[ CAS No. 58584-86-4 ] {[proInfo.proName]}

Name: 58584-86-4|Ethyl 2,6-dichloronicotinate|95%
Brand: Ambeed
SKU: A417787
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Quality Control of [ 58584-86-4 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 58584-86-4 ]

SDS Specification

Alternatived Products of [ 58584-86-4 ]

Product Details of [ 58584-86-4 ]

CAS No. :	58584-86-4	MDL No. :	MFCD09757510
Formula :	C₈H₇Cl₂NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KKYBVLDQTWQETN-UHFFFAOYSA-N
M.W :	220.05	Pubchem ID :	12263987
Synonyms :

Calculated chemistry of [ 58584-86-4 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.25
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	50.34
TPSA :	39.19 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) :	-5.52 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.35
Log Po/w (XLOGP3) :	2.99
Log Po/w (WLOGP) :	2.57
Log Po/w (MLOGP) :	1.82
Log Po/w (SILICOS-IT) :	2.82
Consensus Log Po/w :	2.51

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.23
Solubility :	0.129 mg/ml ; 0.000587 mol/l
Class :	Soluble
Log S (Ali) :	-3.48
Solubility :	0.0734 mg/ml ; 0.000333 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.75
Solubility :	0.0395 mg/ml ; 0.000179 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.92

Safety of [ 58584-86-4 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 58584-86-4 ]

* 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.

Upstream synthesis route of [ 58584-86-4 ]
Downstream synthetic route of [ 58584-86-4 ]

[ 58584-86-4 ] Synthesis Path-Upstream 1~10

1
[ 125850-02-4 ]
[ 623-47-2 ]
[ 1604-14-4 ]
[ 58584-86-4 ]

Reference： [1] Synthesis, 1991, # 9, p. 765 - 768
[2] Synthesis, 1991, # 9, p. 765 - 768

2
[ 87486-37-1 ]
[ 623-47-2 ]
[ 1604-14-4 ]
[ 58584-86-4 ]
[ 130879-42-4 ]
[ 130879-41-3 ]

Reference： [1] Tetrahedron, 1990, vol. 46, # 16, p. 5715 - 5732
[2] Tetrahedron, 1990, vol. 46, # 16, p. 5715 - 5732

3
[ 38496-18-3 ]
[ 64-17-5 ]
[ 58584-86-4 ]

Yield	Reaction Conditions	Operation in experiment
85.2%	for 40 h; Reflux; Inert atmosphere	Esterification of 2,6-dichloronicotinic acid (25.5 g, 0.1328 mmol) in EtOH (200 proof, 200 mL) catalyzed with 96percent H₂SO₄(1.7 g) at refluxing temperature for 40 h under N₂gave the desired ethyl 2,6-dichloronicotinate as grey solid (24.89 g, 0.1131 mmol, yield 85.2percent) after a normal work-up. (0723) ¹H NMR (300 MHz, DMSO-d₆): δ 8.30 (d, J=8.1 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 4.33 (q, J=7.2 Hz, 2H) and 1.30 (t, J=7.2 Hz, 3H) ppm.
67%	at 85℃; for 72 h;	A mixture 2,6-dichloronicotinic acid (5.0 g, 26.2 mmol) and concentrated H₂SO₄ (1 ml.) in EtOH (30 ml.) is heated at 85 ⁰C for 3 days. Upon cooling to room temperature, the reaction mixture is diluted with dichloromethane (200 ml_), washed with saturated NaHCO₃ solution (2x100 ml.) and brine (50 ml_). The organic layer is dried, concentrated and the crude residue is purified by flash column with EtOAC/heptanes (2/8) to afford the desired product as a white solid (3.8 g, 67 percent). LC-MS ( (ESI) m/z 220.0 (M+1 ). ¹H NMR (400 MHz, CD₂CI₂) δ ppm 7.38 (s, 1 H), 7.36 (s, 1 H), 4.39 (q, J=7.1 Hz, 2 H), 1.39 (t, J=IA Hz, 3 H).
65%	for 16 h; Reflux	Preparation 30: ethyl 2-ethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)nicotinate; Step 1 : ethyl 2,6-dichloronjcotjnate; To a solution of 2,6-dichloronicotinic acid (10 g, 52.08 mmol) in ethanol (50 mL) was added concentrated sulfuric acid (1.0 mL) and the mixture was heated to refluxed for 16 h. The reaction was concentrated. The solid residue was diluted with ethyl acetate (50 mL) and washed with water (50 mL), 1M aqueous sodium carbonate (50 mL) and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give the title compound (7.38 g, 65percent) as a light orange solid. 1 H NMR (500 MHz, DMSO-Cf₆) δ ppm 1.32 (t, J=7.07 Hz, 3 H) 4.35 (q, J=7.24 Hz, 2 H) 7.72 (d, J=8.05 Hz, 1 H) 8.31 (d, J=8.05 Hz, 1 H). Step 2: ethyl 6-chloiO-2-ethoxynicotinate

Reference： [1] Patent: US2015/291629, 2015, A1, . Location in patent: Paragraph 0722-0723
[2] Patent: WO2009/150230, 2009, A1, . Location in patent: Page/Page column 134
[3] Patent: WO2010/116282, 2010, A1, . Location in patent: Page/Page column 65
[4] Journal of Medicinal Chemistry, 2014, vol. 57, # 10, p. 4273 - 4288
[5] Patent: US2006/194801, 2006, A1, . Location in patent: Page/Page column 38-39
[6] Patent: EP1955697, 2008, A1, . Location in patent: Page/Page column 20
[7] Patent: WO2006/112828, 2006, A1, . Location in patent: Page/Page column 66-67

4
[ 38496-18-3 ]
[ 122-51-0 ]
[ 58584-86-4 ]

Reference： [1] Patent: US2008/171732, 2008, A1, . Location in patent: Page/Page column 39-40

5
[ 38496-18-3 ]
[ 64-17-5 ]
[ 122-51-0 ]
[ 58584-86-4 ]

Reference： [1] Patent: WO2008/85119, 2008, A1, . Location in patent: Page/Page column 184-185

6
[ 125850-02-4 ]
[ 623-47-2 ]
[ 1604-14-4 ]
[ 58584-86-4 ]

Reference： [1] Synthesis, 1991, # 9, p. 765 - 768
[2] Synthesis, 1991, # 9, p. 765 - 768

7
[ 87486-37-1 ]
[ 623-47-2 ]
[ 1604-14-4 ]
[ 58584-86-4 ]
[ 130879-42-4 ]
[ 130879-41-3 ]

Reference： [1] Tetrahedron, 1990, vol. 46, # 16, p. 5715 - 5732
[2] Tetrahedron, 1990, vol. 46, # 16, p. 5715 - 5732

8
[ 58584-86-4 ]
[ 65515-32-4 ]

Reference： [1] Patent: EP2085383, 2009, A1, . Location in patent: Page/Page column 22

9
[ 58584-86-4 ]
[ 55304-73-9 ]

Reference： [1] Journal of Organic Chemistry, 1982, vol. 47, # 14, p. 2800 - 2802

10
[ 58584-86-4 ]
[ 55304-90-0 ]

Reference： [1] Journal of Organic Chemistry, 1982, vol. 47, # 14, p. 2800 - 2802

[ 58584-86-4 ] Synthesis Path-Downstream 1~88

1
[ 125850-02-4 ]
[ 623-47-2 ]
[ 1604-14-4 ]
[ 58584-86-4 ]

Reference： [1]Synthesis,1991,p. 765 - 768
[2]Synthesis,1991,p. 765 - 768

2
[ 87486-37-1 ]
[ 623-47-2 ]
[ 1604-14-4 ]
[ 58584-86-4 ]
[ 130879-42-4 ]
[ 130879-41-3 ]

Reference： [1]Tetrahedron,1990,vol. 46,p. 5715 - 5732
[2]Tetrahedron,1990,vol. 46,p. 5715 - 5732

3
[ 870459-83-9 ]
[ 58584-86-4 ]
[ 911842-18-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 5035 - 5038

4
[ 58584-86-4 ]
[ 911842-77-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 5035 - 5038

5
[ 58584-86-4 ]
1-(4-tert-butyl-phenyl)-6-chloro-3-(3-methoxy-phenoxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 5035 - 5038

6
[ 58584-86-4 ]
[ 911843-66-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 5035 - 5038

7
[ 58584-86-4 ]
1-(4-tert-butyl-phenyl)-6-chloro-3-(3-methanesulfonyl-phenoxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 5035 - 5038

8
[ 58584-86-4 ]
[ 911843-69-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 5035 - 5038

9
[ 58584-86-4 ]
1-(4-tert-butyl-phenyl)-6-chloro-3-(3-trifluoromethyl-phenoxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 5035 - 5038

10
[ 58584-86-4 ]
1-(4-tert-butyl-phenyl)-6-chloro-3-(4-trifluoromethyl-pyridin-2-yloxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 5035 - 5038

11
[ 58584-86-4 ]
[ 911843-18-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 5035 - 5038

12
[ 58584-86-4 ]
[ 911846-66-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 5035 - 5038

13
[ 58584-86-4 ]
[ 55304-73-9 ]

Reference： [1]Journal of Organic Chemistry,1982,vol. 47,p. 2800 - 2802

14
[ 58584-86-4 ]
[ 81688-03-1 ]

Reference： [1]Journal of Organic Chemistry,1982,vol. 47,p. 2800 - 2802

15
[ 58584-86-4 ]
[ 81688-04-2 ]

Reference： [1]Journal of Organic Chemistry,1982,vol. 47,p. 2800 - 2802

16
[ 58584-86-4 ]
[ 81688-05-3 ]

Reference： [1]Journal of Organic Chemistry,1982,vol. 47,p. 2800 - 2802

17
[ 58584-86-4 ]
[ 81688-06-4 ]

Reference： [1]Journal of Organic Chemistry,1982,vol. 47,p. 2800 - 2802

18
[ 58584-86-4 ]
[ 81687-96-9 ]

Reference： [1]Journal of Organic Chemistry,1982,vol. 47,p. 2800 - 2802

19
[ 58584-86-4 ]
[ 81687-98-1 ]

Reference： [1]Journal of Organic Chemistry,1982,vol. 47,p. 2800 - 2802

20
[ 58584-86-4 ]
[ 81687-99-2 ]

Reference： [1]Journal of Organic Chemistry,1982,vol. 47,p. 2800 - 2802

21
[ 58584-86-4 ]
[ 81688-00-8 ]

Reference： [1]Journal of Organic Chemistry,1982,vol. 47,p. 2800 - 2802

22
[ 58584-86-4 ]
[ 81688-01-9 ]

Reference： [1]Journal of Organic Chemistry,1982,vol. 47,p. 2800 - 2802

23
[ 58584-86-4 ]
[ 81688-02-0 ]

Reference： [1]Journal of Organic Chemistry,1982,vol. 47,p. 2800 - 2802

24
[ 58584-86-4 ]
[ 81687-97-0 ]

Reference： [1]Journal of Organic Chemistry,1982,vol. 47,p. 2800 - 2802

25
[ 58584-86-4 ]
ethyl 2-chloro-6-[(4-methylphenyl)sulfanyl]nicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 11. 5g (92.4mmol) in 55mL of N,N-dimethylformamide was added 10.8g (96.0mmol) of potassium tert-butoxide at 0C, and the mixture was stirred for 15 minutes at room temperature. This mixture was added by dripping to a solution of 19.56g (88.9mmol) of <strong>[58584-86-4]ethyl 2,6-dichloronicotinate</strong> in 150mL of N,N-dimethylformamide at -30C for 15 minutes, and the mixture was stirred for 1 hour at the same temperature. Then, the reaction mixture was poured into ice water and extracted with a mixture solution of ethyl acetate/hexane (2/1) . The organic layer was washed with water and saturated saline solution, then, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give ethyl 2-chloro-6-[(4-methylphenyl)sulfanyl]nicotinate intermediate as pale brown oil.Then, this compound was dissolved in 180mL of tetrahydrofuran and 31.4g (92.4mmol) of 20% sodium ethoxide-ethanol solution was added to this solution, and the mixture was ref luxed for 2 hours. After the reaction mixture was cooled to the room temperature, the mixture was filtrated, and the filtrate was removedunderreducedpressure. The residue was diluted with chloroform and the organic layer was washed with water and saturated saline solution, then, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate = 5/1) to give 23.4g (83%) of the title compound.

Reference： [1]Patent: WO2004/111054,2004,A1 .Location in patent: Page 39

26
[ 58584-86-4 ]
[ 100-51-6 ]
[ 863903-07-5 ]
[ 863903-09-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 0.583333h;	The first step of Scheme 5: A dry round bottom flask was charged with NaH (264 mg of a 60% dispersion in mineral oil, 6.6 mmole) and the reagent washed twice with hexane. 5 mL dry DMF was added and benzyl alcohol (0.62 mL, 6.0 mmole) was added dropwise. After H2 evolution had ceased the reaction mixture was added dropwise to a 0 C. solution (10 mL) of <strong>[58584-86-4]2,6-dichloro-nicotinic acid ethyl ester</strong> (1.33 g, 6.0 mmole). It was stirred 15 minutes, and then allowed to stir another 20 minutes at room temperature. The reaction mixture was then poured into 150 mL water and extracted with ether (3×75 mL). Combined organic phases were washed with water, brine and dried over MgSO4. Filtration and evaporation gave the crude product which was then purified by chromatography on silica gel using a gradient of hexane/EtOAc (0 to 4%) as eluent. Pure fractions were combined and evaporated to give 818 mg (47%) of a 1:1 mixture of 2-benzyloxy-6-chloro-nicotinic acid ethyl ester and 6-benzyloxy-2-chloro-nicotinic acid ethyl ester.

Reference： [1]Patent: US2005/203081,2005,A1 .Location in patent: Page/Page column 10; 27

27
[ 58584-86-4 ]
[ 98-80-6 ]
[ 31676-61-6 ]

Yield	Reaction Conditions	Operation in experiment
34%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 60℃;	The first step of Scheme 9: A pressure tube was charged with <strong>[58584-86-4]2,6-dichloronicotinic acid ethyl ester</strong> (221 mg, 1.0 mmole), phenylboronic acid (134 mg, 1.1 mmole), potassium carbonate (346 mg, 2.5 mmole) and Pd(PPh3)4 (29 mg, 2.5 mol %) and 1 mL DME added followed by 1.5 mL water. The tube was capped and heated to 60 C. overnight. The reaction mixture was then cooled to room temperature and diluted with ether. The organic phase was washed with 1N NaOH, water, brine and dried over MgSO4. Filtration and evaporation gave the crude product which was purified by preparative thin layer chromatography (5% EtOAc/Hex). The product band was isolated to give 199 mg of a colorless oil that solidified on standing. NMR analysis showed a 6:1 mixture of 2-chloro-6-phenyl-nicotinic acid ethyl ester:2,6-diphenylnicotinic acid ethyl ester. The solid was recrystallized from hexane to give 90 mg (34%) of 2-chloro-6-phenylnicotinic acid ethyl ester as a white crystalline solid. 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 1.43 (t, J=7.07 Hz, 3H) 4.44 (q, J=7.07 Hz, 2H) 7.49 (m, 3H) 7.73 (d, J=8.08 Hz, 1H) 8.05 (m, 2H) 8.24 (d, J=8.08 Hz, 1H). The structure was also confirmed by NOE analysis.

Reference： [1]Patent: US2005/203081,2005,A1 .Location in patent: Page/Page column 11; 29

28
[ 38496-18-3 ]
[ 64-17-5 ]
[ 58584-86-4 ]

Yield	Reaction Conditions	Operation in experiment
85.2%	With sulfuric acid; for 40h;Reflux; Inert atmosphere;	Esterification of 2,6-dichloronicotinic acid (25.5 g, 0.1328 mmol) in EtOH (200 proof, 200 mL) catalyzed with 96% H2SO4 (1.7 g) at refluxing temperature for 40 h under N2 gave the desired ethyl 2,6-dichloronicotinate as grey solid (24.89 g, 0.1131 mmol, yield 85.2%) after a normal work-up. (0723) 1H NMR (300 MHz, DMSO-d6): delta 8.30 (d, J=8.1 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 4.33 (q, J=7.2 Hz, 2H) and 1.30 (t, J=7.2 Hz, 3H) ppm.
67%	With sulfuric acid; at 85℃; for 72h;	A mixture 2,6-dichloronicotinic acid (5.0 g, 26.2 mmol) and concentrated H2SO4 (1 ml.) in EtOH (30 ml.) is heated at 85 0C for 3 days. Upon cooling to room temperature, the reaction mixture is diluted with dichloromethane (200 ml_), washed with saturated NaHCO3 solution (2x100 ml.) and brine (50 ml_). The organic layer is dried, concentrated and the crude residue is purified by flash column with EtOAC/heptanes (2/8) to afford the desired product as a white solid (3.8 g, 67 %). LC-MS ( (ESI) m/z 220.0 (M+1 ). 1H NMR (400 MHz, CD2CI2) delta ppm 7.38 (s, 1 H), 7.36 (s, 1 H), 4.39 (q, J=7.1 Hz, 2 H), 1.39 (t, J=IA Hz, 3 H).
65%	With sulfuric acid; for 16h;Reflux;	Preparation 30: ethyl 2-ethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)nicotinate; Step 1 : ethyl 2,6-dichloronjcotjnate; To a solution of 2,6-dichloronicotinic acid (10 g, 52.08 mmol) in ethanol (50 mL) was added concentrated sulfuric acid (1.0 mL) and the mixture was heated to refluxed for 16 h. The reaction was concentrated. The solid residue was diluted with ethyl acetate (50 mL) and washed with water (50 mL), 1M aqueous sodium carbonate (50 mL) and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give the title compound (7.38 g, 65%) as a light orange solid. 1 H NMR (500 MHz, DMSO-Cf6) delta ppm 1.32 (t, J=7.07 Hz, 3 H) 4.35 (q, J=7.24 Hz, 2 H) 7.72 (d, J=8.05 Hz, 1 H) 8.31 (d, J=8.05 Hz, 1 H). Step 2: ethyl 6-chloiO-2-ethoxynicotinate

		Intermediate 21; Preparation of 2-chloro-6-(cyclopropylethynyl)nicotinic acid; Ethyl 2,6-dichloropyridine-3-carboxylate 2,6-dichloropyridine-3-carboxylic acid (2.0 g, 10.42 mmol) was placed in 100 mL EtOH, 2 mL conc. H2SO4 was added and the mixture was refluxed for 18 h. The reaction mixture was cooled and the pH adjusted to 5 with satd. aqueous NaHCO3 and then extracted with EtOAc. The organic layer was separated and dried (Na2SO4). Removal of solvent in vacuo furnished 2.1 g of the ethyl ester which was used in the next step without further purification. m/z=220.6 (M+1).
		Sulfuric acid was added to an ethanol solution of 2,6-dichloronicotinic acid and heated under reflux for 24 hours. After adding saturated sodium bicarbonate aqueous solution thereto, ethanol was evaporated under a reduced pressure. The residue was extracted with ethyl acetate and the organic layer was concentrated under a reduced pressure. Potassium carbonate was added to a DMF solution of the obtained ethyl 2,6-dichloronicotinate, and cyclopentylamine was added thereto, followed by stirring at 0C for 1 hour and at room temperature for 6 hours. By post-treating the reaction liquid, ethyl 6-chloro-2-[(cyclopropylmethyl)amino]nicotinate was obtained.
		To a solution of 2,6-dichloronicotinic acid (37g) in 200 mL ethanol was added 4 mL of con. H2SO4 and the mixture was refluxed overnight. The ethanol was evaporated off and the EPO <DP n="68"/>residue was dissolved in ethyl acetate, washed with water, 10% sodium carbonate solution, brine, dried with sodium sulfate, filtered and evaporated to yield the desired product (37.29g) as white solid (Rf : 1.553min., Condition B, M+H+ : 220).

Reference： [1]Patent: US2015/291629,2015,A1 .Location in patent: Paragraph 0722-0723
[2]Patent: WO2009/150230,2009,A1 .Location in patent: Page/Page column 134
[3]Patent: WO2010/116282,2010,A1 .Location in patent: Page/Page column 65
[4]Journal of Medicinal Chemistry,2014,vol. 57,p. 4273 - 4288
[5]Patent: US2006/194801,2006,A1 .Location in patent: Page/Page column 38-39
[6]Patent: EP1955697,2008,A1 .Location in patent: Page/Page column 20
[7]Patent: WO2006/112828,2006,A1 .Location in patent: Page/Page column 66-67

29
[ 6746-94-7 ]
[ 58584-86-4 ]
[ 908247-90-5 ]

Yield	Reaction Conditions	Operation in experiment
31%	With copper(l) iodide; triethylamine;bis-triphenylphosphine-palladium(II) chloride; In toluene; at 20℃; for 24h;	Ethyl 2-chloro-6-(2-cyclopropylethynyl)pyridine-3-carboxylate <strong>[58584-86-4]Ethyl 2,6-dichloropyridine-3-carboxylate</strong> (2.0 g, 9.1 mmol), ethynylcyclopropane (1.6 mL of a 70% w/v solution in toluene, 13.63 mmol), copper(I) iodide (173 mg, 0.9 mmol), bis(triphenylphosphine) palladium(II) chloride (1.28 g, 1.82 mmol) were stirred in 40 mL triethylamine at room temperature for 24 h. The solvent was removed in vacuo and the residue was purified by column chromatography using 10-50% EtOAc/hexane to give the product (0.7 g, 31%) as a brown oil. m/z=250 (M+1).

Reference： [1]Patent: US2006/194801,2006,A1 .Location in patent: Page/Page column 38-39

30
[ 141-52-6 ]
[ 58584-86-4 ]
[ 872355-43-6 ]

Yield	Reaction Conditions	Operation in experiment
84%	In dichloromethane; at 0 - 20℃;	Step 2: ethyl 6-chloiO-2-ethoxynicotinate; To a solution of <strong>[58584-86-4]ethyl 2,6-dichloronicotinate</strong> (5.0 g, 22.72 mmol) in dichloromethane (25 ml_) at 00C was added sodium ethoxide (2.12 g, 29.5 mmol) slowly. The reaction was stirred at 00C for 3 h and then warmed to ambient temperature over 16 h. The reaction was diluted with dichloromethane (20 ml_) and water (20 ml_) and the layers were separated. The aqueous layer was extracted an additional time with dichloromethane (20 ml_). The organic layers were combined, washed with brine (20 ml_), dried over magnesium sulfate, filtered, and concentrated to give the title compound (4.38 g, 84%) as a light yellow solid. 1 H NMR (400 MHz, DMSO-Cf6) delta ppm 1.22 - 1.40 (m, 6 H) 4.27 (q, J=7.03 Hz, 2 H) 4.37 (q, J=7.03 Hz, 2 H) 7.18 (d, J=8.00 Hz, 1 H) 8.15 (d, J=8.00 Hz, 1 H).
72.4%	In dichloromethane; at 0 - 20℃;	Substitution of NaOEt (5.8 g, 1.5 eq) with <strong>[58584-86-4]ethyl 2,6-dichloronicotinate</strong> (12.5 g, 56.8 mmol) in CH2Cl2 was performed (Reference: US2005/0288299A1) by slow addition of the base solid to the bis-chloro ester solution at 0 C. and stirred for 3 h with the cooling, then overnight from 0 C. to r.t. More CH2Cl2 and water were added, separated, dried and evaporated giving a liquid (11.62 g) that crystallized slowly overnight. The solid was recrystallized from dry-ice-cooling pentane affording the desired ethyl 6-chloro-2-ethoxynicotinate as white crystals (9.45 g, 41.15 mmol, yield 72.4%). (0725) M.p. 33-35 C. 1H NMR (300 MHz, DMSO-d6): delta 8.13 (d, J=8.1 Hz, 1H), 8.16 (d, J=8.1 Hz, 1H), 4.34 (q, J=7.2 Hz, 2H), 4.24 (q, J=7.2 Hz, 2H), 1.31 (t, J=7.2 Hz, 3H) and 1.27 (t, J=7.2 Hz, 3H) ppm.
	In dichloromethane; at -2 - 3℃; for 4h;	To a solution of <strong>[58584-86-4]2,6-dichloro-nicotinic acid ethyl ester</strong> (37.29 g) in dichloromethane (200 mL) at -2 0C was added NaOEt (17.36g) slowly and stirred at -2 0C for Ih and then at 3 0C for 3 h. The reaction mixture was diluted with water, the organic layer was dried with sodium sulfate, filtered and evaporated to give white solid (31.6 g) (Rf: 1.78min., Condition B, M+H+ : 230).

Reference： [1]Patent: WO2010/116282,2010,A1 .Location in patent: Page/Page column 66
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 4273 - 4288
[3]Patent: US2015/291629,2015,A1 .Location in patent: Paragraph 0724-0725
[4]Patent: WO2006/112828,2006,A1 .Location in patent: Page/Page column 67

31
[ 38496-18-3 ]
[ 122-51-0 ]
[ 58584-86-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; In ethanol; at 150℃; for 0.25h;Microwave irradiation;	(a) Ethyl2,6-dichloronicotinate 2,6-Dichloronicitinic acid (3.84 g, 20 mmol) was dissolved in EtOH (16 mL), sulfuric acid (1.96 g, 20 mmol) and triethyl ortoformate (4.45 g, 30 mmol) were added. The reaction mixture was heated in a microwave oven (single node heating) at 150 C. for 15 min. The mixture was extracted with EtOAc (3*20 mL) from 10% Na2CO3 (20 mL). The combined organic phases were extracted with water (50 mL), dried (Na2SO4), filtered and concentrated in vacuo to give ethyl2,6-dichloronicotinate. The crude material was used in the next step without further purification.

Reference： [1]Patent: US2008/171732,2008,A1 .Location in patent: Page/Page column 39-40

32
[ 892493-65-1 ]
[ 58584-86-4 ]
[ 1039037-26-7 ]

Yield	Reaction Conditions	Operation in experiment
30%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 150℃; for 0.166667h;Microwave irradiation;	(b) Ethyl6-[4-(tert-butoxycarbonyl)piperidin-1-yl]-2-chloronicotinate Ethyl2,6-dichloronicotinate (1.25 g, 5.68 mmol) was dissolved in DMF (16 mL), 4-piperidinecarboxylic acid tert-butyl ester hydrogen chloride (1.39 g, 6.25 mmol) and DIPEA (2.9 mL, 17 mmol) were added. The reaction mixture was heated in a microwave at 150° C. in a microwave oven (single node heating) for 10 min, the solvent was concentrated in vacuo and brine (8 mL) was added and the water phase was extracted with DCM (3*), the organic phase was dried (phase separator) and concentrated in vacuo. The residue was purified by flash chromatography, heptane/Et2O 10:1 to 4:1 as eluent, to give ethyl6-[4-(tert-butoxycarbonyl)piperidin-1-yl]-2-chloronicotinate. Yield: 630 mg (30percent).
30%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 150℃; for 0.166667h;Microwave irradiation;	(b) Ethyl 6-[4-(ter/-butoxycarbonyl)piperidin-l-yl]-2-chloronicotinateEthyl 2,6-dichloronicotinate (1.25 g, 5.68 mmol) was dissolved in DMF (16 mL), 4- piperidinecarboxylic acid tert-butyl ester hydrogen chloride (1.39 g, 6.25 mmol) and DIPEA (2.9 mL, 17 mmol) were added. The reaction mixture was heated in a microwave at 1500C in a microwave owen (single node heating) for 10 min, the solvent was concentrated in vacuo and brine (8 mL) was added and the water phase was extracted with DCM (3x), th organic phase was dried (phase separator) and concentrated in vacuo. The residue was purified by flash chromatography, heptane/Et2O 10:1 to 4:1 as eluent, to give ethyl 6-[4-(ter/-butoxycarbonyl)piperidin-l-yl]-2-chloronicotinate. Yield: 630 mg (30percent).

Reference： [1]Patent: US2008/171732,2008,A1 .Location in patent: Page/Page column 40
[2]Patent: WO2008/85119,2008,A1 .Location in patent: Page/Page column 185

33
[ 919354-21-5 ]
[ 58584-86-4 ]
[ 1039068-61-5 ]

Yield	Reaction Conditions	Operation in experiment
19%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120 - 150℃; for 0.333333h;Microwave irradiation;	(a) Ethyl6-{4-[(benzylsulfonyl)carbamoyl]piperidin-1-yl}-2-chloronicotinate A micro wave vial was charged with DIPEA (2.73 g, 21.1 mmol), <strong>[58584-86-4]ethyl2,6-dichloronicotinate</strong> (Example 43(a)) (1.547 g, 7.03 mmol), N-(benzylsulfonyl)piperidine-4-carboxamide (Example 6(d)) (2.28 g, 8.08 mmol) and DMF and the mixture was heated to 120 C. for 10 minutes followed by 150 C. for 10 minutes using microwave single node heating. Ratio of the two possible regioisomers was ca. 1:1 together with some bis-addition adduct. The crude product was purified by first using HPLC (Kromasil C8, 10 mum, using a gradient of MeCN with an acidic second eluent (H2O/MeCN/AcOH, 95/5/0.1)) followed by flash chromatography using a stepwise gradient of heptane/EtOAc 1/1 then heptane/EtOAc 1/1+0.15% FA and finally heptane/EtOAc 1/2+0.15% FA. (Rf product (heptane/EtOAc 1/2+0.15% FA)=0.47) to give ethyl6-{4-[(benzylsulfonyl)carbamoyl]piperidin-1-yl}-2-chloronicotinate. Yield: 610 mg (19%).

Reference： [1]Patent: US2008/171732,2008,A1 .Location in patent: Page/Page column 46

34
[ 38496-18-3 ]
[ 64-17-5 ]
[ 122-51-0 ]
[ 58584-86-4 ]

Yield	Reaction Conditions	Operation in experiment
	sulfuric acid; at 150℃; for 0.25h;Microwave irradiation;	Example 104Ethyl 2-[(2-acetamidoethyl)thio]-5-chloro-6-(4-[(4- chlorobenzytysulfonyljcarbamoytypiperidin-l-ytymcotmate30 <n="186"/>(a) Ethyl 2,6-dichloronicotinate2,6-Dichloronicitinic acid (3.84 g, 20 mmol) was dissolved in EtOH (16 mL), sulfuric acid (1.96 g, 20 mmol) and triethyl ortoformate (4.45 g, 30 mmol) were added. The reaction mixture was heated in a microwave owen (single node heating) at 150 0C for 15 min. The mixture was extracted with EtOAc (3x20 mL) from 10% Na2CO3 (20 mL). The combined organic phases were extracted with water (50 mL), dried (Na2SO4), filtered and concentrated in vacuo to give ethyl 2,6-dichloronicotinate. The crude material was used in the next step without further purification.

Reference： [1]Patent: WO2008/85119,2008,A1 .Location in patent: Page/Page column 184-185

35
[ 58584-86-4 ]
[ 108-91-8 ]
ethyl 6-chloro-2-(cyclohexylamino)nicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 1h;	By allowing <strong>[58584-86-4]ethyl 2,6-dichloronicotinate</strong> and cyclohexanamine to undergo the reaction at 50C for 1 hour in DMF in the presence of potassium carbonate, ethyl 6-chloro-2-(cyclohexylamino)nicotinate was obtained. By carrying out hydrolysis of an ethanol solution of this at 70C for 18 hours in the presence of 1 M sodium hydroxide, 6-chloro-2-(cyclohexylamino)nicotinic acid was obtained.

Reference： [1]Patent: EP1955697,2008,A1 .Location in patent: Page/Page column 40

36
[ 58584-86-4 ]
[ 2516-47-4 ]
[ 939819-12-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 7h;	Sulfuric acid was added to an ethanol solution of 2,6-dichloronicotinic acid and heated under reflux for 24 hours. After adding saturated sodium bicarbonate aqueous solution thereto, ethanol was evaporated under a reduced pressure. The residue was extracted with ethyl acetate and the organic layer was concentrated under a reduced pressure. Potassium carbonate was added to a DMF solution of the obtained <strong>[58584-86-4]ethyl 2,6-dichloronicotinate</strong>, and cyclopentylamine was added thereto, followed by stirring at 0C for 1 hour and at room temperature for 6 hours. By post-treating the reaction liquid, ethyl 6-chloro-2-[(cyclopropylmethyl)amino]nicotinate was obtained.

Reference： [1]Patent: EP1955697,2008,A1 .Location in patent: Page/Page column 20

37
[ 6629-62-5 ]
[ 58584-86-4 ]
[ 1016230-33-3 ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 2137 - 2146

38
[ 58584-86-4 ]
[ 65515-32-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate; In methanol; dichloromethane; at 20℃; for 48h;	Production Example 7 1.00 g of <strong>[58584-86-4]ethyl 2,6-dichloronicotinate</strong> was dissolved in 10 mL of methylene chloride, and 1.05 g of sodium methoxide (28 wt% of methanol solution) was added thereto at room temperature. After stirring at room temperature for 2 days, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 511 mg of methyl 6-chloro-2-methoxynicotinate as a white solid.

Reference： [1]Patent: EP2085383,2009,A1 .Location in patent: Page/Page column 22

39
[ 58584-86-4 ]
[ 57260-71-6 ]
[ 1201675-60-6 ]

Yield	Reaction Conditions	Operation in experiment
82%	With triethylamine; In tetrahydrofuran; for 12h;Reflux;	2,6-Dichloronicotinic acid ethyl ester (3.20 g, 14.5 mmol), 1-Boc-piperazine (3.25 g, 17.4 mmol) and Et3N (4.32 mL, 29.0 mmol) are stirred in THF (60 mL) at reflux in a 250 mL round-bottom flask for 12 h. Upon cooling to room temperature the reaction mixture is extracted between EtOAc/water (600/200 mL). The organic layer is washed with brine (100 mL), dried, concentrated and purified by flash column chromatography with EtOAc/heptanes (1/3) to afford the above product as a white solid (4.4 g, 82%). 1H-NMR (400 MHz, CD2CI2) delta <n="137"/>ppm 7.92 (d, J=7.8 Hz, 1 H), 6.71 (d, J=7.8 Hz, 1 H), 4.30 (q, J=7.0 Hz, 2 H), 3.49 - 3.50 (m, 4 H), 3.36 - 3.39 (m, 4 H), 1.44 (s, 9 H), 1.34 (t, J=7.0 Hz, 3 H).

Reference： [1]Patent: WO2009/150230,2009,A1 .Location in patent: Page/Page column 134-135

40
[ 58584-86-4 ]
[ 57260-71-6 ]
[ 1201675-64-0 ]

Yield	Reaction Conditions	Operation in experiment
16%	With triethylamine; In tetrahydrofuran; for 12h;Reflux;	2,6-Dichloronicotinic acid ethyl ester (3.20 g, 14.5 mmol), 1-Boc-piperazine (3.25 g, 17.4 mmol) and Et3N (4.32 ml_, 29.0 mmol) are stirred in THF (60 ml.) at reflux in a 250 ml_ round-bottom flask for 12 h. Upon cooling to room temperature the reaction mixture is extracted between EtOAc/water (600/200 ml_). The organic layer is washed with brine (100 ml_), dried over sodium sulfate, concentrated and purified by flash column chromatography with EtOAc/heptanes (1/3) to afford the above product as a viscous oil (0.88 g, 16%). MS (ESI) m/z 370.2 (M+1 ). 1H-NMR (400 MHz, CDCI3) delta ppm 8.03 (d, J=8.8 Hz, 1 H), 6.49 (d, <n="140"/>J=8.8 Hz, 1 H), 4.33 (q, J=7.1 Hz, 2 H), 3.65 - 3.68 (m, 4 H), 3.52 - 3.55 (m, 4 H), 1.49 (s, 9 H), 1.37 (t, J=IA Hz, 3 H).

Reference： [1]Patent: WO2009/150230,2009,A1 .Location in patent: Page/Page column 137-138

41
[ 1310692-54-6 ]
[ 58584-86-4 ]
[ 1310692-50-2 ]

Reference： [1]Chemistry and biodiversity,2011,vol. 8,p. 841 - 849

42
[ 767-00-0 ]
[ 58584-86-4 ]
[ 1256591-49-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;	Example 174-[5-[4-(2-aminoethyl)-piperidine-1-carbonyl]-6-(4-trifluoromethoxy-phenoxy)-pyridine-2-yloxy]benzamidinea) 2-Chloro-6-(4-cyano phenoxy)nicotinic Acid Ethyl Ester96.7 mg (0.7 mmol) of potassium carbonate was added to a stirred solution of 2,6-dichloro nicotinic acid ethyl ester 0.15 g (0.7 mmol) in 10 ml of N,N-dimethyl-formamide (DMF) cooled to 5 C. This was followed by dropwise addition (over a period of 10 min) of 4-cyano phenol 80 mg (0.68 mmol) dissolved in 2 ml of DMF. The reaction mixture was allowed to stir at RT for 2 h, concentrated under reduced pressure and the residue was dissolved in 100 ml of ethylacetate. The organic layer was washed with water and dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography using hexane:ethylacetate (8:2) as eluants to afford 0.13 g of the required product. 1H NMR (DMSO-d6): delta 1.3 (3H, t), 4.3 (2H, q), 7.26 (1H, s), 7.38 (1H, s), 7.48 (2H, d), 7.96 (2H, d).

Reference： [1]Patent: US2012/136002,2012,A1 .Location in patent: Page/Page column 18-19

43
[ 58584-86-4 ]
[ 1256588-76-7 ]

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 1152 - 1157

44
[ 58584-86-4 ]
[ 1256591-07-7 ]

Reference： [1]Patent: US2012/136002,2012,A1
[2]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 1152 - 1157

45
[ 58584-86-4 ]
[ 1256591-08-8 ]

Reference： [1]Patent: US2012/136002,2012,A1
[2]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 1152 - 1157

46
[ 767-00-0 ]
[ 58584-86-4 ]
[ 1256591-06-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 4h;	Example 52-(1-{2,6-Bis-[4-carbamimidoyl-phenoxy]-pyridine-3-carbonyl}-piperidin-4-yl)-ethylaminea) 2,6-Bis(4-Cyano Phenoxy)-nicotinic Acid Ethyl EsterPotassium carbonate 1.58 g (11.5 mmol) was added to a stirred solution of <strong>[58584-86-4]2,6-dichloro-nicotinic acid ethyl ester</strong> 1.0 g (4.6 mmol) in 5 ml of DMF and stirred for 10 min. 4-Hydroxy-benzonitrile 1.36 g (11.5 mmol), dissolved in 5 ml of DMF, was added dropwise to the stirred DMF solution and the flask was stirred at 80 C. for 4 h. The reaction mixture was poured into ice-cold water and the result was partitioned using ethyl acetate. The organic phase was washed with 1 M of Na2CO3 and saturated brine solution, dried over sodium sulphate and concentrated. The oily residue was purified by column chromatography using hexane-ethyl acetate (10:2) to afford 1.6 g of the required product. Percentage purity: 84.8%, (M+1)=385.1. 1H NMR (DMSO-d6): 1.36 (3H, t), 4.22 (214, q), 6.78 (1H, d), 7.06 (4H, d), 7.58 (4H, d), 8.21 (1H, d).

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 1152 - 1157
[2]Patent: US2012/136002,2012,A1 .Location in patent: Page/Page column 12

47
[ 767-00-0 ]
[ 58584-86-4 ]
[ 1256591-50-0 ]

Reference： [1]Patent: US2012/136002,2012,A1

48
[ 58584-86-4 ]
[ 5961-59-1 ]
[ 1421676-38-1 ]

Yield	Reaction Conditions	Operation in experiment
54%	at 160℃; for 0.5h;Microwave irradiation;	General procedure: Method B (microwave irradiation): A mixture of 2 (1.0 mmol), substituted aniline (1.5 mmol), and anhydrous potassium carbonate (414 mg, 3.0 mmol) in 3 mL of t-BuOH was heated at 120-160 C with microwave-assistance for 10-30 min with stirring. The reaction mixture was then poured into ice-water, pH adjusted to ?3.0 with aq HCl (2 N), and solid crude product was filtered. The product was then purified by the same methods as in Method A above.

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 632 - 642

49
[ 58584-86-4 ]
[ 1467746-28-6 ]

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 1152 - 1157

50
[ 58584-86-4 ]
[ 1467746-30-0 ]

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 1152 - 1157

51
[ 58584-86-4 ]
[ 1467746-34-4 ]

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 1152 - 1157

52
[ 58584-86-4 ]
[ 1467746-38-8 ]

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 1152 - 1157

53
[ 58584-86-4 ]
[ 1467746-23-1 ]

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 1152 - 1157

54
[ 58584-86-4 ]
[ 1256591-23-7 ]

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 1152 - 1157

55
[ 58584-86-4 ]
[ 1256591-24-8 ]

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 1152 - 1157

56
[ 58584-86-4 ]
[ 1256591-25-9 ]

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 1152 - 1157

57
[ 58584-86-4 ]
[ 1256591-26-0 ]

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 1152 - 1157

58
[ 58584-86-4 ]
[ 1256588-86-9 ]

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 1152 - 1157

59
[ 58584-86-4 ]
[ 1256591-12-4 ]

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 1152 - 1157

60
[ 58584-86-4 ]
[ 1467746-31-1 ]

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 1152 - 1157

61
[ 58584-86-4 ]
[ 1467746-35-5 ]

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 1152 - 1157

62
[ 58584-86-4 ]
[ 1467746-39-9 ]

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 1152 - 1157

63
[ 58584-86-4 ]
[ 1256588-80-3 ]

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 1152 - 1157

64
[ 58584-86-4 ]
[ 1467746-32-2 ]

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 1152 - 1157

65
[ 58584-86-4 ]
[ 1467746-36-6 ]

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 1152 - 1157

66
[ 58584-86-4 ]
[ 1467746-40-2 ]

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 1152 - 1157

67
[ 58584-86-4 ]
[ 1246765-43-4 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 4273 - 4288

68
[ 58584-86-4 ]
[ 1246766-02-8 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 4273 - 4288

69
[ 58584-86-4 ]
[ 1246766-03-9 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 4273 - 4288

70
[ 58584-86-4 ]
ethyl 6-(4-bromo-3-formylphenoxy)-2-ethoxynicotinate [ No CAS ]

Reference： [1]Patent: US2015/291629,2015,A1

71
[ 58584-86-4 ]
ethyl 2-ethoxy-6-(3-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinate [ No CAS ]

Reference： [1]Patent: US2015/291629,2015,A1

72
[ 58584-86-4 ]
ethyl 2-ethoxy-6-(3-(hydroxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinate [ No CAS ]

Reference： [1]Patent: US2015/291629,2015,A1

73
[ 58584-86-4 ]
ethyl 2-ethoxy-6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinate [ No CAS ]

Reference： [1]Patent: US2015/291629,2015,A1

74
[ 58584-86-4 ]
N-[(2-amino-3-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide [ No CAS ]

Reference： [1]Patent: US2016/95858,2016,A1

75
[ 58584-86-4 ]
N-[(2-acetamido-3-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide hydrochloride [ No CAS ]

Reference： [1]Patent: US2016/95858,2016,A1

76
[ 58584-86-4 ]
2-chloro-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxylic acid [ No CAS ]

Reference： [1]Patent: US2016/95858,2016,A1

77
[ 58584-86-4 ]
N-[(2-amino-3-pyridyl)sulfonyl]-2-chloro-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide [ No CAS ]

Reference： [1]Patent: US2016/95858,2016,A1

78
3-[dideuterio-(2,2,3,3-tetramethylcyclopropyl)methoxy]-1H-pyrazole [ No CAS ]
[ 58584-86-4 ]
ethyl 2-chloro-6-[3-[dideuterio-(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1-yl]pyridine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With 1,4-diaza-bicyclo[2.2.2]octane; potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere;	A round bottom flask was charged under nitrogen with3-[dideuterio-(2,2,3,3-tetramethylcyclopropyl)methoxy]-lH-pyrazole (485 mg, 2.471 mmol), <strong>[58584-86-4]ethyl 2,6-dichloropyridine-3-carboxylate</strong> (545 mg, 2.477 mmol), K2C03 (513 mg, 3.712 mmol) (freshly ground in a mortar) and anhydrous DMF (4.128 mL). DABCO (50 mg, 0.4457 mmol) was added and the mixture was stirred at room temperature under nitrogen for 16 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and water (50 mL) and the two phases were separated. The aqueous phase was further extracted with ethyl acetate (2 x 30 mL), and the combined extracts were washed with brine and dried over sodium sulfate, after which the solvent was removed under reduced pressure. The material was subjected to flash chromatography on silica gel using a gradient of 0-20% ethyl acetate in hexanes. The pure fractions were combined and the solvents removed under reduced pressure to provide a white solid; ethyl 2-chloro-6-[3-[dideuterio-(2,2.3,3-tetramethylcyclopropyl)methoxy]pyrazol-l -yl]pyridine-3-carboxylate (505 mg, 54%) ESI-MS m/z calc. 379.16318, found 380.1 (M+l)+; Retention time: 0.9 minutes lH NMR (400 MHz, DMSO) delta 8.42 (d, J = 2.9 Hz, 1H), 8.39 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 6.24 (d, J = 2.9 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H), 1.11 (s, 6H), 1.04 (s, 6H), 0.74 (s, 1H).

Reference： [1]Patent: WO2018/64632,2018,A1 .Location in patent: Paragraph 00503; 00504

79
3-(dispiro[2.0.2.1]heptan-7-ylmethoxy)-1H-pyrazole [ No CAS ]
[ 58584-86-4 ]
ethyl 2-chloro-6-(3-(dispiro[2.0.2.1]heptan-7-ylmethoxy)-1H-pyrazol-1-yl)nicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With 1,4-diaza-bicyclo[2.2.2]octane; potassium carbonate; In dimethyl sulfoxide; for 24h;	A mixture of 3-(dispiro[2.0.2. l]heptan-7-ylmethoxy)-lH-pyrazole (0.94 g, 4.9 mmol), <strong>[58584-86-4]ethyl 2,6-dichloropyridine-3-carboxylate</strong> (1.15 g, 5.23 mmol), potassium carbonate (0.83 g, 6.0 mmol), and l,4-diazabicyclo[2.2.2]octane (0.12 g, 1.1 mmol) in DMSO (16 mL) was stirred for 24 hours. The reaction was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine and water, dried over sodium sulfate, and evaporated under vacuum. The residue was purified by silica gel column chromatography eluting with 0-20% ethyl acetate in hexanes to give ethyl 2-chloro-6-(3-(dispiro[2.0.2.1]heptan-7-ylmethoxy)-lH-pyrazol-l-yl)nicotinate (1.39 g, 75% yield) as a colorless solid. ESI-MS m/z calc. 373.11932, found 374.2 (M+l)+; Retention time: 0.87 minutes. *H NMR (400 MHz, Chloroform-d) delta 8.36 (d, J = 2.8 Hz, 1H), 8.27 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 5.96 (d, J = 2.9 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 4.30 (d, J = 7.0 Hz, 2H), 1.94 (t, J = 7.0 Hz, 1H), 1.42 (t, J = 7.1 Hz, 3H), 1.02-0.89 (m, 4H), 0.75-0.65 (m, 2H), 0.65-0.53 (m, 2H)
75%	With 1,4-diaza-bicyclo[2.2.2]octane; potassium carbonate; In dimethyl sulfoxide; for 24h;	A mixture of 3-(dispiro[2.0.2.1]heptan-7-ylmethoxy)-1H-pyrazole (0.94 g, 4.9 mmol), <strong>[58584-86-4]ethyl 2,6-dichloropyridine-3-carboxylate</strong> (1.15 g, 5.23 mmol), potassium carbonate (0.83 g, 6.0 mmol), and 1,4-diazabicyclo[2.2.2]octane (0.12 g, 1.1 mmol) in DMSO (16 mL) was stirred for 24 hours. The reaction was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine and water, dried over sodium sulfate, and evaporated under vacuum. The residue was purified by silica gel column chromatography eluting with 0-20% ethyl acetate in hexanes to give ethyl 2- chloro-6-(3-(dispiro[2.0.2.1]heptan-7-ylmethoxy)-1H-pyrazol-1-yl)nicotinate (1.39 g, 75% yield) as a colorless solid. ESI-MS m/z calc.373.11932, found 374.2 (M+1)+; Retention time: 0.87 minutes.1H NMR (400 MHz, Chloroform-d) delta 8.36 (d, J = 2.8 Hz, 1H), 8.27 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 5.96 (d, J = 2.9 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 4.30 (d, J = 7.0 Hz, 2H), 1.94 (t, J = 7.0 Hz, 1H), 1.42 (t, J = 7.1 Hz, 3H), 1.02-0.89 (m, 4H), 0.75- 0.65 (m, 2H), 0.65-0.53 (m, 2H)

Reference： [1]Patent: WO2018/64632,2018,A1 .Location in patent: Paragraph 00766; 00767
[2]Patent: WO2018/107100,2018,A1 .Location in patent: Page/Page column 246-248

80
3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]-1H-pyrazole [ No CAS ]
[ 58584-86-4 ]
ethyl 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With 1,4-diaza-bicyclo[2.2.2]octane; potassium carbonate; In N,N-dimethyl-formamide; at 20 - 30℃; for 25h;	A mixture of DMF (180.0 mL), <strong>[58584-86-4]ethyl 2,6-dichloropyridine-3-carboxylate</strong> (approximately 29.97 g, 136.2 mmol), 3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]-lH-pyrazole (30.0 g, 136.2 mmol), and K2CO3, (325 mesh, approximately 24.48 g, 177.1 mmol) was added to a stirred reactor at 20 C. DABCO (approximately 2.292 g, 20.43 mmol) was then added to the reactor, and the mixture was stirred at 20 C for 1 hour, and then the temperature was increased to 30 C, and the mixture stirred for 24 hours to complete the reaction. The mixture was cooled to 20 C; then water (360 mL) was added slowly. The mixture was then drained from the reactor and the solid was isolated by filtration. The solid was then washed with water (2 x 150 mL), and then the solid was dried under vacuum at 55 C to afford ethyl 2-chloro-6-[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridine-3-carboxylate (51.37 g, 93%) as a fine, beige colored solid. 1H NMR (400 MHz, DMSO-c4) delta 8.44 (d, J= 2.9 Hz, 1H), 8.41 (d, J= 8.5 Hz, 1H), 7.75 (d, J= 8.5 Hz, 1H), 6.21 (d, J= 2.9 Hz, 1H), 4.34 (m, 4H), 2.09 (t, J= 7.1 Hz, 2H), 1.34 (t, J= 7.1 Hz, 3H), 1.00 - 0.84 (m, 4H).
93%	With 1,4-diaza-bicyclo[2.2.2]octane; potassium carbonate; In N,N-dimethyl-formamide; at 20 - 30℃; for 25h;	A mixture of DMF (180.0 mL), <strong>[58584-86-4]ethyl 2,6-dichloropyridine-3-carboxylate</strong> (approximately 29.97 g, 136.2 mmol), 3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]-1H-pyrazole (30.0 g, 136.2 mmol), and K2CO3, (325 mesh, approximately 24.48 g, 177.1 mmol) was added to a stirred reactor at 20 C. DABCO (approximately 2.292 g, 20.43 mmol) was then added to the reactor, and the mixture was stirred at 20 C. for 1 hour, and then the temperature was increased to 30 C., and the mixture stirred for 24 hours to complete the reaction. The mixture was cooled to 20 C.; then water (360 mL) was added slowly. The mixture was then drained from the reactor and the solid was isolated by filtration. The solid was then washed with water (2*150 mL), and then the solid was dried under vacuum at 55 C. to afford ethyl 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylate (51.37 g, 93%) as a fine, beige colored solid. 1H NMR (400 MHz, DMSO-d6) delta 8.44 (d, J=2.9 Hz, 1H), 8.41 (d, J=8.5 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 6.21 (d, J=2.9 Hz, 1H), 4.34 (m, 4H), 2.09 (t, J=7.1 Hz, 2H), 1.34 (t, J=7.1 Hz, 3H), 1.00-0.84 (m, 4H).

Reference： [1]Patent: WO2018/64632,2018,A1 .Location in patent: Paragraph 00275; 00276
[2]Patent: US2019/119253,2019,A1 .Location in patent: Paragraph 0501; 0502

81
[ 58584-86-4 ]
N-(4-hydroxyphenyl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide [ No CAS ]

Reference： [1]Patent: WO2018/64632,2018,A1

82
[ 58584-86-4 ]
2-chloro-N-(2-hydroxyphenyl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide [ No CAS ]

Reference： [1]Patent: WO2018/64632,2018,A1

83
[ 58584-86-4 ]
N-(2-hydroxyphenyl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide [ No CAS ]

Reference： [1]Patent: WO2018/64632,2018,A1

84
[ 58584-86-4 ]
2-chloro-N-(3-hydroxyphenyl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide [ No CAS ]

Reference： [1]Patent: WO2018/64632,2018,A1

85
[ 58584-86-4 ]
N-(3-hydroxyphenyl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide [ No CAS ]

Reference： [1]Patent: WO2018/64632,2018,A1

86
[ 58584-86-4 ]
2-chloro-N-(2-chlorophenyl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide [ No CAS ]

Reference： [1]Patent: WO2018/64632,2018,A1

87
[ 58584-86-4 ]
N-(2-chlorophenyl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide [ No CAS ]

Reference： [1]Patent: WO2018/64632,2018,A1

88
[ 58584-86-4 ]
(5S)-7-(benzenesulfonyl)-3,3,5-trimethyl-12-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2,7,13-triazatricyclo[7.4.0.02,6]trideca-1⁽⁹⁾,10,12-trien-8-one [ No CAS ]

Reference： [1]Patent: WO2018/64632,2018,A1

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[ 58584-86-4 ] Synthesis Path-Upstream 1~10

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