Structure of 33689-29-1
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CAS No. : | 33689-29-1 |
Formula : | C5H8O3 |
M.W : | 116.12 |
SMILES Code : | COC(=O)C1(O)CC1 |
MDL No. : | MFCD02093884 |
InChI Key : | KPJWVJURYXOHOO-UHFFFAOYSA-N |
Pubchem ID : | 2733178 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 8 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.8 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 26.52 |
TPSA ? Topological Polar Surface Area: Calculated from |
46.53 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.42 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.19 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-0.38 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.38 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.43 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.18 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.31 |
Solubility | 57.1 mg/ml ; 0.492 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.33 |
Solubility | 54.2 mg/ml ; 0.466 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.15 |
Solubility | 83.0 mg/ml ; 0.714 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-7.14 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.17 |
* 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 |
---|---|---|
86% | pyridinium p-toluenesulfonate; In dichloromethane; at 25℃; for 3h; | Hydroxy-cyclopropanecarboxylic acid methyl ester (5.07 g, 43.71 mmol) was dissolved in methylene chloride (75 mL) and 3,4-dihydro-2H-pyran (3.86 g, 45.90 mmol) was added followed by pyridinium-p-toluene-sulfonic acid (1.10 g, 4.37 mmol). The reaction stirred at 25 C. for 3 h. The reaction was concentrated in vacuo to give a clear oil. The oil was dissolved in diethyl ether (75 mL), washed with saturated aqueous brine solution (25 mL), dried over sodium sulfate and concentrated in vacuo to an oil. The oil was passed through a plug of silica gel (Merck silica gel 60, 40-63 mum; 100% ethyl acetate) to afford 1-(tetrahydro-pyran-2-yloxy)-cyclopropanecarboxylic acid methyl ester (7.49 g, 86%) as a clear oil: H1-NMR (400 MHz, CDCl3) delta 1.14-1.42 (4H, m), 1.88-3.46 (6H, m), 3.46-3.54 (1H, m), 3.70-3.72 (3H, m), 3.82-3.90 (1H, m), 4.81-4.96 (1H, m). |
60% | With pyridinium p-toluenesulfonate; In dichloromethane; at 23℃; for 16h;Sealed tube; | Methyl 1-hydroxycyclopropanecarboxylate (1.12 g, 9.65 mmol) was dissolved in DCM (15 mL) and3,4-dihydro-2H-pyran (0.9 mL, 10.13 mmol) was added, followed by pyridmnium p-toluenesulfonate (0.242 g, 0.965 mmol). The colorless solution was stirred at RT in a sealed vessel for 16 h. The reaction mixture was concentrated in vacuo. The white suspension was partitioned between brine (20 mL) and Et20 (20 mL) and the layers were separated. The organic layer was washed with brine (2x 5mL) and dried on Na2504 before concentration in vacuo. The product was purified using CC (silica, gradient heptane/EtOAc, 1:0-. 8:2)to give the desired product (1.16 g, 60%) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 60h; | A solution of methyl 1-hydroxy-1-cyclopropane carboxylate (2.03 g, 17.5 mmol)DMF (35 mL) was treated sequentially with imidazole (1.19 g, 17.5 mmol) and tertbutyldimethylsilyl chloride (2.77 g, 18.4 mmol). The resulting mixture was stirred for 60 h at ambient temperature. The reaction mixture was diluted with water, and extracted with Et20 (2x). The organic extracts were washed with water (3x) and brine (lx), then dried over anhydrous Na2SO4(), filtered and concentrated in vacuo to afford the title compound (3.45 g, 86% yield). ?H NMR (400 IVIHz, CDC13) 3.71 (s, 3H), 1.33-1.30 (m, 2H), 1.08-1.05 (m, 2H), 0.87 (s, 9H), 0.14 (s, 6H). |
With 1H-imidazole; In dichloromethane; for 12h;Inert atmosphere; | Step 1 Methyl 1-(tert-butyldimethylsilyloxy)cyclopropanecarboxylate Methyl 1-hydroxycyclopropanecarboxylate 5a (350 mg, 3.02 mmol) was dissolved in 30 mL of dichloromethane, followed by addition of tert-butyldimethylsilyl chloride (495 mg, 3.30 mmol) and imidazole (306 mg, 4.49 mmol). After reacting for 12 hours, the reaction mixture was mixed with 20 mL of dichloromethane, and extracted with saturated sodium chloride solution (20 mL*3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title product methyl 1-(tert-butyldimethylsilyloxy)cyclopropanecarboxylate 5b (600 mg, colourless oil), which was used directly in the next step without further purification. | |
With 1H-imidazole; In dichloromethane; at 20 - 30℃; for 12h; | Methyl 1-hydroxycyclopropanecarboxylate 5a (350 mg, 3.02 mmol) was dissolved in 30 mL of dichloromethane, followed by addition of tert-butyldimethylsilyl chloride (495 mg, 3.30 mmol) and imidazole (306 mg, 4.49 mmol). After reacting for 12 hours, the reaction mixture was mixed with 20 mL of dichloromethane, and extracted with saturated sodium chloride solution (20 mL*3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title product methyl 1-(tert-butyldimethylsilyloxy)cyclopropanecarboxylate 5b (600 mg, colourless oil), which was used directly in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Example B6 A 0 C. solution of <strong>[33689-29-1]methyl 1-hydroxycyclopropane-1-carboxylate</strong> (1 g, 8.61 mmol) in DMF (10 mL) was treated with NaH (60% in mineral oil, 0.689 g, 17.22 mmol), stirred at 0 C. for 0.5 h, treated with iodomethane (0.646 mL, 10.33 mmol), allowed to slowly warm to RT and stirred for 2 h. The mixture was quenched with satd. NH4Cl, diluted with water and extracted with Et2O (3*). The combined organics were washed with water, then brine, dried and concentrated to afford methyl 1-methoxycyclopropane-1-carboxylate (1.10 g, 98%). 1H NMR (400 MHz, DMSO-d6): delta 3.62 (s, 3H), 3.27 (s, 3H), 1.12-1.11 (m, 4H). | |
98% | Example B18 A 0 C. solution of <strong>[33689-29-1]methyl 1-hydroxycyclopropane-1-carboxylate</strong> (1 g, 8.61 mmol) in DMF (10 mL) was treated with NaH (60% in mineral oil, 0.689 g, 17.22 mmol), stirred at 0 C. for 0.5 h, treated with iodomethane (0.646 mL, 10.33 mmol), allowed to slowly warm to RT and stirred for 2 h. The mixture was quenched with satd. NH4Cl, diluted with water and extracted with Et2O (3×). The combined organics were washed with water, then brine, dried and concentrated to afford methyl 1-methoxycyclopropane-1-carboxylate (1.10 g, 98%). 1H NMR (400 MHz, DMSO-d6): delta 3.62 (s, 3H), 3.27 (s, 3H), 1.12-1.11 (m, 4H). | |
With sodium hydride; In tetrahydrofuran; at 0℃; for 18h; | Step A: 1-METHOXV-CVCLOPROPANECARBOXYLIC acid methyl ester 1-Hydroxy-cyclopropanecarboxylic acid methyl ester (1.16 gm, 10 MMOL) was dissolved in 10 ml of tetrahydrofuran and cooled under a nitrogen atmosphere to 0 C. Sodium hydride (0.52 gm, 60 % oil dispersion) was added portionwise followed by lodomethane (1 ml) and stirred for 18 hrs. The reaction mixture was quenched with ammonium chloride and extracted with ETHYLACETATE to obtain 2 gm of title product. (MH+= 130) |
With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 18h; | According to WO 2005/014577 methyl l-hydroxycyclopropanecarboxylate (1.01 g, 8.70 mmol) was dissolved under argon in THF (10 ml) and cooled using an ice-bath. Sodium hydride (60%, 0.52 g, 13.00 mmol) was added portionwise followed by iodomethane (1 ml, 16.06 mmol) and the mixture was stirred for 18 hours at room temperature. The mixture was quenched with saturated solution OfNH4Cl (20ml) and extracted with EtOAc. The organic extracts were combined, dried, filtered and evaporated in vacuo to give 620 mg of the crude product which was used as such.1H NMR (400 MHz, CDCl3) delta 3.76 (s, 3H), 3.43 (s, 3H), 1.25-1.17 (b, 4H), | |
4.0 g | To a solution of <strong>[33689-29-1]methyl 1-hydroxycyclopropanecarboxylate</strong> (3.2 g) in tetrahydrofuran (40 ml), sodium hydride (55% oil, 1.3 g) was added under ice cooling, and the mixture was stirred at the same temperature as above for 15 minutes. Methyl iodide (2.3 ml) was added to the reaction solution, and the mixture was stirred overnight at room temperature. 1 N hydrochloric acid was added to the reaction solution, followed by extraction with a n-hexane-ethyl acetate mixed solution. The extract was washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (4.0 g). 1H-NMR (CDCl3) delta: 1.13-1.32 (4H, m), 3, 42 (3H, s), 3.75 (3H, s). | |
00512] Step A: NaH (738 mg, 18.44 mmol; 60% dispersion in oil) was added to a solution of <strong>[33689-29-1]methyl 1-hydroxycyclopropanecarboxylate</strong> (1.83 g, 14.18 mmol) in anhydrous THF (15 mL) cooled on an ice bath. The mixture was stirred for 15 minutes then iodomethane (3.22 g, 1.42 mL, 22.69 mmol) was added slowly, and the resulting mixture stirred at ambient temperature for 18 hours. The reaction mixture was quenched with ammonium chloride and extracted with EtOAc (3 X 20 mL). The combined organic extracts were washed with water, <n="167"/>dried over MgSO4, and filtered. The filtrate was evaporated under reduced pressure to give methyl 1-methoxycyclopropanecarboxylate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; triethylamine; In methanol; | Preparation of Methyl 1-hydroxy-1-cyclopropanecarboxylate 1-Hydroxy-1-cyclopropanecarboxylic acid (587 mg, 5.75 mmol) was dissolved in methanol (20 mL) under nitrogen. Thionyl chloride (4 drops) were added and the reaction was stirred overnight at room temperature. Triethylamine was then added until the reaction was alkaline as judged by moistened pH paper. The solvent was then removed on the rotary evaporator. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | To a solution of Compound 1 ( 5.00 g, 25.6 mmol ) and methyl 1-hydroxy-l- cyclopropane carboxylate ( 3.97 g, 30.8 mmol ) in THF ( 100 mL ) was added sodium hydride ( 60 %, 1.23 g, 30.8 mol ) at -78 C and the mixture was stirred at room temperature for 3hours. The reaction mixture was quenched with 1 M aqueous citric acid and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( hexane : ethyl acetate = 15 : 1 ) to give Compound 2 ( 6.91 g, 98 % ) as a solid. MS: 275/277 [M+H]+, APCI |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
e) 4-(1 -Methoxycarbonylcvclopropoxy)-3-nitrobenzoic acid methyl ester; To a suspension of 20.81 mmol of sodium hydride in 10 ml of dry N,N-dimethyl- formamide at 00C is added a solution of 17.34 mmol of methyl 1 -hydroxy-1 - cyclopropane carboxylate in 10 ml of dry N,N-dimethylformamide. The reaction mixture is stirred at 00C for 1 hour, before the addition of 27.74 mmol of methyl 4-fluoro-3-nitrobenzoate. The reaction mixture is stirred at 00C for 1 hour, then at room temperature for 3 hours, poured onto saturated aqueous ammonium chloride, <n="57"/>extracted with tert-butyl methyl ether (3X), dried over sodium sulphate and concentrated. Purification by flash chromatography (SiO2 60F) affords the title compound as a thick yellow oil. Rf = 0.48 (EtOAc-heptane 1 :1 ); Rt = 4.18 (gradient I). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 1. Methyl 1-(benzyloxy)cyclopropanecarboxylate At 0 C., methyl 1-hydoxycycloprppanecarboxylate was added to a suspension of NaH and DMF. After stirring for 10 min., benzylbromide was added and the reaction mixture was allowed to gradually warm to rt while stirring overnight. The reaction mixture was poured into ice water and extracted with ether (3*100 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated in-vacuo. The crude product was purified by flash chromatography, eluding with hexane/ether (3:1, 2:1, 1:1, 1:2) to give 600 mg of yellow oil. 1H NMR confirmed the structure of the isolated product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; In dichloromethane; at 20℃; for 14h;Inert atmosphere; | To a stirred solution of 2-(4-(quinolin-2-ylmethoxy) phenyl) acetyl chloride (2.0 g, 6.557 mmol) in DCM (50 mL), DMAP (1.4 g, 13.114 mmol) was added followed by methyl 1- hydroxycyclopropanecarboxylate (1.1 g, 9.836 mmol) under a nitrogen atmosphere at RT and the mixture was stirred for 14 h. After complete consumption of the starting material (by TLC), the reaction mixture was quenched with water (10 mL) and the aqueous layer was extracted with DCM (2 x 50 mL). The combined organic layers were washed with a saturated NaHCO3 solution (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford crude methyl l-(2-(4-(quinolin-2-ylmethoxy) phenyl) acetoxy) cyclopropanecarboxylate (2.0 g,) as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 1. Methyl l-[(6-chloropyrazin-2-yl)oxy1cyclopropanecarboxylateSodium hydride (0.258 g, 60% dispersion in mineral oil, 6.46 mmol) was added to a solution of methyl 1 -hydroxy cyclopropanecarboxylate (0.5 g, 4.31 mmol) in anhydrous DMF (14.4 mL) at 0 C and the mixture was stirred for 30 min. 2,6-Dichloropyrazine (0.642 g, 4.31 mmol) was added and the resulting mixture was allowed to stir at 0 C for additional 1 h before quenched by two drops of water. The reaction mixture was concentrated in vacuo and the residue was applied to silica gel chromatography, eluting with a gradient of ethyl acetate: hexane 5:95 to 50:50 to afford the title compound, which was contaminated with residual DMF. MS APCI: [M + H]+ m/z = 229.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydride; In tetrahydrofuran; mineral oil; at -78 - 20℃; for 2h; | To a solution of 2,4,6-trichloro-5-methoxy-pyrimidine (213 mg, 1.00 mmol) and <strong>[33689-29-1]1-hydroxy-cyclopropanecarboxylic acid methyl ester</strong> (139 mg, 1.20 mmol) in THF (4 mL) was added sodium hydride (48 mg, 1.20 mmol, 60% dispersion in mineral oil) at -78 C. The resulting mixture was allowed to warm to RT and stirred for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo affording 1-(2,6-Dichloro-5-methoxy-pyrimidin-4-yloxy)-cyclopropanecarboxylic acid methyl ester as a white solid (300 mg, quantitative). LCMS: RT=3.49 min, [M+H]+=341/343/345. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.75 g | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h; | Piperidine-1-carbonyl chloride (1.599 mL) was added to a solution of <strong>[33689-29-1]methyl 1-hydroxycyclopropanecarboxylate</strong> (1 mL) and DIEA (3.04 mL) in DCM (15 mL). The resulting solution was stirred at rt for 2 h, then diluted with DCM and the organic layer was wahed with iN HC1, water and brine, dried (Mg504), filtered andconcentrated. The residue was purified with silica gel gel to yield Cap L-7 Step a (0.75 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.66 g | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h; | To a solution of <strong>[33689-29-1]methyl 1-hydroxycyclopropanecarboxylate</strong> (0.741 mL, 8.61 mmol) was added diisopropylcarbamic chloride (1.550 g, 9.47 mmol) and DIEA (2.256 mL, 12.92 mmol) in DCM (15 mL). The resulting solution was stirred at rt for 2 h, then diluted with DCM and the organic layer was washed with 1 N HC1,water and brine, dried (Mg504), filtered and concentrated. The residue was purified via Biotage (15% to 30% EtOAc/Hex; 25 g column) to yield Cap L-9 Step a (0.66 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of <strong>[33689-29-1]methyl 1-hydroxycyclopropanecarboxylate</strong> (Aldrich) (1.0 g, 8.8 mmol) and 15-crown-5 (cat. amount) in THF (30 ml) was added NaH (400 mg, 10 mmol) at room temperature. The resulting mixture was stirred at room temperature for 30 min and then added 1-bromo-2,5-difluoro-4-nitrobenzene (Aldrich) (2 g, 8.4 mmol). The mixture was stirred at room temperature for additional 16 hrs. When TLC indicated the reaction was completed, the reaction mixture was quenched with saturated NH4Cl aqueous solution. After removal of the organic solvent, the mixture was extracted with ethyl acetate (*3). The combined organic phases were washed with brine (*3), dried over anhydrous Magnesium sulfate and filtered. The filtration was concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography on silica gel using a gradient 0-10% ethyl acetate in hexanes to afford the title compound as yellow solid. LC-MS: Rt=1.43 mins; MS m/z [M+H]+ 333.9; Method 5-95AB 1.5minLC_v003 1H NMR (400 MHz, CDCl3) delta 8.15 (1H, d), 6.98 (1H, d), 3.57 (3H, s), 1.38 (2H, m), 1.18 (2H, m). | ||
Step 1 : methyl 1-(5-bromo-4-fluoro-2-nitrophenoxy)cvclopropanecarboxylate: To a mixture of <strong>[33689-29-1]methyl 1-hydroxycyclopropanecarboxylate</strong> (Aldrich) (1.0 g, 8.8 mmol) and 15- crown-5 (cat. amount) in THF (30 ml) was added NaH (400 mg, 10 mmol) at room temperature. The resulting mixture was stirred at room temperature for 30 min and then added 1-bromo-2,5- difluoro-4-nitrobenzene (Aldrich) (2 g, 8.4 mmol). The mixture was stirred at room temperature for additional 16 hrs. When TLC indicated the reaction was completed, the reaction mixture was quenched with saturated NH4CI aqueous solution. After removal of the organic solvent, the mixture was extracted with ethyl acetate (x3). The combined organic phases were washed with brine (x3), dried over anhydrous Magnesium sulfate and filtered. The filtration was concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography on silica gel using a gradient 0-10% ethyl acetate in hexanes to afford the title compound as yellow solid. LC-MS: Rt=1.43 mins; MS m/z [M+H]+ 333.9; Method 5-95AB 1.5minLC_v003 1H NMR (400 MHz, CDCI3) delta 8.15 (1 H, d), 6.98 (1 H, d), 3.57 (3H, s), 1.38 (2H, m), 1.18 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | Step 1. methyl l-(2-bromo-6-nitrophenoxy)cyclopropanecarboxylate Sodium hydride in mineral oil (22 mg, 0.94 mmol) was added to a solution of <strong>[33689-29-1]methyl 1-hydroxycyclopropanecarboxylate</strong> (40 mg, 0.4 mmol) (Acros Organics cat 3021 1) in tetrahydrofuran (2 mL). After 10 min 15-Crown-5 (5 L, 0.02 mmol) and l-bromo-2-fluoro- 3 -nitrobenzene (100 mg, 0.4 mmol) (Ark Pharma cat AK-35754) were added. The reaction mixture was stirred at room temperature overnight then quenched with methanol (lmL) and partitioned between ethyl acetate and water. The combined organic layers were washed with brine, dried over MgS04, filtered, and concentrated to yield crude product. The product was purified by FCC on silica gel eluting a hexane: ethyl acetate gradient to afford methyl l-(2- bromo-6-nitrophenoxy)cyclopropanecarboxylate as a semisolid (50 mg, 40%). LCMS calculated for CiiHnBrNOs (M+H)+: m/z = 316.1, 318.1 ; found = 315.9, 318.0 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Step 2. Methyl l-[2-bromo-4-(methylsulfonyl)-6-nitrophenoxy]cyclopropanecarboxylate Sodium hydride in mineral oil (110 mg, 4.7 mmol) was added to a solution of <strong>[33689-29-1]methyl 1-hydroxycyclopropanecarboxylate</strong> (100 mg, 0.8 mmol) in N,N-dimethylformamide (20 mL) at 0 C. After 5 min, l-bromo-2-fluoro-5-(methylsulfonyl)-3-nitrobenzene (250 mg, 0.84 mmol) was added and the reaction was stirred at 0 C for 1 h. The reaction was quenched with MeOH (3 mL) and partitioned between water and ethyl acetate. The combined organic layer was washed with brine, dried over MgSCn, filtered and concentrated to give crude material. The product was purified by FCC on silica gel eluting with hexane:ethyl acetate gradient to give methyl l-[2-bromo-4-(methylsulfonyl)-6- nitrophenoxy]cyclopropanecarboxylate as a yellow oil (0.10 g, 67%). LCMS calculated for Ci2Hi3BrM)7S (M+H)+: m/z = 394.0 396.0; found: 394.0, 395.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sodium hydride; In tetrahydrofuran; mineral oil; at -78 - 23℃; for 18h; | Compound 1-8A mixture of Inter mediate-2 (15 mg, 1 equiv.) and <strong>[33689-29-1]methyl 1-hydroxycyclopropanecarboxylate</strong> (14 mg, 3 equiv.) in THF was cooled to -78 C. Contents were treate with sodium hydride (5.3 mg, 60% suspension in mineral oil, 3 equiv.) and warmed to 23 C and stirred for 18 h. The contents were concentrated in vacuo, and the residue was purified via silica gel chromatography utilizing a 0-30% ethyl acetate/hexanes gradient to deliver the desired compound (16 mg, 84%>) as a white solid. 1H-NMR (500 MHz, CDCb) delta 8.47 (s, 2 H), 7.23-7.17 (m, 1 H), 7.16 (s, 1 H), 7.02 (t, 1 H), 6.98 (t, 1 H), 6.93-6.88 (m, 1 H), 6.58 (s, 1 H), 5.95 (s, 2 H), 3.70 (s, 3 H), 1.76-1.71 (m, 2 H), 1.45-1.40 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | To a suspension of NaH (960 mg, 24 mmol.) in THF (20 mL) at C was added dropwise a solution of methyl 1 -hydroxycyclopropane- 1 -carboxylate (2.32 g, 20 mmol, 1.25 eq) in THF (4 mL) and stirred for 10 min. Then 3-(hrom.om.ethyl)thiophene (2.83 g, 16 mmol) was added followed by the addition of TBAI (590 mg, 1.6 mmol). The reaction mixture was allowed to warm to r.t. and stirred for overnight. The reaction mixture was quenched by the addition of water and extracted with EtoAc (3x40 mL). The organic layer was washed with brine, dried over a2S04 and concentrated. The residue was purified on silica gel (1:8 ethyl acetate /hexanes) to give HYC-258 as colorless oil. (2.1 g, 63%). 1H NMR (400 MHz, CDC13) delta 7.35-7.29 (m, 1H), 7.27 - 7.23 (m, 1H), 7.12 (d, J = 4.9 Hz, 1H), 4.68 (s, 2H), 3.80 (s, 3H), 1.40 - 1.33 (m, 2H), 1.28 - 1.21 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | General procedure: To a mixture of methyl 1 -hydro xycyclopropanecarboxylate (3.00 g, 25.82 mmol) in THF (100 mL) was added NaH (1.55 g, 38.7 mmol, 60% purity) in portions at 0 C under N2 atmosphere. The mixture was stirred at 0 C for 30 minutes, then 5-bromo-2-chloro-3-nitro-pyridine (6.13 g, 25.8 mmol) in THF (20 mL) was added dropwise. The mixture was stirred at 0 C for 1.5 h. The solution was quenched with water (50 mL) and then extracted with ethyl acetate (3 x 100 mL). The combined organic layers was washed with brine (2 x 200 mL), dried over Na2S04, filtered, and then concentrated in vacuo. The residue was purified by chromatography to give the title compound (5.35 g, 65% yield) as a red solid. LCMS m/z = 316.9 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | A flask was charged with <strong>[33689-29-1]methyl 1-hydroxycyclopropane-1-carboxylate</strong> (362 mg, 3.12 mmol, 1.50 equiv) and THF (10 mL). Sodium hydride (125 mg, 3.12 mmol, 1.50 equiv, 60% in mineral oil) was added at 0 C. The mixture was stirred for 20 min at rt before 2-fluoro-4-(trifluoromethyl)benzaldehyde (400 mg, 2.08 mmol, 1.00 equiv) was added. The resulting solution was stirred for 1 h at rt and quenched with water (30 mL). The resulting solution was extracted with DCM (2*50 mL) and the organic layers were combined, washed with brine (2*30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on a silica gel column with EtOAc/petroleum ether (1/10) to provide 180 mg (29% yield) of methyl 1-(2-formyl-5-(trifluoromethyl)phenoxy)cyclopropane-1-carboxylate as a light yellow oil. | |
24% | A flask was charged with methyl 1 -hydroxycyclopropane- 1 -carboxylate (1.36 g,11.7 mmol, 1.50 equiv) and THF (10 mL). Sodium hydride (0.780 g, 19.5 mmol, 2.50 equiv, 60% in mineral oil) was added at 0 C. The mixture was stirred for 20 mm at room temperature. 2-Fluoro-4-(trifluoromethyl)benzaldehyde (1.50 g, 7.81 mmol, 1.00 equiv) was added. The resulting solution was stirred for 1 h at room temperature and quenched with water (30 mL). The resulting solution was extracted with DCM (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 530 mg (24% yield) of methyl 1-(2-formyl-5- (trifluoromethyl)phenoxy)cyclopropane-1-carboxylate as a yellow oil. ?H NMR (300 IVIHz, Chloroform-cl) oe 10.50 (s, 1H), 8.00 - 7.97 (m, 1H), 7.38 - 7.27 (m, 2H), 3.79 (s, 3H), 1.82 - 1.70 (m, 2H), 1.52 - 1.44 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | At 10 C, Methyl 1-hydroxy-1-cyclopropanecarboxylate (50.00 g, 0.43 mol) was added to tetrahydrofuran (400 mL).Nitrogen protection, adding 60% sodium hydride (34.4 g, 0.86 mol) in batches at the same temperature.After the addition was completed at 10 C for 15 minutes, bromoacetonitrile (103.2 g, 0.86 mol) was further added, and the reaction was carried out at 10 C for 15 minutes. Then, water (100 mL) was slowly added dropwise at 0 C, and water (400 mL) was added.The aqueous phase was extracted with ethyl acetate (200 mL*2), and the organic phase was combined, and the organic phase was washed with saturated brine (100 mL).Concentrated organic phase,Sand column chromatography (petroleum ether: ethyl acetate = 4:1 to 3:1)Get 61.3g of light yellow liquid,That is, Intermediate 1, the yield was 92%. |
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