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[ CAS No. 83282-91-1 ] {[proInfo.proName]}

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3d Animation Molecule Structure of 83282-91-1
Chemical Structure| 83282-91-1
Chemical Structure| 83282-91-1
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Product Details of [ 83282-91-1 ]

CAS No. :83282-91-1 MDL No. :MFCD08688060
Formula : C9H8F4O2 Boiling Point : -
Linear Structure Formula :- InChI Key :YFHZSPDQKWFAPH-UHFFFAOYSA-N
M.W : 224.15 Pubchem ID :11172116
Synonyms :

Calculated chemistry of [ 83282-91-1 ]

Physicochemical Properties

Num. heavy atoms : 15
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.33
Num. rotatable bonds : 3
Num. H-bond acceptors : 6.0
Num. H-bond donors : 1.0
Molar Refractivity : 43.26
TPSA : 29.46 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.89 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.16
Log Po/w (XLOGP3) : 1.09
Log Po/w (WLOGP) : 3.26
Log Po/w (MLOGP) : 2.93
Log Po/w (SILICOS-IT) : 3.75
Consensus Log Po/w : 2.64

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.01
Solubility : 2.17 mg/ml ; 0.00967 mol/l
Class : Soluble
Log S (Ali) : -1.3
Solubility : 11.2 mg/ml ; 0.05 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -3.88
Solubility : 0.0293 mg/ml ; 0.000131 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.77

Safety of [ 83282-91-1 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338 UN#:N/A
Hazard Statements:H317-H319 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 83282-91-1 ]

* 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 [ 83282-91-1 ]

[ 83282-91-1 ] Synthesis Path-Downstream   1~66

  • 1
  • (1R)-trans-2,2-dimethyl-3-((Z)-1-propenyl) cyclopropanecarboxylic acid chloride [ No CAS ]
  • [ 83282-91-1 ]
  • [4-(methoxymethyl)-2,3,5,6-tetrafluorophenyl]methyl} (1R)-trans-2,2-dimethyl-3-((Z)-1-propenyl)cyclopropanecarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
88% With pyridine In tetrahydrofuran at 20℃; for 8h;
  • 3
  • [ 83282-91-1 ]
  • methyl 1R-2,2-dimethyl-3-(1-propenyl)cyclopropane carboxylate [ No CAS ]
  • 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl 1R-2,2-dimethyl-3-(1-propenyl)cyclopropane carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
97% With 2,6-di-tert-butyl-4-methyl-phenol; lithium methanolate In n-heptane at 104 - 105℃; for 11h;
  • 4
  • [ 83282-91-1 ]
  • [ 4489-14-9 ]
  • [ 53955-46-7 ]
  • [ 26770-95-6 ]
  • [ 56650-12-5 ]
  • [ 271241-14-6 ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran at 0 - 20℃; for 8h; Reference Production Example Reference Production Example Into 10 ml of tetrahydrofuran were dissolved 1.0 g of 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol and 0.42 g of ethyl cyanoacetate, 0.9 g of 3-(2-methyl-1-propenyl)-2,2-dimethylcyclopropanecarboxylic chloride (ratio of stereo isomer: (1R)-trans/(1R)-cis/(1S)-trans/(1S)-cis = 93.9/2.5/3.5/0.1} was added to the mixture under ice-cooling, and the mixture was stirred for 8 hours at room temperature. The reaction mixture was poured into ice-and-water, and extracted with 80 ml of ethyl acetate twice. The organic layers were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to obtain 1.4 g of 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl 2,2-dimethyl-3-(2-methyl-1-propenyl) cyclopropanecarboxylate given by the formula (4).1H-NMR (CDCl3, TMS) ä (ppm): 1.13 (s, 3H), 1.26 (s, 3H), 1.38 (d, 1H), 1.69 (brs, 6H), 2.10 (dd, 1H), 3.40 (s, 3H), 4.59 (s, 2H), 4.87 (d, 1H), 5.24 (dd, 2H)
  • 5
  • [ 83282-91-1 ]
  • zircornium(IV) n-propoxide [ No CAS ]
  • tetra{2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyloxy}zirconium [ No CAS ]
YieldReaction ConditionsOperation in experiment
In propan-1-ol; xylene at 143 - 145℃; 2 Example 2; To 500 ml four-neck flask, 186 g of xylene and 1.70 g of a solution of tetrapropoxyzirconium in propanol (75% in content)were charged. In the resultant solution, 0.42 g of propanol as solvent was contained. The resultant solution was heated to 143 to 145° C. under stirring at a normal pressure, and 15.9 g of a mixture of propanol and xylene was distilled off. Analysis of the distilled mixture by GC internal standard method showed that 0.38 g of propanol was contained therein. The resultant solution was cooled below 80° C., and then 44.8 g of 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl alcohol, 10 g of xylene and 0.74 g of 2,6-di-tert-butyl-4-methylphenol as stabilizing agent were charged. The mixture was heated to 143 to 145° C. under stirring at a normal pressure, and 68.3 g of a mixture of propanol and xylene was distilled off to obtain a solution containing a zirconium catalyst. Analysis of the distilled mixture by GC internal standard method showed that 0.94 g of propanol was contained therein. A theoretical amount of propanol produced by exchanging all propoxide contained in tetrapropoxyzirconium is 0.92 g. Thus, it is clear that, by this stage of operations, propanol in the solution was almost entirely distilled off, a ligand exchange was progressed quantitatively, and tetra{2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyloxy}zircon ium was contained as main constituent in the solution. The resultant solution was cooled below 80° C., and then 37.0 g of 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylic acid was charged thereto. To the reactor, Dean-Stark trap was equipped, and the reaction was conducted with stirring for eight hours at 145 to 147° C., removing water by-produced during the reaction into the trap, and a solution containing 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate was obtained. Yield: 98% (based on 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl alcohol. Content of by-product: propyl 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate was not detected (detection lower limit: 0.04%)
  • 6
  • [ 83282-91-1 ]
  • [ 40447-55-0 ]
  • [ 240494-70-6 ]
YieldReaction ConditionsOperation in experiment
With lithium methanolate In n-heptane at 95 - 105℃; for 16h; Heating / reflux;
With lithium methanolate In n-heptane at 95 - 105℃; for 17h; Heating / reflux;
YieldReaction ConditionsOperation in experiment
(Crystallization Purification) (Crystallization Purification) Fifteen grams (15 g) of the crude product of the objective compound (GC area percentage: 89% of the objective compound and 9.5% of the by-product compound) produced by the present method was added to a mixture of 7.5 g of toluene and 10 g of hexane and dissolved completely under heating to 66.3° C. of the inner temperature. The solution was cooled with stirring at a rate of about 20° C. per one hour. At the time of 30° C. of the inner temperature, no crystals were precipitated. After about 10 mg of the purified objective compound was added at 29.9° C. of the inner temperature, the solution was cooled to 20.1° C. of room temperature at the same rate, continued to stir for 2 days, and further cooled with ice. After stirring at 2.5+-1° C. of the inner temperature for 3 hours, the solution was filtered at the same temperature. The filtrate was rinsed with 10 g of hexane and dried under a reduced pressure to give 4.05 g of purified 4-methoxymethyl-2,3,5,6-tetrafluorobenzenemethanol.
Specific insecticidally useful compounds according to the invention include the esters derived from each of: 4-methyl-2,3,5,6-tetrafluorobenzyl alcohol pentafluorobenzyl alcohol 4-allyl-2,3,5,6-tetrafluorobenzyl alcohol 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol 3-phenoxybenzyl alcohol α-cyano-3-phenoxybenzyl alcohol 6-phenoxypyrid-2-ylmethanol 1-cyano-1-(6-phenoxypyrid-2-yl)methanol 3-(4-chlorophenoxybenzyl) alcohol ...
  • 8
  • [ 92339-07-6 ]
  • [ 83282-91-1 ]
YieldReaction ConditionsOperation in experiment
With potassium hydroxide; nitrogen; dimethyl sulfate; In water; toluene; Production Example 1 Into a reaction vessel that was charged nitrogen, 5.00 g (23.1 mmol) of <strong>[92339-07-6]2,3,5,6-tetrafluoro-1,4-benzenedimethanol</strong>, 15.00 g of water and 1.30 g (23.1 mmol) of potassium hydroxide were charged subsequently, and heated to 60 C. with stirring. At this time, solid <strong>[92339-07-6]2,3,5,6-tetrafluoro-1,4-benzenedimethanol</strong> was completely dissolved to be a clear solution. Then, a mixture of 15.0 g of toluene and 3.07 g (23.1 mmol) of dimethyl sulfate was added at 55+-5 C. After stirring at 50+-5 C. for 1.5 hours, 0.64 g (11.4 mmol) of potassium hydroxide and 1.51 g (12.6 mmol) of dimethyl sulfate were added. After 1.5 hours, 0.66 g (11.7 mmol) of potassium hydroxide and 1.51 g (12.6 mmol) of dimethyl sulfate were further added and stirred at the same temperature for 1.5 hours. Allowing the reaction mixture to cool to room temperature, the layers of the reaction mixture were separated and the water layer was extracted with 30 ml of ethyl acetate. The organic layers were combined, washed with 30 ml of water, concentrated, and dried under reduced pressure to give 5.22 g of crude 4-methoxymethyl-2,3,5,6-tetrafluorobenzenemethanol.
With sodium hydroxide; nitrogen; dimethyl sulfate; In water; toluene; Production Example 2 Into a reaction vessel that was charged nitrogen, 5.00 g (23.1 mmol) of <strong>[92339-07-6]2,3,5,6-tetrafluoro-1,4-benzenedimethanol</strong>, 15.00 g of water and 6.85 g (46.3 mmol) of 27% aqueous sodium hydroxide solution were charged subsequently, and heated to 65 C. with stirring. The starting compound was completely dissolved to be clear solution. Then, the reaction mixture was allowed to cool to room temperature with stirring. At this time, some precipitate was observed. To the reaction mixture, 20.0 g of toluene was added and then 4.33 g (32.6 mmol) of dimethyl sulfate was added dropwise over 7.5 hours at room temperature. After the addition, the pH of the aqueous layer became 13.5. The layers of the reaction mixture were separated, and the pH of the aqueous layer was adjusted to about 3 by adding 10% sulfric acid. The aqueous layer was extracted with 30 ml of ethyl acetate, and the combined organic layers were washed with 30 ml of water, concentrated, and dried under a reduced pressure to give 5.22 g of crude 4-methoxymethyl-2,3,5,6-tetrafluorobenzenemethanol.
  • 9
  • [ 1634-04-4 ]
  • [ 92339-07-6 ]
  • [ 83282-91-1 ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide; nitrogen; In water; dimethyl sulfate; Production Example 4 Into a reaction vessel that was charged nitrogen, 10.00 g (46.26 mmol) of <strong>[92339-07-6]2,3,5,6-tetrafluoro-1,4-benzenedimethanol</strong>, 19.99 g of water and 13.71 g (92.51 mmol) of 27% aqueous sodium hydroxide solution were charged subsequently, and heated to 67.2 C. with stirring. The starting compound was completely dissolved to be clear solution. Then, the reaction mixture was heated to keep the internal temperature 50+-3 C. To the reaction mixture, 30.0 g of methyl tert.-butyl ether was added and then 6.14 g (46.26 mmol) of dimethyl sulfate was added in one portion at 50+-3 C. Subsequent portions of dimethyl sulfate were added 2 h(2.5 g), 3.5 h(3.15 g), 5 h(3.1 g), 6.5 h(3.1 g) and 8 h(3.1 g); portions of 27% aqueous sodium hydroxide as well 5 h(6.86 g) and 7 h(6.86 g); later from the first addition of dimethyl sulfate. One hour later from the final addition of dimethyl sulfate, the reaction mixture was cooled down to room temperature. The layers of the reaction mixture were separated. The organic layer was washed with 25 g of 10% aqueous sodium hydroxide for 4 times, concentrated and dried under reduced pressure to give 9.30 g of crude 4-methoxymethyl-2,3,5,6-tetrafluorobenzenemethanol.
  • 10
  • [ 83282-91-1 ]
  • water thrice [ No CAS ]
  • [ 128-37-0 ]
  • (1R)-trans-norchrysanthemic acid methyl ester [ No CAS ]
  • (1R)-trans-2,2-dimethyl-3-((Z)-1-propenyl)cyclopropanecarboxylic acid [2,3,5,6-tetrafluoro-4-(methoxymethyl)phenyl]methyl}ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; sodium hydroxide; lithium methanolate In n-heptane; water 2 Example 2 Example 2 Into a 1000 ml separable flask were added 78.1 g of methyl 1R-trans-2,2-dimethyl-3-(1-propenyl)cyclopropanecarbo,ylate (0.464 mol, E/Z={fraction (1/9)}, wherein E/Z ratio is a geometrical isomer ratio with respect to the double bond), 0,79 g (0.004 mol) of 2,6-di-t-butyl-4-methylphenol, 320 g of n-heptane, and 0.34 g of (0.009mol) of lithium methoxide, and 80.0 g (0.357 mol) of melted 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl alcohol and 160 g of n-heptane were added in parallel thereto over 4 hours at 104 to 105° C. while removing a distillate fraction at the temperature. The amount of the distillate removed by this operation was 161.5 g. The reaction mixture was further heated at the temperature for 7 hours under simultaneous addition of n-heptane, while a distillate fraction was removed. The amount of the distillate thus removed was 566.9 g. After cooling the reaction mixture, it was washed with 160 g of water thrice, 240 g of 5% aqueous sodium hydroxide solution twice, 160 g of water once, 80 g of 1% hydrochloric acid twice, and 80 g of water twice in this sequence. One portion (49.9 g) of the obtained organic layer (376.7 g, hereinafter referred to as "solution A") was concentrated to give 18.7 g of a residue. The residue was analyzed by gas-chromatography using internal standard method to show that the content of 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl 1R-trans-2,2-dimethyl-3-(1-propenyl)cyclopropanecarboxylate was 85.9%, wherein E/Z ratio is a geometrical isomer ratio with respect to the double bond. Based on the analysis, the concentration of the "solution A" was found to be 32.2% and the yield of the desired compound in this reaction was found to be 94.2%. 326.7 g of the solution A was charged in a 1000 ml separable flask and solvent was removed therefrom at 105 to 123° C. at normal pressure. To the resulting residue was added 555 g of water at one time and a component that makes an azeotrope with water was distilled off for 7 hours at 85 to 107° C., and water was further removed under reduced pressure to give 107.0 g of 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl 1R-trans-2,2-dimethyl-3-(1-propenyl)cyclopropanecarboxylate. Gas-chromatography analysis of the product showed that the yield of the desired product, E/Z=1/9, wherein E/Z ratio is a geometrical isomer ratio with respect to the double bond) was 97,2% (recovery ratio from solution A was 98.9%).
  • 11
  • [ 83282-91-1 ]
  • [ 10026-11-6 ]
  • [ 10453-89-1 ]
  • [ 271241-14-6 ]
YieldReaction ConditionsOperation in experiment
68% In 5,5-dimethyl-1,3-cyclohexadiene 13 Example 13 Example 13 In a 10 ml test tube-type reactor, 0.34 g of 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylic acid, 0.45 g of 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl alcohol, 4.7 mg of zirconium tetrachloride, and 5 ml of xylene were charged. The reactor was equipped with a Dean-Stark trap and a condenser, and the reaction mixture was stirred under reflux for 8 hours at 145° C. while water generated as a by-product during reaction was being separated and collected in the trap. A reaction mixture thereof was analyzed with gas chromatography to find that 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate was obtained in a yield of 68% (selectivity: 98%) based on the material alcohol.
  • 12
  • [ 83282-91-1 ]
  • zirconium(IV) tetraisopropoxide [ No CAS ]
  • 2,2-Dimethyl-3-(1'-propenyl)-cyclopropane-carboxylic acid [ No CAS ]
  • (2,3,5,6-tetrafluoro-4-methoxymethylphenyl)methyl 2,2-dimethyl-3-(1-propenyl)cyclopropanecarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
83% In 5,5-dimethyl-1,3-cyclohexadiene 12 Example 12 Example 12 In a 10 ml test tube-type reactor, 0.16 g of 2,2-dimethyl-3-(1-propenyl)cyclopropanecarboxylic acid, 0.22 g of 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl alcohol, 3.3 mg of zirconium tetraisopropoxide, and 5 ml of xylene were charged. The reactor was equipped with a Dean-Stark trap and a condenser, and the reaction mixture was stirred under reflux for 8 hours at 145° C. while water generated as a by-product during reaction was being separated and collected in the trap. A reaction mixture thereof was analyzed with gas chromatography to find that 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl 2,2-dimethyl-3-(1-propenyl)cyclopropanecarboxylate was obtained in a yield of 83% (selectivity: 98%) based on the material alcohol.
  • 13
  • [ 83282-91-1 ]
  • [ 10453-89-1 ]
  • [ 271241-14-6 ]
YieldReaction ConditionsOperation in experiment
70% In 5,5-dimethyl-1,3-cyclohexadiene 31 Example 31 Example 31 In a 10 ml test tube-type reactor, 0.34 g of 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylic acid, 0.45 g of 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl alcohol, 13.6 mg of a hafnium tetrachloride·2tetrahydrofuran complex, and 5 ml of xylene were charged. The reactor was equipped with a Dean-Stark trap and a condenser, and the reaction mixture was stirred under reflux for 8 hours at 145° C. while water generated as a by-product during reaction was being separated and collected in the trap. A reaction mixture thereof was analyzed with gas chromatography to find that 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate was obtained in a yield of 70% (selectivity: 99%) based on the material alcohol.
  • 14
  • [ 83282-91-1 ]
  • 2,2-Dimethyl-3-(1'-propenyl)-cyclopropane-carboxylic acid [ No CAS ]
  • (2,3,5,6-tetrafluoro-4-methoxymethylphenyl)methyl 2,2-dimethyl-3-(1-propenyl)cyclopropanecarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
80% In 5,5-dimethyl-1,3-cyclohexadiene 29 Example 29 Example 29 In a 10 ml test tube-type reactor, 0.16 g of 2,2-dimethyl-3-(1-propenyl)cyclopropanecarboxylic acid, 0.22 g of 2,3,5,6-tetrafluoro-4-((methoxymethyl)benzyl alcohol, 4.6 mg of a hafnium tetrachloride·2tetrahydrofuran complex, and 5 ml of xylene were charged. The reactor was equipped with a Dean-Stark trap and a condenser, and the reaction mixture was stirred under reflux for 8 hours at 145° C. while water generated as a by-product during reaction was being separated and collected in the trap. A reaction mixture thereof was analyzed with gas chromatography to find that 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl 2,2-dimethyl-3-(1-propenyl)cyclopropanecarboxylate was obtained in a yield of 80% (selectivity: 99%) based on the material alcohol.
  • 15
  • [ 83282-91-1 ]
  • [ 74609-46-4 ]
  • 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl (+/-)-3-(Z-2-chloro-3,3,3-trifluoro-prop-1-en-1-yl)-2,2-dimethylcyclopropane carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With pyridine; thionyl chloride In toluene 17 EXAMPLE 17 EXAMPLE 17 This Example illustrates the preparation of 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl (+-)-3-(Z-2-chloro-3,3,3-trifluoro-prop-1-en-1-yl)-2,2-dimethylcyclopropane carboxylate (Product I). A mixture of thionyl chloride (3.0 ml) and (+-)-3-(Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropane carboxylic acid, (0.200 g) was heated at the reflux temperature for 5 hours, and then kept at the ambient temperature for 16 hours. After removing the excess thionyl chloride by evaporation under reduced pressure (the last traces being removed by azeotropic distillation with toluene) the resultant acid chloride was added to a mixture of 4-methoxymethyltetrafluoro-benzyl alcohol (0.18 g), dry pyridine (0.065 g) and dry toluene (10 ml), and the resultant mixture stirred at the ambient temperatures for 2 hours and then stood at the ambient temperature for a further 16 hours. After adding toluene (10 ml) the mixture was washed successively with dilute hydrochloric acid (2 N, 20 ml), water and saturated sodium bicarbonate solution, dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent under reduced pressure. The residual oil was purified by preparative thick layer chromatography (2 mm thick silica gel/chloroform eluent) to give 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl (+-)-3-(Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropane carboxylate, identified by n.m.r. and infra red spectroscopy.
  • 16
  • [ 83282-91-1 ]
  • 3-(2-methyl-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride [ No CAS ]
  • [ 271241-14-6 ]
YieldReaction ConditionsOperation in experiment
With pyridine In tetrahydrofuran P.3 PRODUCTION EXAMPLE 3 PRODUCTION EXAMPLE 3 3-(2-methyl-1-propenyl)-2,2-dimethylcyclo-propanecarboxylic acid chloride {containing the stereoisomers in a ratio of (1R)-trans form (1R)-cis form: (1S)-trans form: (1S)-cis form=49:1:49:1} is added to a mixture of 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol, pyridine and tetrahydrofuran under ice-cooling. The resulting mixture is heated to room temperature and stirred at room temperature. The reaction mixture is poured into ice water and extracted with ethyl acetate. The combined ethyl acetate layer is washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant residue is subjected to silica gel column chromatography to obtain 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl 3-(2-methyl-1-propenyl)-2,2-dimethylcyclopropane-carboxylate (hereinafter referred to as the present compound 3).
  • 17
  • [ 83282-91-1 ]
  • [ 942435-98-5 ]
YieldReaction ConditionsOperation in experiment
95% With 1-methyl-4-butylimidazolium tetrafluoroborate; hydrogen at 160℃; for 4 - 8h; 1; 2 Example 1; Into a 50 ml flask equipped with a reflux condenser, 5 g of slurry of sponge cobalt (commercially available from Aldrich, Raney (a registered trade mark of W. R. Grace) 2700 Cobalt), 5 g of 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol and 5 g of 1-methyl-4-butylimidazolium tetrafluoroborate were charged. After removing water from the obtained mixture at 8 kPa and at an inner temperature of 80°C, a gas phase part in the flask was substituted with nitrogen. Further, the gas phase part was substituted with hydrogen and a 1L-volume rubber balloon full filed with hydrogen was equipped with the flask. The mixture was heated to 160°C to effect reaction at 160°C for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and 20 g of hexane and 20 g of water were added thereto. After removing an insoluble matters by filtration from the mixture obtained, the filtrate obtained was left at rest and separated to an organic layer and an aqueous layer. The aqueous layer was extracted twice with 20 g of hexane. The hexane layers were mixed with the previous obtained organic layer to concentrate to obtain 4.5 g of a pale yellow oil containing 4-methoxymethyl-2,3,5,6-tetrafluorotoluene. The purity was 98% and the yield was 95%. Alternatively, 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol was recovered in 3%. GC-MS:M+=208 1H-NMR (δppm, CDCl3, TMS standard): 2.29 (s, 3H), 3.39 (s, 3H), 4.56 (s, 2H) Example 2 The reaction was conducted according to a same manner as that of Example 1, except that the used amount of slurry of cobalt sponge was 4.5 g and the reaction time was 8 hours, to obtain 4.6 g of a pale yellow oil containing 4-methoxymethyl-2,3,5,6-tetrafluorotoluene. The purity was 99% and the yield was 98%. Alternatively, 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol was recovered in 2%.
95% With hydrogen In toluene at 150℃; for 18h; 4 Example 4; Into a 200 ml pressure-resistant reaction tube, 4.5 g of slurry of sponge cobalt (commercially available from Aldrich, Raney (a registered trade mark of W. R. Grace) 2700 Cobalt), 5 g of 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol and 15 g of toluene were charged. After a gas phase part in the reaction tube was substituted with nitrogen, the gas phase part was substituted twice with hydrogen at 0.4 MPa. The hydrogen pressure in the reaction tube was adjusted to a gauge pressure of 0.4 MPa, and then, the tube was heated to 150°C to effect reaction at 150°C for 18 hours. During this period, the gauge pressure was increased up to 0.8 MPa and then decreased to 0.6 MPa. After completion of the reaction, the reaction mixture was cooled to room temperature and 10 g of water was added thereto. After removing an insoluble matters by filtration from the mixture obtained, the insoluble matters were washed with 10 g of toluene. The wash liquid obtained was mixed with the previously obtained filtrate, leaving at rest followed by separating an organic layer. The organic layer was concentrated to obtain 4.7 g of a pale yellow oil containing 4-methoxymethyl-2,3,5,6-tetrafluorotoluene. The purity was 94% and the yield was 95%.
86% With hydrogen; methyltrioctylammonium bistriflamide at 150℃; for 5h; 3 Example 3; Into a 50 ml flask equipped with a reflux condenser, 900 mg of slurry of sponge cobalt (commercially available from Aldrich, Raney (a registered trade mark of W. R. Grace) 2700 Cobalt), 1.12 g of 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol and 5 g of trioctylmethylammonium bis(trifluoromethanesulfonyl)imide were charged. After removing water from the obtained mixture at 8 kPa and at an inner temperature of 80°C, a gas phase part in the flask was substituted with nitrogen. Further, the gas phase part was substituted with hydrogen and a 1L-volume rubber balloon full filed with hydrogen was equipped with the flask. The mixture was heated to 150°C to effect reaction at 150°C for 5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and 5 g of hexane and 10 g of water were added thereto. After removing an insoluble matters by filtration from the mixture obtained, the filtrate obtained was left at rest and separated to an organic layer, an aqueous layer and an ionic liquid layer. The ionic liquid layer was extracted twice with 5 g of hexane. The hexane layers were mixed with the previous obtained organic layer to concentrate to obtain 916 mg of a pale yellow oil containing 4-methoxymethyl-2,3,5,6-tetrafluorotoluene. The purity was 98% and the yield was 86%. Alternatively, 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol was recovered in 4%.
  • 18
  • [ 942435-98-5 ]
  • [ 83282-91-1 ]
YieldReaction ConditionsOperation in experiment
85% With sulfuric acid; water at 50℃; for 0.5h; 6 Example 6 Into a 50 ml flask, 190 mg of the oil containing 4-methoxymethyl-2,3,5,6-tetrafluorotoluene, which was obtained in the above-mentioned Example 1, and 2 g of 90% sulfuric acid were charged and the resultant mixture was heated to 50°C and kept while stirring at 50°C for 30 minutes. After the reaction, the mixture was cooled to room temperature and diluted with 10g of water and then, 5 g of ethyl acetate was added thereto. The organic layer obtained was analyzed by a gas chromatography internal standard method to find out that the yield of 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol was 85%.
  • 19
  • [ 83282-91-1 ]
  • (1R)-trans-3-difluoromethyl-2,2-dimethylcyclopropanecarboxylic acid [ No CAS ]
  • [ 1160509-06-7 ]
YieldReaction ConditionsOperation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In chloroform at 20℃; for 18h; 2 Production Example 2To a solution of 273 mg (1.22 mmol) of 4- methoxymethyl-2, 3, 5, 6-tetrafluorobenzylalcohol and 240 mg (1.46 mmol) of ( IR) -trans-3-difluoromethyl-2, 2- dimethylcyclopropane carboxylic acid in 5 mL of chloroform were added 335 mg (1.75 mol) of l-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride and 5 mg of 4-dimethylaminopyridine, and the mixture was stirred at room temperature for 18 hours. Water was poured into the reaction mixture, followed by extraction with ethyl acetate The organic layer was dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (product name: silica gel, 60 N (spherical, neutral), manufactured by Kanto Chemical Co., Inc.) to obtain 182 mg of 4- methoxymethyl-2, 3, 5, 6-tetrafluorobenzyl (IR) -trans-3- difluoromethyl-2 , 2-dimethylcyclopropanecarboxylate represented by the following formula:(Present compound (2))(hereinafter referred to as the present compound (2)) as a clear colorless liquid. 1H-NMR(CDCl3) δ (ppm) : 1.25 (3H, s) , 1.28 (3H, s) , 1.80-1.82 (IH, m) , 1.88-1.95 (IH, m) , 3.41 (3H, s) , 4.59 (2H, s) , 5.26 (2H, m) , 5.63 (IH, dt, J=6.2, 55.9Hz) .
  • 20
  • [ 62172-93-4 ]
  • [ 83282-91-1 ]
YieldReaction ConditionsOperation in experiment
3.6 g With sodium tetrahydroborate; zinc(II) chloride In diethylene glycol dimethyl ether for 5h; Reflux;
  • 21
  • [ 83282-91-1 ]
  • [ 10453-89-1 ]
  • [ 271241-14-6 ]
  • n-propyl 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
97% Stage #1: 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl alcohol With zircornium(IV) n-propoxide In propan-1-ol; xylene at 143 - 145℃; Stage #2: chrysanthemumic acid With 2,6-di-tert-butyl-4-methyl-phenol In propan-1-ol; xylene at 145 - 147℃; for 8h; 1 Example 1; To 500 ml four-neck flask, 186 g of xylene, 1.70 g of a solution of tetrapropoxyzirconium in propanol (75% in content) and 44.8 g of 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl alcohol were charged, and the resultant solution was heated to 143 to 145° C. under stirring at a normal pressure, and then 18.6 g of a mixture of propanol and xylene was distilled off to obtain a solution containing an zirconium catalyst. The resultant solution was cooled below 80° C., and then 37.0 g of 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropane-carboxylic acid, 18 g of xylene and 0.74 g of 2,6-di-tert-butyl-4-methylphenol as stabilizing agent were charged. To the reactor, Dean-Stark trap was equipped, and the reaction was conducted under stirring for eight hours at 145 to 147° C., removing water by-produced during the reaction into the trap, and a solution containing 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl 2,2-dimethyl-3-(2-methyl-1-propenyl) cyclopropanecarboxylate was obtained. Yield: 97% (based on 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl alcohol) Content of by-product: 0.5% of propyl 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate; Comparative Example 1; To 500 ml four-neck flask, 186 g of xylene and 1.70 g of a solution of tetrapropoxyzirconium in propanol (75% in content) were charged, and the resultant solution was heated to 143 to 145° C. under stirring at a normal pressure, and then 18.6 g of a mixture of propanol and xylene was distilled off. The resultant solution was cooled below 80° C., and then 44.8 g of 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl alcohol, 37.0 g of 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylic acid, 18 g of xylene and 0.74 g of 2,6-di-tert-butyl-4-methylphenol as stabilizing agent were charged. To the reactor, Dean-Stark trap was equipped, and the reaction was conducted under stirring for eight hours at 145 to 147° C., removing water by-produced during the reaction into the trap, and a solution containing 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate was obtained. Yield: 97% (based on 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl alcohol. Content of by-product: 5.2% of propyl 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate
  • 22
  • [ 83282-91-1 ]
  • [ 1052115-15-7 ]
  • [ 1065124-65-3 ]
  • [ 1246640-77-6 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl alcohol With zirconium(IV) tetraisopropoxide In isopropyl alcohol; xylene Reflux; Stage #2: (1R)-trans-3-(2-cyano-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid In isopropyl alcohol; xylene at 80℃; Reflux; 27 Example 27 8.0 g of 2,3,5,6-tetrafluoro-4-methoxymethyl-benzyl alcohol, 0.3 g of a 70% by weight zirconium tetraisopropoxide/2-propanol solution and 55 g of xylene were mixed. The obtained mixture was heated to reflux and thereafter 39 g of the distillate was removed. The obtained mixture was cooled to 80°C and thereafter 7.4 g of the compound (7) (Z-isomer/E-isomer ratio = 96/4) was added. The obtained mixture was stirred at the xylene reflux temperature for 13 hours. The operation was performed while removing by-product water out of the system by azeotropy with xylene. The obtained mixture was cooled to room temperature and thereafter 13 g of xylene was added. The obtained mixture was washed in 5% by weight sulfuric acid, a 5% by weight aqueous solution of sodium hydroxide and water, and thereafter concentrated under reduced pressure to obtain 13. 4g of the compound (3). When the compound was analyzed by a gas chromatography area percentage method, the Z-isomer/E-isomer ratio was 95/5.
  • 23
  • [ 83282-91-1 ]
  • [ 1170284-11-3 ]
  • [ 1050205-35-0 ]
YieldReaction ConditionsOperation in experiment
With lithium methanolate In n-heptane for 9h; Reflux; 24 Example 24 9.13 g of 2,3,5,6-tetrafluoro-4-methoxymethyl-benzyl alcohol, 7.50 g of the compound (6), 74 mg of lithium methoxide and 74 mL of heptane were mixed. The obtained mixture was refluxed for 9 hours while removing by-product methanol out of the system by azeotropy with heptane. During the reflux, 20 mL of heptane was added to the system. The amount of the mixture of methanol and heptane removed out of the system was 50 mL. The obtained reaction mixture was cooled to room temperature, and thereafter toluene and saline were added thereto, mixed and the mixture was separated. The obtained organic layer was washed in saturated saline and dried over anhydrous sodium sulfate. After removing sodium sulfate by filtration, the obtained filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 14.2 g of the compound (3).
  • 24
  • [ 83282-91-1 ]
  • [ 1332340-78-9 ]
  • [ 1332340-92-7 ]
YieldReaction ConditionsOperation in experiment
With pyridine In toluene at 20℃; for 12h; 1 Production Example 14-methoxymethyl-2 , 3, 5, 6-tetrafluorobenzyl alcohol (0.70 g, 3.13 mmol) and 0.7 mL of pyridine were added to mL of toluene, and a toluene solution (5 mL) of (lR)-trans-3- [ (1EZ) -2-cyano-2- (methylthio) ethenyl ] -2 , 2- dimethylcyclopropanecarboxylic acid chloride (0.71 g, 3.10 mmol) was added thereto. After stirring the mixture at room temperature for 12 hours, the reaction solution was poured into 5 mL of 5% hydrochloric acid and 30 mL of ice water and the solution was extracted with ethyl acetate. The organic layer was washed with 20 mL of saturated brine and 5 mL of saturated sodium bicarbonate water respectively, and then dried over magnesium sulfate. After concentration of the organic layer under reduced pressure, the residue was subjected to silica gel chromatography to obtain 0.43 g of4-methoxymethyl-2 , 3, 5, 6-tetrafluorobenzyl= (1R) -trans-3- [ (IE) -2-cyano-2- (methylthio) ethenyl] -2,2- dimethylcyclopropane carboxylate (hereinafter referred to as the compound of the present invention (1) ) represented by the following formula:as a fraction having higher polarity.Pale yellow liquid: 1 H-NMR (CDC13 , MS) δ (ppm) : 1.23(s,3H),1.33(s,3H), 1.80(d,lH), 2.40(s,3H), 2.52 (dd, 1H) , 3.41(s,3H), 4.59(s,2H), 5.26(s,2H), 6.15(d,lH)
  • 25
  • [ 83282-91-1 ]
  • trans-3-(2-chloro-vinyl)-2,2-dimethylcyclopropane carboxylic acid [ No CAS ]
  • C17H17ClF4O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
84% Stage #1: trans-3-(2-chloro-vinyl)-2,2-dimethylcyclopropane carboxylic acid With thionyl chloride at 50℃; Stage #2: 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl alcohol With pyridine In benzene
  • 26
  • [ 83282-91-1 ]
  • [ 1338068-82-8 ]
  • [ 1338069-09-2 ]
YieldReaction ConditionsOperation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In chloroform at 20℃; for 3h; 1 To a chloroform solution (10 mL) of 4-methoxymethyl- 2, 3, 5, 6-tetrafluorobenzyl alcohol (594 mg, 2.65 mmol) and (1R) -trans-3- ['(1Z) -2-cyano-l , 3-butadienyl ] -2 , 2- dimethylcyclopropanecarboxylic acid (478 mg, 2.50 mmol), 1- ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (516 mg, 2.70 mmol) and 4-dimethylaminopyridine (15 mg) were added. After stirring at room temperature for 3 hours, water was poured into the reaction solution and the solution was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure condition, and the residue was subjected to silica gel column chromatography to obtain 771 mg of 4- methoxymethyl-2 , 3, 5, 6-tetrafluorobenzyl= (1R) -trans-3- [ (1Z) - 2-cyano-l, 3-butadienyl] -2, 2-dimethylcyclopropane carboxylate (hereinafter referred to as the present invention compound (1)) represented by the following formula: Pale yellow liquid: 1 H-NMR (CDC13 , TMS) δ (ppm) : 1.21 (s, 3H) , 1.35(s,3H), 1.81(d,lH), 2.54(m,lH), 3.41(s,3H), 4.58(d,2H), 5.26(s,2H), 5.28(d,lH), 5.56(d, 1H) , 5.95(d,lH), 6.24(dd,lH)
  • 27
  • [ 83282-91-1 ]
  • [ 1338068-76-0 ]
  • [ 1338069-12-7 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl alcohol With pyridine In tetrahydrofuran at 20℃; Cooling with ice; Stage #2: (1R)-trans-3-[(1Z, 3E)-2-cyano-1,3-pentadienyl]-2,2-dimethylcyclopropanecarboxylic acid chloride In tetrahydrofuran 2 4 -methoxymethyl-2 , 3, 5, 6-tetrafluorobenzyl alcohol (560 mg, 2.50 mmol) was dissolved in tetrahydrofuran (10 mL) and0.35 mL of pyridine was added. the solution,. tetrahydrofuran solution (5 mL) of ( 1R) -trans-3- [ ( 1Z , 3E) -2- cyano-1, 3-pentadienyl ] -2, 2-dimethylcyclopropanecarboxylic acid chloride (Z/E = 85/15) (570 mg, 2.55 mmol) was added under ice cooling. After stirring, at room temperature for 12 hours, water was poured into the reaction solution and the solution was extracted with ethyl acetate. The organic layer was washed in turn with 5% hydrochloric acid, saturated sodium bicarbonate water and saturated brine, and then dried over magnesium sulfate. After concentration under reduced pressure condition, the residue was subjected to silica gel column chromatography to obtain 760 mg of 4- methoxymethyl-2 , 3,5, 6-tetrafluorobenzyl= (1R) -trans-3- [ (1Z, 3E) -2-cyano-l, 3-pentadienyl] -2, 2-dimethylcyclopropane carboxylate (hereinafter referred to as the present invention compound (2)) represented by the following formula: Colorless liquid : H-NMR(CDC13 ,TMS) δ (ppm) : 1.21 (s, 3H) ,1.34(s,3H), 1.75(d,lH, J=5.6 Hz), 1.82 (d, 3H, J=6.8 Hz), 2.52 (dd,lH, J=9.5,5.3 Hz), 3.40(s,3H), 4.58(s,2H), 5.25(s,2H), 5.79(d,lH), 5.95(d,lH), 6.10(m,lH)
  • 28
  • [ 83282-91-1 ]
  • [ 1052115-15-7 ]
  • [ 1050205-35-0 ]
YieldReaction ConditionsOperation in experiment
In xylene Reflux; 6 Example 6 A mixture of 2.24 g of 2,3,5,6-tetrafluoro-4-methoxymethyl-benzyl alcohol, 70 mg of zirconium chloride and 20 ml of xylene was refluxed by heating at 145° C. for about 10 minutes, then, 10 ml of xylene was distilled off. The resultant mixture was allowed to cool to 80° C., to this was added 1.97 g of (1R,3R)-3-(2-cyano-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid obtained in Example 1, and the resultant mixture was stirred at the xylene reflux temperature while removing water by-produced out of the reaction system under the xylene azeotropic condition, to obtain 2,3,5,6-tetrafluoro-4-methoxymethyl-benzyl (1R,3R)-3-(2-cyano-1-propenyl)-2,2-dimethylcyclopropanecarboxylate.
  • 29
  • [ 83282-91-1 ]
  • [ 1219734-00-5 ]
  • [ 1208235-77-1 ]
  • [ 1208235-75-9 ]
YieldReaction ConditionsOperation in experiment
With toluene-4-sulfonic acid In toluene for 6h; Reflux; 8 According to the process as described in preparation example 3, 1R,-(Z)-3-(3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropane carboxylic acid (20.8 g, 0.1 mol, prepared from 1R-methyl 3-aldehydeo-2,2-dimethylcyclopropane carboxylate with cis-trans ratio of 1:9 as starting material) was reacted with 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl alcohol (22.4 g, 0.1 mol) to obtain 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl-1R-(Z)-3-(3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropane carboxylate with cis-trans ratio of 1:9 (compound 7, 33.6 g; content: 98.2%). The molecular formula of the compound is C18H17F7O3 (molecular weight: 414), 1H NMR (1H (ppm) CDCl3) 1.29 (m, 6H); 1.69 (d, 1H); 2.44 (m, 1H); 3.40 (s, 3H); 4.59 (s, 2H); 5.30 (s, 2H); 5.60 (m, 1H); 5.80 (m, 1H), optical rotation α=+37.2°.
  • 30
  • [ 83282-91-1 ]
  • [ 1219734-00-5 ]
  • [ 1208235-73-7 ]
YieldReaction ConditionsOperation in experiment
90.7% With toluene-4-sulfonic acid In toluene for 6h; Reflux; 3 To a 500 ml flask were added 1R-(Z)-3-(3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropane carboxylic acid with cis-trans ratio of 1:1 (20.8 g, 0.1 mol, prepared as described in preparation example 2) and 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl alcohol (22.4 g, 0.1 mol) and toluene (180 ml), and then a water separator was installed to the flask. To the mixture was added p-toluenesulfonic acid (0.1 g) and heated to reflux. The reaction is carried out in absence of water for 6 hrs, during which toluene (20 ml) was added, and then the reaction was cooled to room temperature, washed with water (once, 100 g), dilute hydrochloric acid (once, 100 g, 5%), sodium bicarbonate solution (once, 100 g, 5%), and finally water (once, 100 g). The toluene layer was collected and heated under vacuum (10 mmHg) to 100° C. to remove solvent toluene and obtain 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl-1R-(Z)-3-(3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropane carboxylate (compound 1, 36.9 g; content: 98.3%; yield:90.7%; cis-trans ratio:1:1). The molecular formula of the compound is C18H17F7O3 (molecular weight: 414), 1H NMR (1H (ppm) CDCl3) 1.29 (m, 6H); 1.69 (d, 1H); 2.44 (m, 1H); 3.40 (s, 3H); 4.59 (s, 2H); 5.30 (s, 2H); 5.60 (m, 1H); 5.80 (m, 1H), optical rotation α=+37.2°.
  • 31
  • [ 83282-91-1 ]
  • [ 1425039-47-9 ]
  • [ 1425039-41-3 ]
YieldReaction ConditionsOperation in experiment
940 mg With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In chloroform at 20℃; for 12h; 2 To a chloroform solution (5 mL) of 4-methoxymethyl- 2 , 3 , 5 , 6-tetrafluorobenzyl alcohol (550 mg, 2.46 mmol) and (1R) -trans-3- [ (IE) -2-cyano-2-ethoxyethenyl] -2, 2- dimethylcyclopropanecarboxylic acid (508 mg, 2.43 mmol) were added l-ethyl-3- ( 3-dimethylaminopropyl ) carbodiimide hydrochloride (610 mg, 3.18 mmol) and 4- dimethylaminopyridine (20 mg) . After stirring the reaction mixture at room temperature for 12 hours, water was poured into the reaction solution and the solution was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and then concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 940 mg of 4-methoxymethyl- 2,3,5, 6-tetrafluorobenzyl (1R) -trans-3- [ (E) -2-cyano-2- ethoxyethenyl ] -2, 2-dimethylcyclopropane carboxylate (hereinafter, referred to as the compound (2) of the present invention) represented by the following formula: [0079] Colorless liquid: XH-NMR (CDC13, TMS) δ (ppm) : 1.18 (s,3H), 1.28(t, 3H) , 1.32(s,3H), 1.59(d,lH), 2.29(m,lH), 3.41(s,3H), 3.85 (q,2H), 4.59(s,2H), 5.25(s,2H), 5.30(d,lH)
  • 32
  • [ 83282-91-1 ]
  • [ 1425039-46-8 ]
  • [ 1425039-40-2 ]
YieldReaction ConditionsOperation in experiment
0.46 g With pyridine In toluene at 20℃; for 12h; 1 4-Methoxymethyl-2 , 3, 5, 6-tetrafluorobenzylalcohol (0.30 g, 1.34 mmol) and pyridine (0.2 mL) were added toluene (5 mL) , and thereto was added a toluene (2 mL) solution of (lR)-trans-3-[ (E) -2-cyano-2-methoxymethyl] -2,2- dimethylcyclopropanecarboxylic acid chloride (0.28 g, 1.31 mmol). After stirring the reaction mixture at room temperature for 12 hours, the reaction solution was poured into a mixture consisting of 5mL of 5% hydrochloric acid and 30 mL of iced water and the resulting solution was extracted with ethyl acetate. The reaction mixture was washed with 20 mL of saturated brine and 5 mL of saturated sodium bicarbonate aqueous solution, and the organic layer was dried over magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was subjected to a silica gel column chromatography to obtain 0.46 g of 4-methoxymethyl-2, 3, 5, 6-tetrafluorobenzyl (1R)- trans-3-[(E) -2-cyano-2-methoxyethenyl ] -2 , 2- dimethylcyclopropane carboxylate (hereinafter, referred to as the compound (1) of the present invention) represented, by the following formula: [0077] Pale yellow liquid: 1H-NMR (CDC13, TMS ) δ (ppm) : 1.19(s,3H), 1.32(s,3H), 1.59(d,lH), 2.29(m,lH), 3.40(s,3H), 3.62(s,3H), 4.59(s,2H), 5.25(s,2H), 5.26(d,lH)
  • 33
  • [ 83282-91-1 ]
  • [ 6995-48-8 ]
  • [ 1462940-63-1 ]
YieldReaction ConditionsOperation in experiment
With dmap; dicyclohexyl-carbodiimide In acetonitrile at 20℃; for 10h; General procedures for chiral esters 3 General procedure: A solution of acid 2 (2 mmol) and substituted tetrafluorobenzyl alcohol(2 mmol) in CH3CN (10 mL) was stirred at room temperature, to whicha catalytic amount of DMAP (0.1 g)and dicyclohexylcarbodiimide (2.4 mmol) was added after the solid in thesolution has absolutely dissolved. And then the mixture was stirred for another10 h. The precipitate of DCU was removed by filtration through a Buchnerfunnel, and the filtrate was washed with two 20 mL portions of saturated sodiumcarbonate solution and three 20 mL portions of saturated sodium chloridesolution. The organic layer was dried over anhydrous sodium sulfate andconcentrated with a rotary evaporator, and theresidue was purified by silica gel column-chromatography(ethyl acetate/petroleum ether) to give thedesired products 3.
With dmap; dicyclohexyl-carbodiimide In acetonitrile at 20℃; for 10h; General proceduresfor chiral esters 3 General procedure: A solution of 1 (8 mmol) in THF/H2O (40 mL THF, 10 mL H2O) was cooled to 0oC, to which lithium hydroxide (9.6 mmol) and hydrogen peroxide (19.2 mmol) was added. After 12 hours reaction, a small amount of sodium sulfite was added in to remove the excess hydrogen peroxide. Then 2 N HCl was added dropwise to adjust the pH value to 2-3. The reaction mixture was extracted with ether (2×30 mL). The combined organic layers were washed with brine (50 mL), concentrated under vacuum, and puried by silica gel chromatography to get pure acids 2 and auxiliary sultam. A solution of acid 2 (2 mmol) and substituted tetrafluorobenzyl alcohol (2 mmol) in CH3CN (10 mL) was stirred at room temperature, to which a catalytic amount of DMAP (0.1 g) and dicyclohexylcarbodiimide (2.4 mmol) was added after the solid in the solution has absolutely dissolved. And then the mixture was stirred for another 10 h. The precipitate of DCU was removed by filtration through a Buchner funnel, and the filtrate was washed with two 20 mL portions of saturated sodium carbonate solution and three 20 mL portions of saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated with a rotary evaporator, and the residue was purified by silica gel column-chromatography (ethyl acetate/petroleum ether) to give the desired products 3. Their physico-chemical properties and the spectra data are as follows:
  • 34
  • [ 83282-91-1 ]
  • [ 22573-51-9 ]
  • [ 1462940-74-4 ]
YieldReaction ConditionsOperation in experiment
With dmap; dicyclohexyl-carbodiimide In acetonitrile at 20℃; for 10h; General procedures for chiral esters 3 General procedure: A solution of acid 2 (2 mmol) and substituted tetrafluorobenzyl alcohol(2 mmol) in CH3CN (10 mL) was stirred at room temperature, to whicha catalytic amount of DMAP (0.1 g)and dicyclohexylcarbodiimide (2.4 mmol) was added after the solid in thesolution has absolutely dissolved. And then the mixture was stirred for another10 h. The precipitate of DCU was removed by filtration through a Buchnerfunnel, and the filtrate was washed with two 20 mL portions of saturated sodiumcarbonate solution and three 20 mL portions of saturated sodium chloridesolution. The organic layer was dried over anhydrous sodium sulfate andconcentrated with a rotary evaporator, and theresidue was purified by silica gel column-chromatography(ethyl acetate/petroleum ether) to give thedesired products 3.
  • 35
  • [ 83282-91-1 ]
  • [ 1610701-01-3 ]
  • [ 1462941-11-2 ]
YieldReaction ConditionsOperation in experiment
With dmap; dicyclohexyl-carbodiimide In acetonitrile at 20℃; for 10h; General procedures for chiral esters 3 General procedure: A solution of acid 2 (2 mmol) and substituted tetrafluorobenzyl alcohol(2 mmol) in CH3CN (10 mL) was stirred at room temperature, to whicha catalytic amount of DMAP (0.1 g)and dicyclohexylcarbodiimide (2.4 mmol) was added after the solid in thesolution has absolutely dissolved. And then the mixture was stirred for another10 h. The precipitate of DCU was removed by filtration through a Buchnerfunnel, and the filtrate was washed with two 20 mL portions of saturated sodiumcarbonate solution and three 20 mL portions of saturated sodium chloridesolution. The organic layer was dried over anhydrous sodium sulfate andconcentrated with a rotary evaporator, and theresidue was purified by silica gel column-chromatography(ethyl acetate/petroleum ether) to give thedesired products 3.
With dmap; dicyclohexyl-carbodiimide In acetonitrile at 20℃; for 10h; General proceduresfor chiral esters 3 General procedure: A solution of 1 (8 mmol) in THF/H2O (40 mL THF, 10 mL H2O) was cooled to 0oC, to which lithium hydroxide (9.6 mmol) and hydrogen peroxide (19.2 mmol) was added. After 12 hours reaction, a small amount of sodium sulfite was added in to remove the excess hydrogen peroxide. Then 2 N HCl was added dropwise to adjust the pH value to 2-3. The reaction mixture was extracted with ether (2×30 mL). The combined organic layers were washed with brine (50 mL), concentrated under vacuum, and puried by silica gel chromatography to get pure acids 2 and auxiliary sultam. A solution of acid 2 (2 mmol) and substituted tetrafluorobenzyl alcohol (2 mmol) in CH3CN (10 mL) was stirred at room temperature, to which a catalytic amount of DMAP (0.1 g) and dicyclohexylcarbodiimide (2.4 mmol) was added after the solid in the solution has absolutely dissolved. And then the mixture was stirred for another 10 h. The precipitate of DCU was removed by filtration through a Buchner funnel, and the filtrate was washed with two 20 mL portions of saturated sodium carbonate solution and three 20 mL portions of saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated with a rotary evaporator, and the residue was purified by silica gel column-chromatography (ethyl acetate/petroleum ether) to give the desired products 3. Their physico-chemical properties and the spectra data are as follows:
  • 36
  • [ 83282-91-1 ]
  • [ 6995-49-9 ]
  • [ 1462940-68-6 ]
YieldReaction ConditionsOperation in experiment
With dmap; dicyclohexyl-carbodiimide In acetonitrile at 20℃; for 10h; General procedures for chiral esters 3 General procedure: A solution of acid 2 (2 mmol) and substituted tetrafluorobenzyl alcohol(2 mmol) in CH3CN (10 mL) was stirred at room temperature, to whicha catalytic amount of DMAP (0.1 g)and dicyclohexylcarbodiimide (2.4 mmol) was added after the solid in thesolution has absolutely dissolved. And then the mixture was stirred for another10 h. The precipitate of DCU was removed by filtration through a Buchnerfunnel, and the filtrate was washed with two 20 mL portions of saturated sodiumcarbonate solution and three 20 mL portions of saturated sodium chloridesolution. The organic layer was dried over anhydrous sodium sulfate andconcentrated with a rotary evaporator, and theresidue was purified by silica gel column-chromatography(ethyl acetate/petroleum ether) to give thedesired products 3.
With dmap; dicyclohexyl-carbodiimide In acetonitrile at 20℃; for 10h; General proceduresfor chiral esters 3 General procedure: A solution of 1 (8 mmol) in THF/H2O (40 mL THF, 10 mL H2O) was cooled to 0oC, to which lithium hydroxide (9.6 mmol) and hydrogen peroxide (19.2 mmol) was added. After 12 hours reaction, a small amount of sodium sulfite was added in to remove the excess hydrogen peroxide. Then 2 N HCl was added dropwise to adjust the pH value to 2-3. The reaction mixture was extracted with ether (2×30 mL). The combined organic layers were washed with brine (50 mL), concentrated under vacuum, and puried by silica gel chromatography to get pure acids 2 and auxiliary sultam. A solution of acid 2 (2 mmol) and substituted tetrafluorobenzyl alcohol (2 mmol) in CH3CN (10 mL) was stirred at room temperature, to which a catalytic amount of DMAP (0.1 g) and dicyclohexylcarbodiimide (2.4 mmol) was added after the solid in the solution has absolutely dissolved. And then the mixture was stirred for another 10 h. The precipitate of DCU was removed by filtration through a Buchner funnel, and the filtrate was washed with two 20 mL portions of saturated sodium carbonate solution and three 20 mL portions of saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated with a rotary evaporator, and the residue was purified by silica gel column-chromatography (ethyl acetate/petroleum ether) to give the desired products 3. Their physico-chemical properties and the spectra data are as follows:
  • 37
  • [ 83282-91-1 ]
  • [ 22573-54-2 ]
  • [ 1462940-79-9 ]
YieldReaction ConditionsOperation in experiment
With dmap; dicyclohexyl-carbodiimide In acetonitrile at 20℃; for 10h; General procedures for chiral esters 3 General procedure: A solution of acid 2 (2 mmol) and substituted tetrafluorobenzyl alcohol(2 mmol) in CH3CN (10 mL) was stirred at room temperature, to whicha catalytic amount of DMAP (0.1 g)and dicyclohexylcarbodiimide (2.4 mmol) was added after the solid in thesolution has absolutely dissolved. And then the mixture was stirred for another10 h. The precipitate of DCU was removed by filtration through a Buchnerfunnel, and the filtrate was washed with two 20 mL portions of saturated sodiumcarbonate solution and three 20 mL portions of saturated sodium chloridesolution. The organic layer was dried over anhydrous sodium sulfate andconcentrated with a rotary evaporator, and theresidue was purified by silica gel column-chromatography(ethyl acetate/petroleum ether) to give thedesired products 3.
  • 38
  • [ 83282-91-1 ]
  • [ 1610701-03-5 ]
  • [ 1462941-12-3 ]
YieldReaction ConditionsOperation in experiment
With dmap; dicyclohexyl-carbodiimide In acetonitrile at 20℃; for 10h; General procedures for chiral esters 3 General procedure: A solution of acid 2 (2 mmol) and substituted tetrafluorobenzyl alcohol(2 mmol) in CH3CN (10 mL) was stirred at room temperature, to whicha catalytic amount of DMAP (0.1 g)and dicyclohexylcarbodiimide (2.4 mmol) was added after the solid in thesolution has absolutely dissolved. And then the mixture was stirred for another10 h. The precipitate of DCU was removed by filtration through a Buchnerfunnel, and the filtrate was washed with two 20 mL portions of saturated sodiumcarbonate solution and three 20 mL portions of saturated sodium chloridesolution. The organic layer was dried over anhydrous sodium sulfate andconcentrated with a rotary evaporator, and theresidue was purified by silica gel column-chromatography(ethyl acetate/petroleum ether) to give thedesired products 3.
With dmap; dicyclohexyl-carbodiimide In acetonitrile at 20℃; for 10h; General proceduresfor chiral esters 3 General procedure: A solution of 1 (8 mmol) in THF/H2O (40 mL THF, 10 mL H2O) was cooled to 0oC, to which lithium hydroxide (9.6 mmol) and hydrogen peroxide (19.2 mmol) was added. After 12 hours reaction, a small amount of sodium sulfite was added in to remove the excess hydrogen peroxide. Then 2 N HCl was added dropwise to adjust the pH value to 2-3. The reaction mixture was extracted with ether (2×30 mL). The combined organic layers were washed with brine (50 mL), concentrated under vacuum, and puried by silica gel chromatography to get pure acids 2 and auxiliary sultam. A solution of acid 2 (2 mmol) and substituted tetrafluorobenzyl alcohol (2 mmol) in CH3CN (10 mL) was stirred at room temperature, to which a catalytic amount of DMAP (0.1 g) and dicyclohexylcarbodiimide (2.4 mmol) was added after the solid in the solution has absolutely dissolved. And then the mixture was stirred for another 10 h. The precipitate of DCU was removed by filtration through a Buchner funnel, and the filtrate was washed with two 20 mL portions of saturated sodium carbonate solution and three 20 mL portions of saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated with a rotary evaporator, and the residue was purified by silica gel column-chromatography (ethyl acetate/petroleum ether) to give the desired products 3. Their physico-chemical properties and the spectra data are as follows:
  • 39
  • [ 83282-91-1 ]
  • [ 22573-54-2 ]
  • [ 1462940-74-4 ]
YieldReaction ConditionsOperation in experiment
With dmap; dicyclohexyl-carbodiimide In acetonitrile at 20℃; for 10h; General proceduresfor chiral esters 3 General procedure: A solution of 1 (8 mmol) in THF/H2O (40 mL THF, 10 mL H2O) was cooled to 0oC, to which lithium hydroxide (9.6 mmol) and hydrogen peroxide (19.2 mmol) was added. After 12 hours reaction, a small amount of sodium sulfite was added in to remove the excess hydrogen peroxide. Then 2 N HCl was added dropwise to adjust the pH value to 2-3. The reaction mixture was extracted with ether (2×30 mL). The combined organic layers were washed with brine (50 mL), concentrated under vacuum, and puried by silica gel chromatography to get pure acids 2 and auxiliary sultam. A solution of acid 2 (2 mmol) and substituted tetrafluorobenzyl alcohol (2 mmol) in CH3CN (10 mL) was stirred at room temperature, to which a catalytic amount of DMAP (0.1 g) and dicyclohexylcarbodiimide (2.4 mmol) was added after the solid in the solution has absolutely dissolved. And then the mixture was stirred for another 10 h. The precipitate of DCU was removed by filtration through a Buchner funnel, and the filtrate was washed with two 20 mL portions of saturated sodium carbonate solution and three 20 mL portions of saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated with a rotary evaporator, and the residue was purified by silica gel column-chromatography (ethyl acetate/petroleum ether) to give the desired products 3. Their physico-chemical properties and the spectra data are as follows:
  • 40
  • [ 83282-91-1 ]
  • [ 22573-51-9 ]
  • [ 1462940-79-9 ]
YieldReaction ConditionsOperation in experiment
With dmap; dicyclohexyl-carbodiimide In acetonitrile at 20℃; for 10h; General proceduresfor chiral esters 3 General procedure: A solution of 1 (8 mmol) in THF/H2O (40 mL THF, 10 mL H2O) was cooled to 0oC, to which lithium hydroxide (9.6 mmol) and hydrogen peroxide (19.2 mmol) was added. After 12 hours reaction, a small amount of sodium sulfite was added in to remove the excess hydrogen peroxide. Then 2 N HCl was added dropwise to adjust the pH value to 2-3. The reaction mixture was extracted with ether (2×30 mL). The combined organic layers were washed with brine (50 mL), concentrated under vacuum, and puried by silica gel chromatography to get pure acids 2 and auxiliary sultam. A solution of acid 2 (2 mmol) and substituted tetrafluorobenzyl alcohol (2 mmol) in CH3CN (10 mL) was stirred at room temperature, to which a catalytic amount of DMAP (0.1 g) and dicyclohexylcarbodiimide (2.4 mmol) was added after the solid in the solution has absolutely dissolved. And then the mixture was stirred for another 10 h. The precipitate of DCU was removed by filtration through a Buchner funnel, and the filtrate was washed with two 20 mL portions of saturated sodium carbonate solution and three 20 mL portions of saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated with a rotary evaporator, and the residue was purified by silica gel column-chromatography (ethyl acetate/petroleum ether) to give the desired products 3. Their physico-chemical properties and the spectra data are as follows:
  • 41
  • [ 83282-91-1 ]
  • (1R)-3-[(E)-2-methoxycarbonylpropenyl]-2,2-dimethylcyclopropanecarboxylic acid [ No CAS ]
  • 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl (1R,3S)-3-[(E)-2-methoxycarbonyl-1-propenyl]-2,2-dimethylcyclopropanecarboxylate [ No CAS ]
  • 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl (1R,3R)-3-[(E)-2-methoxycarbonyl-1-propenyl]-2,2-dimethylcyclopropanecarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
1: 79 mg 2: 21 mg With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride at 20℃; for 19h; 2 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol (100 mg, 0.44mmol) and (1R)-3-[(E)-2 - methoxycarbonyl-1-propenyl]-2,2-dimethylcyclopropanecarboxylic acid (2 ml) in chloroform solution (78 mg, 0.37mmol, 3R: 3S=4:1) 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (86 mg, 0.37mmol) was added to 4-dimethylaminopyridine (3 mg). After stirring at room temperature for 19 hours, the reaction was poured into water, which was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, formula [7 a] 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl (1R, 3R)-3-[(E)-2-methoxycarbonyl-1-propenyl]-2,2-dimethylcyclopropane carboxylate are shown in (hereinafter, referred to as compound (2) of the present invention. ) 79 mg was obtained. 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl (1R,3S)-3-[(E)-2-methoxycarbonyl-1-propenyl]-2,2-dimethylcyclopropanecarboxylate (hereinafter, referred to as compound (3) of the present invention. ) 21 mg was obtained.
  • 42
  • [ 83282-91-1 ]
  • [ 61914-47-4 ]
  • [ 915288-13-0 ]
YieldReaction ConditionsOperation in experiment
96% With pyridine In toluene at 20 - 25℃; for 0.5h; 6 Example 1 Synthesis of (f?S)-3-allyl-2-methyl-4-oxocyclopent-2-enyl (1 f?,3/:?)-2,2-dimethyl - (0119) 3-(2-methylprop-1 -enyl) cyclopropanecarboxylate (D-trans-allethrin) General procedure: In 1 liter three necked bottom flask with a stirrer, 51 .0 g (0.33 moles) of (f?S)-3- allyl-2-methyl-4-oxocyclopent-2-enyl-1 -ol with a purity of 99% (%w/w) were mixed with 180 ml of toluene and cooled to 5°C under nitrogen atmosphere. The solution was added with 34.5 g (0.43 moles) of pyridine and added slowly and under stirring with 65.0 g (0.34 moles) of (1 R,3R)-2,2-dimethyl-3-(2-methylprop- 1 -enyl) cyclopropane carboxylic acid chloride with a purity of 98.0% (% w/w), keeping the temperature at 5°C-10°C . After the addition, the reaction was heated to 15°-20°C under stirring for further 3 hours. (0121) 4.1 g (0.05 moles) of 1 ,3-diaminopropane were added and the reaction was maintained under stirring for further Vz hour. The reaction was then added with an acid aqueous solution (0.36 moles of HCI 33%(%w/w) in 135 ml of water), stirred and the organic phase separated off. The organic phase was then washed with water, separated and washed again with 65 ml of an aqueous solution containing 8% (% w/v) of sodium carbonate. The organic phase was separated and evaporated u.v at 40°C/ 0.2 kPa. (0122) 98.5 g of a crude product with a purity of 96.8% (% w/w) was obtained (yield 95%) whose NMR analysis is in accordance with the structure. (0123) The amount of chrysanthemic anhydride was less than 0.02% (%w/w) by GC analysis as previously reported. (0124) 1H-NMR (300 MHz, CDCIs): 1 .15 (s, 2.25H), 1 .1 6 (s, 0.75H), 1 .27 (s, 2.25H), 1 .29 (s, 0.75H), 1 .41 (d, 0.25H, 3J = 5.5 Hz), 1 .43 (d, 0.75H, 3J = 5.5 Hz), 1 .70 - 1 .75 (m, 6H), 2.02 (s, 2.25H), 2.04 (s, 0.75H), 2.10 (dd, 1 H, 3J = 7.7 Hz, 3J = 5.2 Hz), 2.24 (dd, 0.75H, 2J = 18.7 Hz, 3J = 2.0 Hz), 2.31 (dd, 0.25H, 2J = 18.7 Hz, 3J = 2.0 Hz), 2.86 (dd, 0.25H, 2J = 18.7 Hz, 3J = 7.3 Hz), 2.88 (dd, 0.75H, 2J = 18.7 Hz, 3J = 6.3 Hz), 2.99 (d, 2H, 3J = 6.4 Hz), 4.92 (dm, 1 H, 3J = 7.5 Hz), 5.02 (m, 2H), 5.69 (m, 1 H), 5.77 (m, 1 H). (0125) 13C-NMR (75 MHz, CDCIs): 13.75 (CH3), 13.87 (CH3), 18.34 (CH3), 20.24 (CH3), 20.37 (CH3), 21 .95 (CH3), 22.00 (CH3), 25.39 (CH3), 26.97 (CH2), 28.93 (Cq), 32.81 (CH), 33.01 (CH), 34.37 (CH), 34.42 (CH), 41 .46 (CH2), 41 .88 (CH2), 72.47 (CH), 72.77 (CH), 1 15.78 (CH2), 120.60 (CH), 120.67 (CH), 133.41 (CH), 135.70 (Cq), 141 .15 (Cq), 141 .22 (Cq), 1 65.76(Cq), 1 65.86 (Cq), 172.12 (Cq), 203.59 (Cq), 203.65 (Cq).
  • 43
  • [ 83282-91-1 ]
  • 2,2-dimethyl-3-[(1Z)-3,3,3-trifluoroprop-1-enyl]-cyclopropanecarboxylic acid chloride [ No CAS ]
  • 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl 2,2-dimethyl-3-[(1Z)-3,3,3-trifluoroprop-1-enyl]cyclopropanecarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
96% With pyridine In toluene at 20 - 25℃; for 1h; 7 Example 1 Synthesis of (f?S)-3-allyl-2-methyl-4-oxocyclopent-2-enyl (1 f?,3/:?)-2,2-dimethyl - (0119) 3-(2-methylprop-1 -enyl) cyclopropanecarboxylate (D-trans-allethrin) General procedure: In 1 liter three necked bottom flask with a stirrer, 51 .0 g (0.33 moles) of (f?S)-3- allyl-2-methyl-4-oxocyclopent-2-enyl-1 -ol with a purity of 99% (%w/w) were mixed with 180 ml of toluene and cooled to 5°C under nitrogen atmosphere. The solution was added with 34.5 g (0.43 moles) of pyridine and added slowly and under stirring with 65.0 g (0.34 moles) of (1 R,3R)-2,2-dimethyl-3-(2-methylprop- 1 -enyl) cyclopropane carboxylic acid chloride with a purity of 98.0% (% w/w), keeping the temperature at 5°C-10°C . After the addition, the reaction was heated to 15°-20°C under stirring for further 3 hours. (0121) 4.1 g (0.05 moles) of 1 ,3-diaminopropane were added and the reaction was maintained under stirring for further Vz hour. The reaction was then added with an acid aqueous solution (0.36 moles of HCI 33%(%w/w) in 135 ml of water), stirred and the organic phase separated off. The organic phase was then washed with water, separated and washed again with 65 ml of an aqueous solution containing 8% (% w/v) of sodium carbonate. The organic phase was separated and evaporated u.v at 40°C/ 0.2 kPa. (0122) 98.5 g of a crude product with a purity of 96.8% (% w/w) was obtained (yield 95%) whose NMR analysis is in accordance with the structure. (0123) The amount of chrysanthemic anhydride was less than 0.02% (%w/w) by GC analysis as previously reported. (0124) 1H-NMR (300 MHz, CDCIs): 1 .15 (s, 2.25H), 1 .1 6 (s, 0.75H), 1 .27 (s, 2.25H), 1 .29 (s, 0.75H), 1 .41 (d, 0.25H, 3J = 5.5 Hz), 1 .43 (d, 0.75H, 3J = 5.5 Hz), 1 .70 - 1 .75 (m, 6H), 2.02 (s, 2.25H), 2.04 (s, 0.75H), 2.10 (dd, 1 H, 3J = 7.7 Hz, 3J = 5.2 Hz), 2.24 (dd, 0.75H, 2J = 18.7 Hz, 3J = 2.0 Hz), 2.31 (dd, 0.25H, 2J = 18.7 Hz, 3J = 2.0 Hz), 2.86 (dd, 0.25H, 2J = 18.7 Hz, 3J = 7.3 Hz), 2.88 (dd, 0.75H, 2J = 18.7 Hz, 3J = 6.3 Hz), 2.99 (d, 2H, 3J = 6.4 Hz), 4.92 (dm, 1 H, 3J = 7.5 Hz), 5.02 (m, 2H), 5.69 (m, 1 H), 5.77 (m, 1 H). (0125) 13C-NMR (75 MHz, CDCIs): 13.75 (CH3), 13.87 (CH3), 18.34 (CH3), 20.24 (CH3), 20.37 (CH3), 21 .95 (CH3), 22.00 (CH3), 25.39 (CH3), 26.97 (CH2), 28.93 (Cq), 32.81 (CH), 33.01 (CH), 34.37 (CH), 34.42 (CH), 41 .46 (CH2), 41 .88 (CH2), 72.47 (CH), 72.77 (CH), 1 15.78 (CH2), 120.60 (CH), 120.67 (CH), 133.41 (CH), 135.70 (Cq), 141 .15 (Cq), 141 .22 (Cq), 1 65.76(Cq), 1 65.86 (Cq), 172.12 (Cq), 203.59 (Cq), 203.65 (Cq).
  • 44
  • [ 83282-91-1 ]
  • (1R)-trans-3-[(E)-2-methoxy-1-ethenyl]-2,2-dimethylcyclopropanecarboxylic acid [ No CAS ]
  • 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl (1R)-trans-3-[(E)-2-methoxy-1-ethenyl]-2,2-dimethylcyclopropanecarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
34 mg With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In chloroform at 20℃; for 24h; 5 Production Example 5 4-Methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol(50 mg, 0.22 mmol)(1 R) -trans-3 - [(E) -2-methoxy-1-ethenyl]-2,2-dimethylcyclopropanecarboxylic acid(56 mg, 0.33 mmol) in chloroform (4 mL)Was added 1-ethyl-3- (3-dimethylaminopropyl)Carbodiimide hydrochloride (63 mg, 0.33 mmol)And 4-dimethylaminopyridine (3 mg) were added.After stirring at room temperature for 24 hours, water was poured into the reaction solution,This was extracted with ethyl acetate. After drying the organic layer with magnesium sulfate,Concentrated under reduced pressure, the residue was subjected to silica gel column chromatography,The compound represented by the following formula (XIV)4-methoxymethyl-2,3,5,6-tetrafluorobenzyl(1 R) -trans-3 - [(E) -2-methoxy-1-ethenyl]-2,2-dimethylcyclopropanecarboxylate (hereinafter referred to as "This compound is referred to as the present compound 29. )34 mg was obtained.
  • 45
  • [ 83282-91-1 ]
  • (1R)-trans-3-[(Z)-2-methoxy-1-ethenyl]-2,2-dimethylcyclopropanecarboxylic acid [ No CAS ]
  • 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl (1R)-trans-3-[(Z)-2-methoxy-1-ethenyl]-2,2-dimethylcyclopropanecarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In chloroform at 20℃; for 22h; 6 Production Example 6 4-Methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol(40 mg, 0.18 mmol) and (1 R)- trans-3 - [(Z) -2-methoxy-1-ethenyl]-2,2-dimethylcyclopropanecarboxylic acid (46 mg, 0.27 mmol)In chloroform (3 mL) was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (52 mg, 0.27 mmol) and 4-dimethylaminopyridine(3 mg) was added. After stirring at room temperature for 22 hours, water was poured into the reaction solution,This was extracted with ethyl acetate. After drying the organic layer with magnesium sulfate,Concentrated under reduced pressure, the residue was subjected to silica gel column chromatography,The following formula (XV)4-methoxymethyl-2,3,5,6-tetrafluorobenzyl(1 R) -trans-3 - [(Z) -2-methoxy-1-ethenyl]-2,2-dimethylcyclopropanecarboxylate (hereinafter referred to as "Is referred to as the present compound 30. )mg was obtained.
  • 46
  • [ 83282-91-1 ]
  • 3-(3-fluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid [ No CAS ]
  • 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl 3-(3-fluoro-1-propenyl)-2,2-dimethylcyclopropane-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
33.2 g With toluene-4-sulfonic acid In toluene for 6h; Reflux; 3 Preparation of 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl-3-(3-fluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate(Compound 75) In a 500 ml flask,Injection of 3-(3-fluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid 17.2 g (0.1 mol), 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl alcohol, 22.4 g (0.1 mol), 180 ml of toluene, equipped with a water separator, and then 0.1 g of p-toluenesulfonic acid, followed by heating To reflux, with water reaction for 6 hours, add 20ml of toluene in the middle, cool to room temperature, wash once with 100g of water, wash once with 100g of 5% diluted hydrochloric acid, wash once with 100g of 5% sodium bicarbonate solution, and finally 100g The water was washed once again, and the toluene layer was collected and heated to 100° C. under a negative pressure of 10 mmHg to desolventize the solvent to obtain Compound 75 which was 33.2 g in weight and 96.5% in content.
  • 47
  • [ 83282-91-1 ]
  • (1R,trans)-(Z)-3-(3-fluoro-1-propenyl)-2,2-dimethylcyclopropane-1-carboxylic acid [ No CAS ]
  • 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl-(1R),trans-(Z)-3-(3-fluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
31.6 g With toluene-4-sulfonic acid In toluene for 6h; Reflux; 4 Preparation of 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl-1R, trans-Z-3-(3-fluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate Acid ester(Compound 76) In a 500 ml flask,Put 1R, trans-Z-3-(3-fluoro-1-propenyl)-2,2-dimethylcyclopropane carboxylic acid17.2 g (0.1 mol) 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl alcohol 22.4 g (0.1 mol), 180 ml toluene, equipped with a water separator, and then added 0.1 g of p-toluenesulfonic acid , Heat to reflux, react with water for 6 hours, add 20ml of toluene in the middle, cool to room temperature, wash once with 100g of water, wash once with 100g of 5% diluted hydrochloric acid, and wash once with 100g of 5% sodium bicarbonate solution. The last 100 g of water is washed once again, and the toluene layer is collected and heated to 100 DEG C under a negative pressure of 10 mmHg to desolventize the solvent to obtain compound 76, which has a weight of 31.6 g and a content of 98.2%. The molecular formula of the compound: C18H19F5O3 molecular weight 378,
31.6 g With toluene-4-sulfonic acid In water; toluene for 6h; Reflux; 4 Preparation of 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl-1R,trans-Z-3-(3-fluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate acid ester (Compound 76) In a 500 ml flask, 1R, trans-Z-3-(3-fluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid 17.2 g (0.1 mol) was charged.2,3,5,6-tetrafluoro-4-methoxymethylbenzyl alcohol 22.4g (0.1mol), 180ml of toluene, equipped with a water separator, and then added 0.1g of p-toluenesulfonic acid, was heated to reflux for 6 hours with the water of reaction, the reaction intermediate additional 20ml toluene was cooled to room temperature and completed, 100g once with water,100g 5% washed with dilute hydrochloric acid, once, and finally washed with water and then washed with 100g 100g 5% sodium bicarbonate solution once,The toluene layer was collected and heated to 100 ° C under a negative pressure of 10 mmHg to remove the solvent toluene to obtain a compound 76 weight 31.6 g, a content of 98.2%
  • 48
  • [ 83282-91-1 ]
  • (1R),trans-(Z)-3-(3,3-difluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid [ No CAS ]
  • 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl-(1R),trans-(Z)-3-(3,3-difluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
34.2 mg With toluene-4-sulfonic acid In toluene for 6h; Reflux; 5 Preparation of 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl-1R, trans-Z-3-(3,3-difluoro-1-propenyl)-2,2-dimethyl Cyclopropane carboxylate(Compound 86) In a 500 ml flask,Put 1R, trans-Z-3-(3-fluoro-1-propenyl)-2,2-dimethylcyclopropane carboxylic acid19.0 g (0.1 mol), 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl alcohol, 22.4 g (0.1 mol),Add 180ml of toluene, install a water separator, add 0.1g of p-toluenesulfonic acid, heat to reflux, react with water for 6 hours, add 20ml of toluene in the middle, cool to room temperature, wash once with 100g of water, and then use 100g of 5% Wash with dilute hydrochloric acid once, wash once with 100g of 5% sodium bicarbonate solution, and finally wash 100g of water once. Collect the toluene layer and heat it to 100°C under a negative pressure of 10mmHg to desolvate the solvent toluene to obtain the weight of compound 86 which is 34.2g.Content 97.4%. The molecular formula of the compound: C18H18F6O3 molecular weight 396,
34.2 g With toluene-4-sulfonic acid In water; toluene for 6h; Reflux; 5 Preparation of 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl-1R, trans-Z-3-(3,3-difluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate (Compound 86) In a 500 ml flask, 1R,trans-Z-3-(3-fluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid 19.0 g (0.1 mol) was charged 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl alcohol 22.4 g (0.1 mol), 180 ml of toluene, equipped with a water separator,Further, 0.1 g of p-toluenesulfonic acid was added, and the mixture was heated to reflux, and reacted with water for 6 hours. Further, 20 ml of toluene was added in the middle, and the mixture was cooled to room temperature, and washed once with 100 g of water.Wash once with 100g of 5% dilute hydrochloric acid, once with 100g of 5% sodium bicarbonate solution, and then wash once with 100g of water.The toluene layer was collected and heated to 100 ° C under a negative pressure of 10 mmHg to remove the solvent toluene to obtain a compound 86 weight 34.2 g, a content of 97.4%
  • 49
  • [ 83282-91-1 ]
  • None [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 24 h / 2 - 30 °C 2: phosphorus tribromide / tetrahydrofuran / 8 h / 0 - 5 °C 3: hydrogen; magnesium oxide; 5%-palladium/activated carbon / methanol 4: hydrogen bromide; tetrabutylammomium bromide / Reflux
  • 50
  • [ 83282-91-1 ]
  • 2,3,6-trifluoro-4-methylbenzyl alcohol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 24 h / 2 - 30 °C 2: phosphorus tribromide / tetrahydrofuran / 8 h / 0 - 5 °C 3: hydrogen; magnesium oxide; 5%-palladium/activated carbon / methanol 4: hydrogen bromide; tetrabutylammomium bromide / Reflux
  • 51
  • [ 83282-91-1 ]
  • 3-(2-chloro-2-trifluoromethyl-vinyl)-2,2-dimethylcyclopropanecarboxylic acid-2,3,6-trifluoro-4-methyl-benzyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 24 h / 2 - 30 °C 2: phosphorus tribromide / tetrahydrofuran / 8 h / 0 - 5 °C 3: hydrogen; magnesium oxide; 5%-palladium/activated carbon / methanol 4: hydrogen bromide; tetrabutylammomium bromide / Reflux 5: triethylamine / toluene / 6 h / 5 - 30 °C
  • 52
  • [ 83282-91-1 ]
  • [4-(methoxymethyl)-2,3,5-trifluorophenyl]methanol [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% With lithium aluminium tetrahydride In tetrahydrofuran at 2 - 30℃; for 24h; 1 Example 1: Synthesis of 2,3,5-trifluoro-4-methoxymethyl-benzyl alcohol In a four-necked flask,11.2 g of 2,3,5,6-tetrafluoro-4-methoxymethyl-benzyl alcohol was dissolved in 50 mL of tetrahydrofuran.The temperature was lowered to 2 ° C, and 2.28 g of lithium aluminum hydride was added in 4 portions at this temperature.The temperature was slowly raised to 30 ° C, and the reaction was stirred at this temperature for 24 hours.The reaction system was cooled to 0 ° C, and the pH of the system was adjusted to 6.7 with dilute hydrochloric acid having a mass fraction of 5%, and then extracted with 3*50 mL of ethyl acetate.The solvent was removed under reduced pressure to give 9.1 g of 2,3,5-trifluoro-4-methoxymethyl-benzyl alcohol.The yield was 89%.
19.3 g With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 6h; Inert atmosphere; Reflux; Under a nitrogen atmosphere, at 0 ° C., a mixture of 5.43 g of lithium aluminum hydride and 150 mL of tetrahydrofuran was added.[4- (methoxymethyl) -2,3,5,6-tetrafluorophenyl] methanolA solution of 30 g and 150 mL of tetrahydrofuran was slowly added.. The resulting mixture was stirred under reflux for 6 hours. The obtained mixture was cooled to 10 ° C., a 10% aqueous sulfuric acid solution was added, and the mixture was extracted with tert-butyl methyl ether. The obtained organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained is silica gelSubjected to chromatography[4- (methoxymethyl) -2,3,5-trifluorophenyl] methanol19.3 g were obtained.
  • 53
  • [ 83282-91-1 ]
  • 2,3,5-trifluoro-4-methoxymethylbenzyl bromide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 24 h / 2 - 30 °C 2: phosphorus tribromide / tetrahydrofuran / 8 h / 0 - 5 °C
  • 54
  • [ 83282-91-1 ]
  • 2,3,5-trifluoro-4-methoxymethyltoluene [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 24 h / 2 - 30 °C 2: phosphorus tribromide / tetrahydrofuran / 8 h / 0 - 5 °C 3: hydrogen; magnesium oxide; 5%-palladium/activated carbon / methanol
  • 55
  • 1,4-bis(methoxymethyl)-2,3,5,6-tetrafluorobenzene [ No CAS ]
  • [ 83282-91-1 ]
  • [ 92339-07-6 ]
YieldReaction ConditionsOperation in experiment
47.1%Chromat.; 41.6%Chromat. A 2-liter reaction flask was charged with 140 g of the compound (I), 420 g of a 70% aqueous sulfuric acid solution, and 1120 g of propionic acid, and the mixture was heated to 140 to 145 C for 10 hours, and the reaction was stopped and the temperature was lowered. The reaction liquid was extracted with 700 g of chloroform, and the organic phase was combined, and the chloroform was removed by distillation under reduced pressure to obtain 159.5 g of the mixture (II) (HPLC detection: 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl alcohol propionate 35.5%, 2,3,5,6-tetrafluoro-1,4-benzenedimethanol dipropionate 20.2%, 2,3,5,6-tetrafluoro-1,4-benzenedimethanol monopropionate 16.8%, 2,3,5,6-tetrafluoro-1,4-benzenedimethanol4.8 %, 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl alcohol 11.8% and 1,4-bis(methoxymethyl)-2,3,5,6-tetrafluorobenzene 9.1 %, Used in the next step of the reaction. The obtained mixture (II) was added to a 2 liter reaction flask, 1250 g of water and 370 g of potassium carbonate were added, and the mixture was heated to 90-95 C for 12 hours, the reaction was stopped, and the temperature was lowered to obtain a mixture (III) (HPLC detection: 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl alcohol 47.1%, 2,3,5,6-tetrafluoro-1,4-benzenedimethanol 41.6%, 1,4-bis(methoxymethyl)-2,3,5,6-tetrafluorobenzene 9.1%), used in the next step.
  • 56
  • 1,4-bis(methoxymethyl)-2,3,5,6-tetrafluorobenzene [ No CAS ]
  • [ 83282-91-1 ]
YieldReaction ConditionsOperation in experiment
75.7% Stage #1: 1,4-bis(methoxymethyl)-2,3,5,6-tetrafluorobenzene With sulfuric acid; propionic acid In water at 140 - 145℃; for 10h; Stage #2: With potassium carbonate In water at 90 - 95℃; for 12h; Stage #3: With dimethyl sulfate In water; toluene at 40 - 45℃; for 2h; 1-5 Example 1 A 2-liter reaction flask was charged with 140 g of the compound (I), 420 g of a 70% aqueous sulfuric acid solution, and 1120 g of propionic acid, and the mixture was heated to 140 to 145 ° C for 10 hours, and the reaction was stopped and the temperature was lowered. The reaction liquid was extracted with 700 g of chloroform, and the organic phase was combined, and the chloroform was removed by distillation under reduced pressure to obtain 159.5 g of the mixture (II) (HPLC detection: 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl alcohol propionate 35.5%, 2,3,5,6-tetrafluoro-1,4-benzenedimethanol dipropionate 20.2%, 2,3,5,6-tetrafluoro-1,4-benzenedimethanol monopropionate 16.8%, 2,3,5,6-tetrafluoro-1,4-benzenedimethanol4.8 %, 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl alcohol 11.8% and 1,4-bis(methoxymethyl)-2,3,5,6-tetrafluorobenzene 9.1 %, Used in the next step of the reaction. The obtained mixture (II) was added to a 2 liter reaction flask, 1250 g of water and 370 g of potassium carbonate were added, and the mixture was heated to 90-95 ° C for 12 hours, the reaction was stopped, and the temperature was lowered to obtain a mixture (III) (HPLC detection: 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl alcohol 47.1%, 2,3,5,6-tetrafluoro-1,4-benzenedimethanol 41.6%, 1,4-bis(methoxymethyl)-2,3,5,6-tetrafluorobenzene 9.1%), used in the next step. To the system, 250 g of toluene was added, the temperature was controlled at 40 to 45 ° C, and 60 g of dimethyl sulfate was slowly added dropwise. After the addition was completed, the system was kept at 40 to 45 ° C for 2 hours, and the reaction was stopped and the temperature was lowered. The reaction solution was allowed to stand for stratification, the organic phase was separated, the aqueous phase was extracted with 200 g of toluene, the organic phase was combined, the solvent was distilled off under reduced pressure, and the concentrate was subjected to distillation under reduced pressure to obtain a product (V) 99.8 g, content: 99.2%. The yield was 75.7%, and 16.1 g of the compound (I) was recovered, the content was 98.2%, and the recovery was 11.5%.
  • 57
  • 1,4-bis(methoxymethyl)-2,3,5,6-tetrafluorobenzene [ No CAS ]
  • [ 64-19-7 ]
  • [ 83282-91-1 ]
  • 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl alcohol acetate [ No CAS ]
  • (2,3,5,6-tetrafluoro-1,4-phenylene)bis(methylene) diacetate [ No CAS ]
  • 2,3,5,6-tetrafluoro-1,4-benzenedimethanol monoacetate [ No CAS ]
  • [ 92339-07-6 ]
YieldReaction ConditionsOperation in experiment
11.6%Chromat.; 32.5%Chromat.; 22.4%Chromat.; 17.8%Chromat.; 5.4%Chromat. With sulfuric acid; In water; at 120 - 125℃; for 8h;Large scale; 150 g of compound (I) and 600 g of 60% aqueous sulfuric acid solution were added to a 2-liter reaction flask.900 g of acetic acid, stirred and heated to 120-125 C for 8 hours, the reaction was stopped and the temperature was lowered. The reaction solution was extracted with 960 g of toluene, and the organic phase was combined to obtain a toluene solution of the mixture (II) 1125 g. (HPLC detection: 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl alcohol acetate 32.5%, 2,3,5,6-tetrafluoro-1,4-benzenedimethanol diacetate 22.4%, 2,3,5,6-tetrafluoro-1,4-benzenedimethanol monoacetate 17.8%, 2,3,5,6-tetrafluoro-1,4-benzenedimethanol 5.4%, 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl alcohol 11.6% and 1,4-bis(methoxymethyl)-2,3,5,6-tetrafluorobenzene 8.2 %), Used in the next step of the reaction.
  • 58
  • 1,4-bis(methoxymethyl)-2,3,5,6-tetrafluorobenzene [ No CAS ]
  • [ 802294-64-0 ]
  • [ 83282-91-1 ]
  • 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl alcohol propionate [ No CAS ]
  • 2,3,5,6-tetrafluoro-1,4-benzenedimethanol dipropionate [ No CAS ]
  • 2,3,5,6-tetrafluoro-1,4-benzenedimethanol monopropionate [ No CAS ]
  • [ 92339-07-6 ]
YieldReaction ConditionsOperation in experiment
11.8%Chromat.; 35.5%Chromat.; 20.2%Chromat.; 16.5%Chromat.; 4.8%Chromat. With sulfuric acid; In water; at 140 - 145℃; for 10h; A 2-liter reaction flask was charged with 140 g of the compound (I), 420 g of a 70% aqueous sulfuric acid solution, and 1120 g of propionic acid, and the mixture was heated to 140 to 145 C for 10 hours, and the reaction was stopped and the temperature was lowered. The reaction liquid was extracted with 700 g of chloroform, and the organic phase was combined, and the chloroform was removed by distillation under reduced pressure to obtain 159.5 g of the mixture (II) (HPLC detection: 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl alcohol propionate 35.5%, 2,3,5,6-tetrafluoro-1,4-benzenedimethanol dipropionate 20.2%, 2,3,5,6-tetrafluoro-1,4-benzenedimethanol monopropionate 16.8%, 2,3,5,6-tetrafluoro-1,4-benzenedimethanol4.8 %, 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl alcohol 11.8% and 1,4-bis(methoxymethyl)-2,3,5,6-tetrafluorobenzene 9.1 %, Used in the next step of the reaction.
  • 59
  • [ 83282-91-1 ]
  • (E/Z)-cis-3-(2-chloro-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid chloride [ No CAS ]
  • (1R)-trans-4-methoxymethyl-2,3,5,6-tetrafluorobenzyl 2,2-dimethyl-3-(2-chloropropenyl)cyclopropanecarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
96% With pyridine In cyclohexane at 20℃; for 4h; 10 synthesis(1R)-trans-4-methoxymethyl-2,3,5,6-tetrafluorobenzyl 2,2-dimethyl-3-(E/Z-2-chloropropenyl)cyclopropanecarboxylate Acid ester Add in a 100mL three-necked flaskTrans-4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol 5.6 g (25 mmol), Pyridine 3g,Cyclohexane 40mL,Slow drop(1R)-trans-2,2-dimethyl-3-(2-chloropropenyl)cyclopropanecarboxylic acid chloride 6g (30mmol),The reaction was carried out for 4 hours at room temperature.The organic phase is sequentially treated with 20 mL of 5% sodium hydroxide solution,Wash with 5% hydrochloric acid solution and saturated sodium chloride solution,dry,After desolvation, a pale yellow viscous liquid is obtained.Column chromatography (petroleum ether / ethyl acetate = 20/1)After getting a pale yellow liquid 9.5g,The yield was 96%.
  • 60
  • [ 83282-91-1 ]
  • trans-2,2-dimethyl-3-(2-chloropropenyl)cyclopropanecarboxylic acid chloride [ No CAS ]
  • trans-4-methoxymethyl-2,3,5,6-tetrafluorobenzyl 2,2-dimethyl-3-(2-chloropropenyl)cyclopropanecarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
96% With pyridine In cyclohexane at 20℃; for 4h; 8 Synthesis of trans-4-methoxymethyl-2,3,5,6-tetrafluorobenzyl 2,2-dimethyl-3-(E/Z-2-chloropropenyl)Cyclopropane carboxylate Add in a 100mL three-necked flaskTrans-4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol 5.6 g (25 mmol),Pyridine 3g,Cyclohexane 40mL,Slowly add trans-2,2-dimethyl-3-(2-chloropropenyl)cyclopropanecarboxylic acid chloride 6g(30mmol),The reaction was carried out for 4 hours at room temperature.The organic phase is sequentially treated with 20 mL of 5% sodium hydroxide solution,5% hydrochloric acid solution and saturated chlorineSodium solution washing,Dry, desolvent to obtain a pale yellow viscous liquid, after column chromatography (petroleum ether / ethyl acetate = 20/1)Light yellow liquid 9.5g,The yield was 96%.
  • 61
  • [ 83282-91-1 ]
  • (E/Z)-trans-3-(2-Chloro-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid chloride [ No CAS ]
  • (1R)-cis-4-methoxymethyl-2,3,5,6-tetrafluorobenzyl 2,2-dimethyl-3-(2-chloropropenyl)cyclopropanecarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
96% With pyridine In toluene at 20℃; for 4h; 9 synthesis(1R)-cis-4-methoxymethyl-2,3,5,6-tetrafluorobenzyl 2,2-dimethyl-3-(E/Z-2-chloropropenyl)cyclopropanecarboxylate Acid ester Add in a 100mL three-necked flask4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol 5.6 g (25 mmol),Pyridine 2.5g,Toluene 40mL,Slow drop(1R)-cis-2,2-dimethyl-3-(2-chloropropenyl)cyclopropanecarboxylic acid chloride 6g(29mmol),The reaction was carried out for 4 hours at room temperature.Wash with 20 mL of 5% sodium hydroxide solution, 5% hydrochloric acid solution and saturated sodium chloride solution.dry,After desolvation, a pale yellow viscous liquid is obtained.After column chromatography (petroleum ether / ethyl acetate = 20/1), 9.5 g of pale yellow liquid was obtained.The yield was 96%.
  • 62
  • [ 83282-91-1 ]
  • cis-2,2-dimethyl-3-(2-chloropropenyl)cyclopropanecarboxylic acid chloride [ No CAS ]
  • cis-4-methoxymethyl-2,3,5,6-tetrafluorobenzyl 2,2-dimethyl-3-(2-chloropropenyl)cyclopropanecarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
96% With pyridine In 5,5-dimethyl-1,3-cyclohexadiene at 20℃; for 4h; 4 Synthesis of cis-4-methoxymethyl-2,3,5,6-tetrafluorobenzyl 2,2-dimethyl-3-(2-chloropropenyl)cyclopropanecarboxylate Add in a 100mL three-necked flask4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol 5.6 g (25 mmol),Pyridine 2.5g,Xylene 40mL,Slow dropCis-2,2-dimethyl-3-(2-chloropropenyl)cyclopropanecarboxylic acid chloride 6g (29mmol),The reaction was carried out for 4 hours at room temperature.Solve in 20 mL of 5% sodium hydroxide solution, 5% hydrochloric acid solution and saturated sodium chlorideLiquid washing,dry,After desolvation, a pale yellow viscous liquid is obtained.After column chromatography (petroleum ether / ethyl acetate = 20/1), 9.5 g of pale yellow liquid was obtained.The yield was 96%.
  • 63
  • [ 83282-91-1 ]
  • (1R,trans)-(Z)-3-(2-fluorovinyl)-2,2-dimethylcyclopropanecarboxylic acid chloride [ No CAS ]
  • 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl (1R,trans)-(Z)-3-(2-fluorovinyl)-2,2-dimethylcyclopropanecarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
85.7% With pyridine In toluene at 0 - 20℃; for 6h; 1 Example 1:2,3,5,6-tetrafluoro-4-methoxymethylbenzyl (1R,trans)-Z-3-(2-fluorovinyl)-2,2-dimethylcyclopropanecarboxylate Synthesis of a compound of the formula A of the present invention 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl alcohol 22.4 g (0.1 mol) was placed in a 500 ml four-necked flask.10.0 g of pyridine, dissolved in 200 ml of toluene, and stirred for stirring.(1R,trans)-Z-3-(2-fluoro-1-vinyl)-2,2-dimethylcyclopropanecarboxylic acid chloride 17.7 g (0.1 mol) was added dropwise at 0 to 5 °C.The mixture was diluted for 2 hours and reacted at 20 ° C for 4 hours.Wash with 30 ml of 5% hydrochloric acid and then with 30 ml of 5% aqueous sodium hydrogencarbonate solution.The oil layer is heated to 100 ° C under a negative pressure of 10 mmHg to remove the solvent toluene.The compound 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl (1R,trans)-Z-3-(2-fluorovinyl)-2,2-dimethylcyclopropanecarboxylate is a colorless transparent liquid,The weight was 31.2 g, the content was 98.5%, and the yield was 85.7%.
  • 64
  • [ 83282-91-1 ]
  • 3-(3-fluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid [ No CAS ]
  • 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl 3-(3-fluoro-1-propenyl)-2,2-dimethylcyclopropane-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
33.2 g With toluene-4-sulfonic acid In water; toluene for 6h; Reflux; 3 Preparation of 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl-3-(3-fluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate (Compound 75) In a 500 ml flask, 17.2 g (0.1 mol) of 3-(3-fluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid was charged.2,3,5,6-tetrafluoro-4-methoxymethylbenzyl alcohol 22.4g (0.1mol), 180ml of toluene, equipped with a water separator, and then added 0.1g of p-toluenesulfonic acid,Heated to reflux, with water for 6 hours, Add 20 ml of toluene to the reaction, cool to room temperature, wash once with 100 g of water, wash once with 100 g of 5% diluted hydrochloric acid, wash once with 100 g of 5% sodium bicarbonate solution, and then wash once again with 100 g of water.The toluene layer was collected and heated to 100 °C under a negative pressure of 10 mmHg to remove the solvent toluene to obtain a compound 75 weight of 33.2 g, a content of 96.5%
  • 65
  • [ 83282-91-1 ]
  • [ 851896-05-4 ]
  • (2,3,5,6-tetrafluoro-4-methoxymethylphenyl)methyl 2,2-dimethyl-3-(1-propenyl)cyclopropanecarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
95.3% Stage #1: 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl alcohol; methyl 2,2-dimethyl-3-(1-propenyl)-cyclopropanecarboxylate With 2,6-di-tert-butyl-4-methyl-phenol; sodium hydrogensulfite In n-heptane; water at 40 - 50℃; for 0.5h; Stage #2: With lithium methanolate In water at 102℃; 9.38 g of methyl 2,2-dimethyl-3-((Z)-1-propenyl)cyclopropanecarboxylate, 10.2 g of [4-(methoxymethyl)-2,3,5,6-tetrafluorophenyl]methanol 0.15 g of 2,6-di-tert-butyl-p-cresol, 10.2 g of heptane and 10.0 g of 1% by weight aqueous sodium bisulfite solution were mixed,After washing at 40 to 50 ° C. for 30 minutes, the layers were separated and the aqueous layer was removed.After washing with 5.0 g of water in the same manner, 30.6 g of heptane and 0.059 g of lithium methoxide were added. [4-(Methoxymethyl)-2,3,5,6-tetrafluorophenyl]methanol is converted to [4-(methoxymethyl)-2,3,5,6-tetrafluorophenyl]methyl 2,2-dimethyl-3-((Z)-1-propenyl)cyclopropanecarboxylate. The mixture was heated to reflux while removing methanol produced at 102 ° C. until the amount became 2% or less.Then, after cooling to room temperature and washing with water, the heptane solution was concentrated under reduced pressure,17.3 g of 4-(methoxymethyl)-2,3,5,6-tetrafluorophenyl]methyl 2,2-dimethyl-3-((Z) -1-propenyl)cyclopropanecarboxylate were obtained as an oil. .The content of compound (A) was measured by liquid chromatography analysis of the obtained 2,2-dimethyl-3-((Z)-1-propenyl)cyclopropanecarboxylate. Similarly, the concentration of the compound (A) was measured while changing the concentration of the sodium bisulfite solution.In the case where washing with an aqueous solution of sodium hydrogen sulfite was not performed, washing with subsequent water was also omitted. (*) Using an aqueous solution containing 0.5% Na2SO3 in addition to 1% NaHSO3 as seen in the table above, by washing with bisulfite aqueous solution,generation of the compound (A) as an impurity can be suppressed.
  • 66
  • [ 83282-91-1 ]
  • 2-(4-chlorophenyl)-3-methylbutyric acid [ No CAS ]
  • 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl 4'-chlorophenyl-α-isopropylacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
70 mg With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In chloroform at 20℃; for 18h; 3 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl alcohol (55 mg, 0.246 mmol) And 4'-chlorophenyl-α-isopropylacetic acid (52 mg, 0.245 mmol) in chloroform solution (2 mL) 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (47 mg, 0.244 mmol) and 4-dimethylaminopyridine (3 mg) were added to the mixture. After stirring at room temperature for 18 hours, water was added to the reaction solution, and this was extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, concentrated under reduced pressure conditions, and the residue is subjected to silica gel column chromatography according to the following formula (VI). 70 mg of 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl 4'-chlorophenyl-α-isopropylacetate (Compound 3 of the present invention) represented by the above was obtained.
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