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Structure of 51632-16-7 * Storage: {[proInfo.prStorage]}
* 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.
Stage #1: With phosphorus tribromide In dichloromethane at 0 - 20℃; for 0.5 h; Stage #2: With water; sodium hydrogencarbonate In dichloromethane
-Phenoxybenzyl bromide. 3-Phenoxybenzyl alcohol (2.09 g, 10.0 mmol) in 18.7 mL of anhydrous CH2Cl2was treated at 0 0C with a solution of PBr3 (0.35 mL, 3.80 mmol) in CH2C12(4.7O mL) and the solution was allowed to reach room temperature during 30 min. The reaction was quenched with saturated aqueous NaHCO3 and extracted with Et2O. The organic phase was dried (MgSO4), concentrated in vacuo and purified by flash chromatography (hexanes/EtOAc (8:2), to afford 1.98 g of bromide as a colorless oil (72percent yield). Spectral analysis were consistent to the reported data. (Surman, M.D; Mulvihill, M.J. J. Org. Chem. 2002, <n="62"/>67, 4115-4121).
Reference：
[1] Archiv der Pharmazie, 1983, vol. 316, # 7, p. 598 - 608
[2] Journal of Medicinal Chemistry, 2010, vol. 53, # 8, p. 3389 - 3395
[3] Patent: WO2008/110583, 2008, A1, . Location in patent: Page/Page column 60
[4] Tetrahedron Letters, 1985, vol. 26, # 32, p. 3863 - 3866
[5] Journal of Organic Chemistry, 2002, vol. 67, # 12, p. 4115 - 4121
[6] Tetrahedron, 2002, vol. 58, # 17, p. 3361 - 3370
[7] Patent: US4748186, 1988, A,
[8] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 21, p. 9498 - 9510
[9] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 13, p. 3465 - 3477
[10] Bioorganic Chemistry, 2019, vol. 83, p. 535 - 548
[11] Organic and Biomolecular Chemistry, 2015, vol. 13, # 17, p. 4879 - 4895
[12] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 36 - 51
[13] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 13, p. 3285 - 3297
2
[ 3586-14-9 ]
[ 51632-16-7 ]
Yield
Reaction Conditions
Operation in experiment
86%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 3 h; Reflux
A solution of m-(phenoxy)toluene (3.68 g; 20 mmol) in 45 mL CCl4 was treated with N-bromosuccinimide (5.34 g; 30 mmol) and azo-bis(isobutyronitrile) (15 mg) and the reaction mixture was refluxed for 3 h. The solution was allowed to cool to room temperature and then placed in an ice bath. A white precipitate formed which was filtered off and the filtrate was evaporated, leaving pure compound 1 as a yellow oil (4.5 g; 86percent yield). 1H NMR (CDCl3): δ 4.4 (s, 2H), 6.9-7.41 (m, 9H). This was used in the next step. To sodium azide (3.25 g; 50 mmol) in dry DMSO (80 mL) was added compound 12 (4.5 g; 17.1 mmol) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was cooled in an ice bath and quenched with water (50 mL). The aqueous layer was extracted with ethyl ether (3 .x. 30 mL). The combined ethyl ether extracts were washed with water (2 .x. 20 mL) and dried over anhydrous sodium sulfate. The solvent was removed, leaving a crude product which was purified using flash chromatography (silica gel/methylene chloride/hexanes) to give compound 13 as a colorless oil (3.31 g; 60percent yield). 1H NMR (CDCl3): δ 4.25 (s, 2H), 6.07-7.45 (m, 9H).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 19, p. 5749 - 5755
[2] Pest Management Science, 2000, vol. 56, # 10, p. 875 - 881
[3] Pesticide Science, 1999, vol. 55, # 8, p. 850 - 856
[4] Patent: US6136863, 2000, A,
[5] Patent: US6136863, 2000, A,
3
[ 558-13-4 ]
[ 13826-35-2 ]
[ 51632-16-7 ]
Reference：
[1] Patent: US2002/10172, 2002, A1,
4
[ 77-48-5 ]
[ 3586-14-9 ]
[ 51632-16-7 ]
[ 3991-61-5 ]
Reference：
[1] Patent: US4709100, 1987, A,
5
[ 3586-14-9 ]
[ 51632-16-7 ]
[ 53874-67-2 ]
Reference：
[1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1990, vol. 39, # 3.2, p. 573 - 577[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1990, # 3, p. 652 - 656
6
[ 13749-38-7 ]
[ 3586-14-9 ]
[ 7440-44-0 ]
[ 51632-16-7 ]
[ 53874-67-2 ]
Reference：
[1] Patent: US4393246, 1983, A,
7
[ 591-17-3 ]
[ 51632-16-7 ]
Reference：
[1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1990, vol. 39, # 3.2, p. 573 - 577[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1990, # 3, p. 652 - 656
8
[ 108-95-2 ]
[ 51632-16-7 ]
Reference：
[1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1990, vol. 39, # 3.2, p. 573 - 577[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1990, # 3, p. 652 - 656
9
[ 71288-79-4 ]
[ 51632-16-7 ]
[ 49660-93-7 ]
Reference：
[1] Patent: US4079149, 1978, A,
10
[ 51632-16-7 ]
[ 446-34-4 ]
[ 452-80-2 ]
Reference：
[1] Patent: US4243819, 1981, A,
11
[ 51632-16-7 ]
[ 446-34-4 ]
[ 69409-98-9 ]
Reference：
[1] Patent: US4243819, 1981, A,
12
[ 51632-16-7 ]
[ 83493-63-4 ]
[ 80844-07-1 ]
Reference：
[1] Russian Journal of Organic Chemistry, 1993, vol. 29, # 1.2, p. 170[2] Zhurnal Organicheskoi Khimii, 1993, vol. 29, # 168, p. 202 - 203
With phosphorus tribromide; In dichloromethane; for 3h;Cooling with ice;
3-Phenoxybenzaldehyde (1.20 g, 6.1 mmol) was added to a 50 mL round bottom flask.Add 6mL THF and 6mLDME dissolves it,Add NaBH4 (464 mg, 12.2 mmol) in portions under ice bath.The reaction was continued to stir for 3 hours under an ice bath.The TLC detects the tracking reaction, and after the reaction is completed, the reaction solution is slowly added with an appropriate amount of deionized water to quench it.Extracted with ethyl acetate and water,Take the organic phase and evaporate it,Purification by column chromatography gave a colorless oil.That is, 3-phenoxybenzyl alcohol (1.20 g, yield 99.2%).The obtained 3-phenoxybenzyl alcohol (450 mg, 2.3 mmol) was added to a 50 mL round bottom flask.Dissolve it in 10 mL of DCM, add PBr3 liquid (0.3 mL, 2.5 mmol) dropwise under ice bath and keep the ice bath for 3 small reactions.Time. After the reaction is completed, the excess saturated NaHCO3 solution is slowly added to the reaction solution under stirring to adjust the reaction system.It is weakly alkaline, extracted with dichloromethane and water, and the solvent of the organic phase is evaporated and purified by silica gel column chromatography to obtain colorless oil.Liquid, 3-phenoxybenzyl bromide (350 mg, yield 85.3%). The resulting 3-phenoxybenzyl bromide (350 mg, 1.9 mmol)Dissolve with 10 mL of DMF, add to a 50 mL round bottom flask, then add p-coumaric acid ethyl ester (434 mg, 2.3 mmol) andK2CO3 (1.56g, 11.3mmol), reacted at 50 C for 6 hours, after the reaction was completed, extracted with ethyl acetate and water, combined withAfter the organic phase was evaporated to dryness, then purified by column chromatographyYield 58.6%). The obtained white solid (410 mg, 1.1 mmol) was added to a 100 mL round bottom flask and dissolved in 20mLDCMIn the process of maintaining the ice bath, Br2 (0.2 mL, 3.9 mmol) was added dropwise and the reaction was continued for 10 min in an ice bath. TLC testAfter the completion of the reaction, Na2S2O3 (1.90 g, 12.0 mmol) and 20 mL of water were added to the reaction mixture, and stirred at room temperature for 5 min, thenThe organic phase was extracted with dichloromethane and water and evaporated to ethylamine The pale yellow solid to be obtained, KOH(280 mg, 5.0 mmol) and 15 mL of isopropanol were placed in a 100 mL round bottom flask, and the reaction was stirred at 87 C for 6 hours. After the reactionAfter the reaction, the reaction solution was adjusted to be acidic with a 3 mol/L aqueous solution of HCl, and then extracted with ethyl acetate and water, and the organic phase was evaporated to dryness.Purification by column chromatography gave a white solid, which gave the final product 0011 (143 mg, the total yield of the last two steps was 39.7%, purity96.5%).
72%
-Phenoxybenzyl bromide. 3-Phenoxybenzyl alcohol (2.09 g, 10.0 mmol) in 18.7 mL of anhydrous CH2Cl2was treated at 0 0C with a solution of PBr3 (0.35 mL, 3.80 mmol) in CH2C12(4.7O mL) and the solution was allowed to reach room temperature during 30 min. The reaction was quenched with saturated aqueous NaHCO3 and extracted with Et2O. The organic phase was dried (MgSO4), concentrated in vacuo and purified by flash chromatography (hexanes/EtOAc (8:2), to afford 1.98 g of bromide as a colorless oil (72% yield). Spectral analysis were consistent to the reported data. (Surman, M.D; Mulvihill, M.J. J. Org. Chem. 2002, <n="62"/>67, 4115-4121).
With pyridine; dibromo sulfoxide; In toluene;
(a) A solution of 3-phenoxybenzyl alcohol (36.0 grams, 0.18 mole) in toluene (95 ml) was added dropwise during a thirty minute period to a stirred solution of thionyl bromide (50 grams, 0.24 mole), pyridine (0.5 gram) and toluene (175 ml) while maintaining the temperature below 30 C. After the addition was complete,the reaction mixture was heated at 50-60 C. for two hours. Upon cooling, the reaction mixture was concentrated under reduced pressure leaving a residue. This residue was dissolved in toluene (200 ml) and washed with water (10*100 ml) until a neutral pH was obtained. The dried (magnesium sulfate) toluene layer was concentrated under reduced pressure leaving a residue. This residue was distilled yielding 38.5 grams of 3-phenoxybenzyl bromide, b.p. 120-144 C./0.05 mmHg. The NMR spectrum was consistent with the proposed structure.
m-Phenoxybenzyl bromide. Triphenylphosphine (3.40 g, 13.0 mmoles) and carbontetrabromide (4.20 g, 13.0 mmoles) were added successively to a solution of m-phenoxybenzyl alcohol (1.5 mL, 8.6 mmoles). After 4 h at rt the mixture was concentrated and was purified by silica gel column (hexanes, then ethyl acetate:hexanes, 5:95) to give the desired bromide (1.3 g, 57%) as a yellow oil. MS(M-Br)-=183.
Reference Production Example 6 To a solution of 575 mg (5 mmol) of 5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one in 7 ml of dry acetonitrile was added 726 mg (5.25 mmol) of potassium carbonate was added. A solution of 1.32 g (5 mmol) of 3-phenoxybenzylbromide in 9 ml of dry acetonitrile was added dropwise thereto at 55 C. After the mixture was stirred at the same temperature for additional 5.5 hours, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. To the resultant solid residue (1.36 g) was added a mixture of equal amounts of tert-butyl methyl ether and n-hexane. The mixture was cooled and the deposited solid was washed, ice-cooled, collected by filtration, and dried to obtain a residue. The residue was recrystallized from tert-butyl methyl ether to obtain 0.27 g of 5-methoxy-4-(3-phenoxybenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one as white powder.
ethyl 1-(p-chlorophenyl)-β-oxo-cyclopropanepropionate[ No CAS ]
[ 51632-16-7 ]
ethyl 1-(p-chlorophenyl)-β-oxo-α-(m-phenoxybenzyl)-cyclopropanepropionate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With sodium; In ethanol; ethyl acetate;
EXAMPLE 7 Preparation of Ethyl 1-(p-chlorophenyl)-beta-oxo-alpha-(m-phenoxybenzyl)cyclopropanepropionate STR15 A mixture of sodium (0.31 g, 13.5 mmol) in ethanol (90 mL) is stirred at room temperature until the sodium dissolves. The resultant solution is heated to 70 C., treated dropwise with a solution of ethyl 1-(p-chlorophenyl)-beta-oxocyclopropanepropionate (3.4 g, 12.8 mmol) in ethanol, stirred at 70 C. for one hour, treated dropwise with a solution of alpha-bromo-m-tolyl phenyl ether (4.0 g, 15.2 mmol) in ethanol, stirred at reflux overnight, stirred at room temperature for two days, and concentrated in vacuo to obtain a residue. A solution of the residue in ethyl acetate is washed sequentially with water, 10% sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain an oil. Chromatography of the oil using silica gel and a 19:1 hexanes/ethyl acetate solution gives the title product as a colorless oil (5.24 g, 92%) which is identified by NMR spectral analysis.
92%
With sodium; In ethanol; ethyl acetate;
EXAMPLE 7 Preparation of Ethyl 1-(p-chlorophenyl)-beta-oxo-alpha-(m-phenoxybenzyl) cyclopropanepropionate A mixture of sodium (0.31 g, 13.5 mmol) in ethanol (90 mL) is stirred at room temperature until the sodium dissolves. The resultant solution is heated to 70 C, treated dropwise with a solution of ethyl 1-(p-chloro-phenyl)-beta-oxocyclopropanepropionate (3.4 g, 12.8 mmol) in ethanol, stirred at 70 C for one hour, treated dropwise with a solution of alpha-bromo-m-tolyl phenyl ether (4.0 g, 15.2 mmol) in ethanol, stirred at reflux overnight, stirred at room temperature for two days, and concentrated in vacuoto obtain a residue. A solution of the residue in ethyl acetate is washed sequentially with water, 10% sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated in vacuoto obtain an oil. Chromatography of the oil using silica gel and a 19:1 hexanes/ethyl acetate solution gives the title product as a colorless oil (5.24 g, 92%) which is identified by NMR spectral analysis.
N-(4-tert-butylbenzyl)-N-methyl-3-phenoxybenzylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87.8%
With sodium chloride; sodium carbonate; In chloroform; water; N,N-dimethyl-formamide;
In 20 ml of N,N-dimethylformamide, 2.79 g of N-(4-tert-butylbenzyl)methylamine and 1.67 g of sodium carbonate were mixed, to which a solution of 3.77 g of <strong>[51632-16-7]3-phenoxybenzyl bromide</strong> in 25 ml of N,N-dimethylformamide was added dropwise under ice cooling. The temperature of the reaction mixture was allowed to rise to room temperature, at which a reaction was allowed to proceed for 12 hours. Chloroform and water were added to the reaction mixture to conduct liquid-liquid extraction. An organic layer was collected and then washed with water and a saturated aqueous solution of sodium chloride. The resulting solution was dried over anhydrous sodium sulfate and was then concentrated. The concentrate was purified by chromatography on a silica gel column (eluent:hexane:chloroform:ethyl acetate=9:1:0?0:10:0?0:0:100). Relevant fractions were concentrated, whereby 4.49 g of N-(4-tertiary-butylbenzyl)-N-methyl-3-phenoxybenzylamine (Compound 1) were obtained (yield: 87.8%). The following is its NMR data (CDCl3 delta ppm): 1.28(9H,s), 2.18(3H,s), 3.476(2H,s), 3.483(2H,s), 6.86-7.35(13H,m).
EXAMPLE 32 This Example illustrates the preparation of 1,1,1-trifluoro-2-(4-ethoxyphenyl)-3-(3-phenoxybenzyloxy)propane from 1,1,1-trifluoro-2-(4-ethoxyphenyl)propan-3-ol A mixture of 1,1,1-trifluoro-2-(4-ethoxyphenyl)propan-3-ol (0.4 g), <strong>[51632-16-7]3-phenoxybenzyl bromide</strong> (0.45 g), tetra-n-butylammonium hydrogen sulphate (0.05 g) and aqueous sodium hydroxide solution (40% w/v, 5.0 cm3) was stirred at the ambient temperature for 6 hours after which it was partitioned between water and diethyl ether. The ethereal phase was separated, washed twice with water, dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent under reduced pressure. The residual oil (0.75 g) was purified by chromatography on a silica gel column eluted with a mixture of hexane (23 parts by volume) and ethyl acetate (2 parts by volume) to yield 1,1,1-trifluoro-2-(4-ethoxyphenyl)-3-(3-phenoxybenzyloxy)propane (0.21 g) as a viscous oil. IR (liquid film):1617, 1590, 1520, 1490, 1448, 1260, 1220, 1170, 1126, 1076, 1050, 700 cm-1 1 H NMR (CDCl3) (ppm):1.42 (3H,t); 3.55 (1H,q); 3.8 (1H,m); 3.95 (1H,m); 4.0 (2H,q); 4.46 (ABq,2H); 6.8-7.4 (13H,m) 19 F NMR (CDCl3) (ppm--relative to CFCl3) -68.43 (3F,d)
With sodium hydroxide; In hexane; ethyl acetate;
EXAMPLE 52 The Example illustrates the preparation of (RS)-1,1,1-trifluoro-2-(4-ethoxyphenyl)-3-(3-phenoxybenzyloxy)propane from (RS)-1,1,1-trifluoro-2-(4-ethoxyphenyl)propan-3-ol. A mixture of (RS)-1,1,1-trifluoro-2-(4-ethoxyphenyl)propan-3-ol (0.4 g), <strong>[51632-16-7]3-phenoxybenzyl bromide</strong> (0.45 g), tetra-n-butyl-ammonium hydrogen sulphate (0.05 g) and aqueous sodium hydroxide solution (40% w/v, 5.0 cm3) was stirred at the ambient temperature for 6 hours after which it was partitioned between water and diethyl ether. The ethereal phase was separated, washed twice with water, dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent under reduced pressure. The residual oil (0.75 g) was purified by chromatography on a silica gel column eluted with a mixture of hexane (23 parts by volume) and ethyl acetate (2 parts by volume) to yield (RS)-1,1,1-trifluoro-2-(4-ethoxyphenyl)-3-(3-phenoxybenzyloxy)propane (0.21 g) as a viscous oil. IR (liquid film):1617, 1590, 1520, 1490, 1448, 1260, 1220, 1170, 1126, 1076, 1050, 700 cm-1 1 H NMR (CDCl3):1.42 (3H,t); 3.55 (1H,q); 3.8 (1H,m); 3.95 (1H,m); 4.0 (2H,q); 4.46 (ABq,2H); 6.8-7.4 (13H,m) 19 F NMR (CDCl3):-68.43 (3F,d)
With sodium hydroxide; In hexane; ethyl acetate;
EXAMPLE 11 This Example illustrates the preparation of (RS)-1,1,1-trifluoro-2-(4-ethoxyphenyl)-3-(3-phenoxybenzyloxy)propane from (RS)-1,1,1-trifluoro-2-(4-ethoxyphenyl)propan-3-ol. A mixture of (RS)-1,1,1-trifluoro-2-(4-ethoxyphenyl)propan-3-ol (0.4 g), <strong>[51632-16-7]3-phenoxybenzyl bromide</strong> (0.45 g), tetra- n -butyl-ammonium hydrogen sulphate (0.05 g) and aqueous sodium hydroxide solution (40% w/v, 5.0 cm3) was stirred at the ambient temperature for 6 hours after which it was partitioned between water and diethyl ether. The ethereal phase was separated, washed twice with water, dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent under reduced pressure. The residual oil (0.75 g) was purified by chromatography on a silica gel column eluted with a mixture of hexane (23 parts by volume) and ethyl acetate (2 parts by volume) to yield (RS)-1,1,1-trifluoro-2-(4-ethoxyphenyl)-3-(3-phenoxybenzyloxy)propane (0.21 g) as a viscous oil. IR (liquid film): 1617, 1590, 1520, 1490, 1448, 1260, 1220, 1170, 1126, 1076, 1050, 700 cmmin1 1H NMR (CDCl3): 1.42 (3H,t); 3.55 (1H,q); 3.8 (1H,m); 3.95 (1H,m); 4.0 (2H,q); 4.46 (ABq,2H); 6.8-7.4 (13H,m) 19F NMR (CDCl3): -68.43 (3F,d) GLC retention time: 11.15 minutes.
2-methyl-5-(3-phenoxyphenyl)-3-pentanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethyl borane; In tetrahydrofuran;
a) Preparation of intermediate 2-methyl-5-(3-phenoxyphenyl)-3-pentanone To a solution of potassium bis (trimethylsilyl) amide (20.9 g, 0.105 mol) in 200 ml tetrahydrofuran at 0 C. was added 2-methyl-3-butanone (12 ml, 0.112 mol). After 15 minutes, triethylborane (100 ml of a 1.0M solution in hexanes) was added, followed by 24.8 g (0.094 mole) <strong>[51632-16-7]3-phenoxybenzyl bromide</strong>. The mixture was stirred at 25 C. for 18 hours, poured into 300 ml water and extracted with ether. The organic phase was dried, filtered and concentrated, leaving a yellow oil. The crude ketone product was purified by chromatography over silica gel using 5% ethyl acetate in hexanes, producing 16.8 g of product, a light yellow oil.
2-(6-chloropyridine-3-yl)-2-methylpropan-1-ol[ No CAS ]
[ 51632-16-7 ]
tetra(n-butyl)ammonium hydrogen sulfate[ No CAS ]
2-Methyl-2-(6-chloro-pyrid-3-yl)-propyl 3-phenoxy-benzyl ether[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In methanol; sodium hydroxide; toluene;
(1.6) 2-(6-Chloro-pyrid-3-yl)-2-methyl-propyl 3-phenoxy-benzyl ether 1.9 g (10.2 mmol) of 2-(6-chloro-pyrid-3-yl)-2-methylpropanol are dissolved in 15 ml of toluene, 2.7 g (10.3 mmol) of <strong>[51632-16-7]3-phenoxy-benzyl bromide</strong> are added and a solution of 0.6 g (1.8 mmol) of tetra-n-butylammonium hydrogen sulfate in 5 g of 50% strength sodium hydroxide solution is added. The mixture is stirred at 70-80 C. for 2 hours, mixed with a mixture of 2 ml of methanol and 2 ml of concentrated ammonia water and finally all distributed between water and toluene. The organic phase is washed with ammonium chloride solution, the solvent is removed and the crude product is purified through a silica gel column. 2.4 g (62.9% of theory) of a weakly yellowish oil are thus obtained. The oil is distilled in the bulb tube at 0.03 mbar and 230-240 C. apparatus temperature.
EMBODIMENT 7 trans-1-Isopropyl-2-((3-phenoxy)phenyl)methoxy)indane Following procedures similar to those described in Embodiments 2 and 3 above, 1-isopropyl-1H-indene was converted by hydroboration to 1-isopropyl-2-indanol and the trans form recovered and reacted with 3-phenoxybenzyl bromide to give the desired product.
66
[ 51632-16-7 ]
[ 17881-97-9 ]
dimethyl(phenyl)silylmethyl 3-phenoxybenzyl ether[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; tetrabutylammomium bromide; In water;
EXAMPLE 1 Dimethylphenylsilylmethyl 3-phenoxybenzyl ether (Method A) STR6 A mixture of dimethylphenylsilylmethanol (0.33 gram), 50% aqueous sodium hydroxide solution (1.20 gram), <strong>[51632-16-7]3-phenoxybenzyl bromide</strong> (0.44 gram), and TBAB (0.07 gram) was stirred for 15 hours at room temperature. The reaction mixture was added with water and extracted with ethyl ether. The ether layer was washed with saturated sodium chloride solution, dried, and evaporated under vacuum to remove the solvent. The residue was purified by column chromatography over silica gel (20 gram) using as the eluent n-hexane:ethyl acetate (100:1), to obtain the title compound. Yield 0.32 gram. Physicochemical properties of the product are listed in Table 2.
With tetrabutylammomium bromide; potassium carbonate; In water;
EXAMPLE 43 Dimethyl(4-ethoxyphenyl)silylmethyl 3-phenoxybenzyl ether (Method A) STR8 A mixture of dimethyl(4-ethoxyphenyl)silylmethanol (0.22 gram), <strong>[51632-16-7]3-phenoxybenzyl bromide</strong> (0.24 gram), TBAB (0.07 gram), potassium carbonate (0.40 gram) and water (1.0 gram) was stirred 15 hours at 80 C. After cooling, the reaction mixture was extracted with ethyl ether, and the extract was washed with saturated sodium chloride solution, dried, and evaporated under vacuum to remove the solvent. The residue was purified by column chromatography over silica gel (13 gram) using n-hexane:ethyl acetate (100:1.2) as the eluent to obtain the title compound. Yield 0.23 gram. Physicochemical properties of the product are listed in Table 2.
In tetrahydrofuran;
EXAMPLE 44 Dimethyl(4-ethoxyphenyl)silylmethyl 3-phenoxybenzyl ether (Method A) STR9 Dimethyl(4-ethoxyphenyl)silylmethanol (0.25 gram), 50% sodium hydride (0.17 gram), and <strong>[51632-16-7]3-phenoxybenzyl bromide</strong> (0.2 gram) were dissolved in 3 ml of THF and the resulting mixture was stirred for 2.5 hours at 80 C. After cooling, the mixture was added with ice, diluted with ethyl ether, and washed with saturated sodium chloride solution. The ether layer was dried and evaporated under vacuum to remove the solvent. The residue was purified by column chromatography over silica gel (15 gram) using n-hexane:ethyl acetate (100:1.2) as the eluent to obtain the title compound. Yield 0.32 gram. Physicochemical properties of the product are listed in Table 2.
trans-5-Chloro-1-isopropyl-2-((3-phenoxyphenyl)methoxy)indane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EMBODIMENT 4 trans-5-Chloro-1-isopropyl-2-((3-phenoxyphenyl)methoxy)indane Following procedures similar to those described in Embodiment 3 above, the desired product was prepared from trans-5-chloro-1-isopropyl-2-indanol and <strong>[51632-16-7]3-phenoxybenzyl bromide</strong>.
N-(4-chlorophenyl)isoleucine is prepared by the reaction of 4-chloroaniline with the sodium salt of alpha-bromo-3-methylpentanoic acid neat at 100. By the above procedure, <strong>[51632-16-7]m-phenoxybenzyl bromide</strong> is reacted with N-(4-methylphenyl)isoleucine to prepare the m-phenoxybenzyl ester of N-(4-methylphenyl)isoleucine. MS m/e 403.3 (M+, 3.3), 176.1 (100).
With magnesium; In diethyl ether; Petroleum ether;
E. 1-(4-ethoxyphenyl)-1-(3-(3-phenoxyphenyl)-2-hydroxypropyl)-cyclopropane (Compound e) A Grignard reagent prepared from <strong>[51632-16-7]3-phenoxybenzyl bromide</strong> (0.98 g), magnesium turnings (0.1 g) in dry diethyl ether (15 ml) under an atmosphere of nitrogen, is cooled with vigorous stirring to -78 C. To this is added a solution of 1-(4-ethoxyphenyl)-1-(2-oxoethyl)-cyclopropane (0.5 g) in diethyl ether (15 ml) over 5 min. The resulting mixture is allowed to warm up to room temperature over 1 h. Saturated NH4 Cl solution is added and the mixture extracted with diethyl ether (x3), dried and the solvent evaporated under reduced pressure. The product is purified by t.l.c. on silica eluted with 10% diethyl ether in petroleum ether (b.p. 60-80 C.). Yield 0.25 g, nD 1.5444.
1-hydroxymethyl-1-(3-phenoxybenzyloxymethyl)cyclopropane[ No CAS ]
1-hydroxymethyl-1-(3-phenoxybenzyloxymethyl)cyclopropan-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With tetra-(n-butyl)ammonium iodide; In tetrahydrofuran; ethyl acetate;
EXAMPLE 2 This Example illustrates the preparation of 1-hydroxymethyl-1-(3-phenoxybenzyloxymethyl)cyclopropane. A solution of 1,1-dihydroxymethylcyclopropane (3 g) in tetrahydrofuran (20 cm3) was added dropwise to a suspension of sodium hydride (0.35 g) in tetrahydrofuran (30 cm3). After effervescence has ceased, tetrabutylammonium iodide (1 g) was added to the grey suspension followed by a solution of <strong>[51632-16-7]3-phenoxybenzyl bromide</strong> (3.88 g) in tetrahydrofuran (15 cm3) at the ambient temperature and the mixture stirred for a further 2 hours. The mixture was poured into water and extracted with ethylacetate. The extracts were combined, dried over magnesium sulphate and concentrated by evaporation of the solvent, and the residual oil purified by column chromatography using a silica gel column eluding first with dichloromethane, followed then by ethylacetate, to give 1-hydroxymethyl-1-(3-phenoxybenzyloxymethyl)cyclopropan-1-ol (1.7 g). 1 H nmr (CDCl3) ppm: 0.5 (s, 4H); 2.45 (broad s, 1H); 3.4 (s, 2H); 3.5 (s, 2H); 4.5 (s, 2H); and 6.9-7.5 (m, 9H).
With tetra-(n-butyl)ammonium iodide; In tetrahydrofuran; ethyl acetate;
EXAMPLE 2 This Example illustrates the preparation of 1-hydroxymethyl-1-(3-phenoxybenzyloxymethyl)cyclopropane. A solution of 1,1-dihydroxymethylcyclopropane (3 g) in tetrahydrofuran (20 cm3) was added dropwise to a suspension of sodium hydride (0.35 g) in tetrahydrofuran (30 cm3). After effervescence has ceased, tetrabutylammonium iodide (1g) was added to the grey suspension followed by a solution of <strong>[51632-16-7]3-phenoxybenzyl bromide</strong> (3.88 g) in tetrahydrofuran (15 cm3) at the ambient temperature and the mixture stirred for a further 2 hours. The mixture was poured into water and extracted with ethylacetate. The extracts were combined, dried over magnesium sulphate and concentrated by evaporation of the solvent, and the residual oil purified by column chromatography using a silica gel column eluding first with dichloromethane, followed then by ethylacetate, to give 1-hydroxymethyl-1-(3-phenoxybenzyloxymethyl)cyclopropan-1-ol (1.7 g). 1 H nmr (CDCL3) ppm: 0.5 (s,4H); 2.45 (broad s,1H); 3.4 (s,2H); 3.5 (s,2H): 4.5 (s,2H); and 6.9-7.5 (m,9H).
With (E)-3,3'-(diazene-1,2-diyl)bis(2-methylpropanenitrile); In 1,1,2,2-tetrachloroethylene;
The procedure as in Example 1 was repeated, using the following reagents: 60 g m-phenoxytoluene 97.8 g dibromodimethylhydantoin 4.2 g azoisobutyronitrile, and 600 ml of tetrachloroethylene. The mixture was heated at 64 degrees and kept at this temperature for about 209 minutes. The filtrate was analyzed by gas chromatography and the compositions of the constituents were as follows: m-phenoxytoluene: 59.5% m-phenoxybenzylbromide: 27.36% 6-phenoxytoluene(6-Br-mPHT): 13.12%
3-phenoxybenzyl 2-(4-chlorophenyl)-3-methylbutanimidate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With silver tetrafluoroborate; In dichloromethane;
To a refluxing solution of 2.72 g (12.9 mmol) of 2-(4-chlorophenyl)-3-methylbutyramide and 2.27 g (8.6 mmol) of <strong>[51632-16-7]3-phenoxybenzyl bromide</strong> in a solution of 15 ml dichloromethane and 3 ml ethyl ether is added a solution of 1.83 g (9.5 mmol) of silver tetrafluoroborate in ether. The mixture is refluxed for 2 hours and then separated by pouring into ice cold aqueous ethyl acetate/sodium bicarbonate. The organic phase is washed with water, dried and stripped of solvent. The residue is triturated with ether and filtered. The filtrate is concentrated and chromatographed on silica gel, eluding with 25% ethyl acetate/hexane, and then on plates using 35% ethyl acetate/hexane, to yield 3-phenoxybenzyl 2-(4-chlorophenyl)-3-methylbutanimidate, MS m/e 393 (M+).
EXAMPLE 41 N-(4-fluoro-2-methylphenyl)valine prepared from 4-fluoro-2-methylaniline and alpha-bromoisovaleric acid is reacted with <strong>[51632-16-7]m-phenoxybenzyl bromide</strong> as in Example 38 to give the m-phenoxybenzyl ester of N-(4-fluoro-2-methylphenyl)valine. MS m/e 407.2 (M+, 4.5), 180 (100).
EXAMPLE 55 N-(2-fluoro-4-chlorophenyl)valine and <strong>[51632-16-7]m-phenoxybenzyl bromide</strong> are reacted using the process of Example 42 to yield the m-phenoxybenzyl ester of N-(2-fluoro-4-chlorophenyl)valine, MS m/e 427.1 (M+, 4.1), 200 (100). N-(2-fluoro-4-chlorophenyl)-valine is prepared by heating the potassium salt of alpha-bromoisovaleric acid and 2-fluoro-4-chloroaniline neat at 130 for about 2 hours. Similarly, there is prepared N-(3-methyl-4-fluorophenyl)valine which is esterified using <strong>[51632-16-7]m-phenoxybenzyl bromide</strong> to yield the m-phenoxybenzyl ester of N-(3-methyl-4-fluorophenyl)valine, MS m/e 407.3 (M+, 0.3), 180 (100).
The procedure of this example is used to prepare N-(3-chloro-4-fluorophenyl)valine and N-(3-fluoro-4-methylphenyl)valine, each of which is reacted with <strong>[51632-16-7]m-phenoxybenzyl bromide</strong> to yield the m-phenoxybenzyl ester of N-(3-chloro-4-fluorophenyl)valine [MS m/e 427 (M+, 3.2), 200 (100)] and the m-phenoxybenzyl ester of N-(3-fluoro-4-methylphenyl)valine. nmr (CDCl3) delta centered at 0.97 [d, 6, J=7 Hz, CH(CH3)2 ], 2.11 STR22 and 5.10 ppm (s, 2, ArCH2 O). IR (neat 1732 cm-1 (C=O).
trans-2,2-dimethyl-3-[2-(2-methylprop-2-yl)pyrimidin-5-yl]cyclopropane carboxylic acid[ No CAS ]
[ 51632-16-7 ]
3-phenoxybenzyl (+/-)-trans-2,2-dimethyl-3-[2-(2-methylprop-2-yl)pyrimidin-5-yl]cyclopropane carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In dichloromethane; ethyl acetate; acetone;
EXAMPLE 8 This Example illustrates the preparation of 3-phenoxybenzyl trans-2,2-dimethyl-3-[2-(2-methylprop-2-yl)pyrimidin-5-yl]cyclopropane carboxylate. A mixture of trans-2,2-dimethyl-3-[2-(2-methylprop-2-yl) pyrimidin-5-yl]cyclopropane carboxylic acid (500 mg), 3-phenoxybenzylbromide 552 mg), anhydrous potassium carbonate (304 mg) and acetone (10 cm3) was heated at the reflux temperature for 2 hours with stirring after which it was kept at the ambient temperature for 16 hours. After removing the solid precipitate by filtration the filtrate was concentrated by evaporation under reduced pressure. The residual oil was subjected to high performance liquid chromatography (Gilson) using a silica column and, as eluent, a mixture of dichloromethane (100 parts by volume) and ethyl acetate (2 parts by volume). The product, 3-phenoxybenzyl trans-2,2-dimethyl-3-[2-(2-methylprop-2-yl)-pyrimidin-5-yl]cyclopropane carboxylate (800 mg) was obtained as an oil and identification was confirmed by n.m.r. and infra red spectroscopy. 1 H NMR (CDCl3) delta: 0.98 (s,3H); 1.40 (s,12H); 2.02 (d,1H); 2.56 (d,1H); 5.15 (s,2H); 6.8-7.5 (m,9H); Infra red (liquid film): 2960, 1730, 1590, 1490, 1260, 1220, 1160 cm-1. Mass spectroscopy (M+): 430.
With sodium iodide; In 1,2-dimethoxyethane; ice-water; hexane; toluene;
EXAMPLE 4 3-Phenoxybenzyl 2-phenyl-2-trifluoromethylethyl ether STR24 Sodium hydride (138 mg; 5.75 mmol) was suspended in dimethoxyethane (20 ml). There was then added in turn, with stirring, 2-phenyl-2-trifluoromethylethanol (1.0 g; 5.25 mmol), a spatula full of sodium iodide and <strong>[51632-16-7]3-phenoxybenzyl bromide</strong> (1.39 g; 5.25 mmol). After stirring for 4 hours at room temperature, the mixture was added to ice-water, extracted with ether, the extract washed with water, dried over sodium sulphate and concentrated. After chromatogrpahy on silica gel using a mixture of hexane and toluene, there was obtained 1.14 g of product (=58.3% of theory).
3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylic acid, oxalyl chloride[ No CAS ]
[ 51632-16-7 ]
3-phenoxybenzyl 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanimidate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With ammonia;
EXAMPLE 5 Following the method of Example 1, 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropaneamide, from 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylic acid, oxalyl chloride and ammonia, is reacted with <strong>[51632-16-7]3-phenoxybenzyl bromide</strong> to give 3-phenoxybenzyl 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanimidate.
α-(2-fluoro-4-methylphenylamino)isovaleric acid, potassium carbonate[ No CAS ]
[ 51632-16-7 ]
[ 446-34-4 ]
[ 452-80-2 ]
Yield
Reaction Conditions
Operation in experiment
With hydrogen; In tetrahydrofuran; N,N,N,N,N,N-hexamethylphosphoric triamide; ethanol;
(2-Fluoro-4-methylaniline is prepared from 3-fluoro-4-nitrotoluene in a Parr bottle using platinum oxide and hydrogen in ethanol.) To a mixture of 5.15 mmole of alpha-(2-fluoro-4-methylphenylamino)isovaleric acid, potassium carbonate (6.44 mmole), 4 ml of HMPT and 3 ml of THF, stirred, is added 5.13 mmole of <strong>[51632-16-7]m-phenoxybenzyl bromide</strong>. The reaction is stirred overnight at RT. The reaction is poured into 5% sodium hydroxide/ether, extracted with water (2*) and then washed with water (2*), dried over sodium sulfate and rotoevaporated under vacuum. The crude product is subjected to preparatory TLC eluding with 10% ether/hexane to give m-phenoxybenzyl ester of N-(2-fluoro-4-methylphenyl)valine. nmr (CDCl3) delta 0.98 [d, 3, J-7 Hz, CH(CH3)2 ], 1.02 [d, 3, J=7 Hz, CH(CH3)2 ], 2.22 STR20 and 5.13 ppm (s, 2, ArCH2 O). IR (neat)) 1734 cm-1 (C=O).
3-(β-cyano-p-methylstyryl)-2,2-dimethyl-cyclopropanecarboxylic acid[ No CAS ]
[ 51632-16-7 ]
trans 3-(β-cyano-p-methylstyryl)-2,2-dimethyl-cyclopropanecarboxylic acid, m-phenoxybenzyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In N-methyl-acetamide;
EXAMPLE 7 Preparation of (Z)-cis and trans 3-(beta-cyano-p-methylstyryl)-2,2-dimethyl-cyclopropanecarboxylic acid, m-phenoxybenzyl ester m-Phenoxybenzylbromide (3.68 g; 0.014 mole) is added to a solution of 3-(beta-cyano-p-methylstyryl)-2,2-dimethyl-cyclopropanecarboxylic acid (3.19 g; 0.0125 mole) and triethylamine (1.27 g; 0.0125 mole) in dry dimethylformamide and the reaction mixture stirred for 18 hours at room temperature. The reaction mixture, containing some precipitated salts, is poured into water and extracted with ether (2*75 ml). The combined ether extracts are washed several times with water, then with sodium bicarbonate solution and saturated sodium chloride solution. Evaporation of the ether solution yields 3.42 g (62.5%) of a yellow oil. Purification of this yellow oil by dry column chromatography (silica gel; eluent: 1:1 methylene chloride:hexane) affords 0.96 of the trans isomer and 0.6 of the cis isomer. Analysis calculated for C29 H27 NO3: C 79.61; H 6.22; N 3.20; (trans) found: C 79.39; H 6.44; N 3.01; (cis) found: C 79.33; H 6.53; N 2.85.
EXAMPLE 1 Into a 200 ml four necked flask equipped with a distillation column, 36.9 g (0.2 mole) of m-phenoxytoluene and 1.0 g of powdery activated carbon were charged and heated at 180 C. while stirring and then, 71.1 g of 1,2-dibromotrichloroethane (0.24 mole) was added dropwise for 30 minutes and the reaction was continued at the temperature for 3 hours. After the reaction, the reaction mixture was analyzed by a gas chromatography, 1,2-dibromotrichloroethane disappeared, and the production of 27.5 g of m-phenoxybenzyl bromide and 20.2 g of m-phenoxybenzylidene dibromide were found.
3'-phenoxy-benzyl 2,2-dimethyl-3-(2-phenylthio-2-chlorovinyl)-cyclopropane carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In N-methyl-acetamide; dichloromethane;
EXAMPLE 3 STR21 24.3 g (0.05 mol) of the sodium salt of 2,2-dimethyl-3-(2-phenylthio-2-chlorovinyl)-cyclopropanecarboxylic acid were dissolved in 150 ml of dimethylformamide and heated to 120 C., together with 15.8 g (0.06 mol) of <strong>[51632-16-7]3-phenoxybenzyl bromide</strong> for 4 hours. After completion of the reaction, the dimethylformamide was distilled off in vacuo and the residue was taken up in 200 ml of methylene chloride. It was then extracted by shaking with twice 150 ml of water, the organic phase was dried over sodium sulphate and the solvent was stripped off in vacuo. The last remnants of solvent were removed by brief incipient distillation under 1 mm Hg at 60 C. bath temperature. 15 g (53.8% of theory) of 3'-phenoxy-benzyl 2,2-dimethyl-3-(2-phenylthio-2-chlorovinyl)-cyclopropane carboxylate were obtained as a yellow oil having a refractive index nD23 of 1.5948.
(1R,trans)-2,2-dimethyl-3-((cyclopropylmethoxyimino)methyl)cyclopropanecarboxylic acid[ No CAS ]
[ 51632-16-7 ]
3-phenoxybenzyl (1R,trans)-2,2-dimethyl-3-((cyclopropylmethoxyimino)methyl)cyclopropanecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EMBODIMENT 23 3-Phenoxybenzyl (1R,cis)-2,2-dimethyl-3-((cyclopropylmethoxyimino)methyl)cyclopropanecarboxylate Following a procedure similar to that of Embodiments 4 and 22 above, 2.3 g of <strong>[51632-16-7]3-phenoxybenzyl bromide</strong> was treated with 1.8 g of (1R,cis)-2,2-dimethyl-3-((cyclopropylmethoxyimino)methyl)cyclopropanecarboxylic acid to yield (a) 1.9 g of the desired carboxylate product, as a colorless oil, as a mixture of E- and Z-isomers; [alpha]D25 +12.5 (CHCl3; c=0.02 g/cc).
(1R,cis)-2,2-dimethyl-3-((allyloxyimino)methyl)cyclopropanecarboxylic acid[ No CAS ]
[ 51632-16-7 ]
3-phenoxybenzyl (1R,cis)-2,2-dimethyl-3-((allyloxyimino)methyl)cyclopropanecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In dichloromethane; ethyl acetate;
EMBODIMENT 4 (3-phenoxybenzyl (1R,cis)-2,2-dimethyl-3-((allyloxyimino)methyl)cyclopropanecarboxylate A solution of 3.7 g of <strong>[51632-16-7]3-phenoxybenzyl bromide</strong> and 2.8 g of (1R,cis)-2,2-dimethyl-3-((allyloxyimino)methyl)cyclopropanecarboxylic acid (prepared by a method similar to that shown in Embodiment I) and 1.4 g of triethylamine in 30 ml of ethyl acetate was refluxed for 21/2 hours. The reaction mixture was diluted with ether and washed with water. The ether phase was dried over magnesium sulfate, filtered and stripped to give an oil. This oil in methylene chloride was passed through a florisil column to give 2.5 g of the desired product as an oil [alpha]D25 +22.9 (CHCl; c=0.012 g/cc).
1-hydroxymethyl-1-(3-phenoxybenzyloxymethyl)cyclopropane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With tetra-(n-butyl)ammonium iodide; In tetrahydrofuran; ethyl acetate;
EXAMPLE 2 This Example illustrates the preparation of 1-hydroxymethyl-1-(3-phenoxybenzyloxymethyl)cyclopropane. A solution of 1,1-dihydroxymethylcyclopropane (3 g) in tetrahydrofuran (20 cm3) was added dropwise to a suspension of sodium hydride (0.35 g) in tetrahydrofuran (30 cm3). After effervescence has ceased, tetrabutylammonium iodide (1 g) was added to the grey suspension followed by a solution of <strong>[51632-16-7]3-phenoxybenzyl bromide</strong> (3.88 g) in tetrahydrofuran (15 cm3) at the ambient temperature and the mixture stirred for a further 2 hours. The mixture was poured into water and extracted with ethylacetate. The extracts were combined, dried over magnesium sulphate and concentrated by evaporation of the solvent, and the residual oil purified by column chromatography using a silica gel column eluding first with dichloromethane, followed then by ethylacetate, to give 1-hydroxymethyl-1-(3-phenoxybenzyloxymethyl)cyclopropane (1.7 g). 1 H nmr (CDCl3) ppm: 0.5 (s,4H); 2.45 (broad s,1H); 3.4 (s,2H); 3.5 (s,2H); 4.5 (s,2H); and 6.9-7.5 (m,9H).
1-(4-ethoxyphenyl)-2,2-difluorocyclopropane-1-methanol[ No CAS ]
3-phenoxybenzyl 1-(4-ethoxyphenyl)-2,2-difluorocyclopropylmethyl ether[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In N-methyl-acetamide; water;
PRODUCTION EXAMPLE 3 Synthesis of the Compound (25) 132 Milligrams (3.3 mmoles) of sodium hydride (as 60% oil suspension) was suspended in 5 ml of dimethylformamide, and to the resulting suspension was added dropwise a solution of 789 mg (3.0 mmole) of 3-Phenoxybenzyl bromide and 752 mg (3.3 mmole) of 1-(4-ethoxyphenyl)-2,2-difluorocyclopropyl-1-carbinol in 3 ml of dimethylformamide. Stirring was then continued at an inner temperature of 40 C. to 50 C. until the evolution of hydrogen came to an end. Thereafter, the reaction mixture was cooled to room temperature and stirred overnight. The reaction mixture was then poured into 50 ml of water and extracted with two 20-ml portions of ether. The ether layer was dried over anhydrous magnesium sulfate, and after removing ether by evaporation, the residue was separation-purified by column chromatography on silica gel to obtain 1.09 g of 3-phenoxybenzyl 1-(4-ethoxyphenyl)-2,2-difluorocyclopropylmethyl ether as a colorless liquid.
With pyridine; In 5,5-dimethyl-1,3-cyclohexadiene; water;
EXAMPLE 2 52.6 g of the brominated product of m-tolylphenyl ether containing 26.3 g of <strong>[51632-16-7]3-phenoxybenzyl bromide</strong> was added to a mixed solution of 100 ml of xylene and 50 ml of water, and then 11.9 g of pyridine was added thereto. The mixture was heated to 70 to 75C, kept at the same temperature for 3 hours while stirring and then cooled to room temperature (about 20 - 30C). The lower aqueous layer which separated was removed, washed with a small amount of xylene, evaporated and then dried under a reduced pressure to obtain 34.5 g of colorless, crystalline 3-phenoxybenzyl pyridinium bromide (m.p. 120 - 121C).
EXAMPLE 1 37.5 g of the brominated product of m-tolylphenyl ether containing 26.3 g of <strong>[51632-16-7]3-phenoxybenzyl bromide</strong> was mixed with 100 ml of toluene, and then a solution of 15.1 g of triethylamine in 30 ml of toluene was added dropwise thereto. After the additon, the mixture was maintained at 90 to 100C for 1 hour while stirring and then cooled. The separated crystals were filtered out, washed with toluene and then dried under a reduced pressure to obtain 35.8 g of 3-phenoxybenzyl triethyl ammonium bromide (m.p. 160 - 163C).
2-(2,2-Dichlorovinyl)-3-spirobutane-cyclopropane carboxylic acid[ No CAS ]
[ 51632-16-7 ]
3-phenoxybenzyl-2-(2,2-dichlorovinyl)-3-spirobutane-cyclopropane-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
20%
With potassium carbonate; In hexane; acetone;
EXAMPLE III 3-Phenoxybenzyl-2-(2,2-dichlorovinyl)-3-spirobutanecyclopropane-1-carboxylate 2-(2,2-Dichlorovinyl)-3-spirobutane-cyclopropane carboxylic acid (0.5g), <strong>[51632-16-7]3-phenoxybenzyl bromide</strong> (0.6g) and potassium carbonate (0.2g) were mixed together in acetone (50 ml) and slurried for 24 hours. The mixture was filtered and the filtrate evaporated. The residue obtained was separated into the respective cis- and trans isomer by chromotography on silica gel using a 1:20 mixture of acetone in hexane as eluent. The products were obtained as oils. Analysis (+-) Trans-isomer (n D21 = 1.5707): yield 45% Calculated for C22 H20 O3 NCl2: C 65.5; H 5.0; Cl 17.6% Found: C 65.6; H 5.2; Cl 17.3% (+-) Cis-isomer (n D19 = 1.5759): yield 20% Calculated for C22 H20 O3 NCl2: C 65.5; H 5.0; Cl 17.6% Found: C 65.7; H 4.9; Cl 18.0%
EXAMPLE 1 This Example illustrates the preparation of the N-(3-phenoxybenzyl)hexamethylenetetraminium bromide. 3-Phenoxybenzyl bromide (2.0 g) was carefully added to a stirred solution of hexamethylene tetramine (2.1 g) in carbon tetrachloride (20 ml) at the ambient temperature. The precipitate which formed was collected after a period of five minutes by filtration and washed with acetone to yield N-(3-phenoxybenzyl)hexamethylenetetraminium bromide.
1-(4-fluorophenyl)-2-methylpropan-1-one oxime[ No CAS ]
[ 51632-16-7 ]
[ 26393-91-9 ]
Yield
Reaction Conditions
Operation in experiment
In N-methyl-acetamide; methanol; dimethylformanide; toluene;
EXAMPLE 6 1-(4-fluorophenyl)-2-methyl-1-propanone, O-(3-phenoxyphenylmethyl)oxime (6) 1.8 g of 1-(4-fluorophenyl)-2-methyl-1-propanone oxime in 10 ml of 20% dimethylformanide in toluene was added to 0.5 g of sodium hydride (1.0 of a 50% dispersion in oil) in 20 ml of 20% dimethylformamide in toluene at 70-80 over a 10-minute period. A solution of 2.9 g of <strong>[51632-16-7]3-phenoxybenzyl bromide</strong> in 15 ml of 20% dimethylformamide in toluene was added over a 5-minute period. The mixture was stirred at 100-110 for 3 hours, and then was cooled to room temperature. 5 ml of methanol was added and the mixture was poured onto a mixture of ice and hydrochloric acid. The resulting mixture was extracted with diethyl ether. The extract was washed with 10% sodium bicarbonate solution, and dried (Na2 SO4). The solvent was evaporated and the residue was chromatographed on silica gel using toluene as eluent. Two fractions were obtained. After removal of the solvent, the first fraction was an oil, (6A), identified as a 3:1 mixture of the E and Z isomers of 6, n22D (refractive index) = 1.5740. On removal of solvent from the second fraction, an oil (6B) was obtained and identified as a 1:1 mixture of the E and Z isomers of 6, n22D = 1.5712.
With sodium bicarbonate; sodium chloride; triethylamine; In N-methyl-acetamide;
EXAMPLE 6 Into a solution of 3.9 g alpha-(4-methylanilino)-isovaleric acid in 50 ml of dimethylformamide were added 5.4 g of 3-phenoxybenzylbromide. 4 ml of triethylamine were added into the mixture with stirring and the reaction was carried out at 60-80 C. for 3 hrs. The reaction mixture was dissolved into ether and the ethereal solution was thoroughly washed with aqueous solution of sodium hydrogen carbonate and then with aqueous solution of sodium chloride. After drying the solution over sodium sulfate, ether was removed under reduced pressure to yield 7.2 g of 3'-phenoxybenzyl alpha-(4-methylanilino)-isovalerate.
4.85 g of 3B, 5.25 g of <strong>[51632-16-7]3-phenoxybenzyl bromide</strong> and 50 ml of tetrahydrofuran were mixed. 0.53 g of sodium hydride was added to the stirred mixture at room temperature. Heat of reaction raised the mixture temperature to about 35. The mixture was refluxed for 2.5 hours, then filtered. The filtrate was stripped of solvent. The resulting liquid product was dissolved in methylene chloride; the solution was washed with water, dried (MgSO4) and stripped of solvent.
2-(2-benzothienyl)-3-methylbutanoic acid[ No CAS ]
[ 51632-16-7 ]
[ 584-08-7 ]
[ 75894-09-6 ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran; N,N,N,N,N,N-hexamethylphosphoric triamide;
(D) A mixture of 2-(2-benzothienyl)-3-methylbutanoic acid (1 g, 4.3 mmol), <strong>[51632-16-7]3-phenoxybenzyl bromide</strong> (1.1 g, 4.3 mmol) and K2 CO3 (8.6 mmol) in 25 ml of THF/HMPA (1:1) is stirred overnight. The reaction is worked up by diluting with ether, washing with water, drying over Na2 SO4, and solvent removed to yield 3-phenoxybenzyl 2-(2benzothienyl)-3-methylbutanoate which can be further purified by preparing thin layer chromatography eluding with 5 percent ether/hexane.
2-(5-chloro-2-benzothienyl)-3-methylbutanoic acid[ No CAS ]
[ 51632-16-7 ]
[ 584-08-7 ]
3-phenoxybenzyl 2-(5-chloro-2-benzothienyl)-3-methylbutanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In N,N-dimethyl-formamide;
EXAMPLE 6 A mixture of 20 ml DMF, 2-(5-chloro-2-benzothienyl)-3-methylbutanoic acid (0.5 g), K2 CO3 (0.51 g) and <strong>[51632-16-7]3-phenoxybenzyl bromide</strong> (0.44 g) is stirred, under nitrogen, for about 15 hours. The mixture is then taken up in ether, washed with water and brine, dried over Na2 SO4 and solvent removed. The crude product is plated developing with 10% ether/hexane to give 3-phenoxybenzyl 2-(5-chloro-2-benzothienyl)-3-methylbutanoate.
ethyl 2-isopropyl-4-(o-chlorophenyl)-3-butenoate[ No CAS ]
m-phenoxybenzyl 2-isopropyl-4-(o-chlorophenyl)-3-butenoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 7 The process of Example 3 is repeated using o-chlorophenylacetaldehyde to prepare ethyl 2-isopropyl-4-(o-chlorophenyl)-3-butenoate, which is hydrolyzed (potassium hydroxide-water/methanol) to the acid, 2-isopropyl-4-(o-chlorophenyl)-3-butenoic acid. The acid is reacted with <strong>[51632-16-7]m-phenoxybenzyl bromide</strong> as in Example 1 to yield m-phenoxybenzyl 2-isopropyl-4-(o-chlorophenyl)-3-butenoate. MS m/e 420 (M+).
With ammonia; thiourea; In water; isopropyl alcohol;
(c) Manufacture of m-phenoxybenzylmercaptan A solution of 30.8 g of <strong>[51632-16-7]m-phenoxybenzyl bromide</strong> in 70 ml of isopropanol is reacted with 9.5 g of thiourea in 30 ml of water and the reaction mixture is refluxed briefly. After cooling, 25 ml of a 25% ammonia solution are added and the mixture is heated briefly to reflux and then allowed to cool, whereupon it is acidified with 18% hydrochloric acid and extracted with methylene chloride. The extract is dried over magnesium sulfate and concentrated, affording the compound of the formula STR7 with a boiling point of 114-116 C.'0.05 mm Hg.
With potassium carbonate; In N-methyl-acetamide; water;
EXAMPLE 2 To 12 g of 3-benzoylpropionic acid and 9.3 g of potassium carbonate in 100 ml of dimethylformamide (DMF), under nitrogen, is added <strong>[51632-16-7]m-phenoxybenzyl bromide</strong> (17.1 g). The reaction is stirred about 4 hr and then water added followed by extraction with ether. The combined extracts are washed with water, saturated sodium chloride, dried over calcium sulfate and rotoevaporated to give m-phenoxybenzyl 3-benzoylpropionate which can be further purified by prep. TLC eluding with 15% ethyl acetate/hexane.
3-(p-chlorophenyl)-1,2-difluoro-4-methyl-1-pentene[ No CAS ]
[ 51632-16-7 ]
4-(p-Chlorophenyl)-2,3-difluoro-5-methyl-1-(m-phenoxyphenyl)-2-hexene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With n-butyllithium;Zinc chloride; tetrakis(triphenylphosphine)palladium (0); In tetrahydrofuran; hexane; pentane;
EXAMPLE 5: Preparation of 4-(p-Chlorophenyl)-2,3-difluoro-5-methyl-1-(m-phenoxyphenyl)-2-hexene, (E) A solution of 3-(p-chlorophenyl)-1,2-difluoro-4-methyl-1-pentene (0.69 g, 0.003 mol) in tetrahydrofuran is cooled to -70C, treated with a 2.5 M solution of n-butyllithium in hexane (1.2 mL), stirred at -60C for 1 hour, treated with a 0.5 M solution of zinc chloride in tetrahydrofuran (6 mL), stirred at -60C for 1 hour, treated sequentially with a solution of tetrakis(triphenylphosphine)palladium(0) (0.081 g) in tetrahydrofuran and a solution of alpha-bromo-m-tolyl phenyl ether (0.789 g, 0.003 mol) in tetrahydrofuran, stirred at room temperature overnight, diluted with water, acidified with 10% hydrochloric acid, and extracted with methylene chloride. The combined organic extracts are washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuoto obtain an oil. Column chromatography of the oil using silica gel and pentane affords an oil which is purified by Kugelrohr distillation to give the title product as a pale, yellow oil (0.46 g) which is identified by NMR spectral analyses.
With n-butyllithium;Zinc chloride; tetrakis(triphenylphosphine)palladium (0); In tetrahydrofuran; hexane; pentane;
EXAMPLE 30 Preparation of 4-(p-Chlorophenyl)-2,3-difluoro-5-methyl-1-(m-phenoxyphenyl)-2-hexene (E)- A solution of 3-(p-chlorophenyl)-1,2-difluoro-4-methyl-1-pentene (0.69 g, 0.003 mol) in tetrahydrofuran is cooled to -70 C, treated with a 2.5 M solution of n-butyllithium in hexane (1.2 mL), stirred at -60 C for 1 hour, treated with a 0.5 M solution of zinc chloride in tetrahydrofuran (6 mL), stirred at -60 C for 1 hour, treated sequentially with a solution of tetrakis(triphenylphosphine)palladium(0) (0.081 g) in tetrahydrofuran and a solution of alpha-bromo-m-tolyl phenyl ether (0.789 g, 0.003 mol) in tetrahydrofuran, stirred at room temperature overnight, diluted with water, acidified with 10% hydrochloric acid, and extracted with methylene chloride. The combined organic extracts are washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuoto obtain an oil. Column chromatography of the oil using silica gel and pentane affords an oil which is purified by Kugelrohr distillation to give the title product as a pale, yellow oil (0.46 g) which is identified by NMR spectral analyses.
With n-butyllithium;Zinc chloride; tetrakis(triphenylphosphine)palladium (0); In tetrahydrofuran; hexane; pentane;
EXAMPLE 30 Preparation of 4-(p-Chlorophenyl)-2,3-difluoro-5-methyl-1-(m-phenoxyphenyl)-2-hexene, (E)- A solution of 3-(p-chlorophenyl)-1,2-difluoro-4-methyl-1-pentene (0.69 g, 0.003 mol) in tetrahydrofuran is cooled to -70 C., treated with a 2.5 M solution of n-butyllithium in hexane (1.2 mL), stirred at -60 C. for 1 hour, treated with a 0.5 M solution of zinc chloride in tetrahydrofuran (6 mL), stirred at -60 C. for 1 hour, treated sequentially with a solution of tetrakis(triphenylphosphine)palladium(0) (0.081 g) in tetrahydrofuran and a solution of alpha-bromo-m-tolyl phenyl ether (0.789 g, 0.003 mol) in tetrahydrofuran, stirred at room temperature overnight, diluted with water, acidified with 10% hydrochloric acid, and extracted with methylene chloride. The combined organic extracts are washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain an oil. Column chromatography of the oil using silica gel and pentane affords an oil which is purified by Kugelrohr distillation to give the title product as a pale, yellow oil (0.46 g) which is identified by NMR spectral analyses.
4-trifluoromethoxy-β,β-dimethylatropic acid[ No CAS ]
P2 O5[ No CAS ]
[ 51632-16-7 ]
[ 75391-55-8 ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In acetone; benzene;
EXAMPLE 35 Preparation of m-Phenoxybenzyl 4-trifluoromethoxy-alpha-isopropenylphenylacetate To a solution of 4-trifluoromethoxy-beta,beta-dimethylatropic acid (13.9 g, 0.05 mol) and triethylamine (6.1 g, 0.06 mol) in acetone (100 ml) is added m-phenoxybenzylbromide (13.2 g, 0.05 mol) at ice bath temperature and then refluxed for 4 hours. The mixture is poured into cold dilute hydrochloric acid and extracted with ether. The ether layer is washed with 10% hydrochloric acid, water, dried (Na2 SO4) and evaporated to give the hydroxy ester which is dehydrated with P2 O5 in benzene at 80 C. for 18 hours. Filtration and removal of the solvent gives the crude ester. Purification of the material by dry column chromatography with silica gel using 50:50 methylene chloride-hexanes as solvent gives the product as pale yellow gum.
With sodium bicarbonate; sodium chloride; triethylamine; In N-methyl-acetamide;
EXAMPLE 6 Into a solution of 3.5 g alpha-(3-butenylamino)-isovaleric acid in 50 ml of dimethylformamide were added 5.4 g of 3-phenoxybenzylbromide. 4 ml of triethylamine were added into the mixture with stirring and the reaction was carried out at 60-80 C. for 3 hrs. The reaction mixture was dissolved into ether and the ethereal solution was thoroughly washed with aqueous solution of sodium hydrogen carbonate and then with aqueous solution of sodium chloride. After drying the solution over sodium sulfate, ether was removed under reduced pressure to yield 6.1 g of 3'-phenoxybenzyl alpha-(3-butenylamino)-isovalerate.
m-phenoxybenzyl 3-(2,2,2-trifluoroethoxy)-2,2-dimethylcyclopropanecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide;
B. To 10 ml DMF is added 0.88 g 3-(2,2,2-trifluoroethoxy)-2,2-dimethylcyclopropanecarboxylic acid (4.l4 mmol) and 1.146 g potassium carbonate (8.29 mmol), after which is added 12 g <strong>[51632-16-7]m-phenoxybenzyl bromide</strong>. This mixture is stirred under nitrogen for 15 hr. The reaction mixture is extracted with ether and the ether phase is washed with water (3X) and brine, and dried over sodium sulfate. The solvent is then removed to yield m-phenoxybenzyl 3-(2,2,2-trifluoroethoxy)-2,2-dimethylcyclopropanecarboxylate, MS m/e 394.1 (M+).
3-phenylthio-2,2-dimethylcyclopropanecarboxylic acid[ No CAS ]
[ 51632-16-7 ]
m-phenoxybenzyl 3-phenylthio-2,2-dimethylcyclopropanecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Using the method of Example 3, the above product is hydrolyzed to 3-phenylthio-2,2-dimethylcyclopropanecarboxylic acid, which is then reacted with <strong>[51632-16-7]m-phenoxybenzyl bromide</strong> to yield m-phenoxybenzyl 3-phenylthio-2,2-dimethylcyclopropanecarboxylate.
With sodium hydride; In 1,4-dioxane; N,N-dimethyl-formamide; at 0 - 20℃;
Amide 14H (53 mg, 99 mumol) was added to a flamed dried round bottom flask under nitrogen. The amide was dissolved with 2.6 mL of 1 : 1 DMF:dioxane. The solution was cooled to 0 C with an ice bath. Sodium hydride (60%, 12 mg, 298 mumol) was added at once to the amide solution and stirred at 0 C for 30 minutes. The ice bath was removed and stirred at room temperature overnight. LCMS confirmed the formation of the alkylated product. Solvent was removed under vacuum. To the residue, 25% TFA/DCM (3 mL) was slowly added, and the solution was stirred at room temperature for 3 hours. Solvent was removed under vacuum and the residue was redissolved in methanol (2 mL) and purified on a preparative LCMS (acetonitrile: water) to obtain 72 mg (67%) of the TFA salt of 14J.
With sodium hydride; In 1,4-dioxane; N,N-dimethyl-formamide; at 0 - 20℃;
Amide 13 A (79 mg, 147 mumol) was added to a flamed dried round bottom flask under nitrogen and dissolved with 3.9 mL of 1 : 1 DMF:dioxane. The solution was cooled to 0 C with an ice bath. Sodium hydride (60%, 18 mg, 442 mumol) was added at once to the amide solution and stirred at 0 C for 30 minutes. The ice bath was removed and the reaction mixture was continuously stirred at room temperature overnight. LCMS confirmed the formation of the alkylated product. Solvent was removed under vacuum (Step 1).[0391] To the residue, 25% TFA/DCM (3 mL) was slowly added and the solution was stirred at room temperature for 3 hours. Solvent was removed under vacuum and the residue was redissolved in methanol (2 mL) and purified on a PREP LCMS (acetonitrile: water) to obtain 72 mg (45%) of the TFA salt of 13C.
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