concentrated under vacuum. Acetone (150 ml) was added to the mixture and filtered. The resultant mixture was <n="19"/>concentrated and the residue diluted with toluene (8ml) and methanol (75ml). Sodium methoxide (8.2 gms) was added to the mixture and stirred for 14 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. Diisopropyl ether (150ml) was added to the residue and the reaction mixture filtered to obtain Esomeprazole sodium. Yield: 23.4gms. percentYield: 46.8percent. Chiral Purity of (S)-Esomeprazole sodium salt: 99.64percent. | |
46% | Step S3: 117.0 g (0.356 mol) of Compound III was dissolved in 500 mL of toluene,Heating to 50 ° C,0.8 g water (0.046 mol, 13percent molar equivalent) was added,44.0 g of D-diethyl tartrate (0.213 mol, 60percent molar equivalent),11.2 g of isopropyl titanate (0.107 mol, 30percent molar equivalent),Stir at 50 ° C for 50 minutes.Cool down to 25 ° C,10.8 g of triethylamine (0.107 mol, 30percent molar equivalent) was added.62.3 g of 85percent cumene hydroperoxide (CHP) (0.349 mol, 98percent molar equivalent) were added dropwise.The temperature is controlled at 25 °C.After the completion of the dropwise addition, the mixture was stirred for 1 hour.600mL 12.5percent ammonia water quenched the reaction,After stirring for 20 minutes, the solution was allowed to stand for separation.The organic phase was washed with 600 mL of 12.5percent aqueous ammonia.Combine the aqueous ammonia phase and adjust the pH to 8 with hydrochloric acid.Extracted with 500 mL of dichloromethane,The aqueous phase was extracted once more with 300 mL of dichloromethane.The organic phase is combined with a 0.25percent aqueous solution of edetate disodium,Washed with saturated saline,Dry over anhydrous sodium sulfate for more than 15 hours.Filtration to obtain 100 g of a solution of the compound IV in methylene chloride; the moisture content was determined to be 0.20percent;Yield 90percent,Purity ?98.9percent,Chiral purity ? 98.9percent.60 g of compound IV in dichloromethane was added to 10.0 g of 50percent aqueous sodium hydroxide solution (70percent molar equivalent)Stir the precipitated solid,Stir the reaction for 15 hours.filter.The solid was beaten with 400 mL of acetonitrile for 7 hours.filter,Drying to obtain 28.0 g of esomeprazole sodium salt,Yield 46percent,Purity ?99.1percent,Chiral purity ? 99.1percent. |
In a 3.0 lit RB flask was charged 400 ml of Toluene followed by 32 ml of (-)-Diethyl D tartrate and 28 ml Titanium isopropoxide and stirred to obtain a clear solution at 25-3O0C, under nitrogen. To the above solution was added 100 g of 5-Methoxy-2[((4-methoxy-3,5-dimethyl-2- pyridyl)methyl)-thio]-lH-benzimidazole (Omeprazole sulfide) followed by 1.0 ml of ethanol and 1.0 ml of D.M. Water at 25-3O0C and stirred for 10-15 min. The reaction mixture was gradually heated to 43 +/- 2 0C internal temperature and was strictly maintained at 43 +/- 2°C for 1.5 to 2 hours. The reaction mixture was cooled to 0 to -50C using ice water bath. To the cooled mixture was added cumene hydroperoxide (CEtaP, 70percent aqueous solution) using addition funnel and temperature strictly maintained between 0 to -5°C. The reaction temperature was gradually raised to 10-15 0C and. maintained for 80 to 90 minutes strictly at 10-15 0C To the reaction mixture, was added at 10-20 0C, a solution of Sodium hydroxide in D.M. Water and stirring was continued for 15-20 min at temperature 10-200C. The aqueous layer was separated and washed with toluene. The aqueous layer was transferred to a 3.0 L 3neck RBF equipped with overhead stirrer, thermometer pocket and nitrogen adapter. Methyl isobutyl ketone was added to the aqueous under stirring at temperature 25-30 0C. The pH of above mixture was adjusted using acetic acid to pH=7 to 7.8 and stirred the reaction mixture for 15-20 min at 25 - 35°C. The organic layer was separated .The aqueous layer was reextracted with MESK and the pooled layers were dried over anhydrous Sodium sulphate. To the MIBK solution was added 52.9 g of Sodium methoxide solution in Methanol (31percent w/w) and stirred for 15 minutes at temperature 25-300C. The solvents were distilled out from the above obtained clear solution on rotavapour at 45-500C under vacuum till the total volume is 300 to 400ml. To the above mixture, acetonitrile was added at 25-30 0C, under stirring. The obtained mass was stirred under nitrogen for 6-8 hr maintaining temperature 25 - 300C. The product was filtered at 25-30 0C, and washed with acetone and followed by acetonitrile and suck dried for 15-20min. The product was dried on rotavapour under vacuum at temperature 40-450C, till moisture content was less than 5percent. HPLC analysis: chiral purity: about 97.8percent Yield: 64.5g Sulfone: about 2.6 percent Sulfide: Not detected | ||
1.7 kg | The reactor was charged successively with 11.2 kg of toluene, 3.2 kg (9.71 mol, 1 eq) of Intermediate 1 (EL1)Purified water 22.7g (1.26mol, 0.13eq), the reaction mixture was heated to 50-55 ° C, stirred for 10min,1.20 kg (5.83 mol, 0.6 eq) of D - (-) - tartaric acid diethyl ester (D - (-) - DET)After stirring for 15 min, 0.83 kg (2.91 mol, 0.30 eq) of tetraisopropyl titanate (TIP) was added over 5 min,Temperature control at 50-55 , 0.1kg toluene washing, heat 50 ~ 55 reaction 1h.The temperature of the reaction mixture was lowered to 20-30 ° C and N, N-diisopropylethylamine (DIPEA) 0.38 kg (2.91 mol, 0.30 eq) and 0.1 kg of toluene.1.87 kg (content: 75percent, 9.22 mol, 0.95 eq) of cumene hydroperoxide (CHP)Dissolved in toluene 1.87kg solution, with time 45min. Dropping is completed,Maintain the reaction temperature 20 ~ 30 reaction 30min. TLC monitoring, the reaction is completed. Ammonia solution (concentrated aqueous ammonia 5.0kg + purified water 5.0kg) 10.0kg × 3 The reaction solution was extracted three times, the combined aqueous,Add toluene 5.0kg stripping time, the aqueous phase was cooled to 0 ~ 5 , ethyl acetate was added 12.0kg,Control the internal temperature 0 ~ 10 ° C dropping about 11.0kg of glacial acetic acid to adjust the pH to 7 ~ 8, the ethyl acetate layer was separated,Aqueous phase was added ethyl acetate 6.0kg × 2 extraction twice, the combined ethyl acetate layer was added to the reaction vessel,4.0 kg of 10percent sodium thiosulfate aqueous solution, 4.0 kg of 10percent NaCl aqueous solution,4.0percent 20percent NaCl aqueous solution was washed with anhydrous sodium sulfate was added 1.0kg stirring and drying for 1 hour, filtered,The filter cake was washed with ethyl acetate 1.0kg, the filtrate was concentrated under reduced pressure (bath temperature 40 ~ 45 ) to give an oily liquid.To the above-obtained orange oily liquid was added acetone 6.4kg, the internal temperature 10 ~ 20 for 1h,A small amount of white solid precipitated, filtered, the filter cake was washed with acetone 0.2kg,The filtrate was concentrated under reduced pressure (bath temperature 40 ~ 45 ° C) to give an oily liquid. The reaction kettle was charged with 3.32 kg of methanol, stirred, and 368.8 g (9.22 mol, 0.95 eq) of sodium hydroxideAfter stirring and dissolving, the temperature is lowered to 0-5 DEG C, the above oily liquid is dissolved in 9.6kg of methanol, the inner temperature is controlled at 0-5 DEG C, the solution is added into the reaction kettle dropwise, the reaction solution is heated to the inner temperature of 20-30 DEG C and stirred for 0.5h ,Methanol was distilled off under reduced pressure (bath temperature: 40-45 ° C), methanol (3 kg × 3) was added to replace methanol, 0.5 kg of methanol was added,16.0kg of acetonitrile and stirred for 5 hours at 15-25 and then filtered. The cake was washed with 3.0kg of 3percent methanol in acetonitrile. The resulting solid was vacuum dried at 40-45 ° C for 8-10 hours to obtain 2.39kg of white solid.23.9kg of acetone was added to the reaction vessel with stirring, 2.39kg of the above white solid was added,The reaction mixture was heated to an internal temperature of 35 to 40 ° C, stirred for 1 hour, filtered while hot, and the filter cake was washed once with 2.0 kg of acetone,Filter cake 40 ~ 45 vacuum drying 8 to 10 hours,The white solid was esomeprazole sodium crude 2.39kg. The yield is 67percent based on EL1. The reactor was added methanol 12.6kg, stirring, at 25 ° C,Add esomeprazole sodium crude1.8kg dissolved,Add medicinal charcoal 90g, stirred at room temperature 25 ~ 30 ° C for 30 minutes, filtered with precision, washed with methanol 3.0kg,Precision filtration, the filtrate into the D-zone, 40 ~ 45 vacuum distillation, to a volume of about 3 ~ 5L,Add ethyl acetate 3.0kg × 3, replace the methanol, add ethyl acetate 9.0kg, 5 ~ 15 stirring 5h.Filtration, the filter cake was washed with ethyl acetate 0.5kg, vacuum dried (60 ~ 65 ) 13 ~ 15h,Finished esomeprazole sodium 1.7kg, the yield of 94percent. | |
8.9 g | Add in a dry four-necked bottle5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio-1H-benzimidazole 6.2 g (18.8 mol), toluene 25 ml, stirred Warm to 60 °C. Add purified water 44 ml (2.4 mol),D-(-) diethyl tartate 2.35 g (11.4 mol) and titanium isopropoxide 1.6 g (5.6 mol),The reaction was stirred at 60 ° C for 1 hour, cooled to 30 ° C, and 0.72 g (5.6 mol) of N,N-diisopropylethylamine was added.And 3.47 g (18.2 mol) of cumene hydroperoxide (80percent), and reacted at room temperature for 2.5 hours with stirring.Add 25percent ammonia solution (3 * 20 ml) and extract the aqueous phase.Adjust pH 8 with dilute hydrochloric acid and extract with dichloromethane (2*9 ml).The organic phase was combined, washed with brine, dried over anhydrous magnesiumConcentration under reduced pressure gave a brown viscous oil (4.9 g). Add acetone to dissolve,2.78 ml of 4.5 M sodium hydroxide solution was added under stirring, and stirred for 0.5 h, and an appropriate amount of toluene was added.A white solid was produced, and after repeated concentration, 3 ml of acetone was added, and a large amount of white solid precipitated.Filter, wash, vacuum dry,Get 3.95gCrude 5-methoxy-2-((S)-((4-methoxy-3,5-dimethyl-2-pyridyl)methyl)sulfinyl)-1H-benzimidazole sodium.HPLC analysis showed a chemical purity of 98.7percent and an optical purity of 99.0percent. Follow these steps:10 g of 5-methoxy-2-((S)-((4-methoxy-3,5-dimethyl-2-pyridyl)methyl)sulfinyl)-1H-benzimidazole The crude sodium product was added to 60 ml of ethanol at room temperature, and the temperature was lowered to -20 ° C until the solution was completely dissolved. 180 ml of acetonitrile was added dropwise, and the mixture was stirred at 40 ° C for 4 hours, and a white solid was precipitated, filtered, washed, and dried under vacuum to obtain 5-methoxy. Benzyl-2-((S)-((4-methoxy-3,5-dimethyl-2-pyridyl)methyl)sulfinyl)-1H-benzimidazole sodium refined product 8.9 g, HPLC The purity was 99.68percent and the optical purity was 99.92percent. |
Yield | Reaction Conditions | Operation in experiment |
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93.5% | With C68H72N4O10Ti2; dihydrogen peroxide; In water; ethyl acetate; at 0℃; for 24h; | 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. |
With tert.-butylhydroperoxide; In water; toluene; at -20℃; for 12h; | 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 (70%, 96 mul, 0.064 mmol) was slowly added. After 12 hours at -20 C., the solution was extracted three times with aqueous ammonium hydroxide (12.5% NH3, 3×5 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 93%. | |
With oxygen; NADP; In aq. phosphate buffer; isopropyl alcohol; at 25℃; for 24h;pH 9.0;Enzymatic reaction; | General procedure: The Activity FIOP and enantioselectivity (% 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 muL 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, 10% (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. |
Yield | Reaction Conditions | Operation in experiment |
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In a 100 ml flask, 7.5 gm diethyl (-)-D-tartrate and 5.16 gm titanium(IV) isopropoxide and 0.13 ml water were taken at room temperature, and the mixture was heated to 65 - 70 degrees for 1 hour. After cooling to room temperature, 10 gm 5-methoxy[(2-(4-methoxy)- 3,5-dimethyl-2-pyridinyl] methylsulfenyl]-lH-benzimidazole was added and heated until a clear solution was obtained. The mixture then stirred for 0.5 hours at heating and cooled to room temperature. 6.9 gm Cumene hydroperoxide was added slowly. After addition, the reaction was monitored by HPLC for the following with the results listed below: | ||
In a 100 ml flask, 7.5 gm diethyl (-)-D-tartrate, 20 ml methylene chloride, 5.16 gm titanium(IV) isopropoxide and 0.13 gm water were taken at room temperature, and the mixture was heated to 65 - 70 degrees for 1 hour. After cooling to room temperature, 10 gm PMT was added and heated until a clear solution was obtained. The mixture then <n="21"/>stirred for 0.5 hours at heating and cooled to room temperature. 6.9 gm Cumene hydroperoxide was added slowly. After addition, the reaction was monitored by HPLC for the following with the results listed below: | ||
With dihydrogen peroxide;Mn-complex of (R,R)-1,2-bis(3,5-di-tert-butyl-2-hydroxybenzylamino)cyclohexane; In water; acetonitrile; at -10℃; for 5h;Product distribution / selectivity; | 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 %) are dissolved in acetonitrile (45 ml). The reaction mixture is cooled to -100C and 30% 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 56% of sulfoxide (1a) with 67% ee (S-enriched) and 5% of sulfone. |
With dihydrogen peroxide;Mn-complex of (S,S)-1,2-bis(2-hydroxybenzylamino)cyclohexane; In water; acetonitrile; at 0 - 20℃; for 3.5h; | 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 30% aqueous H2O2 is added dropwise. The mixture is stirred for several hours. Then, it is poured portionwise into a cold (0 0C) 10% 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. | |
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 (80% 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. | ||
19%Chromat. | With iron(III)-acetylacetonate; 2,4-dichloro-6-[(E)-[[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]imino]methyl]phenol; dihydrogen peroxide; p-N,N-dimethylaminobenzoic acid; In dichloromethane; water; at 15℃; for 1.5h; | General procedure: 79.3 mg (273 mumol) of S-dichloro chiral ligand and 32.2 mg (91.1 mumol) of iron(III) acetylacetonate were dissolved in 0.6 mL of ethyl acetate at 25° C., and stirred for more than 30 min. To the mixed solution were added 7.8 mg (45.5 mumol) of lithium 4-dimethylaminobenzoate and 0.3 mL of ethyl acetate, and the suspension was stirred for more than 30 min. 0.3 g (911 mumol) of sulfide A and 0.9 mL of ethyl acetate were added and the suspension was stirred for more than 30 min. After the mixture was cooled to ?5° C., 186 muL (1.82 mmol) of 30percent aqueous hydrogen peroxide solution was added dropwise for 2 min or more. After 4.5 hours, the reaction mixture was analyzed under HPLC analysis condition 1. sulfoxide A 88percent; sulfone A 11percent; sulfide A 0percent 98percent ee |
Yield | Reaction Conditions | Operation in experiment |
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83% | In a 1 L flask under nitrogen atmosphere, 50 gm 5-methoxy[(2-(4- methoxy)-3,5-dimethyl-2-pyridinyl] methylsulfenyI]-lH-benzimidazole (also termed as pyremetazole or PMT) was mixed with 160 ml toluene and heated to 65-70 degrees. To this mixture 18.8 gm diethyl (-)-D-tartrate and 45 ml toluene, 5.9 gm diisopropyl ethyl amine, 12.9 gm titanium(IV) isopropoxide were added and continue to stir at 60-65 degree for 1 hour. To this mixture after cooling, trityl hydroperoxide solution in toluene(279 ml having 47 gm tritylhydroperoxide) was added room temperature. The mixture was maintained under stirring for 3 hours at room temperature. The reaction mixture was analyzed for sulphoxide and sulfone. The sulfone content was less than 1percent.To the reaction mixture 30 ml methanol, 0.1 gm KI, and 2.74 gm potassium methoxide was added and stirred. The mixture cooled to 20 degree and filtered, washed with 150 mlToluene-methanol mixture, followed by 50 ml Methanol. Yield =83percent. The HPLC analysis of product shows:Esomeprazole (as potassium salt) 99.21percent (99percent ee) and sulfone content 0.59percent. | |
80% | In a 1 L flask under nitrogen atmosphere, 50 gm pyremetazole was mixed with 160 ml toluene and heated to 65-70 degrees. To this mixture 18.8 gm diethyl (+)-L-tartrate and45 ml toluene, 12.9 gm titanium(IV) isopropoxide were added and continue to stir at 60-65 degree for 1 hour. To this mixture after cooling, 1.5 gm DMSO and trityl hydroperoxide solution in toluene (279 ml having 27percent tritylhydroperoxide content) was added room temperature. The mixture was maintained under stirring for 3 hours at room temperature. The reaction mixture was analyzed for sulphoxide and sulfone. The sulfone content was less than 1.0percent.To the reaction mixture 30 ml methanol, 0.1 gm KJ, and 2.74 gm potassium methoxide was added and stirred. The mixture cooled to 20 degree and filtered, washed with 150 mlToluene-methanol mixture, followed by 50 ml Methanol. Yield 80percent. The HPLC analysis of product shows:Esomeprazole (as potassium salt) 99.3percent, e.e. 99percent and sulfone content 0.90percent. | |
65 - 70% | In a 100 ml flask, 7.5 gm diethyl (-)-D-tartrate, 1.17 gm diisopropyl ethyl amine, 5.16 gm titanium(IV) isopropoxide and 0.13 ml water were taken at room temperature, and the mixture was heated to 65 - 70 degrees for 1 hour. After cooling to room temperature, 10 gm 5-methoxy [(2-(4-methoxy)-3,5-dimethyl-2-pyridiny 1] methylsulfenyl]- 1 H- benzimidazole (also termed as pyrmetazole or PMT) was added and heated until a clear solution was obtained. The mixture then stirred for 0.5 hours at heating and cooled to room temperature. 6.9 gm Cumene hydroperoxide was added slowly. After addition, the reaction was monitored by HPLC for the following with the results listed below: <n="19"/>Isolation:To the reaction mixture 30 ml methanol, 0.1 gm KI, and 2.74 gm potassium methoxide was added and stirred. To this 30 ml toluene was added and filtered to obtain a crude esomeprazole potassium salt. Yield 65-70percent. The analysis of crude product is as follows: |
In a 100 ml flask, 7.5 gm diethyl (-)-D-tartrate, 1.17 gm diisopropyl ethyl amine, 5.16 gm titanium(IV) isopropoxide and 0.13 ml water were taken at room temperature, and the mixture was heated to 65 - 70 degrees for 1 hour. After cooling to room temperature, 10 gm 5-methoxy[(2-(4-methoxy)-3,5-dimethyl-2-pyridinyl] methylsulfenyl]-lH- benzimidazole (also termed as pyrmetazole or PMT) was added and heated until a clear solution was obtained. The mixture then stirred for 0.5 hours at heating and cooled to room temperature. 0.71 gm DMSO and 6.9 gm Cumene hydroperoxide was added slowly. <n="20"/>After addition, the reaction was monitored by HPLC for the following with the results listed below:Isolation:To the reaction mixture 30 ml methanol, 0.1 gm KI, and 2.74 gm potassium methoxide was added and stirred. To this 30 ml toluene was added and filtered to obtain a crude product. The analysis of crude product is as follows: | ||
The example 2 was repeated by varying the molar amounts of trityl hydroperoxide and the results are summarized below:Reaction mass:Purification of the above obtained product was carried out in THF in place of methanol and the results are as follows: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Pyrmethyl alcohol (8.8 g, 52.6 mmol) was dissolved in toluene (75 [ML,] water content 0.12 mg/ml) moistened with water [(180 GEL,] 10 mmol) at room temperature. To the stirred solution, at [25-30 °C,] thionyl chloride (8.15 g, 68.5 mmole) was added slowly over 60 min. (flow rate of 0.083 ml/min). Conversion of the reaction was analysed with HPLC as in Example 1. Conversion over 99.5percent. Water (2.3 ml) was added to quench any excess of thionyl chloride. An alkaline (13.5 g, 168.3 mmol 50 percent w/w sodium hydroxide) aqueous (80 ml) solution of metmercazole (9.8 g, 54.2 mmol) was added followed by additional sodium hydroxide (8.8 g, 110.5 mmol, 50 percent w/w sodium hydroxide) to reach pH>12.5. The temperature was allowed to increase to 45 °C during the additions. The reaction mixture was left with vigorous stirring for approximately two hours at [45 °C.] The agitating was interrupted and the phases were left to separate. The aqueous phase was discarded. The organic phase, comprising pyrmetazole, was washed with water and was analysed for residues of pyrmethyl alcohol (less than 0.1 percent mol).; Example 5 Pyrmethyl alcohol (8.8 g, 52.6 mmol) was dissolved in toluene (75 ml, water content 0.12 mg/ml) moistened with water [(375) J. I,] 20.8 mmol) at room temperature. To the stirred solution, at [25-35 °C,] thionyl chloride (9.33 g, 78.4 mmol) was added slowly over 60 min. (flow rate of 0.095 ml/min). Conversion of the reaction was analysed with HPLC as in Example 1. Conversion over 99.5 percent. The synthesis continued in the same way as described in Example 4. The product phase, comprising pyrmetazole, was analysed for residue of pyrmethyl alcohol (less than 0.1 percent mol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.7 g (9.45 mmol) of Ti(OPr)4 and 3.93 g of (_S)-lactic acid methyl ester (general formula IV: X = OMe, rVc ) (37.8 mmol) are placed in a 3-neck 100-ml flask, purged with an inert gas (argon), equipped with a mechanical stirrer and a thermometer. The resulting solution is heated up to a temperature in the range of 55 to 60 0C and 4.47 g (13.5 mmol) of the compound of formula III are added to the solution. The resulting thick slurry is stirred at a temperature in the range of 55 to 60 0C for 30 minutes. Then 60 mul of water are added to the reaction mixture. The reaction mixture is stirred at the same temperature for another 60 minutes. Subsequently, the reaction flask is put in a cooling bath and cooled to an inner temperature of +5 to +10 0C. Then, 2.25 ml of 88percent cumene hydroperoxide are added to the flask. The resulting slurry-like reaction mixture is stirred at a temperature in the range of +5 to +10 0C for 15 hours. Then, the reaction mixture is diluted with 75 ml of a 12.5percent solution of NH4OH under cooling to +5 to +10 0C and stirred for 30 minutes. The separated solid fraction is filtered off through a paper filter. The filter cake is washed with another 25 ml of the 12.5percent solution OfNH4OH. 75 ml of dichloromethane are added to the filtrate and pH of the mixture is adjusted to pH 8 to 9 with acetic acid under stirring and cooling with ice. The dichloromethane fraction is separated and the aqueous layer is extracted with another 30 ml of dichloromethane. The combined dichloromethane fractions are dried with anhydrous sodium sulfate and concentrated until dryness in a rotary vacuum evaporator. The evaporation residue is taken with 120 ml of ethyl methyl ketone and 6.5 ml of a solution of KOH in methanol (3 g of KOH in 25 ml of methanol) are added to the resulting mixture under cooling with ice. The resulting solution is seeded and left at standstill at a temperature of +5 to + 10 0C for 5-10 hours. Separated crystals are aspirated through frit. Wet crystals are dissolved in 20 ml of water in an Erlenmeyer flask. 25 ml of dichloromethane are added to the solution, pH of the mixture is adjusted to pH 8 to 9 with acetic acid under stirring and cooling with ice. The dichloromethane fraction is separated and the aqueous layer is extracted with another 10 ml of dichloromethane. The combined dichloromethane fractions are dried with anhydrous sodium sulfate and concentrated to dryness in a rotary vacuum evaporator. 120 ml of ethyl methyl ketone are added to the evaporation residue and 6.5 ml of a solution of KOH in methanol (3 g of KOH in 25 ml of methanol) are added to the resulting mixture under cooling with ice. The resulting solution is seeded and left at standstill at a temperature of +5 to +10 °C for 5-10 hours. Separated crystals are aspirated through frit. Wet crystals are dissolved in 20 ml of water in an Erlenmeyer flask. 25 ml of dichloromethane are added to the solution, pH of the mixture is adjusted to pH 8 to 9 with acetic acid under stirring and cooling with ice. The dichloromethane fraction is separated and the aqueous layer is extracted with another 10 ml of dichloromethane. The combined dichloromethane fractions are dried with anhydrous sodium sulfate and concentrated to dryness in a rotary vacuum evaporator. 30 ml of acetonitrile are added to the evaporation residue and a 50percent solution of NaOH (0.7 g) is added under cooling with ice. The solution is seeded and left at standstill at a temperature of + 5 to + 1O0C until the next day. The separated product is aspirated and 1.35 g of the sodium salt of esomeprasole are obtained, which, after re-purification, provide the sodium salt of esomeprazole with the following purity. HPLC chemical purity: 99.85 percent. HPLC on the chiral phase (CHIRALPAK AD-H.(R)., mobile phase 50percent hexane : 50percent ethanol, detection 302 am): enantiomeric excess 99.8 percent. |
Tags: Omeprazole sulfide | Ufiprazole | Pyridines | Sulfides | Benzimidazoles | Ethers | Other Compounds | Proton Pump | Organic Building Blocks | Small Molecule Positive Drugs | Membrane Transporter/Ion Channel | Heterocyclic Building Blocks | 73590-85-9
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