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Chemical Structure| 86604-75-3 Chemical Structure| 86604-75-3

Structure of 86604-75-3

Chemical Structure| 86604-75-3

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Product Details of [ 86604-75-3 ]

CAS No. :86604-75-3
Formula : C9H13Cl2NO
M.W : 222.11
SMILES Code : CC1=CN=C(CCl)C(C)=C1OC.[H]Cl
MDL No. :MFCD00277472
InChI Key :LCJDHJOUOJSJGS-UHFFFAOYSA-N
Pubchem ID :11694258

Safety of [ 86604-75-3 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H302-H314
Precautionary Statements:P260-P264-P270-P280-P301+P330+P331-P303+P361+P353-P304+P340-P305+P351+P338-P310-P363-P405-P501
Class:8
UN#:3261
Packing Group:

Computational Chemistry of [ 86604-75-3 ] Show Less

Physicochemical Properties

Num. heavy atoms 13
Num. arom. heavy atoms 6
Fraction Csp3 0.44
Num. rotatable bonds 2
Num. H-bond acceptors 2.0
Num. H-bond donors 0.0
Molar Refractivity 57.39
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

22.12 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

0.0
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

2.78
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

3.1
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

1.73
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

3.21
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.16

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-3.18
Solubility 0.147 mg/ml ; 0.000664 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-2.9
Solubility 0.279 mg/ml ; 0.00126 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-3.95
Solubility 0.025 mg/ml ; 0.000112 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

High
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

Yes
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-5.68 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

0.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

1.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

2.09

Application In Synthesis of [ 86604-75-3 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 86604-75-3 ]

[ 86604-75-3 ] Synthesis Path-Downstream   1~8

  • 1
  • [ 97963-62-7 ]
  • [ 86604-75-3 ]
  • [ 138786-81-9 ]
  • 2
  • [ 86604-75-3 ]
  • [ 149765-16-2 ]
  • N-(4-chloro-5-iodo-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)pivalamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
80% With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; Step 5. N-[4-Chloro-5-iodo-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide A mixture of <strong>[149765-16-2]N-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethyl-propionamide</strong> (37.8 g, 0.1 mol), 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine hydrochloride (23.1 g, 0.104 mol), finely powdered K2CO3, (41.5 g, 0.3 mol, 3.0 eq.), and anhydrous DMF (200 mL) was stirred at rt overnight. The solvent was evaporated, and the residue taken up in CH2Cl2 (500 mL), washed with brine (200 mL*3), evaporated, and recrystallized from MeOH to give the title product as a white powder (42.0 g, 80% yield; HPLC purity 98%). tR: 6.49 min. 1H-NMR (DMSO-d6) δ 10.16 (br. s, 1H), 8.04 (s, 1H), 7.72 (s, 1H), 5.46 (s, 2H), 3.73 (s, 3H), 2.33 (s, 3H), 2.15 (s, 3H), 1.21 (s, 9H).
  • 3
  • [ 37052-78-1 ]
  • [ 86604-75-3 ]
  • [ 73590-85-9 ]
YieldReaction ConditionsOperation 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.

  • 5
  • [ 98968-72-0 ]
  • [ 86604-75-3 ]
  • tert-butyl (2-fluorophenyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate [ No CAS ]
  • 6
  • [ 98968-72-0 ]
  • [ 86604-75-3 ]
  • tert-butyl (2-fluoro-5-morpholinophenyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate [ No CAS ]
  • 7
  • [ 97963-62-7 ]
  • [ 86604-75-3 ]
  • [ 102625-64-9 ]
YieldReaction ConditionsOperation in experiment
94% With sodium hydroxide; In ethanol; at 80℃; for 8h; In a 500 mL three-necked flask,2-Chloromethyl-3,4-dimethoxypyridine hydrochloride (22.4 g,100 mmol), <strong>[97963-62-7]5-difluoromethoxy-2-mercapto-1H-benzimidazole</strong> (21.6 g, 104 mmol), 80 g / L sodium hydroxide solution(110 mL),Ethanol (150 mL) and the mixture was heated to 80 C and stirred for 8 hours. The ethanol was recovered and the residue was extracted with dichloromethane (150 mL)extraction. Add anhydrous sodium sulfate drying overnight, vacuum recovery of dichloromethane was crude. Recrystallization from ethyl acetate-petroleum ether gave a white solid which was dried to give 5-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methyl] Benzimidazole, product yield 94%.
  • 8
  • [ 86604-75-3 ]
  • [ 164513-38-6 ]
  • 2-[(5-bromo-4-methylpyridin-2-yl)oxy]methyl}-4-methoxy-3,5-dimethylpyridine [ No CAS ]
YieldReaction ConditionsOperation in experiment
94% With silver carbonate; In toluene; at 110℃; for 6h;Darkness; General procedure: To a mixture of 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine hydrochloride (600 mg,2.7 mmol) and 5-bromo-2-hydroxy-3-methylpyridine (1a;510 mg, 2.7 mmol) in toluene (6.0 mL) was added Ag2CO3(1.9 g, 6.8 mmol). The mixture was stirred at 110C in the darkfor 6 h. After cooling to room temperature, the mixture wasfiltered through a Celite pad. The filtrate was concentratedin vacuo. The residue was purified by column chromatographyon silica gel (hexane/EtOAc) to give the product (360 mg,39%). 1H-NMR (DMSO-d6) δ: 2.11 (3H, s), 2.21 (3H, s), 2.23(3H, s), 3.74 (3H, s), 5.36 (2H, s), 7.78-7.83 (1H, m), 8.09-8.13(1H, m), 8.19 (1H, s); MS m/z: 337 (M + H)+
 

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