54453-94-0|Ethyl 6-chloro-2,4-dimethylnicotinate| Ambeed

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Quality Control of [ 54453-94-0 ] Purity: 97% SDS Specification

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Product Details of [ 54453-94-0 ]

CAS No. :	54453-94-0
Formula :	C₁₀H₁₂ClNO₂
M.W :	213.66
SMILES Code :	O=C(OCC)C1=C(C)N=C(Cl)C=C1C
MDL No. :	MFCD22418372
InChI Key :	KSAOHRAUUCSNRU-UHFFFAOYSA-N
Pubchem ID :	71721008

Safety of [ 54453-94-0 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P264-P270-P301+P312-P330

Computational Chemistry of [ 54453-94-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	14
Num. arom. heavy atoms	6
Fraction Csp3	0.4
Num. rotatable bonds	3
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	55.27
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.	2.62
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	2.8
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.53
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.	1.84
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	3.13
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.58

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.05
Solubility	0.191 mg/ml ; 0.000896 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.	-3.28
Solubility	0.112 mg/ml ; 0.000525 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	-3.9
Solubility	0.0267 mg/ml ; 0.000125 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.	-5.62 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)	2.09

Application In Synthesis of [ 54453-94-0 ]

* 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 [ 54453-94-0 ]

[ 54453-94-0 ] Synthesis Path-Downstream 1~35

1
[ 54453-94-0 ]
[ 630082-81-4 ]

Yield	Reaction Conditions	Operation in experiment
88%		To a solution of 6-chloro-2,4-dimethyl-nicotinic acid ethyl ester (0.200 g, 0.930 mmol) in EtOH (1 mL) was added 4N NaOH (1 mL), and the mixture was heated at 90 C. for 1 h. After the mixture was cooled to room temperature EtOH was removed and the aqueous residue was acidified with 4N HCl to afford a white precipitate. The precipitate (0.152 g, 88%) was collected by filtration and dried under vacuum to give 6-chloro-2,4-dimethyl-nicotinic acid as a white solid. 1H NMR (CD3OD) δ 2.37 (s, 3H), 2.51 (s, 3H), 7.23 (s, 1H)

References: [1]Patent: US2005/277668,2005,A1 .Location in patent: Page/Page column 16.
[2]Journal of the Chemical Society,1898,vol. 73,p. 590.
[3]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6950 - 6954.

2
[ 36853-14-2 ]
[ 54453-94-0 ]

Yield	Reaction Conditions	Operation in experiment
89%	With trichlorophosphate; at 110℃; for 4h;	(a) Ethyl 6-chloro-2,4-dimethylnicotinate; POCl3 (2.5 ml, 27 mmol) was added to ethyl 2,4-dimethyl-6-oxo~l,6-dihydropyridine-3- carboxylate [Chem. Pharm. Bull. Japan 1980, 28, 2244] (1.33 g, 6.8 mmol) and the mixture was heated at 110 C for 4 hours. The reaction was cooled and poured into ice and the excess POCl3 was allowed to react. The mixture was then extracted with EtOAc (2 x 100 ml) and the organic phase was washed with water (50 ml) and brine (50 ml). The solution was dried (Mg5O4). concentrated in vacuo and purified through a short plug of silica (10% EtOAc in hexanes) to provide ethyl 6-chloro-2,4-dimethylnicotinate. Yield: 1.30 g (89%). 1H NMR (400 MHz, CDCl3): 6 1.40 (3H, t, J= 7.1 Hz), 2.33 (3H, s), 2.53 (3H, s), 4.42 (2H-, q, J= 7.1 Hz)/7.05 (1H, s). M5 m/z: 214'(M+1).
89%	With trichlorophosphate; at 110℃; for 4h;	(a) Ethyl 6-chloro-2,4-dimethylnicotinate; POCl3 (2.5 ml, 27 mmol) was added to ethyl 2,4-dimethyl-6-oxo~l,6-dihydropyridine-3- carboxylate [Chem. Pharm. Bull. Japan 1980, 28, 2244] (1.33 g, 6.8 mmol) and the mixture was heated at 110 C for 4 hours. The reaction was cooled and poured into ice and the excess POCl3 was allowed to react. The mixture was then extracted with EtOAc (2 x 100 ml) and the organic phase was washed with water (50 ml) and brine (50 ml). The solution was dried (Mg5O4). concentrated in vacuo and purified through a short plug of silica (10% EtOAc in hexanes) to provide ethyl 6-chloro-2,4-dimethylnicotinate. Yield: 1.30 g (89%). 1H NMR (400 MHz, CDCl3): 6 1.40 (3H, t, J= 7.1 Hz), 2.33 (3H, s), 2.53 (3H, s), 4.42 (2H-, q, J= 7.1 Hz)/7.05 (1H, s). M5 m/z: 214'(M+1).

References: [1]Patent: WO2018/149419,2018,A1 .Location in patent: Paragraph 00868; 00869.
[2]Patent: WO2006/73361,2006,A1 .Location in patent: Page/Page column 195.
[3]Patent: WO2006/73361,2006,A1 .Location in patent: Page/Page column 195.
[4]Journal of the Chemical Society,1898,vol. 73,p. 590.

3
ethyl aminocrotonate [ No CAS ]
[ 54453-94-0 ]

References: [1]Journal of the Chemical Society,1897,vol. 71,p. 303.
Chemische Berichte,1887,vol. 20,p. 446.

4
[ 405058-67-5 ]
[ 54453-94-0 ]

Yield	Reaction Conditions	Operation in experiment
44%	With trichlorophosphate; for 2h;Heating / reflux;	A solution of 2,4-dimethyl-1-oxy-nicotinic acid ethyl ester (1.95 g, 10.0 mmol) in POCl3 (8 mL) was heated at reflux for 2 h. After cooled to room temperature the reaction mixture was poured to ice (20 mL) and neutralized with saturated Na2CO3. The aqueous mixture was extracted with CH2Cl2 (4×20 mL), and the combined extract was dried (Na2SO4). After filtration the solvent was removed under vacuum, and the residue was purified by flash column chromatography on silica gel (CH2Cl2) to afford 6-chloro-2,4-dimethyl-nicotinic acid ethyl ester as a pale yellow liquid (0.945 g, 44%). 1H NMR (CDCl3) δ 1.40 (t, 3H, J=7.2 Hz), 2.32 (s, 3H), 2.53 (s, 3H), 4.41 (q, 2H, J=7.2 Hz), 7.05 (s, 1H).

References: [1]Patent: US2005/277668,2005,A1 .Location in patent: Page/Page column 16.
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6950 - 6954.

5
[ 2971-79-1 ]
[ 54453-94-0 ]
[ 898228-92-7 ]

Yield	Reaction Conditions	Operation in experiment
74%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 110℃; for 14h;	(b) Ethyl 6-(4-(methxycarbonyl)piperidin-1-yl)-2,4-dimethylnicotinate; Ethyl 6-chloro-2,4-dimethyhiicotinate (1.04 g. 4.9 mmol), methyl piperidine-4-carboxylate (1.4 g, 9.7 mmol) and DIPEA (2.3 ml, 15 mmol) were combined in DMA (8 ml) and heated at 110 C for 14 hours: The reaction was cooled and partitioned between saturated aqueous NH4Cl (100 ml) and EtOAc (200 ml). The organic phase was washed with additional NH4Cl (2 x 75 ml), water (3 x 75 ml) and brine (50 ml). The organic phase was then dried (Mg5O4), concentrated in vacuo and purified by column chromatography (15% to 20% EtOAc in hexanes) to provide ethyl 6-(4-(methoxycarbonyl)piperidin-1-yl)-2,4-dimethyhiicotinate. Yield: 1.15 g (74%).1H NMR (400 MHz, CDCl3): 6 1.37 (3H, t, J= 7.1 Hz), 1.68-1.78 (2H, m), 1.96-1.99 (2H, m), 2.30 (3H, s), 2.46 (3H, s), 2.52-2.58 (1H, m), 2.93-2.99 (2H, m), 3.70 (3H, s), 4.28-4.36 (4H, m), 6.28 (1H, s). M5 "V2: 321 (M+l).
74%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 110℃; for 14h;	(b) Ethyl 6-(4-(methxycarbonyl)piperidin-1-yl)-2,4-dimethylnicotinate; Ethyl 6-chloro-2,4-dimethyhiicotinate (1.04 g. 4.9 mmol), methyl piperidine-4-carboxylate (1.4 g, 9.7 mmol) and DIPEA (2.3 ml, 15 mmol) were combined in DMA (8 ml) and heated at 110 C for 14 hours: The reaction was cooled and partitioned between saturated aqueous NH4Cl (100 ml) and EtOAc (200 ml). The organic phase was washed with additional NH4Cl (2 x 75 ml), water (3 x 75 ml) and brine (50 ml). The organic phase was then dried (Mg5O4), concentrated in vacuo and purified by column chromatography (15% to 20% EtOAc in hexanes) to provide ethyl 6-(4-(methoxycarbonyl)piperidin-1-yl)-2,4-dimethyhiicotinate. Yield: 1.15 g (74%).1H NMR (400 MHz, CDCl3): 6 1.37 (3H, t, J= 7.1 Hz), 1.68-1.78 (2H, m), 1.96-1.99 (2H, m), 2.30 (3H, s), 2.46 (3H, s), 2.52-2.58 (1H, m), 2.93-2.99 (2H, m), 3.70 (3H, s), 4.28-4.36 (4H, m), 6.28 (1H, s). M5 "V2: 321 (M+l).

References: [1]Patent: WO2006/73361,2006,A1 .Location in patent: Page/Page column 195.
[2]Patent: WO2006/73361,2006,A1 .Location in patent: Page/Page column 195.

6
[ 54453-94-0 ]
[ 5188-07-8 ]
[ 1014703-53-7 ]

Yield	Reaction Conditions	Operation in experiment
	at 50 - 70℃;	step 1 - To a solution of 130a (163 mg, 0.77 mmol, CASRN 54453-94-0) in dioxane or DMF was added NaSMe (excess) and the reaction mixture was stirred at 50-70 C until all starting material was consumed. The reaction mixture was allowed to cool to RT then diluted with aq. NaHC?3 was added, and the resulting mixture was extracted with EtOAc, dried (Na2SO4) and concentrated. The crude product was purified by ISCO eluting with an EtOAc/hexane gradient (5-15% EtOAc over 60 min).

References: [1]Patent: WO2008/34731,2008,A1 .Location in patent: Page/Page column 89.

7
[ 64-17-5 ]
[ 24186-78-5 ]
[ 54453-94-0 ]

Yield	Reaction Conditions	Operation in experiment
74%		A suspension of 2,4-dimethyl-6-oxo-l,6-dihydro-3-pyridinecarboxylic acid (890 mg, 5.32 mmol) in phosphorus oxychloride (8.9 mL, 95.19 mmol), was stirred at 80 C for 6 hrs. The reaction mixture was cooled to r.t. and then the solvent was evaporated. The residue was cooled to 0 C and EtOH (3.5 mL) was added dropwise. The mixture was stirred at r.t. for 30 min, then partitioned between EtOAc and H2O. The organic phase was concentrated in vacuo and the residue was taken up with phosphorus oxychloride (4 mL) and stirred for an additional 18 hrs at 80 C. The mixture was cooled to r.t. and then the solvent was evaporated. The residue was cooled to 0 C and EtOH (3 mL) was added dropwise. The mixture was stirred at r.t. for 1.5 hrs and then partitioned between EtOAc and H2O. The organic phase was concentrated under reduced pressure and the residue was purified by normal phase column chromatography on a 25 g silica gel column using a 0 to 20% gradient of EtOAc in cyclohexane as eluent. The title compound (842 mg, 3.94 mmol, 74% yield) was obtained as a colorless oil. NMR (400 MHz, DMSO-de) d 7.37 (s, 1H), 4.38 (q, J= 7.19 Hz, 2H), 2.43 (s, 3H), 2.30 (s, 3H), 1.33 (t, J= 7.15 Hz, 3H). MS-ESI (m/z) calc’d for C10H13CINO2 [M+H]+: 214.1, 216.1. Found 214.1, 216.1.
		EXAMPLE 30; Tetrahydro-furan-3-carboxylic Acid [(S)-3-[5-(6-ethynyl-2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-(3-fluoro-phenyl)-propyl]-amide (I-52); step 1-; A mixture of 68b (5.0 g, 29.91 mmol) was suspended in POCl3 (50 mL) and stirred at 85 C. degrees over night. The solvent was mostly evaporated. The residue was slowly poured into ice cold EtOH, stirred for 30 min and then partitioned between EtOAc and brine. The layers were separated and the aqueous layer was extracted EtOAc. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified via SiO2 chromatography which afforded 136a sufficiently pure to be used in the next step.
		step 1 - A suspension of 80 (5g, 29.9 mmol) in 50 ml of POCI3 was stirred at 80 C overnight, cooled to RT and carefully evaporated. The residue was cooled to 0 C and EtOH (20 mL) was dropwise. The mixture was stirred at RT for 30 min then partitioned between EtOAc and H2O. The aqueous layer was back extracted with EtOAc. Combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (0 to 10% EtOAc) to afford 82a.

References: [1]Patent: WO2020/191261,2020,A1 .Location in patent: Page/Page column 87.
[2]Patent: US2007/191335,2007,A1 .Location in patent: Page/Page column 45.
[3]Patent: WO2008/34731,2008,A1 .Location in patent: Page/Page column 76.

8
[ 54453-94-0 ]
[ 1014703-03-7 ]

Yield	Reaction Conditions	Operation in experiment
	With chloro-trimethyl-silane; sodium iodide; In propiononitrile; at 60 - 75℃; for 4.5h;	step 2 - A mixture of 82a (1 g, 4.68 mmol), NaI (2.09, 13.94 mmol), TMSCl (0.59 ml, 4.67 mmol) in propionitrile (10 mL) was stirred at 60 C for 1 h and then at 75 C for3.5 h before being cooled to RT and partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was back extracted with EtOAc and the combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by Si?2 chromatography eluting with an EtOAc/hexane gradient (0 to 5% EtOAc) to afford 1.26 g of 6-iodo-2,4-dimethyl-nicotinic acid ethyl ester (coeluting with about 15% of 82a).

References: [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 704 - 708.
[2]Patent: WO2008/34731,2008,A1 .Location in patent: Page/Page column 76-77.

9
[ 64-17-5 ]
[ 1207180-46-8 ]
[ 54453-94-0 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 704 - 708.

10
[ 54453-94-0 ]
[ 81290-20-2 ]
[ 916160-53-7 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 704 - 708.

11
[ 54453-94-0 ]
[ 115-19-5 ]
[ 1056618-27-9 ]

Yield	Reaction Conditions	Operation in experiment
		step 2-; To a solution of 136a (1.0 g, 4.68 mmol) in DME (25 mL) was added water (11 mL), K2CO3 (1.98 g, 18.72 mmol), Cu(I)I (0.036 g, 0.187 mmol), P(Ph)3 (0.098 g, 0.374 mmol) and 10% Pd/C (0.1 g, 93.6 μmol). The mixture stirred at RT for 30 minutes, then 2-methyl-3-butyn-2-ol (1.8 mL, 18.60 mmol) was added and the mixture stirred at 80 C. for 6 h then cooled to RT. The mixture was filtered through CELITE and the filter cake washed with EtOAc. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified via SiO2 chromatography which afforded 136b which was used directly in the following step.

References: [1]Patent: US2007/191335,2007,A1 .Location in patent: Page/Page column 45.

12
[ 37669-78-6 ]
[ 54453-94-0 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6950 - 6954.

13
[ 54453-94-0 ]
[ 871492-83-0 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6950 - 6954.

14
[ 54453-94-0 ]
6-Chloro-N-((R)-3-{4-[(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6950 - 6954.

15
[ 54453-94-0 ]
6-chloro-N-((R)-3-{4-[(6-cyano-pyridin-2-ylmethyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6950 - 6954.

16
[ 54453-94-0 ]
[7-tert-butyl-5-(4-chloro-3-fluorophenyl)furo[3,2-b]pyridin-2-yl]-(2,2-dimethylpiperazin-1-yl)methanone dihydrochloride [ No CAS ]
6-[4-[7-tert-butyl-5-(4-chloro-3-fluorophenyl)furo[3,2-b]pyridine-2-carbonyl]-3,3-dimethylpiperazin-1-yl]-2,4-dimethylpyridine-3-carboxylic acid [ No CAS ]

References: [1]Patent: WO2018/57588,2018,A1 .

17
[ 54453-94-0 ]
[7-tert-butyl-5-(4-chloro-3-fluorophenyl)furo[3,2-b]pyridin-2-yl]-(2,2-dimethylpiperazin-1-yl)methanone dihydrochloride [ No CAS ]
ethyl 6-[4-[7-tert-butyl-5-(4-chloro-3-fluorophenyl)furo[3,2-b]pyridine-2-carbonyl]-3,3-dimethyl-piperazin-1-yl]-2,4-dimethylpyridine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
197.7 mg	With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 125℃; for 48h;	To a solution of [7-tert-butyl-5-(4-chloro-3-fluoro-phenyl)furo[3,2-b]pyridin-2-yl]-(2,2- dimethylpiperazin- 1-yl)methanone (Dihydrochloride salt) (Intermediate D) (350 mg, 0.677mmol) in NMP (5 mL) are added ethyl 6-chloro-2,4-dimethyl-pyridine-3-carboxylate (187 mg, 0.875 mmol) and cesium carbonate (792 mg, 2.43 mmol), and the mixture is heated at 125C for two days. The reaction mixture is combined with that of a previous batch (200 mg scale). The mixture is diluted with water and extracted three times with EtOAc and the combined organic extracts are washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by flash chromatography to afford the title compound as a yellow foam (197.7 mg). ethyl 6-[4-[7-tert-butyl-5-(4-chloro-3- fluorophenyl)furo[3,2-b]pyridine-2-carbonyl]-3,3-dimethyl-piperazin-1-yl]-2,4-dimethyl-pyridine-3-carboxylate 1H NMR (400 MHz, DMSO-d6) 6 8.19 (d, J = 11.0 Hz, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.85 (s, 1H), 7.73 (t, J = 8.1 Hz, 1H), 7.56 (s, 1H), 6.39 (s, 1H), 4.28 (q, J = 7.1 Hz, 2H), 4.09 (t, J =5.6 Hz, 2H), 3.94 (s, 2H), 3.65 (t, J = 5.5 Hz, 2H), 2.37 (s, 3H), 2.26 (s, 3H), 1.56 (s, 9H), 1.53 (s, 6H),1.30 (t, J = 7.1 Hz, 3H). ESI-MS m/z calc. 620.2566, found 621.54 (M+1)+; Retention time: 1.35 minutes using Method J.

References: [1]Patent: WO2018/57588,2018,A1 .Location in patent: Paragraph 0311.

18
[ 54453-94-0 ]
5-chloro-2-(tributylstannyl)pyridine [ No CAS ]
ethyl 6-(5-chloro-2-pyridyl)-2,4-dimethylpyridine-3-carboxylate [ No CAS ]

References: [1]Patent: WO2018/149419,2018,A1 .Location in patent: Paragraph 00877.

19
[ 41867-20-3 ]
[ 54453-94-0 ]

References: [1]Patent: WO2018/149419,2018,A1 .

20
[ 54453-94-0 ]
[ 918144-18-0 ]

References: [1]Patent: WO2006/138350,2006,A2 .

21
[ 54453-94-0 ]
[ 916160-53-7 ]

References: [1]Patent: WO2008/34731,2008,A1 .

22
[ 54453-94-0 ]
[ 1014703-54-8 ]

References: [1]Patent: WO2008/34731,2008,A1 .

23
[ 54453-94-0 ]
[ 280566-37-2 ]

References: [1]Patent: WO2008/34731,2008,A1 .

24
[ 54453-94-0 ]
[ 1014703-57-1 ]

References: [1]Patent: WO2008/34731,2008,A1 .

25
[ 54453-94-0 ]
[ 1014703-55-9 ]

References: [1]Patent: WO2008/34731,2008,A1 .

26
[ 101251-72-3 ]
[ 54453-94-0 ]

References: [1]Patent: WO2020/191261,2020,A1 .
[2]Patent: WO2020/191261,2020,A1 .
[3]Patent: WO2020/191261,2020,A1 .

27
[ 24186-78-5 ]
[ 64-17-5 ]
[ 54453-94-0 ]

Yield	Reaction Conditions	Operation in experiment
42.73%		A suspension of 6-hydroxy-2,4-dimethylnicotinic acid (1.3 g, 7.78 mmol, 1 eq) in Phosphorus(V) oxychloride (13.09 mL, 139.99 mmol, 18 eq) was stirred at 100 C overnight. Then the mixture was cooled to room temperature and evaporated to dryness. The residue was cooled to 0 C and EtOH (7 mL) was added dropwise. The mixture was stirred at r.t. for 1.5 hrs, then partitioned between EtOAc and H2O. The organic phase was concentrated in vacuo and the residue was purified by normal phase chromatography on a 50 g silica gel column, using as eluent a gradient of EtOAc in cyclohexane, from 0 to 20% to afford the title compound (710 mg, 3.323 mmol, 42.73% yield) as a colorless oil. NMR (400MHz, CDCh) d 7.06 (s, 1H), 4.44 (q, J= 7.1 Hz, 2H), 2.55 (s, 3H), 2.34 (s, 3H), 1.42 (t, J= 7.2 Hz, 3H). MS-ESI (m/z) calc’d for C10H13CINO2 [M+H]+: 214.1. Found 214.2.

References: [1]Patent: WO2020/191261,2020,A1 .Location in patent: Page/Page column 147.

28
[ 54453-94-0 ]
N-(3-(2-fluorophenyl)-1H-indazol-5-yl)-5,7-dimethyl-[1,2,3]triazolo[1,5-a]pyridine-6-carboxamide [ No CAS ]