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[ CAS No. 867-13-0 ] {[proInfo.proName]}

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Chemical Structure| 867-13-0
Chemical Structure| 867-13-0
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Product Details of [ 867-13-0 ]

CAS No. :867-13-0 MDL No. :MFCD00009177
Formula : C8H17O5P Boiling Point : -
Linear Structure Formula :(CH3CH2O)2P(O)CH2C(O)OCH2CH3 InChI Key :GGUBFICZYGKNTD-UHFFFAOYSA-N
M.W : 224.19 Pubchem ID :13345
Synonyms :
Chemical Name :Ethyl 2-(diethoxyphosphoryl)acetate

Calculated chemistry of [ 867-13-0 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 14
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.88
Num. rotatable bonds : 8
Num. H-bond acceptors : 5.0
Num. H-bond donors : 0.0
Molar Refractivity : 52.69
TPSA : 71.64 Ų

Pharmacokinetics

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) : -7.32 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.85
Log Po/w (XLOGP3) : 0.49
Log Po/w (WLOGP) : 1.82
Log Po/w (MLOGP) : 0.51
Log Po/w (SILICOS-IT) : 0.52
Consensus Log Po/w : 1.04

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.01
Solubility : 21.9 mg/ml ; 0.0976 mol/l
Class : Very soluble
Log S (Ali) : -1.56
Solubility : 6.12 mg/ml ; 0.0273 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.86
Solubility : 3.12 mg/ml ; 0.0139 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 3.69

Safety of [ 867-13-0 ]

Signal Word:Danger Class:9
Precautionary Statements:P261-P264-P270-P271-P280-P302+P352-P304+P340-P305+P351+P338-P310-P330-P362+P364-P403+P233-P501 UN#:3082
Hazard Statements:H302-H315-H318-H335-H411 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 867-13-0 ]

* 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.

  • Upstream synthesis route of [ 867-13-0 ]
  • Downstream synthetic route of [ 867-13-0 ]

[ 867-13-0 ] Synthesis Path-Upstream   1~2

  • 1
  • [ 867-13-0 ]
  • [ 1191-95-3 ]
  • [ 27741-65-7 ]
YieldReaction ConditionsOperation in experiment
79%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0 - 10℃; for 1.16667 h; Inert atmosphere
Stage #2: at 0 - 10℃; for 2.5 h; Inert atmosphere
To a slurry of NaH (8.0 g, 60percent in oil) in THF (150mL), was added triethyl phosphonoacetate (44.8 g)in 25 mL of THF dropwise at 0-10 oC over 40 min. The reactionmixture was stirred at 0-10 oC for another 0.5 h. Then cyclobutanone(5, 14.0 g) in 25 mL of THF was added dropwise at 0-10 oCover 30 min. The reaction mixture was stirred at 0-10 oC for 2 h. Atotal of 50 mL of water was then added slowly at 20-30 oC. Theorganic solvent was removed under reduced pressure followed by addition of 150mL of water. The aqueous solution was extracted with MTBE (3 x 100 mL). Thecombined organic phase was washed with water (100 mL). It was then dried overanhydrous MgSO4. Filtration followed by evaporation gave the crudeproduct, which was purified by fractional distillation at 81-82 oC/19mbar to give 22.2 g (79percent yield) of Compound 9 as a colorless liquid. 1HNMR (500 MHz,CDCl3) δ 5.58 (m, 1H), 4.13(q, 2H, J = 7.1 Hz), 3.15-3.12 (m, 2H),2.85-2.82 (m, 2H),2.12-2.06 (m, 2H),1.26 (t, 3H, J = 7.1 Hz); 13C NMR (125 MHz, CDCl3) δ 167.60, 166.60, 112.38, 59.53, 33.75, 32.32, 17.66, 14.36; MS (m/z)140.1; ESI-HRMS m/zcalcd for C8H12O2 [M + H]+ 141.0910, found 141.0911.
79%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0 - 10℃; for 1.16667 h;
Stage #2: at 0 - 10℃; for 2.5 h;
To a slurry of NaH (8.0 g, 60 in oil) in THF (150 mL) , was added triethyl phosphonoactate (44.8 g) in 25mL of THF dropwise at 0-10 over 40 min. The reaction mixture was stirred at 0-10 for another 0.5 h. Then cyclobutanone (14.0 g) in 25 mL of THF was added dropwise at 0-10 over 30 min. The reaction mixture was stirred at 0-10 for 2 h. A total of 50 mL of water was then added slowly at 20-30 . The organic solvent was removed under reduced pressure followed by addition of 150 mL of water. The aqueous solution was extracted with MTBE (3 x 100 mL) . The combined organic phase was washed with water (100 mL) . It was then dried over anhydrous MgSO4. Filtration followed by evaporation gave the crude product, which was purified by fractional distillation at 81-82 /19 mbar to give 22.2 g (79 yield, 99 purity) of Compound 12 as a colorless liquid.1HNMR(400 MHz, CDCl3) δ 5.56 (m, 1H) , 4.13 (q, 2H, J 7.2 Hz) , 3.12 (m, 2H) , 2.81 (m, 2H) , 2.08 (m, 2H) , 1.25 (t, 3H, J 7.2 Hz) 13CNMR(100 MHz, DMSO-d6) δ167.2, 165.3, 111.8, 58.9, 33.3, 31.8, 17.1, 14.0 MS (m/z) 140.1.
75%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.166667 h;
Stage #2: at 20℃; for 4 h;
(0203) Triethyl phosphonoacetate (3.32 g, 1.0 equiv) was dissolved in abs. tetrahydrofuran and added to a suspension, cooled down to 0° C., of sodium hydride (0.58 g, 1.02 equiv, 60percent dispersion) in abs. tetrahydrofuran (5 mL). The resulting reaction mixture was stirred at a temperature of 0° C. for 10 minutes and then admixed with a solution of cyclobutanone (1.0 g, 1.0 equiv) in abs. tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for a further 4 h. After the cautious addition of water, the reaction mixture was concentrated under reduced pressure and admixed with dichloromethane. The aqueous phase was then repeatedly extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), ethyl cyclobutylideneacetate (1.5 g, 75percent of theory) was isolated. Ethyl cyclobutylideneacetate (1.0 g, 1.0 equiv) was dissolved in methanol and admixed with a 1 M solution of KOH in aq. methanol. The resulting reaction mixture was stirred at room temperature for 16 h, then neutralized with dil. HCl, admixed with water, concentrated under reduced pressure and then admixed with dichloromethane. The aqueous phase was then repeatedly extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), cyclobutylideneacetic acid (0.40 g, 51percent of theory) was isolated. Aniline (0.26 g, 1 equiv.) was dissolved in dichloromethane (5 mL) and cooled down to a temperature of 0° C., and diisopropylethylamine (1.98 mL, 4.0 equiv.), cyclopentylideneacetic acid (0.30 g, 1.0 equiv.) and N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (0.97 g, 1.1 equiv.) were added. The resulting reaction mixture was stirred at room temperature for 3 h, and water and dichloromethane were then added. The aqueous phase was then repeatedly extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 2-cyclobutylidene-N-phenylacetamide (0.27 g, 54percent of theory) was isolated. In the next step, aluminum trichloride (0.42 g, 3.0 equiv.) was initially charged in abs. dichloroethane (5 mL) under argon in a baked-out round-bottom flask and then, while cooling with ice, a solution of 2-cyclobutylidene-N-phenylacetamide (0.20 g, 1.0 equiv.) in abs. dichloroethane (5 mL) was added. The resulting reaction mixture was stirred at room temperature for a further 4 h and then added cautiously to ice-water. After adding aqueous HCl and dichloromethane, the aqueous phase was extracted repeatedly with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated cautiously under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 1′H-spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one was isolated as a colorless solid. 1′H-Spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one (0.2 g, 1 equiv.) was added to conc. acetic acid (1.5 mL) and then cautiously admixed at 0° C. with fuming nitric acid (0.5 mL). The resulting reaction mixture was then stirred at 90° C. for 2 h and, after cooling to room temperature, cautiously diluted with ice-water. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 6′-nitro-1′H-spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one (100 mg, 78percent of theory) was isolated as a colorless solid. 6′-Nitro-1′H-spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one (100 mg, 1.0 equiv.) was dissolved under argon in abs. dioxane (2 mL) and admixed with fine cesium carbonate powder (400 mg, 3.0 equiv.). After stirring at room temperature for 5 min, cyclobutylmethyl bromide (110 mg, 2.0 equiv.) and potassium iodide (35 mg, 0.1 equiv.) were added at room temperature. The resulting reaction mixture was stirred at 150° C. under microwave conditions for 1 h and, after cooling to room temperature, water and ethyl acetate were added. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 1-(cyclopropylmethyl)-6′-nitro-1′H-spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one (70 mg, 60percent of theory) was isolated as a colorless solid. In the next step, 1-(cyclopropylmethyl)-6′-nitro-1′H-spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one (50 g, 1 equiv.) was added together with zinc dust (55 mg, 5 equiv.) and ammonium chloride (90 mg, 10 equiv.) to methanol/water (5:1) and the mixture was stirred under argon at a temperature of 70° C. for 2 h. After cooling to room temperature, the reaction mixture was poured onto ice-water and then adjusted to pH 12 with 6 N NaOH. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 6′-amino-1-(cyclopropylmethyl)-1′H-spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one (35 mg, 70percent of theory) was isolated as a colorless solid. 6′-Amino-1-(cyclopropylmethyl)-1′H-spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one (100 mg, 1.0 equiv.) was dissolved together with 4-methylphenylsulfonyl chloride (81 mg, 1.1 equiv) in abs. dichloromethane (5 mL) in a baked-out round-bottom flask under argon, then pyridine (0.15 mL, 5 equiv.) was added and the mixture was stirred at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure, the remaining residue was admixed with dil. HCl and dichloromethane, and the aqueous phase was extracted repeatedly with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 4-methyl-N-[1′-(cyclopropylmethyl)-2′-oxo-2′,3′-dihydro-1′H-spiro[cyclobutyl-1,4′-quinolin]-6′-yl]phenylsulfonamide (70 mg, 43percent of theory) was isolated as a colorless solid. 1H-NMR (400 MHz, d6-DMSO δ, ppm) 10.05 (s, 1H, NH), 7.62 (d, 2H), 7.36 (d, 2H), 7.12 (m, 2H), 6.96 (m, 1H), 3.76 (m, 2H), 2.61 (s, 2H), 2.33 (s, 3H), 2.03-1.92 (m, 5H), 1.79 (m, 1H), 0.97 (m, 1H), 0.36 (m, 2H), 0.22 (m, 2H).
16%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.0833333 h;
Stage #2: at 27℃; for 2 h;
To a stirred suspension of 60percent NaH (1.23 g, 51.35 mmol) in THF (50 mL), ethyl 2-(diethoxyphosphoryl)acetate (6.23 mL, 31.38 mmol) in 10 mL THF was added at 0°C and stirred for 5 mm at same temperature. Then cyclobutanone 75 (2 g, 28.53 mmol) in THF (10 mL) was added to it and allowed to stir at room temperature for 2h. Then the reaction mixture was quenched with cold water and extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain ethyl 2-cyclobutylideneacetate 76 as colorless liquid (0.65 g, 16percent yield). 1HNMR (400 MHz, CDC13): ö 5.57 (s, 1H), 4.13 (q, 2H), 3.12 (t, 2H), 2.82 (t, 2H), 2.12-2.04 (m, 2H), 1.26 (t, 3H).
96% With NaH In tetrahydrofuran Synthesis of Cyclobutylidene-acetic acid ethyl ester (2)
NaH (60percent dispersion in oil, 1.80 g, 44.94 mmol) was suspended in dry tetrahydrofuran (80 mL) and cooled to 0° C. Triethylphosphonoacetate (9.33 mL, 47.08 mmol) was added and the mixture stirred at 0° C. for 15 minutes.
Cyclobutanone (1) (3.0 g, 42.8 mmol) in THF (20 mL) was then added and the mixture allowed to warm to room temperature.
After 2 hours, the mixture was partitioned between diethyl ether (200 mL) and water (150 mL).
The organic phase was separated, washed with brine, dried (MgSO4), and the solvent removed in vacuo at 600 mm Hg.
The residue was purified by flash chromatography (silica, ethyl acetate:pentane 1:19) to give 5.81 g (96percent) of (2) as a colorless oil.
1H NMR, 400 MHz (CDCl3): δ1.27 (3H, t, J=6 Hz), 2.09 (2H, m), 2.82 (2H, m,) 3.15 (2H, m), 4.14 (2H, q, J=6 Hz), 5.58 (1H, s).
MS (ES+) m/e: 141 ([MH+], 100percent). IR (film) ν cm-1: 1088, 1189, 1336, 1673, 1716, 2926.
80% With ammonium chloride; sodium hexamethyldisilazane In tetrahydrofuran Step A
Ethyl 3,3-trimethylene acrylate
A solution of triethylphosphonoacetate (17 mL, 85.6 mmol), in 150 mL dry THF was cooled to -78° C. A solution of sodium hexamethyldisilazide (86 mL, 1.0M in THF, 86 mmol) was added.
The mixture was warmed to 0 C for 30 min and cyclobutanone (5 grams, 71.3 mmol) was added.
The mixture was warmed to room temperature and stirred overnight.
Sat'd ammonium chloride was added and the mixture was extracted with ethyl acetate.
The organic was dried over sodium sulfate and concentrated.
Flash chromatography (30/1 hexane/ether) afforded 8.0 grams (80percent) of the desired compound. 1H NMR (300 MHz, CDCl3).
δ1.25 (t, 3H), 2.0-2.2 (p, 2H), 2.8-2.9 (t, 2H), 3.1-3.2 (t, 2H), 4.1-4.2 (q, 2H), 5.58 (s, 1H).

Reference: [1] Journal of Organic Chemistry, 2016, vol. 81, # 3, p. 1057 - 1074
[2] Journal of the Chemical Society. Perkin Transactions 2, 1999, # 5, p. 937 - 945
[3] Tetrahedron Letters, 2015, vol. 56, # 45, p. 6287 - 6289
[4] Patent: WO2016/37534, 2016, A1, . Location in patent: Page/Page column 19
[5] Patent: US2017/27172, 2017, A1, . Location in patent: Paragraph 0203
[6] Patent: WO2015/25197, 2015, A1, . Location in patent: Paragraph 000149
[7] Journal of Medicinal Chemistry, 2005, vol. 48, # 15, p. 5025 - 5037
[8] Patent: US6635673, 2003, B1,
[9] Patent: US6248755, 2001, B1,
[10] European Journal of Organic Chemistry, 2017, vol. 2017, # 31, p. 4530 - 4542
[11] Molecules, 2018, vol. 23, # 11,
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  • [ 867-13-0 ]
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Reference: [1] Patent: US2006/128790, 2006, A1, . Location in patent: Page/Page column 67
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