4-Chloro-2-methoxynicotinaldehyde

Cat.NO.:A241753 Purity:98%

Product Details of [ 1008451-58-8 ]

CAS No. :	1008451-58-8
Formula :	C₇H₆ClNO₂
M.W :	171.58
SMILES Code :	O=CC1=C(OC)N=CC=C1Cl
MDL No. :	MFCD13188720
InChI Key :	FURZPPOFSODEOQ-UHFFFAOYSA-N
Pubchem ID :	53407928

Safety of [ 1008451-58-8 ]

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

Computational Chemistry of [ 1008451-58-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.14
Num. rotatable bonds	2
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	41.13
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	39.19 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.55
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.25
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.56
Log P_o/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.	0.52
Log P_o/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	2.12
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.4

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.96
Solubility	1.87 mg/ml ; 0.0109 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.	-1.67
Solubility	3.66 mg/ml ; 0.0213 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	-2.71
Solubility	0.333 mg/ml ; 0.00194 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.	-6.46 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	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)	1.62

Application In Synthesis of [ 1008451-58-8 ]

* 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.

Upstream synthesis route of [ 1008451-58-8 ]
Downstream synthetic route of [ 1008451-58-8 ]

[ 1008451-58-8 ] Synthesis Path-Upstream 1~2

1
[ 72141-44-7 ]
[ 68-12-2 ]
[ 1008451-58-8 ]

Yield	Reaction Conditions	Operation in experiment
60%	Stage #1: With lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; for 1 h; Stage #2: at -78℃; for 1 h;	To a solution of LDA (1.0 M solution in hexane) (29.3 mL, 29.3 mmol) in THF (45 mL) was added a solution of 4-chloro-2-methoxypyridine (3.5 g, 24.38 mmol) in THF (8 mL) dropwise at -78 °C. The reaction mixture turned into light yellow solution and was stirred at-78 °C for 1 h, then DMF (3.78 mL, 48.8 mmol) was added dropwise. The reaction mixture was stirred at -78 °C for lh. The reaction mixture was quenched with saturated NH₄C1 solution at -78 °C and the resulting mixture was stirred for 10 min and warmed up to rt. The resulting mixture was mixed with saturated NaHC0₃ solution and ethyl acetate. The organic layer was separated and washed with saturated NaHC0₃ solution, dried over MgS0₄. The filtrate was concentrated in vacuo. The residue was dissolved in DCM, purified via silica gel flash column chromatography, eluting with 0-25percent ethyl acetate in hexane to give Intermediate 24A (white solid, 2.6 g, 15.15 mmol, 60percent yield). LC-MS Anal. Calc’d for CvHeClNC 171.01, found [M+H] 172.1. T_r = 0.71 min (Method A). NMR (499MHz, chloroform-d) δ 10.47 (s, 1H), 8.20 (d, J=5.5 Hz, 1H), 7.01 (d, J=5.5 Hz, 1H), 4.08 (s, 3H)

References:

[1] Patent: WO2018/209049, 2018, A1, . Location in patent: Paragraph 00233.

2
[ 64-17-5 ]
[ 140-29-4 ]
[ 1008451-58-8 ]

References:

[1] Patent: WO2012/11081, 2012, A1, . Location in patent: Page/Page column 27.

[ 1008451-58-8 ] Synthesis Path-Downstream 1~27

1
[ 1008451-58-8 ]
[ 1008451-63-5 ]
[ 1008451-65-7 ]

Yield	Reaction Conditions	Operation in experiment
97%	With acetic acid; In methanol; at 20℃; for 48h;	Aldehyde (508 mg, 2.96 mmol, 1.0 eq.) was added to a heterogeneous mixture of the diaminophthalimide (840 mg, 2.96 mmol, 1.0 eq.) in MeOH/AcOH (3/1 ; 40 mL) and stirred at ambient temperature for 48 h. The reaction mixture was concentrated in vacuo to a residual solid and purified by flash chromatography (Rf=O.30; 20% EtOAc/DCM) to isolate fractions corresponding to the desired product (1.25 g, 97%, 84% pure). 1H NMR (CDCl3) 10.90 (br s, 1H), 8.18 (d, J=5.5 Hz, 1H), 7.15 (d, J=5.5Hz, 1H), 4.15 (t, J=6.7 Hz, 2H), 3.65 (t, J=6.7Hz, 2H). ESMS (m/z)

References: [1]Patent: WO2009/117097,2009,A1 .Location in patent: Page/Page column 107-108.

2
[ 1008451-58-8 ]
C₁₆H₂₂N₄O₂ [ No CAS ]
C₂₃H₂₄ClN₅O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 0 – 50℃;	A solution of the aldehyde ( 189 mg, 1.1 mmol, 1.0 eq.) in MeOH ( 10 mL) was added drop wise to a 0-5 C solution of the lactam (0.31 g, 1.1 mmol; from step1) in MeOH (10 mL) and stirred at room temperature for 14 h and at 50 C for Id. The reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo to a residue and purified by flash chromatography [10% (5% aq. NH4OH/MeOH)/DCM;Rf=O.40) to isolate fractions corresponding to the desired product. The isolated product was used as such in the next step.

References: [1]Patent: WO2009/117097,2009,A1 .Location in patent: Page/Page column 109-110.

3
[ 64-17-5 ]
[ 140-29-4 ]
[ 1008451-58-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydroxylamine hydrochloride; triethylamine; for 3.5h;Reflux;	2.1 Synthesis of N-hydroxy-2-phenylacetamidinePlaced successively in 60 mL of ethanol are 4.60 mL of phenylacetonitrile (39.85 mmol, 1 eq.), 3.46 g of hydroxylamine hydrochloride (49.82 mmol, 1 .25 eq.) and 8.33 mL of triethylamine (59.78 mmol, 1.5 eq.). The medium is brought to reflux for3.5 h and evaporated. The residue is taken up in dichloromethane and washed with water. The organic phase is dried over sodium sulfate, filtered and evaporated. The residue is chromatographed on silica gel, eluting with a 1/1 ethyl acetate/heptane mixture. 2.9 g of N-hydroxy-2-phenylacetamidine are obtained.

References: [1]Patent: WO2012/11081,2012,A1 .Location in patent: Page/Page column 27.

4
[ 1008451-58-8 ]
[ 76-02-8 ]
[ 1823-00-3 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In toluene; at 4 – 85℃; for 2.5h;	2.2 Synthesis of 3-benzyl-5-trichloromethyiri .2.41oxadiazole0.41 mL of trichloroacetyl chloride (3.66 mmol, 1.1 eq.) are added to a solution, cooled to 4C, of 0.5 g of <strong>[1008451-58-8]N-hydroxy-2-phenylacetamidine</strong> (3.33 mmol, 1 eq.) and of 1 mL of pyridine (12.36 mmol, 3.7 eq.) in 4 mL of toluene. The medium is brought to 85C for 2.5 h, evaporated and taken up in diethyl ether. The organic phase is washed with water, dried over sodium sulfate, filtered and evaporated to give 0.83 g of 3-benzyl-5-trichloromethyl[1.2.4]oxadiazole. 2.3 Synthesis of 3-benzyiri .2.41oxadiazol-5-ylamine0.83 g of 3-benzyl-5-trichloromethyl[1 .2.4]oxadiazole (3 mmol, 1 eq.) are placed in 6 mL of methanol and 6 mL of a 7 N aqueous solution of ammonia (42 mmol, 14 eq.) are added. After 3 days, the medium is evaporated and the residue is chromatographed on silica gel, eluting with a gradient of ethyl acetate in heptane that varies from 25% to 50%. 0.270 g of 3-benzyl[1 .2.4]oxadiazol-5-ylamine is obtained.

References: [1]Patent: WO2012/11081,2012,A1 .Location in patent: Page/Page column 27.

5
[ 1008451-58-8 ]
[ 1604803-28-2 ]
[ 1604803-33-9 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrabutyl ammonium fluoride; In tetrahydrofuran; at 25℃; for 0.5h;	A solution of (3-nitro-4-trimethylsilanylmethyl-phenyl)-carbamic acid tert-butyl ester (1.00 g, 3.08 mmol) and <strong>[1008451-58-8]4-chloro-2-methoxynicotinaldehyde</strong> (529 mg, 3.08 mmol) in THF (10 mL) was added tetra-butylammonium fluoride (121 mg, 462 muiotaetaomicron) at 25C, the color of the solution changed to dark blue after the addition. The reaction mixture was stirred at 25C for 30 min. The solution of crude {4-[2-(4-chloro-2-methoxy- pyridin-3-yl)-2-hydroxy-ethyl]-3-nitro-phenyl}-carbamic acid tert-butyl ester (crude 1.30 g, 3.08 mmol) was used directly for next step.

References: [1]Patent: WO2014/60328,2014,A1 .Location in patent: Page/Page column 15.

6
[ 1008451-58-8 ]
tert-butyl 4-(5,6-diamino-1,3-dioxoisoindolin-2-yl)piperidine-1-carboxylate [ No CAS ]
tert-butyl 4-(2-(4-chloro-2-methoxypyridin-3-yl)-5,7-dioxoimidazo[4,5-f]isoindol-6(1H,5H,7H)-yl)piperidine-1-carboxylate [ No CAS ]

References: [1]Journal of Heterocyclic Chemistry,2016,vol. 53,p. 1430 – 1438.

7
[ 1008451-58-8 ]
[ 271-73-8 ]
2-methoxy-4-(1H-pyrazolo[3,4-b]pyridin-1-yl)nicotinaldehyde [ No CAS ]

References: [1]Journal of Organic Chemistry,2017,vol. 82,p. 7420 – 7427.

8
[ 271-63-6 ]
[ 1008451-58-8 ]
2-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinaldehyde [ No CAS ]

References: [1]Journal of Organic Chemistry,2017,vol. 82,p. 7420 – 7427.

9
[ 1008451-58-8 ]
C₁₆H₂₂N₄O₂ [ No CAS ]
C₂₂H₂₂ClN₅O₃*(x)ClH [ No CAS ]

References: [1]Patent: WO2009/117097,2009,A1 .

10
[ 1008451-58-8 ]
[ 73874-95-0 ]
tert-butyl N-[1-(3-formyl-2-methoxypyridin-4-yl)piperidin-4-yl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 100℃; for 0.666667h;	A mixture of <strong>[1008451-58-8]4-chloro-3-formyl-2-methoxypyridine</strong> (0.43 g, 2.51 mmol), 4- Boc-aminopiperidine (0.7 g, 3.5 mmol), and DIEA (1.0 mL, 2.5 eq.) in ACN (14 mL) was stirred at 100 C for 40 min. After removal of the volatile solvent, the residue was purified by column chromatography to afford the title compound (0.84 g, 100%). MS (M+H)+: 336.5.

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