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Chemical Structure| 22509-74-6 Chemical Structure| 22509-74-6

Structure of N-Carbethoxyphthalimide
CAS No.: 22509-74-6

Chemical Structure| 22509-74-6

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Product Details of [ 22509-74-6 ]

CAS No. :22509-74-6
Formula : C11H9NO4
M.W : 219.19
SMILES Code : O=C(N1C(OCC)=O)C2=CC=CC=C2C1=O
MDL No. :MFCD00005893
InChI Key :VRHAQNTWKSVEEC-UHFFFAOYSA-N
Pubchem ID :31187

Safety of [ 22509-74-6 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302
Precautionary Statements:P280-P305+P351+P338

Computational Chemistry of [ 22509-74-6 ] Show Less

Physicochemical Properties

Num. heavy atoms 16
Num. arom. heavy atoms 6
Fraction Csp3 0.18
Num. rotatable bonds 3
Num. H-bond acceptors 4.0
Num. H-bond donors 0.0
Molar Refractivity 58.01
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

63.68 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.56
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

1.86
Log Po/w (WLOGP)?

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

1.06
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.

1.21
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

1.15
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.37

Water Solubility

Log S (ESOL):?

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

-2.45
Solubility 0.777 mg/ml ; 0.00355 mol/l
Class?

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

Soluble
Log S (Ali)?

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

-2.82
Solubility 0.333 mg/ml ; 0.00152 mol/l
Class?

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

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

-2.55
Solubility 0.616 mg/ml ; 0.00281 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

Yes
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

Yes
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.

-6.32 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

0.0
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

1.0 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)

1.78

Application In Synthesis of [ 22509-74-6 ]

* 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 [ 22509-74-6 ]

[ 22509-74-6 ] Synthesis Path-Downstream   1~20

  • 1
  • [ 22509-74-6 ]
  • [ 6850-65-3 ]
  • [ 104618-31-7 ]
YieldReaction ConditionsOperation in experiment
81% for 0.0833333h;Heating; 4-Amino-cyclohexanol (2.627 g, 22.81 mmol) and 1,3-Dioxo-1,3-dihydro-isoindole-2-carboxylic acid ethyl ester (5 g, 22.81 mmol) were placed in a large test-tube and heated with a heat gun until both had melted and then for an additional 5 minutes. The resulting solution was allowed to cool and a solid formed. This solid was transferred to a flask, taken up in CH2Cl2 and purified via chromatography (75% EtOAc/Hex) to give 4.57 g of 2-(4-Hydroxy-cyclohexyl)-isoindole-1,3-dione (81% yield). LCMS (m/z): M+H+MeCN=287.1.
56.82% With potassium carbonate; In water; at 20℃; for 2h; [00486] To a solution of ethyl 1 ,3-dioxoisoindoline-2-carboxylate (1 .67 g, 7.19 mmol) in water (16 mL) was added 4-aminocyclohexanol (1 .31 g, 8.63 mmol), followed by K2CO3 (1 .59 g, 1 1 .5 mmol). The mixture was stirred at room temperature for 2 h. TLC (PE: EA = 1 :1 ) showed the reaction was complete. The mixture was filtered and the solid was dried under vacuum to give 2-(4- hydroxycyclohexyl)isoindoline-1 ,3-dione (1 g, 56.82%) as a brown solid.
56.82% With potassium carbonate; at 20℃; for 2h; To a solution of ethyl 1,3-dioxoisoindoline-2-carboxylate (1.67 g, 7.19 mmol) in water (16 mL) was added 4-aminocyclohexanol (1.31 g, 8.63 mmol), followed by K2CO3 (1.59 g, 11.5 mmol). The mixture was stirred at room temperature for 2 h. TLC (PE:EA=1:1) showed the reaction was complete. The mixture was filtered and the solid was dried under vacuum to give 2-(4-hydroxycyclohexyl)isoindoline-1,3-dione (1 g, 56.82%) as a brown solid.
  • 2
  • [ 22509-74-6 ]
  • [ 24629-25-2 ]
  • [ 152903-43-0 ]
  • 3
  • [ 22509-74-6 ]
  • [ 1482-98-0 ]
  • Nγ-phthaloyl-L-2,4-diaminobutanoic acid hydrochloride [ No CAS ]
  • 4
  • [ 22509-74-6 ]
  • [ 27489-62-9 ]
  • [ 99337-98-1 ]
YieldReaction ConditionsOperation in experiment
98% With potassium carbonate; In water monomer; at 20℃; for 0.5h; K2CO3 (10.50 g, 75.97 mmol) was added to a solution of 190 (5.00 g, 43.41 mmol) in H2O(50 mL). N-(ethoxycarbonyl)phthalimide (10.24 g, 49.92 mmol) was added under stirring andthe reaction mixture was stirred for 30 min at room temperature. The resulting precipitate wasfiltered off and washed with H2O (50 mL). Removal of the residual solvent in vacuo affordedthe product as a beige solid (4.94 mg, 98%, Rf = 0.2 in EtOAc/PE 1/3), mp: 183-185 C (Lit.5mp: 177-178 C). 1H NMR (400 MHz, DMSO-d6): δ (ppm) 7.85 - 7.80 (m, 4H), 4.64 (d, J =4.3 Hz, 1H), 3.99 - 3.91 (m, 1H), 3.49 - 3.41 (m, 1H), 2.19 - 2.08 (m, 2H), 1.93 - 1.90 (m,2H), 1.69 - 1.66 (m, 2H), 1.32 - 1.21 (m, 2H). 13C NMR (100 MHz, DMSO-d6): δ (ppm) 168.30,134.80, 131.90, 123.40, 68.50, 49.90, 35.10, 27.80. HRMS (ESI-MS): m/z [M+H+] calculatedfor C14H16NO3+: 246.1125, found 246.1126; C14H15NO3 (245.28).
44% With potassium carbonate; In water monomer; at 0 - 20℃; A7 (5759mg, 50mmol) and N-ethoxycarbonylphthalimide (B1, 10960mg, 50mmol) were placed in a reaction flask, 110mL of water was added, the temperature was lowered to 0C, and K2CO3 (13820mg, 100mmol) was added in batches , returned to room temperature, and stirred overnight. Filtration, and the filter cake was washed with water (30 mL×3). The solid obtained by filtration was dissolved in ethanol (190 mL), water (380 mL) was added, the solid was left to stand for 1 h, the solid was precipitated, filtered, and the filter cake was washed with ethanol/water (1:2) mixed solvent (20 mL×3), and dried at room temperature overnight. , and then dried under reduced pressure at 45 C. for 1 h to obtain B2 (white solid, 5371 mg, yield 44%).
With triethylamine; In tetrahydrofuran; for 18h;Heating / reflux; Step 1: trans-2-(4-Hydroxy-cyclohexyl)-isoindole-1,3-dione A mixture of 31 grams of trans-4-aminocyclohexanol, 550 mL of anhydrous THF, 45 mL of triethylamine and 53 g of N-carboethoxy-phthalimide was heated to reflux for 18 h, cooled, and diluted with 1500 mL of ethyl acetate. The solution was washed with 250 mL of 10% HCl, 100 mL of saturated sodium bicarbonate then dried over magnesium sulfate. Concentration under reduced pressure gave 66 g of product as a white crystalline solid contaminated with ethyl carbamate. This material was sufficiently pure for the next step, although it could be recrystallized from boiling ethyl acetate-hexane. 1H NMR (400 MHz, CDCl3) 7.8 (m, 2H), 7.7 (m, 2H), 4.15 (m, 1H), 3.7 (m, 1H), 2.3 (dd, 2H), 2.1 (d, 2H), 1.78 (d, 2H), 1.4 (dd, 2H).
  • 5
  • trans-4-hydroxycyclohexylamine hydrochloride [ No CAS ]
  • [ 22509-74-6 ]
  • [ 104618-31-7 ]
YieldReaction ConditionsOperation in experiment
84% With potassium carbonate; In water; at 20℃; for 1h; 2-(4-Hydroxy-cyclohexyl)-isoindole-1,3-dione; K2CO3 (19.4 g, 140.6 mmol) was added to a solution of trans-4-aminocyclohexanol hydrochloride (9.0 g, 59.35 mmol) in water (150 ml.) followed by N-carbethoxy phthalimide (18.8 g, 85.96 mmol). A white precipitate was formed immediately. Stirring continued at RT for 1 h. The precipitate was filtered off, washed with water and dried to afford 12 g (84 %) of 2-(4-hydroxy-cyclohexyl)-isoindole-1 ,3-dione. 1H-NMR (300 MHz, DMSO-d6) delta 1.18 - 1.40 (m, 3H), 1.60 - 1.76 (m, 2H), 1.80 - 2.00 (m, 2H), 2.04 - 2.23 (dq, 2H), 3.40 - 3.50 (m, 1 H), 3.89 - 4.03 (tt,1 H), 4.6 (br.s, 1 H,), 7.15 - 7.39 (m,1 H), 7.80 (m, 3H). m/z: 246 (M+1 )+
  • 6
  • trans-4-hydroxycyclohexylamine hydrochloride [ No CAS ]
  • [ 22509-74-6 ]
  • [ 99337-98-1 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In water; at 20℃; for 3h; N-Ethoxycarbonylphthalimide (100g; 0.46 mol) was added to a mixture of trans-4- hydroxycyclohexylamine hydrochloride (69g; 0.46 mol), potassium carbonate (158g;1.15mol) and water (11) at room temperature. After stirring for 3h the title compound was isolated by filtration, washing with water then ethyl acetate, 95g.
  • 7
  • [ 22509-74-6 ]
  • [ 50910-54-8 ]
  • [ 99337-98-1 ]
YieldReaction ConditionsOperation in experiment
81% With potassium carbonate; In water; at 20℃; for 1h; 12A: 2-((/ra«^)-4-Hydroxycyclohexyl)isoindoline~l ,3H -dione[00150] A mixture of (irans)-4-aminocyclohexanol, HC1 (5 g, 33.0 mmol) and ethyl l,3-dioxoisoindoline-2-carboxylate (7.23 g, 33.0 mmol) in water (50 mL) was treated with K2C03 (11.39 g, 82 mmol) and stirred at room temperature for 1 h. The mixture became very viscous, more water (50 mL) was added and it was stirred for another 2 h. The white solid was collected by filtration, washed with water, and air- dried to provide 12A (6.52g, 81 % yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.66-7.84(m, 4H); 4.56(br. s, 1H); 3.79-3.93(m, 1H); 3.29-3.45(m, 1H); 1.97-2.14(m, 2H); 1.76- L91(m, 2H); 1.50-1.67(m, 2H); 1.09-1.28(m, 2H).
With potassium carbonate; In water; at 20℃; for 3h; N-Ethoxycarbonylphthalimide (10Og; 0.46 mol) was added to a mixture of trans-4- hydroxycyclohexylamine hydrochloride (69 g; 0.46 mol), potassium carbonate (158 g; 1.15 mol) and water (1 L) at room temperature. After stirring for 3h the title compound (95 g) was isolated by filtration, washing with water then ethyl acetate,.
  • 9
  • [ 22509-74-6 ]
  • [ 770-05-8 ]
  • 4-(2-N-phthaloyl-1-hydroxyethyl)phenol [ No CAS ]
YieldReaction ConditionsOperation in experiment
81% With sodium carbonate; In water; 4-(2-N-Phthaloyl-1-hydroxyethyl)phenol (9) N-(ethoxycarbonyl)phthalimide (1.092 g. 4.98 mmol) was added to a vigorously stirring solution of <strong>[770-05-8]octopamine hydrochloride</strong> 8 (0.727 g, 3.83 mmol) and sodium carbonate (0.811 g, 7.65 mmol) in water (20 ml). The resulting solution was vigorously stirred overnight, during this time the crude white product precipitated. After filtration, the product was washed with water (3*3 ml) giving analytically pure 9 (0.879 g, 81%) as a white solid: mp C.; 1H NMR (270 MHz, DMSOd6) delta9.33 (s, 1H, ArOH), 7.84(m, 4H, Pth), 7.14(d, J=8.4 Hz, 2H Ar-H), 6.69(d, J=8.4 Hz, 2H, Ar-H), 5.47(d, I=4.1 Hz, 1H, ROH), 4.79 (1H, m, ArCH(OH)), 3.65 (2H, m, CH2NPth); 13C NMR (67.5 MHz, DMSO-d6) delta168.6, 157.4, 134.9, 133.3, 132.2, 127.7. 123.4, 115.4, 69.4, 45.8;
  • 10
  • [ 22509-74-6 ]
  • trans-4-hydroxycyclohexylamine hydrochloride [ No CAS ]
  • [ 104618-31-7 ]
YieldReaction ConditionsOperation in experiment
69% With potassium carbonate; In tetrahydrofuran; water; at 20℃; for 72h; Commercially available 4-aminocyclohexanol hydrogen chloride salt (25 g, 164 mmol) was dissolved in water (350 mL). Then potassium carbonate (72 g, 328 mmol) was added, followed by a solution of commercially available N-carbethoxyphthalimide in tetrahydrofurane (300 mL). The reaction mixture was then vigorously stirred at room temperature for 3 days. Tetrahydrofurane was evaporated under reduced pressure and the remaining aqueous phase was extracted with dichloromethane (2×300 mL) until the aqueous phase was clear. The combined organic phase was dried over Na2SO4, filtered and the solvents were evaporated under reduced pressure to afford the title compound as a white solid (28 g, 69%).1H-NMR (400 MHz, CDCl3): delta=1.32-1.43 (m, 2H), 1.70-1.75 (m, 2H), 2.04-2.09 (m, 2H), 2.25-2.38 (m, 2H), 3.67-3.77 (m, 1H), 4.05-4.13 (m, 1H), 7.63-7.7.68 (m, 2H), 7.76-7.7.80 (m, 2H)
3.10 g (76%) With sodium carbonate; In water; ethyl acetate; Step 1 A solution of 4-aminocyclohexanol hydrochloride (2.52 g, 16.6 mmol) in water (20.0 mL) was treated with N-carbethoxyphthalimide (3.82 g, 17.4 mmol) and Na2CO3 (3.77 g, 35.6 mmol). The reaction was stirred at room temperature for 15.6 hours. The reaction was cooled to 0 C. and quenched with 10% HCl, filtered, and washed with water to give a white solid. The solid was dissolved in ethyl acetate washed with water, brine, dried over MgSO4 and concentrated in vacuo to give 3.10 g (76%) of 2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione as a colorless solid: mp 176.9-177.0 C.; 1H NMR (400 MHz, Acetone-d6) delta7.82 4.09, 3.74, 3.62, 2.28, 2.04, 1.76, 1.39; 13C NMR (100 MHz, acetone-d6) delta168.7, 135.1, 133.0, 123.6, 69.5, 50.8, 35.7, 28.3; IR (mull) 3389, 3318, 2953, 2930, 2876, 2861, 1767, 1703, 1463, 1393, 1377, 1088, 1075, 1061, 720 cm-1; HRMS (FAB) calcd for C14H16NO3: 246.1130, found 246.1128; Anal. Calcd for C14H15NO3: C, 68.56; H, 6.16; N, 5.71. Found: C, 68.39; H, 6.21; N, 5.70.
In tetrahydrofuran; water; EXAMPLE 1 3-Amino-6-cyano-1,2,3,4-tetrahydrocarbazole hydrochloride A solution of 4-aminocyclohexanol hydrochloride (6.08 g, 0.04 mole) in water (60 ml) was brought to pH 8 with aqueous sodium bicarbonate solution. N-carbethoxy-phthalimide (8.76 g, 0.04 mole) was added followed by tetrahydrofuran (until homogenous solution was obtained). The clear solution was stirred at room temperature overnight. During this time a white solid was precipitated. The tetrahydrofuran was removed in vacuo and the remaining aqueous solution was extracted with ethyl acetate until the solution was clear. The ethyl acetate extracts were combined, washed with water, dried (MgSO4) and concentrated to give 4-phthalimido cyclohexanol as a white solid (7.1 g).
In tetrahydrofuran; water; Example 1 3-Amino-6-cyano-1,2,3,4-tetrahydrocarbazole hydrochloride A solution of 4-aminocyclohexanol hydrochloride (6.08 g, 0.04 mole) in water (60 ml) was brought to pH 8 with aqueous sodium bicarbonate solution. N-carbethoxy-phthalimide (8.76 g, 0.04 mole) was added followed by tetrahydrofuran (until homogenous solution was obtained). The clear solution was stirred at room temperature overnight. During this time a white solid was precipitated. The tetrahydrofuran was removed in vacuo and the remaining aqueous solution was extracted with ethyl acetate until the solution was clear. The ethyl acetate extracts were combined, washed with water, dried (MgSO4) and concentrated to give 4-phthalimido cyclohexanol as a white solid (7.1 g).

  • 11
  • [ 253168-94-4 ]
  • water(2 mL each) [ No CAS ]
  • [ 22509-74-6 ]
  • 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsutfonyleethyl]isoindoline-1,3-dione [ No CAS ]
  • 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methyl-sulfonylethyl]isoindoline-1,3-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% With hydrogenchloride; sodium bicarbonate; In water; acetonitrile; EXAMPLE 5 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsutfonyleethyl]isoindoline-1,3-dione A mixture of 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (200 mg, 0.73 mmol) and sodium hydrogen carbonate (80 mg, 0.95 mmol) in acetonitrile and water(2 mL each) was stirred under nitrogen at room temperature for 2 minutes. To the resulting solution was added N-ethoxycarbonylphthalimide (170 mg, 0.78 mmol). After 17 hours, the resulting solution was stirred with hydrochloric acid (2 mL, 4 N), and water (30 mL) at room temperature for 30 minutes. The resulting suspension was filtered and the solid was washed with water (2*25 mL), and then dried in a vacuum oven overnight (60 C., <1 torr) to yield 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]isoindoline-1,3dione as a solid (206 mg, 70% yield): mp, 151.0-152.0 C.; 1 H NMR (CDCl3); delta 1.46 (t, J=6.9 Hz, 3H, CH3), 2.84 (s, 3H, CH3), 3.78 (dd, J=4.8, 14.4 Hz, I H, CHH), 3.84 (s, 3H, CH3), 4.10 (q, J=7 Hz, 2H, CH2), 4.54 (dd, J=10.1, 14.4 Hz, 1H, CHH), 5.90 (dd, J=4.8, 1 0.1 Hz, 1H, NCH), 6.83 (d, J=8.5 Hz, 1H, Ar), 7.11-7.15 (m, 2H, Ar), 7.67-7.73 (m, 2H, Ar), 7.80-7.84 (m, 2H, Ar); 13 C NMR (CDCl3) delta 14.63, 41.49, 48.84, 54.82, 55.89, 64.45, 111.43, 112.50, 120.43, 123.51, 129.56, 131.58, 134.17, 148.57, 149.63, 167.80; Anal Calcd for C20 H21 NO6 S: C, 59.54; H, 5.25; N, 3.47. Found: C, 59.66; H, 5.28; N, 3.29.
  • 12
  • [ 38222-83-2 ]
  • [ 89644-52-0 ]
  • [ 19243-04-0 ]
  • [ 22509-74-6 ]
  • 7-acetamido-1-heptyl triflate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With trifluoromethylsulfonic anhydride; In dichloromethane; benzene; A. 7-Acetamido-1-heptyl triflate (35). To a solution of 7-amino-1-heptanol (42.7 mmol) in benzene (100 mL) is added N-carbethoxyphthalimide (10.3 g, 47.0 mmol). The solution is stirred at room temperature for 5 h. The solvent is removed in vacuo to provide an oil, which is purified by flash chromatography. To a solution of 7-acetamido-1-heptanol (22.2 mmol) in dry dichloromethane (50 mL) is added <strong>[38222-83-2]2,6-di-tert-butyl-4-methylpyridine</strong> (4.6 g, 22.2 mmol) and triflic anhydride (3.7 mL, 22.2 mmol) at 0° C. The reaction is stirred at room temperature for 20 min, poured into water, and extracted with dichloromethane. The combined extracts are dried over anhydrous sodium sulfate and concentrated in vacuo and to afford 7-acetamido-1-heptyl triflate (35) which is used without further purification.
  • 13
  • [ 38222-83-2 ]
  • [ 2508-29-4 ]
  • [ 22509-74-6 ]
  • [ 63273-48-3 ]
  • [ 149831-83-4 ]
YieldReaction ConditionsOperation in experiment
With trifluoromethylsulfonic anhydride; In dichloromethane; benzene; A. 5-Phthalimido-1-pentyl triflate (15). To a solution of 5-aminopentanol (42.7 mmol) in benzene (100 mL) is added N-carbethoxyphthalimide (10.3 g, 47.0 mmol). The solution is stirred at room temperature for 5 h. The solvent is removed in vacuo to provide an oil, which is purified by flash chromatography. To a solution of 5-phthalimido-1-pentanol (22.2 mmol) in dry dichloromethane (50 mL) is added <strong>[38222-83-2]2,6-di-tert-butyl-4-methylpyridine</strong> (4.6 g, 22.2 mmol) and triflic anhydride (3.7 mL, 22.2 mmol) at 0° C. The reaction is stirred at room temperature for 20 min, poured into water, and extracted with dichloromethane. The combined extracts are dried over anhydrous sodium sulfate and concentrated in vacuo and to afford 5-phthalimido-1-pentyl triflate (15) which is used without further purification.
  • 14
  • [ 22509-74-6 ]
  • [ 22838-46-6 ]
  • [ 55007-43-7 ]
YieldReaction ConditionsOperation in experiment
280 mg (39.4%) With sodium carbonate; In water; acetonitrile; EXAMPLE 31 To a stirred solution of <strong>[22838-46-6]3-amino-3-phenylpropionic acid methyl ester hydrochloride</strong> (0.50 g, 2.3 mmol) and sodium carbonate (0.25 g, 2.3 mmol) in 10 mL of water was added N-carboethoxyphthalimide (0.51 g, 2.3 mmol) in 7 mL of acetonitrile. The reaction progress was monitored by TLC (ethyl acetate/hexane; 1:2) which showed that the reaction was complete in one hour. The reaction mixture was partially concentrated to remove the acetonitrile. The resulting slurry was filtered and the solid was washed with 20 mL of water. The solid was dried in vacuo (60 C., <1 mm) to afford 280 mg (39.4%) of methyl 3-phthalimido-3-phenylpropionate as a white powder: mp 75-76 C.; 1H NMR (DMSO-d6, 250 MHz) delta 7.26-7.83 (m, 9H), 5.68-5.75 (m, 1H), 3.55 (S, 3H), 3.37-3.66 (m, 2H); 13C NMR (DMSO-d6) delta 170.7, 167.6, 138.6, 134.7, 131.0, 128.6, 127.8, 126.9, 123.3, 51.6, 49.9, 35.3. Anal. Calcd for C18 H15 NO4: C, 69.89; H, 4.89; N, 4.53; Found: C, 69.69; H, 4.83; N, 4.49.
280 mg (39.4%) With sodium carbonate; In water; acetonitrile; EXAMPLE 31 To a stirred solution of <strong>[22838-46-6]3-amino-3-phenylpropionic acid methyl ester hydrochloride</strong> (0.50 g, 2.3 mmol) and sodium carbonate (0.25 g, 2.3 mmol) in 10 mL of water was added N-carboethoxyphthalimide (0.51 g, 2.3 mmol) in 7 mL of acetonitrile. The reaction progress was monitored by TLC (ethyl acetate/hexane; 1:2) which showed that the reaction was complete in one hour. The reaction mixture was partially concentrated to remove the acetonitrile. The resulting slurry was filtered and the solid was washed with 20 mL of water. The solid was dried in vacuo (60 C., <1 mm) to afford 280 mg (39.4%) of methyl 3-phthalimido-3-phenylpropionate as a white powder: mp 75-76 C.; 1H NMR (DMSO-6, 250 MHz) delta7.26-7.83 (m, 9H), 5.68-5.75 (m, 1H), 3.55 (S, 3H), 3.37-3.66 (m, 2H); 13C NMR (DMSO-d6) delta170.7, 167.6, 138.6, 134.7, 131.0, 128.6, 127.8, 126.9, 123.3, 51.6, 49.9, 35.3. Anal. Calcd for C18 H15 NO4: C, 69.89; H, 4.89; N, 4.53; Found: C, 69.69; H, 4.83; N, 4.49.
  • 15
  • [ 22509-74-6 ]
  • [ 119479-32-2 ]
  • [ 110658-33-8 ]
YieldReaction ConditionsOperation in experiment
35% To a solution of Boc-allyl glycine (3 g, 13.95 nimol) and sodium carbonate (1.48 g, 13.95 mniol) in distilled water (21 niL) at O0C was added N- ethoxycarbonylphthalimide (3.07 g, 13.95 mmol). The reaction mixture was stirred vigorously for 10 minutes, then filtered and the filtrate was acidified with 6N HCl to pH- 3. This was then extracted with ethyl acetate several times, and the combined organic layers were dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate to afford the title compound (1.2 g, 35%). MS (ES) for C13H11NO4 (MW=245.23): positive 246 (M+H).
  • 16
  • [ 22509-74-6 ]
  • [ 17983-30-1 ]
  • trans-2-[(3-hydroxycyclohexyl)methyl]-1H-isoindole-1,3(2H)-dione [ No CAS ]
  • cis-2-[(3-hydroxycyclohexyl)methyl]-1H-isoindole-1,3(2H)-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
Under a nitrogen atmosphere, lithium aluminum hydride (92 mg, 2.44 mmol) was added to a solution of 1-cyanocyclohexan-3-one (100 mg, 0.812 mmol) in tetrahydrofuran (2 ml) at room temperature, and the resulting mixture was refluxed. After 5 hours, water, an aqueous sodium hydroxide solution and water were added in that order to the reaction solution, and the resulting mixture was filtered under reduced pressure. Thereafter, 1M-hydrochloric acid-diethyl ether (974 mul, 0.974 mmol) was added to the filtrate. The resulting mixture was concentrated under reduced pressure, and to an aqueous solution (4 ml) of the resulting residue were added potassium carbonate (202 mg, 1.46 mmol), ethoxycarbonylphthalimide (196 mg, 0.893 mmol) and acetonitrile (1 ml) at room temperature. After 21 hours, the reaction solution was poured into water and extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) and purified again by a silica gel column chromatography (eluent: chloroform/ethyl acetate) to obtain cis-2-[(3-hydroxycyclohexyl)methyl]-1Hisoindole-1,3(2H)-dione (83.5 mg, 40%, cis : trans = 12 : 1).
  • 17
  • [ 22509-74-6 ]
  • [ 56239-26-0 ]
  • [ 478832-25-6 ]
YieldReaction ConditionsOperation in experiment
81% With potassium carbonate; In water; at 20℃; EXAMPLE 86[0124] Preparation of 4-((R)-Tetrahydrofuran-3-yloxy)-5-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-N-((ls,4S)-4-methoxycyclohexyl)pyrimidin-2-amineJ.: Preparation of Starting Material 4-Methoxycyclohexanamine HydrochlorideReagents and Conditions: a) K2CO3 H2; b) KHMDS, MeI, and THF; c) NH2NH2, EtOH, then 4M HCI H2N HCIStep 1-1: Preparation of 2-((ls,4s)-4-Hydroxycyclohexyl)isoindoline-l,3-dione (2) [0125] To a stirred solution of cis-4-aminocyclohexanol HCl (107 mg, 0.71 mmol) in H2O(1.7 mL) at room temperature was added K2CO3 (174 mg, 1.25 mmol), followed by N- carboethoxyphthalimide (174 mg, 0.79 mmol). After stirring at room temperature for 30 min, the solid was filtered, washed with H2O, and dried in vacuo to provide the title compound (140 mg, 81percent) as a white solid. 1H NMR (300 MHz, CDCl3) delta 7.82 (m, IH), 7.79 (m, IH), 4.10 (m, IH), 2.64 (m, IH), 1.5-2.0 (set of m, 4H). MS (ESI) m/z: Found: 491 (2M+ + 1), CaIc. 245(M+).
  • 18
  • [ 170564-98-4 ]
  • [ 22509-74-6 ]
  • [ 644961-00-2 ]
YieldReaction ConditionsOperation in experiment
64.6% With sodium carbonate; In tetrahydrofuran; water; at 20℃; for 18h; Ethyl 1,3-dioxoisoindoline-2-carboxylate (17.3 g, 79.1 mmol) (Aldrich) was added to a mixture of <strong>[170564-98-4](R)-3-amino-3-phenylpropan-1-ol</strong> (9.97 g, 65.9 mmol) and sodium carbonate (10.6 g, 98.9 mmol) in a 1:1 mixture of THF-H2O (200 mL). Mixture was stirred at room temperature for 18 hours and then diluted with ethyl acetate. The aqueous phase was extraced with ethyl acetate (2×) and the combined organic phase was washed with water and brine, dried (magnesium sulfate), filtered, and concentrated. The residue was purified by flash chromatography eluting with 0-40% ethyl acetate in hexanes to give ((R)-2-(3-hydroxy-1-phenylpropyl)isoindoline-1,3-dione. (Yield 11.99 g, 64.6%).
  • 19
  • [ 121010-86-4 ]
  • [ 22509-74-6 ]
  • C12H10N2O3 [ No CAS ]
  • 20
  • [ 22509-74-6 ]
  • [ 88319-43-1 ]
  • (R)-2-(1,3-dioxoisoindolin-2-yl)-4,4-dimethylpentanoic acid [ No CAS ]
 

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