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[ CAS No. 7226-23-5 ] {[proInfo.proName]}

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Cat. No.: {[proInfo.prAm]}
Chemical Structure| 7226-23-5
Chemical Structure| 7226-23-5
Structure of 7226-23-5 * Storage: {[proInfo.prStorage]}

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Quality Control of [ 7226-23-5 ]

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Product Details of [ 7226-23-5 ]

CAS No. :7226-23-5 MDL No. :MFCD00006550
Formula : C6H12N2O Boiling Point : No data available
Linear Structure Formula :OC(NCH3)2(CH2)3 InChI Key :GUVUOGQBMYCBQP-UHFFFAOYSA-N
M.W : 128.17 Pubchem ID :81646
Synonyms :
Chemical Name :1,3-Dimethyltetrahydropyrimidin-2(1H)-one

Calculated chemistry of [ 7226-23-5 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.83
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 0.0
Molar Refractivity : 43.05
TPSA : 23.55 ?2

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.17 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.69
Log Po/w (XLOGP3) : -0.13
Log Po/w (WLOGP) : -0.39
Log Po/w (MLOGP) : 0.41
Log Po/w (SILICOS-IT) : 0.05
Consensus Log Po/w : 0.33

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -0.55
Solubility : 35.9 mg/ml ; 0.28 mol/l
Class : Very soluble
Log S (Ali) : 0.09
Solubility : 157.0 mg/ml ; 1.23 mol/l
Class : Highly soluble
Log S (SILICOS-IT) : -0.29
Solubility : 66.3 mg/ml ; 0.518 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.49

Safety of [ 7226-23-5 ]

Signal Word:Danger Class:
Precautionary Statements:P201-P202-P264-P270-P280-P301+P312+P330-P305+P351+P338+P310-P308+P313-P405-P501 UN#:
Hazard Statements:H302-H318-H361 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 7226-23-5 ]

* 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 [ 7226-23-5 ]

[ 7226-23-5 ] Synthesis Path-Downstream   1~3

  • 1
  • [ 7226-23-5 ]
  • [ 27935-87-1 ]
  • [ 1798-06-7 ]
  • 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% With n-butyllithium; diisopropylamine; In tetrahydrofuran; EXAMPLE 10 3-Cyclopentyl-2-[4-(1H-indol-5-yl)-phenyl]-N-thiazol-2-yl-propionamide A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The yellow reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-iodophenylacetic acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL). The reaction mixture turned dark in color and was allowed to stir at -78 C. for 45 min, at which time, a solution of iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 42 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then quenched with a 10% aqueous hydrochloric acid solution (100 mL). The resulting aqueous layer was extracted with ethyl acetate (3*200 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1*200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a cream solid: mp 121-122 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
70% With n-butyllithium; diisopropylamine; In tetrahydrofuran; EXAMPLE 25 3-Cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-N-pyridin-2-yl-propionamide A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The yellow reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-iodophenylacetic acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL). The reaction mixture turned dark in color and was allowed to stir at -78 C. for 45 min, at which time, a solution of iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 42 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then quenched with a 10% aqueous hydrochloric acid solution (100 mL). The resulting aqueous layer was extracted with ethyl acetate (3*200 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1*200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a cream solid: mp 121-122 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
70% With n-butyllithium; diisopropylamine; In tetrahydrofuran; EXAMPLE 28 3-Cyclopentyl-N-pyridin-2-yl-2-(4-pyridin-3-yl-phenyl)-propionamide A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The yellow reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-iodophenylacetic acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL). The reaction mixture turned dark in color and was allowed to stir at -78 C. for 45 min, at which time, a solution of iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 42 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then quenched with a 10% aqueous hydrochloric acid solution (100 mL). The resulting aqueous layer was extracted with ethyl acetate (3*200 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1*200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a cream solid: mp 121-122 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
70% With n-butyllithium; diisopropylamine; In tetrahydrofuran; EXAMPLE 29 3-Cyclopentyl-N-pyridin-2-yl-2-(4-pyridin-4-yl-phenyl)-propionamide A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The yellow reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-iodophenylacetic acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL). The reaction mixture turned dark in color and was allowed to stir at -78 C. for 45 min, at which time, a solution of iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 42 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then quenched with a 10% aqueous hydrochloric acid solution (100 mL). The resulting aqueous layer was extracted with ethyl acetate (3*200 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1*200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a cream solid: mp 121-122 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
70% With n-butyllithium; diisopropylamine; In tetrahydrofuran; EXAMPLE 35 1-[3-Cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propionyl]-3-methyl Urea A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The yellow reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-iodophenylacetic acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL). The reaction mixture turned dark in color and was allowed to stir at -78 C. for 45 min, at which time, a solution of iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 42 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then quenched with a 10% aqueous hydrochloric acid solution (100 mL). The resulting aqueous layer was extracted with ethyl acetate (3*200 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1*200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a cream solid: mp 121-122 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
70% With n-butyllithium; diisopropylamine; In tetrahydrofuran; EXAMPLE 36 1-[3-Cyclopentyl-2-(4-pyridin-3-yl-phenyl)-propionyl]-3-methyl-urea A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The yellow reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-iodophenylacetic acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL). The reaction mixture turned dark in color and was allowed to stir at -78 C. for 45 min, at which time, a solution of iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 42 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then quenched with a 10% aqueous hydrochloric acid solution (100 mL). The resulting aqueous layer was extracted with ethyl acetate (3*200 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1*200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a cream solid: mp 121-122 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
70% With n-butyllithium; diisopropylamine; In tetrahydrofuran; EXAMPLE 37 1-{3-Cyclopentyl-2-[4-(1H-indol-5-yl)-phenyl]-propionyl}-3-methyl-urea A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The yellow reaction mixture was stiffed at -78 C. for 30 min and then treated dropwise with a solution of 4-iodophenylacetic acid (15.25 g, 5 8.19 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL). The reaction mixture turned dark in color and was allowed to stir at -78 C. for 45 min, at which time, a solution of iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 42 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then quenched with a 10% aqueous hydrochloric acid solution (100 mL). The resulting aqueous layer was extracted with ethyl acetate (3*200 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1*200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a cream solid: mp 121-122 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
70% With n-butyllithium; diisopropylamine; In tetrahydrofuran; EXAMPLE 5 3-Cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The yellow reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-iodophenylacetic acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL). The reaction mixture turned dark in color and was allowed to stir at -78 C. for 45 min, at which time, a solution of iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 42 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then quenched with a 10% aqueous hydrochloric acid solution (100 mL). The resulting aqueous layer was extracted with ethyl acetate (3*200 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1*200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a cream solid: mp 121-122 C.; EL-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
70% With n-butyllithium; diisopropylamine; In tetrahydrofuran; EXAMPLE 8 3-Cyclopentyl-2-(4-pyridin-3-yl-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The yellow reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-iodophenylacetic acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL). The reaction mixture turned dark in color and was allowed to stir at -78 C. for 45 min, at which time, a solution of iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 42 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then quenched with a 10% aqueous hydrochloric acid solution (100 mL). The resulting aqueous layer was extracted with ethyl acetate (3*200 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1*200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a cream solid: mp 121-122 C.; EL-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
70% With n-butyllithium; diisopropylamine; In tetrahydrofuran; EXAMPLE 9 3-Cyclopentyl-2-(4-pyridin-4-yl-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The yellow reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-iodophenylacetic acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL). The reaction mixture turned dark in color and was allowed to stir at -78 C. for 45 min, at which time, a solution of iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 42 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then quenched with a 10% aqueous hydrochloric acid solution (100 mL). The resulting aqueous layer was extracted with ethyl acetate (3*200 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1*200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a cream solid: mp 121-122 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
57.8% With n-butyllithium; diisopropylamine; In tetrahydrofuran; EXAMPLE 1 3-Cyclopentyl-2-(4-ethynyl-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (11.2 mL, 80.13 mmol) in tetrahydrofiran (120 mL) cooled to -78 C. was treated with a 2.5M solution of n-butyllithium in hexanes (32 mL, 80.13 mmol). This solution was stirred at -78 C. for 30 min and then treated with a solution of (4-iodo-phenyl)-acetic acid (9.67 g, 36.9 mmol) in tetrahydrofuran (88 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (29 mL). The reaction mixture was allowed to stir at -78 C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (8.53 g, 40.6 mmol). The reaction mixture was allowed to slowly warm to 25 C. where it was stirred at 25 C. for 18 h. At this time, the reaction mixture was quenched with water (5 mL) and then concentrated in vacuo. The residue was diluted with water (800 mL) and then acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2*800 mL). The combined organic extracts were washed with water (1*600 mL) and a saturated aqueous sodium chloride solution (1*600 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (7.34 g, 57.8%) as a white solid: mp 105-107 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
57.8% With n-butyllithium; diisopropylamine; In tetrahydrofuran; EXAMPLE 10 3-Cyclopentyl-2-(4-pyrimidin-5-ylethynyl-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (11.2 mL, 80.13 mmol) in tetrahydrofuran (120 mL) cooled to -78 C. was treated with a 2.5M solution of n-butyllithium in hexanes (32 mL, 80.13 mmol). This solution was stirred at -78 C. for 30 min and then treated with a solution of (4-iodo-phenyl)-acetic acid (9.67 g, 36.9 mmol) in tetrahydrofuran (88 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (29 mL). The reaction mixture was allowed to stir at -78 C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (8.53 g, 40.6 mmol). The reaction mixture was allowed to slowly warm to 25 C. where it was stirred at 25 C. for 18 h. At this time, the reaction mixture was quenched with water (5 mL) and then concentrated in vacuo. The residue was diluted with water (800 mL) and then acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2*800 mL). The combined organic extracts were washed with water (1*600 mL), a saturated aqueous sodium chloride solution (1*600 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (7.34 g, 57.8%) as a white solid: mp 105-107 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
57.8% With n-butyllithium; diisopropylamine; In tetrahydrofuran; EXAMPLE 3 3-Cyclopentyl-2-[4-(3-methoxy-prop-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide A solution of diisopropylamine (11.2 mL, 80.13 mmol) in tetrahydrofuran (120 mL) cooled to -78 C. was treated with a 2.5M solution of n-butyllithium in hexanes (32 mL, 80.13 mmol). This solution was stirred at -78 C. for 30 min and then treated with a solution of (4-iodo-phenyl)-acetic acid (9.67 g, 36.9 mmol) in tetrahydrofuran (88 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (29 mL). The reaction mixture was allowed to stir at -78 C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (8.53 g, 40.6 mmol). The reaction mixture was allowed to slowly warm to 25 C. where it was stirred at 25 C. for 18 h. At this time, the reaction mixture was quenched with water (5 mL) and then concentrated in vacuo. The residue was diluted with water (800 mL) and then acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2*800 mL). The combined organic extracts were washed with water (1*600 mL) and a saturated aqueous sodium chloride solution (1*600 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (7.34 g, 57.8%) as a white solid: mp 105-107 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
57.8% With n-butyllithium; diisopropylamine; In tetrahydrofuran; EXAMPLE 4 3-Cyclopentyl-2-[4-(3-hydroxy-3-methyl-pent-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide A solution of diisopropylamine (11.2 mL, 80.13 mmol) in tetrahydrofuran (120 mL) cooled to -78 C. was treated with a 2.5M solution of n-butyllithium in hexanes (32 mL, 80.13 mmol). This solution was stirred at -78 C. for 30 min and then treated with a solution of (4-iodo-phenyl)-acetic acid (9.67 g, 36.9 mmol) in tetrahydrofuran (88 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (29 mL). The reaction mixture was allowed to stir at -78 C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (8.53 g, 40.6 mmol). The reaction mixture was allowed to slowly warm to 25 C. where it was stirred at 25 C. for 18 h. At this time, the reaction mixture was quenched with water (5 mL) and then concentrated in vacuo. The residue was diluted with water (800 mL) and was acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2*800 mL). The combined organic extracts were washed with water (1*600 mL) and a saturated aqueous sodium chloride solution (1*600 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (7.34 g, 57.8%) as a white solid: mp 105-107 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
57.8% With n-butyllithium; diisopropylamine; In tetrahydrofuran; EXAMPLE 5 3-Cyclopentyl-2-[4-(4-hydroxy-pent-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide A solution of diisopropylamine (11.2 mL, 80.13 mmol) in tetrahydrofuran (120 mL) cooled to -78 C. was treated with a 2.5M solution of n-butyllithium in hexanes (32 mL, 80.13 mmol). This solution was stirred at -78 C. for 30 min and then treated with a solution of (4-iodo-phenyl)-acetic acid (9.67 g, 36.9 mmol) in tetrahydrofuran (88 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (29 mL). The reaction mixture was allowed to stir at -78 C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (8.53 g, 40.6 mmol). The reaction mixture was allowed to slowly warm to 25 C. where it was stirred at 25 C. for 18 h. At this time, the reaction mixture was quenched with water (5 mL) and then concentrated in vacuo. The residue was diluted with water (800 mL) and was acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2*800 mL). The combined organic extracts were washed with water (1*600 mL) and a saturated aqueous sodium chloride solution (1*600 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (7.34 g, 57.8%) as a white solid: mp 105-107 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
57.8% With n-butyllithium; diisopropylamine; In tetrahydrofuran; EXAMPLE 6 3-Cyclopentyl-2-[4-(3-hydroxy-prop-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide A solution of diisopropylamine (11.2 mL, 80.13 mmol) in tetrahydrofuran (120 mL) cooled to -78 C. was treated with a 2.5M solution of n-butyllithium in hexanes (32 mL, 80.13 mmol). This solution was stirred at -78 C. for 30 min and then treated with a solution of (4-iodo-phenyl)-acetic acid (9.67 g, 36.9 mmol) in tetrahydrofuran (88 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (29 mL). The reaction mixture was allowed to stir at -78 C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (8.53 g, 40.6 mmol). The reaction mixture was allowed to slowly warm to 25 C. where it was stirred at 25 C. for 18 h. At this time, the reaction mixture was quenched with water (5 mL) and then concentrated in vacuo. The residue was diluted with water (800 mL) and then acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2*800 mL). The combined organic extracts were washed with water (1*600 mL) and a saturated aqueous sodium chloride solution (1*600 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (7.34 g, 57.8%) as a white solid: mp 105-107 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
57.8% With n-butyllithium; diisopropylamine; In tetrahydrofuran; EXAMPLE 7 3-Cyclopentyl-2-[4-(3-dimethylamino-prop-1-ynyl)-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (11.2 mL, 80.13 mmol) in tetrahydrofuran (120 mL) cooled to -78 C. was treated with a 2.5M solution of n-butyllithium in hexanes (32 mL, 80.13 mmol). This solution was stirred at -78 C. for 30 min and then treated with a solution of (4-iodo-phenyl)-acetic acid (9.67 g, 36.9 mmol) in tetrahydrofuran (88 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (29 mL). The reaction mixture was allowed to stir at -78 C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (8.53 g, 40.6 mmol). The reaction mixture was allowed to slowly warm to 25 C. where it was stirred at 25 C. for 18 h. At this time, the reaction mixture was quenched with water (5 mL) and then concentrated in vacuo. The residue was diluted with water (800 mL) and then acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2*800 mL). The combined organic extracts were washed with water (1*600 mL) and a saturated aqueous sodium chloride solution (1*600 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (7.34 g, 57.8%) as a white solid: mp 105-107 C.; EI-HRMS In/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
57.8% With n-butyllithium; diisopropylamine; In tetrahydrofuran; EXAMPLE 8 3-Cyclopentyl-2-[4-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide A solution of diisopropylamine (11.2 mL, 80.13 mmol) in tetrahydrofuran (120 mL) cooled to -78 C. was treated with a 2.5M solution of n-butyllithium in hexanes (32 mL, 80.13 mmol). This solution was stirred at -78 C. for 30 min and then treated with a solution of (4-iodo-phenyl)-acetic acid (9.67 g, 36.9 mmol) in tetrahydrofuran (88 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (29 mL). The reaction mixture was allowed to stir at -78 C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (8.53 g, 40.6 mmol). The reaction mixture was allowed to slowly warm to 25 C. where it was stirred at 25 C. for 18 h. At this time, the reaction mixture was quenched with water (5 mL) and then concentrated in vacuo. The residue was diluted with water (800 mL) and then acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2*800 mL). The combined organic extracts were washed with water (1*600 mL) and a saturated aqueous sodium chloride solution (1*600 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (7.34 g, 57.8%) as a white solid: mp 105-107 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
57.8% With n-butyllithium; diisopropylamine; In tetrahydrofuran; EXAMPLE 9 3-Cyclopentyl-2-(4-pyridin-2-ylethynyl-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (11.2 mL, 80.13 mmol) in tetrahydrofuran (120 mL) cooled to -78 C. was treated with a 2.5M solution of n-butyllithium in hexanes (32 mL, 80.13 mmol). This solution was stirred at -78 C. for 30 min and then treated with a solution of (4-iodo-phenyl)-acetic acid (9.67 g, 36.9 mmol) in tetrahydrofuran (88 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (29 mL). The reaction mixture was allowed to stir at -78 C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (8.53 g, 40.6 mmol). The reaction mixture was allowed to slowly warm to 25 C. where it was stirred at 25 C. for 18 h. At this time, the reaction mixture was quenched with water (5 mL) and then concentrated in vacuo. The residue was diluted with water (800 mL) and then acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2*800 mL). The combined organic extracts were washed with water (1*600 mL) and a saturated aqueous sodium chloride solution (1*600 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (7.34 g, 57.8%) as a white solid: mp 105-107 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.

  • 2
  • [ 7226-23-5 ]
  • imidazopyridine [ No CAS ]
  • [ 272-97-9 ]
  • [ 170499-26-0 ]
  • [ 170497-69-5 ]
YieldReaction ConditionsOperation in experiment
With NaH; sodium bromide; In tetrahydrofuran; methanol; Step 3: 1-N,N-Dimethylcarbamoyl-6-(4-fluorophenyl)-3-{4-[(1H-2-methylimidazo[4.5-c]pyrid-1-yl)methyl]benzoyl}indole. To a solution of imidazo[4,5-c]pyridine (407 mg, 3.06 mmol) in THF (15 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2-1H-pyrimidinone (5 mL) was added NaH (110 mg, 4.59 mmol) in a single portion and the resulting solution was stirred for 1 hour at ambient temperature. In a separate flask, NaBr (630 mg, 6.11 mmol) was added to a solution of 6-(4-fluorophenyl)-3-(4-chloromethylbenzoyl)indole-1-carboxylic acid dimethylamide (1.33 g, 3.06 mmol), prepared as in step 2, in THF (15 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2-1H-pyrimidinone (5 mL). The resulting yellow suspension was stirred for 1 hour at ambient temperature, after which the imidazopyridine solution was added dropwise via syringe. The reaction mixture was stirred for 3 hours at ambient temperature and then was partitioned between brine and ethyl acetate. The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed twice with brine, dried over MgSO4, filtered, and concentrated in vacuo. Chromatography on silica gel (2%, then 4% methanol/CH2 Cl2) provided 1-N,N-dimethylcarbamoyl-6-(4-fluorophenyl)-3-{4-[(1H-2-methylimidazo[4.5-c]pyrid-1-yl)methyl]benzoyl}indole. (228 mg). mp 257-259 C. 1 H NMR (DMSO-d6, 300 MHz) delta2.59 (s, 3H), 3.03 (s, 6H), 5.67 (s, 2H), 7.25-7.35 (m, 4H), 7.6-7.7 (m, 2H), 7.7-7.8 (m, 2H), 7.8-7.9 (m, 3H), 8.15 (s, 1H), 8.30 (d, 1H, J=8.4 Hz), 8.3 1 (d, 1H, J=5.7 Hz), 8.87 (s, 1H). MS (DCI/NH3) m/e 532 (M+H)+. Anal calcd for C32 H26 FN5 O2.0.8H2 O: C, 70.39; H, 5.09; N, 12.83. Found: C, 70.38; H, 5.39; N, 12.82.
  • 3
  • [ 7226-23-5 ]
  • [ 101990-45-8 ]
  • [ 141872-21-1 ]
  • Ethyl 2-[N-(6-bromopyridin-3-ylmethyl)-N-propyl]amino}pyridine-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; n-butyllithium; 1,1,1,3,3,3-hexamethyl-disilazane; In tetrahydrofuran; ethyl acetate; Petroleum ether; EXAMPLE VIII Ethyl 2-[N-(6-bromopyridin-3-ylmethyl)-N-propyl]amino}pyridine-3-carboxylate STR29 3.2 ml of a 1.6N solution of n-butyllithium are added at -20 C. to a solution of 0.87 g (5.4 mmol) of hexamethyldisilazane in 5.5 ml of THF. The solution prepared in this way is added dropwise at from -10 C. to 0 C. to a solution of 1.07 g (5.13 mmol) of ethyl 2-propylaminopyridine-3-carboxylate and 1.25 g of 1,3-dimethyltetrahydro-2(1H)-pyrimidinone (DMPU) in 4 ml of THF. After stirring at this temperature for 10 min, 2 g (8 mmol) of <strong>[101990-45-8]2-bromo-5-bromomethylpyridine</strong> dissolved in 12 ml of THF are added slowly dropwise. After removing the cooling bath, the mixture is stirred at 20 C. for 36 h. After that, 2 drops of conc. hydrochloric acid are added, the solvent is removed in vacuo, and the residue is taken up in ethyl acetate, which is then washed three times with water. The organic phase is dried over sodium sulphate and concentrated, and the residue is purified on silica gel using petroleum ether/ethyl acetate (20:1). Yield: 1.14 g (59% of theory) Rf =0.35 (petroleum ether/ethyl acetate=5:1)
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