Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 3699-66-9 | MDL No. : | MFCD00009159 |
Formula : | C9H19O5P | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | BVSRWCMAJISCTD-UHFFFAOYSA-N |
M.W : | 238.22 | Pubchem ID : | 107155 |
Synonyms : |
Triethyl 2-phosphonopropionate
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.89 |
Num. rotatable bonds : | 8 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 57.5 |
TPSA : | 71.64 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.11 cm/s |
Log Po/w (iLOGP) : | 2.65 |
Log Po/w (XLOGP3) : | 0.9 |
Log Po/w (WLOGP) : | 2.2 |
Log Po/w (MLOGP) : | 0.83 |
Log Po/w (SILICOS-IT) : | 0.75 |
Consensus Log Po/w : | 1.47 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.36 |
Solubility : | 10.5 mg/ml ; 0.0441 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.99 |
Solubility : | 2.44 mg/ml ; 0.0102 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.89 |
Solubility : | 3.09 mg/ml ; 0.013 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 4.09 |
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: |
* 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 |
---|---|---|
80% | Stage #1: With sodium hydride In tetrahydrofuran for 0.5 h; Stage #2: With water; potassium hydroxide In ethanol for 1 h; Reflux |
Example 4 Masking Agents A. Synthesis of 2-propionic-3-methylmaleic anhydride masking agent precursor (carboxydimethylmaleic anhydride or CDM) 2-propionic-3-methylmaleic anhydride To a suspension of sodium hydride (0.58 g, 25 mmol) in 50 mL anhydrous tetrahydrofuran was added triethyl-2-phosphonopropionate (7.1 g, 30 mmol). After evolution of hydrogen gas had stopped, dimethyl-2-oxoglutarate (15 g, 20 mmol) in 10 mL anhydrous tetrahydrofuran was added and stirred for 30 min. 10 mL water was then added, and the tetrahydrofuran was removed by rotary evaporation. The resulting solid and water mixture was extracted with 3×50 mL ethyl ether. The ether extractions were combined, dried with magnesium sulfate, and concentrated to a light yellow oil. The oil was purified by silica gel chromatography elution with 2:1 ether:hexane to yield 4 g (82percent yield) of pure triester. The 2-propionic-3-methylmaleic anhydride was then formed by dissolving of this triester into 50 mL of a 50150 mixture of water and ethanol containing 4.5 g (5 equivalents) of potassium hydroxide. This solution was heated to reflux for 1 h. The ethanol was then removed by rotary evaporation and the solution was acidified to pH 2 with hydrochloric acid. This aqueous solution was then extracted with 200 mL ethyl acetate, isolated, dried with magnesium sulfate, and concentrated to a white solid. This solid was then recrystallized from dichloromethane and hexane to yield 2 g (80percent yield) of 2-propionic-3-methylmaleic anhydride. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: furfural In tetrahydrofuran; hexane at 0 - 20℃; Inert atmosphere; | |
98% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: furfural In tetrahydrofuran; mineral oil for 0.5h; Inert atmosphere; | |
97% | With sodium hydride In benzene 1.) 25 deg C, 30 min, 2.) 25 deg C, 6 h; |
95 % Spectr. | With caesium carbonate In 1,4-dioxane; water at 70℃; for 1.5h; | |
With sodium hydride In tetrahydrofuran; mineral oil at -78 - 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With sodium hydride In diethyl ether; mineral oil at 0 - 50℃; for 4.16667h; Inert atmosphere; | Synthesis of ethyl (1-methylpiperidin-4-ylidene)propanoate (1) Synthesis of ethyl (1-methylpiperidin-4-ylidene)propanoate (1) N-methyl-4-piperidone (0.5 gm, 4.42 mmol) was dissolved in anhydrous ether (5 mL) in a dry flask under argon and triethyl-2-phosphonopropionate (1.58 gm,6.63 mmol) was added, followed by addition of sodium hydride (0.12 gm, 4.86 mmol) at0°C for 10 mm. The reaction mixture was heated at reflux (50°C) for 4 hr when thin layerchromatographic (TLC) analysis demonstrated that no starting material remained. Solventwas evaporated under vacuum, the residue was dissolved in dichloromethane (50 mL) andthe solution washed with water (3 x 50 mL). The organic phase was dried (Mg504),evaporated to dryness and purified on a silica gel column using 2% methanol in dichloromethane. The pure compound 1 (0.54 gm) was obtained in 62% yield. 1H NMR 1 (CDC13) ö: 4.15 (m, 2H), 2.41-2.36 (m, 7H), 2.15 (s, 3H), 2.00 (t, J = 7.2, 4H), 1.19 (t, J = 7.6, 3H). MS: (M+1) calculated 198.27, found 198.35. |
61% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran at 0℃; for 0.25h; Inert atmosphere; Stage #2: 1-Methyl-4-piperidone In tetrahydrofuran at 0 - 20℃; Inert atmosphere; | |
With sodium hydride 1.) benzene, RT, 1 h, 2.) benzene, 15 min; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With sodium hydride In tetrahydrofuran at 0 - 20℃; for 1h; | Synthesis of ethyl 2-(l-benzylpiperidin-4-ylidene)propanoate (01) To a stirred solution of l -benzylpiperidin-4-one (1) (9 g, 47.5 mmol, 1 eq) in THF (90 mL) was added 60% NaH (3.8 g, 95.1 mmol, 2 eq) at 0°C. Then added a solution of ethyl 2- (diethoxyphosphoryl)propanoate (2) (16.3 mL, 76 mmol, 1.6 eq) in THF (10 mL) dropwise and the reaction mixture was allowed to stir at RT for 1 h. After completion of reaction by TLC, the reaction mixture was quenched with ice cold water and extracted with EtOAc (2 X 100 mL). The combined organic layers were washed with brine (50 mL) dried over sodium sulfate and concentrated. The crude was purified by silica column chromatography by eluting with 20% EtOAc in Flexane to afford ethyl 2-(l-benzylpiperidin-4-ylidene)propanoate (01) as a pale yellow liquid (10 g , yield:76%). TLC system: EtOAc/hexane (30:70), Rf value:~0.6; NMR (400 MHz, CDCh) d 7.34-7.25 (m, 5H), 4.18 (d, J= 7.2 Hz, 2H), 3.51 (s, 2H), 2.64-2.57 (m, 2H), 2.49-2.44 (m, 4H), 2.37-2.35 (m, 2H), (0230) 1.85 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H). |
With sodium hydride 1.) benzene, RT, 1 h, 2.) benzene, 15 min; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium hydride In tetrahydrofuran for 8h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: 4-methoxy-benzaldehyde In tetrahydrofuran; hexane at 0 - 20℃; Inert atmosphere; | |
84% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Stage #2: 4-methoxy-benzaldehyde In tetrahydrofuran; mineral oil at 20℃; for 2h; | |
80% | With tetramethylammonium tetrafluoroborate; Azobenzene In N,N-dimethyl-formamide Ambient temperature; controlled potential electrolysis; cathode: Hg; electrode ref.: AgI/Ag; |
With sodium hydride In tetrahydrofuran; mineral oil at -78 - 20℃; for 3h; | ||
Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 1h; Inert atmosphere; Stage #2: 4-methoxy-benzaldehyde In tetrahydrofuran; mineral oil at 0 - 20℃; for 24h; Inert atmosphere; | ||
Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Stage #2: 4-methoxy-benzaldehyde In tetrahydrofuran; mineral oil for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With sodium hydride In tetrahydrofuran at 0 - 20℃; for 2h; | |
89% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran at 0 - 20℃; Stage #2: cyclopentanone In tetrahydrofuran at 0℃; | |
With sodium hydride In 1,2-dimethoxyethane 1.) 0 deg C, 20 min; 2.) RT, 30 min; 3.) reflux, 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With n-butyllithium In tetrahydrofuran; hexane at -76℃; Inert atmosphere; Stage #2: acetone In tetrahydrofuran; hexane at 0 - 20℃; for 24h; Inert atmosphere; | I19 Example I19: 2,3-dimethylbut-2-enoic acid ethyl ester Commercially available triethyl 2-phosphonopropionate (22.5 ml, 103 mmol, CAS [3699-66-9]) was placed in dry tetrahydrofuran (65 ml) under argon atmosphere, cooled to -76°C and 2.5M solution of n-butyllithium in hexanes (39.2 ml, 98 mmol) was slowly added dropwise under stirring. Colorless solid precipitated and the reaction mixture was left to warm to 0°C. Acetone was added dropwise to the reaction mixture (14.4 ml, 196 mmol) and the contents of the reaction vessel was stirred at room temperature for 24 hours. The reaction product was isolated by the adding of 100 ml of 3% aqueous sulfuric acid solution and extraction with diethyl ether. Organic layer was separated, washed twice with water, 6% aqueous sodium bicarbonate solution and brine, dried and concentrated on evaporator at 30° C and 400 mbar. The residue was distilled under reduced pressure, collecting fraction of the product that distills in the range 59-62° C and pressure range 5.3-5.6 mbar, to obtain 11.2 g of a colorless liquid (80% yield).1H NMR (300 MHz, CDCl3) 5: 4.19 (q, J = 7.1 Hz, 2H), 2.00 (d, J = 1.3 Hz, 3H), 1.85 (s, 3H), 1.80 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H.13C NMR (75 MHz, CDC ) d: 169.90, 142.77, 122.76, 60.09, 22.92, 22.45, 15.75, 14.43. |
69% | With sodium hydride | |
66% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 1h; Inert atmosphere; Stage #2: acetone In tetrahydrofuran; hexane at 20℃; Inert atmosphere; |
56% | With sodium hydride In benzene | |
With sodium ethanolate 1.) EtOH, 10 min, 2.) EtOH; Yield given. Multistep reaction; | ||
With sodium hydride In 1,2-dimethoxyethane 1.) 0 deg C, 20 min; 2.) RT, 30 min; 3.) reflux, 8h; | ||
With sodium hydride 1.) dimethoxyethane, 0 deg C, 20 min, 2.) dimethoxyethane, reflux; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: cyclohexanedione monoethylene ketal In tetrahydrofuran at 0℃; for 2h; | 157A; 197A 15 7A. Ethyl 2-( 1 ,4-dioxaspiro [4.5 ]decan-8-ylidene)propanoate To a suspension of NaH (0.307 g, 7.68 mmol) in THF (8 mL) cooled at 0°C wasadded ethyl 2-(diethoxyphosphoryl)propanoate (1.830 g, 7.68 mmol) slowly. After30mm, 1 ,4-dioxaspiro[4.5]decan-8-one (1 g, 6.40 mmol) was added. The resulting mixture was stirred at 0°C for 2h, then warmed to RT overnight. The mixture was quenched with water and the THF was removed in vacuo. The residue was dissolved in EtOAc,washed with water and brine. The solution was dried over Na2SO4, filtered and concentrated. The crude material was purified by ISCO(EtOAc/Hex 0-30%). Fractions containing the product were concentrated to yield ethyl 2-( 1 ,4-dioxaspiro [4.5] decan-8- ylidene)propanoate (1.2 g, 78% yield) a light yellow oil. ‘H NMR (400MHz, CHLOROFORM-d) ö 4.19 (q, J=7.1 Hz, 2H), 4.03 - 3.89 (m, 4H), 2.68 - 2.53 (m, 2H),2.46 - 2.28 (m, 2H), 1.89 (s, 3H), 1.78 - 1.66 (m, 4H), 1.30 (t, J=7.1 Hz, 3H). |
78% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Stage #2: cyclohexanedione monoethylene ketal In tetrahydrofuran; mineral oil at 0 - 20℃; | Intermediate 143 A. ethyl 2-(l,4-dioxaspiro[4.5]decan-8-ylidene)propanoate To a suspension of NaH (0.307 g, 7.68 mmol) in THF (8 mL) cooled at 0°C was added ethyl 2-(diethoxyphosphoryl)propanoate (1.830 g, 7.68 mmol) slowly. After 30min, l,4-dioxaspiro[4.5]decan-8-one (1 g, 6.40 mmol) was added. The resulting mixture was stirred at 0°C for 2 hours, then warmed up to room temperature for overnight. The mixture was quenched with water, THF was removed under reduced pressure. The residue was dissolved in EtOAc, washed with water, brine, dried over Na2S04 and concentrated. The crude was purified by ISCO(EtO Ac/Hex 0-30%). Fractions containing the product were concentrated to yield Intermediate 143 A (1.2 g, 78% yield) a light yellow oil. 1H NMR (400MHz, CHLOROFORM-d) δ 4.19 (q, J=7.1 Hz, 2H), 4.03 - 3.89 (m, 4H), 2.68 - 2.53 (m, 2H), 2.46 - 2.28 (m, 2H), 1.89 (s, 3H), 1.78 - 1.66 (m, 4H), 1.30 (t, J=7.1 Hz, 3H) |
78% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: cyclohexanedione monoethylene ketal In tetrahydrofuran at 0 - 20℃; | 1A Preparation 1A. Ethyl 2-(1,4-dioxaspiro[4.5]decan-8-ylidene)propanoate To a suspension of NaH (0.307 g, 7.68 mmol) in THF (8 mL) cooled at 0 °C was added ethyl 2-(diethoxyphosphoryl)propanoate (1.830 g, 7.68 mmol) slowly. After 30 min, l,4-dioxaspiro[4.5]decan-8-one (1 g, 6.40 mmol) was added. The resulting mixture was stirred at 0 °C for 2h, then warmed to rt overnight. The mixture was quenched with water, and THF was removed under reduced pressure. The residue was dissolved in EtO Ac, washed with water, brine, dried over Na2S04, filtered, and concentrated. The crude material was purified by ISCO (EtO Ac/Hex 0-30%). Fractions containing the product were concentrated to yield Preparation 1 A (1.2 g, 78% yield) as a light yellow oil. 1HNMR (400MHz, chloroform-d) δ 4.19 (q, J=7.1 Hz, 2H), 4.03 - 3.89 (m, 4H), 2.68 - 2.53 (m, 2H), 2.46 - 2.28 (m, 2H), 1.89 (s, 3H), 1.78 - 1.66 (m, 4H), 1.30 (t, J=7.1 Hz, 3H). |
78% | With sodium hydride In tetrahydrofuran at 0℃; | |
With sodium hydride In tetrahydrofuran Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In n-heptane; at 60℃; for 15h; | To a stiiTed solution of ethyl 2-(diethoxyphosphoryl)propanoate (450 fiL, 2.1 mmol) in heptane (5 mL) was added 2,2-dimethoxy acetaldehyde (60% in water, 1 .0 mL, 4.2 mmol). The solution was stiiTed for 15 h at 60C. After the reaction was cooled, water was added and the mixture was extracted with CH2C1 and filtered through a phase separator and a silica plug. Concentration under reduced pressure afforded (is)-ethyl 4,4-dimethoxy-2-methylbut-2-enoate (480 mg, > 100%). The procedure was adapted from Tetrahedron 2002, 2533 |
In n-heptane; water; at 60℃; for 15h; | Step (a): To a stirred solution of ethyl 2-(diethoxyphosphoryl)propanoate (450 muL, 2.1 mmol) in heptane (5 mL) was added 2,2-dimethoxy acetaldehyde (60% in water, 1.0 mL, 4.2 mmol). The solution was stirred for 15 h at 60 C. After the reaction was cooled, water was added and the mixture was extracted with CH2Cl2 and filtered through a phase separator and a silica plug. Concentration under reduced pressure afforded (E)-ethyl 4,4-dimethoxy-2-methylbut-2-enoate (480 mg, >100%). The procedure was adapted from Tetrahedron 2002, 2533. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium methylate; In methanol; DMF (N,N-dimethyl-formamide); at 20℃; for 0.333333h; | Reference Example 13; (1) 6-hydroxymethylpyridine-2-carbaldehyde (2.95 g) and triethyl 2-phosphonopropionate (5.12 g) were dissolved in 20 mL of dry DMF, and to the solution was added a solution of 1.30 g of sodium methoxide in 10 mL of methanol dropwise, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was thrown into ice-water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexane - ethyl acetate = 1:1) to give 2.42 g of ethyl (E)-3-(6-hydroxymethylpyridin-2-yl)- 2-methylacrylate as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: 4-methyl-benzaldehyde In tetrahydrofuran; hexane at 0 - 20℃; Inert atmosphere; | |
98.8% | With sodium tertiary butoxide In <i>N</i>-methyl-acetamide; lithium hydroxide monohydrate | R.1 Preparation of ethyl 2-methyl-3-(4-methylphenyl)-2-propenoate Reference Example 1 Preparation of ethyl 2-methyl-3-(4-methylphenyl)-2-propenoate To dimethylformamide (1802 ml) that had been cooled to - 10ØC was added sodium tert-butoxide (528.6 g) and the solution was stirred at -5 to 0ØC for 30 min. Triethyl 2-phosphonopropionate (1310 g) was added dropwise thereto at 10ØC or below. The solution was stirred at 2 to 5ØC for 1 hr, and 4-methylbenzaldehyde (600.8 g) was added dropwise thereto at 10ØC or below and the solution was stirred at room temperature for 1 hr. Water was added thereto and the solution was extracted with toluene. The extract was washed with water and the solvent was distilled off to give the title compound as an oil (1009 g, yield 98.8%). 1H-NMR (CDCl3) δ: 1.35(3H, t, J = 7.1 Hz), 2.12(1H, s), 2.37(3H, s), 4.27(2H, q, J = 7.1 Hz), 7.13-7.32(4H, m), 7.66(1H, s) |
91% | In lithium hydroxide monohydrate; N,N-dimethyl-formamide; paraffin | Ethyl 2-methyl-3-(4-methylphenyl)-2-propenoate Ethyl 2-methyl-3-(4-methylphenyl)-2-propenoate To a suspension of sodium hydride (a 60% dispersion in liquid paraffin, 15.0 g, 375 mmol) in N,N-dimethylformamide (160 ml) was added at 0° C. a solution of triethyl 2-phosphonopropionate (87.7 g, 368 mmol) in N,N-dimethylformamide (10 ml) and the resulting mixture was stirred at the same temperature for 1 hour. To the reaction solution was added 4-methylbenzaldehyde (43.3 g, 361 mmol) and the resulting mixture was stirred at room temperature for 1 hour. Water was added into the reaction solution and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried on magnesium sulfate, and then concentrated under reduced pressure to obtain 66.7 g (91% yield) of the oily title compound. 1H-NMR (CDCl3) δ: 1.34 (3H, t, J=7.0 Hz), 2.12 (3H, d, J=1.4 Hz), 2.37 (3H, s), 4.26 (2H, q, J=7.0 Hz), 7.19 (2H, d, J=8.4 Hz), 7.31 (2H, d, J=8.4 Hz), 7.66 (1H, s). |
91% | In lithium hydroxide monohydrate; N,N-dimethyl-formamide; paraffin | Ethyl 2-methyl-3-(4-methylphenyl)-2-propenoate Ethyl 2-methyl-3-(4-methylphenyl)-2-propenoate To a suspension of sodium hydride (a 60% dispersion in liquid paraffin, 15.0 g, 375 mmol) in N,N-dimethylformamide (160 ml) was added at 0ØC a solution of triethyl 2-phosphonopropionate (87.7 g, 368 mmol) in N,N-dimethylformamide (10 ml) and the resulting mixture was stirred at the same temperature for 1 hour. To the reaction solution was added 4-methylbenzaldehyde (43.3 g, 361 mmol) and the resulting mixture was stirred at room temperature for 1 hour. Water was added into the reaction solution and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried on magnesium sulfate, and then concentrated under reduced pressure to obtain 66.7 g (91% yield) of the oily title compound. 1H-NMR (CDCl3) δ: 1.34 (3H, t, J = 7.0 Hz), 2.12 (3H, d, J = 1.4 Hz), 2.37 (3H, s), 4.26 (2H, q, J = 7.0 Hz), 7.19 (2H, d, J = 8.4 Hz), 7.31 (2H, d, J = 8.4 Hz), 7.66 (1H, s). |
With sodium hydride In tetrahydrofuran; mineral oil at -78 - 20℃; for 3h; | ||
Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 1h; Inert atmosphere; Stage #2: 4-methyl-benzaldehyde In tetrahydrofuran; mineral oil at 0 - 20℃; for 24h; Inert atmosphere; | ||
Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Stage #2: 4-methyl-benzaldehyde In tetrahydrofuran; mineral oil for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran at 0 - 25℃; for 1h; Stage #2: N-phenylpyrrole-2-carbaldehyde In tetrahydrofuran at -10 - 25℃; for 0.666667h; | 1 Ethyl-(2Z)-2-methyl-3-[1-phenylpyrrol-2-yl]prop-2-enoate Into a 250 mL flask, a solution of triethyl 2-phosphonopropionate (32 mL, 150 mmoles) in 20 mL of THF was added slowly to a mixture of sodium hydride (4.8 g, 200 mmoles) in 10 mL of THF at 0° C. The slurry was warmed to room temperature and stirred for one hour; the temperature was lowered to -10° C. Then a solution of 1-phenylpyrrole-2-carbaldehyde (24.4 g, 142 mmoles) in 50 mL of THF was added in a period of 10 minutes. The mixture slowly formed a precipitate. The precipitate was partially broken with a spatula and the reaction mixture was slowly warmed to room temperature over 30 minutes. A saturated aqueous solution of NH4Cl (20 mL) was carefully added. The product was extracted in ether (2×100 mL), the ether extracts washed with brine and dried over sodium sulfate. The solvent was removed in a rotary evaporator, and the crude product was washed with hexane to give an orange oil. The oil crystallized over a period of several days and was triturated with small portions of hexane (5×10 mL), filtered and the solid dried in vacuo to give 25.8 g (71 percent) of a light-tan crystalline material. 1H NMR (CDCl3): 7.4 (m, 4H), 7.3 (m, 2H), 7.0 (dd, 1H), 6.7 (dd, 1H), 6.4 (t, 1H), 4.1 (q, 2H), 2.2 (d, 3H), 1.2 (t, 3); 13C {1H} NMR (CDCl3) 168.8, 139.2, 129.6, 129.2, 127.6, 127.5, 126.3, 125.0, 122.9, 114.3, 110.2, 60.4, 14.3, 14.2. |
With NaH; ammonium chloride In tetrahydrofuran | 5 Synthesis of Ethyl[2Z]-2-methyl-3-[1-phenylpyrrol-2-yl]prop-2-enoate Synthesis of Ethyl[2Z]-2-methyl-3-[1-phenylpyrrol-2-yl]prop-2-enoate Triethyl 2-phosphonopropionate (0.714 mol, 153 ml) was dissolved in THF (75 ml) and added slowly to NaH (1.0 mol, 24.3 g) in THF (60 ml) at 0° C. The mixture was slowly warmed to room temperature and stirring was continued for 1 h after gas evolution had ceased. The temperature was lowered to -10° C. and a solution of the above described 1-Phenylpyrrole-2-carbaldehyde (0.665 mol, 113.0 g) in 200 ml of THF was added dropwise. The flask and contents were warmed to room temperature over a 30 minute period resulting in a thick precipitate which decoupled the magnetic stirrer. A saturated solution of NH4Cl (100 ml) was added cautiously dissolving the precipitate to give a two phase solution. After evaporating the THF, the crude product was extracted with ether (2*200 ml). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: thiophene-2-carbaldehyde In tetrahydrofuran; hexane at 0 - 20℃; Inert atmosphere; | |
98% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: thiophene-2-carbaldehyde In tetrahydrofuran; mineral oil for 0.5h; Inert atmosphere; | |
In tetrahydrofuran | 1 4-(4-Methoxybenzyl)amino-6-methylthieno[3,2-c]pyridine Preparation 1 4-(4-Methoxybenzyl)amino-6-methylthieno[3,2-c]pyridine To a solution of 5.1 g of sodium hydride in oil (prewashed by decantation with hexane.) in 60 ml of dry tetrahydrofuran was added dropwise 30 g of triethyl 2-phosphonopropionate over a period of 30 minutes under dry argon atmosphere at room temperature. After the mixture was stirred for further 1 hour, a solution of 11.8 g of 2-thiophenealdehyde in 30 ml of tetrahydrofuran was added dropwise. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate. Drying agent was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel to give 11.0 g of ethyl 2-methyl-3-(2-thienyl)acrylate as a yellow oil. |
With sodium hydride In tetrahydrofuran; mineral oil at -78 - 20℃; for 3h; | ||
Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Stage #2: thiophene-2-carbaldehyde In tetrahydrofuran; mineral oil for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In tetrahydrofuran; mineral oil; | (a) A solution of triethyl 2-phosphonopropionate (50.0 g) in dry tetrahydrofuran (75 ml) was added dropwise to a stirred suspension of sodium hydride (60percent in mineral oil, 8.0 g) in dry tetrahydrofuran (275 ml) under nitrogen and stirred at 20° C. for 10 minutes until a clear solution was formed. <strong>[24686-78-0]1-Benzoyl-4-piperidone</strong> (34.5 g) in dry tetrahydrofuran (75 ml) was added dropwise to the clear solution and the reaction mixture heated under reflux for 16 hours. After quenching the reaction mixture with 5M hydrochloric acid (20 ml), the resulting solid was removed by filtration. Excess ether was added to the filtrate, the aqueous layer separated off and the ethereal layer washed (water), dried, filtered and concentrated to give ethyl 2-(1-benzoyl-4-piperidylidene)propionate as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With N-ethyl-N,N-diisopropylamine; lithium chloride In acetonitrile at 20℃; for 24h; | 42 Description 41 (639 mg, 3.53 mmol) was added to a solution of ethyl 2-(diethoxyphosphoryl)propanoate (0.980 ml, 4.6 mmol), lithium chloride (2.10 g, 49.4 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.10 ml, 8.83 mmol) in anhydrous acetonitrile (10 ml) and the mixture stirred at room temperature for 24hr. Aqueous ammonium chloride (120 ml) and water (50 ml) were added and the reaction extracted into dichloromethane (x 5), then the combined organic phases were dried (MgSO4) and evaporated. The crude material was purified by flash column chromatography on silica (eluent: 13% ethyl acetate in hexane) to give the title compound as a white solid (875 mg, 94%). 1H NMR (400MHz, DMSO) δ 8.48 (1 H, s), 7.63 (1 H, d, J 1.2), 4.23 (2 H, q, J7.1), 2.28 (3 H, d, J 1.2), 1.29 (3 H, t, J7.1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran at 0℃; for 1h; Stage #2: (E)-2-decenal In tetrahydrofuran at 0℃; for 2h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran at 0℃; for 1h; Stage #2: allyl bromide In tetrahydrofuran at 20℃; for 12h; | Ethyl 2-(diethoxyphosphoryl)-2-methylpent-4-enoate (3) To a solution of ethyl 2-(diethoxyphosphoryl)propanoate (1, 10.0 g, 42 mmol) in THF (100 mL) at 0 °C, NaH (2 g, 50 mmol)was added. The mixture was stirred at 0 °C for 1 h. Then 3-bromoprop-1-ene (2, 6.1 g, 50 mmol) wasadded. The mixture was stirred at RT overnight. NH4Claq (50 mL) was added at 0 °C, THF wasremoved and the mixture extracted with DCM (3 × 200 mL). The combined organic layers were driedover anhydr-MgSO4, filtered and concentrated to give compound 3 as yellow oil (12 g, 100% yield)which was used in the next step without further purification. MS (ES+) C12H23O5P requires: 278,found: 279. 3: [M + H]+; 1H NMR (600 MHz, CDCl3) δ 5.74-5.62 (m, 1H; 4-H), 5.15-5.07 (m, 2H, 5-H), 4.23-4.12 (m,6H; OCH2CH3), 2.91 (ddd, J = 13.3, 10.3, 6.8 Hz, 1H; 3a-H), 2.40 (dddd, J = 13.8, 9.0, 8.0, 1.0 Hz, 1H; 3b-H), 1.41 (d, J = 16.5 Hz, 3H; 2-CH3), 1.33 (t, J = 7.1 Hz, 6H; OCH2CH3), 1.28 (td, J = 7.1, 0.8 Hz, 3H;OCH2CH3); 13C NMR (151 MHz, CDCl3) δ 171.1 [s, (d, J = 3.8 Hz); C-1], 132.5 [d, (d, J = 13.8 Hz); C-4],119.2 (t; C-5), 63.0 [t, (d, J = 7.1 Hz); OCH2CH3], 62.7 [t, (d, J = 7.2 Hz) ; OCH2CH3], 61.4 (t; OCH2CH3),48.0 [s, (d, J = 134.3 Hz); C-2], 38.4 [t; (d, J = 3.8 Hz); C-3], 17.2 [q; (d, J = 4.6 Hz); CH3-2], 16.5 [q, (d, J =4.1 Hz); OCH2CH3], 16.4 [q, (d, J = 4.1 Hz); OCH2CH3], 14.1 (q; OCH2CH3). |
82% | With sodium hydride In tetrahydrofuran at 20℃; for 24h; | |
12 g | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran at 0℃; for 1h; Stage #2: allyl bromide In tetrahydrofuran at 20℃; | 3.1 ethyl 2-(diethoxyphosphoryl)-2-methylpent-4-enoate: To a solution of ethyl 2-(diethoxyphosphoryl)propanoate (10.0 g, 42 mmol) in THF (100 mL) at 0 °C was added NaH (2 g, 50 mmol). The mixture was stirred at 0 °C for 1 h. The 3- bromoprop-l-ene (6.1 g, 50 mmol) was added. The mixture was stirred at RT overnight. Added aq NH4CI (50 mL) at 0 °C and the solvent was removed, extracted with DCM (3 χ 200 ml), the combined organic layers were dried over anhydr-MgS04, filtered and concentrated to give a yellow oil (12 g, crude). MS (ES+) C12H23O5P requires: 278, found: 279 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.47% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: N-tert-butyloxycarbonylpiperidin-4-one In tetrahydrofuran at 20 - 25℃; for 3h; Inert atmosphere; | |
92% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 1h; Inert atmosphere; Stage #2: N-tert-butyloxycarbonylpiperidin-4-one In tetrahydrofuran; mineral oil at 0 - 20℃; Inert atmosphere; | 8 5.1.8. tert-Butyl 4-(1-ethoxy-1-oxopropan-2-ylidene)piperidine-1-carboxylate (10) To a mixture of triethyl 2-phosphonopropionate (13.9 mL, 65.0 mmol) in THF (80 mL) was added portionwise sodium hydride (60% oil dispersion, 2.60 g, 65.0 mmol) at 0 °C, and the mixture was stirred under N2 atmosphere for 1 h. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (9.96 g, 50.0 mmol) in THF (25 mL) was added to the mixture, and the resulting mixture was stirred at room temperature for 1 h. The reaction was quenched by addition of water and diluted with saturated aqueous NH4Cl solution. The mixture was extracted with AcOEt, washed with brine, and dried over Na2SO4. After removal of the solvent, the residue was purified by silica gel column chromatography (hexane/AcOEt = 95/5 to 60/40) to give the title compound as a colorless oil (13.1 g, 92%). 1H NMR (300 MHz, CDCl3) δ 1.30 (3H, t, J = 7.2 Hz), 1.47 (9H, s), 1.88 (3H, s), 2.35 (2H, t, J = 5.9 Hz), 2.63 (2H, t, J = 5.9 Hz), 3.38-3.53 (4H, m), 4.20 (2H, q, J = 7.2 Hz). |
With sodium hydride In tetrahydrofuran |
Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium t-butanolate In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; Stage #2: N-tert-butyloxycarbonylpiperidin-4-one In tetrahydrofuran at 0 - 20℃; for 2h; Inert atmosphere; | 31-1 tert-butyl 4-(1-ethoxy-1-oxopropan-2-ylidene )piperidine-1-carboxylate To a solution of ethyl2-(diethoxyphosphoryl)propanoate (15.55 g, 65.33 mmol) in THF(60 mL) was added t-BuONa (6.76 g, 70.35 mmol) at 0°C under nitrogen atmosphere. After5 stirring at 0°C for 1h, tert-butyl4-oxopiperidine-1-carboxylate (10.0 g, 50.25 mmol) in THF (40mL) was added at 0°C. The resulting mixture was stirred at 0°C tort for 2h. The mixture wasquenched by the addition of saturated ammonium chloride (50 mL) and then extracted withEtOAc (300 mL). The organic phase was washed with water (40 mL x 2) and dried overanhydrous Na2S04. The organic phase was concentrated and the residue was purified by column10 chromatography (silica gel: 300-400 mesh, PE/EtOAc = 10/1) to afford tert-butyl4-(1-ethoxy-1-oxopropan-2-ylidene )piperidine-1-carboxylate. LRMS m/z (M-99) 184.3 found, 184.2 required. | |
Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran at 20℃; for 0.583333h; Stage #2: N-tert-butyloxycarbonylpiperidin-4-one In tetrahydrofuran at 20℃; for 1h; | 10.1 [00154] Step 1: A 100-mL 3 -neck round-bottom flask was charged with anhydrous THF (20 mL) and 60% dispersion sodium hydride (0.574 g, 14.35 mmol) and placed under nitrogen atmosphere. At ambient temperature, ethyl 2- (diethoxyphosphoryl)propanoate (3.42 g, 14.35 mmol) was added to the suspension via syringe over a period of 5 min and the mixture stirred for 30 min. The resulting clear mixture was treated with a solution of tert-butyl 4-oxopiperidine-l-carboxylate (2.2 g, 11.04 mmol) in anhydrous THF (5 mL) and the reaction continued at ambient temperature for 1 h. At the conclusion of this period, the mixture was quenched with saturated NH4Cl solution and the mixture was then extracted with EtOAc (3 x 50 mL). The extract was washed with brine, dried (MgSO4) and concentrated to give the crude product. The crude product was purified by flash chromatography using an 80 g silica gel gradient elution from 20: 1 Hex/EtOAc to 6: 1 Hex/EtOAc. The fractions containing the product were pooled and concentrated on a rotary evaporator to give tert-butyl 4-(l-ethoxy-l-oxopropan-2-ylidene)piperidine-l-carboxylate as a colorless liquid. 1H-NMR (500 MHz, CDCl3) δ ppm 4.18 (2 H, q, J=I.15 Hz), 3.43 (4 H, dt, J=23.71, 5.88 Hz), 2.61 (2 H, t, J=5.77 Hz), 2.33 (2 H, t, J=5.77 Hz), 1.86 (3 H, s), 1.45 (9 H, s), 1.26 - 1.31 (3 H, m, J=7.15 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran at 20℃; for 0.583333h; Stage #2: 1-(4-chloro-3-methoxyphenyl)piperidin-4-one In tetrahydrofuran at 20℃; for 1h; | 13.3 [00178] Step 3: A suspension of 60% dispersion sodium hydride (65.1 mg, 1.627 mmol) in anhydrous THF (2.5 mL) was treated with a solution of trimethyl phosphonoacetate (235 μL, 1.627 mmol) in THF (1 mL) over 5 min. The mixture was stirred at RT for 30 min and then treated with a solution of l-(4-chloro-3- methoxyphenyl)piperidin-4-one (300 mg, 1.252 mmol) in THF (3 mL). The reaction was stirred at RT for 1 h before it was partitioned between saturated NH4Cl and EtOAc. The extract was dried (Na2SO4) and concentrated to give the crude product, which was purified by flash chromatography (12 g silica gel cartridge and gradient elution from 0 to 30% EtOAc/hexanes) to afford methyl 2-(l-(4-chloro-3- methoxyphenyl)piperidin-4-ylidene)acetate (288 mg, 0.974 mmol, 78 % yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ ppm 7.19 (1 H, d, J=8.79 Hz), 6.49 (1 H, d, J=2.42 Hz), 6.44 (1 H, dd, J=8.79, 2.64 Hz), 5.73 (1 H, s), 3.88 (3 H, s), 3.70 (3 H, s), 3.26 - 3.34 (4 H, m, J=5.82, 5.49, 5.33, 5.33 Hz), 3.10 (2 H, t, J=5.38 Hz), 2.45 (2 H, t, J=5.27 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran at 10℃; for 1h; Stage #2: 4-(4-hydroxyphenyl)cyclohexan-1-one With N,N,N',N'-tetramethylguanidine In tetrahydrofuran at 10 - 20℃; for 18h; | 17.i Intermediate 17: trans-εthyl 2-[4-(4-Uhydrazino(oxo)acetyllamino}phenyl) cyclohexyllpropanoate; i) Ethyl 2-[4-(4-hydroxyphenyl)cyclohexylidenelpropanoate; A solution of ethyl 2-(diethoxyphosphoryl)propanoate (12.5 g, 52.6 mmol) in THF (10 mL) was added in one portion to a stirred mixture of sodium hydride (60 % in mineral oil, 2.3 g, 57.6 mmol) in THF (75 mL) and the reaction mixture was stirred at 100C under an argon atmosphere for I h. In a separate flask tetramethylguanidine (6.61 g, 57.4 mmol) was added in one portion to a solution of 4-(4-hydroxyphenyl)cyclohexanone (9.1 g, 47.8 mmol) in THF (40 mL) at 100C under an argon atmosphere and the stirred mixture was warmed to room temperature over 1 h. This mixture was added in one portion to the ethyl 2-(diethoxyphosphoryl)propanoate mixture at 10 0C and the combined reaction mixture was warmed to ambient temperature and stirred for 18 h under an argon atmosphere. A saturated aqueous solution of ammonium chloride (75 mL) and EtOAc (100 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were dried and concentrated in vacuo to leave a residue. The residue was triturated with a mixture of ether and isohexane (2:1), filtered and the filtrate was concentrated in vacuo to give the title compound (6.9 g, 53 %) as a solid; 1R NMR δ 1.21 (3H, t), 1.33-1.5 (2H, m), 1.78-2.1 (4H, m), 1.84 (3H, s), 2.6-2.78 (2H, m), 2.99-3.09 (IH, m), 4.12 (2H, q), 6.67 (2H, d), 7.02 92H, d), 9.08 (IH, s); MS m/e MH+ 275. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran at 0℃; for 0.25h; Stage #2: c-4-Iodo-3-propoxybenzaldehyde In tetrahydrofuran at 20℃; for 12h; | 31.d d-Ethyl (E)-3-(4-iodo-3-propoxyphenyl)-2-methylacrylate d-Ethyl (E)-3-(4-iodo-3-propoxyphenyl)-2-methylacrylateA solution of 1.8 g (7.7 mmol) of triethyl 2-phosphonopropionate in 25 mL of tetrahydrofuran is added to a suspension of 310 mg (7.7 mmol) of 60% sodium hydride in oil, precooled to 0° C. After stirring at 0° C. for 15 minutes, a solution of 1.5 g (5.2 mmol) of 4-iodo-3-propoxybenzaldehyde in 10 mL of tetrahydrofuran is added. The reaction medium is stirred at room temperature for 12 hours. Saturated ammonium chloride solution is added and the reaction medium is extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a 7/3 heptane/ethyl acetate mixture. 1.6 g (84%) of ethyl (E)-3-(4-iodo-3-propoxyphenyl)-2-methylacrylate are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran for 0.333333h; Stage #2: 3-butoxy-4-iodobenzaldehyde In tetrahydrofuran at 20℃; for 2.5h; | 19.h h-Ethyl (E)-3-(3-butoxy-4-iodophenyl)-2-methylacrylate h-Ethyl (E)-3-(3-butoxy-4-iodophenyl)-2-methylacrylateA solution of 8.25 mL (37.8 mmol) of 2-triethyl phosphonopropionate in 20 mL of tetrahydrofuran is added to a mixture of 1.52 g (37.8 mmol) of sodium hydride in 15 mL of tetrahydrofuran. The reaction medium is stirred for 20 minutes. A solution of 3.83 g (12.6 mmol) of 3-butoxy-4-iodobenzaldehyde in 15 mL of tetrahydrofuran is then added to the reaction mixture and the reaction medium is then stirred at room temperature for 2 hours 30 minutes. The reaction medium is poured into saturated ammonium chloride solution and extracted with ethyl acetate. The organic phases are combined, washed with water and then with saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated off and the residue (10.7 g) is purified by chromatography on silica gel eluted with a 95/5 heptane/ethyl acetate mixture. 4.8 g (97%) of ethyl (E)-3-(3-butoxy-4-iodophenyl)-2-methylacrylate are obtained in the form of a yellow oil that crystallizes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran at 0 - 20℃; Stage #2: ortho-anisaldehyde In tetrahydrofuran at 0℃; | 8.1 Example 8; Standard Procedure for the Synthesis of Protected Tether Boc-T81(1R,8S) (FIG. 6); Step 8-1. 3-(2-Methoxy-phenyl)-2-methyl-acrylic acid ethyl ester (T81-2).; To a suspension of sodium hydride (65% in oil, 26.4 g, 661 mmol, washed thoroughly with hexanes to remove oil) in THF (746 mL) at 0° C. was added (EtO)2P(O)CH(Me)CO2Et (144 mL, 661 mmol). The mixture was stirred at room temperature for 30 min, then the solution cooled to 0° C. and aldehyde T81-1 (60.0 g, 441 mmol) slowly added. The reaction was stirred during O/N with monitoring by TLC [(ethyl acetate:hexanes, 2:7), Rf=0.49 (UV, CMA)]. A saturated solution of ammonium chloride was added and the aqueous phase extracted with Et2O (3×), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ethyl acetate/hexanes, 2/8) to give T81-2 as a yellow oil (97-100% yield). |
97% | With sodium hydride In tetrahydrofuran | 11.P The synthesis of Boc-T114 required the lengthy sequence illustrated starting from 2-methoxybenzaldehyde (114-1). The key step is the kinetic resolution of intermediate 114-4 using PS Amano lipase. (Nordin, O.; Nguyen, B.-V.; Vörde, C.; Erik Hedenström, E.; Högberg, H.-E. J. Chem. Soc., Perkin Trans. 1 2000, 367-376.) This provides 114-5a as the free alcohol, which can be transformed into T114a and T114d, with (S)-methyl lactate (114-0) and (R)-methyl lactate, respectively, in the subsequent reaction to form 114-8. Similarly, use of intermediate 114-5b also produced in the resolution process can provide T114b and T114c, with (S)-methyl lactate (114-0) and (R)-methyl lactate, respectively. In this manner, all of the four diastereomers of this tether can be accessed. Alternative protecting groups, such as Ddz or Fmoc, can be introduced using standard methods in the final step as required. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 1 - 30℃; for 0.333333h; Stage #2: 4-chloro-3-[(1,3,4-trimethyl-1H-pyrazol-5-yl)oxy]benzaldehyde In tetrahydrofuran; mineral oil for 1h; | 82 Example 82 ethyl (2E)-3-{4-chloro-3-[(1,3,4-trimethyl-1H-pyrazol-5-yl)oxy]phenyl}-2-methylacrylate; To a solution of ethyl 2-(diethoxyphosphoryl)propionate (0.472 mL) in tetrahydrofuran (20 mL) was added 60% sodium hydride (oil, 88 mg), and the mixture was stirred at room temperature for 20 min. 4-Chloro-3-[(1,3,4-trimethyl-1H-pyrazol-5-yl)oxy]benzaldehyde (529 mg) obtained in Reference Example 64 was added to the reaction mixture, and the mixture was stirred for 1 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate 9:1 - 2:1, v/v) to give the title compound as a colorless oil (590 mg, yield 85%). 1H-NMR (300 MHz, CDCl3)δ:1.33 (t, J = 7.2 Hz, 3 H), 1.76 (s, 3 H), 1.99 (d, J= 1.5 Hz, 3 H), 2.19 (s, 3 H), 3.59 (s, 3 H), 4.25 (q, J = 7.2 Hz, 2 H), 6.65 (d, J = 1.9 Hz, 1 H), 7.07 (dd, J = 8.2, 1.9 Hz, 1 H), 7.43 - 7.50 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran at 20 - 50℃; for 0.916667h; Stage #2: 3-(2-methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)-propen-1-al In tetrahydrofuran at 50℃; Reflux; Stage #3: With hydrogenchloride; water In tetrahydrofuran | 3.C.i C) Preparation of compounds (III) with all dotted lines being C=C i) Preparation of2-Methyl-5-(2-methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)- penta-2,4-dienoic acid ethyl esterNaH (55%, 168.0 mg, 3.85 mmol) and THF (5.0 ml) were placed in a reactor and 2-(diethoxy-phosphoryl)-propionic acid ethyl ester (939.0 mg, 3.94 mmol) was added dropwise at room temperature to the suspension over a 10 minutes period. The mixture was heated at 500C for 45 minutes 3-(2-methyl-3-methylene-bicyclo[2.2.1]hept-2-exo- yl)-propen-l-al (566.0 mg, 3.21 mmol) in THF (2.0 ml) was added dropwise to the ylide at 500C. Once the addition finished, the mixture was refluxed for 1 hour. The mixture was then cooled down to room temperature and hydrolyzed with aqueous HCl 5%. The reaction was extracted twice with Et2O. The combined organic layers were washed with water, aqueous saturated NaHCθ3 and brine. The solution was dried over Na2SO4, filtered off and solvents were removed under vacuum to give a crude which was further purified by bulb to bulb distillation under reduced pressure to afford the title compound (651.0 mg) in 78% yield. 1H NMR: 7.18 (d, J=I 1.2, IH), 6.31 (dd, 3l=15.2, J2=11.2, IH), 6.05 (d, J=15.2, IH),4.98 (s, IH), 4.56 (s, IH), 4.20 (q, J=7.1, 2H), 2.73 (d, J=3.2, IH), 2.09 (d, J=3.1, IH), 1.92 (d, J=1.2, 3H), 1.73-1.65 (m, 2H), 1.61-1.57 (m, IH), 1.52-1.43 (m, IH), 1.34-1.27 (m, IH), 1.29 (t, J=7.1, 3H), 1.19-1.18 (m, IH), 1.18(s, 3H). 13C NMR: 168.6, 161.8, 150.2, 138.8, 125.5, 123.0, 103.2, 60.4, 49.6, 47.0, 46.4, 37.1,30.1, 23.5, 23.0, 14.3, 12.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 77% 2: 10% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 20℃; for 0.166667h; Stage #2: quinoline 2-carbaldehyde In dimethyl sulfoxide at 20℃; for 2h; | 64 Example 64; Ethyl (E)-2-methyl-3- (2-quinolinyl)-2-propenoate (25a); Ethyl (Z)-2-methyl-3-(2-quinolinyl)-2-propenoate (25b) To a solution of potassium tert-butylate (0.5 g, 4.5 MMOL) in dimethyl sulfoxide (10 ml), triethyl 2-phosphonopropionate (0.99 g, 4.2 MMOL) was added and the resulting solution was stirred for 10 minutes at room temperature. Quinolin-2-carbaldehyde (1) (0.5 g, 3.2 MMOL) was added to this solution, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (50 ml) and the product was extracted with diethyl ether (3 x 50 ML). The extract was washed with water and dried (NA2SO4). The solvent was removed under reduced pressure and isomers of the reaction product were separated on silica gel with acetate-hexane (1: 7) as eluent affording the (E)-isomer (25A) (0.59 g, 77%) and the (Z) -isomer (25b) (0.08 g, 10%) as oils. (E) -isomer (25a) :'H NMR (DMSO-D6, HMDSO), No. : 1.29 (3H, t, J=7.5 Hz, CH3) ; 2.41 (3H, d, J=0. 9 Hz, CH3) ; 4.25 (2H, q, J=7.5 Hz, CH2) ; 7.52-7. 92 (4H, m, C9H3N, CH); 7.92- 8.12 (2H, m, C9H2N) ; 8.41 (1H, d, J=9.5Hz, C9H2N). (Z) -isomer (25b) :'H NMR (DMSO- D6, HMDSO), B : 1.05 (3H, t, J=7.0 Hz, CH3) ; 2.08 (3H, d, J=1.8 Hz, CH3) ; 4.19 (2H, q, J=7.0 Hz, CH2) ; 6.83 (1 H, q, J=1.8 Hz, CH=); 7.45 (1 H, d, J=8.5 Hz, CGHN) ; 7.49-8. 01 (4H, m, C9H4N) ; 8.27 (1 H, d, J=8. 5Hz, C9HN). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran at 0 - 20℃; for 1.5h; Stage #2: 5-methylthiophene-2-carboxaldehyde In tetrahydrofuran at 0 - 20℃; for 5h; | 92 (Example 92), Synthesis of ethyl (2Z)-2-methyl-3-[5-methylthiophen-2-yl]-2-propenoate Under nitrogen atmosphere, a reactor was loaded with 60% sodium hydride (87.1 g, 2.15 mol) and dry THF (130 mL). A solution of triethyl 2-phosphonopropionate (239 mL, 1.54 mol) in dry THF(160 mL) was added dropwise into the reactor in an ice bath. The mixture was stirred at room temperature for 1.5 hours, and successively, in an ice bath, a solution of 5-methylthiophene-2-carboxyaldehyde (180.0 g, 1.43 mol) in dry THF (430 mL) was added dropwise thereto under ice bath cooling and stirred at room temperature for 5 hours. An aqueous saturated ammonium chloride solution was added to the resulting reaction mixture and the mixture was extracted with diethyl ether to obtain an organic layer. The organic layer was washed with a saturated brine and dried over magnesium sulfate anhydride. The solvent was distilled off under reduced pressure to obtain ethyl (2Z)-2-methyl-3-[5-methylthiophen-2-yl]-2-propenoate (291.8 g, 97.0%) as a dark red liquid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With n-butyllithium In tetrahydrofuran; hexanes at -78℃; for 0.166667h; Stage #2: p-(iodophenyl)carboxaldehyde In tetrahydrofuran; hexanes at -78℃; for 0.5h; | 7 (E)-3- .-3-(4-Iodo-phenyl .-2-methYl-acrylic acid ethyl ester (Reagent 7); A stirred, cooled (-78°C) solution of triethyl-2-phosphonopropionate (10g, 41. 9mmol) in anhydrous tetrahydrofuran (100mL) was treated with a 1.6M solution of n-butyl lithium in hexanes (25mL, 40mmol). After 10 min, the reaction mixture was cannulated into a cooled (-78°C) solution of 4-iodo-benzaldehyde (4.66g, 20mmol) in tetrahydrofuran (25mL). After 30 minutes, it was quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether (x2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford an oil that was subjected to flash column chromatography over silica gel (230-400mesh) using 9-10% ethyl acetate in hexane as the eluent to afford the title compound (6.3g, 99%). 'H NMR (300 MHz, CDC13) : 6 7.71 (d, 2H, J= 8.4Hz), 7.58 (s, 1H), 7.12 (d, 2H, J = 8.4Hz), 4.27 (q, 2H, J= 7.2Hz), 2.08 (d, 3H, J= 1. 5Hz), 1. 35 (t, 3H, J= 7. 2Hz) |
83% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: p-(iodophenyl)carboxaldehyde In tetrahydrofuran; hexane at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Triethylphosphonopropionate (4.5 g) was dissolved in THF (15 mL), sodium hydride (1.59 g) was added under ice-cooling, and the mixture was stirred for 30 minutes. To the solution was added a solution obtained by dissolving <strong>[153203-80-6]3,5-dichloro-4-formyl-benzoic acid</strong> (3.9 g) in THF (10 mL), and the mixture was further stirred for 1 hour and 20 minutes. The reaction solution was extracted with ethyl acetate, and a solvent was distilled off until a weight including a weight of the solvent became 11.7 g. The precipitated crystal was filtered off, and washed with a mixed solvent of ethyl acetate and n-heptane (1 : 2) to obtain 3 (E)-3,5-dichloro-4-(2-ethyloxycarbonylphenylpropyl)benzoic acid (13, 3.98 g). Melting point: 145C NMR (CDCl3) delta ppm: 8.07 (s, 2H), 7.47 (s, 1H), 4.32 (q, 2H, J = 7.0 Hz), 1.79 (s, 3H), 1.38 (t, 3H, J = 7.0 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In tetrahydrofuran; for 2.0h; | Triethylphosphonopropionate (26.3 g) was dissolved in THF (150 mL), a THF solution of sodium hydride (6.3 g), and <strong>[111829-72-2]4-bromo-2,6-dichlorobenzaldehyde</strong> (6, 20 g) obtained in the first step was added dropwise, and the mixture was stirred for 2 hours. The reaction solution was extracted with ethyl acetate, and purified by column chromatography to obtain ethyl (E)-3-(4-bromo-2,6-dichlorophenyl)-2-methylacrylate (6, 21.2 g). Melting point: 32C NMR (CDCl3) delta ppm: 7.52 (s, 2H), 7.35 (s, 1H), 4.28 (q, 2H, J = 7.0 Hz), 1.76 (s, 3H), 1.33 (t, 3H, J = 7.0 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | 5.6mL (2.5mol/L) butyl lithium was added to a solution of 3.4g (14mmol) ethyl 2-diethoxyphosphorylbutanoate (Sigma Aldrich) in 12mL dry DME under N2 atmosphere at RT. After 5min, 1.3g (11mmol) (2S)-2-phenyloxirane (Sigma Aldrich) was added dropwise. The mixture was stirred for 20min at RT and then heated at 130C under MW irradiation for 90min. Aqueous NH4Cl was added and the product was extracted with Et2O. The combined organic layers were dried over Na2SO4 and concentrated. The dry residue was purified by column chromatography (eluent: EtOAc/hexane, 0:100-10:100) to give the ethyl cyclopropanecarboxylate 11a (2.9g, 90%). 1H NMR (CDCl3) delta (ppm): 7.25-7.20 (m, 2H), 7.19-7.13 (m, 1H), 7.12 (d, J=7.3Hz, 2H), 4.13-4.06 (m, 2H), 2.75-2.71 (m, 1H), 1.63-1.59 (m, 1H), 1.24-1.19 (m, 3H), 1.12-1.07 (m, 1H), 0.91 (s, 3H). MS (ESI): m/z: 205 [M+H]+. | |
A. (1 R,2S)-1 -Methyl-2-phenyl-cyclopropanecarboxylic acid ethyl esterTriethyl 2-phosphonopropionate (3.57 mL, 16.65 mmol) was dissolved in dry DME (20 mL) under argon and a solution of n-Bu-Li 1.6 M in hexane (10.40 mL, 16.65 mmol) was added dropwise. The mixture was stirred for 5 mm at RT then (S)-2-phenyl-oxirane (1 g, 8.32 mmol) was added in one portion. The reaction mixture was heated overnight at 110C. After cooling to RT, the reaction mixture was poured into sat. aq. NH4CI and extracted with Et20 (2 x 50 mL). The combined organic layers were dried (phase separator) and concentrated. The product was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 pm, 3OxlOOmm, flow:40 mL/min, eluent: 40% to 100% CH3CN in H20 in 20 mm, CH3CN and H20 containing 0.1% TEA), the pure fractions were combined and lyophilized to afford the title compound. MS (LC/MS): 205 [M4-H]+, tR (H PLC conditions b): 5.41 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran at 0 - 20℃; for 1h; Stage #2: 5-(3-Chlorophenyl)-7-formyl-8-methoxy-2-(methylamino)quinazoline In tetrahydrofuran at 0 - 20℃; for 2h; | 85 7-[E-(2-ethoxycarbonyl-1-propenyl)]-5-(3-chlorophenyl)-8-methoxy-2-(methylamino)quinazoline (Compound 85) Example 85 7-[E-(2-ethoxycarbonyl-1-propenyl)]-5-(3-chlorophenyl)-8-methoxy-2-(methylamino)quinazoline (Compound 85) Sodium hydride (0.146 g, 3.66 mmol) was suspended in THF (6 mL), and triethyl 2-phosphonopropionate (0.785 mL, 3.66 mmol) was dropped thereto under ice cooling, and then the mixture was stirred at room temperature for 1 hour. Next, to the mixture was added a suspension of Compound 82 (0.500 g, 1.53 mmol) in THF (4 ml) slowly under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Next, saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane = 63/35) to give Compound 85 (0.503 g, 80 %). 1H NMR (CDCl3, δ):1.24 (t, J = 7.2 Hz, 3H), 2.05 (d, J = 1.7 Hz, 3H), 3.15 (d, J = 5.1 Hz, 3H), 4.06 (s, 3H), 4.13-4.22 (m, 2H), 5.42 (brs, 1H), 7.07 (s, 1H), 7.11-7.17 (m, 1H), 7.35-7.44 (m, 4H), 8.73 (brs, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; lithium chloride In acetonitrile at 20℃; for 0.5h; Inert atmosphere; | (S,E)-ethyl 2-methyl-6-(2,3,5-trimethoxy-4-methylphenyl)hept-2-enoate: General procedure: A flame-dried flask was charged with LiCl (1.2 equiv, 1.2 mmol) and MeCN (5 mL), followed by addition of triethyl 2-phosphonopropionate (1.2 equiv, 1.2 mmol) (or triethyl phosphonoacetate (1.2 equiv, 1.2 mmol)) and DBU (1.1 equiv, 1.1 mmol). Then a solution of 15 (1 equiv, 1 mmol) in MeCN (5 mL) was added. The reaction was stirred at room temperature for 0.5 h before being diluted with Et2O (30 mL), washed with H2O (2x 20 mL) and dried with MgSO4 and concentrated. The crude product was purified by silica gel chromatography (15:85, EtOAc:hexanes) to give pale yellow oil enoate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: 4-bromo-benzaldehyde In tetrahydrofuran; hexane at 0 - 20℃; Inert atmosphere; | |
83% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Stage #2: 4-bromo-benzaldehyde In tetrahydrofuran; mineral oil at 20℃; for 2h; | |
Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.25h; Stage #2: 4-bromo-benzaldehyde In N,N-dimethyl-formamide at 0 - 20℃; for 18h; | 5.1 Intermediate 5Synthesis of N-[(E)-3-(4-bromo-phenyl)-2-methyl-acryloyl]-guanidineNaH (60% assay, 412 mg, 10.3 mmol) was suspended in DMF (50 mL) and then cooled to 0° C. Tri-ethyl-2-phosphonopropionate (2.24 mL, 10.3 mmol) in THF (10 mL) was added dropwise in a slow manner to the solution and then stirred for 15 minutes. Then, 4-bromobenzaldehyde (1.57 g, 8.49 mmol) in DMF (3 mL) was added thereto in a slow manner and stirred for 18 hours while gradually heating it from 0° C. to room temperature. EtOAc was added to the reaction solution, washed with water and saturated saline and then dried over anhydrous MgSO4. The solvent was eliminated in vacuo to obtain a residue.The resulting residue was dissolved in THF (50 mL) and MeOH (20 mL), 1N NaOH (40 mL, 40 mmol) was added and then stirred at room temperature for 8 hours. The solvent was eliminated in vacuo, 2N HCl was added to acidify the solution and the precipitated crystals was filtrated to obtain white crystals of the objective carboxylic acid (729 mg, 35%).MS: 242 |
With sodium hydride In tetrahydrofuran; mineral oil at -78 - 20℃; for 3h; | ||
Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 1h; Inert atmosphere; Stage #2: 4-bromo-benzaldehyde In tetrahydrofuran; mineral oil at 0 - 20℃; for 24h; Inert atmosphere; | ||
Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Stage #2: 4-bromo-benzaldehyde In tetrahydrofuran; mineral oil for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 81Synthesis of N-[(E)-3-(4'-hydroxy-5-trifluoromethyl-biphenyl-2-yl)-2-methyl-acryloyl]-guanidine<Step 1>NaH (60% assay, 237 mg, 5.92 mmol) was suspended in DMF (50 mL) and then cooled to 0 C. Triethyl 2-phosphonopropionate (1.29 mL, 5.92 mmol) in DMF (20 mL) was added dropwise in a slow manner to the resulting solution and stirred for 15 minutes. Then, <strong>[85118-24-7]2-bromo-4-trifluoromethylbenzaldehyde</strong> (1.00 g, 3.95 mmol) in DMF (5 mL) was added thereto in a slow manner and stirred for 18 hours while gradually heating it from 0 C. to room temperature. EtOAc was added to the reaction solution, washed with water and saturated saline and then dried over anhydrous MgSO4. The solvent was eliminated in vacuo to obtain a residue.The resulting residue was dissolved in THF (30 mL) and MeOH (20 mL), 1 N NaOH (10 ml, 10 mmol) was added thereto and stirred at room temperature for 8 hours. The solvent was eliminated in vacuo, 2N HCl was added to acidify the solution and then the precipitated crystals were filtrated to obtain white crystals of the objective carboxylic acid (460 mg, 38%).MS: 310 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
<Step 2>NaH (60percent assay, 193 mg, 4.82 mmol) was suspended in DMF (10 mL) and then cooled to 0° C. Triethyl 2-phosphonopropionate (1.05 mg, 4.82 mmol) in DMF (10 mL) was added dropwise in a slow manner to the solution and then stirred for 15 minutes. Then, the aldehyde obtained from Step 1 (640 mg, 3.22 mmol) in DMF (3 mL) was added thereto in a slow manner and then stirred for 18 hours while gradually heating it from 0° C. to room temperature. EtOAc was then added to the reaction solution, washed with water and saturated saline and then dried over anhydrous MgSO4. The solvent was eliminated in vacuo to obtain a residue. The resulting residue was then dissolved in THF (10 mL) and MeOH (4 mL), 2 N NaOH (8 mL, 8 mmol) was added thereto and then stirred at room temperature for 8 hours. The solvent was then eliminated in vacuo, 2 N HCl was added to acidify the solution and then the crystals precipitated were filtrated to obtain white crystals of the objective carboxylic acid (600 mg, 93percent).MS: 256 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 2-(4-methoxyphenoxy)benzaldehyde In tetrahydrofuran at 0 - 20℃; for 14.5h; | 50.2 NaH (60% assay, 48.6 mg, 1.22 mmol) was suspended in THF (5 mL) and then cooled to 0° C. 2-phosphonopropionic acid triethyl (307 mg, 1.22 mmol) in THF (2 mL) was added dropwise in a slow manner to the solution and then stirred for 30 minutes. Then, the aldehyde obtained from Step 1 (185 mg, 0.810 mmol) in THF (1 mL) was added in a slow manner and stirred for 14.5 hours while gradually heating it from 0° C. to room temperature. EtOAc was added to the reaction solution, washed with water and saturated saline and then chided over anhydrous MgSO4. The solvent was then eliminated in vacuo to obtain a residue. The resulting residue was dissolved in THF (4 mL) and MeOH (2 mL), 2 N NaOH (2 mL, 4.0 mmol) was added thereto and then stirred at 50° C. for 5 hours. The solvent was eliminated in vacuo, 2 N HCl was added to acidify the solution and then the crystals precipitated were filtrated to obtain white crystals of the objective carboxylic acid (217 mg, 94.1% from Step 1).MS: 285 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
<Step 2>NaH (60% assay, 114 mg, 2.85 mmol) was suspended in DMF (10 mL) and then cooled to 0 C. Triethyl-2-phosphonopropionate (0.62 mL, 2.85 mmol) in DMF (5 mL) was added dropwise in a slow manner to the solution and then stirred for 15 minutes. Then, the aldehyde obtained from Step 1 in DMF (3 mL) was added thereto in a slow manner and then stirred for 18 hours while gradually heating it from 0 C. to room temperature. EtOAc was added to the reaction solution, washed with water and saturated saline and then dried over anhydrous MgSO4. Then, the solvent was eliminated in vacuo to obtain a residue. The resulting residue was dissolved in THF (5 mL) and MeOH (2 mL), 1 N NaOH (4 mL, 4 mmol) was added thereto and then stirred at room temperature for 8 hours. Then, the solvent was eliminated in vacuo, 2 N HCl was added to acidify the solution and then the crystals precipitated were filtrated to obtain white crystals of the objective carboxylic acid (90 mg, 17%).MS: 272 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
<Step 3>NaH (60% assay, 1.13 g, 28.3 mmol) was suspended in THF (40 mL) and then cooled to 0 C. Tri-ethyl-2-phosphonopropionate (6.74 g, 28.3 mmol) in THF (5 mL) was added in a slow manner to the resulting suspension. After stirring it for 15 minutes, the aldehyde obtained from Step 2 (2.49 g, 9.435 mmol) in THF (5 mL) was added thereto and then stirred for 1 hour while gradually raising the temperature to room temperature. EtOAc was added thereto and then washed with NaHCO3 solution, water and saturated saline. After drying it over anhydrous MgSO4, the solvent was eliminated in vacuo to obtain a crude product (an ester intermediate).MS: 349The resulting crude product was dissolved in a mixed solution of THF/MeOH (v/v=5/3, 40 mL). Then, 2N NaOH (30 mL, 60 mmol) was added to the solution and stirred at 50 C. for 6 hours. After cooling it to 0 C., 2N HCl was added to acidify the solution, dichloromethane was added thereto, washed with water and saturated saline and then dried over anhydrous MgSO4. After the solvent was eliminated in vacuo, it was purified by silica gel column chromatography (Hexane/EtOAc) to obtain the objective carboxylic acid (2.04 g, 68%).MS: 321 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran at 0℃; for 0.25h; Stage #2: C15H14O2 In tetrahydrofuran at 20℃; | 4.2 NaH (60% assay, 53.6 mg, 1.34 mmol) was suspended in THF (5 mL) and then cooled to 0° C. Triethyl 2-phosphonopropionate (319 mg, 1.34 mmol) in THF (2 mL) was added in a slow manner to the suspension. After stirring it for 15 minutes, the aldehyde obtained from Step 1 (202 mg, 0.893 mmol) in THF (2 mL) was added thereto and then stirred overnight while gradually heating it to room temperature. EtOAc was added thereto, washed with NaHCO3, water and saturated saline, and then dried over anhydrous MgSO4. After eliminating the solvent in vacuo, it was purified by silica gel column chromatography (Hexane/EtOAc) to obtain the objective ester (258 mg, 93.0%).1H-NMR (d-DMSO, 300 MHz) ς 1.26 (t, 3H, J=7.0 Hz), 1.44 (t, 3H, J=7.0 Hz), 2.01 (s, 3H), 4.07 (q, 2H, J=7.0 Hz), 4.20 (q, 2H, J=7.0 Hz), 6.91 (d, 2H, J=8.8 Hz), 7.23 (d, 2H, J=8.8 Hz), 7.31 (s, 1H), 7.33-7.40 (m, 3H), 7.54 (bs, 1H), 7.98 (d, 1H, J=16 Hz)MS: 311 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; paraffin oil (nujol) at 0℃; Stage #2: 1-(3-amino-4-fluorophenyl)ethanone In tetrahydrofuran; paraffin oil (nujol) at 20℃; Reflux; | 45A; 46A Example 45A and Example 46AEthyl(2E)-3-(3-amino-4-fluorophenyl)-2-methylbut-2-enoate and Ethyl(2Z)-3-(3-amino-4-fluorophenyl)-2-methylbut-2-enoate; At 0° C., 6.92 ml (7.68 g, 32.3 mmol) of triethyl 2-phosphonopropionate were slowly added dropwise to a suspension of 1.29 g of sodium hydride (60% in paraffin oil; 32.3 mmol) in 24.7 ml of THF. The reaction mixture was stirred for 30 min, and 2.47 g (purity 90%, 14.5 mmol) of 3-amino-4-fluoroacetophenone were then added. The reaction mixture was stirred initially at RT for 1 h and then under reflux for 2 h, then cooled back to RT and stirred overnight. The mixture was then poured into water and extracted three times with in each case 100 ml of ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated and the residue was purified by flash chromatography on silica gel (mobile phase toluene/ethyl acetate 5:1). This gave, in separated form, 612 mg (15% of theory) of the 2E isomer (Example 45A) and 529 mg (13% of theory) of the 2Z isomer (Example 46A).2E Isomer (Example 45A):LC-MS (Method 6): Rt=1.05 min; m/z=238 (M+H)+.1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.22-1.29 (m, 3H), 1.69 (d, 3H), 2.11 (d, 3H), 4.17 (d, 2H), 6.30 (ddd, 1H), 6.56 (dd, 1H), 6.97 (dd, 1H).2Z Isomer (Example 46A):LC-MS (Method 6): Rt=0.99 min; m/z=238 (M+H)+.1H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.85 (t, 3H), 1.86-1.92 (m, 3H), 1.94-2.01 (m, 3H), 3.82 (q, 2H), 6.24 (ddd, 1H), 6.51 (dd, 1H), 6.87 (dd, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | At RT, triethyl 2-phosphonopropionate (29.8 g, 0.125 mol) was added to a suspension of NaH (60% disp./mineral oil, 4.77 g, 0.120 mol) in DME (180 ml), and the mixture was stirred for one hour. A solution of <strong>[75321-85-6]2-fluorophenylacetaldehyde</strong> (16.2 g, 0.117 mol) in DME (60 ml) was then added dropwise, and the mixture was stirred for a further three hours and then poured into an NH4Cl solution (10%, 400 ml). The mixture was extracted with MTBE (3×250 ml) and the combined organic phases were dried over sodium sulfate and concentrated, giving the desired product in the form of a light- yellow oil (18.6 g, 72%). 1H NMR (300 MHz, CDCl3) delta 7.21-7.15 (m, 2H), 7.10-7.02 (m, 2H), 6.85 (t, J=1.2 Hz, 1H), 4.16 (q, J=6 Hz, 2H), 3.53 (d, J=7.5 Hz, 2H), 1.95 (s, 3H), 1.28 (t, J=5.1 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With lithium hexamethyldisilazane In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: C18H29BrO3Si In tetrahydrofuran for 2h; Inert atmosphere; | Preparation of compound 12: General procedure: A solution of triethyl-2-phosphonopropionate (1.34 mL, 6.1 mmol) in THF (25 mL) at 0°C was added with 1.0 M in THF LiHMDS (6.1 mL, 6.1 mmol) with caution after stirred at same temperature for 30 min. The aldehyde 11 (2.2 g, 5.1 mmol) in 3 mL dry THF was added dropwise into the reaction flask. After 2 hours, 10 mL sat. aqueous NH4Cl was added to quench the reaction. After extraction with ethyl acetate, the combined organic layer was dried over brine and Na2SO4, and concentrated in vacuo to give light yellow oil. The yellow oil was purified by chromatography, eluting with mixture solvents (ethyl acetate : hexane = 1 : 45) to give the pure colorless oil 12 in 95% with a trace mount of Z isomer. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With lithium hexamethyldisilazane In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: C19H31BrO4Si In tetrahydrofuran for 2h; Inert atmosphere; | Preparation of compound 12: General procedure: A solution of triethyl-2-phosphonopropionate (1.34 mL, 6.1 mmol) in THF (25 mL) at 0°C was added with 1.0 M in THF LiHMDS (6.1 mL, 6.1 mmol) with caution after stirred at same temperature for 30 min. The aldehyde 11 (2.2 g, 5.1 mmol) in 3 mL dry THF was added dropwise into the reaction flask. After 2 hours, 10 mL sat. aqueous NH4Cl was added to quench the reaction. After extraction with ethyl acetate, the combined organic layer was dried over brine and Na2SO4, and concentrated in vacuo to give light yellow oil. The yellow oil was purified by chromatography, eluting with mixture solvents (ethyl acetate : hexane = 1 : 45) to give the pure colorless oil 12 in 95% with a trace mount of Z isomer. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | All flasks used in the reaction were heated under vacuum for 30 minutes and purged with argon for 10 minutes. Sodium hydride (150 mg, 1.2 eq., 60% in mineral oil) was added into a solution of triethyl 2-phosphonopropionate (1 mL, 1 eq.) in THF (18 mL) in portions under argon. After the reaction mixture was stirred at ambient temperature for 30 min, alpha-Ketoglutaric acid diethyl ester (600 mg, 3 mmol) was added and the mixture stirred for 1 h at room temperature. After the reaction was complete as detected by TLC, a saturated aqueous solution of ammonium chloride (10 mL) was added dropwise. After quenching the reaction, the reaction mixture was poured into a separatory funnel and extract with ether (20 mL×3). The organic phase was combined and dried by magnesium sulfate. The crude product was purified by silica gel chromatography eluted with PE: EtOAc = 10:1 to give product 1 (785 mg, 91%) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51.8% | Stage #1: 1,2:5,6-di-O-isopropylidene-D-mannitol With sodium periodate; sodium hydrogencarbonate In water at 20℃; for 2h; Stage #2: ethyl 2-diethoxyphosphorylpropionate With potassium carbonate In water at 20℃; for 120h; | I To a stirred solution of D-mannitol diacetonide 1 (13.0 g , 49.6 mmol) in sodium bicarbonate (5% aq, 60 ml), added a saturated solution of sodium periodate (12.74 g, 59.5 mmol) drop wise at r.t. Upon the addition, the mixture was kept stirring at r.t. for 2 hours. Then ethyl 2-(diethoxyphosphoryl)propanoate 2 (23.0 g, 99.2 mmol) was added followed by potassium carbonate (14.3 g, 103.6 mmol), the mixture was kept stirring at r.t. for another 120 hours. The mixture was added to 500 ml water, extracted with EtOAc (300ml_x3). The combined organic layer was dried over anhydrous sodium sulfate, concentrated and then chromatographed with PE:EA(30/1 ) to give the desired compound 3 5.5 g as a colorless oil, yield:51.8% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With n-butyllithium In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Darkness; Stage #2: (E)-3-(tri-n-butylstannyl)-2-propenal In tetrahydrofuran for 3h; Inert atmosphere; Darkness; stereoselective reaction; | 4.7 Ethyl (2E,4E)-2-Methyl-5-(tributylstannyl)penta-2,4-dienoate (28) To a cooled (0 °C) solution of ethyl 2-(diethoxyphosphoryl)propanoate (27) (1.43 mL, 6.66 mmol) in THF (25 mL) was added dropwise n-BuLi (2.56 mL, 2.49M in THF, 6.37 mmol). After stirring at that temperature for 0.5 h, a solution of (E)-3-(tributylstannyl)acrylaldehyde (2.0 g, 5.8 mmol) in THF (5 mL) was added and the mixture was stirred for 3 h. H2O was added and the mixture was extracted with CH2Cl2 (3x). The combined organic layers were dried (Na2SO4) and the solvent was removed. The residue was purified by column chromatography (silica gel, 96:2:2 hexane/EtOAc/Et3N) to afford 2.43 g (98 %) of a colorless oil identified as ethyl (2E,4E)-2-methyl-5-(tributylstannyl)penta-2,4-dienoate (28). 1H NMR (400.13.16 MHz, C6D6): δ 7.51 (d, J=10.7Hz, 1H), 7.06 (dd, JH-H=18.6, 10.7Hz, 1H), 6.71 (d, JH-H=18.6Hz, JH-Sn=68.3Hz, 1H), 4.07 (q, J=7.1Hz, 2H), 2.05 (s. 3H), 1.71-1.44 (m, 6H), 1.43-1.28 (m, 6H), 1.12-0.85 (m, 18H) ppm. 13C NMR (100.62 MHz, (CD3)2CO): δ 168.6, 145.4, 142.9, 140.5 (1JC-Sn=72.4Hz), 126.7, 60.9, 28.8 (2JC-Sn=20.9Hz, 3x), 27.9 (3JC-Sn=53.8Hz, 3x), 14.7, 14.0 (3x), 12.9, 10.2 (1JC-119Sn=347.9Hz, 1JC-117Sn=332.6Hz, 3x) ppm. HRMS (ESI+): Calcd. for C20H39O2119Sn ([M+H]+), 431.1970; found, 431.1977. IR (NaCl): υ 2956 (s, C-H), 2926 (s, C-H), 1707 (s, C=O), 1263 (s), 1253 (s)cm-1. UV (MeOH): λmax 274nm |
70% | With n-butyllithium In tetrahydrofuran at 25℃; for 3h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With hydrogen; sodium hydride In tetrahydrofuran at 0℃; Inert atmosphere; | |
71% | With sodium hydride | |
71% | With sodium hydride | Disubstituted maleic anhydride-acyl chloride 2 was prepared in situ from 2-propionic-3-methylmaleic anhydride 1, which in turn was assembled via a Horner-Emmons reaction from dimethyl-2-oxo-glutarate and triethyl-2-phosphonopropionate, all following the procedures of Naganawa, Ichikawa, and Isobe. [Naganawa 1994] Acyl chloride 2: 1H NMR (600 MHz, CDCl3): δ 3.31 (2H, t, 3J=6.9 Hz), 2.80 (2H, t, 3J=6.9 Hz), 2.13 (3H, s). 13C NMR (151 MHz, CDCl3): δ 173.0, 165.5, 165.4, 143.3, 140.4, 43.6, 20.3, 9.9. |
63% | With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; | 1.1 (1) First prepare 2-carboxyethyl-3-methyl maleic anhydride (CMA): Add to a suspension of sodium hydride (1.4 g, 58 mmol) in THF (200 mL).2-Triethyl phosphonium propionate(19.5g, 69.5mmol),The reaction is allowed to react until the H2 gas is no longer produced.Dimethyl 2-oxoglutarate (7.5 g, 43 mmol) was added to the previously mixed solution and stirred at 0 ° C for 30 minutes.Thereafter, a saturated aqueous ammonium chloride solution (200 mL) was added to the reaction solution to terminate the reaction.The crude product was extracted with diethyl ether.And using a rotary evaporator to remove the ether,Silica gel column chromatography (ethyl acetate / n-hexane = 1/10 (V / V),Rf = 0.7) The purified mixture was purified to give a yellow oil.The obtained yellow oil was dissolved in a mixture of ethanol (180 mL) and 2M aqueous KOH (100 mL) and reflux for 1 hour.After cooling to room temperature, the mixture was acidified to pH 2.0 with aqueous HCl.It was extracted with ethyl acetate. Finally, the CMA in the solution was recrystallized from a mixed solvent of THF and n-hexane to give a white solid (5.0 g, yield: 63%).The final product was characterized by a nuclear magnetic 1H spectrum.The solvent was CDCl3, as shown in Figure 3, and the results showed that the CMA was successfully synthesized with a purity of 95%. |
Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran Cooling with ice; Stage #2: dimethyl 2-ketoglutarate In tetrahydrofuran for 0.5h; Cooling with ice; | ||
Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; Inert atmosphere; Stage #2: dimethyl 2-ketoglutarate In tetrahydrofuran; mineral oil at 0℃; Inert atmosphere; | General procedure: Following the method described in a previous report17 with some modifications, 2-(2'-carboxyethyl) maleic anhydride (6) was prepared. Briefly, NaH (0.18 g, 4.6 mmol) was added slowly into a solution of triethyl phosphonoacetate (0.84 g, 3.7 mmol) in anhydrous THF (15 mL) at 0°C under a nitrogen atmosphere. Dimethyl-2-oxoglutarate (0.50 g, 2.9 mmol) was added to the solution after the evolution of hydrogen gas had stopped. The reaction mixture was further stirred while maintaining the temperature at 0°C. After the reaction completion was confirmed by TLC, a saturated aqueous solution of NH4Cl was added dropwise. Following the removal of THF by rotary evaporation, the resulting solid and water mixture was extracted with EA several times. The organic phase was combined, washed with deionized water and brine, dried over MgSO4, and concentrated by rotary evaporation. The crude product was purified by silica gel chromatography eluted with EA/hexane to yield pure triester as a colorless oil. Next, 2-(2'-carboxyethyl) maleic acid was formed by dissolving this triester in a 2M KOH solution in ethanol. This solution was allowed to reflux for 1 h. Deionized water was added, and the hot reaction mixture was cooled to the ambient temperature. After removal of ethanol by evaporation, the aqueous phase was washed with DCM several times and acidified to pH 2 using concentrated HCl. The aqueous phase was then extracted with EA. The organic phase was dried over MgSO4 and concentrated under reduced pressure to produce anhydride (6) as a white solid. | |
Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran at 0℃; Inert atmosphere; Stage #2: dimethyl 2-ketoglutarate In tetrahydrofuran at 0℃; Inert atmosphere; | 1.1 Synthesis of Compound 1 Briefly, Compound 1 was synthesized according to the following procedure.First, NaH (0.37 g, 9.2 mmol)Was dissolved in anhydrous THF (30 mL)To a solution of triethyl-2-phosphonopropionate (1.64 g, 6.89 mmol) inWas added slowly to the solution at 0 C under a nitrogen atmosphere.After the release of hydrogen gas has ceased,Dimethyl-2-oxoglutarate (1.00 g, 5.74 mmol) was added to the solution. The reaction mixture was further stirred while maintaining the temperature at 0 C. After completion of the reaction was confirmed by TLC, a saturated aqueous NH4Cl solution was added dropwise. THF was removed by rotary evaporation, and the resulting mixture of solid and water was extracted several times with EA. The organic phases were combined, washed with DI water (DIW) and brine, dried over MgSO4 and concentrated by diffractive evaporation. The residue was eluted with EA / hexanes to give silica gel |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 0.5h; Stage #2: (S)-tert-butyl 2-(4-(benzyloxy)phenyl)-1-(4-formyl-5-phenylthiazol-2-yl)ethylcarbamate In tetrahydrofuran; mineral oil at 20℃; for 4h; | 6 5.1.6 (S,E)-Ethyl 3-(2-(2-(4-(benzyloxy)phenyl)-1-(tert-butoxycarbonylamino)ethyl)-5-phenylthiazol-4-yl)-2-methylacrylate (6c) General procedure: (EtO)2P(O)CH(CH3)CO2Et (614 mg, 6.0 eq, 2.58 mmol) in dry THF (2 mL) was added to a suspension of NaH (189 mg, 11.0 eq, 4.73 mmol, 60% in mineral oil) in dry THF (8 mL) at 0 °C. The reaction mixture was stirred for 30 min at room temperature. Then aldehyde 5c (221 mg, 1.0 eq, 0.43 mmol) in THF (5 mL) was added. The mixture was stirred at room temperature for 4 h. The reaction was quenched with saturated NH4Cl and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by chromatography (petroleum ether/ethyl acetate = 12:1) to give ester 6c (224 mg, 87%). 1H NMR (300 MHz, CDCl3): δ 1.29 (t, 3H, J = 7.8 Hz), 1.42 (s, 9H), 2.36 (m, 3H), 3.28 (d, 2H, J = 6.9 Hz), 4.22 (q, 2H, J = 7.8 Hz), 5.03 (s, 2H), 5.20 (br, 2H), 6.88 (d, 2H, J = 9.0 Hz), 7.07 (d, 2H, J = 9.0 Hz), 7.33-7.43 (m, 9H), 7.55 (d, 1H, J = 2.7 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 0.5h; Stage #2: (S)-tert-butyl 2-(4-(benzyloxy)phenyl)-1-(4-formyl-5-isobutylthiazol-2-yl)ethylcarbamate In tetrahydrofuran; mineral oil at 20℃; for 4h; | 6 General procedure: (EtO)2P(O)CH(CH3)CO2Et (614 mg, 6.0 eq, 2.58 mmol) in dry THF (2 mL) was added to a suspension of NaH (189 mg, 11.0 eq, 4.73 mmol, 60% in mineral oil) in dry THF (8 mL) at 0 °C. The reaction mixture was stirred for 30 min at room temperature. Then aldehyde 5c (221 mg, 1.0 eq, 0.43 mmol) in THF (5 mL) was added. The mixture was stirred at room temperature for 4 h. The reaction was quenched with saturated NH4Cl and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by chromatography (petroleum ether/ethyl acetate = 12:1) to give ester 6c (224 mg, 87%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.66% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: N-benzhydryl 3-azetidinone In tetrahydrofuran at 20 - 25℃; for 3h; Inert atmosphere; | |
66% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran for 1h; Inert atmosphere; Cooling with ice; Stage #2: N-benzhydryl 3-azetidinone In tetrahydrofuran at 20℃; Inert atmosphere; | Ethyl 2-Fl -(diphenylmethyl)azetidin-3 -ylideneipropanoate Sodium hydride (60%, 202 mg, 5.06 mmol) was suspended in anhydrous THF (15mL) and cooled in an ice bath. Ethyl 2-(diethoxyphosphoryl)propanoate (1.2 g, 5.06mmol) was added dropwise under nitrogen and the mixture was stirred in an ice bath for 1 h. 1-(Diphenylmethyl)azetidin-3-one (1 g, 4.21 mmol) was added in portions as a solid and the mixture was stirred at room temperature for 1 h, then left to stir at room temperature overnight. Water (50 mL) was added and the mixture was extracted withDCM (3 x 50 mL). Brine was added, and the aqueous and organic layers were separated. The organic layer was dried over sodium sulfate and concentrated. The resulting crude yellow oil was purified by FCC, eluting with 0-50% EtOAc, to afford a clear oil which crystallised upon standing. The solids were sonicated with heptane and the remaining solid was collected by filtration. The filtrate was concentrated and sonicated with heptaneto afford a second crop of solid. The filtrate was concentrated and the residue was sonicated with heptane to afford a further crop of solid material. The resultant solids were collected and combined to afford the title compound (892 mg, 66%) as a white solid.oH (250 MHz, CDC13) 7.56-7.39 (m, 4H), 7.38-7.15 (m, 6H), 4.63-4.45 (m, 1H), 4.24- 4.01 (m, 4H), 3.96-3.76 (m, 2H), 1.72-1.58 (m, 3H), 1.27-1.14 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | General procedure: Ethyl 2-(diethoxyphosphoryl)-2-(pyridin-3-ylmethyl)pentanoate (31e). Triethyl 2-phosphonoalkanoate 30e (0.8 g, 3 mmol) in 2 ml of THF was added dropwisely to a cooled suspension of sodium hydride (60% in oil, 0.2 g, 4.5 mmol) in THF (2 ml). It was stirred on ice bath for 15 min and then for 45 min at room temperature. In another flask was placed 3-picolyl chloride hydrochloride (0.5 g, 3 mmol) in DMF (4 ml) and was added sodium hydride (60% in oil, 0.18 g, 5.1 mmol). The mixture was stirred for 0.5 h at room temperature. Then 3-picolyl chloride in DMF was added via a Pasteur pipette (with cooling in ice bath) and reaction mixture was stirred at 50 C. After 3 h reaction was cooled down and quenched with saturated solution of NH4Cl (0.5 ml). Then THF was evaporated, residue was dissolved in water (pH 9, Na2CO3(aq)), and extracted with CH2Cl2 (4 x 15 ml). After drying over Na2SO4, the organic phase was evaporated and the residue subjected to column chromatography |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With n-butyllithium In 1,2-dimethoxyethane at 20℃; for 0.0833333h; Inert atmosphere; Stage #2: styrene oxide In 1,2-dimethoxyethane at 20 - 130℃; for 1.83333h; Inert atmosphere; Microwave irradiation; | 4.1.1.1 Ethyl (1R,2S)-1-methyl-2-phenyl-cyclopropanecarboxylate (11a) General procedure: 5.6mL (2.5mol/L) butyl lithium was added to a solution of 3.4g (14mmol) ethyl 2-diethoxyphosphorylbutanoate (Sigma Aldrich) in 12mL dry DME under N2 atmosphere at RT. After 5min, 1.3g (11mmol) (2S)-2-phenyloxirane (Sigma Aldrich) was added dropwise. The mixture was stirred for 20min at RT and then heated at 130°C under MW irradiation for 90min. Aqueous NH4Cl was added and the product was extracted with Et2O. The combined organic layers were dried over Na2SO4 and concentrated. The dry residue was purified by column chromatography (eluent: EtOAc/hexane, 0:100-10:100) to give the ethyl cyclopropanecarboxylate 11a (2.9g, 90%). |
41% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With n-butyllithium In 1,2-dimethoxyethane; n-heptane at 0℃; for 0.0833333h; Stage #2: styrene oxide In 1,2-dimethoxyethane; n-heptane at 100℃; | Intermediate 98A: Ethyl-1-methyl-2-phenylcyclopropane-1-carboxylate, as a mixture of trans enantiomers Triethyl 2-phosphonopropionate (1.0 mL, 4.7 mmol) was dissolved in 1,2-dimethoxyethane (20 mL) and n-Butyllithium (1.9 mL of a 2.5M soln in heptane, 4.7 mmol) was added dropwise at 0° C. After 5 minutes, racemic 2-phenyloxirane (0.27 mL, 2.3 mmol) was added dropwise and the resulting solution was heated at 100° C. overnight. The following day the mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride (10 mL). The mixture was diluted with ethyl acetate (50 mL) and washed with brine (2*30 mL), dried (sodium sulfate), filtered and concentrated at reduced pressure. The residue was purified by Biotage Isolera chromatography (silica gel, eluting with heptanes-EtOAc, 99:1 to 7:3) giving the title compound (386 mg, 41% yield) as a colourless oil. 1H NMR (500 MHz, Chloroform-d) δ 7.40-7.16 (m, 5H), 4.25-4.16 (m, 2H), 2.87-2.75 (m, 1H), 1.76-1.67 (m, 1H), 1.31 (t, J=7.1 Hz, 3H), 1.21-1.15 (m, 1H), 1.01 (s, 3H) LCMS (Analytical Method A): Rt=1.33 mins; MS (ESIpos) m/z=205 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | General procedure: 5.6mL (2.5mol/L) butyl lithium was added to a solution of 3.4g (14mmol) ethyl 2-diethoxyphosphorylbutanoate (Sigma Aldrich) in 12mL dry DME under N2 atmosphere at RT. After 5min, 1.3g (11mmol) (2S)-2-phenyloxirane (Sigma Aldrich) was added dropwise. The mixture was stirred for 20min at RT and then heated at 130C under MW irradiation for 90min. Aqueous NH4Cl was added and the product was extracted with Et2O. The combined organic layers were dried over Na2SO4 and concentrated. The dry residue was purified by column chromatography (eluent: EtOAc/hexane, 0:100-10:100) to give the ethyl cyclopropanecarboxylate 11a (2.9g, 90%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.3 g | Description 34Ethyl 2-(dihydrofuran-3(211)-ylidene)propanoate (D34)To a solution of sodium hydride (1.394 g) in THF (60 mL) at 0 °C was added dropwise ethyl 2-(diethoxyphosphoryl)propanoate (8.29 g) under N2. The mixture was stirred at 0°C for 30 mm until the mixture became clear, then <strong>[22929-52-8]dihydrofuran-3(2H)-one</strong> (1.5 g) was added. The mixture was stirred at RT for 2 hours and then quenched by water (100 mL). The mixture was extracted with EtOAc(3 x50 mL). The combined organic layer was washed with brine (100 mL), dried and evaporated under vacuum. The crude product was purified by column chromatography (silica gel, petroleum ether/EtOAc = 30:1) to afford the title compound (1.3 g). MS (ESI): C9H1403 requires 170; found 171 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Example 4 Masking Agents A. Synthesis of 2-propionic-3-methylmaleic anhydride masking agent precursor (carboxydimethylmaleic anhydride or CDM) 2-propionic-3-methylmaleic anhydride To a suspension of sodium hydride (0.58 g, 25 mmol) in 50 mL anhydrous tetrahydrofuran was added triethyl-2-phosphonopropionate (7.1 g, 30 mmol). After evolution of hydrogen gas had stopped, dimethyl-2-oxoglutarate (15 g, 20 mmol) in 10 mL anhydrous tetrahydrofuran was added and stirred for 30 min. 10 mL water was then added, and the tetrahydrofuran was removed by rotary evaporation. The resulting solid and water mixture was extracted with 3×50 mL ethyl ether. The ether extractions were combined, dried with magnesium sulfate, and concentrated to a light yellow oil. The oil was purified by silica gel chromatography elution with 2:1 ether:hexane to yield 4 g (82% yield) of pure triester. The 2-propionic-3-methylmaleic anhydride was then formed by dissolving of this triester into 50 mL of a 50150 mixture of water and ethanol containing 4.5 g (5 equivalents) of potassium hydroxide. This solution was heated to reflux for 1 h. The ethanol was then removed by rotary evaporation and the solution was acidified to pH 2 with hydrochloric acid. This aqueous solution was then extracted with 200 mL ethyl acetate, isolated, dried with magnesium sulfate, and concentrated to a white solid. This solid was then recrystallized from dichloromethane and hexane to yield 2 g (80% yield) of 2-propionic-3-methylmaleic anhydride. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.1% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In N,N-dimethyl-formamide for 0.5h; Stage #2: C10H16O In N,N-dimethyl-formamide at 0℃; | Synthesis of (2E,4E,6E)-ethyl 2,4,6,8-tetramethylnona-2,4,6-trienoate (Int5) To a pre-cooled stirred suspension of sodium hydride (7.52 g, 0.1881 moles, 60 wt %) in dry DMF (11 mL) was added ethyl 2-(diethoxyphosphoryl) propanoate (34.4 g, 0.1447 mole) drop wise and stirring was continued for 30 min. Then Int4 (22 g, 0.1447 mole) in 3 mL of dry DMF was added slowly and the reaction mixture was stirred for 30-40 min at 0° C. and monitored by TLC. After completion of the reaction it was quenched with saturated sodium bicarbonate solution at 0° C. and extracted with diethyl ether (3×150 mL). The combined organic layers were washed with water and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude residue which was further purified by column chromatography on silica gel using 4% EtOAc in n-hexane to obtain Int5 as a light yellow colored liquid (28 g, 82.1% yield). 1H NMR (CDCI3, 8 ppm): 7.18 (s, 1H), 6.0 (s, 1H), 5.25-5.3 (d, 1H), 4.15-4.25 (q, 2H), 2.55-2.65 (m, 1H), 2.1 (s, 3H), 2.0 (s, 3H), 1.8 (s, 3H), 1.35-1.45 (t, 3H), 0.95-1.0 (d, 6H); Mass (m/z): 237.3 (M++H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In tetrahydrofuran; mineral oil; at -78 - 0℃; | Compound 5 was added sodium hydride in dry tetrahydrofuran was added at 0 triethyl2-phosphonopropionate conditions under cooling conditions dropped to -78 compound 4. Quenched with saturated ammonium chloride solution and after reaction for 3hours at room temperature. The organic phase was extracted with ether, dried,concentrated, and column chromatography (petroleum ether / ethyl acetate system) to givecompound 5 as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With n-butyllithium In 1,2-dimethoxyethane at 0 - 20℃; for 0.5h; Inert atmosphere; Stage #2: (2S)-2-(4-fluorophenyl)oxirane In 1,2-dimethoxyethane at 80℃; for 12h; Inert atmosphere; | 145 Ethyl (1R)-2-(4-fluorophenyl)-1-methylcyclopropane-1-carboxylate Ethyl (1R)-2-(4-fluorophenyl)-1-methylcyclopropane-1-carboxylate (0486) In a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen were combined a solution of ethyl 2-(diethoxyphosphoryl)propanoate (3.45 g, 14.48 mmol, 2.00 equiv) in ethylene glycol dimethyl ether (20 mL), followed by the addition of n-BuLi (2.5M) (5.8 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 30 min at room temperature. To this was added 2-(4-fluorophenyl)oxirane (1 g, 7.24 mmol, 1.00 equiv). The resulting solution was allowed to react, with stirring, for an additional 12 h while the temperature was maintained at 80° C. in an oil bath. The reaction mixture was cooled to room temperature and then quenched by the addition of 20 mL of water. The resulting solution was extracted with 3×50 mL of EtOAc, and the organic layers were combined, dried over anhydrous Na2SO4, concentrated under vacuum. The residue was applied onto a silica gel column with EtOAc/petroleum ether (1:100), affording 1 g (62%) of the product as a yellow oil. |
62% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With n-butyllithium In 1,2-dimethoxyethane at 0 - 20℃; for 0.5h; Stage #2: (2S)-2-(4-fluorophenyl)oxirane In 1,2-dimethoxyethane at 80℃; for 12h; | Intermediate A: (1R,2S)-2-(4-fluorophenyl)-1-methylcyclopropanamine [0117] A solution of ethyl 2-(diethoxyphosphoryl)propanoate (3.45 g, 14.48 mmol, 2.00 equiv) in ethylene glycol dimethyl ether (20 mL) was treated with n-BuLi (2.5M) (5.8 mL) dropwise with stirring at 0oC. The resulting solution was stirred for 30 min at room temperature. To this was added 2-(4-fluorophenyl)oxirane (1 g, 7.24 mmol, 1.00 equiv). The resulting solution was stirred for 12 h while the temperature was maintained at 80oC in an oil bath. The reaction mixture was cooled to RT. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with ethyl acetate and the organic layers was dried and concentrated. The residue was chromatographed on silica gel and eluted with ethyl acetate/petroleum ether (1:100). This resulted in 1 g (62%) of ethyl (1R)-2-(4- fluorophenyl)-1-methylcyclopropane-1-carboxylate as yellow oil. A solution of ethyl (1R)-2- (4-fluorophenyl)-1-methylcyclopropane-1-carboxylate (1 g, 4.50 mmol, 1.00 equiv) in methanol/H2O (10/2 mL) and potassium hydroxide (1.26 g, 22.46 mmol, 4.99 equiv) was stirred for 10 h at room temperature. The resulting solution was diluted with H2O. The pH value of the solution was adjusted to 2 with hydrochloric acid (2 mol/L). The resulting solution was extracted with ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 800 mg (92%) of (1R)-2-(4-fluorophenyl)-1-methylcyclopropane-1-carboxylic acid as yellow oil. A solution of (1R)-2-(4-fluorophenyl)-1-methylcyclopropane-1-carboxylic acid (400 mg, 2.06 mmol, 1.00 equiv) in toluene (10 mL) was mixed with diphenoxyphosphoryl azide (680 mg, 2.47 mmol, 1.20 equiv), and triethylamine (312 mg, 3.08 mmol, 1.50 equiv). The resulting solution was stirred for 30 min at 90oC in an oil bath. Then, tert-butanol (2 mL) was added. The resulting solution was allowed to react, with stirring, for an additional 12 h while the temperature was maintained at 90oC in an oil bath. The reaction mixture was cooled to room temperature and the resulting solution was diluted with ethyl acetate. The resulting mixture was washed with H2O. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was chromatographed on a silica gel column and eluted with ethyl acetate/petroleum ether (1:100). This resulted in 350 mg (64%) of tert-butyl N-[(1R)-2-(4-fluorophenyl)-1-methylcyclopropyl]carbamate as yellow oil. A solution of tert- butyl N-[(1R,2S)-2-(4-fluorophenyl)-1-methylcyclopropyl]carbamate (350 mg, 1.32 mmol, 1.00 equiv) in methanol (HCl) (10 mL) was stirred for 2 h at room temperature. The resulting solution was diluted with 10 mL of H2O. The pH value of the solution was adjusted to 9 with saturated sodium bicarbonatesolution. The resulting solution was extracted with 3x10 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 200 mg (92%) of (1R,2S)-2-(4-fluorophenyl)-1- methylcyclopropan-1-amine as yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil Cooling with ice; Inert atmosphere; Stage #2: 5-Hexen-2-one In tetrahydrofuran; mineral oil at 20℃; for 72h; Inert atmosphere; | 4.7 Ethyl (E,Z)-2,3-dimethyl-2,6-heptadienoate (7) A solution of triethyl 2-phosphonopropanoate (50.1g, 210mmol) in dry THF (50mL) was added dropwise to a stirred and ice-cooled suspension of 60% NaH in mineral oil (8.42g, 210mmol) in dry THF (100mL) under argon. After the completion of H2 evolution to give a homogeneous solution of the sodio enolate, a solution of 6 (20.5g, 210mmol) in dry THF (30mL) was added dropwise. No exothermic reaction could be observed. The mixture was stirred for 3d at room temperature (20°C). It was then diluted with ice and water, and extracted with Et2O. The Et2O extract was washed successively with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was distilled to give 36.2g (95%) of 7 [an almost 1:1 mixture of its (E)- and (Z)-isomers] as a colorless oil, bp 85-95°C/7Torr; nD18=1.4618; νmax (film): 3078 (w), 2980 (m), 2932 (m), 2871 (w), 1714 (s), 1640 (m), 1446 (m), 1365 (m), 1277 (s), 1210 (s), 1101 (s), 911 (m), 772 (m); δH (CDCl3): 1.297 (1.5H, t, J=6.8Hz), 1.303 (1.5H, t, J=6.8Hz), 1.78 (1.5H, s), 1.85 (1.5H, s), 1.87 (1.5H, s), 1.98 (1.5H, s), 2.12-2.28 (3H, m), 2.43 (1H, t, J=7.2Hz), 4.18 (1H, q, J=7.2Hz), 4.20 (1H, q, J=7.2Hz), 4.90-5.10 (2H, m), 5.77-5.90 (1H, m); GC-MS [column: HP-5MS, 0.25mm i.d.×30m; carrier gas, He; press 61kPa; temp: 70-230°C (+10°C/min)]: tR 8.32 (49.3%), 8.69min (47.4%) (total 96.7%); MS of 7 with tR=8.32min (70eV, EI): m/z: 182 (5) [M+], 167 (2), 153 (38), 137 (33), 113 (65), 109 (100), 95 (26), 93 (23), 81 (18), 79 (14), 67 (38), 43 (27); MS of 7 with tR=8.69min (70eV, EI): m/z: 182 (6) [M+], 167 (3), 153 (40), 137 (59), 125 (22), 113 (92), 109 (100), 95 (27), 93 (25), 81 (22), 79 (16), 67 (58), 55 (18), 53 (17), 43 (33). HRMS calcd for C11H18O2: 182.1307, found: 182.1305 (short tR) and 182.1322 (long tR). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran for 1h; Inert atmosphere; Reflux; Stage #2: 3,3-dimethylcyclohexanone In tetrahydrofuran at 20℃; Inert atmosphere; Reflux; | Ethyl (2E)-4-(3,3-Dimethylcyclohexyl)pent-2-enoate (38); Typical Procedure General procedure: A soln of ethyl 2-(diethoxyphosphoryl)acetate (2.93 g, 13.1 mmol) in THF (25 mL) was added dropwise to a stirred suspension of NaH (65 %wt, 483 mg, 13.1 mmol) in THF (150 mL). After stirring for 1 h at reflux, a solution of 37 (2.00 g, 11.9 mmol) in THF (25 mL) was added dropwise at r.t. The resulting mixture was stirred overnight at reflux, and then poured onto ice/H2O (1:1, 100 mL). 2 M aq HCl (15 mL) was added, and the aqueous layer was extracted with Et2O (2 × 100 mL).The combined organic extracts were washed with H2O (2 × 100 mL) and brine (50 mL), dried (Na2SO4), and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, pentane/Et2O, 99:1, Rf= 0.14) to provide 38 (2.03g, 72%) as a colorless liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran for 0.25h; Cooling with ice; Inert atmosphere; Stage #2: 4-nitrobenzaldehdye In tetrahydrofuran at 20℃; for 10h; | General procedures for preparing methyl (E)-2-methyl-3-(4-nitrophenyl) acrylate (2) General procedure: Under an argon atmosphere, in the solution of THF (40.00 mL)containing sodium hydride (0.52 g, 21.86 mmol), ethyl 2-(diethoxyphosphoryl)propanoate (5.20 g, 21.86 mmol) was dropped in tardilyin an ice bath. After stirring 15 min, 4-nitrobenzaldehyde (3.00 g, 19.87mmol) dissolved in THF was slowly added into the above reaction mixture. Then the reaction flask was removed to room temperature.After stirring with the aid of a magnetic agitator for 10 h, the reaction accomplished with thin-layer chromatography (TLC) monitoring and was interrupted using water then extracted using ethyl acetate (3 ×50.00 mL). The next procedure is to dry over, filter and concentrate the organic phase. Later column chromatography (V/V, PE:EA = 6:1) onsilica gel was chosen to purify the residue and finally give the olefin 2 asa yellow color solid (4.25 g, 91% yield). 1H NMR (400 MHz, CDCl3) δ7.97-7.89 (m, 2H), 7.39 (s, 1H), 7.29-7.21 (m, 2H), 3.99 (q, J = 7.1 Hz,2H), 1.87-1.78 (m, 3H), 1.06 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz,CDCl3) δ 167.75, 147.14, 142.54, 135.97, 132.27, 130.26, 123.61,61.30, 14.29, 14.20. HRMS (APCI-TOF, m/z): calcd for C12H12NO4(M H)- 234.0772, found 234.0769. |
80% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran at 0℃; for 0.25h; Inert atmosphere; Stage #2: 4-nitrobenzaldehdye In tetrahydrofuran at 0 - 20℃; for 10h; Inert atmosphere; | Preparation of ethyl (E)-2-methyl-3-(4-nitrophenyl)acrylate (5) via Homer-Wadsworth-Emmons olefination Sodium hydride (60% dispersion in mineral oil, 2.78 mmol, 111 mg, 1.05 equiv.) was suspended in freshly distilled anhydrous THF (5 mL) in a round-bottom flask under argon. Temperature was cooled down to 0oC and trietyl-2-phosphonopropionate (2.91 mmol, 625 µL, 1.1 equiv.) was added dropwise. After 15 min at 0oC, a solution of p-nitrobenzaldehyde (2.65 mmol, 400 mg in 5 mL of THF, 1.0 equiv.) was added dropwise over 5 minutes. The mixture was stirred for 5 min at 0oC, warmed to room temperature and the reaction was stirred for 10 h. The reaction mixture was quenched with saturated aqueous ammonium chloride. The mixture was extracted three times with Et2O. The organic layers were combined, washed with H2O and brine, dried with MgSO4, concentrated in vacuo and subjected to silica gel chromatography (80:20 hexanes/EtOAc) yielding 500 mg (80%) of 5 as an yellow powder. mp = 100°C. 1H NMR (500 MHz, CDCl3): δ 1.37 (t, J = 7.1 Hz, 3H), 2,12 (d, J = 1.6 Hz, 3H), 4.30 (q, J = 7.1 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 7.69 (s, 1H), 8.26 (d, J = 8.8 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ 14.2, 14.3, 61.3, 123.6, 130.2, 132.2, 136.0, 142.5, 167.8. IR (ATR, ZnSe): 3110, 2989, 1697, 1589, 1514, 1341, 1251, 1202, 1109 cm-1. HRMS (ESI-TOF, m/z) calcd for C12H14NO4 (M+H)+ = 236.0917, found 236.0922. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil for 0.5h; Inert atmosphere; Stage #2: α-methyl-trans-cinnamaldehyde In tetrahydrofuran; mineral oil at 0 - 20℃; for 1h; Inert atmosphere; | Ethyl (2E,4E)-2,4-dimethyl-5-phenylpenta-2,4-dienoate (47) To a stirred suspension of sodium hydride (3.0 g, 75.64 mmol; 60 % mineral oil dispersion, 1.2 equiv.) in dry THF (80 mL), was added ethyl 2- (diethoxyphosphoryl)propanoate (46, 22.8 g, 82.08 mmol, 1.2 equiv.) in dry THF (10 mL) in dropwise under nitrogen atmosphere and then stirred for 30 min. Aldehyde 45(10.0 g, 68.4 mmol, 1.0 equiv.) in dry THF (10 mL) was added dropwise to the above reaction mixture at 0 °C and then stirred at room temperature for 1 h. The reaction mixture was quenched with 10 % aq. HCl, extracted with diethyl ether, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel (100-200 mesh) column chromatography, eluted with 5 % EtOAc in pet ether to afford the title compound 47 (6.6 g, 42 %) as a pale-yellow liquid. |
Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 1h; Stage #2: α-methyl-trans-cinnamaldehyde In tetrahydrofuran; mineral oil |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48.2% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In tetrahydrofuran; mineral oil at 0 - 20℃; | 70.1 Step-1 To a suspension of sodium hydride (60% in mineral oil, 0.487g, 12.81 mmol, 1.3 eq) in THF (50 mL) was added ethyl 2-(diethoxyphosphoryl)propanoate (2.23 g, 9.37 mmol, 1.0 eq)dropwise at 0°C and the mixture was allowed to stir at the same temperature for 30 minutes. To this mixture was added a solution of tert-butyl 4-formylpiperidine-1-carboxylate (2.0 g, 9.37 mmol, 1.0 eq) in THF (5 mL) and the resulting mixture was allowed to stir at RT for 2 h. Progress of reaction was monitored by TLC. After completion, reaction mixture was diluted with saturated aq. NH4C1 (100 mL) and extracted with ethyl acetate (3 x 50 mL). Combined organiclayer was washed with brine, dried over anhydrous Na2SO4 and evaporated to dryness under vacuum to afford crude which was purified by Combi-Flash on silica gel using ethyl acetatehexane system as eluent to afford (Z)-tert-butyl 4-(3-ethoxy-2-methyl-3-oxoprop-1- enyl)piperidine- 1 -carboxylate (1.34 g, 48.2 %).LCMS: 298 [M+1] |
48.2% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In tetrahydrofuran; mineral oil at 20℃; for 2h; | 70.1; 71.1 Step-1 To a suspension of sodium hydride (60% in mineral oil, 0.487 g, 12.81 mmol, 1.3 eq) in THF (50 mL) was added ethyl 2-(diethoxyphosphoryl)propanoate (2.23 g, 9.37 mmol, 1.0 eq) dropwise at 0° C. and the mixture was allowed to stir at the same temperature for 30 minutes. To this mixture was added a solution of tert-butyl 4-formylpiperidine-1-carboxylate (2.0 g, 9.37 mmol, 1.0 eq) in THF (5 mL) and the resulting mixture was allowed to stir at RT for 2 h. Progress of reaction was monitored by TLC. After completion, reaction mixture was diluted with saturated aq. NH4Cl (100 mL) and extracted with ethyl acetate (3*50 mL). Combined organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated to dryness under vacuum to afford crude which was purified by Combi-Flash on silica gel using ethyl acetate-hexane system as eluent to afford (Z)-tert-butyl 4-(3-ethoxy-2-methyl-3-oxoprop-1-enyl)piperidine-1-carboxylate (1.34 g, 48.2%). |
Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium t-butanolate In tetrahydrofuran at 0 - 20℃; for 1h; Inert atmosphere; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; | 16-1 (Z)-tert-butyl 4-(3-ethoxy-2-methyl-3-oxoprop-1-enyl)piperidine-1-carboxylate To a solution of t-BuONa (379 mg, 3.94 mmol) in anhydrous THF (20 mL) at 0 °C underN2 balloon was added ethyl2-(diethoxyphosphoryl)propanoate ( 871 mg, 3.66 mmol). And the10 mixture was stirred at room temperature for 1h. After cooling to 0°C, tert-butyl4-formylpiperidine-1-carboxylate (600 mg, 2.81 mmol) was added. The resulting mixture wasstirred at room temperature for 1h. LRMS showed the reaction was completed. The mixture wasquenched with sat. NH4Cl (20 mL), diluted with EtOAc (200 mL), washed with brine (30 mLx3),dried (Na2S04) and concentrated. The residue was purified by column chromatography (silica15 gel, PE/ EtOAc = 10/ 1 to 5/1) to give (Z)-tert-butyl4-(3-ethoxy-2-methyl-3-oxoprop-1-enyl)piperidine-1-carboxylate. LRMS m/z (M+Na), 320.2 found, 320.2 required. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a stirred suspension of NaH (60% dispersion in mineral oil) (101 mg, 4.20 mmol) in THF (3 mL) was added ethyl 2-(diethoxyphosphoryl)propanoate (0.47 mL, 2.23 mmol) at 0 C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 h. Again the reaction mixture was cooled 0 C and <strong>[34246-54-3]3-ethylbenzaldehyde</strong> (0.19 mL, 1 .49 mmol) in THF (2 mL) was added and the stirring was continued at room temperature for 16h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2x20 mL). Separated organic layer was washed with saturated NaHC03, dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 3% EtOAc/ hexanes to afford ethyl (E)-3-(3-ethylphenyl)-2-methylacrylate (250 mg, 77%) as white colour syrup.Ethyl (E)-3-(3-ethylphenyl)-2-methylacrylate:1H NMR (500MHz, CDCI3): delta 7.69 (s, 1 H), 7.35- 7.30 (m, 1 H), 7.26-7.23 (m, 2H), 7.18 (d, J = 7.5 Hz, 1 H), 4.29 (q, J = 7.0 Hz, 2H), 2.69 (q, J = 7.7 Hz, 2H), 2.14 (d, J=1 .2 Hz, 3H), 1.37 (t, J = 7.1 Hz, 3H), 1.27 (t, J = 7.7 Hz, 3H); LC-MS (ESI): 82.65%; m/z 218.9 [M+H]+at RT 3.15 min; (column; Ascentis Express C-18 (50 x 3.0mm, 2.7muGammaeta); 0.025% Aq TFA + 5% ACN: ACN + 5% 0.025% Aq TFA; 1 .2 mL/min). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 1h; Inert atmosphere; Stage #2: 3-benzyloxy cyclobutanone In tetrahydrofuran; mineral oil at 0 - 25℃; for 16h; Inert atmosphere; | 275; 276 Ethyl 2-(3-benzyloxycyclobutylidene)propanoate: To a mixture of NaH (2.7 g, 68.10 mmol, 60% in mineral oil) in anhydrous THF (100 mL) was added ethyl 2- diethoxyphosphorylpropanoate (20.3 g, 85.12 mmol) dropwise at 0 °C under N2. The mixture was stirred at 0 °C for 1 h. To the mixture was added 3-benzyloxycyclobutanone (10.0 g, 56.75 mmol) dropwise with stirring at 0 °C, then warmed to 25 °C and stirred for 16 h. The reaction mixture was quenched with saturated aqueous H4CI (40 mL) at 0 °C, diluted with water (20 mL) and extracted with EtOAc (3 χ 50 mL). The combined organics were washed with brine (50 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 1 :0 to 30: 1) to afford the title compound (14 g, 95%) as a yellow oil. LCMS: m/z = 261.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium ethanolate; In ethanol; pentane; for 0.75h;Reflux; Cooling; | Ethyl 2-(diethoxyphosphoryl)propanoate (80.0 g, 335 mmol, 1.5 eq) was added to a stirred solution of <strong>[5779-93-1]2,3-dimethylbenzaldehyde</strong> (30.0 g, 224 mmol, 1.0 eq) in pentane (300 mL) at room temperature. A solution of NaOEt (21percent w/w in EtOH, 109 mL, 293 mmol, 1.3 eq) was subsequently added dropwise under stirring, while cooling the reaction mixture with a water bath. Once the addition was completed, the resulting mixture was stirred at reflux for 45 minutes. The reaction mixture was then cooled to 0° C. and quenched by addition of aqueous NaOH (1 N , 300 mL). The organic layer was separated and washed again with NaOH (1 N, 300 mL). The combined aqueous layers were extracted with Et2O (3 x), washed with sat. aqueous NaHCO3, brine (twice), dried over MgSO4, filtered and concentrated in vacuo to afford an orange crude oil. Bulb-to bulb distillation (0.15 mbar, oven temp. 150-155° C.) afforded the product as a colorless oil (46.5 g, 213 mmol, 95percent yield; 94:6 mixture of E-Z isomers). 1H-NMR (major diastereoisomer):7.79 (s, 1H), 7.13-7.06 (m, 2H), 7.01 (m, J=3.00, m), 4.28 (q, J=7.13, 2H), 2.29 (s, 3H), 2.17 (s, 3H), 1.90 (d, J=1.40, 3H), 1.35 (t, J=7.13, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran at 0℃; for 0.166667h; Stage #2: 8-methoxy-2,3-dihydrobenzo-[b][1,4]dioxine-6-carbaldehyde In tetrahydrofuran at 0℃; for 1h; | 54.1 Step-1 To a stirred ice cold solution of NaH (0.543 g, 13.60 mmol, 1.2 eq) in THF (20 mL) was added ethyl 2-(diethoxyphosphoryl)propanoate (2.96 g, 12.47 mmol, 1.1 eq) and resulting mixture was stirred at 0°C for 10 minutes. To this mixture was added a solution of 8-methoxy- 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde (2.2 g, 11.34 mmol, 1 eq) and reaction mixture was allowed to stir at the same temperature for 1 h. Progress of reaction was monitored by TLCand LCMS. After completion, reaction mixture was diluted with saturated aq. ammonium chloride solution (100 mL) and extracted with ethyl acetate (3 x 100 mL). Combined organic layer was dried over anhydrous. Removal of solvent under reduced pressure afforded crude which was purified by Combi-Flash on silica gel using ethyl acetate-hexane system as eluent to afford ethyl (2E)-3 -(8-methoxy-2, 3 -dihydro- 1 ,4-benzodioxin-6-yl)-2-methylprop-2-enoate(2 .3g, 73 %). |
73% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran at 0℃; for 0.166667h; Stage #2: 8-methoxy-2,3-dihydrobenzo-[b][1,4]dioxine-6-carbaldehyde In tetrahydrofuran at 0℃; for 1h; | 54.1 Step-1 To a stirred ice cold solution of NaH (0.543 g, 13.60 mmol, 1.2 eq) in THF (20 mL) was added ethyl 2-(diethoxyphosphoryl)propanoate (2.96 g, 12.47 mmol, 1.1 eq) and resulting mixture was stirred at 0° C. for 10 minutes. To this mixture was added a solution of 8-methoxy-2,3-dihydro-1,4-benzodioxine-6-carbaldehyde (2.2 g, 11.34 mmol, 1 eq) and reaction mixture was allowed to stir at the same temperature for 1 h. Progress of reaction was monitored by TLC and LCMS. After completion, reaction mixture was diluted with saturated aq. ammonium chloride solution (100 mL) and extracted with ethyl acetate (3*100 mL). Combined organic layer was dried over anhydrous. Removal of solvent under reduced pressure afforded crude which was purified by Combi-Flash on silica gel using ethyl acetate-hexane system as eluent to afford ethyl (2E)-3-(8-methoxy-2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylprop-2-enoate (2.3 g, 73%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.91% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; Stage #2: 1-methylpyrazole-4-carbaldehyde In tetrahydrofuran; mineral oil at 0 - 20℃; | 68.1 Step-1 To a suspension of sodium hydride (60 % in mineral oil), (472 mg, 11.8 mmol, 1.2 eq) in THF (50 mL) was added ethyl 2-(diethoxyphosphoryl)propanoate (2.16 g, 9.08 mmol, 1.2 eq) dropwise at 0°C and the mixture was allowed to stir at the same temperature for 30 minutes. To this mixture was added a solution of 1-methyl-1H-pyrazole-4-carbaldehyde (1.0 g, 9.08 mmol,1.0 eq) in THF (5 mL) and the resulting mixture was allowed to stir at room temperature for 2 h. Progress of reaction was monitored by TLC. After completion, reaction mixture was diluted with saturated aq. NH4C1 (100 mL) and extracted with ethyl acetate (3 x 50 mL). Combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and evaporated to dryness under vacuum to afford crude which was purified by Combi-Flash on silica gel using ethylacetate-hexane system as eluent to afford ethyl (2E)-2-methyl-3-(1-methyl-1H-pyrazol-4- yl)prop-2-enoate (1.6 g, 90.91 %). |
90.91% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Stage #2: 1-methylpyrazole-4-carbaldehyde In tetrahydrofuran; mineral oil at 20℃; for 2h; | 68.1 Step-1 To a suspension of sodium hydride (60% in mineral oil), (472 mg, 11.8 mmol, 1.2 eq) in THF (50 mL) was added ethyl 2-(diethoxyphosphoryl)propanoate (2.16 g, 9.08 mmol, 1.2 eq) dropwise at 0° C. and the mixture was allowed to stir at the same temperature for 30 minutes. To this mixture was added a solution of 1-methyl-1H-pyrazole-4-carbaldehyde (1.0 g, 9.08 mmol, 1.0 eq) in THF (5 mL) and the resulting mixture was allowed to stir at room temperature for 2 h. Progress of reaction was monitored by TLC. After completion, reaction mixture was diluted with saturated aq. NH4Cl (100 mL) and extracted with ethyl acetate (3*50 mL). Combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and evaporated to dryness under vacuum to afford crude which was purified by Combi-Flash on silica gel using ethyl acetate-hexane system as eluent to afford ethyl (2E)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)prop-2-enoate (1.6 g, 90.91%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.1% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran at 0℃; for 0.166667h; Stage #2: N-(tert-butoxycarbonyl)-3-aminopropanal In tetrahydrofuran at 20℃; for 0.5h; | 91.2 Step-2 To a solution of ethyl 2-(diethoxyphosphoryl)propanoate (2.9 g, 16.8 mmol, 1 eq) in THF (30 mL) was added NaH (0.8 g, 20 mmol, 1.3 eq) at 0° C. and the reaction mixture was allowed to stir at the same temperature for 10 minutes. To this solution was added tert-butyl (3-oxopropyl)carbamate (4.1 g, 16.8 mmol, 1 eq) and the reaction mixture was allowed to stir at room temperature for 30 minutes. Progress of reaction was monitored by proton NMR. After completion, reaction mixture was diluted with a Aq. ammonium chloride solution (50 mL) and extracted with ethyl acetate (3*100 mL). Combined organic layer was washed with brine (100 mL) and dried over anhydrous sodium sulfate. Removal of solvent afforded crude ethyl (E)-5-((tert-butoxycarbonyl)amino)-2-methylpent-2-enoate (3.9 g, 66.10%) which was used in the next step without further purification. |
Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran at 0℃; for 0.166667h; Stage #2: N-(tert-butoxycarbonyl)-3-aminopropanal In tetrahydrofuran at 0 - 20℃; for 0.5h; | 91.2 Step-2 To a solution of ethyl 2-(diethoxyphosphoryl)propanoate (2.9 g, 16.8 mmol, 1 eq) in THF (30 mL) was added NaH (0.8 g, 20 mmol, 1.3 eq) at 0°C and the reaction mixture was allowed to stir at the same temperature for 10 minutes. To this solution was added tert-butyl (3-oxopropyl)carbamate (4.1 g, 16.8 mmol, 1 eq) and the reaction mixture was allowed to stir atroom temperature for 30 minutes. Progress of reaction was monitored by proton NMR. Aftercompletion, reaction mixture was diluted with a Aq. ammonium chloride solution (50 mL) and extracted with ethyl acetate (3 x 100 mL). Combined organic layer was washed with brine (100 mL) and dried over anhydrous sodium sulfate. Removal of solvent afforded crude ethyl (E)-5-((tert-butoxycarbonyl)amino)-2-methylpent-2-enoate (3.9 g, 66.10 %) which was used in thenext step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Stage #2: 1-[4-methoxy-3-(3-methoxypropoxy)phenyl]propan-2-one In tetrahydrofuran; mineral oil at 0 - 30℃; for 12h; | 6 Ethyl 4-[4-methoxy-3-(3-methoxypropoxy)phenyl]-2,3-dimethylbut-2-enoate To a solution of triethyl 2-phosphonopropionate (50 mL, 220 mmol) in THF (250 mL) at 0 °C was added NaH (60% in mineral oil, 8.9 g, 220 mmol) and the reaction mixture was stirred for 30 min. A solution of 1-[4-methoxy-3-(3-methoxypropoxy)phenyl]propan-2-one (47 g, 186 mmol) in THF (50 mL) was added at 0 °C. The temperature was slowly raised to 30 °C and the reaction stirred for 12 h. Two identical scale batches were run and and each mixture was quenched with H2O (2 x 500 mL). The combined mixture was extracted with EtOAc (3 x 800 mL). The combined organic phase was washed with saturated aqueous brine solution (800 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by normal phase SiO2; chromatography (5% to 30% EtO Ac/petroleum ether) to afford ethyl 4-[4-methoxy-3-(3-methoxypropoxy)phenyl]-2,3-dimethyl-but-2-enoate as a light yellow oil (108 g, 86% yield, m/z: 359 [M+Na] observed). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.3% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With 1,8-diazabicyclo[5.4.0]undec-7-ene; lithium chloride In acetonitrile at 20℃; for 0.5h; Stage #2: 3-(p-methoxybenzyloxy)propanal In acetonitrile at 20℃; for 1h; | (3) Compound A4 Triethyl 2-phosphonopropionate (61.3 g, 257.4 mmol), DBU (23.5 g, 154.5 mmol), and LiCl (7.6 g, 132.4 mmol) were respectively added to a 1000 mL round-bottom flask, followed by 250 mL CH3CN, and the resulting mixture was stirred vigorously at room temperature. After 30 min, the solution of compound A3 (25.0 g, 128.7 mmol) in CH3CN (120 mL) was added dropwise into the above reaction mixture. After stirring at room temperature for 1 h, TLC showed that the reaction was completed. To the reaction mixture was added 200 mL saturated NH4Cl aqueous solution, and the aqueous phase was separated from the mixture and extracted with ethyl acetate (150 mL x 3). The combined organic phase was successively washed with brine (300 mL x 1), dried over Na2SO4, filtered, and concentrated. Purification by column chromatography on silica gel (ethyl acetate/petroleum ether = 1/6) gave the compound A4 as a light yellow oil (30.2 g) in 84.3% yield. 1H NMR(400 MHz, CDCl3) δ 7.26 (d, J 8.6 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H),6.77 (td, J = 7.2, 1.5 Hz, 1H), 4.46 (s, 2H), 4.19 (q, J = 7.1 Hz, 2H), 3.80(s, 3H), 3.53 (t, J = 6.8 Hz, 2H), 2.48 (q, J = 7.0 Hz, 2H), 1.84 (s, 3H),1.29 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 159.2, 138.3,130.3, 129.4, 129.3, 113.8, 72.7, 68.3, 60.5, 55.3, 29.4, 14.3, 12.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In mineral oil at 0℃; for 0.5h; Stage #2: 4-(6-fluoroquinolin-4-yl)cyclohexane-1-one In mineral oil at 20℃; for 2h; | 106.1 Step 1: To a suspension of NaH (60% w/w in mineral oil, 986 mg, 24.6 mmol) in dry THE (25 mE) was added ethyl-2-(diethylphosphono)propanoate (5.9 g, 24.6 mmol) at 0° C. After the mixture was stirred at 0° C. for 30 mm, a solution of compound le (2.0 g, 8.2 mmol) in dry THF (10 mE) was added to the above mixture and the resulting reaction mixture was stirred at tt. for 2 h. The mixture was quenched by aq. NH4C, and extracted with EtOAc (50 mEx3). The combined organic layers were washed with brine (50 mE), dried over dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give compound 106a (2.5 g, yield: 93%) as a white solid. MS (ESI): mlz 328.3 (M+H). ‘H NMR (500 MHz, CDC13) ö 8.81 (d, J=4.5 Hz, 1H), 8.26-8.18 (m, 1H), 7.74 (dd, J=10.5,2.5 Hz, 1H), 7.56-7.48 (m, 1H), 7.31 (d, J=4.5 Hz, 1H), 4.23 (q, J=7.0 Hz, 2H), 3.50-3.40 (m, 1H), 3.32-3.25 (m, 1H), 2.94-2.87 (m, 1H), 2.24-2.10 (m, 4H), 1.94 (s, 3H), 1.78-1.65 (m, 2H), 1.33 (t, J=7.0 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 1h; Stage #2: Dodecanal In tetrahydrofuran; mineral oil at 0 - 20℃; for 16h; | a a) Ethyl (£)-2-methyltetradec-2-enoate To a cooled (0 °C) suspension of sodium hydride (60% in mineral oil dispersion, 130 mg, 3.26 mmol) in THF (10 ml_) was added dropwise ethyl 2-(diethoxyphosphoryl)propanoate (698 mI_, 3.26 mmol) and the mixture was stirred for 1 h at 0 °C. Then, a solution of dodecanal (500 mg, 2.71 mmol) in THF (5 ml_) was added dropwise. The reaction mixture was allowed to slowly warm to room temperature and stirred for additional 16 h. Water (3.75 ml_) was added, the phases were separated and the aqueous layer was extracted with diethyl ether (x2). The combined organic layers were dried over magnesium sulfate, filtered and the solvents were evaporated to give the title compound (622 mg, 85%) which was used in the next synthetic step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: C33H46O5 In tetrahydrofuran at 20℃; Cooling with ice; | 5 Preparation of Compound 2: The phosphonate (A, 3.69 g, 15 mmol) was added to anhydrous tetrahydrofuran (100 mL) and chilled in a salt ice bath to ~0 °C. Potassium tert-butoxide (1.72 g, 15 mmol) was added with vigorous magnetic stirring under nitrogen and the reaction was allowed to stir for 30 min. Compound 1 (8.0 g, 15 mmol) was added and dissolved in tetrahydrofuran (80 mL), the ice bath was removed and the reaction was allowed to warm to RT overnight. The reaction after approximately 16 h total was worked up by partitioning between hexane/ ethyl acetate (50/50, 400 mL) and water (400 mL). The organic layer was washed with an additional portion of water (100 mL) and the organic layer was dried over Na2SC>4, filtered, and the solvent removed in vacuo. The residue was redissolved in a minimal amount of hexane/ethyl acetate 3/1 and passed through a plug of silica gel ~3 x 9 in. The eluant was then roto-evaporated to yield Compound 2 (8.3 g, 12.4 mmol, 83%) of satisfactory purity to utilize in the next step without further purification, NMR (CDCb, 300 MHz) d 8.10 - 8.07 (m, 2H), 7.60 - 7.57 (m, 1H), 7.52 - 7.47 (m, 2H), 6.7, 5.9 (t, 1H), 5.17 (m, 1H), 4.21 - 4.12 (m, 2H), 3.92 - 3.88 (m, 4H), 2.06 (s, 3H), 2.2 - 1.0 (m, 29 H), 0.95 (d, 3H, J = 7 Hz), 0.90 (s, 3H), 0.69 (s, 3H); MS (ES+) 485.45 (M-C7H7O2+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.24% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran at 0℃; for 0.333333h; Stage #2: cyclobutylaldehyde In tetrahydrofuran at 20℃; | 7.1 Step 1. Preparation of Intermediate 7-1 Under ice bath, add triethyl 2-phosphonopropyl ester (2.04g, 10.49mmol) dropwise to NaH (251.65mg, 10.49mmol) in THF (25mL) dispersion, stir at zero for 20min, then add dropwise ring Butyl formaldehyde (840 mg, 9.99 mmol), after the addition is complete, gradually warm to room temperature and stir overnight. After the reaction, it was quenched with saturated ammonium chloride, extracted with ethyl acetate, and the combined organic phase was spin-dried. The crude product was separated and purified by a silica gel column to obtain Intermediate 7-1 (1.6g, 9.51mmol, 95.24% yield). Purification was used directly in the next step. |
95.24% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran for 0.333333h; Inert atmosphere; Cooling with ice; Stage #2: cyclobutylaldehyde In tetrahydrofuran at 20℃; Inert atmosphere; | 1 Step 1, Preparation of Intermediate Za-1-a Under the protection of nitrogen in an ice bath, triethyl 2-phosphonopropyl ester (2.04 g, 10.49 mmol) was added dropwise to a dispersion of 60% by mass sodium hydride (10.49 mmol) in anhydrous THF (25 mL),Stir at zero temperature for 20 min, then add cyclobutylcarbaldehyde (840 mg, 9.99 mmol) dropwise, the dropwise addition is completed, gradually warm to room temperature and stir overnight.After the reaction, it was quenched with saturated ammonium chloride, extracted with ethyl acetate, the combined organic phases were spin-dried, and the crude product was separated and purified by silica gel column to obtain the intermediate Za-1-a (1.6 g, 9.51 mmol, 95.24% yield) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran for 0.25h; Inert atmosphere; Stage #2: 4-nitrobenzaldehdye In tetrahydrofuran at 20℃; for 10h; Inert atmosphere; | 1.1.1 General procedures for preparing methyl (E)-2-methyl-3-(4-nitrophenyl) acrylate(b): General procedure: Under an argon atmosphere, in the solution of dry THF (THF, 40.00 mL) containing sodium hydride (0.52g, 21.86 mmol), ethyl 2-(diethoxyphosphoryl) propanoate (5.56 g, 21.86 mmol) was subsequent added intoand stir 15 min. Next, 4-nitrobenzaldehyde (3.00 g, 19.87 mmol) dissolved in THF was slowly dropped intothe above reaction mixture. After the reaction bottle being removed to room temperature and stirring at roomtemperature for 10 hours, the reaction accomplished by TLC monitoring and was interrupted with water thenextracted using ethyl acetate (EtOAc, 3× 50.00 mL). The next procedure is to dry over, filter and concentratethe organic phase. Later column chromatography (V/V, PEEA = 6:1) on silica gel was chosen to purify theresidue and finally give the olefin b as a yellow color solid (4.25 g, 91% yield). |
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :