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Chemical Structure| 33689-29-1 Chemical Structure| 33689-29-1

Structure of 33689-29-1

Chemical Structure| 33689-29-1

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Product Details of [ 33689-29-1 ]

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

Safety of [ 33689-29-1 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 33689-29-1 ] Show Less

Physicochemical Properties

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
Ertl P. et al. 2000 J. Med. Chem.

46.53 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

1.42
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

-0.19
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

-0.38
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

-0.38
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

0.43
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.18

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-0.31
Solubility 57.1 mg/ml ; 0.492 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-0.33
Solubility 54.2 mg/ml ; 0.466 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-0.15
Solubility 83.0 mg/ml ; 0.714 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

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)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-7.14 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

1.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

1.17

Application In Synthesis of [ 33689-29-1 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 33689-29-1 ]

[ 33689-29-1 ] Synthesis Path-Downstream   1~35

  • 1
  • [ 110-87-2 ]
  • [ 33689-29-1 ]
  • [ 87326-00-9 ]
YieldReaction ConditionsOperation 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.
  • 3
  • [ 33689-28-0 ]
  • [ 124-41-4 ]
  • [ 33689-29-1 ]
  • 4
  • [ 66324-10-5 ]
  • [ 33689-29-1 ]
  • methyl 2,6-dioxo-6-phenylhexanoate [ No CAS ]
  • 5
  • [ 33689-29-1 ]
  • [ 87326-01-0 ]
  • 6
  • [ 33689-29-1 ]
  • [ 814-49-3 ]
  • 1-(Diethoxy-phosphoryloxy)-cyclopropanecarboxylic acid methyl ester [ No CAS ]
  • 7
  • [ 33689-29-1 ]
  • [ 18162-48-6 ]
  • [ 90660-08-5 ]
YieldReaction ConditionsOperation 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.
  • 8
  • [ 103582-19-0 ]
  • [ 288-13-1 ]
  • [ 33689-29-1 ]
  • [ 15366-34-4 ]
  • methyl 1-acetoxycyclopropanecarboxylate [ No CAS ]
  • 9
  • [ 33689-29-1 ]
  • [ 107-30-2 ]
  • [ 910310-53-1 ]
  • 10
  • [ 33689-29-1 ]
  • 1-Trimethylsilanyloxy-cyclopropanecarboxylic acid methyl ester [ No CAS ]
  • 11
  • [ 33689-29-1 ]
  • [ 74-88-4 ]
  • [ 2790-74-1 ]
YieldReaction ConditionsOperation 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.

  • 12
  • [ 17994-25-1 ]
  • [ 33689-29-1 ]
YieldReaction ConditionsOperation 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.
  • 13
  • [ 6299-25-8 ]
  • [ 33689-29-1 ]
  • [ 1190735-24-0 ]
YieldReaction ConditionsOperation 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
  • 14
  • [ 33689-29-1 ]
  • [ 329-59-9 ]
  • [ 959937-72-5 ]
YieldReaction ConditionsOperation 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).
  • 15
  • [ 33689-29-1 ]
  • [ 100-39-0 ]
  • [ 865798-43-2 ]
YieldReaction ConditionsOperation 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.
  • 17
  • [ 1202376-60-0 ]
  • [ 33689-29-1 ]
  • [ 1202376-48-4 ]
YieldReaction ConditionsOperation 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.
  • 18
  • [ 4774-14-5 ]
  • [ 33689-29-1 ]
  • [ 1346172-80-2 ]
YieldReaction ConditionsOperation 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.
  • 19
  • [ 33689-29-1 ]
  • [ 1346172-81-3 ]
  • 20
  • [ 33689-29-1 ]
  • [ 60703-46-0 ]
  • [ 1572048-45-3 ]
YieldReaction ConditionsOperation 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.
  • 21
  • [ 33689-29-1 ]
  • [ 13939-69-0 ]
  • C11H17NO4 [ No CAS ]
YieldReaction ConditionsOperation 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).
  • 22
  • [ 19009-39-3 ]
  • [ 33689-29-1 ]
  • C12H21NO4 [ No CAS ]
YieldReaction ConditionsOperation 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).
  • 23
  • [ 33689-29-1 ]
  • [ 167415-27-2 ]
  • methyl 1-(5-bromo-4-fluoro-2-nitrophenoxy)cyclopropanecarboxylate [ No CAS ]
YieldReaction ConditionsOperation 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).
  • 24
  • [ 58534-94-4 ]
  • [ 33689-29-1 ]
  • methyl 1-(2-bromo-6-nitrophenoxy)cyclopropanecarboxylate [ No CAS ]
YieldReaction ConditionsOperation 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
  • 25
  • [ 33689-29-1 ]
  • 1-bromo-2-fluoro-5-(methylsulfonyl)-3-nitrobenzene [ No CAS ]
  • methyl 1-[2-bromo-4-(methylsulfonyl)-6-nitrophenoxy]cyclopropanecarboxylate [ No CAS ]
YieldReaction ConditionsOperation 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.
  • 26
  • [ 1446358-48-0 ]
  • [ 33689-29-1 ]
  • C22H17F2N5O4 [ No CAS ]
YieldReaction ConditionsOperation 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).
  • 27
  • [ 33689-29-1 ]
  • methyl 1-((2-bromothiophen-3-yl)methoxy)cyclopropane-1-carboxylate [ No CAS ]
  • 28
  • [ 34846-44-1 ]
  • [ 33689-29-1 ]
  • methyl 1-(thiophen-3-ylmethoxy)cyclopropane-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation 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).
  • 29
  • [ 67443-38-3 ]
  • [ 33689-29-1 ]
  • methyl 1-[(5-bromo-3-nitro-2-pyridyl)oxy]cyclopropanecarboxylate [ No CAS ]
YieldReaction ConditionsOperation 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]+.
  • 30
  • [ 33689-29-1 ]
  • tert-butyl 4-(2-(1-(methoxycarbonyl)cyclopropoxy)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate [ No CAS ]
  • 31
  • [ 33689-29-1 ]
  • [ 89763-93-9 ]
  • methyl 1-(2-formyl-5-(trifluoromethyl)phenoxy)cyclopropane-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation 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).
  • 32
  • [ 33689-29-1 ]
  • tert-butyl 1-(2-(1-(methoxycarbonyl)cyclopropoxy)-4-(trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]decane-8-carboxylate [ No CAS ]
  • 33
  • [ 33689-29-1 ]
  • C7H13NO3*ClH [ No CAS ]
  • 34
  • [ 33689-29-1 ]
  • [ 590-17-0 ]
  • C7H9NO3 [ No CAS ]
YieldReaction ConditionsOperation 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%.
  • 35
  • [ 33689-29-1 ]
  • [ 1190735-35-3 ]
 

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