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Product Details of [ 40786-69-4 ]

CAS No. :40786-69-4 MDL No. :MFCD00068616
Formula : C11H14O3 Boiling Point : -
Linear Structure Formula :- InChI Key :QGGRBWUQXAFYEC-UHFFFAOYSA-N
M.W : 194.23 Pubchem ID :2775198
Synonyms :

Calculated chemistry of [ 40786-69-4 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 14
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.36
Num. rotatable bonds : 3
Num. H-bond acceptors : 3.0
Num. H-bond donors : 2.0
Molar Refractivity : 55.26
TPSA : 57.53 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) : -5.5 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.22
Log Po/w (XLOGP3) : 2.79
Log Po/w (WLOGP) : 2.25
Log Po/w (MLOGP) : 1.42
Log Po/w (SILICOS-IT) : 2.39
Consensus Log Po/w : 2.21

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.92
Solubility : 0.233 mg/ml ; 0.0012 mol/l
Class : Soluble
Log S (Ali) : -3.65
Solubility : 0.043 mg/ml ; 0.000222 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.78
Solubility : 0.319 mg/ml ; 0.00164 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.61

Safety of [ 40786-69-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 40786-69-4 ]

* 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 [ 40786-69-4 ]

[ 40786-69-4 ] Synthesis Path-Downstream   1~101

  • 1
  • [ 40786-69-4 ]
  • [ 109-64-8 ]
  • [ 40786-20-7 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; potassium iodide In acetone Heating;
14 3-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-1-bromopropane STR16 EXAMPLE 14 3-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-1-bromopropane STR16 Using the procedure essentially of Example 1 and methyl ethyl ketone as the solvent, 50 g (0.257 mole) of 2,4-dihydroxy-3-n-propylacetophenone and 52 ml (0.51 mole) of 1,3-dibromopropane gave 54 g (67%) of the title compound as a low melting solid, mp 38°-40°. Calc: C, 53.35; H, 6.08; Found; C, 53.11, H, 5.95.
With sodium hydroxide In water 8.a a. a. 4-(3-Bromopropoxy)-2-hydroxy-3propylacetophenone A solution of 7.2 parts of sodium hydroxide in 100 parts of water was added slowly over one hour to a stirred, refluxing mixture of 144 parts of 1,3-dibromopropane, 35 parts of 2,4-dihydroxy-3-propylacetophenone, and 300 parts of water. The mixture was heated for 5 hours and then stirred at room temperature overnight. The organic phase was separated, and the aqeuous phase was extracted with chloroform. The organic layers were combined and evaporated to an oil which was distilled to give a fraction boiling at 32- 36/0.02 mm., which was mostly 1,3-dibromopropane, and a fraction boiling at 172°-180° 10.02 mm. which consisted of 23.5 parts of 4-(3-bromopropoxy)-2-hydroxy-3-propylacetophenone.
With potassium carbonate In acetone 9.1 EXAMPLE 9 (1) A mixture of 2,4-dihydroxy-3-propylacetophenone (2.7 g), 1,3-dibromopropane (2.8 ml) and potassium carbonate (1.9 g) in acetone (50 ml) was refluxed for 3 hours. Insoluble materials were filtered off, and the filtrate was concentrated. The resulting syrup was purified by means of a silica gel flash chromatography (chloroform-hexane=1:1) to give 3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl bromide (2.9 g) as colorless and transparent syrup. NMR(CDCl3)δ: 0.92(3H,t,j=7 Hz), 1.30-1.70(2H,m), 2.33 (2H,m), 2.54(3H,s), 2.63(2H,t,j=6 Hz), 3.60(2H,t,6 Hz), 4.18 (2H,t,j=6 Hz), 6.43(1H,d,j=9 Hz), 7.55(1H,d,9 Hz)

  • 2
  • [ 110-52-1 ]
  • [ 40786-69-4 ]
  • [ 92518-06-4 ]
YieldReaction ConditionsOperation in experiment
78% With potassium carbonate; potassium iodide In acetone for 18h; Heating;
With potassium carbonate; potassium iodide In acetone for 5h; Heating; Yield given;
R.12 Reference Example 12 STR40 By following the same procedure as Reference Example 11 using 1 g of 2,4-dihydroxy-3-propylacetophenone and 4.5 g of 1,4-dibromobutane as starting materials followed by purification by silica gel column chromatography (Eluant: toluene), 1.3 g of 4-(4-bromobutoxy)-2-hydroxy-3-propylacetophenone was obtained as an oily product. Nuclear magnetic resonance spectra (CDCl3, TMS internal standard, ppm)
  • 3
  • [ 2417-73-4 ]
  • [ 40786-69-4 ]
  • 2-[(4-Acetyl-3-hydroxy-2-propylphenoxy) methyl]benzoic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
78% 73 Preparation of 2-[(4-Acetyl-3-hydroxy-2-propylphenoxy) methyl]benzoic acid methyl ester EXAMPLE 73 Preparation of 2-[(4-Acetyl-3-hydroxy-2-propylphenoxy) methyl]benzoic acid methyl ester 1-(2,4-dihydroxy-3-propylphenyl)ethanone was allowed to react with methyl 2-bromomethylbenzoate according to the procedure of Example 69 and the product was purified by recrystallization from hexane to give 2-[4-acetyl-3-hydroxy-2-propylphenoxy)methyl]benzoic acid methyl ester, the title compound, m.p. 90°-93°, in 78% yield. Analysis Calculated for C20 H22 O5: C, 70.16, H, 6.48. Found: C, 69.97; H, 6.36.
With potassium carbonate In acetone Heating;
  • 4
  • [ 111-24-0 ]
  • [ 40786-69-4 ]
  • [ 99453-85-7 ]
YieldReaction ConditionsOperation in experiment
22% With potassium carbonate; potassium iodide In acetone for 18h; Heating;
128 g (73%) With potassium carbonate In <i>N</i>-methyl-acetamide; hexane; ethyl acetate 1 5-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-1-bromopentane STR3 EXAMPLE 1 5-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-1-bromopentane STR3 120 g (0.61 mole) of 2,4-dihydroxy-3-n-propylacetophenone, 284 g (1.23 mole) of 1,5-dibromopentane, and 128 g (0.93 mole) anhydrous potassium carbonate were stirred vigorously in 2 l of dry dimethylformamide for 6 hours in a 5 l 3 neck round bottom flask fitted with drying tube, glass stopper, and mechanical stirrer. The suspended solids were removed by filtration and the solvent removed by rotoevaporation at reduced pressure. The brown, oily residue was dissolved in 1 l of 10% ethyl acetate/hexane and insoluble solids were removed by filtration. The filtrate was concentrated by rotoevaporation to a viscous oil that was purified by high pressure liquid chromatography to give 128 g (73%) of the title compound, as a colorless oil. Calc: C, 55.99; H, 6.75; Br, 23.28; Found: C, 55.72; H, 6.85; Br, 23.51.
With potassium carbonate In <i>N</i>-methyl-acetamide; ethyl acetate n-hexane 4 Preparation 4 Preparation 4 4-(5-bromopentoxy)-2-hydroxy-3-propylacetophenone STR11 A mixture of 120 g (0.61 mole) of 2,4-dihydroxy-3-propylacetophenone, 284 g (1.23 mole) of 1,5-dibromopentane, and 128 g (0.93 mole) of anhydrous potassium carbonate in 2 l of dimethylformamide was stirred vigorously for six hours at room temperature. Insolubles were removed by filtration and the filtrate was concentrated in vacuo. The oily residue was redissolved in 1 l of 10% ethyl acetate-hexane, refiltered, concentrated to dryness, and purified by high performance chromatography on silica gel. The title compound was obtained as 128 g of an analytically pure colorless oil. Analysis. Calcd. for C16 H23 O3 Br: C, 55.99; H, 6.75; Br, 23.28. Found: C, 55.72; H, 6.85; Br, 23.51.
R.13 Reference Example 13 STR41 By following the same procedure as Reference Example 12 using 1 g of 2,4-dihydroxy-3-propylacetophenone and 4.7 g of 1,5-dibromopentane as the raw materials, 1.3 g of 4-(5-bromopentyloxy)-2-hydroxy-3-propylacetophenone was obtained as an oily product. Nuclear magnetic resonance spectra (CDCl3, TMS internal standard, ppm)

  • 5
  • [ 38987-00-7 ]
  • [ 40786-69-4 ]
YieldReaction ConditionsOperation in experiment
palladium/charcoal; In ethanol; hydrogen; Step C: 2,4-Dihydroxy-3-propylacetophenone Dissolve 9.6 gm of 3-allyl-2,4-dihydroxyacetophenone in 100 ml of ethanol; flush with nitrogen and add 0.5 gm of 5% palladium/charcoal catalyst. Hydrogenate in a Parr apparatus at room temperature until 45 p.s.i. of hydrogen is taken up. Filter and strip the filtrate to dryness to obtain the title product. (mp 125-127 C.)
  • 6
  • [ 40786-69-4 ]
  • [ 628-20-6 ]
  • [ 92518-31-5 ]
YieldReaction ConditionsOperation in experiment
83% With potassium carbonate; potassium iodide In butanone for 72h;
  • 7
  • [ 40786-69-4 ]
  • [ 2009-83-8 ]
  • [ 106627-20-7 ]
YieldReaction ConditionsOperation in experiment
20% With potassium carbonate In butanone for 72h; Heating;
With hydrogenchloride; potassium carbonate In butanone 42 6-(4-Acetyl-3-hydroxy-2-propylphenoxy)-1-hexanol EXAMPLE 42 6-(4-Acetyl-3-hydroxy-2-propylphenoxy)-1-hexanol A solution of 10 g. of 2,4-dihydroxy-3-propylacetophenone, 8 g. of potassium carbonate, and 7.1 g. of 6-chloro-1-hexanol in 50 ml. of methyl ethyl ketone was heated to reflux overnight. Upon cooling, dilute hydrochloric acid was added and the resulting organic layer was separated, dried over sodium sulfate, and evaporated to dryness. The residue was purified by chromatography giving 2.87 g. of the title product as an oily solid. Analysis: C17 H26 O4: Calc.: C, 69.36; H, 8.90. Found: C, 69.09; H, 8.56.
  • 8
  • [ 40786-69-4 ]
  • [ 6628-78-0 ]
  • [ 92518-30-4 ]
YieldReaction ConditionsOperation in experiment
81% With potassium carbonate; potassium iodide In butanone for 72h; Heating;
  • 9
  • [ 40786-69-4 ]
  • [ 5454-83-1 ]
  • [ 106627-38-7 ]
YieldReaction ConditionsOperation in experiment
66% With potassium carbonate In N,N-dimethyl-formamide 7 Preparation of 5-(4-Acetyl-3-hydroxy-2-propylphenoxy)pentanoic acid methyl ester EXAMPLE 7 Preparation of 5-(4-Acetyl-3-hydroxy-2-propylphenoxy)pentanoic acid methyl ester A mixture of 2.92 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.91 g of methyl 5-bromopentanoate and 3.1 g of anhydrous potassium carbonate in 35 ml of anhydrous dimethyl formamide was stirred and heated at 75° for 16 hours. The usual workup followed by chromatography on 350 g of silica gel and elution with 5% ethyl acetate-toluene gave 3.07 g (66% yield) of 5-(4-Acetyl-3-hydroxy-2-propylphenoxy)pentanoic acid methyl ester, the titled compound, as an oil. Analysis Calculated for C17 H24 O5: C, 66.21; H, 7.85. Found: C, 66.39; H, 7.80.
66% With potassium carbonate In N,N-dimethyl-formamide 19 5-(4-Acetyl-3-hydroxy-2-propylphenoxy)pentanoic acid methyl ester EXAMPLE 19 5-(4-Acetyl-3-hydroxy-2-propylphenoxy)pentanoic acid methyl ester A mixture of 2.92 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.91 g of methyl 5-bromopentanoate and 3.1 g of anhydrous potassium carbonate in 35 ml of anhydrous dimethyl formamide was stirred and heated at 75° for 16 hours. The usual workup followed by chromatography on 350 g of silica gel and elution with 5% ethyl acetate-toluene gave 3.07 g (66% yield) of 5-(4-Acetyl-3-hydroxy-2-propylphenoxy) pentanoic acid methyl ester, the titled compound, as an oil. Analysis Calculated for C17 H24 O5: C, 66.21; H, 7.85. Found: C, 66.39; H, 7.80.
66% With potassium carbonate In N,N-dimethyl-formamide 52 Preparation of 5-(4-Acetyl-3-hydroxy-2-propylphenoxy) pentanoic acid methyl ester EXAMPLE 52 Preparation of 5-(4-Acetyl-3-hydroxy-2-propylphenoxy) pentanoic acid methyl ester A mixture of 2.92 g of 1-(2,4-dihydroxy-3-propylphenyl) ethanone, 2.91 g of methyl 5-bromopentanoate and 3.1 g of anhydrous potassium carbonate in 35 ml of anhydrous dimethyl formamide was stirred and heated at 75° for 16 hours. The usual workup followed by chromatography on 350 g of silica gel and elution with 5% ethyl acetate-toluene gave 3.07 g (66% yield) of 5-(4-Acetyl-3-hydroxy-2-propylphenoxy) pentanoic acid methyl ester, the titled compound, as an oil. Analysis Calculated for C17 H24 O5: C, 66.21; H, 7.85. Found: C, 66.39; H, 7.80.
32% With potassium carbonate; potassium iodide In acetone for 18h; Heating;

  • 10
  • [ 40786-69-4 ]
  • [ 2969-81-5 ]
  • [ 88420-31-9 ]
YieldReaction ConditionsOperation in experiment
54% With potassium carbonate In N,N-dimethyl-formamide at 75℃; for 12h;
54% With potassium carbonate In water; N,N-dimethyl-formamide 5 Preparation of 4-(4-Acetyl-3-hydroxy-2-propylphenoxy)butanoic acid ethyl ester EXAMPLE 5 Preparation of 4-(4-Acetyl-3-hydroxy-2-propylphenoxy)butanoic acid ethyl ester A mixture of 2.91 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.91 g of ethyl 4-bromobutyrate and 3.1 g of anhydrous potassium carbonate in 35 ml of anhydrous dimethyl formamide was stirred and heated at 75° for 12 hours. The solvent was removed in vacuo, the residue was treated with water and the product was extracted with ethyl acetate. The dried (over magnesium sulfate) extract was concentrated in vacuo and the crude product was purified by chromatography on 200 g of silica gel. Elution with 5% ethyl acetate-toluene gave 2.55 g (54% yield) of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butanoic acid ethyl ester, the titled compound, as an oil. Analysis Calculated for C17 H24 O5: C, 66.21; H, 7.84. Found: C, 66.33; H, 8.00.
54% With potassium carbonate In water; N,N-dimethyl-formamide 50 Preparation of 4-(4-Acetyl-3-hydroxy-2-propylphenoxy) butanoic acid ethyl ester. EXAMPLE 50 Preparation of 4-(4-Acetyl-3-hydroxy-2-propylphenoxy) butanoic acid ethyl ester. A mixture of 2.91 g of 1-(2,4-dihydroxy-3-propylphenyl) ethanone, 2.91 g of ethyl 4-bromobutyrate and 3.1 g of anhydrous potassium carbonate in 35 ml of anhydrous dimethyl formamide was stirred and heated at 75° for 12 hours. The solvent was removed in vacuo, the residue was treated with water and the product was extracted with ethyl acetate. The dried (over magnesium sulfate) extract was concentrated in vacuo and the crude product was purified by chromatography on 200 g of silica gel. Elution with 5% ethyl acetate-toluene gave 2.55 g (54% yield) of 4-(4-acetyl-3-hydroxy-2-propylphenoxy) butanoic acid ethyl ester, the titled compound, as an oil. Analysis Calculated for C17 H24 O5: C, 66.21; H, 7.84. Found: C, 66.33; H, 8.00.
With potassium carbonate In <i>N</i>-methyl-acetamide 18 Preparation of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butanoic acid ethyl ester EXAMPLE 18 Preparation of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butanoic acid ethyl ester A mixture of 15.0 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 15.0 g of ethyl 4-bromobutyrate, 16.0 g of anhydrous potassium carbonate in 200 ml of anhydrous dimethylformamide was stirred and heated at 75° for 24 hours. The solvent was removed in vacuo and the residue was purified by high pressure liquid chromatography using 2.5% ethyl acetate-toluene to yield 7.62 g of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butanoic acid ethyl ester as an oil.
With potassium carbonate In water; N,N-dimethyl-formamide R.3 Reference Example 3 STR31 A mixture of 1.42 g of 2,4-dihydroxy-3-propylacetophenone, 2 g of ethyl 4-bromobutyrate, 1.5 g of potassium carbonate, and 10 ml of N,N-dimethylformamide was stirred overnight at room temperature. After addition of 100 ml of water to the reaction mixture, the product was extracted with 30 ml of toluene. The extract was washed with water, dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue thus formed was applied to silica gel column chromatography and eluted with toluene to provide 1.5 g of ethyl 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butyrate as an oily product.

  • 11
  • [ 40786-69-4 ]
  • [ 14273-90-6 ]
  • [ 88420-36-4 ]
YieldReaction ConditionsOperation in experiment
90% With potassium carbonate In <i>N</i>-methyl-acetamide 29 Preparation of 6-(4-acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid methyl ester EXAMPLE 29 Preparation of 6-(4-acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid methyl ester A mixture of 5.0 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 5.4 g of methyl 6-bromohexanoate and 5.4 g of anhydrous potassium carbonate in 50 ml of anhydrous dimethylformamide was stirred and heated at 75° for 10 hours. The solvent was removed in vacuo and the residue was purified by column chromatography on 125 g of silica gel. Elution with 25% ethyl acetate-hexane gave 7.5 g (90% yield) of 6-(4-acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid methyl ester as an oil.
62% With potassium carbonate In N,N-dimethyl-formamide at 75℃; for 12h;
62% With potassium carbonate In N,N-dimethyl-formamide 9 Preparation of 6-(4-Acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid methyl ester EXAMPLE 9 Preparation of 6-(4-Acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid methyl ester A mixture of 2.72 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.72 g of methyl 6-bromohexanoate and 2.90 g of anhydrous potassium carbonate in 30 ml of anhydrous dimethyl formamide was stirred and heated at 75° for 7 hours. The usual workup followed by chromatography on 200 g of silica gel and elution with 10% ethyl acetate-toluene gave 2.77 g (62% yield) of 6-(4-Acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid methyl ester, the titled compound, as an oil. Analysis Calculated for C18 H26 O5: C, 67.06; H, 8.13. Found: C, 66.92; H, 8.25.
62% With potassium carbonate In N,N-dimethyl-formamide 54 Preparation of 6-(4-Acetyl-3-hydroxy-2-propylphenoxy) hexanoic acid methyl ester EXAMPLE 54 Preparation of 6-(4-Acetyl-3-hydroxy-2-propylphenoxy) hexanoic acid methyl ester A mixture of 2.72 g of 1-(2,4-dihydroxy-3-propylphenyl) ethanone, 2.72 g of methyl 6-bromohexanoate and 2.90 g of anhydrous potassium carbonate in 30 ml of anhydrous dimethyl formamide was stirred and heated at 75° for 7 hours. The usual workup followed by chromatography on 200 g of silica gel and elution with 10% ethyl acetate-toluene gave 2.77 g (62% yield) of 6-(4-Acetyl-3-hydroxy-2-propylphenoxy) hexanoic acid methyl ester, the titled compound, as an oil. Analysis Calculated for C18 H26 O5: C, 67.06; H, 8.13. Found: C, 66.92; H, 8.25.

  • 12
  • [ 40786-69-4 ]
  • [ 2417-72-3 ]
  • [ 87807-95-2 ]
YieldReaction ConditionsOperation in experiment
98% With potassium carbonate In acetone at 45℃; for 4h; 10 [ EXAMPLE 10] [N- [4- (4-ACETYL-3-HYDROXY-2-PROPYL-PHENOXYMETHYL)-BENZOYL]-METHANESULFONAMIDE] Potassium carbonate (2.2 g, 15.9 mmol) was added to a stirred solution of [1- (2,] 4- dihydroxy-3-propyl-phenyl) -ethanone (2.0 g, 10.3 mmol) and [METHYL-4- (BROMOMETHYL)-BENZOATE] (2.6 g, 11.3 mmol) in acetone (100 ml) at [45°C.] The reaction mixture was stirred for four hours and concentrated in vacuo. The resulting oil was washed with brine (2 x 80 ml) and extracted with dichloromethane (2 x 100 ml). The combined organic extracts were dried over [NA2SO4,] filtered and concentrated in vacuo to give a yellow solid. The solid was purified by column chromatography on silica gel (eluting 10-90% ethyl acetate/hexanes) to give [4- (4-ACETYL-3-] hydroxy-2-propyl-phenoxymethyl) -benzoic acid methyl ester as a white solid (3.4 g, 98%). A mixture of [4- (4-ACETYL-3-HYDROXY-2-PROPYL-PHENOXYMETHYL)-BENZOIC] acid methyl ester (3.4 g, 10.0 mmol), 1.0 N lithium hydroxide aqueous solution (50 ml) and tetrahydrofuran (50 ml) was heated to [75°C] for 18 hr and then cooled to rt. The reaction mixture was concentrated in vacuo and acidified to pH 5 with 6.0 N [HCL] aqueous solution. The mixture was washed with brine (200 ml) and extracted with ethyl acetate (2 x 100 ml). The organic layers were dried over [NA2SO4,] filtered and concentrated in vacuo to give [4- (4-ACETYL-3-HYDROXY-2-PROPYL-PHENOXYMETHYL)-] benzoic acid as a yellow solid (3.2 g, 100%). Freshly distilled oxalyl chloride (0.44 ml, 5.0 mmol) was added to a stirred solution [OF 4- (4-ACETYL-3-HYDROXY-2-PROPYL-PHENOXYMETHYL)-] benzoic acid (328 mg, 1.0 mmol) in dichloromethane (25 ml) at rt under nitrogen. Dimethylformamide (0.05 ml) was slowly added to the mixture until bubbling ceased. Mixture was allowed to stir until no starting material was observed by tlc and then concentrated in vacuo to give the acid chloride as a yellow solid. The acid chloride was dissolved in tetrahydrofuran (7.5 ml) and added in one portion to a cooled stirred solution of sodium hydride (120 mg, 3.0 mmol), methane sulfonamide (238 mg, 2.5 mmol) and tetrahydrofuran (5.0 ml) at [0°C.] The reaction mixture was allowed to warm to rt overnight and then carefully quenched with water. The solution was washed with brine (2 x 30 ml) and extracted with ethyl acetate (2 x 60 ml), filtered and concentrated in vacuo to give an oil. The oil was purified by column chromatography (eluting first with 50-100% ethyl acetate/hexanes followed by 5-20% methanol/ethyl acetate) to give [N- [4- (4-ACETYL-3-HYDROXY-2-PROPYL-PHENOXYMETHYL)-BENZOYL]-METHANESULFONAMIDE] as a yellow [FOAM.'H] NMR [(DMSO-D6,] 500 MHz) 12.86 (s, [1H),] 7.96 (d, 2H), 7.82 (d, 1H), 7.42 (d, 2H), 6.73 (d, 1H), 5.28 (s, 2H), 2.90 (s, 3H), 2.61 (m, 2H), 2.58 (s, 3H), 1.49 (m, 2H), 0.91 (t, 3H). MS (ESI): 406 (M + H) [+.]
69% With potassium carbonate In acetone for 15h; Heating;
  • 13
  • [ 40786-69-4 ]
  • [ 74733-27-0 ]
  • 4-(4-Acetyl-3-hydroxy-2-propyl-phenoxymethyl)-2-methoxy-benzoic acid methyl ester [ No CAS ]
  • 14
  • [ 40786-69-4 ]
  • [ 128577-48-0 ]
  • 4-(4-Acetyl-3-hydroxy-2-propyl-phenoxymethyl)-2-bromo-benzoic acid methyl ester [ No CAS ]
  • 15
  • [ 40786-69-4 ]
  • [ 104436-60-4 ]
  • 4-(4-Acetyl-3-hydroxy-2-propyl-phenoxymethyl)-3-methoxy-benzonitrile [ No CAS ]
  • 16
  • [ 40786-69-4 ]
  • [ 88738-86-7 ]
  • methyl 4-(4-acetyl-3-hydroxy-2-propylphenoxy)methylcinnamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In acetone Heating;
With potassium carbonate In acetone 16.c c. c. Methyl 4-(4-acetyl-3-hydroxy-2-propylphenoxy)methylcinnamate A mixture of 1.0 g (5.15 g) of 2,4-dihydroxy-3-propylacetophenone, 1.58 g (6.18 mmol) of methyl 4-bromomethylcinnamate and 0.85 g (6.18 mmol) of anhydrous potassium carbonate in 20 ml of acetone was stirred at reflux for 18 hours. Ether extraction gave 1.01 g of the title compound as a light yellow powder mp 121°-125° C.
  • 17
  • [ 40786-69-4 ]
  • [ 88089-94-5 ]
  • 4-(4-Acetyl-3-hydroxy-2-propyl-phenoxymethyl)-3-nitro-benzoic acid methyl ester [ No CAS ]
  • 18
  • [ 40786-69-4 ]
  • [ 102684-67-3 ]
  • 2-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)-pentoxy]benzaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
59% With potassium carbonate In acetone for 144h; Heating;
With sodium hydroxide; potassium carbonate In ethyl acetate; acetone 15.a (a) A mixture of this compound (11.1 mmoles), 4-acetyl-3-hydroxy-2-propyl phenol (11.62 mmoles) and potassium carbonate (5.55 mmoles) in acetone (30 ml) was refluxed for 5 days, stirred at room temperature for 2 days and then refluxed for 24 hours. The suspension was cooled to room temperature, filtered and the filtrate concentrated. The residue was dissolved in ethyl acetate and then washed with ice-cold 5% sodium hydroxide solution, water and brine. The dried solution was concentrated and the product flash chromatographed to give the desired product.
With sodium hydroxide; potassium carbonate In ethyl acetate; acetone 13.a (a) A mixture of this compound (11.1 mmoles), 4-acetyl-3-hydroxy-2-propyl phenol (11.62 mmoles) and potassium carbonate (5.55 mmoles) in acetone (30 ml) was refluxed for 5 days, stirred at room temperature for 2 days and then refluxed for 24 hours. The suspension was cooled to room temperature, filtered and the filtrate concentrated. The residue was dissolved in ethyl acetate and then washed with ice-cold 5% sodium hydroxide solution, water and brine. The dried solution was concentrated and the product flash chromatographed on silica gel and eluted with ethylacetate/hexane to give the desired product.
  • 19
  • [ 40786-69-4 ]
  • [ 56893-25-5 ]
  • 4-[2-(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-acetyl]-benzoic acid methyl ester [ No CAS ]
  • 20
  • [ 40786-69-4 ]
  • [ 104835-68-9 ]
  • [ 104835-59-8 ]
YieldReaction ConditionsOperation in experiment
79% With potassium carbonate In acetone for 20h; Heating;
  • 21
  • [ 40786-69-4 ]
  • [ 101463-93-8 ]
  • [ 101463-94-9 ]
YieldReaction ConditionsOperation in experiment
78% With potassium carbonate In acetone for 20h; Heating;
  • 22
  • [ 40786-69-4 ]
  • [ 88420-28-4 ]
  • [ 88420-01-3 ]
YieldReaction ConditionsOperation in experiment
59% With potassium carbonate In N,N-dimethyl-formamide; acetone for 17h; Heating;
4.95 g (59%) With potassium carbonate In <i>N</i>-methyl-acetamide; acetone 9 Preparation of [4-acetyl-3-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy]acetic acid ethyl ester EXAMPLE 9 Preparation of [4-acetyl-3-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy]acetic acid ethyl ester A mixture of 3.0 g of 1-[2,4-dihydroxy-3-propylphenyl)ethanone, 6.65 g of [4-acetyl-3-[(5-bromopentyl)oxy]-2-propylphenoxy]acetic acid ethyl ester and 4.3 g of anhydrous potassium carbonate in 100 ml of anhydrous acetone and 50 ml of anhydrous dimethylformamide was stirred at reflux for 24 hours. The reaction mixture was concentrated in vacuo to a red oil which was purified by high pressure liquid chromatography using 25% ethyl acetate-hexane to yield 4.95 g (59%) of [4-acetyl-3-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy] acetic acid ethyl ester as a yellow oil.
  • 23
  • [ 40786-69-4 ]
  • [ 88420-32-0 ]
  • [ 88420-04-6 ]
YieldReaction ConditionsOperation in experiment
76% With potassium carbonate In N,N-dimethyl-formamide; acetone for 17h; Heating;
6.42 g (76%) With potassium carbonate In <i>N</i>-methyl-acetamide; acetone 20 Preparation of 4-4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]butanoic acid ethyl ester EXAMPLE 20 Preparation of 4-4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]butanoic acid ethyl ester A mixture of 3.00 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 6.65 g of 4-[4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]butanoic acid ethyl ester and 4.30 g of anhydrous potassium carbonate in 100 ml of anhydrous acetone and 50 ml of anhydrous dimethylformamide was stirred at reflux for 19 hours. The solvent was removed in vacuo to give a red oil which was purified by high pressure liquid chromatography to yield 6.42 g (76%) of 4-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]butanoic acid ethyl ester as an oil.
  • 24
  • [ 40786-69-4 ]
  • [ 88420-45-5 ]
  • [ 88420-14-8 ]
YieldReaction ConditionsOperation in experiment
84% With potassium carbonate In N,N-dimethyl-formamide; acetone for 17h; Heating;
84% With potassium carbonate In <i>N</i>-methyl-acetamide; acetone 54 Preparation of 4-[4-acetyl-3-[[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyl]oxy]-2-propylphenoxy]butanoic acid ethyl ester EXAMPLE 54 Preparation of 4-[4-acetyl-3-[[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyl]oxy]-2-propylphenoxy]butanoic acid ethyl ester A mixture of 0.96 g (0.005 mole) of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.26 g (0.005 mole) of 4-[4-acetyl-3-[(5-bromopentyl)oxy]-2-propylphenoxy]butanoic acid ethyl ester and 1.36 g (0.010 mole) of anhydrous potassium carbonate in 40 ml of anhydrous acetone and 20 ml of anhydrous dimethylformamide was stirred at reflux for 17 hours. The solvents were removed in vacuo and the residue was purified by HPLC using 25% ethyl acetate-hexane to yield 2.36 g (84% yield) of 4-[4-acetyl-3-[[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyl]oxy]-2-propylphenoxy]butanoic acid ethyl ester as an oil.
  • 25
  • [ 40786-69-4 ]
  • [ 104835-63-4 ]
  • [ 88420-12-6 ]
YieldReaction ConditionsOperation in experiment
77% With potassium carbonate In N,N-dimethyl-formamide; acetone for 17h; Heating;
  • 26
  • [ 40786-69-4 ]
  • [ 88420-47-7 ]
  • [ 88420-16-0 ]
YieldReaction ConditionsOperation in experiment
82% With potassium carbonate In N,N-dimethyl-formamide; acetone for 17h; Heating;
  • 27
  • [ 40786-69-4 ]
  • [ 104835-65-6 ]
  • [ 88420-13-7 ]
YieldReaction ConditionsOperation in experiment
40% With potassium carbonate In N,N-dimethyl-formamide; acetone for 17h; Heating;
40% With potassium carbonate In acetone 51 Preparation of [4-acetyl-3-[2-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester EXAMPLE 51 Preparation of [4-acetyl-3-[2-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester A mixture of 2.55 g (0.005 mole) of [4-acetyl-3-[2-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester, 0.97 g (0.005 mole) of 1-(2,4-dihydroxy-3-propylphenyl)ethanone and 1.00 g (0.0062 mole) of anhydrous potassium carbonate in 60 ml of anhydrous acetone was stirred at reflux for 15 hours. An additional 0.5 g of potassium carbonate was added and reflux was continued for 15 hours. The solvent was removed in vacuo and the residue was chromatographed on 300 g of silica gel. Elution with 30% ethyl acetate-toluene gave 1.25 g (40% yield) of [4-acetyl-3-[2-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester as an oil.
  • 28
  • [ 40786-69-4 ]
  • [ 118684-32-5 ]
  • [ 118684-33-6 ]
  • 29
  • [ 40786-69-4 ]
  • [ 239074-27-2 ]
  • [4-(4-Acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-carbamic acid tert-butyl ester [ No CAS ]
  • 30
  • [ 40786-69-4 ]
  • [ 122444-36-4 ]
  • [ 122443-67-8 ]
YieldReaction ConditionsOperation in experiment
90% With potassium carbonate In acetonitrile for 17h; Heating;
  • 31
  • [ 40786-69-4 ]
  • [ 122444-39-7 ]
  • [ 122443-70-3 ]
YieldReaction ConditionsOperation in experiment
58.2% With potassium carbonate In acetonitrile for 18h; Heating;
  • 32
  • [ 40786-69-4 ]
  • [ 122443-89-4 ]
  • [ 122444-29-5 ]
YieldReaction ConditionsOperation in experiment
84.5% With potassium carbonate In N,N-dimethyl-formamide; acetone for 5.5h; Heating;
  • 33
  • [ 40786-69-4 ]
  • [ 122443-94-1 ]
  • [ 122444-31-9 ]
YieldReaction ConditionsOperation in experiment
78.8% With potassium carbonate In N,N-dimethyl-formamide; acetone for 5.5h; Heating;
  • 34
  • [ 40786-69-4 ]
  • [ 120268-18-0 ]
  • [ 120329-95-5 ]
YieldReaction ConditionsOperation in experiment
96.8% With potassium carbonate In N,N-dimethyl-formamide; acetone for 5.5h; Heating;
  • 35
  • [ 40786-69-4 ]
  • [ 122444-04-6 ]
  • [ 122444-32-0 ]
YieldReaction ConditionsOperation in experiment
88.8% With potassium carbonate In N,N-dimethyl-formamide; acetone for 5.5h; Heating;
  • 36
  • [ 40786-69-4 ]
  • [ 107-14-2 ]
  • [ 106627-37-6 ]
YieldReaction ConditionsOperation in experiment
85% With potassium carbonate; potassium iodide In butanone for 72h;
  • 37
  • [ 40786-69-4 ]
  • [ 105-36-2 ]
  • [ 88420-24-0 ]
YieldReaction ConditionsOperation in experiment
73% With potassium carbonate In N,N-dimethyl-formamide at 75℃; for 12h;
With sodium hydroxide; potassium carbonate In water; toluene; butanone R.10 Reference Example 10 STR38 A mixture of 3 g of 2,4-dihydroxy-3-propylacetophenone, 2.5 g of ethyl bromoacetate, 2.3 g of anhydrous potassium carbonate, and 30 ml of methyl ethyl ketone was refluxed for 5 hours. Then, the solvent was removed under reduced pressure and after addition of 50 ml of toluene, the mixture was washed with water, a diluted aqueous solution of sodium hydroxide, and water successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus formed was recrystallized from a mixture of toluene and n-hexane to provide 2.8 g of ethyl (4-acetyl-3-hydroxy-2-propylphenoxy)acetate (melting point: 66° to 66.5° C.).
  • 38
  • [ 40786-69-4 ]
  • [ 109-70-6 ]
  • [ 79558-02-4 ]
YieldReaction ConditionsOperation in experiment
68% With potassium carbonate; potassium iodide In acetone for 24h; Reflux; Synthesis of 1-[4-(3-chloropropoxy)-2-hydroxy-3-propylphenyl]ethanone 1 A mixture of 2′,4′-dihydroxy-3′-propylacetophenone (1.94g, 0.01mol), KI (0.83g, 0.005mol), 1-bromo-3-chloropropane (6.30g, 0.04mol), and K2CO3 (4.15g, 0.03mol) in 50mL acetone was stirred and heated under reflux for 24h. The solution was filtered out and the filtrate was concentrated under vacuum. The crude product was purified by column chromatography on silica gel (ethyl acetate-petroleum ether, 1:5). Yield 68%, mp 61-62°C. (lit. [37] mp 61.7°C).
67% With potassium carbonate; potassium iodide In acetone for 5h; Heating;
With potassium carbonate In N,N-dimethyl-formamide
  • 39
  • [ 40786-69-4 ]
  • [ 106-95-6 ]
  • [ 99370-47-5 ]
YieldReaction ConditionsOperation in experiment
78% With potassium carbonate; potassium iodide In butanone for 24h; Heating;
With potassium carbonate In acetone 13.a (a) (a) 1-[2-Hydroxy-4-(2-propenyloxy)-3-propylphenyl]ethanone 1-(2,4-Dihydroxy-3-propylphenyl)ethanone (19.4 g), allyl bromide (10.5 g), and anhydrous potassium carbonate (15.2 g) were stirred in dry acetone (200 ml) under reflux for 17 hours. The reaction mixture was cooled, poured into water and the precipitated product extracted with ether, which was washed with water and dried. The solvent was evaporated to leave an orange solid which was recrystallized from 30°-40° petroleum ether to give the sub-title product as 19.9 g of orange needles, m.p. 47°-49°. Analysis: Found: C; 71.85% H; 7.7%. C14 H18 O3 Requires: C; 71.8% H; 7.69%.
  • 41
  • [ 40786-69-4 ]
  • [ 1129-28-8 ]
  • 3-[(4-Acetyl-3-hydroxy-2-propylphenoxy) methyl]benzoic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% 71 Preparation of 3-[(4-Acetyl-3-hydroxy-2-propylphenoxy) methyl]benzoic acid methyl ester EXAMPLE 71 Preparation of 3-[(4-Acetyl-3-hydroxy-2-propylphenoxy) methyl]benzoic acid methyl ester 1-(2,4-dihydroxy-3-propylphenyl)ethanone was allowed to react with methyl 3-bromomethylbenzoate according to the procedure of Example 69 and the product was purified by recrystallization from methylene chloride-ether to give 3-[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]benzoic acid methyl ester, the title compound, mp 141°-143°, in 89% yield. Analysis Calculated for C20 H22 O5: C, 70.16; H, 6.48. Found: C, 69.99; H, 6.41.
With potassium carbonate In acetone Heating;
  • 42
  • [ 40786-69-4 ]
  • [ 89892-38-6 ]
  • 4-(4-Acetyl-3-hydroxy-2-propyl-phenoxymethyl)-2-bromo-benzonitrile [ No CAS ]
  • 43
  • [ 40786-69-4 ]
  • [ 52010-98-7 ]
  • [ 183013-57-2 ]
  • 44
  • [ 40786-69-4 ]
  • [ 106-89-8 ]
  • [ 57161-85-0 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In butan-1-ol for 10h; Heating; Yield given;
With potassium hydroxide In ethanol; water 1.D Step D: Step D: 4-(2,3-epoxypropoxy)-2-hydroxy-3-propylacetophenone Add dropwise a solution of 10.9 gm of potassium hydroxide in 50 ml of absolute ethanol containing 1 ml of water to a refluxing solution of 35 gm of 2,4-dihydroxy-3-propylacetophenone and 42.5 ml of epichlorohydrin in 30 ml of absolute ethanol. Reflux the mixture for 2 hours; cool; extract twice with ether. Combine the ether extracts; wash with water and dry over sodium sulfate. Evaporate to a residue and distill the residue under reduced pressure. Collect the title product at 140°-145° C./2.0-2.5 mm and cool. (yield 26.5 gm)
  • 46
  • [ 40786-69-4 ]
  • [ 91945-01-6 ]
  • [ 664376-75-4 ]
YieldReaction ConditionsOperation in experiment
50% With potassium carbonate In acetone at 60℃; for 18h; 19 EXAMPLE 19 [1-] [[2-HYDROXY-3-PROPYL-4- ( {5- [4- (LH-TETRAAZOL-5-YL) PHENOXY] PENTYL}] oxy) phenyl]-ethanone To stirred a solution of 4- [ (5-bromopentyl) oxy] benzonitrile (2. 5g, 0.9mmol) in acetone (50ml) was added [K2CO3] (2.6g, 1. 7mmol) and 2'4'-dihydroxy-3'-propylacetophenone (1.9g, [L.] [OMMOL).] The reaction mixture was allowed to stir at [60°C] for 18 hours, cooled to ambient temperature and filtered. The filtrate was concentrated in vacuo and the crude product was purified by flash chromatography on silica gel eluting with hexanes: EtOAc (4: 1) to afford 4- [[5-(4-ACETYL-3-HYDROXY-2-PROPYLPHENOXY)] pentyl] [OXY} BENZONITRILE (L. LG,] 50%) as white solid. MS (ESI) 382 [(M++1).] To a degassed solution [OF 4-1 [5- (4-ACETYL-3-HYDROXY-2-PROPYLPHENOXY)-] pentyl] oxy} benzonitrile (300mg, 0. [79MMOL)] in toluene (5ml) was added azidotrimethylsilane (360mg, 3. [LMMOL)] and di-n-butyltin oxide (30mg, [0.] lmmol). The reaction was stirred at 110°C for 20 hours and cooled to ambient temperature. The mixture was purified using preparative- TLC plate, to afford desired 1-[2-hydroxy-3-propyl-4-({5-[4-(1H-tetraazol-5- yl) phenoxy] pentyl} oxy) [PHENYL]-ETHANONE.'H NMR (CD30D, 500MHZ) 88.] 0 (d, 2H), 7.8 (d, 1H), 7.0 (d, 2H), 6.6 (d, 2H), 4.2 (m, 4H), 2.6 (m, 2H), 2.5 (s, 3H), 2.0 (m, 4H), 1.8 (m, 2H), 1.4 (m, 2H), 0.8 (m, 3H). MS (ESI) 425 [(M++1)]
With potassium carbonate In acetone at 45℃;
  • 47
  • [ 910032-57-4 ]
  • [ 40786-69-4 ]
  • L-165041 methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
82% With potassium carbonate In N,N-dimethyl-formamide at 20℃;
  • 48
  • [ 40786-69-4 ]
  • [ 124064-22-8 ]
  • [ 664376-67-4 ]
YieldReaction ConditionsOperation in experiment
90% With potassium carbonate In acetone at 45℃; for 18h; 7 EXAMPLE 7 4 [[4- (4-ACETYL-3-HYDROXY-2-PROPYL-PHENOXY)-BUTOXY]-BENZOIC] acid Potassium carbonate (1.0 g, 7.7 mmol) was added to a stirred solution of [1- (2,] 4- dihydroxy-3-propyl-phenyl) -ethanone (1.0 g, 5.2 [MMOL) AND 4- (4-BROMO-BUTOXY)-BENZOIC] acid methyl ester (1.6 g, 5. [7MMOL)] in acetone (52 ml) at [45°C.] The reaction mixture was stirred for 18 hr, then the acetone was removed in vacuo. The residue was washed with brine (150 ml) and extracted with dichloromethane (180 ml). The organic layer was separated, dried over [NA2SO4,] filtered and then concentrated in vacuo to give a residue that was purified via column chromatography on silica gel (eluting [1-35] % ethyl acetate/hexanes) to give 1.9 g (90%) [OF 4-] [[4- (4-ACETYL-3-HYDROXY-2-PROPYL-PHENOXY)-BUTOXY]-BENZOIC] acid methyl ester as an oil. 1.0 N Lithium hydroxide (22 ml) was added to a solution [OF 4- [4- (4-ACETYL-3-HYDROXY-2-PROPYL-] phenoxy) -butoxy] -benzoic acid methyl ester (1.8 g, 4.5 mmol) in tetrahydrofuran (22 ml). The mixture was [REFLUXED] for 16 hr and then cooled to [0°C.] 1.0 N [HCL] aqueous solution was added to mixture until pH 5. The mixture was washed with brine (2x 60 ml) and extracted with ethyl acetate (2 x 70 ml). Organic extracts were dried over [NA2SO4,] filtered and concentrated in vacuo to give a brown solid. The crude solid was purified by column chromatography on silica gel (eluting first with 1-100% ethyl acetate/hexanes followed by 10-20 % methanol/ethyl acetate) to give [4- [4- (4-ACETYL-3-HYDROXY-2-PROPYL-PHENOXY)-BUTOXY]-BENZOIC] acid as a tan [SOLID.'H] NMR (DMSO-d6, [500MHZ),] 12.84 (s, 1H), 12.61 (s, 1H), 7.89 (d, 2H), 7.82 (d, [1H),] 7.03 (d, 2H), 6.67 (d, 1H), 4.16 (m, 4H), 2.64 (s, 3H), 2.57 (m, 2H), 1.99 (m, 4H), 1.49 (m, 2H), 0.87 (t, 3H). MS (ESI): 387 (M + [H) +.]
  • 49
  • [ 40786-69-4 ]
  • [ 484676-66-6 ]
  • [ 664376-76-5 ]
YieldReaction ConditionsOperation in experiment
54% With potassium carbonate In acetone at 60℃; for 18h; 20 [ EXAMPLE 20] [1- (2-HYDROXY-3-PROPYL-4- {4- [3- ( 1H-TETRAAZOL-5-YL) PHENOXY] BUTOXY} PHENYL)] ethanone To stirred a solution of 3- (4-bromobutoxy) benzonitrile (2.1g, 0. [84MMOL)] in acetone [(50MI)] was added [K2CO3] (2.3g, 1. 7mmol) and 2'4'-dihydroxy-3'-propylacetophenone (1.7g, 0. [89MMOL).] The reaction mixture was allowed to stir at [60°C] for 18 hours, cooled to ambient temperature and filtered. The filtrate was concentrated in vacuo and the crude product was purified by flash chromatography on silica gel eluting with hexanes: EtOAc (4: 1) to afford 3- [[4- (4-ACETYL-3-HYDROXY-2-PROPYLPHENOXY)] butoxy] benzonitrile (1.7g, [54%)] as white solid. MS (ESI) 368 [(M++1).] To a degassed solution of [3- [4- (4-ACETYL-3-HYDROXY-2-PROPYLPHENOXY)] butoxy] benzonitrile (200mg, 0. 54mmol) in toluene (3ml) was added azidotrimethylsilane (250mg, 2. 1mmol) and di- n-butyltin oxide (20mg, [0.] lmmol). The reaction mixture was stirred at 110°C for 20 hours and cooled to ambient temperature. The mixture was purified using preparative TLC plate to afford [1- (2-HYDROXY-3-PROPYL-4-14- [3- (IH-TETRAAZOL-5-YL)] phenoxy] [BUTOXY} PHENYL) ETHANONE. 1H NMR (] CD30D, 500MHz) [8] 7.7 (d, 1H), 7.5 (m, 2H), 7.3 (m, 1H), 6.9 (d, [LH),] 6.6 (d, 2H), 4.2 (m, 4H), 2.6 (m, 2H), 2.5 (s, 3H), 2.1 (m, 4H), 1.5 (m, 2H), 0.9 (m, 3H). MS [(ESI)] 411 [(M++1)]
  • 50
  • [ 40786-69-4 ]
  • [ 664376-63-0 ]
  • [ 664376-64-1 ]
YieldReaction ConditionsOperation in experiment
59% With potassium carbonate In acetone at 45℃; for 16h; 5 EXAMPLE 5 [1- {4- [2-BROMO-4-(2H-TETRAZOL-5-YL)-PHENOXY]-BUTOXY}-2-HYDROXY-3-PROPYL-PHENYL)-ETHANONE] Potassium carbonate (690 mg, 5.0 mmol) was added to a stirred solution of [1-] (2,4-Dihydroxy-3-propyl-phenyl)-ethanone (490 mg, 2.5 mmol) and [3-BROMO-4- (4-BROMO-] butoxy) -benzonitrile (1.00 g, 3.0 mmol) in acetone (40 mL) at [45 °C.] The reaction mixture was stirred for 16 hr, then the acetone was removed in vacuo. The residue was then mixed with dichloromethane (100 mL) and water (100 mL). The organic layer was separated, dried over [MGS04] and then concentrated in vacuo to give a residue that was purified via column chromatography on silica gel (eluting 5-60% ethyl acetate/hexanes) to give 657 mg (59%) of 4- [[4- (4-ACETYL-3-HYDROXY-2-PROPYL-PHENOXY)-BUTOXY]-3-BROMO-BENZONITRILE] as a white solid. [4- [4-] [(4-ACETYL-3-HYDROXY-2-PROPYL-PHENOXY)-BUTOXY]-3-BROMO-BENZONITRILE] (400 mg, 0.90 [MMOL),] trimethylsilylazide (207 mg, 0.24 mL, 1.8 mmol) and dibutyltin oxide (34 mg, 0.135 mmol) were dissolved in toluene (15 mL) and heated to reflux for 16 hr. The reaction mixture was then cooled to rt and applied directly to a silica gel column (eluting first with 20% ethyl acetate/hexanes followed by 10% [MEOH/DICHLOROMETHANE)] to give [1- (4- {4- [2-BROMO-4- (2H-] [TETRAZOL-5-YL)-PHENOXY]-BUTOXY}-2-HYDROXY-3-PROPYL-PHENYL)-ETHANONE] as a white solid NMR (DMSO-d6, [500MHZ),] [8] 12.85 (s, 1H), 8.20 (d, 1H), 8.00 (dd, [1H),] 7.81 (d, 1H), 7.29 (d, 1H), 6.67 (d, [1H),] 4.25-4. 19 (m, 4H), 3.17 (s, 1H), 2.58 (s, 3H), 2.56-2. 52 (m, 2H), 1.98-1. 96 (m, 4H), 1.48-1. 43 (m, 2H), 0.86 (t, 3H). MS [(ES1)] : 489 (M + [H) +.]
  • 51
  • [ 40786-69-4 ]
  • [ 37142-39-5 ]
  • [ 664376-68-5 ]
YieldReaction ConditionsOperation in experiment
28.9% With potassium carbonate In acetone for 6h; Heating / reflux; 9 EXAMPLE 9 [1- (2-HYDROXY-3-METHYL-4- {4- [4- (2H-TETRAZOL-5-YL)-PHENOXY]-BUTOXY}-PHENYL)-ETHANONE] Potassium carbonate (1.577 g, 12.87 mmol) was added to a stirred solution [OF 4-] (2-bromoethoxy) benzonitrile (1.57 g, 6.17 mmol) and [1- (2, 4-DIHYDROXY-3-METHYL-PHENYL)-] ethanone (0.85 g, 5.15 mmol) in acetone (50 mL). The reaction mixture was heated under reflux for 6 hours, filtered and then the acetone was removed in vacuo. The residue that was purified via column chromatography on silica gel (eluting 20-30% ethyl acetate/hexanes) to give 0.51 g (28. [9%)] [OF 4- [4- (4-ACETYL-3-HYDROXY-2-METHYL-PHENOXY)-BUTOXY]-BENZONITRILE] as a white solid. MS (ESI): 340 (M + [H) +. 4- [4- (4-ACETYL-3-HYDROXY-2-METHYL-PHENOXY)-BUTOXY]-BENZONITRILE] (500 mg, 1.47 mmol), trimethylsilylazide (424 mg, 0.49 mL, 3.68 mmol) and dibutyltin oxide (54 mg, 0.22 mmol) were dissolved in toluene (30 mL) and heated to reflux for 16 hr. Silica was added and the toluene was removed in vacuo. The crude material absorbed on silica was purified on the horizon biotage unit (eluting with 10% [MEOH/CHLOROFORM)] to give [1- (2-HYDROXY-3-] [METHYL-4-14- [4- (2H-TETRAZOL-5-YL)-PHENOXY]-BUTOXYL-PHENYL)-ETHANONE] as a white [SOLID.'H] NMR (DMSO-d6, [500MHZ),] [8] 12.84 (s, 1H), 7.95 (d, 2H), 7.80 (d, 1H), 7.14 (d, 2H), 6.66 (d, 1H), 4.17-4. 14 (m, 4H), 2.62 (s, 3H), 2.5 0-2.45 (m, 4H), 1.99 (s, 3H), 1.93-1. 86 (m, 4H).
  • 52
  • [ 40786-69-4 ]
  • [ 37142-39-5 ]
  • [ 664376-69-6 ]
YieldReaction ConditionsOperation in experiment
47% With potassium carbonate In acetone at 60℃; for 18h; 11 EXAMPLE 11 [1- (2-HYDROXY-3-PROPYL-4- {2- [4- (LH-TETRAAZOL-5-YL) PHENOXY] ETHOXY} PHENYL)] ethanone To a stirred solution of 4- (2-bromoethoxy) benzonitrile [(L.] [OG,] 4. [4MMOL)] in acetone [(50ML),] was added [K2CO3] (1.2g, 8.8mmol) and 2'4'-dihydroxy-3'-propylacetophenone (1.3g, 6. [6MMOL).] The reaction mixture was allowed to stir at [60°C] for 18 hours, cooled to ambient temperature and filtered. The filtrate was concentrated in vacuo and the crude material was purified on a Biotage horizon system (eluting [5%-30%] ethyl acetate/hexanes) to afford [4- [2- (4-] acetyl-3-hydroxy-2-propylphenoxy) ethoxy] benzonitrile (0.7g, 47%) as white solid. MS (ESI) 340 [(M++1)] To a degassed solution of [4- [2- (4-ACETYL-3-HYDROXY-2-PROPYLPHENOXY) ETHOXY]] benzonitrile (230mg, 0. [67MMOL)] in toluene (3ml) was added azidotrimethylsilane (310mg, 2. [7MMOL)] and di- n-butyltinoxide (30 mg, 0.1 mmol). The reaction mixture was stirred at 110°C for 20 hours, cooled to ambient temperature and concentrated under reduced pressure. The crude material was purified by semi-preparative HPLC to afford [1- (2-HYDROXY-3-PROPYL-4-2- [4- (LH-TETRAAZOL-5-] yl) phenoxy] [ETHOXYLPHENYL)-ETHANONE. LH NMR (CD30D, 500MHZ) õ] 8.0 (d, 2H), 8.7 (d, [1H),] 7.0 (d, 2H), 7.6 (d, 1H), 4.4 (s, 4H), 2.6 (m, 2H), 2.5 (s, 3H), 1.5 (m, 2H), 0.9 (m, 3H). MS (ESI) 455 [(M++1).]
  • 53
  • [ 40786-69-4 ]
  • [ 849442-26-8 ]
  • 1-[4-(2-chloromethyl-allyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
83% With caesium carbonate In butanone at 20℃; for 6h; XXIX EXAMPLE XXIX; 35-A; 1- [4- (2-CHLOROMETHYL-ALLYLOXY)-2-HYDROXY-3-PROPYL-PHENYL]-ETHANONE; A mixture of 1-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (158 mg, 0.814 MMOL), methanesulfonic acid 2-chloromethyl-allyl ester 5-A (750 mg, 4.06 MMOL), and CS2CO3 (662 mg, 2.03 MMOL) in 2-butanone (3 mL) was stirred at room temperature for 6 h, acidified with 1 N HCI, and extracted with Et20. The extracts were dried, concentrated, and column chromatographed (EtOAc/hexane: 1/7) to provide 190 mg (83%) of the title compound 35-A ; H NMR (300 MHz, CDCI3) 8 7.59 (d, J = 9.0 Hz, 1 H), 6.46 (d, J = 9.0 Hz, 1 H), 5.41 (s, 1 H), 5.37 (s, 1 H), 4.70 (s, 2 H), 4.20 (s, 2 H), 2.66 (t, J = 7. 6 HZ, 2 H), 2.56 (s, 3 H), 1.55 (m, 2 H), 0.95 (t, J = 7.4 Hz, 3 H); MS (ES) m/z: 305 (M+Na+).
  • 54
  • [ 40786-69-4 ]
  • [ 33674-96-3 ]
  • 1-[4-(6-bromo-pyridin-2-ylmethoxy)-2-hydroxy-3-propyl-phenyl]-ethanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine In tetrahydrofuran at 20℃; for 12h; 117 Combine (6-bromo-pyridin-2-yl)-methanol (1.00 g, 5.32 mmol), l-(2,4- dihydroxy-3-propyl-phenyl)-ethanone (1.033 g, 5.32 mmol) and tri-rø-butylphosphine (1.46 mL, 5.85 mmol, Aldrich Chemical Co.) in tetrahydrofuran (5.3 mL), add 1,1'-(azodicarbonyl)dipiperidine (1.48 g, 5.85 mmol, Aldrich Chemical Co.). After 12 hours at ambient temperature, add diethyl ether (white percipitate forms) and filter, collect liquid and remove solvents under reduced pressure. Purify residue by flash chromatography to obtain the title compound as a white solid (854 mg, 2.35 mmol): MS (m/z): 286 (M- BrH).
  • 55
  • [ 40786-69-4 ]
  • [ 16420-13-6 ]
  • [ 74891-62-6 ]
YieldReaction ConditionsOperation in experiment
41% With triethylamine In dichloromethane at 20℃; 106 Stir a mixture of l-(254-dihydroxy-3-propyl-phenyl)-ethanone (2 g, 10.3 mmol), triethylamine (1.6 mL 11.3 mmol), and dichloromethane (40 niL) at room temperature. Add dimethylthiocarbamoyl chloride (1.27 g, 10.3 mmol) and stir at room temperature overnight. Wash the mixture with IM hydrochloric acid (25 mL), dry over magnesium sulfate, filter and concentrate. Purify the residue via silica chromatography eluting with hexanes to 7:3 hexanes:ethyl acetate to afford dimethyl-thiocarbamic acid O-(4-acetyl-3- hydroxy-2-propyl-phenyl) ester (1.2 g, 41 %) as a light yellow solid. Stir the yellow solid in tetradecane (10 mL) at 250 0C for an hour and purify by silica chromatography eluting with hexanes to 6:4 hexanes :ethyl acetate to give the title compound (1.08 g, 90 %) as a white solid. LCMS (m/z) 28O m-I.
  • 56
  • [ 40786-69-4 ]
  • [ 3958-57-4 ]
  • 1-[2-hydroxy-4-(3-nitro-benzyloxy)-3-propyl-phenyl]-ethanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% Stage #1: 1-(2,4-dihydroxy-3-propylphenyl)ethanone; 1-bromomethyl-3-nitrobenzene In N,N-dimethyl-formamide for 0.166667h; Stage #2: With potassium carbonate; caesium carbonate In N,N-dimethyl-formamide at 20 - 70℃; for 2.5h; 125 Add 3-bromomethyl nitrobenzene (10.00 g, 46.3 mmol) to a solution of l-(2,4- dihydroxy-3-propyl-phenyl)-ethanone (8.99 g, 46.3 mmol) in dimethylformamide (60 mL). After 10 minutes add potassium carbonate (9.60 g, 69.4 mmol) and cesium carbonate (15.08 g, 46.3 mmol). Stir at room temperature for one hour, then heat to 7O0C for 1.5 hours. Cool and add water (250 mL). Triturate for 15 minutes. Filter. Wash the solid with water several times, and then wash with hexanes. Dry to afford the title compound as an off white/light gray powder (12.9 g, 85%): 1H NMR (DMSO-J6) δ 0.91 (t, 3H), 1.52 (m, 2H), 2.58 (s, 3H), 2.63 (m, 2H), 5.42 (s, 2H), 6.72 (d, IH), 7.73 (t, IH), 7.83 (d, IH), 7.90 (d, IH), 8.21 (d, IH), 8.34 (s, IH), 12.88 (bs, IH).
  • 57
  • [ 40786-69-4 ]
  • [ 100-11-8 ]
  • 1-[2-hydroxy-4-(4-nitro-benzyloxy)-3-propyl-phenyl]-ethanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
94% With potassium carbonate In acetone for 1h; Heating / reflux; 112 To 2',4'-dihydroxy-3'-propyl acetophenone (3.0 g, 15.4 mmol) and 4-nitrobenzyl bromide (3.6 g, 17 mmol) in acetone (62 mL) is added K2CO3 (3.2 g, 23 mmol). The reaction mixture is refluxed for Ih and cooled to room temperature. The precipitate is filtered, washed with water (5 x 70 mL), and dried to give the title compound (4.8 g, 94%). LC-MS (m/z): 328 (M-I).
  • 58
  • [ 40786-69-4 ]
  • [ 70258-18-3 ]
  • 1-[4-(6-chloro-pyridin-3-ylmethoxy)-2-hydroxy-3-propyl-phenyl]-ethanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
36% Stage #1: 1-(2,4-dihydroxy-3-propylphenyl)ethanone; 2-chloro-5-(chloromethyl)pyridine In N,N-dimethyl-formamide for 0.166667h; Stage #2: With potassium carbonate; caesium carbonate In N,N-dimethyl-formamide at 20 - 70℃; for 3h; 124 Add 5-chloromethyl-2-chloropyridine (4.12 g, 25.4 mmol) to a solution of of 1- (2,4-dihydroxy-3-propyl-phenyl)-ethanone (4.94 g, 25.4 mmol) in dimethylformamide (40 niL). After 10 minutes add potassium carbonate (5.27 g, 38.1 mmol) and cesium carbonate (8.28 g, 25.4 mmol). Stir at room temperature for one hour, and then heat to 70 0C for 2 hours. Cool, partition between ethyl acetate (300 mL) and water (300 mL). Wash twice with water, brine, dry, and concentrate. Dissolve the crude solid in dichloromethane, and add hexane (70 mL) slowly. Triturate and filter to afford the title compound as an orange powder (2.95 g, 36%): 1H NMR (CDCl3) δ 0.94 (t, 3H), 1.55 (sextet, 2H), 2.58 (s, 3H), 2.67 (t, 2H), 5.14 (s, 2H), 6.47 (d, IH), 7.38 (d, IH), 7.60 (d, IH), 7.73 (d, IH), 8.47 (s, IH), 12.75 (s, IH).
  • 59
  • 2-(3-hydroxymethyl-phenylsulfanyl)-isonicotinonitrile [ No CAS ]
  • [ 40786-69-4 ]
  • 2-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylsulfanyl]-isonicotinonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
81% With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran 173 Add triphenylphosphine (1.84 g, 7.02 mmol) and diisopropylazodicarboxylate (1.42 g, 7.02 mmol) to a solution of 5-(3-(hydroxymethyl)phenylthio)picolinonitrile (1.70 g, 7.02 mmol) and l-(2,4-dihydroxy-3-methylphenyl)ethanone (1.17 g, 7.02 mmol) in THF (35.I mL). Stir overnight. Dilute with, ethyl acetate. Wash the mixture with water and brine. Dry, filter and concentrate to afford the title compound (2.00 g, 73%). Use as is. MS (APCI-neg) m/z (rel intensity): 390 (M+H, 100%).
58% Stage #1: 2-(3-hydroxymethyl-phenylsulfanyl)-isonicotinonitrile; 1-(2,4-dihydroxy-3-propylphenyl)ethanone With tributylphosphine In dichloromethane; toluene at -20℃; for 0.0833333h; Stage #2: With 1,1'-azodicarbonyl-dipiperidine In dichloromethane; toluene at 20℃; 97 The title compound is prepared essentially as described in Preparation 42 employing 2-(3-hydroxymethyl-phenylsulfanyl)-isonicotinonitrile (378 mg, 1.56 mmol). The title compound is isolated as a white solid (380 mg, 58%): 1H NMR (DMSOd6) δ 0.80 (t, 3H)5 1.44 (sextet, 2H)5 2.57 (m, 5H), 5.32 (s, 2H)5 6.72 (d, IH)5 7.41 (s5 IH)5 7.56- 7.63 (m, 4H)5 7.68 (s5 IH), 7.82 (d5 IH), 8.63 (d, IH)5 12.84 (s, IH).
  • 60
  • 6-(3-hydroxymethyl-phenylsulfanyl)-nicotinonitrile [ No CAS ]
  • [ 40786-69-4 ]
  • 6-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylsulfanyl]-nicotinonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
38% Stage #1: 6-(3-hydroxymethyl-phenylsulfanyl)-nicotinonitrile; 1-(2,4-dihydroxy-3-propylphenyl)ethanone With tributylphosphine In dichloromethane; toluene at -20℃; for 0.0833333h; Stage #2: With 1,1'-azodicarbonyl-dipiperidine In dichloromethane; toluene at 20℃; 98 The title compound is prepared essentially as described in Preparation 42 employing 6-(3-hydroxymethyl-phenylsulfanyl)-nicotinonitrile (650 mg, 2.68 mmol).The title compound is isolated as a white solid (430 mg, 38%): 1H NMR (DMSO-J6) δ 0.81 (t, 3H), 1.44 (sextet, 2H)5 2.57 (d, 2H)5 2.58 (s, 3H), 5.33 (s5 2H)5 6.73 (d, IH), 7.10 (d, IH)5 7.60 (m5 3H)5 7.70 (m, IH), 7.82 (d, IH)5 8.08 (dd, IH)5 8.81 (dd, IH)5 12.84 (bs, IH).
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran 170 Using the method of Preparation 166 using 6-(3-(hydroxymethyl)phenylthio) nicotinonitrile (1.25 g, 5.15 mmol) and l-(2,4-dihydroxy-3-propylphenyl)ethanone (1.00 g, 5.15 mmol) affords the title compound (3.00 g). MS (APCI-neg) m/z (rel intensity): 417 (M-H, 100%).
  • 61
  • C14H10ClNS [ No CAS ]
  • [ 40786-69-4 ]
  • 3-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylsulfanyl]-benzonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate In N,N-dimethyl-formamide at 60℃; for 1h; 99 Add methanesulfonyl chloride (0.119 g, 1.04 mmol) to a solution of 3-(3- hydroxymethyl-phenylsulfanyl)-benzonitrile (0.250 g, 1.04 mmol) and triethylamine (0.210 g, 2.07 mmol) in dichloromethane (0.2 M). Stir for Ih. Evaporate solvent. Dissolve the residue in ΛζiV-dimethylformamide and add l-(2,4-dihydroxy-3-propyl- phenyl)-ethanone (0.201 g, 1.04 mmol). Add cesium carbonate (0.673 g, 2.07 mmol) and stir for Ih at 60 °C. Dilute the reaction mixture with diethyl ether and wash with water (3x). Purify the residue by flash chromatography, eluting with hexanes, ramping to 50% ethyl acetate/hexanes to elute the title compound (0.331 mg, 0.790 mmol, 76%): MS (m/z): 416 (M-I).
  • 62
  • 6-(3-hydroxymethyl-phenoxy)-nicotinonitrile [ No CAS ]
  • [ 40786-69-4 ]
  • 6-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenoxy]-nicotinonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
33% Stage #1: 6-(3-hydroxymethyl-phenoxy)-nicotinonitrile; 1-(2,4-dihydroxy-3-propylphenyl)ethanone With tributylphosphine In dichloromethane; toluene at -20℃; for 0.0833333h; Stage #2: With 1,1'-azodicarbonyl-dipiperidine In dichloromethane; toluene at 20℃; 42 Mix 6-(3-hydroxymethyl-phenoxy)-nicotinonitrile (1.63 g, 7.18 mmol) and l-(2,4- dihydroxy-3-propyl-phenyl)-ethanone (1.33 g, 6.84 mmol) in 2:1 toluene/dichloromethane (24 mL). Cool to -20 0C and add tributylphosphine (2.6 niL, 10.26 mmol) dropwise. After stirring for 5 minutes, add l,r-(azodicarbonyl)dipiperidine in three batches. Allow the reaction mixture to warm to ambient temperature overnight. Concentrate under reduced pressure to give a yellow solid. Dilute with diethyl ether (50 mL) and cool to 0 0C. Filter the white precipitate and concentrate the filtrate under reduced pressure to give a residue. Purification by flash chromatography, using 5% ethyl acetate/hexanes to 30% ethyl acetate/hexanes as a gradient eluent yields the title compound (0.91 g, 33%): MS (m/z): 401.2 (M-I). 1H NMR (CDCl3) 12.78 (s, IH), 8.50 (s, IH), 7.97 (dd, J = 2.2 Hz, 8.8 Hz, IH), 7.62 (d, J = 8.8 Hz, IH), 7.51 (t, J = 8.0 Hz3 IH)5 7.36 (d, J = 7.8 Hz, IH)3 7.25 (s, IH)3 7.16 (d, J = 8.0 Hz3 IH), 7.09 (d, J = 8.8 Hz, IH)3 6.51 (d, J = 8.8 Hz, IH), 5.22 (s, 2H), 2.72 (t, J = 7.6 Hz, 2H), 2.60 (s, 3H), 1.62- 1.53 (m, 2H)3 0.94 (t, J = 7.6 Hz3 3H).
  • 63
  • [ 40786-69-4 ]
  • [ 16004-15-2 ]
  • 1-[2-hydroxy-4-(4-iodo-benzyloxy)-3-propyl-phenyl]-ethanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
52% With caesium carbonate In acetone for 48h; 144 Add l-bromomethyl-4-iodo-benzene (10.00 g, 33.7 mmol) to a solution of l-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (6.54 g, 33.7 mmol) and cesium carbonate (13.2 g, 40.4 mmol) in acetone (500 mL) and stir. After 48 hours, pour the reaction into water and extract with ethyl acetate. Combine the organic layers, dry with sodium sulfate, filter and concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography eluting with a gradient of ethyl acetate:hexanes to yield the title product as a yellow solid (7.20 g, 52%): 1H NMR (CDCl3) δ 0.95 (t, 3H), 1.56 (sextet, 2H)5 2.56 (s, 3H), 2.69 (t5 2H), 5.09 (s, 2H)5 6.43 (d, IH)5 7.15 (d, 2H)5 7.57 (d5 IH)5 7.73 (d5 2H)5 12.74 (s5 IH).
  • 64
  • [ 40786-69-4 ]
  • [ 67-64-1 ]
  • [ 200355-31-3 ]
YieldReaction ConditionsOperation in experiment
With pyrrolidine In toluene at 20℃; for 5h; Heating / reflux; 74A Example 74; N-1H-indazol-4-yl-N'-(7-methoxy-2,2-dimethyl-8-propyl-3 4-dihydro-2H-chromen-4-yl)urea; Example 74A; A mixture of 2,4-dihydroxy-3-propylacetophenone (1.94 g, 10 mmol), acetone (0.95 mL, 12.9 mmol), and pyrrolidine (1.7 mL, 20.4 mmol) was stirred in 3 mL toluene at rt for 1 h and at reflux (Dean-Stark trap) for 4 h. After cooling to rt, the mixture was diluted with ether (30 mL) and was washed with 2N HCl (10 mL) and H2O (10 mL). Drying over Na2SO4, filtered and evaporation of volatiles in vacuo afforded the crude title compound, which was used without further purification.
  • 65
  • [ 40786-69-4 ]
  • [ 105-36-2 ]
  • 4-acetyl-3-hydroxy-2-propylethyl phenoxyacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
94% With potassium carbonate In water; ethyl acetate; acetone 1.7 EXAMPLE 1 (7) Under a current of argon, a solution of 2.0 g of 4-acetyl-3-hydroxy-2-propylphenol in 15 ml of acetone and 1.44 g of potassium carbonate added thereto at 0° C. were stirred for 10 minutes and then the produced mixture and a solution of 1.91 g of ethyl bromoacetate in 5 ml of acetone added thereto were stirred at normal room temperature for 15 hours. The reaction mixture was combined with water and extracted from ethyl acetate. The consequently separated organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. The residue from drying was concentrated under a vacuum. The concentrate was subjected to silica gel column chromatography. From the hexane-ethyl acetate (4:1 V/V) elude, 2.73 g of 4-acetyl-3-hydroxy-2-propylethyl phenoxyacetate was obtained in the form of white crystals. The yield was 94%.
  • 66
  • [ 40786-69-4 ]
  • [ 51359-78-5 ]
  • [ 172931-85-0 ]
YieldReaction ConditionsOperation in experiment
With potassium iodide; potassium carbonate In N,N-dimethyl-formamide 4 Preparation of (Z)-5-[[4-[(4-acetyl-3-hydroxy-2-propylphenoxymethyl)]phenyl]methylene]-2-thioxo-4-thiazolidinone The 4-(bromomethyl)benzaldehyde was condensed with 1-(2,4-dihydroxy-3-propylphenyl)ethanone by first dissolving the 1-(2,4-dihydroxy-3-propylphenyl)ethanone (0.90 g, 4.63 mmol) in N,N-dimethylformamide (60 ml) under a nitrogen atmosphere. To this solution was then added potassium carbonate (0.64 g, 4.63 mmol), potassium iodide (0.74 g, 4.46 mmol), and the above-prepared aldehyde (0.91 g, 4.57 mmol). This mixture was then warmed to 70° C. and maintained at this temperature for about 30 minutes. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was then allowed to cool and was diluted with water. The mixture was then extracted with ethyl acetate (2*200 ml). The organic layers were combined, washed with water and then brine, dried over magnesium sulfate, and then concentrated in vacuo. The desired intermediate product, 4-[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]benzaldehyde, was then further purified by silica gel chromatography.
  • 67
  • [ 110-52-1 ]
  • [ 40786-69-4 ]
  • [ 32503-27-8 ]
  • [ 92518-06-4 ]
YieldReaction ConditionsOperation in experiment
13.5 g (79%) With sodium hydroxide In dichloromethane; water; ethyl acetate 16 1-[4-(4-Bromobutoxy)-2-hydroxy-3-propylphenyl]ethanone STR24 EXAMPLE 16 1-[4-(4-Bromobutoxy)-2-hydroxy-3-propylphenyl]ethanone STR24 The title compound was prepared according to the procedure of Example 7 using 2,4 dihydroxy-3-n-propylacetophenone (10 g, 0.051 mol) in methylene chloride (100 ml), sodium hydroxide (4.1 g, 0.102 mol) in water (100 ml), 1.4-dibromobutane (38 g, 0.18 mol) and tetra n-butylammonium bisulfate (17.6 g, 0.051 mol). Chromatography of the crude product on silica gel using 15% ethyl acetate/hexane as eluent gave 13.5 g (79%) of the title compound as an oil. Analysis calculated for C15 H21 BrO3: Calc.: C, 54.70; H, 6.43; Br, 24.29. Found: C, 54.50; H, 6.29; Br, 24.60.
13.5 g (79%) With sodium hydroxide In dichloromethane; water; ethyl acetate 16 1-[4-(4-Bromobutoxy)-2-hydroxy-3-propylphenyl]ethanone STR22 Example 16 1-[4-(4-Bromobutoxy)-2-hydroxy-3-propylphenyl]ethanone STR22 The title compound was prepared according to the procedure of Example 7 using 2,4-dihydroxy-3-n-propylacetophenone (10 g, 0.051 mol) in methylene chloride (100 ml), sodium hydroxide (4.1 g, 0.102 mol) in water (100 ml), 1,4-dibromobutane (38 g, 0.18 mol) and tetra-n-butylammonium bisulfate (17.6 g, 0.051 mol). Chromatography of the crude product on silica gel using 15% ethyl acetate/hexane as eluent gave 13.5 g (79%) of the title compound as an oil. Analysis calculated for C15 H21 BrO3: Calc.: C, 54.70; H, 6.43; Br, 24.29. Found: C, 54.50; H, 6.29; Br, 24.60.
  • 68
  • [ 40786-69-4 ]
  • [ 32503-27-8 ]
  • [ 106-93-4 ]
  • [ 57162-00-2 ]
YieldReaction ConditionsOperation in experiment
13.5 g (79%) With sodium hydroxide In dichloromethane; water; ethyl acetate 25 1-[4-(2-Bromoethoxy)-2-hydroxy-3-propylphenyl]ethanone STR33 EXAMPLE 25 1-[4-(2-Bromoethoxy)-2-hydroxy-3-propylphenyl]ethanone STR33 The title compound was prepared according to the procedure of Example 7 using 2,4-dihydroxy-3-n-propylacetophenone (5 g, 0.025 mol) in methylene chloride (50 ml), sodium hydroxide (2 g, 0.05 mol) in water (50 ml), 1,2-dibromoethane (17 g, 0.088 mol) and tetra-n-butylammonium bisulfate (8.7 g, 0.025 mol). Chromatography of the crude product on silica gel using 15% ethyl acetate/hexane as eluent gave 13.5 g (79%) of the title compound as an oil. Analysis calculated for C13 H17 BrO3: Calc.: C, 51.82; H, 5.69; Br, 26.55. Found: C, 51.86; H, 5.81; Br, 26.44.
13.5 g (79%) With sodium hydroxide In dichloromethane; water; ethyl acetate 25 1-[4-(2-Bromoethoxy)-2-hydroxy-3-propylphenyl]ethanone STR31 Example 25 1-[4-(2-Bromoethoxy)-2-hydroxy-3-propylphenyl]ethanone STR31 The title compound was prepared according to the procedure of Example 7 using 2,4-dihydroxy-3-n-propylacetophenone (5 g, 0.025 mol) in methylene chloride (50 ml), sodium hydroxide (2 g, 0.05 mol) in water (50 ml), 1,2-dibromoethane (17 g, 0.088 mol) and tetra-n-butylammonium bisulfate (8.7 g, 0.025 mol). Chromatography of the crude product on silica gel using 15% ethyl acetate/hexane as eluent gave 13.5 g (79%) of the title compound as an oil. Analysis calculated for C13 H17 BrO3: Calc.: C, 51.82; H, 5.69; Br, 26.55. Found: C, 51.86; H, 5.81; Br, 26.44.
  • 69
  • [ 129503-79-3 ]
  • [ 40786-69-4 ]
  • methyl [2-(2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethyl)-2,3-dihydrobenzo[b]furan-5-yl]acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran 18 Methyl [2-(2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethyl)-2,3-dihydrobenzo[b]furan-5-yl]acetate Methyl [2-(2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethyl)-2,3-dihydrobenzo[b]furan-5-yl]acetate To a solution of the compound of Example 18 (1.05 g) and 2,4-dihydroxy-3-propylacetophenone (0.65 g) in THF (10 ml) was added DEAD (0.85 ml) at room temperature. The solution was cooled to about -5° and triphenylphosphine (1.42 g) was added in one portion. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue chromatographed on a column of silica gel (20-230 mesh) eluding with toluene-ethyl acetate (10:1) to give the title compound, m.p. 59°-60°. Analysis, calculated for C24 H28 O6: C, 69.88; H, 6.84. Found: C, 69.92; H, 6.96.
  • 70
  • [ 129503-79-3 ]
  • [ 40786-69-4 ]
  • methyl (2-(4-acetyl-3-hydroxy-2-propylphenoxy)methyl-2,3-dihydrobenzo[b]furan-5-yl)acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran; hexane; ethyl acetate 25 Methyl (2-(4-acetyl-3-hydroxy-2-propylphenoxy)methyl-2,3-dihydrobenzo[b]furan-5-yl)acetate EXAMPLE 25 Methyl (2-(4-acetyl-3-hydroxy-2-propylphenoxy)methyl-2,3-dihydrobenzo[b]furan-5-yl)acetate To a solution of the compound of Example 24 (1.52 g) and 2,4-dihydroxy-3-propylacetophenone (1.33 g) was added, under N2, in dry THF (20 ml), DEAD (1.6 ml), to give an orange solution. The mixture was stirred at room temperature for 15 minutes. To this mixture was added solid triphenylphosphine (2.69 g). The orange solution became a dark red solution in a few seconds and the reaction was exothermic. The reaction mixture was cooled to 0° C. for 5 minutes and then stirred at room temperature for 1 hour. The reaction mixture was evaporated under vacuum and purified by preparative HPLC (Waters 500) using hexane/ethyl acetate (10:4) as eluant. The title compound was obtained as a beige solid by trituration in hexane at 0°, m.p. 77°-78°. Analysis, calculated for C23 H26 O6: C, 69.33; H, 6.58. Found: C, 69.33; H, 6.77.
  • 71
  • 1-(4-bromobutyl)-2,3-dimethoxybenzene [ No CAS ]
  • [ 40786-69-4 ]
  • ethyl acetate n-hexane [ No CAS ]
  • 1-[2-hydroxy-4-[4-(2,3-dimethoxyphenyl)butoxy]-3-propylphenyl]ethanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
88% With sodium iodide; potassium carbonate In acetone 94 1-[2-Hydroxy-4-[4-(2,3-dimethoxyphenyl)butoxy]-3-propylphenyl]ethanone EXAMPLE 94 1-[2-Hydroxy-4-[4-(2,3-dimethoxyphenyl)butoxy]-3-propylphenyl]ethanone A mixture of 4.36 g (15.9 mmol) of 1-(4-bromobutyl)-2,3-dimethoxybenzene, 3.10 g (15.9 mmol) of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 4.4 g (32 mmol) of potassium carbonate and 2.4 g (16 mmol) of sodium iodide in 100 mL of acetone was stirred at reflux for 30 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification by high pressure liquid chromatography using 20% ethyl acetate-hexane gave 5.07 g (88% yield) of 1-[2-Hydroxy-4-[4-(2,3-dimethoxyphenyl)butoxy]-3-propylphenyl]-ethanone as an oil. Anal. Calcd for C23 H30 O5: C, 71.48; H, 7.82. Found: C, 71.58; H, 7.85.
  • 72
  • [ 40786-69-4 ]
  • tris [2-(2-methoxyethoxy)ethyl]amine [ No CAS ]
  • ethyl acetate n-hexane [ No CAS ]
  • [ 79623-17-9 ]
  • [ 123015-07-6 ]
YieldReaction ConditionsOperation in experiment
75% With potassium carbonate In toluene 102 1-[2-Hydroxy-4-[5-(3,4-dimethoxyphenyl)pentyloxy]-3-propylphenyl]-1-ethanon EXAMPLE 102 1-[2-Hydroxy-4-[5-(3,4-dimethoxyphenyl)pentyloxy]-3-propylphenyl]-1-ethanon 3.0 g (0.013 mol) of 5-(3,4-dimethoxyphenyl)pentan-1-ol was converted to the mesylate as described in Example 6. A mixture of this mesylate, 2.6 g (0.013 mol) of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.8 g (0.02 mol) of potassium carbonate and 0.28 mL (0.9 mmol) of tris [2-(2-methoxyethoxy)ethyl]amine (TDA-1) in 75 mL of toluene was stirred at reflux for 6.5 hours. The reaction mixture was washed with half-saturated brine, then with 1N sodium hydroxide, dried and concentrated under reduced pressure to an oil. Purification by HPLC using 25% ethyl acetate-hexane gave 4.05 g (75% yield), mp 72°-75°, of 1-[2-hydroxy-4-[5-(3,4-dimethoxyphenyl)pentyloxy]-3-propylphenyl]-1-ethanone. Anal. Calcd for C24 H32 O5: C, 71.97; H, 8.05. Found: C, 71.82; H, 8.05.
  • 73
  • [ 40786-69-4 ]
  • [ 107-80-2 ]
  • 1-[4-(3-bromobutoxy)-2-hydroxy-3-propylphenyl]ethanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
With tetrabutylammomium bromide; potassium carbonate In acetone R.8 REFERENCE EXAMPLE 8 STR38 REFERENCE EXAMPLE 8 STR38 A mixture of 5.0 g of 2,4-dihydroxy-3-propylacetophenone, 11.1 g of 1,3-dibromobutane, 6.0 g of potassium carbonate and 50 mg of tetra-n-butylammonium bromide in 130 ml of acetone was refluxed overnight. After cooling, the insoluble matter was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=8:1) to give 2.47 g of 1-[4-(3-bromobutoxy)-2-hydroxy-3-propylphenyl]ethanone. Melting point 53°-55° C.
  • 74
  • [ 40786-69-4 ]
  • [ 91362-20-8 ]
  • 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylthio)delta-oxo-benzenebutanol [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In butanone C: Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylthio)-delta-oxo-benzenebutanol The compound A of Step B above (96 mg, 0.29 mmoles), 2,4-dihydroxy-3-propylacetophenone (78 mg, 0.4 mmole) and potassium carbonate (270 mg, 2.0 mmoles) were refluxed in methyl ethyl ketone (3 ml) for twelve hours. The reaction mixture was filtered and purified by chromatography to yield the title compound; m.p. 73°-75°.
  • 75
  • 2-Hydroxymethyl-4-hydroxy-5-acetyl-2,3-dihydrobenzo[[b]furan [ No CAS ]
  • [ 40786-69-4 ]
  • 2-((2-Propyl-3-hydroxy-4-acetylphenoxy)methyl)-4-hydroxy-5-acetyl-2,3-dihydrobenzo[b]furan [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran; ethyl acetate; toluene 5 2-((2-Propyl-3-hydroxy-4-acetylphenoxy)methyl)-4-hydroxy-5-acetyl-2,3-dihydrobenzo[b]furan EXAMPLE 5 2-((2-Propyl-3-hydroxy-4-acetylphenoxy)methyl)-4-hydroxy-5-acetyl-2,3-dihydrobenzo[b]furan The compound of Example 2 (800 mg, 3.84 mmoles) was combined with 2,4-dihydroxy-3-propylacetophenone (740 mg) in 50 ml dry THF. To this solution was added DEAD (0.726 ml). After 5 minutes triphenylphosphine (1.2 g) were added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, taken up in 10/1 toluene/ethyl acetate and the insoluble triphenylphosphine oxide was removed by filtration. The residue after concentration was purified on HPLC using 10/1 toluene/ethyl acetate. The title compound was recrystallized from ether, m.p.: 104°-106°. Analysis, calculated: C, 68.74; H, 6.29. Found: C, 68.94; H, 6.29.
  • 76
  • 3-(2-chloro-4-cyanophenoxy)propyl chloride [ No CAS ]
  • [ 40786-69-4 ]
  • [ 87820-67-5 ]
YieldReaction ConditionsOperation in experiment
With potassium iodide; potassium carbonate In <i>N</i>-methyl-acetamide R.3 REFERENCE EXAMPLE 3 REFERENCE EXAMPLE 3 A mixture of 3-(2-chloro-4-cyanophenoxy)propyl chloride (1.61 g), 2,4-dihydroxy-3-n-propylacetophenone (1.27 g), potassium carbonate (970 mg), potassium iodide (600 mg) and dimethylformamide (3 ml) was stirred under heating at 120° C. for 5 hours. The reaction mixture was diluted with 1N-HCl and extracted with ethyl acetate. The extract was washed with water and dried over sodium sulfate, and the solvent was distilled off. The residue was cooled and the crystals which formed were collected by filtration and recrystallized twice from methanol to give 1.40 g of 1-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-3-(2-chloro-4-cyanophenoxy)propane as colorless crystals melting at 96°-97° C. Infrared absorption spectrum (KBr) cm-1: 2225, 1640-1610. Nuclear magnetic resonance spectrum (CDCl3)δ: 12.69(1H,s), 7.56(1H, pseudo-s), 7.52(1H,d,J=9 Hz), 7.48(1H,dd,J=2 and 8 Hz), 6.93(1H,d,J=8 Hz), 6.43(1H, d,J=9 Hz), 4.28(4H,t,J=5.5 Hz), 2.62(2H,t,J=7 Hz), 2.58(3H,s), 2.42(2H), 1.42(2H,m), 0.88(3H,t,J=7 Hz). Elemental analysis: C21 H22 ClNO4; Calcd.: C, 65.03; H, 5.72; N, 3.61; Found: C, 65.34; H, 5.75; N, 3.72.
  • 77
  • 4-nitro-1-(2-chdloroethoxy)benzene [ No CAS ]
  • [ 40786-69-4 ]
  • 1-{2-Hydroxy-3-propyl-4-[2-(4-nitrophenoxy)ethoxy]phenyl}ethanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium iodide In <i>N</i>-methyl-acetamide; water ii 1-{2-Hydroxy-3-propyl-4-[2-(4-nitrophenoxy)ethoxy]phenyl}ethanone (ii) 1-{2-Hydroxy-3-propyl-4-[2-(4-nitrophenoxy)ethoxy]phenyl}ethanone To sodium hydride (1.78 g, 50% dispersion) in dry dimethylformamide (60 ml) was 2,4-dihydroxy-3-propylacetophenone (7.22 g) in dimethylformamide (20 ml), dropwise with stirring under nitrogen. The solution was heated to 100° C. and 4-nitro-1-(2-chdloroethoxy)benzene (7.5 g) and sodium iodide (5.5 g) were added rapidly. The reaction mixture was left to stir at 100° C. for 20 hours, cooled and evaporated under reduced pressure to leave a brown oil. The oil was taken up in water, extracted with dichloromethane (*3), washed with 2N sodium hydroxide (*2), and aqueous sodium thiosulphate, dried over MgSO4, filtered and evaporated under reduced pressure to give a brown solid. The solid was recrystallized twice from methanol to give a yellow crystalline solid, m.p. 124°-125° C.
  • 78
  • [ 40786-69-4 ]
  • ethyl acetate n-hexane [ No CAS ]
  • [ 26825-92-3 ]
  • [ 33513-42-7 ]
  • 8-(4-acetyl-3-hydroxy-2-propylphenoxy)-octanoic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
58% With potassium carbonate In acetone 11 Preparation of 8-(4-Acetyl-3-hydroxy-2-propylphenoxy)octanoic acid methyl ester EXAMPLE 11 Preparation of 8-(4-Acetyl-3-hydroxy-2-propylphenoxy)octanoic acid methyl ester A mixture of 4.30 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 5.10 g of methyl 8-bromooctanoate and 4.55 g of anhydrous potassium carbonate in 100 ml of anhydrous acetone and 30 ml of anhydrous dimethyl formamide was stirred at reflux for 20 hours. The usual workup followed by purification by high pressure liquid chromatography using a solvent of 15% ethyl acetate-hexane gave 4.5 g (58% yield) of 8-(4-acetyl-3-hydroxy-2-propylphenoxy)octanoic acid methyl ester, the titled compound, mp 39°-41°, after crystallization from hexane. Analysis Calculated for C20 H30 O5: C, 68.55; H, 8.63. Found: C, 68.62; H, 8.81.
58% With potassium carbonate In acetone 56 Preparation of 8-(4-Acetyl-3-hydroxy -2-propylphenoxy) octanoic acid methyl ester EXAMPLE 56 Preparation of 8-(4-Acetyl-3-hydroxy -2-propylphenoxy) octanoic acid methyl ester A mixture of 4.30 g of 1-(2,4-dihydroxy-3-propylphenyl) ethanone, 5.10 g of methyl 8-bromooctanoate and 4.55 g of anhydrous potassium carbonate in 100 ml of anhydrous acetone and 30 ml of anhydrous dimethyl formamide was stirred at reflux for 20 hours. The usual workup followed by purification by high pressure liquid chromatography using a solvent of 15% ethyl acetate-hexane gave 4.5 g (58% yield) of 8-(4-acetyl-3-hydroxy-2-propylphenoxy) octanoic acid methyl ester, the titled compound, mp 39-41°, after crystallization from hexane. Analysis Calculated for C20 H30 O5: C, 68.55; H, 8.63. Found: C, 68.62; H, 8.81.
  • 79
  • methyl 6-bromo-nonanoate [ No CAS ]
  • [ 40786-69-4 ]
  • 6-(4-Acetyl-3-hydroxy-2-propylphenoxy)nonanoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide In ethanol; acetone 48 6-(4-Acetyl-3-hydroxy-2-propylphenoxy)nonanoic acid EXAMPLE 48 6-(4-Acetyl-3-hydroxy-2-propylphenoxy)nonanoic acid Following the procedures of Examples 15 E and 15F, 1.18 g. of methyl 6-bromo-nonanoate and 0.91 g. of 2,4-dihydroxy-3-propylacetophenone were reacted in the presence of 0.65 g. of potassium carbonate in 40 ml. of acetone. Hydrolysis of the ester intermediate with sodium hydroxide in aqueous ethanol gave the title product, M+ =350; NMR.
  • 80
  • [ 40786-69-4 ]
  • [ 79050-33-2 ]
  • 1-{2-Hydroxy-3-propyl-4-[4-(2-bromoethyl)phenylmethoxy]phenyl}ethanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium iodide; sodium carbonate; In dichloromethane; water; butanone; EXAMPLE 2 1-{2-Hydroxy-3-propyl-4-[4-(2-bromoethyl)phenylmethoxy]phenyl}ethanone To a solution of 1-(2,4-dihydroxy-3-propylphenyl)ethanone (10.0 g; 0.051 m) in dry methyl ethyl ketone (100 ml) was added dried anhydrous sodium carbonate (27 g; 5 mol eq) and sodium iodide (0.5 g). To the stirred suspension was added <strong>[79050-33-2]4-(2-bromoethyl)phenylmethylbromide</strong> (14.2 g; 0.051 m) (literature preparation) and the suspension gently heated at reflux overnight. The cooled suspension was evaporated under reduced pressure, the residue taken up in water and extracted with dichloromethane (*2). The organic extract was washed with aqueous sodium hydroxide (2N), then water, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give a yellow oil. The oil was chromatographed on a U30 Sorbsil column using dichloromethane to give a pale yellow oil which crystallized on standing to a white crystalline solid; recrystallized from ethanol m.p. 66-70 C.
  • 81
  • [ 40786-69-4 ]
  • [ 4224-70-8 ]
  • [ 908093-98-1 ]
  • [ 92518-34-8 ]
YieldReaction ConditionsOperation in experiment
With potassium iodide; potassium carbonate In hexane; dichloromethane; ethyl acetate; butanone 24 6-(4-Acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid EXAMPLE 24 6-(4-Acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid The benzhydryl ester of 6-bromohexanoic acid was prepared in situ by reacting 14.6 g. (80 mmoles) of 6-bromohexanoic acid with 17.0 g. (88 mmoles) of diphenyldiazomethane in 200 ml. methylene chloride with a catalytic amount of boron trifluoride etherate. The methylene chloride was removed by evaporating in vacuo and the resulting oil was dissolved in 300 ml. of methyl ethyl ketone. To the resulting solution was added 15.5 g. (80 mmoles) of 2,4-dihydroxy-3-propylacetophenone, 11.0 g. (80 mmoles) of potassium carbonate, and 2 g. of potassium iodide. The reaction was allowed to reflux overnight. The reaction was then filtered, and the solvent removed in vacuo. The resulting oil was dissolved in 200 ml. of ethyl acetate and approximately 50 ml. of hexane was added. This organic solution was washed 3 times each with 250 ml. of dilute potassium carbonate solution. The organic phase was dried over sodium sulfate, filtered, and the solvent evaporated in vacuo. The product was purified by high pressure liquid chromatography (silica gel/0-20% ethyl acetate gradient in hexane) which after crystallization from hexane/ethyl acetate afforded 24.9 g. of diphenylmethyl 6-(4-acetyl-3-hydroxy-2-propylphenoxy)-hexanoate.
  • 82
  • [ 40786-69-4 ]
  • [ 105-39-5 ]
  • [ 88420-24-0 ]
YieldReaction ConditionsOperation in experiment
78% With potassium carbonate In acetone 1 Preparation of (4-Acetyl-3-hydroxy-2-propylphenoxy)acetic acid ethyl ester EXAMPLE 1 Preparation of (4-Acetyl-3-hydroxy-2-propylphenoxy)acetic acid ethyl ester A mixture of 24.25 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 16.0 ml of ethyl chloroacetate and 26 g anhydrous potassium carbonate in 375 ml of anhydrous acetone was stirred at reflux for 17 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to an oil which was crystallized from ethanol to give 27.2 g of (4-acetyl-3-hydroxy-2-propylphenoxy)acetic acid ethyl ester, the titled compound, mp 61°-64°, (78% yield) in two crops. Analysis Calculated for C15 H20 O5: C, 64.27; H, 7.19. Found: C, 64.10; H, 7.12.
  • 83
  • [ 40786-69-4 ]
  • [ 105-39-5 ]
  • [ 88420-24-0 ]
  • [ 104074-06-8 ]
YieldReaction ConditionsOperation in experiment
78% With potassium carbonate In acetone 46 Preparation of (4-Acetyl-3-hydroxy-2-propylphenoxy)acetic acid ethyl ester. EXAMPLE 46 Preparation of (4-Acetyl-3-hydroxy-2-propylphenoxy)acetic acid ethyl ester. A mixture of 24.25 g of 1-(2,4-dihydroxy-3-propylphenyl) ethanone, 16.0 ml of ethyl chloroacetate and 26 g of anhydrous potassium carbonate in 375 ml of anhydrous acetone was stirred at reflux for 17 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to an oil which was crystallized from ethanol to give 27.2 g of (4-acetyl-3-hydroxy-2-propylphenoxy)acetic acid, the titled compound, mp 61°-64°, (78% yield) in two crops. Analysis Calculated for C15 H20 O5: C, 64.27; H, 7.19. Found: C, 64.10; H, 7.12.
  • 84
  • [ 5445-25-0 ]
  • [ 40786-69-4 ]
  • ethyl 2-(4-chlorophenyl)-2-(4-acetyl-2-n-propyl-3-hydroxyphenoxy)acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In N,N-dimethyl-formamide 5 Ethyl 2-(4-chlorophenyl)-2-(4-acetyl-2-n-propyl-3-hydroxyphenoxy)acetate EXAMPLE 5 Ethyl 2-(4-chlorophenyl)-2-(4-acetyl-2-n-propyl-3-hydroxyphenoxy)acetate To a cold, stirred mixture of 8 g of 2,4-dihydroxy-3-n-propylacetophenone and 4 g of potassium carbonate in 250 ml of DMF was added 13 g of Ethyl 2-bromo-2-(4-chlorophenyl)acetate, and stirring was continued at room temperature for 48 hours. The reaction mixture was then diluted with water, extracted with ethyl acetate, dried and evaporated to dryness to give 4 g of the crude product. The crude product was then crystallized from hexane to give 2.8 g of pure product, melting point 94°-95° C.
  • 85
  • ethyl acetate-toluene [ No CAS ]
  • [ 40786-69-4 ]
  • [ 20965-27-9 ]
  • [ 92518-08-6 ]
  • [ 92518-40-6 ]
YieldReaction ConditionsOperation in experiment
83% With potassium carbonate In N,N-dimethyl-formamide 23 Preparation of 7-(4-Acetyl-3-hydroxy-2-propylphenoxy)heptanoic acid EXAMPLE 23 Preparation of 7-(4-Acetyl-3-hydroxy-2-propylphenoxy)heptanoic acid A mixture of 5.8 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 5.4 ml of 7-bromoheptanenitrile and 8.3 g of anhydrous potassium carbonate in 50 ml of dimethyl formamide was stirred and heated at 75° for 20 hours. The reaction mixture was filtered and the filtrate was concentrated on the oil pump. The residual oil was chromatographed on 200 g of silica gel using 5% ethyl acetate-toluene to give 7.5 g (83% yield) of 7-(4-acetyl-3-hydroxy-2-propylphenoxy)heptane nitrile. This was dissolved in 200 ml of ether-methanol (1:1) and cooled in an ice bath while a stream of hydrochloric acid gas was introduced for 10 minutes. The reaction mixture was kept at 3° for 1 hour and at room temperature for 16 hours. Water (40 ml) was added and most of the solvent was removed in vacuo.
83% With potassium carbonate In N,N-dimethyl-formamide 18 7-(4-Acetyl-3-hydroxy-2-propylphenoxy)heptanoic acid EXAMPLE 18 7-(4-Acetyl-3-hydroxy-2-propylphenoxy)heptanoic acid A mixture of 5.8 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 5.4 ml of 7-bromoheptanenitrile and 8.3 g of anhydrous potassium carbonate in 50 ml of dimethyl formamide was stirred and heated at 75° for 20 hours. The reaction mixture was filtered and the filtrate was concentrated on the oil pump. The residual oil was chromatographed on 200 g of silica gel using 5% ethyl acetate-toluene to give 7.5 g (83% yield) of 7-(4-acetyl-3-hydroxy-2-propylphenoxy)heptane nitrile. This was dissolved in 200 ml of ether-methanol (1:1) and cooled in an ice bath while a stream of hydrochloric acid gas was introduced for 10 minutes. The reaction mixture was kept at 3° for 1 hour and at room temperature for 16 hours. Water (40 ml) was added and most of the solvent was removed in vacuo.
83% With potassium carbonate In N,N-dimethyl-formamide 68 Preparation of 7-(4-Acetyl-3-hydroxy-2-propylphenoxy) heptanoic acid. EXAMPLE 68 Preparation of 7-(4-Acetyl-3-hydroxy-2-propylphenoxy) heptanoic acid. A mixture of 5.8 g of 1-(2,4-dihydroxy-3-propylphenyl) ethanone, 5.4 ml of 7-bromoheptanenitrile and 8.3 g of anhydrous potassium carbonate in 50 ml of dimethyl formamide was stirred and heated at 75° for 20 hours. The reaction mixture was filtered and the filtrate was concentrated on the oil pump. The residual oil was chromatographed on 200 g of silica gel using 5% ethyl acetate-toluene to give 7.5 g (83% yield) of 7-(4-acetyl-3-hydroxy-2-propylphenoxy)heptane nitrile. This was dissolved in 200 ml of ether-methanol (1:1) and cooled in an ice bath while a stream of hydrochloric acid gas was introduced for 10 minutes. The reaction mixture was kept at 3° for 1 hour and at room temperature for 16 hours. Water (40 ml) was added and most of the solvent was removed in vacuo.
  • 86
  • [ 5414-19-7 ]
  • [ 40786-69-4 ]
  • 1-[4-[2-(2-bromoethoxy)ethoxy]-2-hydroxy-3-propyl phenyl]ethanone [ No CAS ]
  • 3-[2-(4-Acetyl-3-hydroxy-2-propylphenoxy) ethoxy]propanoic acid semihydrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% With potassium carbonate In acetone 66 Preparation of 3-[2-(4-Acetyl-3-hydroxy-2-propylphenoxy) ethoxy]propanoic acid semihydrate EXAMPLE 66 Preparation of 3-[2-(4-Acetyl-3-hydroxy-2-propylphenoxy) ethoxy]propanoic acid semihydrate A mixture of 1.94 g of 1-(2,4-dihydroxy-3-propylphenyl) ethanone, 7.00 g of bis-2-bromoethyl ether and 1.70 g of anhydrous potassium carbonate in 25 ml of anhydrous acetone was stirred at reflux for 20 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to an oil which was chromatographed on 250 g of silica gel. Elution with 5% ethyl acetate-toluene gave 2.66 g (77% yield) of 1-[4-[2-(2-bromoethoxy)ethoxy]-2-hydroxy-3-propyl phenyl]ethanone as an oil. The low resolution mass spectrum gave the molecular ion peak at m/e 344.
  • 87
  • [ 5414-19-7 ]
  • [ 40786-69-4 ]
  • potassium carbonatein [ No CAS ]
  • 3-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]propanoic acid semihydrate [ No CAS ]
  • 1-[4-[2-(2-bromoethoxy)ethoxy]-2-hydroxy-3-propyl phenyl]ethanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% In acetone 21 Preparation of 3-[2-(4-Acetyl-3-hydroxy-2-propylphenoxy)ethoxy]propanoic acid semihydrate EXAMPLE 21 Preparation of 3-[2-(4-Acetyl-3-hydroxy-2-propylphenoxy)ethoxy]propanoic acid semihydrate A mixture of 1.94 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 7.00 g of bis-2-bromoethyl ether and 1.70 g of anhydrous potassium carbonatein 25 ml of anhydrous acetone was stirred at reflux for 20 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to an oil which was chromatographed on 250 g of silica gel. Elution with 5% ethyl acetate-toluene gave 2.66 g (77% yield) of 1-[4-[2-(2-bromoethoxy)ethoxy]-2-hydroxy-3-propylphenyl]ethanone as an oil. The low resolution mass spectrum gave the molecular ion peak at m/e 344.
  • 88
  • [ 40786-69-4 ]
  • [ 6287-90-7 ]
  • 11-(4-acetyl-3-hydroxy-2-propylphenoxy)-undecanoic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
76% With potassium carbonate; In N,N-dimethyl-formamide; EXAMPLE 13 Preparation of 11-(4-Acetyl-3-hydroxy-2-propylphenoxy)undecanoic acid methyl ester A mixture of 1.00 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 1.44 g of <strong>[6287-90-7]methyl 11-bromoundecanoate</strong> and 1.00 g of anhydrous potassium carbonate in 20 ml of anhydrous dimethyl formamide was stirred and heated at 75 for 2 hours. The usual workup followed by chromatography on 30 g of silica gel and elution with 10% ethyl acetate-toluene gave 1.48 g (76% yield) of 11-(4-Acetyl-3-hydroxy-2-propylphenoxy)undecanoic acid methyl ester, the titled compound, as an oil. Analysis Calculated for C23 H36 O5: C, 70.38; H, 9.24. Found: C, 70.37; H, 9.36.
76% With potassium carbonate; In N,N-dimethyl-formamide; EXAMPLE 58 Preparation of 11-(4-Acetyl-3-hydroxy-2-propylphenoxy) undecanoic acid methyl ester. A mixture of 1.00 g of 1-(2,4-dihydroxy-3-propylphenyl) ethanone, 1.44 g of <strong>[6287-90-7]methyl 11-bromoundecanoate</strong> and 1.00 g of anhydrous potassium carbonate in 20 ml of anhydrous dimethyl formamide was stirred and heated at 75 for 2 hours. The usual workup followed by chromatography on 30 g of silica gel and elution with 10% ethyl acetate-toluene gave 1.48 g (76% yield) of 11-(4-Acetyl-3-hydroxy-2-propylphenoxy) undecanoic acid methyl ester, the titled compound, as an oil. Analysis Calculated for C23 H36 O5: C, 70.38; H, 9.24. Found: C, 70.37; H, 9.36.
  • 89
  • [ 40786-69-4 ]
  • [ 61863-12-5 ]
  • 6-(4-acetyl-3-hydroxy-2-propylphenoxy)-1-chloro-4-hexyne [ No CAS ]
YieldReaction ConditionsOperation in experiment
88% With potassium carbonate In water; acetone 18 Preparation of 6-(4-Acetyl-3-hydroxy-2-propylphenoxy)-1-chloro-4-hexyne EXAMPLE 18 Preparation of 6-(4-Acetyl-3-hydroxy-2-propylphenoxy)-1-chloro-4-hexyne A mixture of 3.10 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 3.13 g of 1-bromo-6-chloro-2-hexyne and 3.30 g of anhydrous potassium carbonate in 35 ml of anydrous acetone was stirred at reflux for 2.5 hours. The solvent was removed in vacuo, water was added to the residue and the pH was adjusted to 4.0. The product was extracted with ether and the dried (over magnesium sulfate) extract was chromatographed on 250 g of silica gel. Elution with 25% ethyl acetate-hexane gave 4.30 g (88% yield) of 6-(4-acetyl-3-hydroxy-2-propylphenoxy)-1-chloro-4-hexyne, the titled compound.
88% With potassium carbonate In water; acetone 63 Preparation of 6-(4-Acetyl-3-hydroxy-2-propylphenoxy)-1-chloro-4-hexyne EXAMPLE 63 Preparation of 6-(4-Acetyl-3-hydroxy-2-propylphenoxy)-1-chloro-4-hexyne A mixture of 3.10 g of 1-(2,4-dihydroxy-3-propylphenyl) ethanone, 3.13 g of 1-bromo-6-chloro-2-hexyne and 3.30 g of anhydrous potassium carbonate in 35 ml of anhydrous acetone was stirred at reflux for 2.5 hours. The solvent was removed in vacuo, water was added to the residue and the pH was adjusted to 4.0. The product was extracted with ether and the dried (over magnesium sulfate) extract was chromatographed on 250 g of silica gel. Elution with 25% ethyl acetate-hexane gave 4.30 g (88% yield) of 6-(4-acetyl- 3-hydroxy-2-propylphenoxy)-1-chloro-4-hexyne, the titled compound.
  • 90
  • [ 16929-64-9 ]
  • [ 40786-69-4 ]
YieldReaction ConditionsOperation in experiment
5% In hexane; water; hydrogen bromide; acetic acid; ethyl acetate; EXAMPLE 13 3'-(n-Propyl)-2',4'-Dihydroxyacetophenone from an Anhydrous Mixture of the Acids. Glacial acetic acid (350 ml) absorbed 19.4 g of hydrogen bromide gas to give a 5% hydrogen bromide in acetic acid solution. <strong>[16929-64-9]1,3-Dimethoxy-2-(n-propyl)benzene</strong> (0.90 g, 5.0 mmol) was dissolved in 5% hydrogen bromide/glacial acetic acid solution and the reaction solution was stirred at reflux temperature for 17 hours then at room temperature for 12 hours. The reaction solution was added to water (500 ml) and the aqueous solution was extracted with ether (2*500 ml). The organic layers were combined, treated and chromatographed as in Example 10 (except that this Example used an additional elution of 5% ethyl acetate in hexane) to yield 0.61 g, 63% of the title product.
With hydrogen bromide; In hexane; water; acetic acid; ethyl acetate; EXAMPLE 10 3'-(n-Propyl)-2',4'-Dihydroxyacetophenone <strong>[16929-64-9]1,3-Dimethoxy-2-(n-propyl)benzene</strong> (0.90 g, 5.0 mmol), 48% aqueous hydrobromic acid (30 ml, 265 mmol), and glacial acetic acid (150 ml) were combined and stirred at reflux temperature for 72 hours. The reaction mixture was cooled to room temperature then added to water (250 ml). The aqueous mixture was extracted with ether (500 ml, 2*). The organic phases were combined, washed with brine (100 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was flash chromatographed over Kieselgel 60 (230-400 mesh, 4 cm diameter*16 cm length) eluted with 1% ethyl acetate in hexane, followed by a step gradient (2%, 3%, 4%) of ethyl acetate in hexane to give 0.4 g, 41% of the title product.
With hydrogen bromide; In hexane; acetic acid; ethyl acetate; EXAMPLE 12 3'-(n-Propyl)-2',4'-Dihydroxyacetophenone from a 10:1 Acid Mixture 1,3-Dimethoxy-2-propylbenzene (0.90 g, 5.0 mmol), glacial acetic acid (150 ml), and 48% aqueous hydrobromic acid (15 ml, 133 mmol) were combined and stirred at reflux temperature for three days. The mixture was allowed to cool to room temperature; poured into water (500 ml), and the aqueous solution extracted with ether (500 ml, 2*). The ether layers were combined, washed with brine, dried over magnesium sulfate, filtered and taken to dryness in vacuo. Flash chromatography as in Example 10 (plus an additional step of 5% ethyl acetate in hexane) yielded the title product: n.m.r.: delta12.97 (s, 1H), 7.52 (d, 1H), 6.38 (d, 1H), 5.79 (s, 1H), 2.63 (t, 2H), 2.56 (s, 3H), 1.58 (m, 2H), 0.98 (t, 3H).
  • 91
  • 9-bromomeothyl-3-cyano-4H-pyrido[1,2-a]pyrimidin-4-one [ No CAS ]
  • [ 40786-69-4 ]
  • [ 108428-04-2 ]
YieldReaction ConditionsOperation in experiment
59% With potassium carbonate In butanone REFERENCE EXAMPLES REFERENCE EXAMPLES 1.30 g (4.92 mmoles) of 9-bromomeothyl-3-cyano-4H-pyrido[1,2-a]pyrimidin-4-one, 0.97 g (5.00 mmoles) of 2,4-dihydroxy-3-n-propylacetophenone and 0.60 g of anhydrous potassium carbonate were added to 100 ml of methyl ethyl ketone, and this mixture was heated under reflux for 45 minutes. After cooling, the crystals which separated out of the reaction solution were collected by filtration and washed with water to obtain 1.10 g (59% yield) of 9-[(4-acetyl-3-hydroxy-2-n-propylphenoxy)methyl]-3-cyano-4H-pyrido[1,2-a]pyrimidin-4-one. These crystals had a melting point of 233°-234° C. The following 18 nitrile derivatives [II] were prepared in substantially the same manner as described above, except that the 9-bromomethyl-3-cyano-4H-pyrido[1,2-a]pyrimidin-4-one was replaced by each of the corresponding compounds [III] and the reaction conditions (such as the molar ratio of reactants, reaction solvent, reaction temperature, reaction time, etc.) were suitably modified.
  • 92
  • [ 38987-00-7 ]
  • ethyl acetate n-hexane [ No CAS ]
  • [ 64-17-5 ]
  • [ 40786-69-4 ]
YieldReaction ConditionsOperation in experiment
palladium; EXAMPLE 7 Preparation of 3-Propyl-2,4-dihydroxyacetophenone A mixture of 3-allyl-2,4-dihydroxyacetophenone from Example 6 (250 g, 1.31 moles) ethyl alcohol (1 L) and 5% palladium on carbon (5 g) was hydrogenated for 2 hours at room temperature using a Parr hydrogenator (Note 1). The catalyst was filtered off on celite and the filtrate was concentrated. The residual solid was powdered and swished for 2 hours at room temperature using 5 ml of 5% ethyl acetate-hexane per 1 gram of product to give the title compound. m.p. 126-128 C. (Note 2), sufficiently pure for use in the next step.
palladium; EXAMPLE 7 Preparation of 3-Propyl-2,4-dihydroxyacetophenone A mixture of 3-allyl-2,4-dihydroxyacetophenone from Example 6 (250 g, 1.31 moles) ethyl alcohol (1 L) and 5% palladium on carbon (5 g) was hydrogenated for 2 hours at room temperature using a Parr hydrogenator (Note 1). The catalyst was filtered off on celite and the filtrate was concentrated. The residual solid was powdered and swished for 2 hours at room temperature using 5 ml of 5% ethyl acetate-hexane per 1 gram of product to give the title compound. m.p. 126-128C. (Note 2), sufficiently pure for use in the next step.
  • 93
  • [4-acetyl-3-[2-(2-chloroethoxy)ethoxy]-2-propylphenoxy]acetic acid ethyl ester [ No CAS ]
  • [ 40786-69-4 ]
  • ethyl acetate n-hexane [ No CAS ]
  • [ 88420-06-8 ]
YieldReaction ConditionsOperation in experiment
70% With potassium iodide; potassium carbonate In <i>N</i>-methyl-acetamide; acetone 27 Preparation of [4-acetyl-3-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester EXAMPLE 27 Preparation of [4-acetyl-3-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester A mixture of 2.94 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 5.85 g of [4-acetyl-3-[2-(2-chloroethoxy)ethoxy]-2-propylphenoxy]acetic acid ethyl ester, 4.2 g of anhydrous potassium carbonate, and 2.25 g of potassium iodide in 100 ml of anhydrous acetone and 50 ml of anhydrous dimethylformamide was stirred at reflux. Additional 2.0 g portions of potassium carbonate were added after 19, 26 and 51 hours. Reflux was continued for a total of 8 days and then the reaction mixture was concentrated in vacuo. The crude product was purified by liquid chromatography using 35% ethyl acetate-hexane to give 5.8 g (70% yield) of [4-acetyl-3-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester.
  • 94
  • [4-acetyl-3-[2-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester [ No CAS ]
  • [ 40786-69-4 ]
  • ethyl acetate n-hexane [ No CAS ]
  • [ 88420-11-5 ]
YieldReaction ConditionsOperation in experiment
70% With potassium carbonate In <i>N</i>-methyl-acetamide; acetone 45 Preparation of [4-acetyl-3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester EXAMPLE 45 Preparation of [4-acetyl-3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester A mixture of 1.16 g (0.006 mole) of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.93 g (0.006 mole) of [4-acetyl-3-[2-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester and 1.65 g (0.012 mole) of anhydrous potassium carbonate in 50 ml of anhydrous acetone and 25 ml of anhydrous dimethylformamide was stirred at reflux for 21 hours. The solvents were removed in vacuo and the residue was purified by HPLC using 40% ethyl acetate-hexane to give 2.45 g (70% yield) of [4-acetyl-3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester as an oil.
  • 95
  • [ 40786-69-4 ]
  • ethyl acetate n-hexane [ No CAS ]
  • [ 88420-37-5 ]
  • [ 88420-07-9 ]
YieldReaction ConditionsOperation in experiment
68% With potassium carbonate In <i>N</i>-methyl-acetamide; acetone 31 Preparation of 6-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]hexanoic acid methyl ester EXAMPLE 31 Preparation of 6-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]hexanoic acid methyl ester A mixture of 2.62 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 6.00 g of 6-[4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]hexanoic acid methyl ester and 3.70 g of anhydrous potassium carbonate in 100 ml of anhydrous acetone and 50 ml of anhydrous dimethylformamide was stirred at reflux for 20 hours. The reaction mixture was concentrated in vacuo and the residue was purified by liquid chromatography using 30% ethyl acetate-hexane to give 5.10 g (68% yield) of 6-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]hexanoic acid methyl ester as an oil.
  • 96
  • [ 40786-69-4 ]
  • ethyl acetate n-hexane [ No CAS ]
  • [ 88420-46-6 ]
  • [ 88420-15-9 ]
YieldReaction ConditionsOperation in experiment
72% With potassium carbonate In <i>N</i>-methyl-acetamide; acetone 57 Preparation of [4-acetyl-3-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]acetic acid ethyl ester EXAMPLE 57 Preparation of [4-acetyl-3-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]acetic acid ethyl ester A mixture of 1.89 g (0.004 mole) of [4-acetyl-3-[3-(3-bromopropoxy)propoxy]-2-propylphenoxy]acetic acid ethyl ester, 0.80 g (0.004 mole) of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, and 1.14 g (0.0082 mole) of potassium carbonate in 40 ml of anhydrous acetone and 20 ml of anhydrous dimethylformamide was stirred at reflux for 20 hours. The solvents were removed in vacuo and the residue was purified by HPLC using 35% ethyl acetate-hexane to give 1.69 g (72% yield) of [4-acetyl-3-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]acetic acid ethyl ester as an oil.
  • 97
  • [4-acetyl-3-[4-(4-iodobutoxy)butoxy]-2-propylphenoxy]acetic acid ethyl ester [ No CAS ]
  • [ 40786-69-4 ]
  • ethyl acetate n-hexane [ No CAS ]
  • [ 88420-17-1 ]
YieldReaction ConditionsOperation in experiment
87% With potassium carbonate In acetone 63 Preparation of [4-Acetyl-3-[4-[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butoxy]butoxy]-2-propylphenoxy]acetic acid ethyl ester EXAMPLE 63 Preparation of [4-Acetyl-3-[4-[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butoxy]butoxy]-2-propylphenoxy]acetic acid ethyl ester A mixture of 1.00 g (0.0052 mole) of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.78 g (0.0052 mole) of [4-acetyl-3-[4-(4-iodobutoxy)butoxy]-2-propylphenoxy]acetic acid ethyl ester and 1.44 g (0.010 mole) of anhydrous potassium carbonate in 75 ml of anhydrous acetone was stirred at reflux for 18 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by HPLC using 35% ethyl acetate-hexane to give 2.72 g (87% yield) of [4-acetyl-3-[4-[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butoxy]butoxy]-2-propylphenoxy]acetic acid ethyl ester as an oil.
  • 98
  • 4-[4-acetyl-3-[2-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoic acid ethyl ester [ No CAS ]
  • [ 40786-69-4 ]
  • ethyl acetate n-hexane [ No CAS ]
  • [ 88420-20-6 ]
YieldReaction ConditionsOperation in experiment
69% With potassium carbonate In <i>N</i>-methyl-acetamide; acetone 70 Preparation of 4-[4-acetyl-3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoic acid ethyl ester EXAMPLE 70 Preparation of 4-[4-acetyl-3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoic acid ethyl ester A mixture of 1.100 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.939 g of 4-[4-acetyl-3-[2-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoic acid ethyl ester and 1.56 g of anhydrous potassium carbonate in 80 ml of anhydrous acetone and 40 ml of anhydrous dimethylformamide was stirred at reflux for 20 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to a dark oil which was purified by high pressure liquid chromatography using 40% ethyl acetatehexane to give 2.413 g (69% yield) of 4-[4-acetyl-3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoic acid ethyl ester as an oil.
  • 99
  • [ 40786-69-4 ]
  • 1-(2,4-dihydroxy)-3-propylphenyl)ethanone [ No CAS ]
  • [ 101463-93-8 ]
  • [ 101463-94-9 ]
YieldReaction ConditionsOperation in experiment
70% With hydrogenchloride; potassium carbonate In N,N-dimethyl-formamide; acetone 4 EXAMPLE 4 EXAMPLE 4 Preparation of [[8-Acetyl-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-naphthalenyl]oxy]acetic acid methyl ester. A mixture of 1.7314 g of 1-(2,4-dihydroxy)-3-propylphenyl)ethanone, 3.5290 g of [[8-acetyl-7-(3-bromopropoxy)-2-naphthalenyl]oxy]acetic acid methyl ester and 1.90 g of anhydrous potassium carbonate in 75 ml of dry acetone was stirred at reflux for 30 hours. An additional 0.1938 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone and 1.0 g of potassium carbonate were added along with 10 ml anhydrous DMF and reflux was continued for 20 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was treated with aqueous hydrochloric acid and extracted with ethyl acetate. The dried (over magnesium sulfate) extract was concentrated in vacuo and the solid residue was recrystallized from methanol-water to give 3.1737 g (70% yield), mp 104°-107°, of [[8-Acetyl-7-[3 -(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-naphthalenyl]oxy]acetic acid methyl ester.
  • 100
  • [ 40786-69-4 ]
  • [ 58929-72-9 ]
  • [ 95265-23-9 ]
  • [[7-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-naphthalenyl]oxy]acetic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
EXAMPLE 33 When [7-hydroxy-2-naphthalenyl)oxy]acetic acid methyl ester is reacted with bis-(3-bromopropyl)ether in accordance with Example 3 and the product is then reacted with 1-(2,4-dihydroxy-3-propylphenyl)ethanone, in accordance with Example 4, an ester is obtained which can be hydrolyzed to give [[7-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-naphthalenyl]oxy]acetic acid.
  • 101
  • [(4-hydroxy-2-naphthalenyl)oxy]acetic acid methyl ester [ No CAS ]
  • [ 40786-69-4 ]
  • [ 58929-72-9 ]
  • [[4-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-naphthalenyl]oxy]acetic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
EXAMPLE 35 When [(4-hydroxy-2-naphthalenyl)oxy]acetic acid methyl ester is reacted with bis-(3-bromopropyl)ether in accordance with Example 3 and the product is then reacted with 1-(2,4-dihydroxy-3-propylphenyl)ethanone in accordance with Example 4, an ester is obtained which can be hydrolyzed to give [[4-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-naphthalenyl]oxy]acetic acid.
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