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Chemical Structure| 31775-67-4 Chemical Structure| 31775-67-4

Structure of 31775-67-4

Chemical Structure| 31775-67-4

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Product Details of [ 31775-67-4 ]

CAS No. :31775-67-4
Formula : C5H12ClNO
M.W : 137.61
SMILES Code : Cl[H].N[C@@H]1CCC[C@H]1O
MDL No. :MFCD02683551

Safety of [ 31775-67-4 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 31775-67-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 8
Num. arom. heavy atoms 0
Fraction Csp3 1.0
Num. rotatable bonds 0
Num. H-bond acceptors 2.0
Num. H-bond donors 2.0
Molar Refractivity 34.87
TPSA ?

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

46.25 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

0.0
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

0.38
Log Po/w (WLOGP)?

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

0.66
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.

0.21
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

0.14
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.28

Water Solubility

Log S (ESOL):?

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

-0.93
Solubility 16.1 mg/ml ; 0.117 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.

-0.92
Solubility 16.7 mg/ml ; 0.121 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

0.2
Solubility 220.0 mg/ml ; 1.6 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

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.

-6.87 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)

1.79

Application In Synthesis of [ 31775-67-4 ]

* 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 [ 31775-67-4 ]

[ 31775-67-4 ] Synthesis Path-Downstream   1~29

  • 2
  • [ 16936-83-7 ]
  • [ 31775-67-4 ]
  • 3
  • [ 85-44-9 ]
  • [ 31775-67-4 ]
  • cis-N-<1-Hydroxy-cyclopentyl-(2)>-phthalamidsaeure [ No CAS ]
  • 7
  • [ 31775-67-4 ]
  • [ 598-21-0 ]
  • trans-N-bromoacetyl-2-aminocyclopentanol [ No CAS ]
  • 8
  • [ 33092-86-3 ]
  • [ 31775-67-4 ]
  • 9
  • [ 33092-88-5 ]
  • [ 31775-67-4 ]
  • 10
  • (±)-trans-2-azidocyclopentanol [ No CAS ]
  • [ 31775-67-4 ]
YieldReaction ConditionsOperation in experiment
99% To a solution of trans-2-azido-cyclopentanol (1.0 g, 7.87 mmol) in EtOAc, was added 10% Pd/C (0.5 g). The mixture was flushed with Ar, and then stirred on Parr apparatus at 40 psi for 2 h at 23. The mixture was filtered through celite and the celite was washed with EtOAc. The filtrate was acidified with 3 mL of 4N HCl in 1,4-dioxane, and a white solid was precipitated. The mixture was filtered and the solid was collected to give the desired product (0.76 g, 99%). 1H NMR (MeOD-d4): delta 4.09-4.04 (m, 1H), 3.29-3.25 (m, 1H), 2.18 (m, 1H), 2.03 (m, 1H), 1.83-1.80 (m, 2H), 1.65-1.58 (m, 2H)
  • 11
  • [ 1271239-29-2 ]
  • [ 31775-67-4 ]
  • 1-(3-ethoxyacryloyl)-3-(cis-2-hydroxycyclopentyl)urea [ No CAS ]
  • 12
  • [ 24424-99-5 ]
  • [ 31775-67-4 ]
  • trans-N-(2-hydroxycyclopentyl)carbamic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
84% With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 20h; N,N-diisopropylethylamine (1.269 mL, 7.27 mmol) was added to a stirred suspension of 2-aminocyclopentanol hydrochloride (1.00 g, 7.27 mmol) and di-t-butyl dicarbonate (1.687 mL, 7.27 mmol) in dichloromethane (45 mL). After 20 h at room temperature, the clear solution was concentrated. Silica gelchromatography, eluting with 0 to 50% ethyl acetate in hexanes, gave tert-butyl trans- 2-hydroxycyclopentylcarbamate as white solid (1.23 g, 84% yield). XH NMR (400 MHz, chloroform-if) delta ppm 5.00 (1 H, br. s.), 3.99-4.29 (1 H, m), 3.81-3.93 (1 H, m), 3.53 (1 H, td, J=7.81, 5.72 Hz), 1.93-2.06 (1 H, m), 1.80-1.93 (1 H, m), 1.61-1.74 (1 H, m), 1.45-1.61 (2 H, m), 1.34 (9 H, s), 1.23-1.32 (1 H, m).
  • 13
  • [ 541-41-3 ]
  • [ 31775-67-4 ]
  • ethyl (+/-)-trans-(2-hydroxycyclopentyl)carbamate [ No CAS ]
  • 14
  • [ 31775-67-4 ]
  • [ 501-53-1 ]
  • [ 144989-61-7 ]
  • 15
  • [ 31775-67-4 ]
  • [ 2937-50-0 ]
  • allyl (+/-)-trans-(2-hydroxycyclopentyl)carbamate [ No CAS ]
  • 16
  • [ 37859-24-8 ]
  • [ 31775-67-4 ]
  • 2-(4-bromophenyl)-N-((1SR,2SR)-2-hydroxycyclopentyl)acetamide [ No CAS ]
  • 17
  • [ 1609530-95-1 ]
  • [ 31775-67-4 ]
  • C12H16ClN3O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 80℃;Sealed tube; Stepl[00186j To a solution of Intermediate 1 (150 mg, 0.73 mmol) in DMA (0.5 mL) was added <strong>[31775-67-4](±)-<strong>[31775-67-4]trans-2-aminocyclopentanol hydrochloride</strong></strong> (111 mg, 0.80 mmol) and iPr2NEt(0.286 mL, 1.61 mmol), the reaction vessel was sealed and heated to 80 C overnight.The reaction was diluted with ethyl acetate, washed with brine, dried and concentrated to give Intermediate 18 as the crude product (yield not determined). LC retention time 1.28 mm [L]. MS(E) m/z: 270 (MHj.
  • 18
  • [ 1216947-01-1 ]
  • [ 31775-67-4 ]
  • 8-fluoro-N-[(1,2-trans)-2-hydroxycyclopentyl]-4-oxo-1-[4-(1H-pyrazol-1-yl)benzyl]-1,4-dihydroquinoline-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.11 g With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; To a solution (5 mL) of 1-[4-(1H-pyrazol-1-yl)benzyl]-8-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.1 g) prepared by referring to a document (Bioorganic and Medicinal Chemistry Letters, 2010, 20, 1334), (trans)-2-aminocyclopentanol hydrochloride (0.057 g) and triethylamine (0.12 mL) in DMF was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.16 g), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the precipitate was collected by filtration and dried to give the title compound (0.11 g) as a pale-yellow solid. MS (ESI+): [M+H]+ 447.2 1H NMR (300MHz, DMSO-d6) delta 1.38-1.95 (5H, m), 2.02-2.18 (1H, m), 3.88-4.10 (2H, m), 5.86 (2H, d, J = 2.8 Hz), 6.47-6.56 (1H, m), 7.25 (2H, d, J = 8.5 Hz), 7.51 (1H, td, J = 8.0, 4.4 Hz), 7.59-7.69 (1H, m), 7.72 (1H, d, J = 1.7 Hz), 7.79 (2H, d, J = 8.5 Hz), 8.21 (1H, d, J = 7.9 Hz), 8.44 (1H, d, J = 2.5 Hz), 9.02 (1H, s), 9.89 (1H, d, J = 7.2 Hz).
  • 19
  • 1-(4-bromobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (6d) [ No CAS ]
  • [ 31775-67-4 ]
  • 1-(4-bromobenzyl)-N-[(1,2-trans)-2-hydroxycyclopentyl]-4-oxo-1,4-dihydroquinoline-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
1.0 g With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; To a solution of 1-(4-bromobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.83 g) known from a document (Journal of Medicinal Chemistry, 2007, 50, 5471) in DMF (20 mL) were added <strong>[31775-67-4](1,2-trans)-2-aminocyclopentanol hydrochloride</strong> (0.38 g), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.1 g) and triethylamine (0.80 mL), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the precipitate was collected by filtration and dried to give the title compound (1.0 g) as a pale-yellow solid. 1H NMR (300MHz, DMSO-d6) delta 1.37-1.94 (5H, m), 2.00-2.17 (1H, m), 3.88-4.10 (2H, m), 5.77 (2H, s), 5.86 (1H, s), 7.13-7.30 (2H, m), 7.44-7.97 (5H, m), 8.29-8.44 (1H, m), 9.08 (1H, s), 10.03 (1H, d, J = 7.4 Hz).
  • 20
  • 1-(4-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid [ No CAS ]
  • [ 31775-67-4 ]
  • 1-(4-fluorobenzyl)-N-(trans-2-hydroxycyclopentyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
65 mg To a solution of 1-(4-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (Intermediate 20), (110 mg) in DMF (2.1 mL) stirred at rt under nitrogen was added HATU (248 mg) and TEA (0.11 mL). This mixture was left to stir for 15 minutes and then <strong>[31775-67-4]trans-2-aminocyclopentanol hydrochloride</strong> (56.0 mg) was introduced. The reaction was left to stir overnight at room temperature, at which point LC-MS indicated completion. The reaction mixture was transferred to a separating flask and EtOAc and water were added. The phases were separated and the aqueous phase was extracted twice more with ethyl acetate. The organic phases were combined, washed with brine and the solvent was removed in vacuo. The residue was purified by column chromatography (normal phase, 25 g, Biotage SNAP cartridge KP-Sil, 25 mL per min, gradient 0% to 100% EtOAc in hexane, followed by 0-15% MeOH/EtOAc) to give the desired product as a racemic mixture of trans isomers (65 mg). LCMS: m/z 354.57 [M+H]+. 1H NMR (400 MHz, CDCl3) ppm 1.64-1.91 (m, 4H) 1.97-2.15 (m, 1H) 2.17-2.35 (m, 1H) 4.05-4.22 (m, 2H) 5.29 (s, 2H) 6.93-7.22 (m, 5H) 7.59 (d, J=8.3 Hz, 1H) 8.09 (s, 1H) 8.48 (d, J=4.7 Hz, 1H) 9.11 (d, J=3.1 Hz, 1H)
65 mg To a solution of 1-(4-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (Intermediate 20), (110 mg) in DMF (2.1 mL) stirred at rt under nitrogen was added HATU (248 mg) and TEA (0.11 mL). This mixture was left to stir for 15 minutes and then <strong>[31775-67-4]trans-2-aminocyclopentanol hydrochloride</strong> (56.0 mg) was introduced. The reaction was left to stir overnight at room temperature, at which point LC-MS indicated completion. The reaction mixture was transferred to a separating flask and EtOAc and water were added. The phases were separated and the aqueous phase was extracted twice more with ethyl acetate. The organic phases were combined, washed with brine and the solvent was removed in vacuo. The residue was purified by column chromatography (normal phase, 25 g, Biotage SNAP cartridge KP-Sil, 25 mL per min, gradient 0% to 100% EtOAc in hexane, followed by 0-15% MeOH/EtOAc) to give the desired product as a racemic mixture of trans isomers (65 mg). LCMS: m/z 354.57 [M+H]+. 1H NMR (400 MHz, CDCl3) ppm 1.64-1.91 (m, 4H) 1.97-2.15 (m, 1H) 2.17-2.35 (m, 1H) 4.05-4.22 (m, 2H) 5.29 (s, 2H) 6.93-7.22 (m, 5H) 7.59 (d, J=8.3 Hz, 1H) 8.09 (s, 1H) 8.48 (d, J=4.7 Hz, 1H) 9.11 (d, J=3.1 Hz, 1H)
  • 21
  • [ 50-00-0 ]
  • [ 31775-67-4 ]
  • [ 87014-71-9 ]
YieldReaction ConditionsOperation in experiment
874 mg With formic acid; at 100℃; To a precooled solution of formaldehyde (25.5 mL) and formic acid (25.5 mL) was added (±)trans-2-aminocyclopentanol, hydrochloride (1.2 g). The solution was heated to 10000 overnight. After cooling, aq. HCI solution (6 M, 50 mL) was added. The solution was then concentrated to remove the excess formaldehyde and formic acid. The remaining solid wasrecrystalized from EA and ethanol. The residue was treated with aq. NaOH solution, extractedwith ether, dried over K2003 and concentrated to afford (±)trans-2-(dimethylamino)cyclopentanol (874 mg) as a light yellow oil. 1H-NMR (500 MHz, ODd3) 6 ppm4.06 (dd, J= 12.6, 5.5 Hz, 1H), 3.54 (s, 1H), 2.44-2.52 (m, 1H), 2.29 (s, 6H), 1.41-1.98 (m, 6H);MS(ES) m/z 130 (MH).
  • 22
  • methyl 5-bromo-3-chloro-2-hydroxy-4-methylbenzoate [ No CAS ]
  • [ 31775-67-4 ]
  • 5-bromo-3-chloro-2-hydroxy-N-((trans)-2-hydroxycyclopentyl)-4-methylbenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
1.7 g With triethylamine; In methanol; dichloromethane; for 72h;Reflux; A mixture of methyl 5-bromo-3-chloro-2-hydroxy-4- methylbenzoate (2.90 g) , trans-2-aminocyclopentanolhydrochloride (2.84 g) and triethylamine (4.20 g) inmethanol/dichloromethane was stirred with heating under reflux for 3 days. The reaction mixture was concentrated, andpurified by silica gel column chromatography (ethylacetate/petroleum ether) to give the title compound (1.70 g) .1H NMR (400 MHz, CDC13) delta 1.65-1.95 (4H, m) , 2.02-2.10 (1H, m) , 2.25-2.35 (1H, m) , 2.55 (3H, s) , 3.55 (1H, brs), 4.02-4.12 (2H, m) , 6.45 (1H, brs), 7.51 (1H, s) . 1H was not observed.
  • 23
  • 5-bromo-3-fluoro-2-hydroxy-4-methoxybenzoic acid [ No CAS ]
  • [ 31775-67-4 ]
  • 5-bromo-3-fluoro-2-hydroxy-N-(trans-2-hydroxycyclopentyl)-4-methoxybenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
1.9 g With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 29℃; for 16h; A mixture of 5-bromo-3-fluoro-2-hydroxy-4-methoxybenzoic acid (2.90 g) , <strong>[31775-67-4]trans-2-aminocyclopentanol hydrochloride</strong> (2.26 g) , WSC hydrochloride (3.17 g) , HOBt (2.23 g) , triethylamine (4.44 g) and dichloromethane (100 mL) was stirred at 29C for 16 hr. The reaction mixture was diluted with dichloromethane (100 mL) and washed with brine (200 mL) . The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (1.90 g) .XH NMR (400 MHz, CDC13) delta 1.50-1.93 (4H, m) , 2.01-2.13 (1H, m) , 2.20-2.32 (1H, m) , 3.66 (1H, brs) , 3.95-4.18 (5H, m) , 6.40 (1H, brs), 7.37 (1H, s) , 12.25 (1H, brs).
  • 24
  • 6-(4-chlorophenyl)-2-(3-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid [ No CAS ]
  • [ 31775-67-4 ]
  • 6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-(cis-2-hydroxycyclopentyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
32.5 mg With dmap; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20.0℃; for 14.0h; A solution of 75 mg intermediate 17, 60 mg cis-2-amino-cyclopentanol hydrochloride (1 :1 ), 165.5 mg HATU, 0.1 1 mL ethyldiisopropylamine and 1 .3 mg 4-dimethylaminopyridine in 2 mL of DMF was stirred at room temperature for 14 hours. Then the reaction mixture was filtered and subjected to RP-HPLC (Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241 , Labcol Vario 4000, column: XBrigde C18 5mu 150x30mm; eluent B: water + 0.2 Vol-% aqueous ammonia (32%); eluent D: methanol; gradient: 3-7min 69-89% D; flow 50.0 mL/min; UV 254 nm) to yield 32.5 mg 6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-(cis-2-hydroxycyclopentyl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide. 1H NMR (400 MHz, DMSO-d6) delta ppm = 1.45 - 1 .64 (m, 3 H), 1.69 - 1 .88 (m, 2 H), 1.90 - 2.05 (m, 1 H), 3.97 - 4.13 (m, 2 H), 5.03 (d, 1 H), 7.38 (tdd, 1 H), 7.50 - 7.71 (m, 5 H), 7.95 - 8.09 (m, 2 H), 8.66 (s, 1 H), 9.70 (d, 1 H).
  • 25
  • 2-(3-fluorophenyl)-6-(4-methoxyphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid [ No CAS ]
  • [ 31775-67-4 ]
  • 2-(3-fluorophenyl)-N-(trans-2-hydroxycyclopentyl)-6-(4-methoxyphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
20 mg With dmap; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 14h; A solution of 100 mg intermediate 2-(3-fluorophenyl)-6-(4-methoxyphenyl)-3-oxo-2,3- dihydropyridazine-4-carboxylic acid, 74.3 mg trans-aminocyclopentanol hydrochloride (1 :1 ), 201 mg HATU, 0.14 mL ethyldiisopropylamine and 1.6 mg 4-dimethylaminopyridine in 2 mL of DMF was stirred at room temperature for 14 hours. Then the reaction mixture was filtered and subjected to RP-HPLC twice (Instrument: Waters Autopurification MS SingleQuad; Column: Waters XBrigde C18 5mu 100x30mm; eluent A: water + 0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-5.5 min 5-100% B; flow 70 mL/min; temperature: 25 C; DAD scan: 210-400 nm and Instrument: Waters Autopurificationsystem; column: Waters XBrigde C18 5mu 100x30mm; eluent A: water + 0.2 Vol-% aqueous ammonia (32%), eluent B: methanol; gradient: 0.00-0.50 min 32% B (25->70mL/min), 0.51-5.50 min 67-87% B (70mL/min), DAD scan: 210-400 nm) to yield 20 mg 2-(3-fluorophenyl)-N-(trans-2-hydroxycyclopentyl)-6-(4- methoxyphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide. 1H NMR (400 MHz, DMSO-d6) delta ppm = 1 .37 - 1.56 (m, 2 H), 1 .57 - 1 .76 (m, 2 H), 1 .76 - 1.88 (m, 1 H), 2.02 - 2.14 (m, 1 H), 3.82 (s, 3 H), 3.93 (quin, 1 H), 3.97 - 4.06 (m, 1 H), 4.94 (d, 1 H), 7.07 (d, 2 H), 7.37 (td, 1 H), 7.49 - 7.56 (m, 1 H), 7.56 - 7.66 (m, 2 H), 7.91 (d, 2 H), 8.60 (s, 1 H), 9.40 (d, 1 H).
  • 26
  • 1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid [ No CAS ]
  • [ 31775-67-4 ]
  • N-((1S,2S)-2-hydroxycyclopentyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide [ No CAS ]
  • 27
  • [ 31775-67-4 ]
  • [ 6287-38-3 ]
  • (1S,2S)-2-((3,4-dichlorobenzyl)amino)cyclopentan-1-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% A solution of 3,4-dichlorobenzaldehyde (400 mg, 2.29 mmol, 1 eq) in methanol(8 mL) was treated with aminocyclopentanol hydrochloride (473 mg, 3.44 mmol, 1.5 eq) and triethylamine (0.5 cm3, 3.58 mmol,1.5 eq), and the mixture stirred at rt for 3 hr. Sodium triacetoxyborohydride (680 mg, 3.21 mmol, 1.4 eq) was then divided into two portions and added to the solution at half-hour intervals, and the solution was left to stir for 18 hr. The reaction mixture was quenched using NaOH (2M, 30 mL) and extracted with dichloromethane (30 mL). The aqueous layer was further extracted with dichloromethane (2 x 30 mL) and the combined organic layers were dried over magnesium sulfate, concentrated in vacuo and purified by column chromatographyeluting with dichloromethane: methanol (95:5) to yield the product as a pale pink solid (368 mg, 65%).
  • 28
  • 2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine4-carboxylic acid [ No CAS ]
  • [ 31775-67-4 ]
  • N-[(cis)-4-hydroxytetrahydrofuran-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
120 mg With dmap; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20.0℃; for 14.0h; A solution of 153 mg intermediate 2-(i -methyl-i H-pyrazol-4-yl)-3-oxo-6-[4- (trifluoromethoxy)phenyl]-2,3-d ihyd ropyridazine-4-carboxylic acid, 112,3 mg cis-4- aminotetrahydro-3-furanol hydrochloride (1:1), 306 mg HATU, 0.28 mL ethyldiisopropylamine and 4 mg 4-dimethylaminopyridine in 3 mL of DMF was stirred at room temperature for 14 hours. Then the reaction mixture was filtered and subjected to RP-HPLC (Instrument: WatersAutopurification MS SingleQuad; Column: Waters XBrigde Ci8 Sp iOOx3Omm; eluent A: water+ 0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-5.5 mm s-i 00% B; flow 70 mLlmin; temperature: 25C; DAD scan: 210-400 nm) to yield 120 mg N-[(cis)-4- hyd roxytetrahydrofuran-3-yl]-2-(i -methyl-i H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethoxy)phenyl]- 2,3-dihydropyridazine-4-carboxamide.1H NMR (400 MHz, DMSO-d6) 6 [ppm] = 3.48 (t, 1 H), 3.65 (dd, 1 H), 3.93 (s, 3 H), 3.94 - 3.98(m, 1 H), 4.01 (t, 1 H), 4.26 - 4.33 (m, 1 H), 4.34 - 4.44 (m, 1 H), 5.70 (d, 1 H), 7.53 (d, 2 H),8.12 (s, 1 H), 8.17 - 8.23 (m, 2 H), 8.56 (s, 1 H), 8.63 (s, 1 H), 9.90 (d, 1 H).
  • 29
  • 2-amino-5-bromo-3,4-dimethylbenzoic acid [ No CAS ]
  • [ 31775-67-4 ]
  • 2-amino-5-bromo-N-(trans-2-hydroxycyclopentyl)-3,4-dimethylbenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.17 g With triethylamine; HATU; at 10 - 35℃; 2-amino-5-bromo-N-(trans-2-hydroxycyclopentyl)-3,4-dimethylbenzamide A mixture of 2-amino-5-bromo-3,4-dimethylbenzoic acid (0.10 g), <strong>[31775-67-4]trans-2-aminocyclopentanol hydrochloride</strong> (0.06 g), triethylamine (0.10 g) and HATU (0.19 g) in DMF (2.0 mL) was stirred at room temperature overnight. To the reaction mixture was added 5% aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.17 g). Further purification was not performed and the compound was used in the next step. MS: [M+H]+ 327.1, 329.1
 

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