2247-88-3|4-Amino-3-fluoropyridine| Ambeed

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Quality Control of [ 2247-88-3 ] Purity: 98% SDS Specification

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Product Details of [ 2247-88-3 ]

CAS No. :	2247-88-3
Formula :	C₅H₅FN₂
M.W :	112.11
SMILES Code :	NC1=C(C=NC=C1)F
MDL No. :	MFCD00234072
InChI Key :	UFIKBUVVVGSMGW-UHFFFAOYSA-N
Pubchem ID :	817122

Safety of [ 2247-88-3 ]

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

Computational Chemistry of [ 2247-88-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	8
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	28.6
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	38.91 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.0
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	0.27
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.23
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.	0.21
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	1.15
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.77

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.26
Solubility	6.16 mg/ml ; 0.0549 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.	-0.65
Solubility	25.2 mg/ml ; 0.225 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	-1.89
Solubility	1.46 mg/ml ; 0.013 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.	-6.79 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)	1.4

Application In Synthesis of [ 2247-88-3 ]

* 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 [ 2247-88-3 ]

[ 2247-88-3 ] Synthesis Path-Downstream 1~35

1
[ 769-54-0 ]
[ 2247-88-3 ]

Yield	Reaction Conditions	Operation in experiment
	With palladium 10% on activated carbon; hydrogen; In methanol; at 25℃; under 760.051 Torr;	Example 4 (0055) Catalytic hydrogenation of 3-fluoro-4-nitropyridine N-oxide (9): 0.1 mg of 3-fluoro-4-aminopyridine N-oxide (9) was dissolved in 4 mL of MeOH in a 50 mL round bottom flask containing a stir bar. While stirring, 3-4 mg of 10percent Pd/C (dry basis) was added and the flask sealed with a rubber septum. The vial was evacuated and backfilled with hydrogen gas from a balloon and the mixture was allowed to react for 10 min. After 10 min, the suspension was passed through a 0.4 m PTFE filter and analyzed by HPLC (conditions C). Reference retention times: 3-fluoro-4-aminopyridine N-oxide (9)=5.80 min, 3-fluoro-4-aminopyridine (10)=7.05 min. Retention time for the product matched within 0.05 min the reference standard. Identity of the product was confirmed by HR-MS (m/z M+ exp.: 112.0416, calc: 112.0437). Product amount was calculated from the area under the curve of the HPLC UV2 trace using a calibration curve.

References: [1]Journal fur praktische Chemie (Leipzig 1954),1988,vol. 330,p. 154 - 158.
[2]Bioorganic and Medicinal Chemistry Letters,1996,vol. 6,p. 333 - 338.
[3]Chemical Communications,2016,vol. 52,p. 7150 - 7152.
[4]Patent: US2017/355648,2017,A1 .Location in patent: Paragraph 0055.

2
[ 96568-05-7 ]
[ 2247-88-3 ]
[ 164151-29-5 ]

References: [1]Journal of Heterocyclic Chemistry,1997,vol. 34,p. 1021 - 1027.

3
[ 2247-88-3 ]
[ 101799-75-1 ]
[ 164151-35-3 ]

References: [1]Journal of Heterocyclic Chemistry,1997,vol. 34,p. 1021 - 1027.

6
[ 695-37-4 ]
[ 2247-88-3 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,1996,vol. 6,p. 333 - 338.

7
FeSO_4.H₂O [ No CAS ]
[ 769-54-0 ]
[ 2247-88-3 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium hydroxide; In water;	EXAMPLE 20 Preparation of 4-Amino-3-fluoropyridine (3-4) 3-Fluoro-4-nitropyridine N-oxide (3-3) (1.0 g, 6.29 mmol) and FeSO4.H2O (15 g, 37.5 mmol) were suspended in water. Approximately 14 mL of NH4OH was added until a dark color persisted. The resulting mixture was heated to 90° C. for 1 hour under a steady stream of nitrogen. The reaction mixture was allowed to cool to ambient temperature. It was then extracted with 20 mL of diethyl ether (4*), dried with anhydrous sodium sulfate, and concentrated in vacuo to yield the title compound 468 mg (66percent) as a brown oil which crystallized upon standing; the product was verified by NMR. 1H NMR (CDCl3): delta 8.18 (d, 1H), 8.03 (d, 1H), 6.65 (t, 1H), 4.3 (br, 2H).

References: [1]Patent: US2003/92679,2003,A1 .

8
[ 849777-11-3 ]
[ 2247-88-3 ]
[ 849777-14-6 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In 1,4-dioxane; at 110℃; for 15h;	Example 10 Synthesis of Compound 45 CI F N\\ Pd (OAc) 2, Binap, Cs2C03, Dioxane HN F F - N CI- N - N CI 45 Preparation of [2-(5-Chloro-2-fluoro-phenyl)-pyrido[2,3-d]pyrimidin-4-yl]-(3-fluoro-pyridin-4- 1-amine : [0110] To A suspension of dioxane (5ml), Pd (OAC) 2 (50MG), BINAP (20MG), 4-AMINO-3- FLUORO-PYRIDINE (42mg) and CS2C03 (200MG) was added the CRUDE imino chloride, 4-CHLORO-2- (5-CHLORO-2-FLUORO-PHENYL)-PYRIDO [2, 3-D] pyrimidine (100 mg, 0. 34mmol) in A sealed tube. The reaction mixture was heated to 110OC for 15H. The reaction mixture was cooled to R. t. and filtered through CELITENo. AND the crude material was purified by silica gel flash column chromatography (95percent to 5percent gradient CH2C12/ETOAC) to afford [2- (5-CHLORO-2-FLUORO-PHENYL)- PYRIDO [2, 3-D] PYRIMIDIN-4-YL]-(3-FLUORO-PYRIDIN-4-YL)-AMINE (27. 3MG).

References: [1]Patent: WO2005/32481,2005,A2 .Location in patent: Page/Page column 41.

9
[ 1015236-21-1 ]
[ 2247-88-3 ]
[ 849777-59-9 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In 1,4-dioxane; at 100℃; for 20h;	Example 11 Synthesis of Compound 46 Preparation of 46 : [0113] To A suspension of dioxane (15ml), Pd (OAC) 2 (LOOM), BINAP (100mg), 4-amino- 3-FLUORO-PYRIDINE (220mg) and CS2C03 (1. 0 G) was added the crude imino chloride, xxx (500 MG) in A sealed tube. The reaction mixture was heated to 100°C for 20 H. The reaction mixture was cooled to R. t. and filtered through CELITE and the crude material was purified by silica gel flash column chromatography (95percent to 5percent gradient CH2CL2/ETOAC) to afford [2- (5-CHLORO-2- FLUORO-PHENYL)-PTERIDIN-4-YL]-(3-FLUORO-PYRIDIN-4-YL)-AMINE (200 MG).

References: [1]Patent: WO2005/32481,2005,A2 .Location in patent: Page/Page column 42.

10
[ 2247-88-3 ]
[ 79-04-9 ]
[ 1111269-71-6 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; at 20℃;	EXAMPLE 29Part A: To a solution of 4-amino-3-fluoro pyridine (560 mg, 5.0 mmol) and Et3N (760 mg, 7.5 mmol) in 20 ml_ of THF, was added chloroacetyl chloride (622 mg, 5.5 mmol). The reaction was stirred at room temperature and monitored by thin layer chromatography. More chloroacetyl chloride was added until 4-amino-3-fluoro pyridine was consumed. It was quenched by adding 20 ml_ of saturated aqueous NaHCpsi3. The mixture was diluted with 150 ml_ of CH2CI2. The organic layer was concentrated and purified by flash chromatography eluting with 35percent EtOAc/CH2CI2 to give 850 mg of the title compound. NMR (400 MHz, CDCI3) delta 8.62 (brs, 1 H), 8.41 (d, 1 H), 8.33 (d, 1 H), 8.26 (t, 1 H), 4.20 (s, 2H).
	With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere;	a)2-Chloro-N-(3-fluoro-pyridin-4-yl)-acetamideA solution of <strong>[2247-88-3]3-fluoro-pyridin-4-ylamine</strong> (0.2 g) in dry dichloromethane (2 mL) under nitrogen at 0° C. was treated with triethylamine (0.28 mL) followed by slow addition of chloroacetyl chloride (0.16 mL).The reaction mixture was allowed to warm up to room temperature.After 2 h, the mixture was partitioned between dichloromethane and water The phases were separated and the aqueous layer was extracted with dichloromethane (*2).The combined organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated to give the crude product which was purified by silica gel chromatography eluting with 0-100percent EtOAc/cyclohexane.The relevant fractions were combined and evaporated to give the title compound (0.11 g) as a pink solid.1H NMR (400 MHz, DMSO-D6): delta 10.55 (s, 1H), 8.56 (d, 1H), 8.35 (d, 1H), 8.16 (dd, 1H), 4.44 (s, 2H).
	With triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;	Example 54: (/?)-l-[(3-Fluoro-pyridin-4-ylcarbamoyl)-methyl]-3-(l-phenyl- cycloheptanecarbonyloxy)-l-azonia-bicyclo[2.2.2]octane chloridea) 2-Chloro-./V-(3-fluoro-pyridin-4-yl)-acetamide <n="107"/> A solution of <strong>[2247-88-3]3-fluoro-pyridin-4-ylamine</strong> (0.2 g) in dry dichloromethane (2 mL) unde nitrogen at O0C was treated with triethylamine (0.28 mL) followed by slow addition o chloroacetyl chloride (0.16 mL). The reaction mixture was allowed to warm up to roo temperature. After 2h, the mixture was partitioned between dichloromethane and wat( The phases were separated and the aqueous layer was extracted with dichloromethane The combined organic layer was washed with brine, dried over sodium sulphate, filtej and concentrated to give the crude product which was purified by silica gel chromatography eluting with 0-100percent EtOAc/cyclohexane. The relevant fractions wei combined and evaporated to give the title compound (0.1 Ig) as a pink solid.1H NMR (400 MHz, DMSO-D6): delta 10.55 (s, IH), 8.56 (d, IH), 8.35 (d, IH), 8.16 (d IH), 4.44 (s, 2H).

References: [1]Patent: WO2009/97233,2009,A1 .Location in patent: Page/Page column 113.
[2]Patent: US2011/172237,2011,A1 .Location in patent: Page/Page column 41.
[3]Patent: WO2009/138707,2009,A1 .Location in patent: Page/Page column 105-106.

11
C₇H₂BrCl₂N₃O*(x)ClH [ No CAS ]
C₇H₂Cl₃N₃O*(x)ClH [ No CAS ]
[ 2247-88-3 ]
[ 1177415-97-2 ]
[ 1177415-98-3 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 20℃;	A 250 mL round bottomed flask was charged with a mixture of 6,8- dichloroimidazo[l,2-b]pyridazine-3-carboxylic acid and 8-bromo-6- chloroimidazo[l,2-b]pyridazine-3-carboxylic acid (1.0 g, 4.31 mmol) ID, 1,2- dichloroethane (33.2 mL), and DMF (0.267 mL, 3.45 mmol). To the resulting white suspension under nitrogen at room temperature was added oxalyl chloride (6.46 mL, 12.93 mmol) solution slowly via syringe, carefully monitoring gas evolution. Following cessation of bubbling, the reaction mixture was fitted with a reflux <n="56"/>condenser and heated to 65 0C for Ih, whereupon it slowly became a light yellow, homogeneous solution. The mixture was cooled to room temperature, toluene was added, and the solution was concentrated in vacuo. (This process was repeated two more times to remove excess oxalyl chloride.) The resulting solid was dried in vacuo. The light yellow solid was then suspended in 1 ,2-dichloroethane (33.2 mL) and charged with <strong>[2247-88-3]3-fluoropyridin-4-amine</strong> (1.160 g, 10.34 mmol) and DIEA (4.52 mL, 25.9 mmol). The resulting light tan suspension stirred overnight at room temperature. The light brown suspension was filtered and washed with copious amounts of dichloromethane, which furnished a mixture of 6,8-dichloro-N-(3-fluoropyridin-4- yl)imidazo[l,2-b]pyridazine-3-carboxamide and 8-bromo-6-chloro-N-(3- fluoropyridin-4-yl)imidazo[l,2-b]pyridazine-3-carboxamide (1.240 g, 84 percent yield) as a tan solid. LC/MS, m/z 325.0 (M+l). HPLC Rt = 2.823 min. LC/MS, m/z 369.8 (M+l). HPLC Rt = 2.946 min. YMC S5 ODS-A column (4.6 x 50 mm). 0percent-100percentB. Solvent B: (90percent MeOH, 10percent H2O, 0.2percent H3PO4). Solvent A: (10percent MeOH, 90percent H2O, 0.2percent H3PO4). Gradient, start percent B = O, final percent B = 100, gradient time 4 min, hold at 100percent 1 min, flow rate 4 mL/min.

References: [1]Patent: WO2009/100375,2009,A1 .Location in patent: Page/Page column 53-54.

12
[ 32315-10-9 ]
[ 1303588-42-2 ]
[ 2247-88-3 ]
[ 1303587-05-4 ]

Yield	Reaction Conditions	Operation in experiment
9%	With triethylamine; In tetrahydrofuran; at 50℃; for 20h;Inert atmosphere;	.To a solution of <strong>[2247-88-3]3-fluoropyridin-4-amine</strong> (38 mg, 0.33 mmo.) and triethylamine (0.3 m L, 2. 1 1 mmol) in THF (5 mL) was added triphosgene (40 mg, 0.1 3 mmol) under a nitrogen atmosphere, and the mixture was stirred at 50 °C for 2 h. Then 2-(3-chlorophenyl)-6,6-dimethyl-6, 7,8,9- tetrahydro-5H-pyrido[2,3-b]azepin-5-one (132; 50 mg, 0. 1 7 mmol) was added and the mixture was stirred at 60 °C for 1 8 h. Saturated sodium bicarbonate solution and EtOAc was added to the reaction mixture, separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and dried ( a^SC^), fi ltered, and concentrated. The residue was purified by preparative thin layer chromatography to gi ve 2-(3-chlorophenyl)-N-(3- fluoropyridin-4-yl)-6,6-dimethy 1-5-0X0-7, 8-dihydro-5H-pyrido[2,3-b]azepine-'9(6H)- carboxamide (Compound 837; 6.3 mg, 9percent) as a white solid. MS (ESI) calcd for C23H20CIFN4O2: 438.13 ; found: 439 [M+H].

References: [1]Patent: WO2011/59839,2011,A1 .Location in patent: Page/Page column 129-130.

13
[ 2247-88-3 ]
[ 1196091-78-7 ]

References: [1]Patent: US2011/172237,2011,A1 .
[2]Patent: WO2009/138707,2009,A1 .

14
[ 671815-99-9 ]
[ 2247-88-3 ]
[ 1318865-32-5 ]

References: [1]Organic and Biomolecular Chemistry,2011,vol. 9,p. 5503 - 5510.

15
C₁₄H₁₇BrClNO₃ [ No CAS ]
[ 2247-88-3 ]
[ 1333400-74-0 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; at 20℃; for 2.5h;	Intermediate 8: {1-[2-Bromo-4-(3-fluoro-pyridine-4-ylcarbamoyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester.To a solution of 3-bromo-4-(1-tert-butoxycarbonylamino-ethyl)-benzoic acid (8352 muiotaetaomicronIota) in dry THF (20 ml) was added Ghosez reagent (2 eq.). The mixture was stirred at RT for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in dry pyridine (20 ml) and 3- fluoro-pyridin-4-ylamine (1.2 eq) was added. The reaction mixture was stirred at RT for 2.5 hours. The pyridine was removed under reduced pressure. The residue was dissolved in 1 N Na2C03 and extracted with EtOAc. The combined organic layers were washed with 1 NaHC03, citric acid and water. The organic layer was dried over MgS04 and the solvent was removed under reduced pressure. The compound was purified by column chromatography (silicagel, DCM/MeOH gradient).

References: [1]Patent: WO2011/107608,2011,A1 .Location in patent: Page/Page column 65.

16
[ 98-88-4 ]
[ 2247-88-3 ]
[ 1315494-51-9 ]

References: [1]Advanced Synthesis and Catalysis,2011,vol. 353,p. 3367 - 3372.
[2]Journal of Organic Chemistry,2019,vol. 84,p. 8006 - 8018.

17
[ 2247-88-3 ]
[ 945127-72-0 ]
N-[(3R,4S)-1-ethyl-3-fluoropiperidin-4-yl]benzamide [ No CAS ]
C₁₄H₁₉FN₂O [ No CAS ]

References: [1]Advanced Synthesis and Catalysis,2011,vol. 353,p. 3367 - 3372.

18
[ 2247-88-3 ]
[ 945127-72-0 ]

References: [1]Advanced Synthesis and Catalysis,2011,vol. 353,p. 3367 - 3372.

19
[ 2247-88-3 ]
[ 945127-72-0 ]
N-[(3R,4S)-1-ethyl-3-fluoropiperidin-4-yl]benzamide [ No CAS ]

References: [1]Advanced Synthesis and Catalysis,2011,vol. 353,p. 3367 - 3372.

20
[ 2247-88-3 ]
(3S,4R)-1-ethyl-3-fluoropiperidin-4-amine dichloride [ No CAS ]

References: [1]Advanced Synthesis and Catalysis,2011,vol. 353,p. 3367 - 3372.
[2]Advanced Synthesis and Catalysis,2011,vol. 353,p. 3367 - 3372.
[3]Advanced Synthesis and Catalysis,2011,vol. 353,p. 3367 - 3372.
[4]Advanced Synthesis and Catalysis,2011,vol. 353,p. 3367 - 3372.

21
[ 2247-88-3 ]
[ 1315494-52-0 ]

References: [1]Advanced Synthesis and Catalysis,2011,vol. 353,p. 3367 - 3372.

22
[ 2247-88-3 ]
[ 1315494-53-1 ]

References: [1]Advanced Synthesis and Catalysis,2011,vol. 353,p. 3367 - 3372.

23
[ 2247-88-3 ]
[ 1315494-54-2 ]

24
[ 117961-93-0 ]
[ 2247-88-3 ]
[ 1366109-59-2 ]

Yield	Reaction Conditions	Operation in experiment
72%	With N-ethyl-N,N-diisopropylamine;dmap; In dichloromethane; at 20℃; for 2h;	Compound 3 (1 mmol) was dissolved in CH2Cl2 and DMAP (6 mg, 0.05 mmol), DIEA (520 mg, 0.7 mL, 4 mmol) and 3-fluoro-4-pyridylamine (224.2 mg, 2 mmol) were added in sequence. The reaction mixture was stirred for 2 h at room temperature. The reaction was quenched with saturated NaHCO3 (20 ml) and extracted with EtOAc. The crude product was purified by ISCO columns. Fractions containing pure product were combined and evaporated. The yellow solid 9 (249 mg, 72percent) was obtained.The boronic acid 5 (23 mg, 0.12 mmol) and 9 (35 mg, 0.1 mmol) was dissolved in 1 mL dimethoxyethane and 1 mL EtOH. The 0.5 ml of 2 M Na2CO3 was added and the mixture was bubbled with Ar for 1 min before add tetrakis(triphenylphosphine)-palladium(0) (Pd(Ph3P)4, 11 mg, 0.01 mmol). The reaction was heated at 110° C. for 30 min under microwave initiator. The reaction mixture was worked-up with EtOAc extraction and product was purified by HPLC and afforded 10 (12.8 mg, 31percent) as white solid. LC-MS: calcd. for C15H10F4N4OSe: 419 (M+1).

References: [1]Patent: US2012/71516,2012,A1 .Location in patent: Page/Page column 60.

25
[ 1111395-08-4 ]
[ 2247-88-3 ]
[ 1111267-55-0 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3544 - 3549.

26
[ 1388892-76-9 ]
[ 2247-88-3 ]
[ 1388892-74-7 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h;Inert atmosphere;	Example 117. 4-[[4-(dimethylamino)cyclohexyl]oxy]-6-ethyl-N-(3-fluoropyridin- 4-yl)thieno[2,3-d]pyrimidine-5-carboxamide (1-192).Mol. Wt.: 349.45 step 1 Mol. Wt.: 443.541-192[00522] To a solution of 4-[[4-(dimethylamino)cyclohexyl]oxy]-6-ethylthieno[2,3- d]pyrimidine-5-carboxylic acid (100 mg, 0.29 mmol, 1.00 equiv) in distilled DMF (5 mL) was added HATU (217 mg, 0.57 mmol, 2.00 equiv), DIEA (1 10.9 mg, 0.86 mmol, 3.00 equiv) and 3- fluoropyridin-4-amine (32 mg, 0.29 mmol, 1.00 equiv) under nitrogen. The resulting solution was stirred for 1 h at room temperature. After evaporation under reduced pressure, the crude product (120 mg) was purified by Prep-HPLC with the following conditions (Waters): Column, SunFire Prep C I 8, 19* 150mm 5um; mobile phase, water with 0.05percent NH4HCO3 and CH3CN (7.0percent CH3CN up to 48.0percent in 10 min); Flow rate, 20 mlJmin; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the corresponding4- [[4-(dimethylamino)cyclohexyl]oxy]-6-ethyl-N-(3-fluoropyridin-4-yl)thieno[2,3-d]pyrirnidine-5- carboxamide (40 mg) as a white solid. MS (ES, m z): 444 [M+H]+. NMR: (400 MHz, CD3OD): 8.55-8.59 (2H, m), 8.50 (1 H, d), 8.40 (1 H, d), 5.19-5.24 (1H, m), 3.07 (2H, q), 2.28 (6H, s), 2.10-2.19 (3H, m), 1.89-1.92 (2H, m), 1.27- 1.43 (5H, m), 1.22- 1.25 (2H, m).

References: [1]Patent: WO2012/97013,2012,A1 .Location in patent: Page/Page column 204.

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References: [1]Inorganic Chemistry,2013,vol. 52,p. 4205 - 4216.

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