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CAS No. : | 36969-89-8 | MDL No. : | MFCD00009514 |
Formula : | C9H19O4P | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | LQZCYXCHWNQBKX-UHFFFAOYSA-N |
M.W : | 222.22 | Pubchem ID : | 580181 |
Synonyms : |
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Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P280-P301+P312-P302+P352-P305+P351+P338 | UN#: | |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid In 1,2-dimethoxyethane | 2 Dimethyl trans-2-(3-Oxo-1-octenyl)cyclopropane-1,1-dicarboxylate [VI, R2 = H, R4 = CH3 and (c) = (CH2)4 ] EXAMPLE 2 Dimethyl trans-2-(3-Oxo-1-octenyl)cyclopropane-1,1-dicarboxylate [VI, R2 = H, R4 = CH3 and (c) = (CH2)4 ] To 5.56 g of a 50% sodium hydride (NaH) suspension, rinsed with dry hexane, suspended in 400 ml dry 1,2-dimethoxyethane is added 27.4 g of the Wittig reagent, dimethyl-(2-oxoheptyl)phosphonate, in 400 ml dry 1,2-dimethoxyethane. The reaction mixture is stirred at room temperature till all NaH reacts to give the sodium salt (about 45 minutes). A solution of 21.6 g of dimethyl 2-formylcyclopropane-1,1-dicarboxylate (V, R2 = H and R4 = CH3), described in Example 1, in 350 ml dry 1,2-dimethoxyethane is added and the mixture is heated at 60° C for 1/2 hr; cooled, and acetic acid is added to render the mixture substantially neutral. After diluting with water the mixture is extracted with ether. The extract is washed with water, dried (MgSO4) and evaporated. The residue is purified by chromatography on silica gel to yield the title compound, nmr (CDCl3) δ 0.88(t,3H), 1.77(m,2H), 3.77(s,3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With potassium hydroxide In dichloromethane at 25℃; for 0.333333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With sodium hydroxide; N-benzyl-N,N,N-triethylammonium chloride for 0.5h; Ambient temperature; | |
72% | With sodium hydroxide In dichloromethane for 0.5h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With sodium hydride In 1,2-dimethoxyethane at 25℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With sodium hydride In 1,2-dimethoxyethane at -25℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sodium hydride In tetrahydrofuran | |
0.25 g | With sodium hydroxide; N-benzyl-N,N,N-triethylammonium chloride In dichloromethane for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: dimethyl 2-oxoheptylphosphonate With sodium hydride In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #2: 3α-hydroxy-2β-formyl-7-(4-carbomethoxybutylidene)bicyclo<3.3.0>octane 3-tetrahydropyranyl ether In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; | 15-dehydro-6α-carbaprostaglandin I2 methyl ester tetrahydropyran-2-yl ether (29) To a stirred suspension of 443 mg (11.7 mmol) of a 63% NaH dispersion in dry THF (80 ml) at room temp was added dropwise a soln of dimethyl 2-oxoheptylphosphonate (2.72 g, 12.3 mmol) in dry THF (4 ml) under argon. After 30 min. a soln of 28 (3.9, 11.1 mmol) in dry THF (10 ml) was added. The mixture was allowed to stir at that temp for 1 hr, and the reaction mixture was quenched by the addition of 3 ml of AcOH. The precipitate was removed by filtration through a pad of silica gel, and the filtrate was concentrated in vacuo. The residue was chromatographed on 100 g of silica gel eluting with AcOEt-cyclohexane (1:9) to give 29 as a pale yellow oil (5.0 g, 100 %) |
100% | Stage #1: dimethyl 2-oxoheptylphosphonate With sodium hydride In tetrahydrofuran at 20℃; Inert atmosphere; Stage #2: 3α-hydroxy-2β-formyl-7-(4-carbomethoxybutylidene)bicyclo<3.3.0>octane 3-tetrahydropyranyl ether In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; | |
With sodium hydride 1.) THF, RT, 30 min, 2.) THF, RT, 1 h; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With sodium hydride In 1,2-dimethoxyethane for 24h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With sodium hydride In tetrahydrofuran; paraffin for 1.5h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With potassium hydroxide In dichloromethane at 25℃; for 0.333333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium hydroxide In dichloromethane at 20℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With potassium hydroxide In dichloromethane at 25℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium hydroxide In dichloromethane at 20℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With sodium hydride In 1,2-dimethoxyethane 1.) room temperature, 1 h, 2.) room temperature, 2 h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sodium hydride In 1,2-dimethoxyethane at 0 - 21℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With sodium hydride In tetrahydrofuran 1.) r.t., 4 h, 2.) -5 deg C, 30 min; r.t., 20 h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With sodium hydroxide; tetraethylbenzylammonium chloride In dichloromethane for 0.5h; | |
With sodium hydroxide; N-benzyl-N,N,N-triethylammonium chloride 1.) CH2Cl2, 2.) CH2Cl2; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sodium hydride In 1,2-dimethoxyethane at 0 - 21℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium hydride In 1,2-dimethoxyethane at 0 - 21℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hexamethyldisilazane In tetrahydrofuran at -78 - 0℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sodium hexamethyldisilazane In tetrahydrofuran at -78 - 0℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With potassium carbonate In 1,4-dioxane; water at 70 - 80℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With RuCl2((S)-binap)(dmf)n; hydrogen In methanol at 50℃; for 80h; Yield given. Yields of byproduct given. Title compound not separated from byproducts; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.2% | With C48H44ClO4P2Ru(1+)*Cl(1-); hydrogen In methanol at 50℃; for 19h; Inert atmosphere; enantioselective reaction; | |
100 % Spectr. | With hydrogen In methanol for 88h; Ambient temperature; | |
With ruthenium trichloride; hydrogen; (S)-(-)-(6,6’-dimethoxybiphenyl-2,2’-diyl)bis(diphenylphosphine) In methanol at 20℃; for 17h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium hydroxide In methanol at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Stage #1: dimethyl 2-oxoheptylphosphonate With sodium hydride In N,N-dimethyl acetamide at 0℃; Stage #2: ethyl (R)-7-(2-formyl-5-oxopyrrolidin-1-yl)heptanoate In N,N-dimethyl acetamide at 20℃; | |
With N-ethyl-N,N-diisopropylamine; lithium chloride In acetonitrile at 20℃; for 17h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: acrolein; (1<i>H</i>-indol-3-ylmethyl)-(4-methoxy-benzyl)-amine With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 0℃; for 0.5h; Stage #2: dimethyl 2-oxoheptylphosphonate With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 0.333333h; Stage #3: With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 96% 2: 1% | With sodium hexamethyldisilazane In tetrahydrofuran at -78 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: dimethyl 2-oxoheptylphosphonate With sodium hydride In tetrahydrofuran at 0 - 20℃; for 1h; Stage #2: (S)-[(2S,4S,5S)-5-(7-Benzyloxy-hept-2-ynyl)-4-(tert-butyl-dimethyl-silanyloxy)-tetrahydro-furan-2-yl]-(tert-butyl-dimethyl-silanyloxy)-acetaldehyde In tetrahydrofuran at 20℃; for 0.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 48% 2: 12% | Stage #1: dimethyl 2-oxoheptylphosphonate With N-ethyl-N,N-diisopropylamine; lithium chloride In acetonitrile at 20℃; Stage #2: 2,4-dimethyl-3-methoxymethoxy-5-oxo-2,5-dihydrothiophene-2-carbaldehyde In acetonitrile at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: dimethyl 2-oxoheptylphosphonate With sodium hydride In 1,2-dimethoxyethane at 0℃; Stage #2: 2-{6',6'-dichlorobicyclo[3.1.0]hex-1'-yl}acetaldehyde In 1,2-dimethoxyethane at 0 - 18℃; for 16.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 1.) LiN(TMS)2 / 1.) THF, 0 deg C, 10 min, 2.) THF, 22 deg C, 3 h 2: CeCl3*7H2O, NaBH4 / methanol / 0.08 h 3: 205 mg / 1 N NaOH / methanol / 1 h / 22 °C | ||
Multi-step reaction with 3 steps 1: 1.) LiN(TMS)2 / 1.) THF, 0 deg C, 10 min, 2.) THF, 22 deg C, 3 h 2: 0.6 mg / LiAlH4, C2H5OH, (S)-(-)-1,1'-bi-2-naphthol / tetrahydrofuran / 3 h / -78 °C 3: 205 mg / 1 N NaOH / methanol / 1 h / 22 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 1.) LiN(TMS)2 / 1.) THF, 0 deg C, 10 min, 2.) THF, 22 deg C, 3 h 2: CeCl3*7H2O, NaBH4 / methanol / 0.08 h | ||
Multi-step reaction with 2 steps 1: 1.) LiN(TMS)2 / 1.) THF, 0 deg C, 10 min, 2.) THF, 22 deg C, 3 h 2: 0.6 mg / LiAlH4, C2H5OH, (S)-(-)-1,1'-bi-2-naphthol / tetrahydrofuran / 3 h / -78 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; lithium chloride | 7 EXAMPLE 7; Synthesis of 7a [0110] Treatment of dibromoolefin 13 with n-BuLi and N,N-dimethylformamide affords ynal 55, which is condensed with dimethyl (2-oxoheptyl)phosphonate in the presence of NEt3 and LiCl to provide enone 56. 56 is reduced to 15S-alcohol 57 by treatment with NaBH4 and CeCCl3, followed by separation of the resulting racemic mixture using HPLC with a chiral stationary phase. Treatment of 57 with DHP and TsOH gives THP ether 58, which is desilylated with TBAF in THF to yield alcohol 59. Oxidation of 59 with TPAP and NMO affords aldehyde 60. 60 is treated with Ph3P(CH2)4CO2H Br in the presence of KOBut, followed by PPTS in MeOH, to give 7. Reaction of 7 with (trimethylsilyl)diazomethane in THF/methanol affords the methyl ester 7a. | |
With triethylamine; lithium chloride In tetrahydrofuran | 22 EXAMPLE 22; Synthesis of 180 [0154] Treatment of dibromoolefin 13 with n-butyllithium in THF at -78° C. affords an intermediate alkynyllithium, which is reacted in situ with DMF to afford ynal 176. This aldehyde is condensed with dimethyl (2-oxoheptyl)phosphonate (commercially available from Aldrich Chemical Company, Milwaukee, Wis.) in the presence of NEt3 and LiCl to provide enone 177, which is reduced using NaBH4/CeCl3 to give alcohol 178. Treatment of 178 with TBAF in THF yields an intermediate diol, which is oxidized with catalytic TEMPO and stoichiometric NCS in CH2Cl2/water using tetra-n-butylammonium hydrogen sulfate under vigorous stirring to give aldehyde 179. The aldehyde is treated with (4-carboxybutyl)triphenylphosphonium bromide/KOBut in THF to give an intermediate acid, which is reacted with trimethylsilyl)diazomethane in THF/methanol to afford methyl ester 180. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; lithium chloride In tetrahydrofuran | 6 Reduction of γ-butyrolactone (26) with DIBAL-H in diethyl ether at -78° C. provides tetrahydrofuranol 27, which is condensed with Ph3P+(CH2)4CO2H Br (commercially available from Aldrich Chemical Company) in THF in the presence of potassium tert-butoxide to afford olefin 28. Oxidation of 28 with catalytic TEMPO/stoichiometric NCS in rapidly stirring water/CH2Cl2 containing catalytic n-Bu4NHSO4 yields aldehyde 29, which is treated with Ph3PCH2I2 and NaHMDS in THF/HMPA at -78° C. to give cis-vinyl iodide 30. Treatment of 30 with NaH in THF generates the sodium carboxylate, which is treated sequentially with tert-butyl lithium in diethyl ether at -78° C. and DMF to provide cis-enal 31. Horner-Emmons olefination of 31 with phosphonate 32 (commercially available from Aldrich Chemical Company) in THF in the presence of NEt3/LiCl gives dienone 33, which is reduced with (-)-Ipc2BCl in THF at 0° C. to give dienol 6 (R=H). Treatment of 6 (R=H) with either diazomethane or ethyl iodide/DBU provides 6 (R=CH3) or 6 (R=C2H5), respectively |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium chloride In 1,2-dimethoxyethane; ethyl acetate | 1.3 Methyl 4-[(2-{(5R)-2-oxo-5-[(1E)-3-oxooct-1-enyl] pyrrolidin-1-yl} ethyl)thio]-butanoate Step 3 Methyl 4-[(2-{(5R)-2-oxo-5-[(1E)-3-oxooct-1-enyl] pyrrolidin-1-yl} ethyl)thio]-butanoate To a solution of sodium hydride (95%, 14 mg, 0.58 mmol) in 3 mL of anhydrous 1,2-dimethoxyethane at 0° C. under an argon atmosphere was added dimethyl 2-oxoheptylphosphonate (ACROS, 0.13 mL, 0.61 mmol). The cooling bath was removed and the reaction was stirred for 2 hours. After this time period, the mixture was cooled to 0° C. and a solution of methyl 4-({2-[(2R)-2-formyl-5-oxopyrrolidin-1-yl]ethyl}thio)butanoate (0.55 mmol) in anhydrous 1,2-dimethoxyethane was added. The reaction was allowed to come to room temperature, stirred for 2 hours and then quenched with an aqueous solution of saturated ammonium chloride. Ethyl acetate (50 mL) was then added and the mixture was partitioned between the two phases. The organic solution was dried (brine, Na2SO4), evaporated via reduced pressure and purified with column chromatography (SiO2, EtOAc/Hexane-1/1) to yield methyl 4-[(2-{(5R)-2-oxo-5-[(1E)-3-oxooct-1-enyl] pyrrolidin-1-yl} ethyl)thio]-butanoate as an oil. This material was taken directly on to the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium chloride In 1,2-dimethoxyethane | 2.3 {(Z)-4-[(R)-2-Oxo-5-((E)-3-oxo-oct-1-enyl)-pyrrolidin-1-yl]-but-2-enyloxy}-acetic Acid Ethyl Ester Step 3 {(Z)-4-[(R)-2-Oxo-5-((E)-3-oxo-oct-1-enyl)-pyrrolidin-1-yl]-but-2-enyloxy}-acetic Acid Ethyl Ester To a solution of sodium hydride (95%, 0.02 g, 0.78 mmol) in 10 mL of anhydrous 1,2-dimethoxyethane at 0° C. under a nitrogen atmosphere was added dimethyl 2-oxoheptylphosphonate (0.17 mL, 0.78 mmol), and the reaction was stirred for 1 hour. A solution of [(Z)-4-((R)-2-formyl-5-oxo-pyrrolidin-1-yl)-but-2-enyloxy]-acetic acid ethyl ester (0.21 g, 0.78 mmol) in 2 mL anhydrous 1,2-dimethoxyethane was added. The reaction was allowed to come to room temperature, stirred for 3 hours and then quenched with an aqueous solution of saturated ammonium chloride. After extraction with ethyl acetate, the organic solution was dried (brine, Na2SO4), evaporated and purified by chromatography to yield {(Z)-4-[(R)-2-oxo-5-((E)-3-oxo-oct-1-enyl)-pyrrolidin-1-yl]-but-2-enyloxy}-acetic acid ethyl ester as an oil. This material was taken directly on to the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride In 1,2-dimethoxyethane; ethyl acetate | 3.a 1-Methyl-2-oxo-3-benzyloxymethyl-4-(3-oxo-octenyl)-imidazolidine VI EXAMPLE 3a 1-Methyl-2-oxo-3-benzyloxymethyl-4-(3-oxo-octenyl)-imidazolidine VI 6.72 g of 1,8-diazabicyclo-(5,4,0)-undec-7-ene(DBU) are introduced into 40 ml of dimethoxyethane (DME). 9.8 g of 2-oxoheptyl-phosphonic acid dimethyl ester, dissolved in 100 ml of absolute DME, are added dropwise at room temperature. The mixture is stirred at room temperature for 30 minutes. 10.5 g of 1-methyl-2-oxo-3-benzyloxycarbonyl-4-formyl-imidazolidine (Example 2), dissolved in 100 ml of absolute DME, are then added dropwise. When the addition has ended, the mixture is stirred at room temperature for about 45 minutes. The mixture is then carefully brought to pH 7 with 2N HCl, while cooling with ice. The reaction mixture is concentrated, the residue taken up in ethyl acetate and the mixture is washed with NaCl solution. The ethyl acetate phase is dried and concentrated in vacuo. Crude yield: 15 g. Column chromatography on SiO2 with ethyl acetate as the eluding agent: Yield: 7.5 g of light oil (53% of theory) C20 H26 N2 O4, molecular weight=358. NMR: (CDCl3) δ ppm 60 MHz: 0.8-0.95 (t, 3H) CH3; 1.1-1.7 (m, 6H) CH2; 2.2-2.6 (m, 2H) CH2 CO; 2.85 (s, 3H) N--CH3; 3.0-3.9 (m, 2H) N--CH2; 4.5-5.0 (m, 1H) N--CH; 5.2 (s, 2H) C6 H5 CH2 O; 6.0-6.9 (ABX spectrum, 2H) CH=CH and 7.3 (s, 5H) C6 H5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride In 1,2-dimethoxyethane; ethyl acetate | 3.a 1-Methyl-2-oxo-3-benzyloxycarbonyl-5-(3-oxo-octenyl)-imidazolidine VI EXAMPLE 3a 1-Methyl-2-oxo-3-benzyloxycarbonyl-5-(3-oxo-octenyl)-imidazolidine VI 9.6 g (63 mmol) of 1,8-diazabicyclo-(5,4,0)-undec-7-ene (DBU) are introduced into 60 ml of dimethoxyethane (DME). 13.9 g (63 mmol) of 2-oxoheptyl-phosphonic acid dimethyl ester, dissolved in 150 ml of absolute DME, are added dropwise at room temperature. The mixture is stirred at room temperature for 30 minutes. 15 g (33 mmol) of 1-methyl-2-oxo-3-benzyloxycarbonyl-5-formyl-imidazolidine (Example 2), dissolved in 150 ml of absolute DME, are then added dropwise. When the addition has ended, the mixture is stirred at room temperature for about 25 minutes. When the reaction has ended, the mixture is carefully brought to pH 7 with 2N HCl, while cooling with ice. The reaction mixture is concentrated, the residue taken up in ethyl acetate and the mixture is washed with NaCl solution. The ethyl acetate phase is dried and concentrated in vacuo. Crude yield: 20 g. Column chromatography on SiO2 with ethyl acetate as the eluding agent: Yield: 9.0 g, colorless crystals, melting point=50°-53° C., (63% of theory) C20 H26 N2 O4, molecular weight=358 NMR: (CDCl3) δ ppm 270 MHz: 0.8-0.95 (t,3H) CH3; 1.2-1.4 (m,4)--CH2 --; 1.5-1.7 (m,2H) CH2; 2.55 (t,2H) CH2 CO; 2.8 (s,3H) N--CH3; 3.6 (m,1H)>CH--N; 4.0-4.15 (m,2H)N--CH2; 5.3 (s,2H) C6 H5 CH2; 6.2-6.6 (ABX spectrum,2H) CH=CH and 7.3-7.5 (m,5H) C6 H5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium bromide; triethylamine In hexane; dichloromethane | 1.N N. N. [1α,2β(5Z),3β(1E),4α,5α,6α]-7-[5,6-Epoxy-3-(3-oxo-1-octenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester To a suspension of 90 mg of dry lithium bromide in 5 ml of dry methylene chloride was added with stirring 140 μl of triethylamine, followed by a solution of 222 mg dimethyl-(2-oxoheptyl) phosphonate (1 mmole) in 1 ml of methylene chloride. After stirring for 15 minutes at room temperature, a solution of 174 mg Part M aldehyde (0.62 mmole) in 3 ml of methylene chloride was added dropwise. The reaction was stirred overnight, whereupon it was diluted with ether and washed with water. The aqueous layer was extracted with ether (X2). The combined ether extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude oily residue was chromatographed on a silica gel column and eluted with 15-30% ethyl acetate in hexane to obtain 175 mg of title enone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | In 1,2-dimethoxyethane; hexane; dichloromethane; ethyl acetate; mineral oil | 5 Preparation of 9-[5-(3-oxooct-1-enyl)thien-2-yl]nonanoic acid methyl ester. EXAMPLE 5 Preparation of 9-[5-(3-oxooct-1-enyl)thien-2-yl]nonanoic acid methyl ester. 3.3 G of 80% sodium hydride in mineral oil suspension was washed with n-pentane and suspended in 600 ml of 1,2-dimethoxyethane; 23.2 g of 2-oxoheptylphosphonic acid dimethyl ester dissolved in 200 ml of 1,2-dimethoxyethane was then added to the suspension dropwise. The mixture was stirred for 1.5 hours at 20° C., then was mixed with 26.8 g of 9-(5-formylthien-2-yl)nonanoic acid methyl ester dissolved in a small amount of 1,2-dimethoxyethane. The reaction mixture was again stirred for 1.5 hours at 25° C. Then, the mixture was acidified to pH 6 with dilute sulfuric acid and concentrated under vacuum. The residue was dissolved in dichloromethane, the dichloromethane solution was dried over sodium sulfate, the solvent was removed by distillation and the residue was purified by column chromatography (silica gel, using hexane and ethyl acetate as eluants). 18.2 G (51% yield) of product, with melting point 29°-31° C., was obtained; ir (film): 1740, 1685 (shoulder), 1660, and 1600 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | In 1,2-dimethoxyethane; dichloromethane; ethyl acetate; toluene; mineral oil | 1 Preparation of 5-[5-(3-oxooct-1-enyl)thien-2-yl]valeric acid methyl ester. EXAMPLE 1 Preparation of 5-[5-(3-oxooct-1-enyl)thien-2-yl]valeric acid methyl ester. 1.6 G of 80% sodium hydride in mineral oil suspension were washed with n-pentane and suspended in 260 ml of 1,2-dimethoxyethane; 11.1 g of 2-oxoheptylphosphonic acid dimethyl ester dissolved in 110 ml of 1,2-dimethoxyethane were added to this suspension dropwise. The reaction mixture was stirred for 1.5 hours at 20° C., then was mixed with 10.3 g of 5-(2-formylthien-2-yl)valeric acid methyl ester dissolved in a small amount of 1,2-dimethoxyethane, and then again stirred for 1.5 hours at 25° C. At the end of that time, the mixture was acidified to pH 6 with dilute sulfuric acid and the reaction mixture was concentrated under vacuum. The residue was dissolved in dichloromethane, the dichloromethane solution was dried over sodium sulfate, the solvent was removed by distillation, and the residue was purified by column chromatography (silica gel, using toluene and ethyl acetate as eluants). The product was obtained as an oil, 7.1 g (48% yield); ir (film): 1740, 1665, 1600 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | In 1,2-dimethoxyethane; hexane; dichloromethane; ethyl acetate; mineral oil | 2 Preparation of 6-[5-(3-oxooct-1-enyl)thien-2-yl]hexanoic acid methyl ester. EXAMPLE 2 Preparation of 6-[5-(3-oxooct-1-enyl)thien-2-yl]hexanoic acid methyl ester. 2.4 G of 80% sodium hydride in mineral oil suspension was washed with n-pentane and suspended in 400 ml of 1,2-dimethoxyethane; 16 g of 2-oxoheptylphosphonic acid dimethyl ester dissolved in 150 ml of 1,2-dimethoxyethane were added to this suspension dropwise. The reaction mixture was stirred 1.5 hours at 20° C., then was mixed with 15.7 g of 6-(5-formylthien-2-yl)hexanoic acid methyl ester dissolved in approximately 100 ml of 1,2-dimethoxyethane, and then again stirred for 1.5 hours at 25° C. Then, the mixture was acidified to pH 6 with diluted sulfuric acid, and the reaction mixture was concentrated under vacuum. The residue was dissolved in dichloromethane, the dichloromethane solution was dried over sodium sulfate, the solvent was removed by distillation, and the residue was purified by column chromatography (silica gel, using hexane and ethyl acetate as eluants). The product was obtained as an oil, 4.4 g (20% yield); ir (film): 1730, 1660, 1605 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | In 1,2-dimethoxyethane; dichloromethane; ethyl acetate; mineral oil; Petroleum ether | 3 Preparation of 7-[5-(3-oxooct-1-enyl)thien-2-yl]heptanoic acid methyl ester. EXAMPLE 3 Preparation of 7-[5-(3-oxooct-1-enyl)thien-2-yl]heptanoic acid methyl ester. 1.52 G of 80% sodium hydride in mineral oil suspension was washed with n-pentane and suspended in 300 ml of 1,2-dimethoxyethane; 10.5 g of 2-oxoheptylphosphonic acid dimethyl ester dissolved in 100 ml of 1,2-dimethoxyethane were added to this suspension dropwise. The reaction mixture was stirred 1.5 hours at 20° C., then was mixed with 10.9 g of 7-(5-formylthien-2-yl)heptanoic acid methyl ester dissolved in a small amount of 1,2-dimethoxymethane, and then again stirred for 1.5 hours at 25° C. At the end of that time, the mixture was acidified to pH with dilute sulfuric acid and the reaction mixture was concentrated under vacuum. The residue was dissolved in dichloromethane, the dichloromethane solution was dried over sodium sulfate, the solvent was removed by distillation, and the residue was purified by column chromatography (silica gel, using petroleum ether and ethyl acetate as eluants). The product was obtained as an oil, 7.8 g (52% yield); ir (film): 1740, 1685 (shoulder), 1660, 1600 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | In 1,2-dimethoxyethane; hexane; dichloromethane; ethyl acetate; mineral oil | 4 Preparation of 8-[5-(3-oxooct-1-enyl)thien-2-yl]octanoic acid methyl ester. EXAMPLE 4 Preparation of 8-[5-(3-oxooct-1-enyl)thien-2-yl]octanoic acid methyl ester. 1.35 G of 80% sodium hydride in mineral oil suspension was washed with n-pentane and suspended in 220 ml of 1,2-dimethoxyethane; then 9.1 g of 2-oxoheptylphosphonic acid dimethyl ester dissolved in 90 ml of 1,2-dimethoxyethane was added to the suspension dropwise. The reaction mixture was stirred for 1.5 hours at 20° C., then 9.8 g of 8-(5-formylthien-2-yl)octanoic acid methyl ester dissolved in 100 ml 1,2-dimethoxyethane was added. Stirring was resumed for 1.5 hours at 25° C. Then, the reaction mixture was acidified to pH 6 with dilute sulfuric acid and concentrated under vacuum. The residue was dissolved in dichloromethane, the dichloromethane solution was dried over sodium sulfate and the solvent was removed by distillation. The resultant residue was purified by column chromatography (silica gel, using hexane and ethyl acetate as eluants). The product was obtained as an oil, 5.7 g (40% yield); ir (film): 1740, 1680 (shoulder), 1660, and 1595 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | In 1,2-dimethoxyethane; hexane; dichloromethane; ethyl acetate; mineral oil | 6 Preparation of 10-[5-(3-oxooct-1-enyl)thien-2-yl]decanoic acid methyl ester. EXAMPLE 6 Preparation of 10-[5-(3-oxooct-1-enyl)thien-2-yl]decanoic acid methyl ester. 1.45 G of 80% sodium hydride in mineral oil suspension was washed with n-pentane and suspended in 250 ml of 1,2-dimethoxyethane; then, 9.7 g of 2-oxoheptylphosphonic acid dimethyl ester dissolved in 100 ml of 1,2-dimethoxyethane was added dropwise to than suspension. The mixture was stirred for 1.5 hours at 20° C., then 11.2 g of 10-(5-formylthien-2-yl)decanoic acid methyl ester dissolved in a small amount of 1,2-dimethoxyethane was added. Stirring was resumed for an additional 1.5 hours at 25° C. Then, the mixture was acidified to pH 6 with dilute sulfuric acid and concentrated under vacuum. The residue was dissolved in dichloromethane, the dichloromethane solution was dried over sodium sulfate, the solvent was removed by distillation, and the residue was purified by column chromatography (silica gel, using hexane and ethyl acetate as eluants). There were thus obtained 8.6 g (58% yield) of the desired product, melting at 45°-47° C.; ir (in KBr): 1740, 1690 (shoulder), 1660, and 1600 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With lithium diisopropyl amide In tetrahydrofuran at -5 - 0℃; for 1.5h; Inert atmosphere; | 1.1k Phosphonate formation Under nitrogen atmosphere 1.85 g of dimethyl methylphosphonate and 1.77 ml of methyl hexanoate are dissolved in 10.2 ml of tetrahydrofuran (THF), under stirring. The solution is cooled to 0/-5°C and at that temperature in a period of approx. 30 minutes the lithium diisopropylamide (LDA) solution is added dropwise. The reaction mixture is stirred at 0/-5°C for 1 hour and then 37 ml of 2 M NaHC03 solution is added. Stirring is continued at room temperature for lhour, the phases are separated, the aqueous phase is extracted with tert-butyl methyl ether (TBME). The united organic phase is washed with saturated sodium chloride solution, evaporated in vacuum and dried by distilling toluene over it in rotadest on a water bath of45±5°C. Yield: 2.718 g (90%) of yellow oil. NMR data: (DMSO), 1H NMR (500 MHz): 3.65 ppm (H-9 and H-10, 6), d, J=11.2 Hz; 3.26 ppm (H-l, 2), m (d), J=22.1 Hz, 2.555 ppm (H-3, 2), t, J=7.2 Hz; 1.45 ppm (H-4, 2), qui (tt), J=7.3 Hz; 1.32-1.15 ppm (H-5 and H-6, 4), m, (in: 1.26 ppm (H-6, 2), m and 1.20 ppm (H-5, 2), m); 0.85 ppm (H-7, 3), t, J=7.2 Hz; 13C NMR (125.8 MHz): 202.23 ppm (C-2), d, J=5.9 Hz; 52.47 ppm (C-9 and C-10, 2), d, J=6.3 Hz; 43.04 ppm (C-3), d, J=1.4 Hz; 40.21 ppm (C-l), d, J=125.5 Hz, 30.50 ppm (C-5); 22.40 ppm (C-4); 21.82 ppm (C-6), 13.72 ppm (C-7); 31P NMR (202.46 MHz): 23.52 ppm (P-8), m. |
77% | Stage #1: dimethyl methane phosphonate With n-butyllithium In tetrahydrofuran; hexane at -70 - -60℃; for 0.5h; Inert atmosphere; Stage #2: methyl hexanoate In tetrahydrofuran; hexane at -70 - 20℃; | The other reaction flask was added with 2560 ml of tetrahydrofuran, protected with argon, cooled to -70 ° C,A 20 M solution of 2.4 M butyllithium n-hexane was added,Dropping methyl methyl phosphate 448 ml, the control temperature did not exceed -60 ° C. After stirring for 30 min, 1600 ml of a tetrahydrofuran solution of methyl caproate was added dropwise (i.e., the methyl ester oil obtained in the above was dissolved in 1600 ml Tetrahydrofuran solution), the control temperature does not exceed -60 , after the end of stirring at -60 ~ -70 20min after the natural rise to room temperature, stirring overnight, evaporated to dry the solvent after adding ethyl acetate 4000ml, with 2000ml saturated salt water And 2000 ml of water were washed once, dried over sodium sulfate, filtered, concentrated, column chromatography (volume ratio of 5: 1 mixture of petroleum ether and ethyl acetate as a developing agent, divided into small polar points and then the volume (1: 1: 1: 1: 1) mixture of ethyl acetate and petroleum ether) to give 400 g of (2-oxoheptyl) phosphonic acid dimethyl ester as an oil having a yield of 77% chain. |
76% | Stage #1: dimethyl methane phosphonate With n-butyllithium In tetrahydrofuran; hexane at -78℃; Inert atmosphere; Stage #2: methyl hexanoate In tetrahydrofuran; hexane at -78 - 20℃; Inert atmosphere; |
70% | Stage #1: dimethyl methane phosphonate With n-butyllithium In tetrahydrofuran; hexane at -78 - -75℃; for 0.5h; Inert atmosphere; Stage #2: methyl hexanoate In tetrahydrofuran; hexane at -78 - 20℃; for 1h; Inert atmosphere; | |
With n-butyllithium In tetrahydrofuran; ether-water | 3.A EXAMPLE 3 A. Preparation of dimethyl 2-oxoheptylphosphonate. A solution of 100 g. of dimethyl methylphosphonate in 670 ml. of anhydrous tetrahydrofuran is cooled to -78°C under an argon atmosphere. To the cold solution are added dropwise under stirring and under argon atmosphere, 495 ml. of a 0.1M solution of n-butyllithium in tetrahydrofuran, maintaining the temperature at -70°C. When the addition is complete, the reaction mixture is maintained under the same conditions for ten additional minutes, a solution of 58 ml. of methyl caproate dissolved in 187 ml. of tetrahydrofuran is then carefully added, maintaining the temperature at -78°C. The reaction mixture is stirred at -78°C for 2 hours, followed by stirring for 4 hours at room temperature. The excess base is neutralized with acetic acid and the solvent is evaporated under high vacuo. The residue is dissolved in ether-water (1:1, 950 ml. each), the ethereal phase is separated, washed with water and dried over magnesium sulfate. The ether is evaporated and the residue is purified by vacuum distillation, thus obtaining the pure dimethyl 2-oxoheptylphosphonate. | |
With n-butyllithium In tetrahydrofuran; ether-water | 1.A PREPARATION 1 A. A solution of 100 g. of dimethyl methylphosphonate in 670 ml. of anhydrous tetrahydrofuran is cooled to -78°C. under an argon atmosphere. To the cold solution are added dropwise under stirring and under argon atmosphere, 495 ml. of a 0.1M solution of n-butyllithium in tetrahydrofuran, maintaining the temperature at -70°C. When the addition is complete the reaction mixture is maintained under the same conditions for 10 additional minutes, a solution of 58 ml. of methyl caproate dissolved in 187 ml. of tetrahydrofuran is then carefully added, maintaining the temperature at -78°C. The reaction mixture is stirred at -78°C. for 2 hours followed by stirring for 4 hours at room temperature. The excess base is neutralized with acetic acid and the solvent is evaporated under high vacuo. The residue is dissolved in ether-water (1:1, 950 ml. each), the ethereal phase is separated, washed with water and dried over magnesium sulfate. The ether is evaporated and the residue is purified by vacuum distillation, thus obtaining the pure dimethyl 2-oxoheptylphosphonate. | |
With n-butyllithium In toluene |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In ethyl acetate; toluene | 13 EXAMPLE 13 EXAMPLE 13 Dimethyl 2-oxoheptylphosphonate (820mg.) and methyl 7-[2β-formyl-3α-hydroxy-5α-(4-phenylbenzoyloxy)-cyclopent-1α-yl]hept-5-cis-enoate (1g.) were suspended under argon in a mixture of toluene (40ml.). Aqueous 1M sodium hydroxide solution (3.9ml.) was added and the two phase mixture was stirred vigorously for 16 hours. The reaction mixture was shaken with ethyl acetate (20 ml.) and saturated brine (20ml.), and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (2 * 40ml.), the combined organic extracts were dried, and the solvent was evaporated. Preparative thin layer chromatography gave the enone, methyl 11α-hydroxy-15-oxo-9α-(4-phenylbenzoyloxy)-5-cis,13-trans-prostadienoate, as a clear oil, RF = 0.8 (ether). M+ for the trimethylsilyl derivative = 618.3366, calculated for C37 H50 O6 Si = 618.3376. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With NaH In tetrahydrofuran; chloroform; acetone | 13 3β-Acetoxy-2α-(3-oxo-1-octenyl)-5-oxocyclopentane-1β-aceticacid, methyl ester 5-cyclic ethylene acetal EXAMPLE 13 3β-Acetoxy-2α-(3-oxo-1-octenyl)-5-oxocyclopentane-1β-aceticacid, methyl ester 5-cyclic ethylene acetal 15 → 16 A solution of dimethyl 2-oxoheptylphosphonate (444 mg., 2.0 mmol) in 10 ml.dry THF is added dropwise to a stirred suspension of NaH (50% oil dispersion 87 mg., 1.8 mmol) in 15 ml. dry THF at 0° under N2.The ylid sodium salt precipitates in part as a gelatinous white precipitate. After 30 minutes at 0°, a solution of 3β-acetoxy-1α-formyl-5-oxocyclopentane-1β-acetic acid, methyl ester 5-cyclic ethylene acetal (515 mg., 1.8 mmol) in 15 ml. THF isadded over 5 minutes. The stirred reaction mixture is allowed to warm to room temperature and stirred for 3 hours, at which time tlc (10% acetone in chloroform) indicates disappearance of starting material. The reaction mixture is cooled to 0°, added to chilled saturated NaH2 PO4, concentrated under vacuum to remove THF, and extracted with ethyl acetate. The latter extract is washed with brine, dried over Na2 SO4, and concentrated to dryness under vacuum. The residue is chromatographed over 50 g. of silica gel eluding with 5% acetone in chloroform to provide pure 3β-acetoxy-2α-(3-oxo-1-octenyl)-5-oxocyclopentane-1β-acetic acid, methyl ester 5-cyclic ethylene acetal. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; sodium chloride In tetrahydrofuran; hexane; ethyl acetate; benzene | R.12 Methyl 9α-acetoxy-11α-(2-tetrahydropyranyloxy)-15-oxo-16ξ-chloroprosta-cis-5,trans-13-dienoate Under an atmosphere of nitrogen, a solution of 6.66 g. of dimethyl 2-oxo-heptylphosphonate in 20 ml. of tetrahydrofuran was added to a suspension of 720 mg. of sodium hydride in 100 ml. of tetrahydrofuran at room temperature and the mixture was stirred at the same temperature for 20 minutes. After cooling to 0° C., there were added to the solution 24 ml. of a 1.38M solution of n-butyllithium in n-hexane at that temperature and the mixture was stirred for 30 minutes. After cooling to -78° C., there was added to the solution thus obtained dropwise a solution of 5.82 g. of benzenesulphonyl chloride in 20 ml. of tetrahydrofuran and the mixture was stirred at -78° C. for 30 minutes and then at room temperature for one hour. The reaction mixture was acidified with acetic acid, diluted with 200 ml. of ethyl acetate, washed with an aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of benzene and ethyl acetate (1:3) as eluent to give 4.56 g. of dimethyl 2-oxo-3-chloroheptylphosphonate having the following physical characteristics: Tlc (developing solvent, ethyl acetate): Rf = 0.41; Ir (liquid film): ν; 1725, 1260, 1190, 1100-1000, 900-780 cm-1; Nmr(cdcl3 solution): δ; 4.44 (1H, dd), 3.80 (6H, d), 3.71-3.02 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
175 mg (58%) | In tetrahydrofuran; ethyl acetate | 1.5 Step 5. Step 5. 7-[2-Oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-ynoic acid methyl ester Sodium hydride (60% dispersion in oil, 37 mg, 0.91 mmol) was added to a solution of dimethyl 2-oxoheptylphosphonate (217 mg, 0.83 mmol) in THF (4 mL) at 0° C. After 10 min at 0° C., the solution was allowed to warm to rt. After 50 min at rt, the solution was recooled to 0° C. and 7-(2-formyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (crude from previous reaction, ~0.92 mmol) in THF (2 mL) was added via cannula. The reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with acetic acid and water (1:1, 15 mL) and extracted with EtOAc (3*40 mL). The combined organic phase was washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (10% →50% EtOAc/CH2Cl2, gradient) afforded 175 mg (58%) of the title compound. |
175 mg (58%) | In tetrahydrofuran; ethyl acetate | 1.5 Step 5. Step 5. 7-[2-Oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-ynoic Acid Methyl Ester Sodium hydride (60% dispersion in oil, 37 mg, 0.91 mmol) was added to a solution of dimethyl 2-oxoheptylphosphonate (217 mg, 0.83 mmol) in THF (4 mL) at 0° C. After 10 min at 0° C., the solution was allowed to warm to rt. After 50 min at rt, the solution was recooled to 0° C. and 7-(2-formyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (crude from previous reaction, ~0.92 mmol) in THF (2 mL) was added via cannula. The reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with acetic acid and water (1:1, 15 mL) and extracted with EtOAc (3*40 mL). The combined organic phase was washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (10%→50% EtOAc/CH2Cl2, gradient) afforded 175 mg (58%) of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
128 mg (95%) | In tetrahydrofuran | 11.3 Step 3. Step 3. 7-[2-Oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-heptanoic acid methyl ester Sodium hydride (60% dispersion in oil, 15 mg, 0.37 mmol) was added to a solution of dimethyl 2-oxoheptylphosphonate (87 mg, 0.33 mmol) in THF (2 mL) at 0° C. After 10 min at 0° C., the solution was allowed to warm to rt. After 1 h at rt, the solution was recooled to 0° C. and 7-(2-formyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester (crude from previous reaction, ~0.37 mmol) in THF (2 mL) was added via cannula. The reaction was allowed to warm to rt. After 17 h at rt, the reaction was quenched with acetic acid (50% aqueous, 20 mL) and extracted with EtOAc (3*20 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient) afforded 128 mg (95%) of the title compound. |
128 mg (95%) | In tetrahydrofuran | 11.3 Step 3. Step 3. 7-[2-Oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-heptanoic Acid Methyl Ester Sodium hydride (60% dispersion in oil, 15 mg, 0.37 mmol) was added to a solution of dimethyl 2-oxoheptylphosphonate (87 mg, 0.33 mmol) in THF (2 mL) at 0° C. After 10 min at 0° C., the solution was allowed to warm to rt. After 1 h at rt, the solution was recooled to 0° C. and 7-(2-formyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester (crude from previous reaction, ~0.37 mmol) in THF (2 mL) was added via cannula. The reaction was allowed to warm to rt. After 17 h at rt, the reaction was quenched with acetic acid (50% aqueous, 20 mL) and extracted with EtOAc (3*20 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient) afforded 128 mg (95%) of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68 mg (85%) | In tetrahydrofuran | 35.2 Step 2. Step 2. 7-[(R)-2-Oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-ynoic acid methyl ester Sodium hydride (60% dispersion in oil, 8.8 mg, 0.22 mmol) was added to a solution of dimethyl 2-oxoheptylphosphonate (52 mg, 0.23 mmol) in THF (1 mL) at 0° C. After 10 min at 0° C., the solution was allowed to warm to rt. After 1 h at rt, the solution was recooled to 0° C. and 7-((R)-2-formyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (crude from previous reaction, ~0.22 mmol) in THF (1 mL) was added via cannula. The reaction was allowed to warm to rt. After 18.5 h at rt, the reaction was quenched with aqueous acetic acid (50%, 5 mL) and extracted with EtOAc (3*10 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient) afforded 68 mg (85%) of 7-[(R)-2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-ynoic acid methyl ester. |
68 mg (85%) | In tetrahydrofuran | 35.2 Step 2. Step 2. 7-[(R)-2-Oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-ynoic Acid Methyl Ester Sodium hydride (60% dispersion in oil, 8.8 mg, 0.22 mmol) was added to a solution of dimethyl 2-oxoheptylphosphonate (52 mg, 0.23 mmol) in THF (1 mL) at 0° C. After 10 min at 0° C., the solution was allowed to warm to rt. After 1 h at rt, the solution was recooled to 0° C. and 7-((R)-2-formyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (crude from previous reaction, ~0.22 mmol) in THF (1 mL) was added via cannula. The reaction was allowed to warm to rt. After 18.5 h at rt, the reaction was quenched with aqueous acetic acid (50%, 5 mL) and extracted with EtOAc (3*10 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2<2% MeOH/CH2Cl2, gradient) afforded 68 mg (85%) of 7-[(R)-2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-ynoic acid methyl ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: dimethyl 2-oxoheptylphosphonate With sodium hydride In tetrahydrofuran at 0℃; Stage #2: (R)-methyl 4-(2-(2-formyl-5-oxopyrrolidin-1-yl)ethyl) benzoate In tetrahydrofuran at 0 - 20℃; Further stages.; | |
90% | Stage #1: dimethyl 2-oxoheptylphosphonate With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: (R)-methyl 4-(2-(2-formyl-5-oxopyrrolidin-1-yl)ethyl) benzoate In tetrahydrofuran at 20℃; for 3h; | 1.5 Intermediate 1.5 : [METHYL 4-(2- {(5R !-2-OXO-5-[(LE)-3-OXOOCT-L-ENYLLPYRROLIDIN] [YL} ETHYL ! BENZOATE A suspension of dimethyl (2-oxoheptyl) -phosphonate (1.5 mL, 7.21 mmol) in THF (40 mL) was cooled to [0 °C] then NaH (0.29 g, 60%, 7.21 mmol) was added portionwise. After 30 min, a THF (10 mL) solution of intermediate 1.4 previously obtained was added dropwise to the reaction mixture. The resulting mixture was stirred at RT for 3 h then was diluted EtOAc (100 mL) and washed with HCl 1M solution (100 mL) and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/hexane) and the product (1.3 g, 90%) was isolated as a colorless oil. [RU 0.] 3 (EtOAc/hexane 2/1); MS (m/z) 372.5 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: dimethyl 2-oxoheptylphosphonate With sodium hydride In tetrahydrofuran at 0 - 20℃; for 1h; Stage #2: Methyl 5-(3-((1R,2R,3R,5R)-5-chloro-2-formyl-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)propyl)thiophene-2-carboxylate In tetrahydrofuran at 0 - 20℃; | 4.a A solution of phosphonate 4-2 (40 μL, 0.19 mmol) in 2.2 mL THF was added to an ice cold mixture of NaH (9 mg, 0.23 mmol, 60%/oil) in 1.6 mL THF by cannula. The mixture was allowed to warm to room temperature and after 1 h, was recooled to 0° C. At this time, a solution of aldehyde 3-1 (80 mg, 0.19 mmol) in 0.6 mL THF was added by cannula, rinsing with 0.6 mL THF. The reaction was allowed to warm to room temperature and after stirring overnight, was quenched by addition of 10 mL saturated NH4Cl solution. The resulting mixture was extracted with ethyl acetate (3×25 mL) and the combined ethyl acetate solution was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (0%→100% ethyl acetate/hexanes) gave the title compound (59 mg, 60%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.5% | Stage #1: dimethyl 2-oxoheptylphosphonate With lithium hydroxide In tert-butyl methyl ether at 20℃; for 1h; Stage #2: (1S,5R,6R,7R)-6-formyl-7-benzoyloxy-2-oxabicyclo[3.3.0]octan-3-one In tert-butyl methyl ether; water at 20℃; for 1h; | 8 Example 8; To a solution of dimethyl (2-oxoheptyl)phosphonate (12) (0.267 g, 1.20 mmol) in t-butyl methyl ether (5 ml), lithium hydroxide monohydrate (48.3 mg, 1.15 mmol) was added, and the mixture was stirred for one hour at room temperature. Water (0.05 ml) and (3aR,4R,5R,6aS)-2-oxo-5-phenylcarbonyloxyhexahydro cyclopenta[b]furan-4-carbo aldehyde (10) (0.274 g, 1.00 mmol) were added thereto, and the mixed solution was stirred for one hour at room temperature. The reaction mixture was added to water and washed twice with t-butyl methyl ether. The organic layers were combined, sequentially washed with saturated sodium bicarbonate water and saturated aqueous sodium chloride, and then dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 100 g; ethyl acetate:hexane=2:3) to give (3aR,4R,5R,6aS)-4-((E)-3-oxo-1-octenyl)-2-oxo-5-phenyl carbonyloxyhexahydrocyclopenta[b]furan (14) (0.339 g; 0.915 mmol; yield: 91.5%) as a colorless oil. 1H-NMR (200 MHz, CDCl3): δ (ppm): 8.05-7.95 (2H, m), 7.65-7.40 (3H, m), 6.73 (1H, dd, J=16, 7.5 Hz), 6.37 (1H, dd, J=16 Hz), 5.42-5.28 (1H, m), 5.19-5.06 (1H, m), 3.00-2.45 (5H, m), 2.55 (2H, J=7.0 Hz), 2.38-2.25 (1H, m), 1.70-1.54 (2H, m), 1.90-1.20 (4H, m), 0.90 (3H, t, J=7.5 Hz) |
Stage #1: dimethyl 2-oxoheptylphosphonate; (1S,5R,6R,7R)-6-formyl-7-benzoyloxy-2-oxabicyclo[3.3.0]octan-3-one With lithium chloride In tetrahydrofuran; dichloromethane at -20℃; for 2.5h; Stage #2: With triethylamine In tetrahydrofuran; dichloromethane at -5℃; for 19h; | 1.A A reactor equipped with a mechanical stirrer, under nitrogen, was charged with (3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate (Corey lactone aldehyde benzoate, Cayman Chemical Catalog No. 70030, 99.2 g, 0.362 mol) in DCM and lithium chloride (1 molar equivalent) dissolved in THF. Some lithium chloride precipitated from solution when the THF and DCM solutions were mixed. Dimethyl 2-oxoheptylphosphonate (1 molar equivalent) was subsequently added to the reactor NEAT and the reagent was rinsed down into the reactor with DCM. The mixture was stirred under nitrogen and cooled to -20° C. The lithium chloride precipitate dissolved as the stirring and cooling continued. After stirring for 2.5 hours, triethylamine (1 molar equivalent) was added NEAT via addition funnel and the temperature was maintained at -5° C. with stirring for 19 hours. The reaction mixture was warmed to 0° C. and treated with 5% aqueous citric acid. The layers were separated and the organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified on silica gel, eluted with hexanes-ethyl acetates (1:1) to afford the title intermediate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | Stage #1: D-Glucose; dimethyl 2-oxoheptylphosphonate With potassium carbonate at 80℃; for 24h; Neat (no solvent); Stage #2: With potassium carbonate In water at 60℃; for 12h; optical yield given as %de; stereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | Stage #1: Lactose; dimethyl 2-oxoheptylphosphonate With potassium carbonate at 80℃; for 24h; Neat (no solvent); Stage #2: With potassium carbonate In water at 60℃; for 12h; optical yield given as %de; stereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: dimethyl 2-oxoheptylphosphonate With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; Inert atmosphere; Stage #2: C20H38O6Si In tetrahydrofuran; mineral oil at 0 - 20℃; for 1h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.4% | Stage #1: dimethyl 2-oxoheptylphosphonate With lithium hydroxide In tert-butyl methyl ether at 20℃; for 2h; Stage #2: methyl 7-((1R,2R,3R,5S)-5-acetoxy-2-formyl-3-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)heptanoate In tert-butyl methyl ether; water at 20℃; for 1h; | 7 Example 7; To a solution of dimethyl (2-oxoheptyl)phosphonate (12) (0.178 g, 0.801 mmol) in t-butyl methyl ether (2 ml), lithium hydroxide monohydrate (32.5 mg, 0.775 mmol) was added and the mixture was stirred for two hours at room temperature. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (2) (0.213 g, 0.535 mmol) in t-butyl methyl ether (2 ml) and water (0.12 ml) were added thereto, and the mixed solution was stirred for one hour at room temperature. The reaction mixture was added to water and extracted twice with t-butyl methyl ether. The organic layers were combined, sequentially washed with saturated sodium bicarbonate water and saturated aqueous sodium chloride, and then dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 100 g; ethyl acetate:hexane=3:7), to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (13) (0.255 g; 0.516 mmol; yield: 96.4%) as a colorless oil. 1H-NMR (200 MHz, CDCl3): δ (ppm): 6.71 (0.5H, dd, J=16, 7.5 Hz), 6.68 (0.5H, dd, J=16, 7.5 Hz), 6.22 (0.5H, d, J=16 Hz), 6.20 (0.5H, d, J=16 Hz), 5.19-5.08 (1H, m), 4.61-4.52 (1H, m), 4.15-3.95 (1H, m), 3.90-3.60 (1H, m), 3.66 (3H, s), 3.50-3.35 (1H, m), 2.75-2.35 (2H, m), 2.65 (2H, t, J=7.0 Hz), 2.29 (2H, t, J=7.5 Hz), 2.06 (3H, s), 1.90-1.15 (23H, m), 0.90 (3H, t, J=7.5 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: dimethyl 2-oxoheptylphosphonate With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 1.5h; Inert atmosphere; Stage #2: ethyl 2-({2-[(2R)-2-formyl-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazole-4-carboxylate In tetrahydrofuran; mineral oil at 0 - 20℃; for 1h; | 5.1.4. Ethyl 2-[(2-{(2R)-2-[(1E)-4-(3-methylphenyl)-3-oxo-1-buten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylate (23a) General procedure: To a stirred solution of dimethyl 3-(3-methylphenyl)-2-oxopropanephosphonate 29a (166 mg, 0.649 mmol) in THF (5 mL) was added sodium hydride (62.5% in mineral oil, 21.5 mg, 0.556 mmol) at 0 °C under argon atmosphere and stirring was further continued at ambient temperature for 90 min. To the stirred suspension was added a solution of the above-described aldehyde 22a in THF (2 mL) at 0 °C and stirring was continued at room temperature for 1 h. The reaction was quenched with saturated aqueous NH4Cl. The reaction mixture was diluted with EtOAc, washed with water, then brine, and dried over MgSO4. The organic layer was evaporated to give an enone 23a as a pale yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: dimethyl 2-oxoheptylphosphonate With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 0.5h; Inert atmosphere; Stage #2: (R)-ethyl 4-(tert-butoxycarbonylamino)-5-oxopentanoate In tetrahydrofuran; mineral oil at 20℃; for 2h; | 5.1.38. Ethyl (4R,5E)-8-(3-chlorophenyl)-4-([(2-methyl-2-propanyl)oxy]carbonyl}amino)-7-oxo-5-octenoate (39) To a stirred solution of the phoshonate 29d (1.56 g, 5.64 mmol) in THF (50 mL) was added sodium hydride (63% in mineral oil, 197 mg, 5.17 mmol) in several portions at 0 °C under argon atmosphere. Stirring was continued at ambient temperature for 30 min. To the stirred suspension was added a solution of the above-described aldehyde 38 in THF (10 mL) at room temperature and stirring was continued for 2 h. The reaction was quenched with acetic acid. The reaction mixture was diluted with EtOAc, washed with water, then brine, dried over MgSO4. The organic layer was evaporated. The resulting residue was purified by column chromatography on silica gel (hexane/EtOAc, 5:1-3:1) to give an enone as a white solid (1.40 g, 73% in 2 steps). 1H NMR (300 MHz, CDCl3): δ 7.31-7.00 (m, 4H), 6.77 (dd, J = 15.6 , 6.0 Hz, 1H), 6.23 (d, J = 15.6 Hz, 1H), 4.81-.466 (m, 1H), 4.47-4.20 (m, 1H), 4.14 (q, J = 7.0 Hz, 1H), 3.82 (s, 2H), 2.38 (t, J = 7.2 Hz, 2H), 2.15-1.75 (m, 2H), 1.41 (s, 9H), 1.24 (t, J = 7.2 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: dimethyl 2-oxoheptylphosphonate With N-ethyl-N,N-diisopropylamine; lithium chloride In acetonitrile at 20℃; Inert atmosphere; Stage #2: 2-dibenzylamino-5-oxo-pentanoic acid benzyl ester In acetonitrile at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: dimethyl 2-oxoheptylphosphonate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.25h; Stage #2: 4-(tert-butyldimethylsilyl)oxyoctan-1-al In tetrahydrofuran; mineral oil at 0℃; | |
76% | With sodium hydride In tetrahydrofuran at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: dimethyl 2-oxoheptylphosphonate With sodium hydride In tetrahydrofuran; mineral oil at -10℃; for 0.25h; Stage #2: 4-chlorobutyraldehyde In tetrahydrofuran; mineral oil at -10℃; for 1.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: dimethyl 2-oxoheptylphosphonate With sodium hydride In 1,2-dimethoxyethane at -5 - 20℃; for 1.25h; Inert atmosphere; Stage #2: (Z)-4-formyl-5-(7-isopropoxy-7-oxohept-2-enyl)cyclopentane-1,3-diyl dibenzoate In 1,2-dimethoxyethane at -5 - 20℃; for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: dimethyl 2-oxoheptylphosphonate With phenylsulfonyl azide; caesium carbonate In acetonitrile at 20℃; for 2h; Stage #2: C11H18O3 In methanol; acetonitrile for 18h; | To a stirring solution of dimethyl (2-oxohept l)phosphonate (0.210 mL, 1 .009 mmol) in ACN (0.841 mL) was added Cs2C< (0.657 g, 2,018 mmol), followed by benzenesuifonyi azide (0.185 g, 1.009 mmol) and the reaction was stirred at room temperature for 2 hours. Then a solution of compound 33, (0.1 g, 0.504 mmol) in ACN/ eOH (0.841 mL 0,168 mL) was added and the reaction was stirred for 18 hours. The reaction mixture was concentrated under reduced pressure to yield an orange oil, which was dissolved in ethyl acetate, washed with 1 citric acid, NaHCX>3, and brine, dried over NagSO^ filtered, and concentrated under reduced pressure to yield compound 33, as a mixture of isomers (O.lg), which was carried through to the next step without further purification. HMR (400 MHz. DMSO-d*) δ 3.72 (s. 2H), 3.14 (, 2H), 2.85 (s, 2H), 2.39-2.47 (m, 1H), 2.28-2,38 (m, 1 H), 1.35-1.88 (m, 16H), 1.25 (s, 12H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: dimethyl 2-oxoheptylphosphonate With N-ethyl-N,N-diisopropylamine; lithium chloride In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; Stage #2: C14H23NO6 In tetrahydrofuran at 0 - 20℃; for 4h; Inert atmosphere; | 22 Meanwhile, under an argon atmosphere, to a solution of a phosphonate, i.e. dimethyl (2-oxoheptyl)phosphonate (10) (3.92 g, 17.6 mmol) in THF (20 mL) was added lithium chloride (746 mg, 17.6 mmol) at a room temperature and the solution was stirred at the same temperature until complete dissolution of lithium chloride. After confirming that lithium chloride was dissolved completely, diisopropylethylamine (3 ml, 17.6 mmol) was added at a room temperature and the solution was stirred at the same temperature for 1 hour to prepare a Horner-Wadsworth-Emmons reagent (HWE reagent) which was used without purification. [0219] To the aldehyde (7j)-containing reaction solution was then added the prepared HWE reagent at 0° C., and the mixture was brought to a room temperature and stirred for 4 hours. A saturated ammonium chloride aqueous solution was added to terminate the reaction and the organic matter was extracted with ethyl acetate 3 times. The combined organic layer was washed with a saturated aqueous sodium chloride solution and dried with magnesium sulfate. Low-boiling organic compounds such as solvents were distilled off under reduced pressure prior to purification by silica gel column chromatography (elution solvent: ethyl acetate:hexane=1:5→1:3) to obtain a desired enone (11) (2.55 g, 6.4 mmol) as a mixture of four diastereomers (Rf values by TLC=0.29, 0.35 (developing solvent: ethyl acetate:hexane=1:2)) with the yield of 80%. [0220] The results of physical and chemical analyses of the diastereomer mixture by 1H NMR, 13C NMR, IR, HRMS (ESI) and Rf measurement by TLC are shown hereinbelow. The results of physical and chemical analyses support the chemical structure of the enone (11). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With N-ethyl-N,N-diisopropylamine; lithium chloride In acetonitrile for 3h; Inert atmosphere; | Compound 18: Dimethyl 2-oxoheptylphosphonate (17, 2.67 g, 12 mmol), N,N-diisopropylethylamine (1.29 g, 10 mmol) and octanal (16, 1.28 g, 10 mmol) were added to a solution of lithium chloride (0.50 g, 12 mmol) in acetonitrile (120 mL) under argon; after stirring for 3 h the reaction mixture was evaporated and purified by silica-gel column using a gradient of petroleum ether/diethylether gradient to give 18 (2.01 g, 9.1 mmol, 91%) [23]: Rf (Petroleum ether/diethyl ether 95:5) = 0.52; 1H-NMR (400 MHz, C6D6): δ = 6.62 (dt, J = 15.7, 6.7 Hz, 1H; H6), 5.93 (bd, J = 15.7 Hz, 1H; H7), 2.29 (t, J = 7.4, 2H; H29), 1.99 (m, 2H; H25), 1.52 (m, 2H), 1.30-1.15 (m, 14H), 0.81 (t, J = 6.2, 6H; H31, H315 ); 13C-NMR (100MHz, C6D6): δ = 198.3 (C8, C), 145.9 (C6, CH), 130.8 (C7, CH), 40.1 (C9, CH2), 32.6 (CH2), 32.1 (2 CH2), 29.6 (2 CH2), 29.5 (CH2), 24.2 (CH2), 23.0 (2 CH2), 14.3 (2 CH3). HRMS (ESI+): m/z calcd for C15H28ONa: 247.2038; found: 247.2033. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With N-ethyl-N,N-diisopropylamine; lithium chloride In acetonitrile for 3h; Inert atmosphere; | Compound 24: Starting from trans-2-octenal (23, 1 g, 8 mmol) and following the same procedure to get 18, compound 24 (1.60 g, 7.2 mmol, 91%) was obtained; Rf (Petroleum ether/diethyl ether 95:5) = 0.42; 1H-NMR (400 MHz, C6D6): δ = 7.10 (dd, J = 15.5, 10.6 Hz, 1H; H8), 5.99 (d, J = 15.5 Hz, 1H; H7), 5.96 (dd, J = 15.3, 10.6 Hz, 1H; H9), 5.82 (dt, J = 15.3, 6.9 Hz, 1H; H10), 2.31 (t, J = 7.2 Hz, 2H; H25), 1.94 (m, 2H; H211), 1.61 (m, 2H), 1.29-1.13 (m, 10H), 0.88 (t, J = 6.8 Hz, 6H; H315, H31); 13C-NMR (100MHz, C6D6): δ = 198.8 (C6, C), 144.6 (CH), 142.1 (CH), 129.5 (CH), 128.6 (CH), 40.9 (CH2), 33.3 (CH2), 31.9 (CH2), 31.7 (CH2), 28.8 (CH2), 24.3 (CH2), 22.9 (CH2), 22.8 (CH2), 14.2 (CH3), 14.2 (CH3).UV max (MeOH) 264 nm (ε = 1469); HRMS (ESI+): m/z calcd for C15H26ONa: 245.1881; found: 245.1883. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23 g | With potassium hydroxide In toluene at -10℃; Inert atmosphere; | 1.1k Ik.) Preparation of [(lR,2R,3aS,9aS)-5-methoxy-l-[(E)-3-oxooct-l-enyl]-2,3,3a,4,9,9a- hexahydro- 1 H-cyclopenta[b]naphthalen-2-yl] 4-phenylbenzoate (TREP-11) 20 g (46.7 mmol) of TREP-9 is dissolved in an inert atmosphere in 200 ml water-free toluene. 30 g of dicyclohexylcarbodiimide (DCC) and 10 ml of dimethyl sulfoxide in phosphoric acid are added. The reaction mixture is heated to 50°C and in portions, a further 5 ml of dimethyl sulfoxide in phosphoric acid are added. When the oxidation is completed, the reaction mixture is cooled to -10°C and at that temperature 4 g (71 mmol) of potassium hydroxide and then 10.9 g (49 mmol) of 2-oxo-heptylphosphoric acid dimethyl ester in toluene solution are added. At the end of the reaction, under agitation, the mixture is poured onto acid solution. The precipitated crystals are filtered off and washed. The phases of the filtrate are separated, the organic phase is washed with 1M sodium hydrogen carbonate solution and then with diluted hydrochloric acid solution. The organic phase is evaporated and purified by chromatography on silica gel column using toluene: hexane eluent. Yield: 23 g (94,3 %) of light brown oil. Alternative method of lk/2 20 g(46,7mmol) of TREP-9 is dissolved in 200ml toluene and 0,9 g potassium bromide and 0,2 g TEMPO/(2,2,6,6-Tetramethyl- piperidin-l-yl)oxyl / catalyst are added to the solution. The reaction mixture is cooled to the range of 0 C- (+10 C) and 150ml sodium hypochlorite solution are added(active chlorine content is 6-14%) and the mixture is stirred at this temperature. When the oxidation is completed the phases of the reaction mixture are separated, organic phase is washed with aqueous solution of Na2S203 , with aqueous solution of KBr and finally with water. 10,9 g (49mmol) 2-oxo-heptylphosphoric acid dimethyl ester and 100 ml 3 M potassium hydroxide solution are added to the organic phase. The reaction mixture is agitated at room temperature. After completion of the reaction the phases are separated and the organic phase is washed with 1 M sodium hydrogen sulfate solution and 15% NaCl solution. The organic phase is evaporated and purified by chromatography on silica gel column using toluene :hexane eluent. Yield: 23 g (94,35%) of light brown oil. NMR data: (CDC13), 1H NMR (500 MHz): 8.00 ppm (H-26 and H-26', 2), m (d), J=8.3 Hz; 7.64-7.56 ppm (H-27, H-27', H-30 and H-30', 4), m, (in: 7.61 ppm (H-27 and H-27', 2), m (d), J=8.4 Hz and 7.59 ppm (H-30 and H-30', 2), m (d), J-7.7 Hz); 7.45 ppm (H-31 and H-31', 2), m (t), J-7.5 Hz; 7.38 ppm (H-32, 1), m (t tt), J=7.3 Hz; 7.165 ppm (H-22, 1), t, J=7.9 Hz; 6.83-6.76 ppm (H-13, H-21 and H-23, 3), m (in: 6.80 ppm (H-21 and H-23, 2), d, J=7.9 Hz and 6.80 ppm (H-13, 1), dd, J=15.8 Hz and 8.3 Hz); 6.12 ppm (H-14, 1), d, J=15.8 Hz; 5.18 ppm (H-ll, 1), td, J=9.6 Hz and 6.2 Hz; 3.83 ppm (H-2, 3), m (s); 2.79-2.70 ppm (H-4 and H-7a, 3), m (in: 2.75 ppm (H-7a, 1), dd, J=14.7 Hz and 5.9 Hz and 2.73 ppm (H-4, 2), d, J=5.5 Hz); 2.62-2.48 ppm (H-7b, H-9, H-lOa and H-16, 5), m (in: 2.565 ppm (H-9, 1), m; 2.55 ppm (H-16, 1), t, J=7.4 Hz; 2.53 ppm (H-lOa, 1), m; 2.515 ppm (H-7b, 1), m); 2.40-2.27 ppm (H-8 and H-12, 2), m (in: 2.36 ppm (H-12, 1), m and 2.31 ppm (H-8, 1), m); 1.67-1.53 ppm (H-17, 2), m (tt), J=7.4 Hz, 1.38- 1.22 ppm (H-lOb, H-18 and H-19, 5), m (in: 1.34 ppm (H-lOb, 1), m (dt), J-11.8 Hz and 9.6 Hz; 1.29 ppm (H-19, 2) m and 1.28 ppm (H-18, 2) m); 0.87 ppm (H-20, 3), m (t), J=6.9 Hz; 13C NMR (125.8 MHz): 200.85ppm (C-15), 166.23 ppm (C-24), 156.99 ppm (C-3), 146.53 ppm (C- 13), 145.89 ppm (C-28), 140.14 ppm (C-29), 139.28 ppm (C-6), 131.85 ppm (C-14), 130.22 ppm (C-26 and C-26', 2), 129.05 ppm (C-31 and C-31 ', 2), 128.93 ppm (C-25), 128.28 ppm (C-32), 127.41 ppm (C-30 and C-31 ', 2), 127.14 ppm (C-27 and C-27', 2), 126.70 (C-22), 126.23 ppm (C-5), 120.93 ppm (C-23), 108.76 ppm (C-21), 77.31 ppm (C-11), 55.69 ppm (C-2), 53.49 ppm (C-12), 40.24 ppm (C-8), 40.16 ppm (C-16), 37.89 ppm (C-10), 33.16 ppm (C-9), 31.88 ppm (C- 7), 31.58 ppm (C-18), 25.32 ppm (C-4), 24.08 ppm (C-17), 22.60 ppm (C-19), 14.05 ppm (C- 20). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: dimethyl 2-oxoheptylphosphonate With sodium hydride In tetrahydrofuran at 0℃; for 1h; Stage #2: S-(p-tolyl) 2-oxo-2-phenylethanethioate In tetrahydrofuran at 0℃; for 0.166667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Stage #1: dimethyl 2-oxoheptylphosphonate With sodium hydride In tetrahydrofuran at 0℃; for 1h; Stage #2: S-phenyl 2-oxo-2-phenylethanethioate In tetrahydrofuran at 0℃; for 0.166667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 6h; Inert atmosphere; Overall yield = 93 %; Overall yield = 0.34 g; Optical yield = 70 %de; | 13. (Z,E)-1-((1R,2R,5R)-2-((methoxymethoxy)methyl)-5-(trimethylsilyl)cyclopent-3-en-1-yl)oct-1-en-3-one ((Z,E)-23). The compound 22 (0.27 g, 1.1 mmol) was dissolved in dry THF (10 mL) and added dropwise to a stirred suspension of 0.12 g (3.0 mmol) of NaH (60%, suspension in mineral oil) and 0.73 g (3.5 mmol) of phosphonate 30 in dry THF (15 mL) at 0°C under argon atmosphere. After stirring for 6 h at 0°C to the solution was added 10 mL sat. NH4Cl and resulting mixture was filtered, evaporated under reduced pressure and extracted 3x20 mL EtOAc. Purification of the product by column chromatography (petroleum ether/ethyl acetate, 20:1) afforded of unseparable 85:15 mixture (1H NMR) of E- and Z-isomers of compound 23 (0.34 g, 93%) as a transparent light yellow viscous oil. [Found: C, 67.15; H, 9.84. C19H34O3Si requires C, 67.34; H, 10.04%]; Rf (petroleum ether/ethyl acetate, 20:1) 0.4; -93 (c 1.3, CH2Cl2) for 85:15-mixture of Z,E-isomers; νmax (liquid film) 2954, 2873, 1699, 1677, 1625, 1465, 1249, 1151, 1110, 1045, 838 cm-1; δH (300 MHz, d-chloroform/chloroform) for mixture of isomers: 6.97 (0.15H, dd, J 15.6, 9.8 Hz, H’C=CHC=O), 6.85 (0.85H, dd, J 15.8, 9.7 Hz, HC=CHC=O), 6.13 (0.15H, d, J 16.0 Hz, HC=CH’C=O), 6.06 (0.85H, d, J 15.7 Hz, HC=CHC=O), 5.79-5.84 (0.15H, m, H-4’), 5.77 (0.85H, dt, J 5.4, 2.4 Hz, H-4), 5.63-5.68 (0.15H, m, H-3’), 5.57 (0.85H, dt, J 5.6, 2.0 Hz, H-3), 4.61-4.64 (0.3H, m, OCH2’O), 4.58 (1.7H, dd, J 8.7, 6.5 Hz, OCH2O), 3.47 (2H, dd, J 6.8, 5.4 Hz, CH2-OMOM, CH2’-OMOM), 3.36 (0.45H, s, CH3’O), 3.34 (2.55H, s, CH3O), 3.09-3.14 (1H, m, H-1, H-1’), 3.07 (1H, td, J 9.8, 3.1 Hz, H-2, H-2’), 2.53 (2H, t, J 7.4 Hz, CH2C=O, CH2’C=O), 1.87 (1H, quint, J 2.7 Hz, H-5, H-5’), 1.59-1.64 (2H, m, CH2CH2C=O, CH2’CH2C=O), 1.25-1.36 (4H, m, (CH2)2CH3, (CH2)2’CH3), 0.90 (3H, t, J 7.2 Hz, CH3CH2, CH3’CH2), 0.03 (9H, s, (CH3)3Si, (CH3)3’Si); δC (125.77 MHz, d-chloroform/chloroform) for mixture of isomers: 201.05 (C=O), 148.91 (C’H=CHC=O), 148.28 (CH=CHC=O), 133.56 (C3’), 132.42 (C3), 130.03 (C4’), 129.21 (C4), 127.62 (CH=CHC=O), 96.67 (OCH2O), 68.95 (C’H2OMOM), 68.20 (CH2OMOM), 55.26 (CH3O), 51.12 (C2’), 50.04 (C2), 45.48 (C1), 42.05 (C5), 39.90 (CH2C=O), 31.45 (CH2CH2CH3), 23.98 (CH2CH2C=O), 22.44 (CH2CH3), 13.89 (CH3CH2), -1.34 ((C’H3)3Si), -2.86 ((CH3)3Si); m/z (APCI): 339 (100%, MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: dimethyl 2-oxoheptylphosphonate With potassium hexamethylsilazane In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere; Stage #2: Corey aldehyde In tetrahydrofuran at 20℃; for 4h; | 1.2; 2.2; 3.2; 4.2; 5.2; 6.2; 7.2; 8.2; 9.2 (2) Synthesis of compound 3 Suspend dimethyl (β-oxoheptyl)phosphonate (10g, 45mmol) in anhydrous THF (50mL) under nitrogen protection at -78°C, and mix KHMDS (45mL, 45mmol, 1M) in THF (100mL) solution Add dropwise to the above suspension. After stirring at -78°C for 30 min, a solution of compound 2 (3.8 g, 22 mmol) in THF (20 mL) was slowly added dropwise to the above suspension. Then, the reaction temperature was slowly raised to room temperature, and the reaction was stirred for 4 hours. After the reaction is complete, add saturated NH4Cl solution (50mL) to quench the reaction, extract with ethyl acetate (200mL×3), combine the organic phases, wash with saturated brine, dry with anhydrous Na2SO4, filter, concentrate, and separate and purify by column chromatography to obtain Light yellow oil (6.9 g, 87%). |
43.8% | Stage #1: Corey aldehyde With sodium thiosulfate for 0.5h; Stage #2: dimethyl 2-oxoheptylphosphonate With potassium carbonate In water; acetone | 2 About 1050 ml of saturated sodium thiosulfate was added to the above reaction solution to oxidize the oxidizing property, and the mixture was stirred for about 30 minutes. The aqueous layer was separated and the organic phase was stripped twice with water twice.Each time, the aqueous phase was combined and the aqueous phase The lower side chain mixed solution and the potassium carbonate aqueous solution were added in portions and stirred for 1 to 1.5 hours. In the present example, the solution was first added with 234 g of the lower side chain and 1800 ml of acetone, and 558 g Potassium carbonate and 900 ml of water; the second batch was a solution of 54 g of the lower side chain and 22 ml of acetone, followed by a solution of 4.8 g of potassium carbonate and 12 ml of water. The third batch was a solution of 1.2 g of the lower side chain And 660 ml of acetone solution, plus 54g potassium carbonate and 360ml water solution, each batch interval of about 5min,And then extracted with ethyl acetate solution three times to get the organic phase, each time ethyl acetate 3000ml, combined organic phase, dry,Filtered, evaporated to dryness and the column chromatography gave 210 g of an oil (3) of the olefin (yield 3) in a yield of 43.8%, wherein the eluentThe ratio of 30: 10: 1 petroleum ether, dichloromethane, methanol mixed solution |
701 g | Stage #1: dimethyl 2-oxoheptylphosphonate With lithium hydroxide monohydrate In acetonitrile at 20℃; for 1.5h; Stage #2: Corey aldehyde In dichloromethane; acetonitrile at 20℃; for 1h; | 2 Step (2) Preparation of Compound II LiOH·H 2 O (293 g, 6.977 mol) and acetonitrile (2 L) were successively added to a 10 L reactor equipped with a thermometer, a mechanical stirring and a dropping funnel. Stirring was started and stirring was carried out for 5 min at room temperature. Next, the lower side chain of 2-oxoheptylphosphonic acid dimethyl ester (968 g, 4.36 mol) was dissolved in 3 L of acetonitrile, and slowly added dropwise to the above system, 30 min after completion, and then stirred at room temperature for 1 h; The intermediate compound I obtained in one was dissolved in 1 L of dichloromethane, and slowly added dropwise to the above reaction system, and the dropwise addition was completed, and the mixture was stirred at room temperature for 1 hour;Add 3 L of saturated sodium chloride solution, and extract the aqueous phase with ethyl acetate (2L*2);The organic phases were combined, washed with saturated sodium chloride and dried over anhydrous sodium sulfate, and then evaporated to give pale yellow, Compound II (701 g, purity 98%). |
Stage #1: dimethyl 2-oxoheptylphosphonate With sodium hydride In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; Stage #2: Corey aldehyde In tetrahydrofuran at 0 - 20℃; for 6h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
125 mg | With potassium phosphate In tetrahydrofuran at 20℃; for 12h; Inert atmosphere; | 16 2-{(2R,4aR,5R,6R,7aS)-6-(acetyloxy)-5-[(1E)-3-oxooct-1-en-1-yl]octahydrocyclopenta [b]pyran-2-yl}-1,3-thiazole-4-carboxylate (Reference Compound 16) Under an argon stream, potassium phosphate (206 mg) was added to a solution of Reference Compound 10 (179 mg) and dimethyl (2-oxoheptyl)phosphonate (216 mg) in tetrahydrofuran (2.0 mL), and the resultant solution was stirred at room temperature for 12 hours. Water was added to the reaction solution, and the resultant solution was extracted with ethyl acetate. An organic layer was washed with water and saturated saline, was then dried over anhydrous sodium sulfate, and was then concentrated under a reduced pressure. A residue was purified by silica gel column chromatography (hexane : ethyl acetate = 4:1 → 1:1) to produce the title compound (125 mg) having the following physical property value. TLC: Rf 0.41 (hexane : ethyl acetate = 1:1); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: dimethyl 2-oxoheptylphosphonate With sodium hexamethyldisilazane In tetrahydrofuran at 0 - 23℃; for 0.583333h; Inert atmosphere; Stage #2: C15H26O5 In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; | Enoate 9 To a solution of ketophosphonate 86 (66 mg, 0.30 mmol) in THF (1 mL) at 0 °C was added sodium bis(trimethylsilyl)amide (1 M solution in THF, 240 μL, 0.24 mmol) dropwise. After stirring at 0°C for 5 min, the ice bath was removed and the reaction was allowed to warm to room temperature and stirred for an additional 30 min. White solid was formed during this period. The reaction mixture was cooled to 0 °C and a solution of aldehyde 7 (68 mg, 0.24 mmol) in THF (2.5 mL) added. The reaction was stirred at 0 °C for 30 min and quenched with water (5 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (hexanes to 17:3 hexanes/ethyl acetate, gradient) to afford enoate 9 (75 mg, 82%) as a colorless oil: [α]D20 +0.04 (CHCl3, c 1.0); 1H NMR (400 MHz, CDCl3) δ 6.71 (dd, J = 5.8, 15.8 Hz, 1H), 6.38 (dd, J = 1.2, 15.8 Hz, 1H), 4.15 (m, 1H), 3.73 (m, 1H), 3.68 (s, 3H), 2.57 (t, J = 7.4 Hz, 2H), 2.31 (t, J = 7.4 Hz, 2H), 1.63 (m, 6H), 1.45 (s, 3H), 1.43 (s, 3H), 1.32 (m, 12H), 0.90 (app t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 200.5, 174.5, 141.8, 130.7, 109.6, 81.0, 80.8, 51.7, 41.2, 34.3, 32.3, 31.7, 29.7, 29.33, 29.2, 27.5, 27.0, 26.2, 25.1, 24.0, 22.7, 14.2. m/z calcd. for C22H38O5 [M+Na]+ 405.2609 found 405.2792. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
105 mg | Stage #1: dimethyl 2-oxoheptylphosphonate With sodium hexamethyldisilazane In tetrahydrofuran at 0 - 23℃; for 0.583333h; Inert atmosphere; Stage #2: C15H26O5 In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; | Enoate 9 To a solution of ketophosphonate 86 (66 mg, 0.30 mmol) in THF (1 mL) at 0 °C was added sodium bis(trimethylsilyl)amide (1 M solution in THF, 240 μL, 0.24 mmol) dropwise. After stirring at 0°C for 5 min, the ice bath was removed and the reaction was allowed to warm to room temperature and stirred for an additional 30 min. White solid was formed during this period. The reaction mixture was cooled to 0 °C and a solution of aldehyde 7 (68 mg, 0.24 mmol) in THF (2.5 mL) added. The reaction was stirred at 0 °C for 30 min and quenched with water (5 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (hexanes to 17:3 hexanes/ethyl acetate, gradient) to afford enoate 9 (75 mg, 82%) as a colorless oil: [α]D20 +0.04 (CHCl3, c 1.0); 1H NMR (400 MHz, CDCl3) δ 6.71 (dd, J = 5.8, 15.8 Hz, 1H), 6.38 (dd, J = 1.2, 15.8 Hz, 1H), 4.15 (m, 1H), 3.73 (m, 1H), 3.68 (s, 3H), 2.57 (t, J = 7.4 Hz, 2H), 2.31 (t, J = 7.4 Hz, 2H), 1.63 (m, 6H), 1.45 (s, 3H), 1.43 (s, 3H), 1.32 (m, 12H), 0.90 (app t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 200.5, 174.5, 141.8, 130.7, 109.6, 81.0, 80.8, 51.7, 41.2, 34.3, 32.3, 31.7, 29.7, 29.33, 29.2, 27.5, 27.0, 26.2, 25.1, 24.0, 22.7, 14.2. m/z calcd. for C22H38O5 [M+Na]+ 405.2609 found 405.2792. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With fluorescein free acid In acetonitrile at 20℃; UV-irradiation; | |
70% | With fluorescein In acetonitrile at 20℃; for 6h; Irradiation; | 31 Embodiment 31: dimethyl (2 - amino -1 - cyano group) (2 - oxygen heptyl) phosphoric acid ester synthetic Under the room temperature condition, dimethyl (2 - oxygen heptyl) phosphonate (111 mg, 0.5 mmol), thiocyanate amine (114, 2 mg, 1.5 mmol), fluorescein (3.3 mg, 2 μM %) is added to 10 ml reaction tube, then adding solvent acetonitrile 2 ml, in 3.0 W under the irradiation of blue LED, in the air reaction 6 hours, detected by TLC. After the completion of the reaction, the reaction mixture is concentrated in vacuo, the remaining crude by column chromatography separation to obtain the dimethyl (2 - amino -1 - cyano group) (2 - oxygen heptyl) phosphoric acid ester white solid 97.3 mg, yield 70%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
348 mg | With triethylamine; lithium chloride In tetrahydrofuran | 4 Following the same procedures as described in Example 1, the en-al was prepared (400mg). This was added slowly to a mixture of the phosphonate (3 equiv; 1.25g) and anhydrous LiCl (3 equiv; 237mg) in 12ml THF. Then triethylamine (3.3 equiv; 876 μl) was added, and the reaction allowed to react for 3-4 hours (until TLC showed completion). The reaction was diluted with ether and washed with water then brine. Dried over sodium sulfate, purified on silica gel using 10-15% ether/hexane to elute. There were 371mg (64%) of the dienone. This was further purified by normal phase HPLC (960/40 heptane/MTBE, 275nm) to yield 348mg of a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: dimethyl 2-oxoheptylphosphonate With potassium carbonate In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; Stage #2: (3aR,4R,5R,6aS)-5-((tert-butyldimethylsilyl)oxy)-2-oxohexahydro-2H-cyclopenta[b]furan-4-carbaldehyde In tetrahydrofuran at -20℃; Inert atmosphere; | 1 Under argon protection,To a solution of anhydrous THF (100 mL), β-carbonyldimethoxyheptyl ester (6.60 g, 30.0 mmol, 1.0 eq) and potassium carbonate (12.5 g, 90 mmol, 3.0 eq) were reacted at room temperature for 1 h, then the compound was added dropwise. 3a (8.52 g, 30 mmol, 1 eq) in THF (75 mL)Concentrated, add ethyl acetate (100 mL) and water (50 mL).The layers were allowed to stand and the aqueous phase was extracted with ethyl acetate (100 mL*2).Wash with saturated brine (50 mL),Dry over anhydrous sodium sulfate and concentrate to give a white solid compound 4a (9.81 g, 86%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.38% | Stage #1: dimethyl 2-oxoheptylphosphonate With lithium hydroxide In tert-butyl methyl ether at 0℃; for 1h; Stage #2: Benzoic acid (3aR,4R,5R,6aS)-4-formyl-2-oxo-hexahydro-cyclopenta[b]furan-5-yl ester In tert-butyl methyl ether at 0 - 10℃; for 0.166667h; | 2; 3; 4 Example 2 Take 11.26g (2-oxoheptyl) dimethyl phosphonate (calculated based on 0.7 equivalent of benzoylcorinolide) and dissolve it in 240ml methyl tert-butyl ether in a 1L reaction flask, ice-salt bath Cool down to lower the internal temperature to below 0°C, add 2.12g of lithium hydroxide (calculated based on 0.7 equivalent of benzoylcorinolide), after the addition, continue to stir for 1h. The benzoyl colinactone aldehyde solution in Example 1 was slowly added, and the internal temperature was maintained at 0C~10°C. After the addition, the reaction was incubated for 1 hour. TLC (PE:EA=1:1) monitors that the reaction is complete. Add 100ml of water to the solution and stir for 10min. The layers were separated by standing, and the organic layer was collected. The aqueous layer was extracted with 80 ml of methyl tert-butyl ether. The organic layers were combined and washed with 200 ml of saturated sodium bicarbonate and 200 ml of saturated brine in turn. The organic phase was dried with 40 g of anhydrous sodium sulfate for 0.5 h. Filter and concentrate at 30C-40C under reduced pressure to obtain orange-red oil, 26.7g. Embodiment 3In Example 2, the red oil was dissolved in 1-fold volume of ethyl acetate (i.e. 26.7 ml) at room temperature, stirred 1h was added, and stirred for 1h. filtration to collect solid and move into 7 vacuum drying oven to dry 4h. to give a white solid 186.9 ml, namely 0 °C - 10 °C 15 - ketone, yield 53.33% 40 °C, 97.2% purity 14.3g.Embodiment 4In Example 2, the red oil 26g was prepared, dissolved in 1-fold volume of ethyl acetate (i.e. 26 ml) at room temperature, stirred 10 for suction filtration, and the solid was collected by stirring in 260 ml × volume ethyl acetate (i.e. 1.5h.), dried 4h. to give a white solid 17g, namely 40 °C ketone, yield 15 - purity 63.38%, see 98.79%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With sodium hydroxide In dichloromethane; water stereoselective reaction; |
Tags: 36969-89-8 synthesis path| 36969-89-8 SDS| 36969-89-8 COA| 36969-89-8 purity| 36969-89-8 application| 36969-89-8 NMR| 36969-89-8 COA| 36969-89-8 structure
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