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Chemical Structure| 1030825-20-7

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Product Details of [ 1030825-20-7 ]

CAS No. :1030825-20-7
Formula : C18H14BrFS
M.W : 361.27
SMILES Code : FC1=CC=C(C2=CC=C(CC3=CC(Br)=CC=C3C)S2)C=C1
MDL No. :MFCD21496340
InChI Key :VLRIERSBZHUCOW-UHFFFAOYSA-N
Pubchem ID :46930432

Safety of [ 1030825-20-7 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 1030825-20-7 ] Show Less

Physicochemical Properties

Num. heavy atoms 21
Num. arom. heavy atoms 17
Fraction Csp3 0.11
Num. rotatable bonds 3
Num. H-bond acceptors 1.0
Num. H-bond donors 0.0
Molar Refractivity 91.83
TPSA ?

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

28.24 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

3.81
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

6.38
Log Po/w (WLOGP)?

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

6.64
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.

5.81
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

7.68
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

6.06

Water Solubility

Log S (ESOL):?

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

-6.5
Solubility 0.000114 mg/ml ; 0.000000316 mol/l
Class?

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

Poorly soluble
Log S (Ali)?

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

-6.76
Solubility 0.0000621 mg/ml ; 0.000000172 mol/l
Class?

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

Poorly 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

-8.58
Solubility 0.000000959 mg/ml ; 0.0000000026 mol/l
Class?

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

Poorly soluble

Pharmacokinetics

GI absorption?

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

Low
BBB permeant?

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

No
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

Yes
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

Yes
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

Yes
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

Yes
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.

-3.97 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

1.0
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

1.0
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

2.0
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

0.0 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<2.0
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)

2.93

Application In Synthesis of [ 1030825-20-7 ]

* 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 [ 1030825-20-7 ]

[ 1030825-20-7 ] Synthesis Path-Downstream   1~35

  • 1
  • [ 1030825-20-7 ]
  • [ 32469-28-6 ]
  • [ 1030825-21-8 ]
YieldReaction ConditionsOperation in experiment
93.7% This embodiment is a method for preparing a cardinol intermediate, and the preparation method comprises the following steps:1) Under the protection of nitrogen,100 g (0.245 mol) of <strong>[1030825-20-7]2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene</strong> was sufficiently dissolved in 300 mL of tetrahydrofuran.At a temperature of -25 ° C to -20 ° C,100 g (0.245 mol) of sec-butylmagnesium chloride. Lithium chloride was added dropwise.After the addition was completed, the reaction was continued for 1 hour;Maintain temperature,Further, 171.6 g (0.368 mol) of 2,3,4,6-tetra-O-(trimethylsilyl)-D-gluconolactone was added dropwise.After the addition is completed,Continue to react for 2 hours;Wherein 2,3,4,6-tetra-O-(trimethylsilyl)-D-gluconolactone is previously dissolved in 200 mL of tetrahydrofuran;2) in the reaction liquid after the reaction in the step 1),51.8 g (0.539 mol) of methanesulfonic acid in methanol was added dropwise.Stir,After natural temperature reaction for 18 hours, at a temperature of -5 ° C to 5 ° C,The reaction was quenched with saturated aqueous sodium bicarbonate;3) adjusting the pH of the reaction solution after the reaction in step 2) with a saturated aqueous solution of sodium hydrogencarbonate to 7-8, and after removing the solvent under reduced pressure,Extracted with methyl n-butyl ether twice,Combine the organic phase,Dissolve the solvent under reduced pressure,Obtaining a yellow viscous solid crude;Add the crude product to 300 mL of methyl n-butyl ether.After fully dissolving, add 600 mL of n-heptane, stir, and precipitate a solid.The solvent was removed and dried under vacuum to obtain the intermediate of cagliflozin; 108.9 g of pale yellow solid was obtained, purity 87.9percent.The yield was 93.7percent.
(1) To a solution of <strong>[1030825-20-7]5-bromo-1-[5-(4-fluorophenyl)-2-thienylmethyl]-2-methylbenzene</strong> (1, 28.9 g) in tetrahydrofuran (480 ml) and toluene (480 ml) was added n-butyllithium (1.6M hexane solution, 50.0 ml) dropwise at -67 to -70 C. under argon atmosphere, and the mixture was stirred for 20 minutes at the same temperature. Thereto was added a solution of 2 (34.0 g) in toluene (240 ml) dropwise at the same temperature, and the mixture was further stirred for 1 hour at the same temperature. Subsequently, thereto was added a solution of methanesulfonic acid (21.0 g) in methanol (480 ml) dropwise, and the resulting mixture was allowed to warm to room temperature and stirred for 17 hours. The mixture was cooled under ice-water cooling, and thereto was added a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the combined organic layer was washed with brine and dried over magnesium sulfate. The insoluble was filtered off and the solvent was evaporated under reduced pressure. The residue was triturated with toluene (100 ml)-hexane (400 ml) to give 1-(1-methoxyglucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]-benzene (3) (31.6 g). APCI-Mass m/Z 492 (M+NH4).
  • 2
  • [ 1030825-20-7 ]
  • [ 898566-17-1 ]
YieldReaction ConditionsOperation in experiment
With sodium iodide; N,N`-dimethylethylenediamine;copper(l) iodide; In diethylene glycol dimethyl ether; toluene; at 110℃; Example 3; 2-(4-Fluoro-phenyl)-5-(5-iodo-2-methyl-benzyl)-thiopheneA 1.0 L four-necked reaction flask was charged with the compound prepared as in Example 2 above (100 g, 276.80 mmoles), sodium Iodide (82 g, 553.59 mmoles) and Copper(l) Iodide (2.6 g, 13.84 mmoles). The resulting mixture was evacuated and purged with argon, then treated with toluene (261 ml_), diglyme (56 ml_) and N,N'-dimethyl-ethane-1 ,2-diamine (2.7 ml_, 27.68 mmoles) and the resulting mixture warmed to 11 O0C overnight. Upon consumption of starting material, the resulting mixture was cooled to room temperature, then filtered through Celite.(R)., washed with EtOAc, and extracted with NH4OH. The organic phase was dried (Na2SO4), filtered and concentrated to yield a solid. The solids were filtered and recrystallized from heptane to yield the title compound as an off white solid (m.p. 1070C). (See also, Klaper, A., Buchwald, S. L., "Copper-Catalyzed HalogenExchange in Aryl Halides: An Aromatic Finkelstein Reaction", J. Am. Chem. Soc, 2002, 124, 14844-14814)
With copper(l) iodide; sodium iodide; N,N`-dimethylethylenediamine; In diethylene glycol dimethyl ether; toluene; at 20℃;Inert atmosphere; Reflux; Example 15; 2-(4-fluorophenyl)-5(5-iodo-2-methylbenzyl)thiophene 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (100 g); (see Nomura S., et al., PCT Publication, WO 2005/012326 A1, published Feb. 10, 2005) was dissolved in toluene (300 mL) at room temperature under N2 atmosphere. Sodium iodide (83 g), copper (I) iodide (2.64 g), N,N'-dimethyl ethylenediamine (2.94 mL) and diglyme (50 mL) was added to the mixture at room temperature. The reaction mixture was heated to reflux temperature and stirred for 36 hours. Ethyl acetate (300 mL) was added to the mixture at 40° C. and the mixture was filtered using activated carbon pre-coated filter. The filtrate was washed twice with 5percent aqueous NH3 solution (100 mL). The organic layer was washed with water (100 mL) and then evaporated. The resulting residue was suspended in methanol (426 mL) at reflux temperature for 75 minutes. The resulting slurry was cooled to 25° C. and stirred for 1 hour. The precipitate was filtered and washed with methanol, then dried at 50° C. in vacuo to give 2-(5-iodo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (94.9 g) as white crystals.m/z (APCI), 409(M++H); mp 109-110° C.; 1H NMR (400 MHz, CDCl3); delta 7.54 (d, 4JHH=1.8 Hz, 1H), 7.45-7.42 (m, 3H), 7.07-6.99 (m, 3H), 6.92 (d, 3JHH=6.0 Hz, 1H), 6.66 (d, 3JHH=3.6 Hz, 1H), 4.05 (s, 2H), 2.26 (s, 3H).
94.9 g With copper(l) iodide; sodium iodide; N,N`-dimethylethylenediamine; In diethylene glycol dimethyl ether; toluene; for 36h;Inert atmosphere; Reflux; 10098] 2-(5-Bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (100 g; see WO 2005/012326 pamphlet) was dissolved in toluene (300 mL) at room temperature under N2 atmosphere. Sodium iodide (83 g), copper (I) iodide (2.64 g), N,N?-dimethyl ethylenediamine (2.94 mL) and diglyme (50 mL) was added to the mixture at room temperature. The reaction mixture was heated to reflux temperature and stirred for 36 hours. Ethyl acetate (300 mL) was added to the mixture at 40° C. and the mixture was filtered using activated carbon pre-coated filtet The filtrate was washed and then evaporated. The resulting residue was suspended in methanol (426 mL) at reflux temperature for 75 minutes. The resulting slurry was cooled to 25° C. and stirred for 1 hout The precipitate was filtered and washed with methanol, then dried at 50° C. in vacuo to give 2-(5-iodo-2-methylbenzyl)-5-(4-fluorophenyl) thiophene (94.9 g) as white crystals. mlz (APCI), 409 (M+ H);mp 109-110° C.
  • 3
  • [ 1132832-75-7 ]
  • [ 1030825-20-7 ]
YieldReaction ConditionsOperation in experiment
97.7% With borane-THF; In tetrahydrofuran; at -20 - -10℃; for 48h; 15 g (5-bromo-2-methylphenyl)[5-(p-fluorophe- nyl)thiophene-2-yl]methanone was weighed and dissolved in 150 ml tetrahydroffiran, and 30 ml of 1 M boranetetrahydroffiran complex was added. The system was reacted at ?20° C. to ?10° C. for 48 hours. After the complete reaction of raw materials, 30 ml water was added. The mixture was extracted with 100 ml dichloromethane, and then the extract was concentrated to give 14.25 g of 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene, with a purity of 98.9percent and in a yield of 97.7percent
84% With triethylsilane; boron trifluoride diethyl etherate; In dichloromethane; acetonitrile; at 0 - 35℃; 56.5 g of (5-bromo-2-methylphenyl)[2-(4-fluorophenyl)thiophene]methanone to be prepared according to Example 5. Dissolve (0.44 mol) in 600 ml of dichloromethane-acetonitrile (1:1, v/v), cool to 0°C in an ice water bath, and add dropwise triethylsilane.100 ml (0.63 mol), and then slowly added 47percent boron trifluoride ether 42 ml (0.33 mol), slowly added to the 20-The reaction was stirred at 35° C. for 4 hours. After the TLC reaction was completed, it was quenched with a saturated light carbonic acid solution and extracted with dichloromethane.The organic phase was washed with water and saturated brine, and the solvent was evaporated under reduced pressure. The residue was re-constituted with dichloromethane-methanol (1:1, v/v). Crystalline 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene, 13.3 g, yield 84percent
70% With triethylsilane; boron trifluoride diethyl etherate; In dichloromethane; acetonitrile; at 0 - 20℃; for 3h; Synthesis of compound 44Ci8Hi4BrFS M = 361.27 g.mol"1 19FNMR (CDCh, 282.5MHz): -115.0 (m, IF, Ar-F).Mass ESf): 133 (29percent); 177 (49percent); 182 (55percent); 184 (70percent); 191 (72percent); 281 (39percent); 360 (95percent); 362 (100percent)F Et3SiH DCM/MeCN Et3SiH (0.99mL, 6.18mmol, 2.9eq) was added at room temperature to a solution of ketone 43 (800mg, 2.13mmol, leq) in anhydrous dichloromethane-acetonitrile (1 :1, v/v, 16mL). The resultant mixture was cooled to 0°C and BF3.Et20 (0.75mL, 5.97mmol, 2.8eq) was slowly added. The reaction mixture was then stirred at room temperature for 3 hours. A saturated aqueous solution of NaHC03 was slowly added at 0°C. The aqueous layer was extracted with dichloromethane and the resultant organic layer was dried over MgS04, filtered and concentrated. The crude mixture was then recristallized with MeOH to afford compound 44 (70percent yield) as yellowish crystals.
With triethylsilane; boron trifluoride diethyl etherate; In dichloromethane; acetonitrile; at -8 - 20℃; Example 2; 2-(5-Bromo-2-methyl-benzyl)-5-(4-fluoro-phenyl)-thiopheneA 3.0 L four-necked round bottom flask was charged with the compound prepared as in Example 1 above (119 g, 0.317 mol), triethylsilane (148 ml_,0.926 mol), dichloromethane (700 ml_) and acetonitrile (700 ml_). The resulting mixture was cooled to -80C in an ice bath, with stirring, then boron thfluohde diethyl etherate (115 ml_, 0.915 mol) was added dropwise, such that the temperature did not exceed O0C. The resulting mixture was warmed to room <n="79"/>temperature and stirred overnight. The resulting mixture was concentrated under reduced pressure, diluted with IPA (1.0 L), filtered and washed with water to yield a solid. Recrystallization of the solid from IPA yielded the title compound as a yellow solid.
3.65 g With triethylsilane; boron trifluoride diethyl etherate; In dichloromethane; acetonitrile; at 0 - 20℃; for 26h; 2-(5-Bromo-2-methyl-benzoyl)-5-(4-fluoro-phenyl)-phenyl)-thiophene (8, 3.75 g) was dissolved in dichloromethane (40 ml) and acetonitrile (40 ml), to which triethylsilane (4.63 ml) was added and cooled to 0 °C. Boron trifluoride etherate (3.45 ml) was added to the suspension and the reaction mixture was left to warm up to room temperature then continued to stir at that temperature for 26 h. The reaction mixture was cooled on ice and 50 ml of NaHCO3 was slowly added, followed by adding dichloromethane (50 ml). Phases were separated and organic phase was dried over sulphate, and then evaporated. The residue was recrystallized from 2-propanol to give 3.65 g of the title compound 1a. 13C NMR (DMSO): 18.52, 32.84, 115.83, 116.00, 118.81, 123.52, 126.86, 126.99, 127.05, 129.50, 130.41, 131.60, 132.37, 135.54, 140.63, 141.16, 142.46, 160.48, 162.42. MS, m/z= 360.
With aluminum (III) chloride; sodium tetrahydroborate; In 1,2-dimethoxyethane; at 0 - 70℃; Aluminum chloride (46.12 g) was added to 1,2-dimethoxyethane (260 mL) at 0°C to 5°C. The reaction mixture was stirred for 30 minutes to 40 minutes at 5°C to 10°C. Sodium borohydride (26.19 g) was slowly added to the reaction mixture at 5°C to 10°C. The reaction mixture was stirred for 25 minutes to 30 minutes at the same temperature. A solution of (5-bromo-2-methylphenyl)[5-(4-fluorophenyl)thiophen-2-yl]methanone (130 g; Example 2) in 1,2-dimethoxyethane (260 mL) was added slowly to the reaction mixture, and then the mixture was stirred for 60 minutes at 15°C to 20°C. The reaction mixture was heated to a temperature of 65 °C to 70°C, and then stirred for 5 hours to 6 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to a temperature of 0°C to 5°C, and then added to pre-cooled de-ionized water (1300 mL) at 0°C to 10°C. The reaction mixture was stirred for 10 minutes to 15 minutes at the same temperature. Ethyl acetate (1300 mL) was added to the reaction mixture, and then the mixture was stirred for 10 to 15 minutes at 25°C to 30°C. The reaction mixture was allowed to settle for 15 minutes and then the layers were separated. The aqueous layer was washed with ethyl acetate (260 mL) and the organic layer was separated. The organic layers were combined, and then washed with an aqueous solution of sodium bicarbonate (32.5 g of sodium bicarbonate in 650 mL of de-ionized water). The organic layer was then washed with de-ionized water (260 mL). The organic layer was concentrated under reduced pressure at a temperature of about 45°C to obtain a solid residue. Methanol (390 mL) was added to the solid residue, and then the mixture was stirred for 60 minutes to 120 minutes at 0°C to 5°C to obtain a solid. The solid was washed with methanol (130 mL), and then dried under reduced pressure at 40°C to 45 °C to obtain 2-(5-bromo-2- methylbenzyl)-5 -(4-fluorophenyl)thiophene . Yield: 93percent

  • 4
  • [ 1030825-20-7 ]
  • [ 32469-28-6 ]
  • C36H57FO6SSi4 [ No CAS ]
  • 5
  • [ 460-00-4 ]
  • [ 1030825-20-7 ]
  • 7
  • [ 21900-41-4 ]
  • [ 1030825-20-7 ]
  • 8
  • [ 1030825-20-7 ]
  • [ 110391-10-1 ]
  • [ 1413373-77-9 ]
YieldReaction ConditionsOperation in experiment
Synthesis of compound 45C53H49F05S M = 817.02 g.mol"1 19FNMR (CDCh, 282.5MHz): -115.2 (m, IF, Ar-F)+; 855.4 [M+K]+ ft-Butyllithium (1.4M in hexanes, 0.30mL, 0.412mmol, l . l eq) was slowly added to a cooled solution (-70°C) of 44 (149mg, 0.412mmol, l . l eq) in anhydrous THF-toluene (1:1, v/v, 4.8mL) under inert atmosphere. The resultant dark blue solution was stirred for 5 min at the same temperature before a cooled solution (-70°C) of cyclohexenone 8 was slowly added. The reaction mixture was stirred for 15 min at -70°C before being poured into water. The organic layer was then dried over sodium sulphate, filtered and concentrated to afford crude 45 (300mg, 98percent yield) as yellow oil which was used in the next step without further purification.
  • 9
  • [ 79669-49-1 ]
  • [ 1030825-20-7 ]
  • 10
  • [ 1030825-20-7 ]
  • [ 1432591-75-7 ]
  • [ 1432591-84-8 ]
YieldReaction ConditionsOperation in experiment
56% 2-(5-Bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (1.5 g, 4.15 mmol) and magnesium powder (0.33 g, 13.7 mmol) were placed in a suitable reactor, followed by THF (9 mL) and 1,2-dibromoethane (95 muL). The mixture was heated to reflux. After the reaction was initiated, a solution of 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (2.5 g, 6.92 mmol) in THF (15 mL) was added dropwise. The mixture was stirred for another 2 hours under reflux, and was then cooled to ambient temperature and titrated to determine the concentration. The thus prepared 3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl magnesium bromide (0.29 M in THF, 17 mL, 5.0 mmol) and AlCl3 (0.5 M in THF, 4.0 mL, 2.0 mmol) were mixed at ambient temperature to give a black solution, which was stirred at ambient temperature for 1 hour. To a solution of 1,6-anhydro-2,4-di-O-tert-butyldiphenylsilyl-beta-D-glucopyranose (0.64 g, 1.0 mmol) in PhOMe (3.0 mL) at ambient temperature was added n-BuLi (0.4 mL, 1.0 mmol, 2.5 M solution in Bu2O). After stirring for about 5 min the solution was then added into the above prepared aluminum mixture via syringe, followed by additional PhOMe (1.0 mL) to rinse the flask. The mixture was concentrated under reduced pressure (50 torr) at 60° C. (external bath temperature) to remove low-boiling point ethereal solvents, and PhOMe (6 mL) was then added. The remaining mixture was heated at 150° C. (external bath temperature) for 5 hours at which time HPLC assay analysis indicated a 68percent yield of 2,4-di-O-tert-butyldiphenylsilyl-1-C-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-beta-D-glucopyranoside. After cooling to ambient temperature, the reaction was treated with 10percent aqueous NaOH (1 mL), THF (10 mL) and diatomaceous earth at ambient temperature, then the mixture was filtered and the filter cake was washed with THF. The combined filtrates were concentrated and the crude product was purified by silica gel column chromatography (eluting with 1:20 MTBE/n-heptane) to give the product 2,4-di-O-tert-butyldiphenylsilyl-1-C-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-beta-D-glucopyranoside (0.51 g, 56percent) as a white powder. [0273] 1H NMR (400 MHz, CDCl3) delta 7.65 (d, J=7.2 Hz, 2H), 7.55 (d, J=7.2 Hz, 2H), 7.48 (dd, J=7.6, 5.6 Hz, 2H), 7.44-7.20 (m, 16H), 7.11-6.95 (m, 6H), 6.57 (d, J=3.2 Hz, 1H), 4.25 (d, J=9.6 Hz, 1H), 4.06 (s, 2H), 3.90-3.86 (m, 1H), 3.81-3.76 (m, 1H), 3.61-3.57 (m, 1H), 3.54-3.49 (m, 2H), 3.40 (dd, J=8.8, 8.8 Hz, 1H), 2.31 (s, 3H), 1.81 (dd, J=6.6, 6.6 Hz, 1H, OH), 1.19 (d, J=4.4 Hz, 1H, OH), 1.00 (s, 9H), 0.64 (s, 9H); 13C NMR (100 MHz, CDCl3) delta 162.1 (d, J=246 Hz, C), 143.1 (C), 141.4 (C), 137.9 (C), 136.8 (C), 136.5 (C), 136.4 (CH×2), 136.1 (CH×2), 135.25 (C), 135.20 (CH×2), 135.0 (CH×2), 134.8 (C), 132.8 (C), 132.3 (C), 130.9 (d, J=3.5 Hz, C), 130.5 (CH), 130.0 (CH), 129.7 (CH), 129.5 (CH), 129.4 (CH), 129.2 (CH), 127.6 (CH×4), 127.5 (CH×2), 127.2 (CH×2), 127.1 (d, J=8.2 Hz, CH×2), 127.06 (CH), 126.0 (CH), 122.7 (CH), 115.7 (d, J=21.8 Hz, CH×2), 82.7 (CH), 80.5 (CH), 79.4 (CH), 76.3 (CH), 72.9 (CH), 62.8 (CH2), 34.1 (CH2), 27.2 (CH3×3), 26.7 (CH3×3), 19.6, (C), 19.3 (CH3), 19.2 (C); LCMS (ESI) m/z 938 (100, [M+NH4]+), 943 (10, [M+Na]+). 2
  • 12
  • [ 1030825-20-7 ]
  • bis(3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl)chloroalane [ No CAS ]
  • 13
  • [ 1030825-20-7 ]
  • [ 74372-90-0 ]
  • C45H43FO5S [ No CAS ]
  • (2S,3S,4R,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Under argon atmosphere, 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (2A, 2.16g) was dissolved in THF (10 ml) and cooled to 0°C. To this solution 8.6 ml of tributyllithium magnesate solution (0.7M in ether/hexanes) was slowly added and left at 0°C for 20 minutes. At 0°C 3 ml of copper cyanide dilithiumchloride complex (1 M) was added and left at 0 < for 30 min. To reaction mixture a solution of (1 S,3R,4R,5S,6R)-4,5- bis(benzyloxy)-3-((benzyloxy)methyl)-2,7-dioxabicyclo[4.1 .0]heptane (1 A, 1 .30 g) in THF (15 ml) was slowly added. After complete addition reaction mixture was left to warm up to r. t. and left overnight to give the mixture containing 22percent trans isomer (2R,3S,4R,5R,6R)- 4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4- methylphenyl)tetrahydro-2H-pyran-3-ol (3A) and 4percent of the cis isomer corresponding to the trans isomer of formula 3A (HPLC). Reaction mixture might be further purified using flash column chromatography (ethyl acetate/heptane 1 :6). MS; M+NH4+ = 732.
  • 14
  • [ 1030825-20-7 ]
  • [ 74372-90-0 ]
  • (2S,3S,4R,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
63% Under argon atmosphere, 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (2A, 4.13 g) was dissolved in THF (15 ml) and cooled to 0 °C. To this solution 5.7 ml of tributyllithium magnesate solution (0.7M in ether/hexanes) was slowly added and left at 0°C for 20 minutes. This solution was slowly (20 min) added to a solution of (1 S,3R,4R,5S,6R)-4,5-bis(benzyloxy)-3-((benzyloxy)methyl)-2,7-dioxabicyclo[4.1 .0] heptane (1 A, 4.71 g) and copper cyanide dilithiumchloride complex (1 M, 0.544 ml) in THF (8 ml). The mixture was stirred at r. t. for several hours (76percent trans 3A), then quenched with saturated ammonium chloride, stirred at r. t. for another hour then extracted with ethyl acetate. Organic phase was further purified using flash column chromatography (ethyl acetate/heptane 1 :6) to give 4.92 g of pure (HPLC 99.0 areapercent) (2R,3S,4R,5R,6R)-4,5- bis(benzyloxy)-6-((benzyloxy)methyl)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4- methylphenyl)tetrahydro-2H-pyran-3-ol (3A) (63percent). MS; M+NH4+ = 732. NMR (1 H, DMSO): 2.28 (s, 3H), 3.41 -3.67 (m, 6H) ; 4.09-4-13 (m, 3H), 4.45-4.54 (m, 3H), 4.73-4.76 (m, 2H); 4.94 (d, 1 H); 5.22 (d, 1 H), 6.80 (d, 1 H), 7.16-7.31 (m, 1 9H), 7.36 (m, 2H), 7.56-7.58 (m, 2H).
  • 15
  • [ 1030825-20-7 ]
  • [ 74372-90-0 ]
  • [ 842133-18-0 ]
  • 16
  • [ 1030825-20-7 ]
  • [ 316790-20-2 ]
  • (2S,3S,4R,5R,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-4,5-bis((4-methoxybenzyl)oxy)-6-(((4-methoxybenzyl)oxy)methyl)tetrahydro-2H-pyran-3-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.5 g Under argon atmosphere, 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (2A, 3.25 g) was dissolved in THF (10 ml) and cooled to 0 ^. To this solution 4.28 ml of tributyllithium magnesate solution (0.7M in ether/hexanes) was slowly added and left at 0°C for 20 minutes. At 0°C 5 ml of copper cyanide dilithiumchloride complex (1 M) was added and left at 0
  • 17
  • [ 1030825-20-7 ]
  • [ 163982-16-9 ]
  • (2R,3R,4R,5S,6S)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-5-hydroxy-2-((pivaloyloxy)methyl)tetrahydro-2H-pyran-3,4-diyl bis(2,2-dimethylpropanoate) [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.5 g Under argon atmosphere, 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (2A, 3.61 g) was dissolved in THF (10 ml) and cooled to 0 °C. To this solution 4.76 ml of tributyllithium magnesate solution (0.7M in ether/hexanes) was slowly added and left at 0°C for 20 minutes. At 0°C 5 ml of copper cyanide dilithiumchloride complex (1 M) was added and left at 0 °C for 30 min. To reaction mixture a solution of (1 S,3R,4R,5S,6R)-3- ((pivaloyloxy)methyl)-2,7-dioxabicyclo[4.1 .0]heptane-4,5-diyl bis(2,2-dimethylpropanoate) (1 C, 1 .87 g) in THF (5 ml) was slowly added. After complete addition reaction mixture was left to warm up to r. t. and left overnight to give the mixture containing (2R,3R,4R,5S,6S)- 6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-5-hydroxy-2- ((pivaloyloxy)methyl)tetrahydro-2H-pyran-3,4-diyl bis(2,2-dimethylpropanoate) (3C). Reaction mixture might be further purified using flash column chromatography (ethyl acetate/heptane 1 :6). MS; M+NH4+ = 714.
  • 18
  • [ 115933-30-7 ]
  • [ 1030825-20-7 ]
  • 19
  • [ 918487-45-3 ]
  • [ 1030825-20-7 ]
  • 20
  • [ 98-03-3 ]
  • [ 1030825-20-7 ]
  • 21
  • [ 249504-38-9 ]
  • [ 1030825-20-7 ]
  • 22
  • [ 1030825-20-7 ]
  • 3,4,5-tris[(trimethylsilyl)oxy]-6-[(trimethylsilyl)oxy]methyl}-tetrahydro-2H-pyran-2-one [ No CAS ]
  • [ 1030825-21-8 ]
YieldReaction ConditionsOperation in experiment
With n-butyllithium; methanesulfonic acid; sodium hydrogencarbonate; In methanol; hexane; dichloromethane; di-isopropyl ether; toluene; Example-1A Preparation of (3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (III) In 500 mL three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel were added 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (Va) (5 g) and 150 mL toluene at 25 C. 1.5 mL (1.6M) n-butyl lithium in hexane was added dropwise at room temperature and the solution was stirred for 30 minutes. This solution was cooled to -78 C. and added dropwise to a solution of 3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (IV) (6.4 g) in 100 mL toluene and the mixture was stirred for 3 hours. The reaction mixture was treated with 2.5 g methanesulfonic acid in 100 mL methanol and stirred for 1 hour. The reaction mixture warmed to room temperature and stirred for 8 hours. Saturated sodium bicarbonate solution was added to the reaction mixture and the separated aqueous layer was extracted with toluene. The organic layer was distilled to remove toluene and the residue was dissolved in 50 mL methylene dichloride, washed with brine, dried over Na2SO4 and evaporated under reduced pressure to obtain residue. The residue was treated with 150 mL diisopropyl ether and stirred at 55 C. for 30 min, cooled, filtered and washed with diisopropyl ether to obtain compound of Formula (III).
With n-butyllithium; methanesulfonic acid; In methanol; hexane; toluene; Example-1 Preparation of (3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (III) In 500 mL three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel were added 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (Va) (5 g) and 150 mL toluene at 25 C. 1.5 mL (1.6M) n-butyl lithium in hexane was added dropwise at room temperature and the solution was stirred for 30 minutes. This solution was cooled to -78 C. and added dropwise to a solution of 3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (IV) (6.4 g) in 100 mL toluene and the mixture was stirred for 3 hours. The reaction mixture was treated with 2.5 g methanesulfonic acid in 100 mL methanol and stirred for 1 hour. The reaction mass was warmed to 25 C. and then added to pre-cool saturated sodium bicarbonate solution and resulting mass was extracted with ethyl acetate. The extract was washed with brine, dried over Na2SO4 and evaporated under reduced pressure to obtain compound of Formula (III).
  • 23
  • [ 1030825-20-7 ]
  • [ 866607-35-4 ]
  • 24
  • [ 67-56-1 ]
  • [ 1030825-20-7 ]
  • [ 32469-28-6 ]
  • [ 1030825-21-8 ]
YieldReaction ConditionsOperation in experiment
92.1% Magnesium powder (12.0g, 500mmol), iodine (1.3g, 10.0mmol) was added to a dry reaction flask,The dried under nitrogen in tetrahydrofuran (50mL) was added to the reaction flask was cooled to 0 ,2 - [(5-bromo-2-methylphenyl) methyl] -5- (4-fluorophenyl) thiophene (II) (36.1g, 100mmol)In tetrahydrofuran (100mL) was slowly added dropwise to the reaction flask, plus complete warmed to 25 ,The reaction was stirred for 5 ~ 8h, cooled to 0 ,The above reaction solution at 0 ,Was added dropwise to 2,3,4,6-tetra (trimethylsilyl) -D- -O- gluconolactone (III) (55.9g,120mmol) in anhydrous tetrahydrofuran (100 mL) solution was added dropwise, and the reaction mixture was stirred for 2 ~ 3h,And under cooling with containing methanesulfonic acid (26.4g, 275mmol) in methanol (150 mL) was added dropwise to the reaction solution in the above,Bi dropwise slowly warmed to room temperature and stirred overnight.After completion of the reaction, the temperature dropped to 0 ,About 300mL saturated sodium bicarbonate solution was added to about pH 7, separated and the aqueous layer was extracted once with 200mL ethylThe combined organic layers with saturated brine (200 mL), washed once, dried over anhydrous magnesium sulfate, suction filtered,The filtrate was distilled under reduced pressure to give a paleYellow solid powder-methyl-1-C- (3 - ((5- (4- fluorophenyl) -2-thienyl) methyl) -4-methyl-phenyl) -D- glucopyranoside (I) 42.0g, yield 92.1percent, HPLC content of 95.9percent.
A solution of 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (100 g; Example 3) in tetrahydrofuran (200 mL) and toluene (300 mL) was added to a solution of -butyl lithium in hexane (3.2M; 76.8 g) and tetrahydrofuran (200 mL) at -75°C to -65°C under nitrogen atmosphere. The reaction mixture was stirred for 20 minutes to 40 minutes at the same temperature. A solution of 2,3,4,6-tetrakis-0-trimethylsilyl-D-glucono-l,5- lactone (194 g) in toluene (500 mL) was added to the reaction mixture at -70°C to -75°C, and then the mixture was stirred for 60 minutes to 90 minutes at the same temperature. A solution of methanesulphonic acid (66 g) in methanol (700 mL) was slowly added to the reaction mixture at -70°C to -75 °C. The reaction mixture was allowed to reach a temperature of 25°C to 30°C, and was then stirred at the same temperature for 12 hours. After completion of the reaction, the reaction mixture was washed with an aqueous solution of sodium bicarbonate (25 g of sodium bicarbonate in 500 mL of de-ionized water) at 25°C to 30°C. Ethyl acetate (500 mL) was added to the organic layer, and then the mixture was stirred for 10 minutes to 15 minutes. The reaction mixture was allowed to settle for 15 minutes, and then the layers were separated. The aqueous layer was washed twice with ethyl acetate (500 mL) and the layers were separated. The organic layers were combined, and then washed with an aqueous solution of sodium chloride (10 g of sodium chloride in 200 mL of de-ionized water). The organic layer was concentrated under reduced pressure at 45°C to obtain an oily residue. The oily residue was dissolved in toluene (300 mL) at 40°C to 45°C to obtain a solution. Hexane (1000 mL) was slowly added to the solution at 25 °C to 30°C under a nitrogen atmosphere. The mixture was stirred at the same temperature for 15 minutes to 20 minutes to obtain a solid. The solid was filtered under reduced pressure under nitrogen atmosphere, and then dried for 20 minutes to 30 minutes under nitrogen atmosphere to obtain l-(l-methoxyglucopyranosyl)- 4-methyl-3-[5-(4-flourophenyl)-2-thienylmethyl]benzene.
  • 25
  • [ 1765-93-1 ]
  • [ 1030825-20-7 ]
  • 26
  • [ 1030825-20-7 ]
  • C70H82O6Si4 [ No CAS ]
  • [ 1358581-37-9 ]
YieldReaction ConditionsOperation in experiment
77.8% With sec.-butyllithium; In tetrahydrofuran; hexane; toluene; at -78 - -65℃; for 2h;Inert atmosphere; Under nitrogen, to a 50mL three-necked flask were added sequentially 4.42g5- bromo-1- [5- (4-fluorophenyl) -2-thienylmethyl] -2-methyl-benzene, 10ml of tetrahydrofuran and 20ml of toluene, followed by stirring dissolved, cooled to -78 , 1.4M sec-butyllithium in n-hexane was added dropwise 9.16ml of dropping the temperature was kept below -70 deg.] C, after the addition was complete the reaction was complete to give lithium 5- 1- [5 - (4-fluorophenyl) -2-thienylmethyl] -2-methyl-benzene. Under nitrogen atmosphere, into a three-necked 250mL flask was added 14.97g Compound B-3 and 40ml of toluene, followed by stirring to dissolve, cooled to -78 deg.] C, the lithium -1- 5- [5- (4-fluorophenyl) -2- thienylmethyl] -2-methyl-benzene was added dropwise, the dropping rate to keep the temperature below -65 deg.] C, after the addition was complete the reaction was kept 2 hours, 12.45g tetraethyl ammonium fluoride dropwise, the reaction was stirred for 1 hour at room temperature , methanol was added dropwise a solution of 10.78g of methanesulfonic acid (4.78g containing methanesulfonic acid), the reaction mixture was stirred at room temperature, the HPLC monitoring of the reaction is complete, add saturated NaHCO3 solution to a pH of about 7.5, the organic layer was separated and the aqueous layer with ethyl acetate. and the combined organic phase was washed with saturated brine, evaporated under reduced pressure, supplemented with 20ml of toluene, evaporated to dryness under reduced pressure by rotary evaporation to give 4.51g of intermediate -2, yield: 77.8percent.
  • 27
  • [ 1030825-20-7 ]
  • C18H42O6Si4 [ No CAS ]
  • [ 1358581-37-9 ]
YieldReaction ConditionsOperation in experiment
76.7% With tert.-butyl lithium; In tetrahydrofuran; toluene; pentane; at -78 - -65℃; for 2h;Inert atmosphere; Under an argon atmosphere, to a 50mL three-necked flask were added sequentially 4.42g5- bromo-1- [5- (4-fluorophenyl) -2-thienylmethyl] -2-methyl-benzene, 10ml of tetrahydrofuran and 25ml of toluene, stirring to dissolve, cooled to -78 , 1.7M solution in pentane of t-butyllithium was added dropwise 7.56ml, dropping the temperature was kept below -70 deg.] C, after the addition was complete the reaction was complete to give lithium 5- 1- [ 5- (4-fluorophenyl) -2-thienylmethyl] -2-methyl-benzene. Under an argon atmosphere, to a three-necked 250mL flask was added 6.18g Compound B-1 and 25ml of toluene, followed by stirring to dissolve, cooled to -78 deg.] C, the lithium -1- 5- [5- (4-fluorophenyl) -2 - thienylmethyl] -2-methyl-benzene was added dropwise, the dropping rate to keep the temperature below -65 deg.] C, after the addition was complete the reaction was kept 2 hours, methanol was added dropwise a solution of 5.96g of hydrochloric acid (containing 1.96 g of hydrochloric acid), after completion of the dropwise addition, the reaction mixture was stirred at room temperature, the HPLC monitoring of the reaction is complete, add saturated NaHCO3 solution to a pH of about 7.5, the organic layer was separated and the aqueous layer extracted with ethyl acetate, the combined organic phase was washed with saturated brine, evaporated under reduced pressure , supplemented with 20ml toluene, evaporated under reduced pressure rotary evaporation to give 4.45g intermediate -2, yield: 76.7percent.
  • 28
  • [ 1030825-20-7 ]
  • (2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-(3-((5-(4-fluorophenyl)-thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran [ No CAS ]
  • 29
  • [ 13096-62-3 ]
  • [ 1030825-20-7 ]
  • (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-2-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
99% Under an argon atmosphere, 300 mL of dehydrated tetrahydrofuran and 90.4 g (250 mmol)2- (2-methyl-5-bromobenzyl) -5- (4-fluorophenyl) thiophene was added to 1000 mLIn a three-neck flask,The temperature of the mixed system was controlled at -78 ° C with an acetone / dry ice bath,To the three-necked flask, 100 mL (2.5 mol / L, 250 mmol, 1 eq)Butyl lithium,The temperature of the reaction system during the dropwise addition was controlled at -78 ° C,After completion of the dropwise addition,And allowed to stand at -78 ° C for 1 hour.Was added dropwise to the reaction system2,3,4,6-tetra-O-benzyl-D-gluconolactone in tetrahydrofuran(2,3,4,6-tetra-O-benzyl-D-gluconolactone, 135.6 g,Tetrahydrofuran (150 mL)While stirring while stirring,After the dropwise addition, the dry ice / acetone bath was removed,The temperature of the reaction system was gradually returned to room temperature, and the reaction was allowed to proceed for 3 hoursAfter the reaction was stopped,The reaction was quenched with saturated NaHCO3 solution under ice-cooling,After quenching, the reaction product solution was extracted with ethyl acetate,The organic phases are combined,Dried over magnesium sulfate and concentrated under reduced pressure,210.1 g of a yellow thick liquid was obtained. The yellow thick liquid was detected and collectedThe results indicated that the yellow thick liquid had the structure of the formula (II-I), the purity was 87.7percentThe yield was 99percent
  • 30
  • [ 64688-68-2 ]
  • [ 1030825-20-7 ]
  • 31
  • (5-bromothiophen-2-yl)(2-methyl-5-nitrophenyl)methanone [ No CAS ]
  • [ 1030825-20-7 ]
  • 32
  • 2-(4-fluorophenyl)-5-((5-amino-2-methylphenyl)methyl)thiophene [ No CAS ]
  • [ 1030825-20-7 ]
YieldReaction ConditionsOperation in experiment
84% 2-(4-Fluorophenyl)-5-((5-amino-2-methylphenyl)) methyl)thiophene (0.1 mmol) and copper bromide (0.1 mmol)) were dissolved in acetone (acetone), stirred to -10 degrees c under cooling with ice, and isobutyl nitrite (0.15 mmol)) was added and reacted for 0.5 -1 hour at the temperature of -10 DEG c. The resulting mixture was concentrated under reduced pressure, dried, and 100 ml (g/ml) of a 40percent hydrobromic acid aqueous solution) was added, reacted for 1 h at 90°C, cooled to room temperature, and washed with ethyl acetate (20 mL × 3) the organic layer was extracted with 10percent sodium bicarbonate (10 mL × 3), washed with purified water (10 mL × 3), and the organic layer was recrystallized to obtain 2-(4-fluorophenyl)-5-((5-bromo-2-methylphenyl))methyl)thiophene (yield 84percent).
  • 33
  • [ 1030825-20-7 ]
  • 2-(4-fluoro-phenyl)-5-(2-methyl-benzyl)-thiophene [ No CAS ]
YieldReaction ConditionsOperation in experiment
88% To the mixture of 20 cc THF and 20 cc Toluene charged 0.25 mole 2-(5-Bromo-2- methyl-benzyl)-5 -(4-fluoro-phenyl)-thiopheneand Cooled to - 78°C. Added n-Butyl lithium (1.9 M in hexane) and Stirred for 30 mm at - 78°C. Slowly added 20 percent Ammonium chloride solution to the reaction mass and raised the temperature from ? 78°C to -50°C. slowlybrought the reaction mass to ambient temperature and stirred for30 mm. Settled and separated layers, extracted the aqueous, layer with 50 cc toluene. Washed the organic layer with 500 cc brine solution. Distilled out the toluene and charged heptane and stirred for 2 to 3 hrs at ambient temperature. Filtered the product and dried at 45 ? 50°C under reduced pressure to obtain 88 percenttitled productMass: (m+1) 283 m/z found 283.51 , HPLC Purity : 97.5 percent
88% To the mixture of 20cc THF and 20cc Toluene charged 0.25 mole 2-(5-Bromo-2- methyl-benzyl)-5-(4-fluoro-phenyl)-thiophene and Cooled to - 78C. Added nButyl lithium (1.9 M in hexane) and Stirred for 30 mm at - 78C. Slowly added 20 percent Ammonium chloride solution to the reaction mass and raised the temperature from - 78C to -5OC. Slowly brought the reaction mass to ambient temperature and stirred for 30 mi n. Settled and separated layers, extracted the aqueous layer with 50 cc toluene. Washed the organic layer with 500 cc brine solution. Distilled out the toluene and charged heptane and stirred for 2 to 3 hrs at ambient temperature. Filtered the product and dried at 45 - 5OC under reduced pressure to obtain 88 percent titled productMass: (m+1) 283 m/z found 283.51 HPLC Purity: 97.5percent
  • 34
  • [ 1030825-20-7 ]
  • [ 32469-28-6 ]
  • [ 107-18-6 ]
  • 2-allyloxy-2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol [ No CAS ]
YieldReaction ConditionsOperation in experiment
To the mixture of 10 ccTHF and 10 cc Toluene added 0.138 mole 2-(5-Bromo-2-methyl- benzyl>-5-(4-fluoro-phenyl)-thiopheneatambient temperature. The reaction mass was stirred for 15 mm. Cooled to -70 to -80°C in dry ice /acetone bath and stirred for 15 mm. Added a solution of 0.014 mole n-Butyl lithium (1.9M in hexanes) at -70 to -80°C. and stirred for lhr. Added solution of 3, 4, 5-Tris-trimethylsilanyloxy-6- trimethylsilanyloxymethyl-tetrahydro-pyran-2-one in 5 cc of Toluene at -70 to -80°C and stirred for 2 to 3hrs. After the compliance of the reaction,thereaction mass was quenched with Methane suiphonic acid and Ally alcohol mixture at -70 to -80°C.Temperature was raised to ambient temperature and stirred over night. Reaction mass was quenched with 30 cc sat.sodiumbicarbonate solution to bring the pH neutral to alkaline. Reaction mass stirred for 30.0 mm. Layers separated and aqueous was extracted with 10 cc of Toluene. Organic layer was combined and washed with water 30cc and sat. brine solution 50 cc. Organic layer was distilled under reduced pressure to recover the toluene. Solid compound thus obtainedwas dissolved in 50cc of toluene and quenched in n-Hexane to obtain 75-79percent the titled compound as crystalline solid.HPLC purity:88-94 percent. JR dataAromatic C- F stretching: 832 cm? Lactones C ? 0 stretching: 1045 ? 1092 cm1 Allylic C- 0 stretching: 1161 cm1Anomeric C-O stretching: 1231 cm1Aromatic C=C stretching: 1510, 1548, 1603, 1703 cm Alkane C ? H stretching: 2892 , 2950 cmAllylic C-H stretching: 2990?3120 cm?Aromatic C ? H stretching: 3050 - 3090 cm Lactones 0 ? H stretching: 3240 ? 3380 cm Dip?Mass(M+Na) 523.28 m/z (M+K) 539.38 m/z
  • 35
  • [ 1030825-20-7 ]
  • 2-allyloxy-2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol [ No CAS ]
  • [ 107-19-7 ]
  • C27H27FO6S [ No CAS ]
YieldReaction ConditionsOperation in experiment
To themixture of 10 ccTHF and 10 cc Toluene added 0.138 mole 2-(5-Bromo-2-methyl- benzyl)-5-(4-fluoro-phenyl)-thiopheneatambient temperature. The reaction mass is stirred for 15 mm. Cooled to -70 to -80°C in dry ice /acetone bath and stirred for 15 mm. Added a solution of 0.0 14 mole n-Butyl lithium (1.9M in hexanes) at -70 to -80°C. and stirred for lhr. Added solution of 3, 4, 5-Tris-trimethylsilanyloxy-6-trimethylsilanyloxymethyl- tetrahydro-pyran-2-one in 5 cc of Toluene at -70 to -80°C and stirred for 2 to 3brs. After the compliance of the reaction, reaction mass is quenched with Methane suiphonic acid and propargyl alcohol mixture at -70 to -80°C. Temperature was raised to ambient temperature and stirred over night. Reaction mass was quenched with 30 cc sat.sodiumbicarbonate solution to bring the pH neutral to alkaline. Reaction mass stirred for 30.0 min;layers separated and aqueous layer was extracted with 10 cc of Toluene. Organic layer was combined and washed with water 30cc and sat. brine solution 50 cc. Organic layer was distilled under reduced pressure to recover the toluene. Solid compound thus obtained was dissolved in 50cc of toluene and quenched in n-Hexane to obtain 75-79percent of the titled compound as crystalline solid. HPLC purity:88-94 percent.JR data:Aromatic C- F stretching: 878 cm1 Lactones C ? 0 stretching: 1045 ? 1092 cm? Propargylic C- 0 stretching: 1161 cm1Anomeric C-O stretching: 1231 cm4Aromatic C=C stretching: 1510, 1548 , 1603 , 1703 cm1 Propargylic C- H stretching: 2125 cm1Alkane C ? H stretching: 2892 , 2950 cm?Aromatic C ? H stretching: 3050 - 3090 cm1 Lactones 0 ? H stretching: 3240 ? 3380 cm4 Dip-Mass;(M+Na) 521.31 mlz (M+K) 537.31 mlz
 

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