[ CAS No. 153034-80-1 ]

Name: 153034-80-1|2-Fluoro-4-iodo-3-picoline|98%
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Quality Control of [ 153034-80-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 153034-80-1 ]

Product Details of [ 153034-80-1 ]

CAS No. :	153034-80-1	MDL No. :	MFCD03095289
Formula :	C₆H₅FIN	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XWSVFBVCHYQCLO-UHFFFAOYSA-N
M.W :	237.01	Pubchem ID :	11776298
Synonyms :

Calculated chemistry of [ 153034-80-1 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.17
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	41.88
TPSA :	12.89 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.11 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.93
Log Po/w (XLOGP3) :	2.3
Log Po/w (WLOGP) :	2.55
Log Po/w (MLOGP) :	2.18
Log Po/w (SILICOS-IT) :	3.21
Consensus Log Po/w :	2.43

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.25
Solubility :	0.133 mg/ml ; 0.00056 mol/l
Class :	Soluble
Log S (Ali) :	-2.21
Solubility :	1.47 mg/ml ; 0.00619 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.65
Solubility :	0.0533 mg/ml ; 0.000225 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.85

Safety of [ 153034-80-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 153034-80-1 ]

* 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 [ 153034-80-1 ]
Downstream synthetic route of [ 153034-80-1 ]

[ 153034-80-1 ] Synthesis Path-Upstream 1~3

1
[ 113975-22-7 ]
[ 74-88-4 ]
[ 153034-80-1 ]

Yield	Reaction Conditions	Operation in experiment
69%	Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1 h; Inert atmosphere Stage #2: at -78℃; for 0.5 h; Inert atmosphere	2-Fluoro-4-iodo-3-methylpyridine (0412) To a solution of LDA (68 mL, 135 mmol) at −78° C. was added a solution of 2-fluoro-3-iodopyridine (30 g, 135 mmol) in THF (100 mL), and the mixture is stirred for 1 hour at −78° C. under nitrogen. MeI (25 mL, 405 mmol) was then added, and the mixture was stirred for 30 min at −78° C. The mixture was quenched with sat. aq. NaHCO₃solution at −78° C. and then extracted with ether. The combined ether extracts were dried with MgSO₄and concentrated in vacuo. The residue was purified by silica gel column chromatography (Petroleum ether:EtOAc=4:1) to give the title compound as a brown solid (22 g, 69percent). (0413) MS (ES+) C₆H₅FIN requires: 237, found: 238 [M+H]+.
72%	With n-butyllithium; diisopropylamine In tetrahydrofuran	EXAMPLE 4 2-Fluoro-4-iodo-3-methylpyridine (6) To a solution of LDA, freshly prepared from diisopropylamine (0.126 mL, 0.899 mmol) and n-BuLi (0.899 mmol), in THF (2 mL) at -78° C. is cannulated a solution of 2-fluoro-3-iodopyridine (200 mg, 0.897 mmol) in 0.4 mL of THF, and the mixture is stirred for 1 hour at -78° C. under nitrogen. Iodomethane (0.17 mL, 2.73 mmol) is added neat and the mixture is stirred for 30 min. at -78° C. The mixture is quenched with saturated sodium bicarbonate solution at -78° C. and then extracted with ether. Combined ether extracts are dried (MgSO₄) and concentrated in vacuo. The residue is purified by radial plc (silica gel, hexanes) to give 154 mg (72percent) of product as an off-white solid having amp of 90-91 ° C.

Reference： [1] Journal of Organic Chemistry, 1993, vol. 58, # 27, p. 7832 - 7838
[2] Tetrahedron, 2004, vol. 60, # 29, p. 6113 - 6120
[3] Tetrahedron Letters, 1995, vol. 36, # 44, p. 7995 - 7998
[4] Patent: US2017/342078, 2017, A1, . Location in patent: Paragraph 0412; 0413
[5] Patent: US5496952, 1996, A,

2
[ 372-48-5 ]
[ 74-88-4 ]
[ 153034-80-1 ]

Reference： [1] Patent: WO2016/89722, 2016, A1, . Location in patent: Page/Page column 35
[2] Patent: WO2016/95204, 2016, A1, . Location in patent: Page/Page column 60; 61

3
[ 22282-70-8 ]
[ 74-88-4 ]
[ 153034-80-1 ]

Yield	Reaction Conditions	Operation in experiment
17.2 g	Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 1 h; Inert atmosphere Stage #2: at -78℃; for 2 h; Inert atmosphere	n-Butyl lithium (1.6M hexane solution, 53.8 mL) was added to a solution of diisopropylamine (8.71 g) in THF (200 mL) at -10 C. After being stirred at the same temperature under nitrogen atmosphere for 1 hour, a solution of 2-fluoro-3-iodopyridine (18.3 g) in THF (70 mL) was added to the reaction mixture at -78 C. The mixture was stirred at the same temperature under nitrogen atmosphere for 1 hour. A solution of iodomethane (12.8 g) in THF (30 mL) was added to the reaction mixture at -78 C. The mixture was stirred at the same temperature under nitrogen atmosphere for 2 hours. The mixture was quenched with aqueous saturated ammonium chloride solution at 0 C and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was passed through NH-silica and concentrated in vacuo. The residue was purified by a silica gel column chromatography (hexane/ethyl acetate) to give the title compound (17.2 g). ¹H NMR (300 MHz, CDCl₃) delta 2.39 (3H, d, J=1.5 Hz), 7.57-7.63 (1H, m), 7.65-7.70 (1H, m).

Reference： [1] Patent: US2015/119412, 2015, A1, . Location in patent: Paragraph 0495; 0496

[ 153034-80-1 ] Synthesis Path-Downstream 1~68

1
[ 113975-22-7 ]
[ 74-88-4 ]
[ 153034-80-1 ]

Yield	Reaction Conditions	Operation in experiment
69%		2-Fluoro-4-iodo-3-methylpyridine (0412) To a solution of LDA (68 mL, 135 mmol) at -78 C. was added a solution of 2-fluoro-3-iodopyridine (30 g, 135 mmol) in THF (100 mL), and the mixture is stirred for 1 hour at -78 C. under nitrogen. MeI (25 mL, 405 mmol) was then added, and the mixture was stirred for 30 min at -78 C. The mixture was quenched with sat. aq. NaHCO3 solution at -78 C. and then extracted with ether. The combined ether extracts were dried with MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (Petroleum ether:EtOAc=4:1) to give the title compound as a brown solid (22 g, 69%). (0413) MS (ES+) C6H5FIN requires: 237, found: 238 [M+H]+.
154 mg (72%)	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	EXAMPLE 4 2-Fluoro-4-iodo-3-methylpyridine (6) To a solution of LDA, freshly prepared from diisopropylamine (0.126 mL, 0.899 mmol) and n-BuLi (0.899 mmol), in THF (2 mL) at -78 C. is cannulated a solution of 2-fluoro-3-iodopyridine (200 mg, 0.897 mmol) in 0.4 mL of THF, and the mixture is stirred for 1 hour at -78 C. under nitrogen. Iodomethane (0.17 mL, 2.73 mmol) is added neat and the mixture is stirred for 30 min. at -78 C. The mixture is quenched with saturated sodium bicarbonate solution at -78 C. and then extracted with ether. Combined ether extracts are dried (MgSO4) and concentrated in vacuo. The residue is purified by radial plc (silica gel, hexanes) to give 154 mg (72%) of product as an off-white solid having amp of 90-91 C.

Reference： [1]Journal of Organic Chemistry,1993,vol. 58,p. 7832 - 7838
[2]Tetrahedron,2004,vol. 60,p. 6113 - 6120
[3]Tetrahedron Letters,1995,vol. 36,p. 7995 - 7998
[4]Patent: US2017/342078,2017,A1 .Location in patent: Paragraph 0412; 0413
[5]Patent: US5496952,1996,A

2
[ 153034-80-1 ]
2-Oxo-butyric acid (1R,2S)-2-(1-methyl-1-phenyl-ethyl)-cyclohexyl ester [ No CAS ]
[ 171366-22-6 ]

Reference： [1]Tetrahedron Letters,1995,vol. 36,p. 7995 - 7998

3
[ 123-38-6 ]
[ 153034-80-1 ]
[ 185137-48-8 ]

Reference： [1]Journal of Organic Chemistry,1996,vol. 61,p. 9623 - 9624
[2]Synlett,2008,p. 2005 - 2010

4
[ 153034-80-1 ]
methyl (4-iodo-3-methyl-pyridin-2-yloxy)-acetate [ No CAS ]

Reference： [1]Tetrahedron,2004,vol. 60,p. 6113 - 6120

5
[ 153034-80-1 ]
4-(1-tert-butoxycarbonylpyrrolidin-2-oyl)-2-fluoro-3-methyl-pyridine [ No CAS ]

Reference： [1]Tetrahedron,2004,vol. 60,p. 6113 - 6120

6
[ 153034-80-1 ]
[ 744257-71-4 ]

Reference： [1]Tetrahedron,2004,vol. 60,p. 6113 - 6120

7
[ 153034-80-1 ]
[ 55854-89-2 ]

Reference： [1]Journal of Organic Chemistry,1996,vol. 61,p. 9623 - 9624

8
[ 153034-80-1 ]
[ 54352-77-1 ]

Reference： [1]Journal of Organic Chemistry,1996,vol. 61,p. 9623 - 9624

9
[ 153034-80-1 ]
[ 185137-49-9 ]

Reference： [1]Journal of Organic Chemistry,1996,vol. 61,p. 9623 - 9624

10
[ 153034-80-1 ]
[ 185137-50-2 ]

Reference： [1]Journal of Organic Chemistry,1996,vol. 61,p. 9623 - 9624

11
[ 153034-80-1 ]
[ 185138-35-6 ]

Reference： [1]Journal of Organic Chemistry,1996,vol. 61,p. 9623 - 9624

12
[ 153034-80-1 ]
[ 146683-25-2 ]

Reference： [1]Tetrahedron Letters,1995,vol. 36,p. 7995 - 7998

13
[ 153034-80-1 ]
(S)-2-(3-Acetoxymethyl-2-fluoro-pyridin-4-yl)-2-hydroxy-butyric acid [ No CAS ]

Reference： [1]Tetrahedron Letters,1995,vol. 36,p. 7995 - 7998

14
[ 153034-80-1 ]
[ 171366-23-7 ]

Reference： [1]Tetrahedron Letters,1995,vol. 36,p. 7995 - 7998

15
[ 153034-80-1 ]
[ 171366-24-8 ]

Reference： [1]Tetrahedron Letters,1995,vol. 36,p. 7995 - 7998

16
[ 98-03-3 ]
[ 153034-80-1 ]
C₁₁H₁₀FNOS [ No CAS ]

Reference： [1]Synlett,2008,p. 2005 - 2010

17
[ 104-87-0 ]
[ 153034-80-1 ]
C₁₄H₁₄FNO [ No CAS ]

Reference： [1]Synlett,2008,p. 2005 - 2010

18
[ 22282-70-8 ]
methyl halide [ No CAS ]
[ 153034-80-1 ]

Reference： [1]Synlett,2008,p. 2005 - 2010

19
[ 153034-80-1 ]
[ 590-86-3 ]
C₁₁H₁₆FNO [ No CAS ]

Reference： [1]Synlett,2008,p. 2005 - 2010

20
[ 153034-80-1 ]
[ 2043-61-0 ]
C₁₃H₁₈FNO [ No CAS ]

Reference： [1]Synlett,2008,p. 2005 - 2010

21
[ 153034-80-1 ]
[ 375853-82-0 ]
[ 1160872-77-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 2409 - 2412

22
[ 1240912-17-7 ]
[ 153034-80-1 ]
[ 1240911-03-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;copper(l) iodide; (+/-)-trans-N,N'-dimethylcyclohexane-1,2-diamine; In N,N-dimethyl-formamide; at 110℃; for 1h;	5-[4-(lH-Pyrazol-l-yl)phenyl]methyI}-2,5-dihydro- 3H-pyrazolo[453-e]cinnolin-3-one (25 mg, 0.073 mmol), copper(I)iodde (14 mg, 0.073 mmol, 1 equiv), tribasic potassium phosphate (93 rag, 0.44 mmol, 6.0 equiv), (+/-)-£r°r°-N,N'-bismetbyH,2- cyclohexanediamine (31 mg, 3.0 equiv) and <strong>[153034-80-1]2-fluoro-4-iodo-3-picoline</strong> (52 mg, 0.22 mmol, 3.0 equiv) were combined in degassed N,N-dimethylformamide (3 mL) and the mixture was placed into an oil bath preheated to 110 0C for 1 hour. The mixture was cooled to ambient temperature, poured into sodium bicarbonate (25 mL, aqueous saturated) and extracted with ethyl acetate (3 X 50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes : ethyl acetate), providing the titled compound: .H-NuMR (400 MHz, CDCl3) 5 8.32 (IH, d, J = 8.1 Hz), 8.15 (IH, d, J- 5.3 Hz), 7.91 (IH, d, J = 2.5 Hz), 7.72 (2H, d, J= 8.5 Hz), 7.72 (IH5 m), 7.67-7.59 (3H, m), 7.46 (IH, m), 7.43 (2H, d, J = 8.3 Hz), 6.47 (IH, m), 5.89 (2H, s), 2.37 (3H, s) ppm; high resolution mass spectrometry (ES+) m/z 452.1623 [(JVRH)+; calculated for C25H19FN7O: 452.1630].

Reference： [1]Patent: WO2010/96338,2010,A1 .Location in patent: Page/Page column 50

23
[ 153034-80-1 ]
[ 1227571-05-2 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; water; In 1,4-dioxane; at 100℃; for 1h;	To a solution of <strong>[153034-80-1]2-fluoro-4-iodo-3-methylpyridine</strong> (1 .68 g, 7.09 mmol) in 1 ,4- dioxane/water (1 :1 , 5.2 ml_) was added concentrated HCI (5.5 ml_). The resulting clear solution was heated to 100 C. After 1 h, the reaction mixture was allowed to cool to ambient temperature and was stirred overnight, during which time a precipate formed. The mixture was filtered and dried to a constant weight to afford 4-iodo-3- methylpyridin-2(1 H)-one as a yellow solid 1 .47 g.
9.82 g	With hydrogenchloride; water; In 1,2-dimethoxyethane; at 100℃; for 1.5h;	12M Hydrochloric acid (13 mL) was added to a solution of <strong>[153034-80-1]2-fluoro-4-iodo-3-methylpyridine</strong> (12.2 g) in DME (15 mL) at room temperature. The mixture was stirred at 100 C for 1.5 hours with an alkali trap. Water (150 mL) was added to the reaction mixture at room temperature. The mixture was stirred at the same temperature for 2 hours. The precipitate was collected by filtration, washed with water. A suspension of the solid in ethanol (20 mL) was stirred at 80 C for 30 minutes. Diisopropyl ether (150 mL) was added to the mixture. The mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with diisopropyl ether to give the title compound (9.82 g). 1H NMR (300 MHz, DMSO-d6) delta 2.14 (3H, s), 6.55 (1H, d, J=6.9 Hz), 6.96 (1H, dd, J=6.9, 0.7 Hz), 11.68 (1H, brs).

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1662 - 1670
[2]Patent: WO2011/73845,2011,A1 .Location in patent: Page/Page column 108
[3]Patent: US2015/119412,2015,A1 .Location in patent: Paragraph 0497; 0498

24
[ 153034-80-1 ]
[ 1312479-35-8 ]

Reference： [1]Patent: WO2011/73845,2011,A1

25
[ 153034-80-1 ]
[ 1312479-36-9 ]

Reference： [1]Patent: WO2011/73845,2011,A1

26
[ 153034-80-1 ]
[ 1312479-37-0 ]

Reference： [1]Patent: WO2011/73845,2011,A1

27
[ 153034-80-1 ]
[ 1312479-38-1 ]

Reference： [1]Patent: WO2011/73845,2011,A1

28
[ 153034-80-1 ]
[ 1312473-93-0 ]

Reference： [1]Patent: WO2011/73845,2011,A1

29
[ 1068471-18-0 ]
[ 153034-80-1 ]
[ 1334589-84-2 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 6691 - 6703

30
[ 1068471-18-0 ]
[ 153034-80-1 ]
[ 1334589-71-7 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 6691 - 6703

31
[ 153034-80-1 ]
[ 1358778-33-2 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1662 - 1670

32
[ 153034-80-1 ]
[ 1358778-34-3 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1662 - 1670

33
[ 153034-80-1 ]
[ 1358778-36-5 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1662 - 1670

34
[ 153034-80-1 ]
C₂₀H₂₅NO₅S [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1662 - 1670

35
[ 153034-80-1 ]
[ 1358778-35-4 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1662 - 1670

36
[ 5452-37-9 ]
[ 153034-80-1 ]
[ 1430849-04-9 ]

Yield	Reaction Conditions	Operation in experiment
	at 130℃;	Example 61A N-cyclooctyl-4-iodo-3-methylpyridin-2-amine <strong>[153034-80-1]2-Fluoro-4-iodo-3-methylpyridine</strong> (700 mg) in cyclooctanamine (3.8 g) was heated at 130 C. overnight, cooled and diluted with dichloromethane. The resulting mixture was loaded onto a silica gel cartridge, eluting with 0-100% dichloromethane in hexanes to provide the title compound.

Reference： [1]Patent: US2013/96120,2013,A1 .Location in patent: Paragraph 1096

37
[ 5452-37-9 ]
[ 153034-80-1 ]
[ 1430846-87-9 ]

Reference： [1]Patent: US2013/96120,2013,A1

38
[ 770-71-8 ]
[ 153034-80-1 ]
[ 1430846-20-0 ]

Yield	Reaction Conditions	Operation in experiment
		Example 27A 2-(tricyclo[3.3.1.13,7]dec-1-ylmethoxy)-4-iodo-3-methyl-pyridine 1-Hydroxylmethyladamantane (249 mg) was dissolved in tetrahydrofuran (3.5 mL) and NaH (24 mg) was added. After the gas evolution ceased, 2-fluoro-4-iodo-3-methylpyridine (237 mg) in tetrahydrofuran (1.5 mL) was added. The reaction mixture was stirred at room temperature for 0.5 hours, quenched with H2O and extracted with ethyl acetate. The combined organic layers were washed with brine and concentrated. The residue was purified by preparative TLC, eluting with petroleum ether to provide the title compound.

Reference： [1]Patent: US2013/96120,2013,A1 .Location in patent: Paragraph 0972

39
[ 153034-80-1 ]
[ 108-93-0 ]
[ 1430752-98-9 ]

Yield	Reaction Conditions	Operation in experiment
		Example 138A 2-(cyclohexyloxy)-4-iodo-3-methylpyridine Cyclohexanol (0.501 g) in tetrahydrofuran (3.5 mL) was treated with NaH (0.1 g) until gas evolution ceased. <strong>[153034-80-1]2-Fluoro-4-iodo-3-methylpyridine</strong> (0.237 g) in tetrahydrofuran (1.5 mL) was added. The reaction mixture was stirred at room temperature for 0.5 hours and was quenched with ice-water. The resulting mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC, and was eluted with petroleum ether to provide the title compound.

Reference： [1]Patent: US2013/96121,2013,A1 .Location in patent: Paragraph 1688

40
[ 153034-80-1 ]
[ 100-61-8 ]
[ 1430753-06-2 ]

Yield	Reaction Conditions	Operation in experiment
	at 180℃; for 18h;Microwave irradiation;	Example 143A 4-iodo-N,3-dimethyl-N-phenylpyridin-2-amine <strong>[153034-80-1]2-Fluoro-4-iodo-3-methylpyridine</strong> (700 mg) in N-methylaniline (2.5 mL) was heated at 180 C. in a Biotage Initiator microwave reactor for 18 hours. The reaction mixture was loaded onto a silica gel cartridge, and was eluted with 0-100% dichloromethane in hexanes to provide the title compound.

Reference： [1]Patent: US2013/96121,2013,A1 .Location in patent: Paragraph 1704

41
[ 100-60-7 ]
[ 153034-80-1 ]
[ 1430753-63-1 ]

Yield	Reaction Conditions	Operation in experiment
	at 180℃; for 18h;Microwave irradiation;	Example 161A N-cyclohexyl-4-iodo-N,3-dimethylpyridin-2-amine <strong>[153034-80-1]2-Fluoro-4-iodo-3-methylpyridine</strong> (700 mg) in N-methylcyclohexanamine (2.2 ml) was heated at 180 C. in a Biotage Initiator microwave reactor for 18 hours. The reaction mixture was loaded onto a silica gel cartridge, and was eluted with 0-100% dichloromethane in hexanes to provide the title compound.

Reference： [1]Patent: US2013/96121,2013,A1 .Location in patent: Paragraph 1793

42
[ 1222491-34-0 ]
[ 153034-80-1 ]
[ 1607429-22-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In dimethyl sulfoxide; at 40℃;	A solution of [(2R,5R)-5-hydroxy-2-methylpiperidin- l-yl] [2-(2H- 1,2,3 -triazol-2- yl)phenyl]methanone (400 mg, 1.40 mmol) and <strong>[153034-80-1]2-fluoro-4-iodo-3-picoline</strong> (662 mg, 2.79 mmol) in DMSO (14.0 mL) was treated with sodium hydride (58.7 mg, 1.47 mmol) in portions. After addition was complete, the reaction was stirred for 10 mm., then heated at 40 C overnight. Thereaction was incomplete; additional <strong>[153034-80-1]2-fluoro-4-iodo-3-picoline</strong> (205 mg) and sodium hydride (82 mg) were added periodically and heating continued overnight. The reaction was quenched by addition of saturated, aqueous NaHCO3, then diluted with water. The reaction mixture was extracted 2x with EtOAc. The organics were washed with brine, dried over Mg504, filtered, and concentrated. The crude material was purified by silica gel gradient chromatography (0-100%ethyl acetate in hexanes), providing the titled compound as a white foam. LRMS mlz (M+H)504.2 found, 504.3 required.

Reference： [1]Patent: WO2014/66196,2014,A1 .Location in patent: Page/Page column 31; 33

43
[ 153034-80-1 ]
[ 1607428-80-7 ]

Reference： [1]Patent: WO2014/66196,2014,A1

44
[ 153034-80-1 ]
[ 1607429-19-5 ]

Reference： [1]Patent: WO2014/66196,2014,A1

45
[ 153034-80-1 ]
[ 1607429-24-2 ]

Reference： [1]Patent: WO2014/66196,2014,A1

46
[ 153034-80-1 ]
[ 1607429-25-3 ]

Reference： [1]Patent: WO2014/66196,2014,A1

47
[ 153034-80-1 ]
[ 1607428-08-9 ]

Reference： [1]Patent: WO2014/66196,2014,A1

48
[ 1431473-04-9 ]
[ 153034-80-1 ]
[ 1607429-23-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In dimethyl sulfoxide; at 40℃;	A solution of benzyl (2R,5R)-5 -hydroxy-2-methylpiperidine- 1 -carboxylate (5.00g, 20.1 mmol) and <strong>[153034-80-1]2-fluoro-4-iodo-3-methylpyridine</strong> (9.51 g, 40.1 mmol) in DMSO (134 mL) was treated with NaH (0.53 g, 22.1 mmol) in portions. After stirring for 15 mins, the reaction was heated at 40 C overnight. The reaction was quenched by addition of saturated, aqueousNH4C1, then diluted further with water. The mixture was extracted two times with EtOAc. The organics were washed with brine, dried over Mg504, filtered, and concentrated. The crude material was purified by silica gel gradient chromatography (0-25% ethyl acetate in hexanes), providing the titled compound as a colorless oil. ?HNMR(400 MHz, CDC13) 7.51 (d, J= 5.4 Hz, 1 H), 7.27 (br s, 3H), 7.22 (d, J= 5.6 Hz, 1H), 7.14 (br s, 2H), 5.17 (s, 1H), 5.00 (br s, 2H),4.62 (t, J= 5.6 Hz, 1H), 4.38 (d, J= 14.8 Hz, 1H), 3.14 (dd, J= 14.7, 1.8 Hz, 1H), 2.22 (s, 3H),2.11-2.20 (m, 1H), 1.91-1.95 (m, 2H), 1.35-1.38 (m, 1H), 1.23 (d, J= 7.0 Hz, 3H) ppm. LRMS m/z (M+H) 467.2 found, 467.1 required.

Reference： [1]Patent: WO2014/66196,2014,A1 .Location in patent: Page/Page column 33; 34; 35

49
[ 22282-70-8 ]
[ 74-88-4 ]
[ 153034-80-1 ]

Yield	Reaction Conditions	Operation in experiment
17.2 g		n-Butyl lithium (1.6M hexane solution, 53.8 mL) was added to a solution of diisopropylamine (8.71 g) in THF (200 mL) at -10 C. After being stirred at the same temperature under nitrogen atmosphere for 1 hour, a solution of 2-fluoro-3-iodopyridine (18.3 g) in THF (70 mL) was added to the reaction mixture at -78 C. The mixture was stirred at the same temperature under nitrogen atmosphere for 1 hour. A solution of iodomethane (12.8 g) in THF (30 mL) was added to the reaction mixture at -78 C. The mixture was stirred at the same temperature under nitrogen atmosphere for 2 hours. The mixture was quenched with aqueous saturated ammonium chloride solution at 0 C and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was passed through NH-silica and concentrated in vacuo. The residue was purified by a silica gel column chromatography (hexane/ethyl acetate) to give the title compound (17.2 g). 1H NMR (300 MHz, CDCl3) delta 2.39 (3H, d, J=1.5 Hz), 7.57-7.63 (1H, m), 7.65-7.70 (1H, m).

Reference： [1]Patent: US2015/119412,2015,A1 .Location in patent: Paragraph 0495; 0496

50
[ 153034-80-1 ]
tert-butyl 4-(4-iodo-3-methyl-2-oxopyridin-1(2H)-yl)piperidine-1-carboxylate [ No CAS ]