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[ CAS No. 13600-42-5 ] {[proInfo.proName]}

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Cat. No.: {[proInfo.prAm]}

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3d Animation Molecule Structure of 13600-42-5

Chemical Structure| 13600-42-5

Chemical Structure| 13600-42-5

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Quality Control of [ 13600-42-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 13600-42-5 ]

SDS Specification

Alternatived Products of [ 13600-42-5 ]

Product Details of [ 13600-42-5 ]

CAS No. :	13600-42-5	MDL No. :	MFCD00084977
Formula :	C₇HCl₂F₃N₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WRXXBTBGBXYHSG-UHFFFAOYSA-N
M.W :	241.00	Pubchem ID :	2736726
Synonyms :

Calculated chemistry of [ 13600-42-5 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	1
Num. H-bond acceptors :	5.0
Num. H-bond donors :	0.0
Molar Refractivity :	43.97
TPSA :	36.68 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) :	-5.37 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.75
Log Po/w (XLOGP3) :	3.38
Log Po/w (WLOGP) :	4.43
Log Po/w (MLOGP) :	2.03
Log Po/w (SILICOS-IT) :	3.67
Consensus Log Po/w :	3.05

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.71
Solubility :	0.0465 mg/ml ; 0.000193 mol/l
Class :	Soluble
Log S (Ali) :	-3.83
Solubility :	0.0357 mg/ml ; 0.000148 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.24
Solubility :	0.014 mg/ml ; 0.0000581 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.09

Safety of [ 13600-42-5 ]

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

Application In Synthesis of [ 13600-42-5 ]

* 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 [ 13600-42-5 ]
Downstream synthetic route of [ 13600-42-5 ]

[ 13600-42-5 ] Synthesis Path-Upstream 1~3

1
[ 13600-42-5 ]
[ 13600-43-6 ]

Yield	Reaction Conditions	Operation in experiment
95.22%	With palladium on activated carbon; hydrogen; triethylamine In tetrahydrofuran for 4 h;	10 wtpercent Pd/C, 100 g (988 mmol) Et3N, 100 g (415 mmol) 2,6-dichloro-3-cyano-4-trifluoromethylpyridine, 1 L THF were added to a 5 L reaction flask, and the reaction flask was replaced with hydrogen three times. The reaction was stirred for 4 hours, and the solid material in the reaction vessel was collected by filtration, and the filtered liquid was distilled under reduced pressure to give 68 g (395 mmol) of 3-cyano-4-trifluoromethylpyridine liquid, yield 95.22percent.

Reference： [1] Patent: CN108191749, 2018, A, . Location in patent: Paragraph 0029; 0052; 0056; 0072; 0078

2
[ 3335-46-4 ]
[ 13600-42-5 ]

Yield	Reaction Conditions	Operation in experiment
79.78%	for 20 h; Reflux	500ml round bottom flask, 84.5 g (414 mmol) of 2,6-dihydroxy-3-cyano-4-(trifluoromethyl) pyridine, 400 grams of phosphorus oxychloride, 35 grams of catalyst, heated to reflux 20 h, central control raw material reaction is complete, change the reflux device for the distillation unit to steal excess phosphorus oxychloride, Pour into ice-water mixture, precipitated solid, dried to give white solid 79.6g, yield 79.78percent.

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 4, p. 475 - 477
[2] Patent: CN107382848, 2017, A, . Location in patent: Paragraph 0043; 0046-0047

3
[ 13600-42-5 ]
[ 158063-66-2 ]

Reference： [1] Patent: CN107286086, 2017, A,
[2] Patent: CN108191749, 2018, A,

[ 13600-42-5 ] Synthesis Path-Downstream 1~64

2
[ 3335-46-4 ]
[ 13600-42-5 ]

Yield	Reaction Conditions	Operation in experiment
79.78%	With trichlorophosphate; for 20h;Reflux;	500ml round bottom flask, 84.5 g (414 mmol) of 2,6-dihydroxy-3-cyano-4-(trifluoromethyl) pyridine, 400 grams of phosphorus oxychloride, 35 grams of catalyst, heated to reflux 20 h, central control raw material reaction is complete, change the reflux device for the distillation unit to steal excess phosphorus oxychloride, Pour into ice-water mixture, precipitated solid, dried to give white solid 79.6g, yield 79.78%.
79.78%	With trichlorophosphate; for 20h;Reflux;	In a 500 ml round bottom flask, 84.5 g (414 mmol) of <strong>[3335-46-4]2,6-dihydroxy-3-cyano-4-(trifluoromethyl)pyridine</strong>, 400 g of phosphorus oxychloride, 35 g of a catalyst, and refluxing for 20 h, The control material was completely reacted, and the refluxing device was distilled to remove excess phosphorus oxychloride, poured into ice water and mixed, and the solid was precipitated to obtain 79.6 g of a white solid substance, and the yield was 79.78%.
	With trichlorophosphate; at 160℃; for 12h;	Step 1. At room temperature, 17 g of <strong>[3335-46-4]2,6-dihydroxy-3-cyano-4-trifluoromethylpyridine</strong> and 68 g of phosphorus oxychloride were sequentially added to a 250 m1 reaction flask, stirring was started, and the reaction liquid was heated to the temperature. About 160 C, the reaction was kept for 12 h, and cooled to room temperature;Step 2: The reaction solution was poured into ice water, and the reaction liquid was adjusted to pH=7 with a saturated sodium hydrogencarbonate solution, and poured into a 500 m1 separatory funnel for separation, and the aqueous phase was extracted three times with 20 ml of dichloroethane to concentrate organic The phase is washed with water, the organic phase is dried, concentrated, and the residue is evaporated under reduced pressure to give 2,6-dichloro-3-cyano-4-trifluoromethylpyridine;

With trichlorophosphate; In dichloromethane; N,N-dimethyl-formamide; at 125℃; for 6h;

two,Dissolving <strong>[3335-46-4]2,6-dihydroxy-3-cyano-4-trifluoromethylpyridine</strong> in dichloroethane,Then after adding phosphorus oxychloride,Add N, N dimethylformamide dropwise,Reflowing at 125 C for 6 h,cool down,Add to the ice water mixture,Stir layering,The aqueous layer is extracted with dichloroethane, combining organic layers,Dry over anhydrous sodium sulfate,Filtering,After the filtrate is steamed,2,6-dichloro-3-cyano-4-trifluoromethylpyridine;

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 475 - 477
[2]Patent: CN107382848,2017,A .Location in patent: Paragraph 0043; 0046-0047
[3]Patent: CN108822028,2018,A .Location in patent: Paragraph 0026; 0029; 0030
[4]Patent: CN108530352,2018,A .Location in patent: Paragraph 0008
[5]Patent: CN109232407,2019,A .Location in patent: Paragraph 0021; 0024; 0031; 0034; 0038; 0041; 0045; 0048

3
[ 13600-42-5 ]
[ 149108-61-2 ]
3-cyano-4-trifluoromethyl-2,6-bis[3'-(N-toluenesulfonylindolyl)]pyridine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2001,vol. 9,p. 1773 - 1780
[2]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 475 - 477

4
[ 13600-42-5 ]
[ 149108-62-3 ]
2,6-bis-[5-methoxy-1-(toluene-4-sulfonyl)-1<i>H</i>-indol-3-yl]-4-trifluoromethyl-nicotinonitrile [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2001,vol. 9,p. 1773 - 1780
[2]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 475 - 477

5
[ 13600-42-5 ]
[ 289503-26-0 ]
2,6-bis-[6-bromo-1-(toluene-4-sulfonyl)-1<i>H</i>-indol-3-yl]-4-trifluoromethyl-nicotinonitrile [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2001,vol. 9,p. 1773 - 1780
[2]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 475 - 477

6
[ 13600-42-5 ]
[ 339540-17-9 ]
2,6-bis-[5-bromo-1-(toluene-4-sulfonyl)-1<i>H</i>-indol-3-yl]-4-trifluoromethyl-nicotinonitrile [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2001,vol. 9,p. 1773 - 1780
[2]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 475 - 477

7
[ 13600-42-5 ]
[ 339540-16-8 ]
3-cyano-4-trifluoromethyl-2,6-bis[3'-(N-toluenesulfonyl-5'-benzyloxyindolyl)]pyridine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2001,vol. 9,p. 1773 - 1780
[2]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 475 - 477

8
[ 13600-42-5 ]
[ 339540-15-7 ]
2,6-bis-[6-methoxy-1-(toluene-4-sulfonyl)-1<i>H</i>-indol-3-yl]-4-trifluoromethyl-nicotinonitrile [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2001,vol. 9,p. 1773 - 1780
[2]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 475 - 477

9
[ 67-56-1 ]
[ 13600-42-5 ]
[ 149108-61-2 ]
2-methoxy-3-cyano-4-trifluoromethyl-6-[3'-(N-toluenesulfonylindolyl)]pyridine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2001,vol. 9,p. 1773 - 1780

10
[ 67-56-1 ]
[ 13600-42-5 ]
[ 149108-62-3 ]
6-methoxy-2-[5-methoxy-1-(toluene-4-sulfonyl)-1<i>H</i>-indol-3-yl]-4-trifluoromethyl-nicotinonitrile [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2001,vol. 9,p. 1773 - 1780

11
[ 67-56-1 ]
[ 13600-42-5 ]
[ 339540-15-7 ]
2-methoxy-3-cyano-4-trifluoromethyl-6-[3'-(N-toluenesulfonyl-6'-methoxyindolyl)]pyridine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2001,vol. 9,p. 1773 - 1780

12
[ 13600-42-5 ]
[ 289503-26-0 ]
2-[6-bromo-1-(toluene-4-sulfonyl)-1<i>H</i>-indol-3-yl]-6-chloro-4-trifluoromethyl-nicotinonitrile [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2001,vol. 9,p. 1773 - 1780

13
[ 13600-42-5 ]
[ 339540-17-9 ]
2-[5-bromo-1-(toluene-4-sulfonyl)-1<i>H</i>-indol-3-yl]-6-chloro-4-trifluoromethyl-nicotinonitrile [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2001,vol. 9,p. 1773 - 1780

14
[ 110-68-9 ]
[ 13600-42-5 ]
6-(butyl-methyl-amino)-2-chloro-4-trifluoromethyl-nicotinonitrile [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5693 - 5697

15
[ 626-58-4 ]
[ 13600-42-5 ]
C₁₃H₁₃N₃ClF₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5693 - 5697

16
[ 2744-08-3 ]
[ 13600-42-5 ]
C₁₆H₁₇N₃ClF₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5693 - 5697

17
[ 42882-26-8 ]
[ 13600-42-5 ]
C₁₆H₁₃N₃ClF₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5693 - 5697

18
[ 5933-40-4 ]
[ 13600-42-5 ]
(R)-(+)-2-chloro-6-[methyl-(1-phenyl-ethyl)-amino]-4-trifluoromethyl-nicotinonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96.16%	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 91℃; for 1h;	The starting materials, 2, 6-dichloro-4-trifluoromethyl-nicotinonitrile (5. 0g, 21mmol) and (R)- (+)-N, alpha-dimethyl benzylamine (2.6 g, 19mmol) were dissolved in 85ml of dry DMF, thenK2CO3 (5.0g) was suspended in the mixture, the reaction was stirred at91 C for 1 h, it was checked by MS. When it was completed, theK2CO3 was filtered out, the solvent was removed to get an oily liquid, it was on vacuum overnight, the crude product was a slight yellow solid. The crude product was washed with hot hexane to yield a pure product (6.16g, 96.16%). MS: 340.1(M+1 for C16H13ClN3F3). LCMS: C-18 Column (25% H20/ 75% CH3CN), Ret. Time: 1.99 min Purity: 99.1%

Reference： [1]Patent: WO2005/49574,2005,A1 .Location in patent: Page/Page column 27
[2]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5693 - 5697

19
[ 19131-99-8 ]
[ 13600-42-5 ]
C₁₆H₁₃N₃ClF₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5693 - 5697

20
[ 13600-42-5 ]
[ 142-84-7 ]
6-dipropylamino-2-chloro-4-trifluoromethyl-nicotinonitrile [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5693 - 5697

21
[ 3886-69-9 ]
[ 13600-42-5 ]
C₁₅H₁₁N₃ClF₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5693 - 5697

23
[ 7713-69-1 ]
[ 13600-42-5 ]
6-(sec-butyl-methyl-amino)-2-chloro-4-trifluoromethyl-nicotinonitrile [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5693 - 5697

24
[ 110-89-4 ]
[ 13600-42-5 ]
C₁₂H₁₁N₃ClF₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5693 - 5697

25
[ 13600-42-5 ]
C₇HN₂OCl₂F₃ [ No CAS ]

Reference： [1]Tetrahedron Letters,2008,vol. 49,p. 832 - 834

26
[ 13600-42-5 ]
[ 503437-19-2 ]

Yield	Reaction Conditions	Operation in experiment
89%	With sulfuric acid; water; nitric acid; at 70 - 100℃; for 1h;	Method 2 Conc. HNO3 (13.3 mL) was added to cooled (0 C.) conc. H2SO4 (60 mL) maintaining the internal temperature below 10 C. After addition, the acid mixture was heated to 70 C. and commercially available (Maybridge) <strong>[13600-42-5]2,6-dichloro-4-(trifluoromethyl)nicotinonitrile</strong> (20.0 g, 83 mmol) was added. The temperature was raised until the internal temperature of the reaction reached 100 C. After heating for 1 h TLC analysis revealed that the reaction was complete. The reaction mixture was cooled to room temperature, and slowly added to ice (100 g) with strong agitation and extracted with Et2O (3*). The organic layers were combined and washed with brine. The solution was dried over Na2SO4 and concentrated in vacuo to give 2,6-dichloro-4-(trifluoromethyl)nicotinic acid (19.1 g, 89%) as an off-white solid: Rf=0.30 (9:1 CH2Cl2:MeOH), 1H-NMR (d6-DMSO, 300 MHz) delta8.18 (s, 1H).
	With water; potassium hydroxide; at 20℃; for 8h;	The <strong>[13600-42-5]2,6-dichloro-3-cyano-4-trifluoromethylpyridine</strong> was stirred with water,Add a concentration of 15% KOH solution,Heated to reflux for 8 h and then transferred to room temperature,Until the temperature dropped to room temperature after ice bath; add concentrated hydrochloric acid to adjust the pH to 2 after filtration,2,6-dichloro-4-trifluoromethyl picolinic acid

Reference： [1]Patent: US6677352,2004,B1 .Location in patent: Page/Page column 48-49
[2]Patent: CN107286086,2017,A .Location in patent: Paragraph 0021; 0022; 0027

27
C₁₆H₂₁N₃O*2ClH [ No CAS ]
[ 13600-42-5 ]
C₂₃H₂₁ClF₃N₅O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With N-ethyl-N,N-diisopropylamine; In ethanol; at 0℃; for 1h;	The piperidine dihydrochloride salt obtained above (341 mg, 0.991 mmol) was dispersed in 20 mL absolute EtOH. The mixture was cooled to 0 C and treated with the dichloro- pyridine (239 mg, 0.991 mmol), then Hunigs base was added dropwise to the resulting solution. After 1 h the solvent was removed in vacuo to yield a light yellow solid. Trituration in CH2C12, followed by filtration afforded 414 mg of monochloro-pyridine as a white solid (88% of theory). ;

Reference： [1]Patent: WO2005/56562,2005,A1 .Location in patent: Page/Page column 70

28
1-(1-methyl-1H-benzoimidazol-2-yl)-2-(piperidin-4-ylamino)-ethanol dihydrochloride [ No CAS ]
[ 13600-42-5 ]
6'-choro-4-[2-hydroxy-2-(1-methyl-1H-benzoimidazol-2-yl)-ethylamino]-4'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62.4%	With N-ethyl-N,N-diisopropylamine; In ethanol; at 0℃; for 2h;	Example 7; : 3-Amino-6-{4-[2-hydroxy-2-(1-methyl-lH-benzoimidazol-2-yl)- ethylamino]-piperidin-1-yl}-4-trifluoromethyl-thieno [2, 3-b] pyridine-2-carboxylic acid amide F F FF F N N NH'F-5-N 11 if N N N CI H CIH ETOH, 0 C, 2h OH CIH CI N CI N I H F F F NH2 Mercapto acetamid/ NaOMe- N N S NHZ DMF, 70 C to 100 C, ON , 'krN OH 7 2, 6-Dichloro-4-trifluoromethyl-nicotinonitrile (277 mg, 1.15 mmol) was dissolved into 10 mL of absolute EtOH and cooled in a wet ice bath. To this was added DIPEA (1.74 mL, 10 mmol) and 1- (l-methyl-lH-benzoimidazol-2-yl)-2- (piperidin-4-ylamino)-ethanol dihydrochloride (400 mg, 1.15 mmol). The mixture was stirred for 2 h. LC-MS anlysis indicated formation of the product. The reaction mixture was concentrated on a rotary evaporator and the residue was dissolved in CH2Cl2 and applied to a SiO2 column and purified (0-10% MeOH/CH2C12) to give an oil, still contaminated with DIPEA. Trituration with EtOAc gave 344 mg, 62.4% of 6'-choro-4-[2-hydroxy-2-(1-methyl-1H- benzoimidazol-2-yl) -ethylamino] -4'-trifluoromethyl-3, 4,5, 6-tetrahydro-2H- [1,2'] bipyridinyl-5'-carbonitrile.

Reference： [1]Patent: WO2005/56562,2005,A1 .Location in patent: Page/Page column 64-65

29
[ 13600-42-5 ]
[ 158063-67-3 ]

Yield	Reaction Conditions	Operation in experiment
90.09%	With sulfuric acid; at 100℃; for 1h;	500 mL round bottom flask, 79.6 g (330 mmo 1) of <strong>[13600-42-5]2,6-dichloro-3-cyano-4-(trifluoromethyl)pyridine</strong> concentrated sulfuric acid 400 grams heated to 100 degrees with stirring l h, after the reaction was added to the water to precipitate a solid, filtered and washed, dried to give a white solid 77 grams, yield 90.09%.
	With sulfuric acid;	(1) 11.3 g of 3-cyano-2,6-dichloro-4-trifluoromethylpyridine was gradually added to 22.6 ml of concentrated sulfuric acid, and then the mixture was heated and reacted at 100 C. for one hour. After completion of the reaction, the mixture was poured into ice water, whereupon white precipitates formed. The precipitates were collected by filtration, and the filtrate was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a white solid. This solid and the precipitates previously obtained, were put together to obtain 9.2 g of 2,6-dichloro-4-trifluoromethyl-3-pyridine carboxamide.
	With sulfuric acid; In water; at 90℃; for 10h;	Step 3. At room temperature, into a 250 ml reaction flask containing 2 g of REOCl nanocatalyst, 10 g of <strong>[13600-42-5]2,6-dichloro-3-cyano-4-trifluoromethylpyridine</strong> and 20 ml of water were sequentially added, stirred, and slowly added dropwise. 25ml concentration of 98% concentrated sulfuric acid, after the addition is completed, the reaction liquid is heated to 90 C, the reaction is kept for 10 hours, and cooled to room temperature;Step 4. Pour the above reaction solution into 100 ml of ice water and stir it a little.There are a lot of white solids, which are filtered, filtered, and dried.The intermediate 2,6-dichloro-4-trifluoromethylnicotinamide was obtained.

With sulfuric acid; sodium bromide;

three,Mixing <strong>[13600-42-5]2,6-dichloro-3-cyano-4-trifluoromethylpyridine</strong> with sodium bromide,Then add 80% sulfuric acid to the solution.After filtration, 2,6-dichloro-4-trifluoromethylnicotinamide is obtained;

Reference： [1]Patent: CN107382848,2017,A .Location in patent: Paragraph 0043; 0048-0049
[2]Patent: US5360806,1994,A
[3]Patent: CN108530352,2018,A .Location in patent: Paragraph 0008
[4]Patent: CN109232407,2019,A .Location in patent: Paragraph 0021; 0025; 0031; 0035; 0038; 0042; 0045; 0049

30
[ 4541-14-4 ]
[ 13600-42-5 ]
[ 846036-02-0 ]

Yield	Reaction Conditions	Operation in experiment
		[1139] A first intermediate compound, 6-(4-Benzyloxy-butoxy)-2-chloro-4-trifluoromethyl-nicotinonitrile, was produced as follows: A solution of 2,6-dichloro-4-(trifluoromethyl)niconitrile (20 g, 83 mmol) in THF (200 mL) was cooled to -70 C. Separately, a solution of 4-benzyloxy-1-butanol (15.41 g, 85.5 mmol) in THF (150 mL) was cooled to -40 C. and 1M potassium t-butoxide in THF (85.5 mL) was added dropwise and the temperature was allowed to reach 10 C. over 15 minutes. The solution thus prepared was added to the solution of 2,6-dichloro-4-(trifluoromethyl)niconitrile at -70 C. over 2 hours, followed by warming to 25 C. for 16 hours. The THF was removed in vacuo and the residue was partitioned between ether and water. The ether phase was washed with 1N citric acid, brine, dried over magnesium sulfate and filtered. The filtrate was evaporated to an oil, which was sufficiently pure to be used in the next step.

Reference： [1]Patent: US2005/43309,2005,A1 .Location in patent: Page/Page column 87

31
[ 54524-31-1 ]
[ 13600-42-5 ]
[ 73874-95-0 ]
[ 850180-46-0 ]

Yield	Reaction Conditions	Operation in experiment
67%		3-Cyano-2,6-dichloro-4-trifluoromethylpyridine (482 mg, 2.00 mmol) was dissolved in 10 mL of absolute EtOH. To this solution at 0 C was added 4-N-boc-aminopiperidine (401 mg, 2.00 mmol) followed by triethylamine (0.30 mL, 2.2 mmol). This mixture was stirred at 0 C for 1 h. A stock solution of mercaptoacetonitrile (1.2 mL, 2.4 mmol) was added followed by triethylamine (0.30 mL, 2.2 mmol). This reaction mixture was heated at 80 C for 4 h. Water was added and the resulting solid was collected by filtration to give a yellow crystalline product (0.59 g, 67%).

Reference： [1]Patent: WO2005/35537,2005,A2 .Location in patent: Page/Page column 59

32
[ 1228430-59-8 ]
[ 13600-42-5 ]
[ 1228431-27-3 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 80℃; for 2h;	[((1R,4S,6R)-3-[6-methyl-3-(2-pyrimidinyl)-2-pyridinyl]carbonyl}-3-azabicyclo[4.1.0]hept-4-yl)methyl]amine D25 (50 mg), 2,6-dichloro-4-(trifluoromethyl)-3-pyridinecarbonitrile (37.3 mg, 0.155 mmol), DIPEA (0.054 ml, 0.309 mmol) were collected in DMSO (2 ml) and shaken at 80 C. for 2 hours, then solvent was removed under vacuum, and the resulting crude was purified on a Biotage SP1 over a 50 g C18 SNAP column (with a gradient of ACN and water, modified with 0.5% HCOOH). Fractions containing the product were collected and neutralised with a 2 g SCX column (washing with MeOH and eluting with 2 M ammonia in MeOH) to give the title compound D111 (31 mg) and a second batch with lower purity (30 mg) which was further purified (Biotage SP1, over a column stacking of 2×4 g Analogix column, eluting with a gradient of DCM and MeOH) to give the title compound D111 (17 mg). UPLC (Acid GEN_QC SS): rt1=0.93 minutes and rt2=0.95 (rotamers present), peaks observed: 528 (M+1). C25H21ClF3N7O requires 527.

Reference： [1]Patent: US2010/144760,2010,A1 .Location in patent: Page/Page column 45

33
[ 96-20-8 ]
[ 13600-42-5 ]
C₁₁H₁₁ClF₃N₃O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With diisopropylamine; at 70℃;sealed tube;	Example VIII. Synthesis of 2-chloro-6-[5-ethyl-2-(2-pyridyl)oxazolidin-3-yl]-4- (trifluoromethyl) pyridine-3-carbonitrile (Compound 17).; Step 1 : Synthesis of 2-chloro-6-(2-hydroxybutylamino)-4-(trifluoromethyl)pyridine- 3-carbonitrile.; Neat 3-cyano-2,6-dichloro-4-trifiuoromethylpyridine (0.641 g, 6 mmol) was added by pipette at a dropwise rate over 3 minutes to 2-aminobutanol (1.5 g, 6 mmol). Di-isopropylamine (0.9 g, 7 mmol) was added after 10 minutes and the resultant mixture was heated in a sealed tube at 70 C for 30 minutes to selectively displace the chlorine at position 6 before quenching in ice-cold water and extracted with dichloromethane. Organic extracts were washed twice with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was washed with diethylether and the resultant solid was used in the next step without further purification. 2-Chloro-6-(2-hydroxybutylarnino)-4-(trifluoromethyl) pyridine-3- carbonitrile was isolated in 55 % yield. 1HNMR (CDCl3, 400 MHz) delta / ppm 6.64 (s, IH), 5.96 (br, IH), 3.78 (br, IH), 3.32 (br, IH), 1.94 (br d, J = 4.1 Hz, IH), 1.65 - 1.50 (m, 4H), 1.02 (t, J = 7.5 Hz, 3H).

Reference： [1]Patent: WO2010/126580,2010,A1 .Location in patent: Page/Page column 21-22

34
[ 16369-05-4 ]
[ 13600-42-5 ]
[ 1253678-11-3 ]

Yield	Reaction Conditions	Operation in experiment
50%	With diisopropylamine; at 70℃;sealed tube;	Example VI. Synthesis of 2-chloro-6-[4-isopropyl-2-(2-pyridyl)oxazolidin-3-yl]-4- (trifluoromethyl) pyridine-3-carbonitrile (Compound 12);.Step 1 : Preparation of 2-chloro-6- [ [ 1 -(hydroxymethyl)-2-methyl -propyl] amino] -4- (trifluoromethyl) pyridine-3-carbonitrile intermediate.; Neat 3-cyano-2,6-dichloro-4-trifluoromethylpyridine (0.641 g, 6 mmol) (Compound 14) was added by pipette at a dropwise rate over 3 minutes to 2-amino- 3-methyl-butan-l-ol (1.5 g, 6 mmol) (Compound 15). Di-isopropylamine (0.9 g, 7 mmol) was added after 10 minutes and the resultant mixture was heated in a sealed tube at 70 C for 30 minutes to selectively displace the chlorine at position 6 before quenching in ice-cold water and extracted with dichloromethane. Organic extracts were washed twice with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was washed with diethylether and the resultant solid was used in the next step without further purification. 2-Chloro-6-[[l- (hydroxymethyl)-2-methyl -propyl] amino] -4-(trifluoromethyl) pyridine-3-carbonitrile (Compound 13) was isolated in 50 % yield. 1HNMR (CDCl3, 400 MHz) delta / ppm 6.66 (s, IH), 5.63 (br, IH), 4.09 (br, 0.7H), 3.81 (t, J = 4.5 Hz, 2.4 H), 2.01 (octet, J= 6.9 Hz, IH), 1.70 (br t, J= 4.9 Hz, 0.9 H), 1.03 (d, J= 6.7 Hz, 3H), 1.00 (d, J= 6.8 Hz, 3H).

Reference： [1]Patent: WO2010/126580,2010,A1 .Location in patent: Page/Page column 18

35
[ 6168-72-5 ]
[ 13600-42-5 ]
[ 1326647-10-2 ]

Yield	Reaction Conditions	Operation in experiment
52%	With diisopropylamine; at 70℃;sealed tube;	Example VII. Synthesis of 2-chloro-6-[4-methyl-2-(2-pyridyl)oxazolidin-3-yl]-4- (trifluoromethyl) pyridine-3-carbonitrile (Compound 16).; Step 1 : Synthesis of 2-chloro-6-[[ 1 -(hydroxymethyl)-2-methyl]amino]-4- (trifluoromethyl) pyridine-3-carbonitrile.; Neat 3-cyano-2,6-dichloro-4-trifluoromethylpyridine (0.641 g, 6 mmol) was added by pipette at a drop wise rate over 3 minutes to 2-aminopropanol (1.5 g, 6 mmol). Di-isopropylamine (0.9 g, 7 mmol) was added after 10 minutes and the resultant mixture was heated in a sealed tube at 70 C for 30 minutes to selectively displace the chlorine at position 6 before quenching in ice-cold water and extracted with dichloromethane. Organic extracts were washed twice with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was washed with diethylether and the resultant solid was used in the next step without further purification. 2-Chloro-6-[[ 1 -(hydroxymethyl)-2-methyl]amino]-4-(trifluoromethyl) pyridine-3-carbonitrile was isolated in 52 % yield.1HNMR (CDCl3, 400 MHz) delta / ppm 6.63 (s, IH), 4.27 (br, 0.8 H), 3.84 - 3.79 (m, 1.2 H), 3.70 - 3.65 (m, 1.3H), 1.80 (br t, 0.8 H), 1.58 (s, 1.3 H), 1.30 (d, J = 6.7 Hz, 3H).

Reference： [1]Patent: WO2010/126580,2010,A1 .Location in patent: Page/Page column 19-20

36
[ 13600-42-5 ]
[ 20989-17-7 ]
[ 1253678-21-5 ]

Yield	Reaction Conditions	Operation in experiment
60%	With diisopropylamine; at 70℃;sealed tube;	Example IX. 2-chloro-6-[4-phenyl-2-(2-pyridyl)oxazolidin-3-yl]-4-(trifluoromethyl) pyridine-3-carbonitrile (Compound 18).; Step 1 : Synthesis of 2-chloro-6-[[l-(hydroxymethyl)-2-phenyl]amino]-4- (trifluoromethyl) pyridine-3-carbonitrile.; Neat 3-cyano-2,6-dichloro-4-trifluoromethylpyridine (0.641 g, 6 mmol) was added by pipette at a dropwise rate over 3 minutes to 2-amino-2-phenylethanol (1.5 g, 6 mmol). Di-isopropylamine (0.9 g, 7 mmol) was added after 10 minutes and the resultant mixture was heated in a sealed tube at 70 C for 30 minutes to selectively displace the chlorine at position 6 before quenching in ice-cold water and extracted with dichloromethane. Organic extracts were washed twice with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was washed with diethylether and the resultant solid was used in the next step without further purification. 2-Chloro-6-[[ 1 -(hydroxymethyl)-2-phenyl]amino]-4-(trifluoromethyl) pyridine-3-carbonitrile was isolated in 60 % yield.1HNMR (CDCl3, 400 MHz) delta / ppm7.42 - 7.33 (m, 5H), 6.51 (br, 2H), 4.06 - 4.03 (m, 1.4 H), 3.96 (br, 1.1 H), 1.89 (br, 0.96 H), 1.60 (m, 1.1 H).

Reference： [1]Patent: WO2010/126580,2010,A1 .Location in patent: Page/Page column 22-23

37
[ 402-45-9 ]
[ 13600-42-5 ]
2-(2-chloro-4-(trifluoromethyl)phenyl)-4-(trifluoromethyl)-6-(4-(trifluoromethyl)phenoxy)-2H-pyrazolo[3,4-b]pyridin-3-amine [ No CAS ]

Reference： [1]Patent: WO2014/126580,2014,A1

38
[ 402-45-9 ]
[ 13600-42-5 ]
2-chloro-4-(trifluoromethyl)-6-(4-(trifluoromethyl)phenoxy)nicotinonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With potassium phosphate; In acetonitrile; at 80℃; for 20h;	Procedure adapted from Akama, T. et al , WO 2009/111676 using 2,6-dichloro-4- (trifluoromethyl)nicotinonitrile (100 mg, 0.411 mmol) mixed with a solution of 4- (trifluoromethyl)phenol (69.4 mg, 0.424 mmol) in acetonitrile (2 mL). To the clear, colorless solution was added potassium phosphate (90 mg, 0.411 mmol) at room temperature causing the reaction mixture to turn a light yellow color. The mixture was heated at 80 C for 20 h, cooled to room temperature and transferred to a 60 mL separatory funnel containing EtOAc (40 mL) and H20 (10 mL). The phases were separated and the organic phase washed with brine (2 x 10 mL), dried (MgS04) and purified by column chromatography (Hexane-EtOAc gradient; 12 g column) to afford the title compound (117 mg, 76%) as a white, crystalline compound: ]H NMR (400 MHz, CDC13) delta 7.79 - 7.71 (m, 2H), 7.36 - 7.26 (m, 3H); 19F NMR (376 MHz, CDCl3) delta -62.28, -64.40; ESIMS m/z 367.1 ([M+H]+).

Reference： [1]Patent: WO2014/126580,2014,A1 .Location in patent: Page/Page column 78

39
[ 546-88-3 ]
[ 13600-42-5 ]
6-chloro-4-(trifluoromethyl)isoxazolo[5,4-b]pyridin-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
4%	at 120℃; for 20h;	General procedure: 6-Chloro-4-(trifluoromethyl)isoxazolo[5,4-b]pyridin-3-amine (68) A neat mixture of <strong>[13600-42-5]2,6-dichloro-4-(trifluoromethyl)nicotinonitrile</strong> (102 mg, 0.42 mmol) and acetohydroxamic acid (315 mg 4.2 mmol) was heated to 120 C for 20 hr. The cooled reaction mixture was then diluted with H20, basified with K2C03, extracted into EtOAc, and the solution dried (Na2S04). Evaporation of the solvents and the chromatography of the residue (Si02/pet. ether/EtOAc 0-20%) gave 68 (4.0 mg, 4% yield), *H NMR [(CD3)2SO] delta 7.95 (d, J = 0.6 Hz, 1H), 6.24 (brs, 2H), HPLC 99.5%, LCMS [M + H] = 238.

Reference： [1]Patent: WO2016/24233,2016,A1 .Location in patent: Page/Page column 46; 47

40
[ 372-20-3 ]
[ 13600-42-5 ]
2-chloro-6-(3-fluorophenoxy)-4-(trifluoromethyl)pyridine-3-carbonitrile [ No CAS ]
6-chloro-2-(3-fluorophenoxy)-4-(trifluoromethyl)pyridine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dimethyl sulfoxide; at 70℃; for 2h;	To a solution of <strong>[13600-42-5]2,6-dichloro-4-(trifluoromethyl)pyridine-3-carbonitrile</strong> (75 mg, 0.311 mmol) in DMSO (1mL) K2C03 (52 mg, 0.373 mmol) and 3-fluorophenol (28 ilL, 0.311 mmol) were added and the mixturewas heated to 70 C and shaken at that temperature for 2 hrs. The mixture was cooled down to RT, diluted with DCM and washed with water. Organic phase was dried and evaporated under reduced pressure. Crude material was purified by FC on silica gel (eluent: Cy to Cy/AcOEt 7:3) affording a mixture of the 2 regioisomers 2-chloro-6-(3-fluorophenoxy)-4-(trifluoromethyl)pyridine-3-carbonitrile and 6-chloro-2-(3-fluorophenoxy)-4-(trifluoromethyl)pyridine-3-carbonitrile (p29, 53 mg, y= 54%). MS (ES) (m/z): 316.9 [M÷H]

Reference： [1]Patent: WO2016/42452,2016,A1 .Location in patent: Page/Page column 109

41
[ 372-20-3 ]
[ 13600-42-5 ]
tert-butyl 9-[5-cyano-6-(3-fluorophenoxy)-4-(trifluoromethyl)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]

Reference： [1]Patent: WO2016/42452,2016,A1

42
[ 1251668-97-9 ]
[ 13600-42-5 ]
ethyl {(1R,5S,6s)-3-[6-chloro-5-cyano-4-(trifluoromethyl)pyridin-2-yl]-3-azabicyclo[3.1.0]hex-6-yl}acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With sodium hydrogencarbonate In ethanol at 20℃; Inert atmosphere;

Reference： [1]Futatsugi, Kentaro; Smith, Aaron C.; Tu, Meihua; Raymer, Brian; Ahn, Kay; Coffey, Steven B.; Dowling, Matthew S.; Fernando, Dilinie P.; Gutierrez, Jemy A.; Huard, Kim; Jasti, Jayasankar; Kalgutkar, Amit S.; Knafels, John D.; Pandit, Jayvardhan; Parris, Kevin D.; Perez, Sylvie; Pfefferkorn, Jeffrey A.; Price, David A.; Ryder, Tim; Shavnya, Andre; Stock, Ingrid A.; Tsai, Andy S.; Tesz, Gregory J.; Thuma, Benjamin A.; Weng, Yan; Wisniewska, Hanna M.; Xing, Gang; Zhou, Jun; Magee, Thomas V. [Journal of Medicinal Chemistry, 2020, vol. 63, # 22, p. 13546 - 13560]

43
ethyl 2-[1R,5S]-3-azabicyclo[3.1.0]hex-6-ylacetate [ No CAS ]
[ 13600-42-5 ]
ethyl 2-{(1R,5S)-3-[6-chloro-5-cyano-4-(trifluoromethyl)pyridin-2-yl]-3-azabicyclo[3.1.0]hex-6-yl}acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With sodium hydrogencarbonate; In ethanol; at 20℃;	A suspension of <strong>[13600-42-5]2,6-dichloro-4-(trifluoromethyl)pyridine-3-carbonitrile</strong> (2.4 g, 9.8 mmol), ethyl (1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-ylacetate (1.7 g, 9.8 mmol) and NaHCO3 (2.6 g, 31 mmol), in ethanol (25 mL) was stirred at rt overnight. The reaction mixture was concentrated, diluted with saturated aqueous NaHCO3 and extracted with EtOAc (3*25 mL). The combined organics were washed with water, dried over Na2SO4, filtered and concentrated. The crude was purified by silica gel chromatography (10-35% EtOAc in n-heptane) to afford the title compound as an off-white solid (2.2 g, 57%). MS (ES+): 374.2 (M+H), 1H NMR (600 MHz, DMSO-d6) delta: 6.90 (s, 1H), 4.07 (q, 2H), 3.79 (m, 2H), 3.67-3.53 (m, 2H), 2.43-2.21 (m, 2H), 1.75-1.57 (m, 2H), 1.19 (t, 3H), 0.81 (dt, 1H).

Reference： [1]Patent: US2017/183328,2017,A1 .Location in patent: Paragraph 0345

44
[ 13600-42-5 ]
(S)-2-(3-hydroxy-3-methylpyrrolidin-1-yl)-6-(4-(2-hydroxyethyl)piperazin-1-yl)-4-(trifluoromethyl)nicotinonitrile [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 7835 - 7849

45
[ 13600-42-5 ]
6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-2-((S)-3-hydroxy-3-methylpyrrolidin-1-yl)-4-(triifluoromethyl)nicotinonitrile [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 7835 - 7849

46
[ 13600-42-5 ]
6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-(3-(hydroxymethyl)piperidin-1-yl)-4-(trifluoromethyl)nicotinonitrile [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 7835 - 7849

47
[ 13600-42-5 ]
[ 90481-32-6 ]
2-chloro-6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-4-(trifluoromethyl)nicotinonitrile [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 7835 - 7849

48
[ 103-76-4 ]
[ 13600-42-5 ]
2-chloro-6-(4-(2-hydroxyethyl)piperazin-1-yl)-4-(trifluoromethyl)nicotinonitrile [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 7835 - 7849

49
[ 13600-42-5 ]
N-cyanomethyl-N,N-bis(4-trifluoromethylnicotinoyl)amine [ No CAS ]

Reference： [1]Patent: CN107286086,2017,A

50
[ 13600-42-5 ]
[ 158063-66-2 ]

Reference： [1]Patent: CN107286086,2017,A
[2]Patent: CN108191749,2018,A
[3]Patent: CN109232407,2019,A

51
[ 13600-42-5 ]
3-cyano-2,6-difluoro-4-(trifluoromethyl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65.5%	With potassium fluoride; 18-crown-6 ether; In N,N-dimethyl-formamide; at 130℃;	A 250 ml four-necked flask was charged with 53 g of 2,6-dichloro-3-cyano-4- (trifluoromethyl)pyridine, KF grams 35 grams, 18 crown ether 10 grams, DMF 250ml, warming to 130 degrees, insulation 3-5 hours, after the reaction was added to the water precipitated a yellow solid, after drying 30 g, hplc 92%, yield 65.5%.
65.5%	With potassium fluoride; 18-crown-6 ether; In N,N-dimethyl-formamide; at 130℃;	Add <strong>[13600-42-5]2,6-dichloro-3-cyano-4-(trifluoromethyl)pyridine</strong> 53 g to a 250 ml four-necked flask.KF 35 grams, 18 crown ether 10 grams, DMF 250ml,Warm up to 130 degrees, keep warm for 3-5 hours,After the reaction is completed, it is added to water to precipitate a yellow solid, and 30 g after drying,Hplc 92%, yield 65.5%.

Reference： [1]Patent: CN107382848,2017,A .Location in patent: Paragraph 0050-0052
[2]Patent: CN108822028,2018,A .Location in patent: Paragraph 0026; 0031; 0032

52
[ 13600-42-5 ]
2,6-difluoro-4-(trifluoromethyl)nicotinamide [ No CAS ]

Reference： [1]Patent: CN107382848,2017,A

53
[ 13600-42-5 ]
[ 13600-43-6 ]

Yield	Reaction Conditions	Operation in experiment
95.22%	With palladium on activated carbon; hydrogen; triethylamine; In tetrahydrofuran; for 4h;	10 wt% Pd/C, 100 g (988 mmol) Et3N, 100 g (415 mmol) <strong>[13600-42-5]2,6-dichloro-3-cyano-4-trifluoromethylpyridine</strong>, 1 L THF were added to a 5 L reaction flask, and the reaction flask was replaced with hydrogen three times. The reaction was stirred for 4 hours, and the solid material in the reaction vessel was collected by filtration, and the filtered liquid was distilled under reduced pressure to give 68 g (395 mmol) of 3-cyano-4-trifluoromethylpyridine liquid, yield 95.22%.

Reference： [1]Patent: CN108191749,2018,A .Location in patent: Paragraph 0029; 0052; 0056; 0072; 0078

54
[ 13600-42-5 ]
flonicamide [ No CAS ]

Reference： [1]Patent: CN108191749,2018,A

55
2,6-dihydroxy-3-cyano-4-trifluoromethylpyridine N-methylmorpholine [ No CAS ]
[ 13600-42-5 ]

Yield	Reaction Conditions	Operation in experiment
88.66%	With trichlorophosphate; at 130℃; for 18h;Inert atmosphere;	Weigh 100g (328mmol) of 2,6-dihydroxy-3-cyano-4-trifluoromethylpyridine N-methylmorpholine salt and 500g (3.26mol) of POCl3 into a 1L three-port reaction bottle with reflux condenser Medium, turn on the condensate. Under nitrogen protection, the temperature of the oil was raised to 130 C, and the reaction was refluxed for 18 hours. After the heating was stopped, the temperature of the material was cooled to 70 C, and distillation under reduced pressure was carried out to recover unreacted POCl 3 . The residue was cooled to 0-5 C, poured into ice-water mixture, and extracted with ethyl acetate three times. The organic phase was combined and dried and concentrated to give 70 g (290 mmol) of 2,6-dichloro-3-cyano-4-trifluoromethylpyridine, yield 88.66%.

Reference： [1]Patent: CN108191749,2018,A .Location in patent: Paragraph 0029; 0052; 0055; 0071; 0077

56
[ 13600-42-5 ]
[ 158062-71-6 ]

Reference： [1]Patent: CN109232407,2019,A

57
[ 13600-42-5 ]
methyl 2-[(3R)-1-[5-cyano-6-[(2S)-2-methylazetidin-1-yl]-4-(trifluoromethyl)-2-pyridyl]pyrrolidin-3-yl]acetate [ No CAS ]

Reference： [1]Patent: US2020/71331,2020,A1

58
[ 13600-42-5 ]
methyl 2-[1-[5-cyano-6-[(2S)-2-methylazetidin-1-yl]-4-(trifluoromethyl)-2-pyridyl]azetidin-3-yl]acetate [ No CAS ]

Reference： [1]Patent: US2020/71331,2020,A1

59
[ 13600-42-5 ]
2-[(3R)-1-[5-cyano-6-[(2S)-2-methylazetidin-1-yl]-4-(trifluoromethyl)-2-pyridyl]pyrrolidin-3-yl]acetic acid [ No CAS ]

Reference： [1]Patent: US2020/71331,2020,A1

60
[ 13600-42-5 ]
2-[1-[5-cyano-6-[(2S)-2-methylazetidin-1-yl]-4-(trifluoromethyl)-2-pyridyl]azetidin-3-yl]acetic acid [ No CAS ]

Reference： [1]Patent: US2020/71331,2020,A1

61
[ 1024038-31-0 ]
[ 13600-42-5 ]
methyl 2-[(3R)-1-[6-chloro-5-cyano-4-(trifluoromethyl)-2-pyridyl]pyrrolidin-3-yl]acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With sodium hydrogencarbonate; In ethanol; at 20℃;	Preparation 3 Methyl 2-[(3R)-1-[6-chloro-5-cyano-4-(trifluoromethyl)-2-pyridyl]pyrrolidin-3-yl]acetate To a RBF add <strong>[13600-42-5]3-cyano-2,6-dichloro-4-(trifluoromethyl)pyridine</strong> (123 mmol, 29.6 g) and EtOH (230 mL). Cool the mixture to 0 C. Add NaHCO3 (368 mmol, 31 g) followed by a solution of methyl (R)-pyrrolidine-3-acetate hydrochloride (23 g, 123 mmol) in EtOH (230 mL). Allow the resulting mixture to warm to RT overnight. Evaporate the reaction mixture to dryness on a rotary evaporator. Add water (200 mL) and extract with MTBE (2*200 mL). Combine the extracts and evaporate to dryness. Purify by chromatography on silica gel using hexane/MTBE (gradient from 20 to 70%) to give the title compound (34.7 g, 99.89 mmol, 81% Yield) as a white solid. ES/MS (m/z): 348.0, 350.0 [M+H]+.

Reference： [1]Patent: US2020/71331,2020,A1 .Location in patent: Paragraph 0055-0056

62
methyl 2-(azetidin-3-yl)acetate trifluoroacetic acid salt [ No CAS ]
[ 13600-42-5 ]
methyl 2-[1-[6-chloro-5-cyano-4-(trifluoromethyl)-2-pyridyl]azetidin-3-yl]acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With sodium hydrogencarbonate; In ethanol; at 20℃; for 16h;	Preparation 5 Methyl 2-[1-[6-chloro-5-cyano-4-(trifluoromethyl)-2-pyridyl]azetidin-3-yl]acetate To a solution of <strong>[13600-42-5]3-cyano-2,6-dichloro-4-(trifluoromethyl)pyridine</strong> (500 mg, 2.03 mmol) in EtOH (15 mL) add NaHCO3 (0.549 g, 6.51 mmol) and methyl 2-(azetidin-3-yl)acetate trifluoroacetic acid salt (0.494 g, 2.03 mmol). Stir the mixture at RT for 16 h. Dilute the reaction mixture with sat. aq. NaCl solution (30 mL). Extract with EtOAc (20 mL*3). Combine the extracts and wash with sat. aq. NaCl solution (30 mL), dry over anhydrous Na2SO4, filter, and concentrate. Purify the residue by column chromatography on silica gel eluting with EtOAc in petroleum ether (gradient 0-30%) to give the title compound (470 mg, 1.41 mmol, 66% Yield) as a white solid. ES/MS (m/z)=333.9 [M+H]+.

Reference： [1]Patent: US2020/71331,2020,A1 .Location in patent: Paragraph 0059-0060

63
[ 877399-35-4 ]
[ 13600-42-5 ]
tert-butyl 3-[4-[6-chloro-5-cyano-4-(trifluoromethyl)-2-pyridyl]pyrazol-1-yl]azetidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 85℃; for 1h;Sealed tube;	To a vial add 3-cyano-2,6-dichloro-4-(trifluoromethyl)pyridine (0.360 g, 1.49 mmol), 1,4-dioxane (7.5 ml), <strong>[877399-35-4]tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate</strong> (0.727 g, 1.98 mmol), tetrakis(triphenylphosphine)palladium(0) (95 mg, 0.08 mmol), and 2M aqueous sodium carbonate (2.8 mL, 5.6 mmol, 2 mol/L). Seal the vessel and heat in a microwave reactor at 85 C. for 1 h. Dilute with saturated sodium bicarbonate and extract twice with EtOAc. Combine the extracts, dry over sodium sulfate, filter and evaporate. Purify the residue by silica gel chromatography using a gradient of 0 to 90% EtOAc/hexanes to give the title compound (0.609 g, 95%). ES/MS (m/z): 426, 428 (M-H).

Reference： [1]Patent: US2020/392118,2020,A1 .Location in patent: Paragraph 0152-0153

64
[ 877399-35-4 ]
[ 13600-42-5 ]
tert-butyl 3-[4-[5-cyano-6-[(2S)-2-methylazetidin-1-yl]-4-(trifluoromethyl)-2-pyridyl]pyrazol-1-yl]azetidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: US2020/392118,2020,A1

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[ 1319804-30-2 ]

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Related Parent Nucleus of
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Ghs Precautionary Statements

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Ghs Hazard Statements

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere