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[ CAS No. 55304-75-1 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}

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

2D 3D

Chemical Structure| 55304-75-1

Chemical Structure| 55304-75-1

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Quality Control of [ 55304-75-1 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 55304-75-1 ]

SDS Specification

Alternatived Products of [ 55304-75-1 ]

Product Details of [ 55304-75-1 ]

CAS No. :	55304-75-1	MDL No. :	MFCD00042245
Formula :	C₆H₂Cl₂F₃N	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UPWAAFFFSGQECJ-UHFFFAOYSA-N
M.W :	215.99	Pubchem ID :	1810337
Synonyms :

Calculated chemistry of [ 55304-75-1 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.17
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	39.26
TPSA :	12.89 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.02 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.01
Log Po/w (XLOGP3) :	3.66
Log Po/w (WLOGP) :	4.56
Log Po/w (MLOGP) :	2.75
Log Po/w (SILICOS-IT) :	3.68
Consensus Log Po/w :	3.33

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.79
Solubility :	0.0351 mg/ml ; 0.000163 mol/l
Class :	Soluble
Log S (Ali) :	-3.62
Solubility :	0.0518 mg/ml ; 0.00024 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.15
Solubility :	0.0153 mg/ml ; 0.0000708 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	1.94

Safety of [ 55304-75-1 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P280-P305+P351+P338	UN#:
Hazard Statements:	H302-H312-H315-H319-H332	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 55304-75-1 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 55304-75-1 ]
Downstream synthetic route of [ 55304-75-1 ]

[ 55304-75-1 ] Synthesis Path-Upstream 1~6

1
[ 81290-20-2 ]
[ 148493-37-2 ]
[ 55304-75-1 ]

Yield	Reaction Conditions	Operation in experiment
97.3%	Stage #1: With potassium fluoride; copper(l) iodide In tetrahydrofuran; N,N-dimethyl-formamide at 20 - 50℃; for 21 h; Stage #2: at 50℃;	Production Example 962- (4-{2- [6- (4-acetylpiperazin-l-yl) -3- (trifluoromethyl)pyridin-2-yl] ethyl }phenyl) acetohydrazide dihydrochloride step 1 [0304] [0305]Potassium fluoride (2.24 g, 38.5 mmol) and copper (I) iodide (7.33 g, 38.5 mmol) were weighed in a flask, and the mixture was heated with a gas burner while gently shaking under high vacuum until the content becomes a pale-yellow green. After cooling to room temperature, anhydrous N, N- dimethylformamide (50 ml) , anhydrous tetrahydrofuran (10 ml) and trimethyl (trifluoromethyl) silane (5.5 ml, 35 mmol) were added. The mixture was heated to 5O⁰C, and stirred for 21 hrs. A mixed solution of 2, β-dichloro-3-iodopyridine (9.59 g, 35.0 mmol) in anhydrous N, N-dimethyIformamide (10 ml)- anhydrous tetrahydrofuran (20 ml) was added dropwise to the above- mentioned reaction mixture at 5O⁰C. After stirring at 50°C for 21 hrs, trimethyl (trifluoromethyl) silane (0.55 ml, 3.5 mmol) was added, and the mixture was stirred for 24 hrs. The reaction mixture was cooled to room temperature, poured into 12percent aqueous ammonia, and the mixture was extracted 3 times with diethyl ether. The combined organic layer was washed successively with 12percent aqueous ammonia, IM hydrochloric acid, <n="113"/>saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:hexane = 1:4) to give 2, 6-dichloro~3- (trifluoromethyl) pyridine (7.32 g, yield 97.3percent)

Reference： [1] Patent: WO2009/145360, 2009, A1, . Location in patent: Page/Page column 111-112

2
[ 261956-65-4 ]
[ 55304-75-1 ]

Yield	Reaction Conditions	Operation in experiment
50%	at 80℃; for 17 h;	2-Chloro-5-trifluoromethyl-pyridine-N-oxide (17, 4 mmol) was dissolved in freshly distilled POCl₃ (4.5 mL). The reaction mixture was heated to 80° C. for 17 h. After cooling to room temperature, the solvent was removed under reduced pressure. Ice was added, and the mixture was allowed to stand for 4 h. The mixture was partition between CH₂Cl₂ (50 mL) and saturated aqueous NaHCO₃. Column chromatography afforded compound 18 as yellow oil (yield: 50percent).; Intermediate 21 (4 mmol) was dissolved in freshly distilled POCl₃(4.5 mL). The reaction mixture was heated to 80° C. for 17 h. After cooling to room temperature, the solvent was removed under reduced pressure. Ice was added, and the mixture was allowed to stand for 4 h. The mixture was partition between CH₂Cl₂(50 mL) and saturated aqueous NaHCO₃. Column chromatography afforded compound 2 as yellow oil (yield: 50percent).

Reference： [1] Patent: US2008/275057, 2008, A1, . Location in patent: Page/Page column 68; 71
[2] Patent: WO2006/42289, 2006, A2, . Location in patent: Page/Page column 57-58

3
[ 55366-30-8 ]
[ 7783-56-4 ]
[ 87-69-4 ]
[ 55304-75-1 ]

Reference： [1] Patent: US3974166, 1976, A,

4
[ 52334-81-3 ]
[ 55304-75-1 ]

Reference： [1] Patent: US2008/275057, 2008, A1,

5
[ 55304-75-1 ]
[ 100366-75-4 ]

Reference： [1] Journal of Organic Chemistry, 1986, vol. 51, # 6, p. 953 - 954

6
[ 110-85-0 ]
[ 55304-75-1 ]
[ 132834-56-1 ]

Reference： [1] Patent: US2004/38985, 2004, A1,

[ 55304-75-1 ] Synthesis Path-Downstream 1~88

1
[ 120-43-4 ]
[ 55304-75-1 ]
[ 132844-45-2 ]

Reference： [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1527 - 1536

2
[ 55304-75-1 ]
[ 3964-52-1 ]
[ 78743-29-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; In dimethyl sulfoxide;	EXAMPLE 1 In a flask, a solution of 1.43 g. of 2-chloro-4-aminophenol in 20 ml. of dimethylsulfoxide and 1.12 g. of potassium hydroxide were charged and the mixture was heated at 140 C. for 1 hour to produce a potassium salt. The reaction mixture was cooled to the ambient temperature. A solution of 2.16 g. of 2,6-dichloro-3-trifluoromethyl pyridine in 10 ml. of dimethylsulfoxide was added dropwise during 10 minutes. The mixture was heated at 100 C. for 2 hours to react them. After the reaction, the reaction mixture was poured into water and extracted with methylene chloride. The extracted product was washed with water and dehydrated over anhydrous sodium sulfate. Methylenechloride was distilled off to obtain 2.16 g. of 3-chloro-4-(5-trifluoromethyl-6-chloro-2-pyridyloxy)aniline (melting point of 76 to 78 C.).

Reference： [1]Chemical and Pharmaceutical Bulletin,1991,vol. 39,p. 2308 - 2315
[2]Patent: US4321388,1982,A

3
[ 55304-75-1 ]
[ 65032-46-4 ]
[ 132844-53-2 ]

Reference： [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1527 - 1536

4
[ 55304-75-1 ]
[ 124-41-4 ]
[ 136353-03-2 ]
[ 136353-04-3 ]

Reference： [1]Journal of Heterocyclic Chemistry,1991,vol. 28,p. 971 - 976
[2]Journal of Heterocyclic Chemistry,1991,vol. 28,p. 971 - 976

5
[ 55304-75-1 ]
[ 132844-48-5 ]
[ 132844-54-3 ]

Reference： [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1527 - 1536

6
[ 55304-75-1 ]
[ 131775-91-2 ]
[ 132844-56-5 ]

Reference： [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1527 - 1536

7
[ 55304-75-1 ]
[ 131775-91-2 ]
[ 108-98-5 ]
[ 132844-57-6 ]

Reference： [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1527 - 1536

8
[ 55304-75-1 ]
[ 108-98-5 ]
[ 132844-49-6 ]

Reference： [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1527 - 1536

9
[ 110-91-8 ]
[ 55304-75-1 ]
[ 1007374-25-5 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In N,N-dimethyl-formamide; at 20℃;	A mixture of compound 2e1 (64 mg, 0.30 mmol), morpholine (0.027 mL, 0.31 mmol) and triethylamine (0.050 mL, 0.36 mmol) in DMF (1 mL) is stirred overnight at ambient temperature. The mixture is then diluted with EtOAc and successively washed with water (4×) and brine. The organic phase is dried with MgSO4, filtered and concentrated to afford intermediate 2e2.

Reference： [1]Patent: US2008/45516,2008,A1 .Location in patent: Page/Page column 31

10
[ 55304-75-1 ]
[ 1692-15-5 ]
[ 1007374-26-6 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 100℃;	A mixture of compound 2e1 (Example 2E) (32 mg, 0.15 mmol), 4-pyridylboronic acid (18 mg, 0.15 mmol), Cs2CO3 (72 mg, 0.22 mmol) and Pd(PPh3)4 (9 mg, 0.01 mmol) in DMF (1 mL) is degassed and heated at 100 C. overnight. The mixture is poured into water and extracted three times with EtOAc. The combined organic extracts are washed with water (4×) and brine, dried with MgSO4, then passed through a short pad of silica gel, eluting with excess EtOAc. After concentration, the crude product is purified by flash chromatography (15 to 50% EtOAc-hexane) to afford compound 2f1.

Reference： [1]Patent: US2008/45516,2008,A1 .Location in patent: Page/Page column 31

11
[ 55304-75-1 ]
C₁₀H₇⁽²⁾H₄ClF₃N₃ [ No CAS ]

Reference： [1]Journal of labelled compounds and radiopharmaceuticals,2002,vol. 45,p. 1169 - 1171

12
[ 55304-75-1 ]
[ 149539-81-1 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2001,vol. 49,p. 1621 - 1627

13
[ 55304-75-1 ]
[ 187480-13-3 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2001,vol. 49,p. 1621 - 1627
[2]Chemical and Pharmaceutical Bulletin,2001,vol. 49,p. 1621 - 1627
[3]Chemical and Pharmaceutical Bulletin,2001,vol. 49,p. 1621 - 1627
[4]Chemical and Pharmaceutical Bulletin,2001,vol. 49,p. 1621 - 1627

14
[ 55304-75-1 ]
[ 187480-17-7 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2001,vol. 49,p. 1621 - 1627

15
[ 55304-75-1 ]
[ 187480-15-5 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2001,vol. 49,p. 1621 - 1627

16
[ 55304-75-1 ]
methyl 2-chloro-6-methylaminopyridine-3-carboxylate [ No CAS ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2001,vol. 49,p. 1621 - 1627

17
[ 55304-75-1 ]
[ 405160-57-8 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2001,vol. 49,p. 1621 - 1627

18
[ 55304-75-1 ]
2-chloro-6-methylamino-3-trimethoxymethylpyridine [ No CAS ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2001,vol. 49,p. 1621 - 1627

19
[ 55304-75-1 ]
[ 1026162-63-9 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2001,vol. 49,p. 1621 - 1627

20
[ 55304-75-1 ]
[ 233585-52-9 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2001,vol. 49,p. 1621 - 1627

21
[ 55304-75-1 ]
methyl 5-bromo-2-chloro-6-methylaminopyridine-3-carboxylate [ No CAS ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2001,vol. 49,p. 1621 - 1627

22
[ 55304-75-1 ]
[ 405160-49-8 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2001,vol. 49,p. 1621 - 1627

23
[ 55304-75-1 ]
5-bromo-2-methoxy-6-methylamino-3-trimethoxymethylpyridine [ No CAS ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2001,vol. 49,p. 1621 - 1627

24
[ 55304-75-1 ]
5-bromo-2-chloro-6-methylamino-3-trimethoxymethylpyridine [ No CAS ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2001,vol. 49,p. 1621 - 1627

25
[ 55304-75-1 ]
[ 405160-56-7 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2001,vol. 49,p. 1621 - 1627

26
[ 55304-75-1 ]
[ 78743-20-1 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1991,vol. 39,p. 2308 - 2315

27
[ 55304-75-1 ]
[ 136353-08-7 ]

Reference： [1]Journal of Heterocyclic Chemistry,1991,vol. 28,p. 971 - 976

28
[ 55304-75-1 ]
[ 136353-07-6 ]

Reference： [1]Journal of Heterocyclic Chemistry,1991,vol. 28,p. 971 - 976

29
[ 55304-75-1 ]
[ 136352-98-2 ]

Reference： [1]Journal of Heterocyclic Chemistry,1991,vol. 28,p. 971 - 976

30
[ 55304-75-1 ]
[ 136353-09-8 ]

Reference： [1]Journal of Heterocyclic Chemistry,1991,vol. 28,p. 971 - 976

31
[ 55304-75-1 ]
[ 136353-10-1 ]

Reference： [1]Journal of Heterocyclic Chemistry,1991,vol. 28,p. 971 - 976

32
[ 55304-75-1 ]
[ 132844-47-4 ]

Reference： [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1527 - 1536

33
[ 55304-75-1 ]
[ 132844-51-0 ]

Reference： [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1527 - 1536

34
[ 55304-75-1 ]
[ 132844-52-1 ]

Reference： [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1527 - 1536

35
[ 55304-75-1 ]
2-[1-[Cyclopropyl-(6-oxo-5-trifluoromethyl-5,6-dihydro-pyridin-2-yl)-amino]-meth-(E)-ylidene]-malonic acid monoethyl ester [ No CAS ]

Reference： [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1527 - 1536

36
[ 55304-75-1 ]
[ 132844-44-1 ]

Reference： [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1527 - 1536

37
[ 55304-75-1 ]
2-[1-[(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-cyclopropyl-amino]-meth-(E)-ylidene]-malonic acid monoethyl ester [ No CAS ]

Reference： [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1527 - 1536

38
[ 55304-75-1 ]
[ 132844-50-9 ]

Reference： [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1527 - 1536

39
[ 55304-75-1 ]
[ 132844-43-0 ]

Reference： [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1527 - 1536

40
[ 55304-75-1 ]
[ 132844-62-3 ]

Reference： [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1527 - 1536

41
[ 55304-75-1 ]
[ 132844-60-1 ]

Reference： [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1527 - 1536

42
[ 55304-75-1 ]
[ 132844-58-7 ]

Reference： [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1527 - 1536

43
[ 55304-75-1 ]
7-Benzenesulfinyl-1-cyclopropyl-4-oxo-6-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester [ No CAS ]

Reference： [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1527 - 1536

44
[ 55304-75-1 ]
1-Cyclopropyl-4-oxo-7-piperazin-1-yl-6-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester [ No CAS ]

Reference： [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1527 - 1536

45
[ 55304-75-1 ]
[ 132844-61-2 ]

Reference： [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1527 - 1536

46
[ 55304-75-1 ]
[ 132844-55-4 ]

Reference： [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1527 - 1536

47
[ 55304-75-1 ]
1-Cyclopropyl-7-(3-ethylaminomethyl-pyrrolidin-1-yl)-4-oxo-6-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester [ No CAS ]

Reference： [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1527 - 1536

48
[ 55304-75-1 ]
[ 132844-59-8 ]

Reference： [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1527 - 1536

49
[ 55304-75-1 ]
7-(3-tert-Butoxycarbonylamino-pyrrolidin-1-yl)-1-cyclopropyl-4-oxo-6-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester [ No CAS ]

Reference： [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1527 - 1536

50
[ 55304-75-1 ]
2-({Cyclopropyl-[6-(4-ethoxycarbonyl-piperazin-1-yl)-5-trifluoromethyl-pyridin-2-yl]-amino}-methylene)-malonic acid diethyl ester [ No CAS ]

Reference： [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1527 - 1536
[2]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1527 - 1536

51
[ 55304-75-1 ]
[ 2393-23-9 ]
[ 683243-59-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In i-Amyl alcohol; at 150℃; for 0.25h;Microwave irradiation;	Example 145 [N- {6- [4- (4-BROMO-6-TRIFLUOROMETHYL-LH-BENZOIMIDAZOL-2-YL)-PIPERAZIN-1-YL]-5-] trifluoromethyl-pyridin-2-yl}-acetamide, trifluoroacetic acid salt. (a) [(6-CHLORO-5-TRIFLUOROMETHYL-PYRIDIN-2-YL)- (4-METHOXY-BENZYL)-AMINE,] trifluoroacetic acid salt. A suspension of 2, 6-dichloro-3-trifluoromethylpyridine (1.08 gm, 5 mmol, Lancaster), 4-methoxybenzyl amine (700 mg, 5 mmol, Aldrich) and sodium bicarbonate (430 mg, 5 mmol) in isoamyl alcohol (5 mL) was heated at [150 C] in a microwave synthesizer for 15 min. The reaction mixture was allowed to cool to room temperature, diluted with MeOH (10 mL) and filtered. The filtrate was evaporated in vacuo and the residue was purified by preparative HPLC (gradient 0. [1%] trifluoroacetic acid in acetonitrile) to provide the title compound as a colorless oil. MS (ESI, pos. ion) [M/Z] : 317 [(M+1).]

Reference： [1]Patent: WO2004/35549,2004,A1 .Location in patent: Page 157

52
[ 55304-75-1 ]
[ 73874-95-0 ]
1-(6-chloro-5-trifluoromethylpyridin-2-yl)piperidin-4-yl-carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With caesium carbonate; In 1,4-dioxane; for 64h;Heating / reflux;	A stirred mixture of D7 (5.0 g, 25 MMOL), 2, 6-dichloro-3-trifluoromethyl- pyridine (5.4 g, 25 MMOL) and cesium carbonate (12.22 g, 37.5 MMOL) in 1,4- dioxane (75 mL) was heated at reflux under argon for 64h. To the mixture, which was cooled to ambient temperature, was added water (250 mL) and DCM (250 mL) with shaking and the layers were separated. The aqueous phase was further extracted with DCM (250 mL) and the combined organic extracts were dried (MGS04) and evaporated in vacuo to an oil. This material was purified by chromatography over silica gel eluting with a gradient of ethyl acetate/hexane to afford the title compounds (5.0 g, 13.2 mmol, 53%). Mass Spectum: C16H2135CIF3N302 REQUIRES 379; Found 380 (MH+).

Reference： [1]Patent: WO2004/78749,2004,A1 .Location in patent: Page 15

53
[ 55304-75-1 ]
[ 313657-75-9 ]
1-(6-chloro-5-trifuoromethyl-pyridin-2-yl)-2-(R)-methyl-4-trityl-piperazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With potassium carbonate; In dimethyl sulfoxide; at 80℃;	A suspension of 3-(R)-methyl-1-trityl-piperazine (from Example 4; 7.80 g, 22.9 mmol), <strong>[55304-75-1]2,6-dichloro-3-trifluoromethylpyridine</strong> (4.50 g, 20.8 mmol) and K2CO3 (4.0 g, 29 mmol) in DMSO (100 mL) was stirred at 80 C. over night. A mixture of EtOAc/toluene (50:50; 500 mL) was added to the filtered solution and the mixture were washed three times with water (1 L). The dried (MgSO4) organic phase was concentrated under reduced pressure and the resulting brown oil was dissolved in heptane/EtOAc (90:10) and filtered through a plug (6060 mm) of silica. Slow evaporation of about two thirds of the solvent at reduced pressure afforded light yellow crystals (6.11 g, 56%). Purity 100% (HPLC); mp 209 C. Fragmenting MS analysis supports the stated structure. Anal. (C30H27ClF3N3) C, H, N.

Reference： [1]Patent: US2003/232814,2003,A1 .Location in patent: Page 9

54
[ 218430-15-0 ]
[ 55304-75-1 ]
[1-(6-chloro-3-trifluoromethylpyridin-2-yl)azetidin-3-yl]carbamic acid t-butyl ester [ No CAS ]
[1-(6-chloro-5-trifluoromethylpyridin-2-yl)azetidin-3-yl]carbamic acid t-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18%; 63%	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 100℃; for 16h;	3-Butoxycarbonylaminoazetidine acetate (synthesis described in WO 98/57640) (2g, 8.61 MMOL), 2, 6-dichloro-5-trifluoromethylpyridine, (2.05g, 9. 47MMOL) and potassium carbonate, (2.5g, 18. 08MMOL) in dry DMF (20ml) were heated to 100C for16h. The 2 isomers were separated by column chromatography. [1-(6-CHLORO-3-TRIFLUOROMETHYLPYRIDIN-2-YL) AZETIDIN-3-YL] carbamic acid t-butyl ester was isolated as a colourless solid, (560mg, 18%). The title COMPOUND, [1- (6-CHLORO-5-TRIFLUOROMETHYLPYRIDIN-2-YL) AZETIDIN-3-YL] carbamic acid t- butyl ester, was also isolated as a colourless solid (1.92g, 63%).

Reference： [1]Patent: WO2004/78744,2004,A2 .Location in patent: Page 17

55
[ 55304-75-1 ]
[ 57260-71-6 ]
4-(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium carbonate; In dimethyl sulfoxide; toluene; at 80℃; for 2h;	To a suspension of tert-butyl-1-piperazine carboxylate (27.0 g, 145 mmol) and K2CO3 (40.0 g, 290 mmol) in DMSO (200 ML) were <strong>[55304-75-1]2,6-dichloro-3-trifluoromethylpyridine</strong> (29.1 g, 135 mmol) and toluene (50 ML) added.The thick slurry was stirred at 80 C. for two hours, followed by addition of toluene (0.5 L) and water (1 L).The phases were separated and the organic phase was washed twice with water.The solvent from the dried (MgSO4) organic phase was evaporated at reduced pressure.The solid residue was recrystallized from EtOAc/heptane to give white crystals (37 g).The filtrate from the recrystallization was concentrated and the residue chromatographed on a column of silica with hexane/EtOAc (90:10) to give further 6.0 g of product (total yield 85%).Purity 99% (HPLC); mp 125 C. Anal. (C15H19ClF3N3O2) C, H, N.
85%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 140℃; for 0.333333h;Sealed tube; Microwave irradiation;	Example A2; 4-(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-piperazine- 1 -carboxylic acid tert-bvXy ester; Preparation of intermediate 2; Cl F p1 o To a stirred solution of <strong>[55304-75-1]2,6-dichloro-3-trifluoromethyl-pyridine</strong>(0.5 g, 0.0023 mol) and JV-Boc-piperazine (0.52 g, 0.0028 mol) in acetonitrile (10 ml) was added diisopropylethylamine (1 ml, 0.0057 mol). The mixture was heated at 140 0C for 20 min. in a sealed tube, under microwave irradiation. The reaction mixture was diluted with dichloromethane and washed with a saturated solution of ammonium chloride in water and water. The organic layer was separated, filtered over cotton and the solvents evaporated in vacuo. The crude product was purified by column chromatography (silica; heptane in dichloromethane 30/70 to 0/100). The desired fractions were collected and evaporated in vacuo to yield A2 (0.72 g, 85%). C15H19CIF3N3O2. 1H NMR (400 MHz, CDCl3) delta ppm: 1.49 (s, 9 H), 3.48 - 3.59 (m, 4 H), 3.60 - 3.69 (m, 4 H), 6.48 (d, J=8.8 Hz, 1 H), 7.69 (d, J=8.8 Hz, 1 H).

Reference： [1]Patent: US2003/232814,2003,A1 .Location in patent: Page 8
[2]Patent: WO2010/12758,2010,A1 .Location in patent: Page/Page column 23-24

56
[ 55304-75-1 ]
[ 42116-44-9 ]
[ 848591-04-8 ]

Reference： [1]Patent: JP2005/82508,2005,A .Location in patent: Page/Page column 21

57
[ 55304-75-1 ]
[ 591-27-5 ]
2,6-bis(3-aminophenoxy)-3-trifluoromethylpyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With hydrogenchloride; potassium carbonate; In water; N,N-dimethyl-formamide; isopropyl alcohol; toluene;	Example 2 To a four necked flask equipped with a thermometer, reflux condenser and stirrer, 400 g of N,N-dimethylformamide (DMF), 40 g of toluene, 45.3 g (0.21 mol) of <strong>[55304-75-1]2,6-dichloro-3-trifluoromethylpyridine</strong>, 48.1 g (0.44 mol) of m-aminophenol and 31.9 g (0.231 mol) of potassium carbonate were charged, heated to 130 C. with stirring and aged at 130 C. for 6 hours, After finishing the reaction, the reaction mixture was cooled to room temperature and filtered to remove organic salts. DMF was distilled off from the filtrate. The residue was dissolved in 300 g of isopropanol (IPA) and 184 g of 36 % HCl was added to the solution. The precipitated hydrochloride was dissolved in 200 g of water, neutralized with a 28% aqueous ammonia solution and extracted with 1,2-dichloroethane (EDC). The EDC layer was washed with water and distilled off the solvent to obtain 33.1 g (44% yield) of the desired product 2,6-bis(3-aminophenoxy)-3-trifluoromethylpyridine. Melting point: 103.0~104.2 C. Elemental analysis (C18 H14 N3 O2 F3) 1H-NMR delta(CDCl3, ppm) 3.66 (4H (1), S), 6.37~6.60 (7H (2), m), 6.88~7.08 (2H (3), m), 7.85 (1H (4), d),

Reference： [1]Patent: US5470943,1995,A

58
[ 261956-65-4 ]
[ 55304-75-1 ]

Yield	Reaction Conditions	Operation in experiment
50%	With trichlorophosphate; at 80℃; for 17h;Product distribution / selectivity;	2-Chloro-5-trifluoromethyl-pyridine-N-oxide (17, 4 mmol) was dissolved in freshly distilled POCl3 (4.5 mL). The reaction mixture was heated to 80 C. for 17 h. After cooling to room temperature, the solvent was removed under reduced pressure. Ice was added, and the mixture was allowed to stand for 4 h. The mixture was partition between CH2Cl2 (50 mL) and saturated aqueous NaHCO3. Column chromatography afforded compound 18 as yellow oil (yield: 50%).; Intermediate 21 (4 mmol) was dissolved in freshly distilled POCl3 (4.5 mL). The reaction mixture was heated to 80 C. for 17 h. After cooling to room temperature, the solvent was removed under reduced pressure. Ice was added, and the mixture was allowed to stand for 4 h. The mixture was partition between CH2Cl2 (50 mL) and saturated aqueous NaHCO3. Column chromatography afforded compound 2 as yellow oil (yield: 50%).
	With trichlorophosphate; at 80℃; for 16h;	2. 2, 6-Dichloro-3-trifluoromethylpyridijiotaeHeat a mixture of 2-chloro-5-trifluoromethylpyridine-N-oxide (40 g, 202.5 mmol) and POCl3(200 mL) to 8O0C and stir for 16 hours. After cooling to room temperature, remove the excess POCl3 under vacuum. Pour the residue into ice water, and neutralize the mixture to pH=7 with solid NaHCO3. Extract the resulting mixture with diethyl ether (3 x 80 mL), dry the combined ether EPO <DP n="59"/>extracts (Na2SO4), filter, and evaporate to give a brown oil. Purification by column chromatography affords the title product as pale yellow solid. 1H NMR (400 MHz, CDCl3) delta 7.97 (d, IH), 7.41 (d, IH).

Reference： [1]Patent: US2008/275057,2008,A1 .Location in patent: Page/Page column 68; 71
[2]Patent: WO2006/42289,2006,A2 .Location in patent: Page/Page column 57-58

59
[ 55304-75-1 ]
[ 17061-62-0 ]
[ 884004-38-0 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-methyl-pyrrolidin-2-one; triethylamine; at 120℃; for 14h;	4. N,N-Bis-(4-methoxyben7yl)-(6-chloro-5-trifluoromethylpyridine-2-yl)omeganine Add bis(4-methoxybenzyl)amine (35.7 g, 138.9 mmol) in 20 mL of N-methylpyrrolidone to a solution of <strong>[55304-75-1]2,6-dichloro-3-trifluoromethylpyridine</strong> (20 g, 92.6 mmol) and triethylamine (19.4 mL, 138.9 mmol) in 100 mL of N-methylpyrrolidone. Raise the temperature to 1200C, and stir the reaction for 14 hours. Quench the reaction mixture by the addition of water (80 mL), followed by extraction with EtOAc (3 x 70 mL). Wash the combined organic extracts with water (2 x 70 mL) and brine (70 mL), and dry over anhydrous Na2SO4. Filter the dried extract and concentrate under vacuum to afford the crude product, which is purified by column chromatography to give a yellow solid. 1H NMR (400 MHz, CDCl3) delta 7.58 (d, IH, J=8.4 Hz), 7.15 (m, 4H), 6.85 (m, 4H), 6.31 (d, IH, J=8.8 Hz), 4.70 (s, 4H), 3.80 (s, 6H). Mass spec. (436.99, M+H).

Reference： [1]Patent: WO2006/42289,2006,A2 .Location in patent: Page/Page column 58

60
[ 55304-75-1 ]
[ 80289-91-4 ]

Yield	Reaction Conditions	Operation in experiment
	With iron(III) chloride; In water;	EXAMPLE 7 In a 200 ml. four necked flask equipped with a thermometer, a refluxing condenser and a chlorine gas inlet pipe, 108 g. of 2,6-dichloro-beta-trifluoromethylpyridine and 81 g. of ferric chloride were charged and chlorine gas was fed to react them by heating at 170 to 210 C. for 17 hours. The reaction mixture was poured into 0.4 liter of hot water to separate an oily product. The oily product was dehydrated over anhydrous sodium sulfate and the product was distilled and further rectified to obtain 30 g. of 2,5,6-trichloro-beta-trifluoromethylpyridine.

Reference： [1]Patent: US4420618,1983,A

61
[ 55304-75-1 ]
[ 60075-04-9 ]
[ 69335-88-2 ]

Yield	Reaction Conditions	Operation in experiment
	In water; dimethyl sulfoxide;	EXAMPLE 1 Methyl alpha-[4-(5'-trifluoromethyl-6'-chloropyrid-2'-yl)-oxy-phenoxy]-propionate A solution of 19.6 g of methyl 2-(4'-hydroxy-phenoxy)-propionate in 20 ml of dimethylsulphoxide is added dropwise, with cooling, to a suspension of 2.4 g of sodium hydride in 30 ml of dimethylsulphoxide. After one hour's stirring, 23.8 g of <strong>[55304-75-1]2,6-dichloro-3-trifluoromethylpyridine</strong> is added dropwise with cooling. After 2 hours, 500 ml of water is added, and extraction is performed with ether. The ether is dried with magnesium sulphate and removed by evaporation. The residue is distilled in a bulb tube at 130 C. (0.01 Torr). Recrystallisation from ether/petroleum ether yields 12 g of the product, which deliquesces from 50 C. upwards without any sharp melting point.

Reference： [1]Patent: US4325729,1982,A

62
[ 55366-30-8 ]
[ 7783-56-4 ]
[ 87-69-4 ]
[ 55304-75-1 ]

Yield	Reaction Conditions	Operation in experiment
	In diethyl ether; water;	2,6-Dichloro-3-trifluoromethylpyridine (Example 14) 266 g (1 mol) of 2,6-dichloro-3-trichloromethylpyridine, obtained by chlorinating 2,6-dichloro-3-chloromethylpyridine with Cl2 under irradiation with UV light, and 5 g of antimony trifluoride are mixed and are heated under gentle reflux in a three-necked flask with an upright condenser (internal temperature of the melt 240C). Portions of 10 g each of antimony trifluoride are added at intervals of 10 minutes each, up to a total quantity of 191 g (1.065 mols). The reaction mixture is then heated under reflux for a further 15 minutes and then the reflux condenser is replaced by a fractionating column and the resulting trifluoromethyl compound is distilled off at normal pressure. The distillate is diluted with 2 l of diethyl ether and the ethereal solution is washed with a solution of 1 kg of tartaric acid in 4 l of water. After distilling off the diethyl ether, 162 g of crude 2,6-dichloro-3-trifluoromethylpyridine are obtained, which, on distillation at 68 - 71C/12 mm Hg, gives 138.4 g (64% of theory) of pure 2,6-dichloro-3-trifluoromethylpyridine.

Reference： [1]Patent: US3974166,1976,A

63
[ 110-85-0 ]
[ 55304-75-1 ]
[ 132834-56-1 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; ethyl acetate;	Preparation of 1-[6-chloro-5-(trifluoromethyl)-2-pyridinyl]piperazine Piperazine (10.337 g; 120 moles) was dissolved in 95% aqeous ethanol (36 l). The solution was heated at reflux, after which a solution of <strong>[55304-75-1]2,6-dichloro-3-(trifluoromethyl)-pyridine</strong> (8640 g; 40 moles) in 95% aqueous ethanol (9 l) was added over 2 hours. The reflux was maintained for another 2 hours. The mixture was cooled to ambient and the precipitated piperazine hydrochloride salt was removed by filtration. The ethanol was removed under vacuum. The residue was dissolved in ethyl acetate (30 l). This solution was washed twice with water (15 l), dried over magnesium sulphate, after which the solvent was removed in vacuo. The residue was poured into water (15 l) while stirring. The resulting solid was filtered off and extensively washed with water.

Reference： [1]Patent: US2004/38985,2004,A1

64
[ 55304-75-1 ]
[ 89444-05-3 ]
[ 89444-04-2 ]

Yield	Reaction Conditions	Operation in experiment
56%; 18%	With hydrazine; In ethanol; at 20℃; for 4h;Product distribution / selectivity;	To the solution of <strong>[55304-75-1]2,6-Dichloro-5-trifluoromethyl-pyridine</strong> (18, 2 g, 9.26 mmol) in ethanol (30 mL) was added hydrazine hydrate (2.9 g, 46 mmol). The reaction mixture was stirred for 4 h at room temperature, then concentrated to remove the solvent, and added ethyl acetate, washed with water. The organic layer was dried over anhydrous Na2SO4. Column chromatography (Silica, petroleum ether/ethyl acetate=4/1~3/1) afforded compound 19 as white solid (yield: 56%) and another isomer 20 (yield: 18%).; Intermediate 4To the solution of 2 (2 g, 9.26 mmol) in ethanol (30 mL) was added hydrazine hydrate (2.9 g, 46 mmol). The reaction mixture was stirred for 4 h at room temperature, then concentrated to remove the solvent, and added ethyl acetate, washed with water. The organic layer was dried over anhydrous Na2SO4. Column chromatography (Silica, petroleum ether/ethyl acetate=4/13/1) afforded compound 4 as white solid (yield: 56%) and another isomer 3 (yield: 18%).

Reference： [1]Patent: US2008/275057,2008,A1 .Location in patent: Page/Page column 68; 71

65
[ 55304-75-1 ]
[ 24424-99-5 ]
[ 74879-18-8 ]
4-(6-chloro-5-trifluoromethyl-pyridin-2-yl)-2-(S)-methyl-piperazine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%		To a suspension of 2-(S)-methylpiperazine (2.65 g, 26.5 mmol) and K2CO3 (4.0 g, 29 mmol) in dry DMSO (50 ML) was slowly added <strong>[55304-75-1]2,6-dichloro-3-trifluoromethylpyridine</strong> (5.70 g, 26.4 mmol).The reaction mixture was stirred at room temperature over night, filtered, diluted with water (ca 1 L) and extracted twice with EtOAc (100 ML).The solvent from the combined dried (MgSO4) organic phases was evaporated at reduced pressure to give a yellow oil (7.4 g).This material was dissolved in MeOH (100 ML), BOC anhydride (6.0 g, 27.5 mmol) was added in one portion and the reaction mixture was stirred at room temperature for two hours.Excess BOC anhydride was quenched with pyridine (3 ML) and the mixture was left at room temperature over night.The solvent was removed at reduced pressure and the resulting oil was chromatographed on a column of silica (60*110 mm) with hexane/EtOAc (95:5, 1 L, followed by 90:10, 1 L and 80:20).Evaporation at reduced pressure of the pure fractions yielded a colorless oil (8.05 g, 80%) that solidified to a white solid over night.Purity 97% (HPLC); mp 86 C. Fragmenting MS analysis supports the stated structure. HRMS m/z calcd for C16H21ClF3N3O2 (M)+ 379.1274, found 379.1286.

Reference： [1]Patent: US2003/232814,2003,A1 .Location in patent: Page 8

66
[ 13889-98-0 ]
[ 55304-75-1 ]
[ 1197294-68-0 ]

Yield	Reaction Conditions	Operation in experiment
13%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 30℃;Heating; Reflux;	step 2 [0307] [0308]To a solution of 2, 6-dichloro-3- (trifluoromethyl) pyridine (2.38 g, 11.0 itimol) in anhydrous dichloromethane (20 ml) was added dropwise N,N-diisopropylethylamine (3.7 ml, 225 mmol) . A solution of 1-acetylpiperazine (1.69 g, 13.2 mmol) in anhydrous dichloromethane (10 ml) was added dropwise at 0C, and the mixture was stirred at room temperature for 5 hrs . The mixture was warmed, heated under reflux for 2.5 hrs, and stirred at room temperature for 14 hrs. The reaction mixture was diluted with dichloromethane and washed with water. The aqueous layer was extracted twice with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate :hexane = 1:4 ? ethyl acetate ? ethanol: ethyl acetate = 1:20) to give l-acetyl-4- [6-chloro-5- (trifluoromethyl) pyridin- 2-yl]piperazine (451 mg, yield 13%) as a yellow solid.

Reference： [1]Patent: WO2009/145360,2009,A1 .Location in patent: Page/Page column 112

67
[ 55304-75-1 ]
2-amino-3-trifluoromethyl-6-chloropyridine [ No CAS ]
6-chloro-5-(trifluoromethyl)pyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ammonia; In 1,4-dioxane; water; at 120℃;Microwave irradiation;	A mixture of <strong>[55304-75-1]2,6-dichloro-3-trifluoromethyl-pyridine</strong> (1.0g, 4.6mmol) and ammonia (saturated aqueous solution '.880', 0.6ml) in 1 ,4-dioxane (4ml) was heated in a sealed tube in a microwave. More ammonia was added and the temperature slowly increased to 120 deg C until ca. 90% conversion achieved (after about 2 hours). The reaction was allowed to stand overnight and the resultant solid was isolated by vacuum filtration and was washed with water. The resultant solid was purified by column chromatography (0-30% ethyl acetate/ petroleum ether) to furnish the 2 regioisomers. 6-Chloro-5-trifluoromethyl-pyridin-2-ylamine 1 H NMR (400 MHz, CDCI3): 7.70 (1 H, d), 6.43 (1 H, d), 5.47-4.30 (2H, m). - 6-Chloro-3- trifluoromethyl-pyridin-2-ylamine - 1 H NMR (400 MHz, CDCI3): 7.66 (1 H, d), 6.75 (1 H, d), 5.17 (2H, s).

Reference： [1]Patent: WO2009/150240,2009,A1 .Location in patent: Page/Page column 131

68
[ 55304-75-1 ]
[ 120-83-2 ]
[ 1186000-15-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 3h;	Reference Example 76; Ethyl 3-(6-(2,4-dichlorophenoxy)-3-(trifluoromethyl)pyridin-2-yl)benzoate; A DMF (15 mL) solution of <strong>[55304-75-1]2,6-dichloro-3-(trifluoromethyl)pyridine</strong> (1.00 g, 4.63 mmol), 2,4-dichlorophenol (792 mg, 4.86 mmol), and potassium carbonate (704 mg, 5.09 mmol) was stirred at 120C for 3 hours. Water was poured into the reaction solution, and the product was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off at reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:99) to give 2-chloro-6-(2,4-dichlorophenoxy)-3-(trifluoromethyl)pyridine in the form of a crude product. Tetrakis(triphenylphosphine)palladium (0) (474 mg, 0.410 mmol) was added at room temperature in a nitrogen atmosphere to a 1,2-dimethoxyethane (20 mL) solution of the above compound (1.17 g), (3-(ethoxycarbonyl)-phenyl)boronic acid (729 mg, 3.76 mmol), and 2 N sodium carbonate aqueous solution (6.8 mL), and the mixture was stirred at 100C over night. Water was poured into the reaction solution, and the product was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off at reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:19) to give 788 mg of the titled compound (yield 51%) in the form of an oily substance. 1H-NMR (CDCl3 ) delta: 1.39 (3H, t, J = 7.1 Hz), 4.28 (2H, q, J = 7.1 Hz), 7.04 (1H, d, J = 8.5 Hz), 7.14 - 7.20 (1H, m), 7.22 - 7.29 (1H, m), 7.41 - 7.50 (2H, m), 7.56 - 7.64 (1H, m), 8.04 - 8.14 (3H, m).

Reference： [1]Patent: EP2253618,2010,A1 .Location in patent: Page/Page column 51

69
[ 130290-79-8 ]
[ 55304-75-1 ]
[ 1263374-37-3 ]
[ 1263374-36-2 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dimethyl sulfoxide; at 120℃; for 18h;Sealed glass bomb;	Step 1. Synthesis of 6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine and 6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-3-(trifluoromethyl)pyridin-2-amine; To a solution of <strong>[55304-75-1]2,6-dichloro-3-(trifluoromethyl)pyridine</strong> (320 mg, 1.482 mmol) in DMSO (1.5 ml) at ambient temperature was added (tetrahydro-2H-pyran-4-yl)methanamine (188 mg, 1.630 mmol) and triethylamine (0.207 ml, 1.482 mmol). The resulting light brown mixture was heated at about 120 C. in a sealed glass bomb for about 18 hours. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (20 mL), washed with saturated NaHCO3 solution and brine, dried over sodium sulfate and concentrated in vacuo to yield 502 mg of a light brown crude liquid, which was purified by column chromatography (5 to 50% ethyl acetate in heptane)to yield the desired products.6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine: 340 mg, 78%: LCMS (m/z): 295.2 [M+H]+; Retention time=0.971 min; and 6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-3-(trifluoromethyl)pyridin-2-amine: 80 mg, 18%. LCMS (m/z): 295.1 [M+H]+; Retention time=1.033 min.
	With triethylamine; In dimethyl sulfoxide; at 120℃; for 18h;	To a solution of <strong>[55304-75-1]2,6-dichloro-3-(trifluoromethyl)pyridine</strong> (320 mg, 1.48 mmol) inDMSO (1.5 mL) at room temperature was added (tetrahydro-2H-pyran-4-yl)methanamine (188 mg, 1.63 mmol) and triethylamine (0.207 mL, 1.48 mmol). The mixture was heated at 120 C in a sealed glass bomb for 18 hrs. The reaction mixture was diluted with EtOAc (20 mL) and the organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate , filtered off and concentrated under reduced pressure. The crude material was purified by column chromatography [silica gel, 120 g, EtOAc/hexane = 10/90 to 50/50] providing 6-chloro-N-((tetrahydro-2H- pyran-4-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine (340 mg) {LCMS (m/z): 295.2[M+H]+; Rt = 0.97 min} and 6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-3- (trifluoromethyl)pyridin-2-amine (80 mg) {LCMS (m/z): 295.1 [M+H]+; Rt = 1.03 min}.
	With triethylamine; In dimethyl sulfoxide; at 120℃; for 18h;Sealed bomb;	To a solution of <strong>[55304-75-1]2,6-dichloro-3-(trifluoromethyl)pyridine</strong> (320 mg, 1.482 mmol) in DMSO (1.5ml) at ambient temperature was added (tetrahydro-2H-pyran-4- yl)methanamine (188 mg, 1.630 mmol) and triethylamine (0.207 ml, 1.482 mmol). The resulting light brown mixture was heated at about 120 C in a sealed glass bomb for about 18 hours. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (20ml_), washed with saturated NaHC03 solution and brine, dried over sodium sulfate and concentrated in vacuo to yield 502 mg of a light brown crude liquid, which was purified by column chromatography ( 5 to 50% ethyl acetate in heptane)to yield the desired products.6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine: 340 mg, 78 %: LCMS (m/z): 295.2 [M+H]+; Retention time = 0.971 min; and 6-chloro-N- ((tetrahydro-2H-pyran-4-yl)methyl)-3-(trifluoromethyl)pyridin-2-amine: 80 mg, 18 %. LCMS (m/z): 295.1 [M+H]+; Retention time = 1.033 min.

	With triethylamine; In dimethyl sulfoxide; at 120℃; for 18h;Sealed glass bomb;	Step 1. Synthesis of 6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-5- (trifluoromethyl)pyridin-2-amine and 6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-3- (trifluoromethyl)pyrid -2-amineTo a solution of <strong>[55304-75-1]2,6-dichloro-3-(trifluoromethyl)pyridine</strong> (320 mg, 1.482 mmol) in DMSO (1.5ml) at ambient temperature was added (tetrahydro-2H-pyran-4- yl)methanamine (188 mg, 1.630 mmol) and triethylamine (0.207 ml, 1.482 mmol). The resulting light brown mixture was heated at about 120 C in a sealed glass bomb for about 18 hours. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (20ml_), washed with saturated NaHC03 solution and brine, dried over sodium sulfate and concentrated in vacuo to yield 502 mg of a light brown crude liquid, which was purified by column chromatography ( 5 to 50% ethyl acetate in heptane)to yield the desired products.6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine: 340 mg, 78 %: LCMS (m/z): 295.2 [M+H]+; Retention time = 0.971 min; and 6-chloro-N- ((tetrahydro-2H-pyran-4-yl)methyl)-3-(trifluoromethyl)pyridin-2-amine: 80 mg, 18 %. LCMS (m/z): 295.1 [M+H]+; Retention time = 1.033 min.
	With triethylamine; In dimethyl sulfoxide; at 120℃; for 18h;	To a solution of <strong>[55304-75-1]2,6-dichloro-3-(trifluoromethyl)pyridine</strong> (320 mg, 1 .48 mmol) in DMSO (1 .5 mL) at room temperature was added (tetrahydro-2H-pyran-4-yl)methanamine (188 mg, 1 .63 mmol) and triethylamine (0.207 mL, 1 .48 mmol). The mixture was heated at 120 C in a sealed glass bomb for 18 hrs. The reaction mixture was diluted with EtOAc (20 mL) and the organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate , filtered off and concentrated under reduced pressure. The crude material was purified by column chromatography [silica gel, 120 g, EtOAc/hexane = 10/90 to 50/50] providing 6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-5- (trifluoromethyl)pyridin-2-amine (340 mg) {LCMS (m/z): 295.2 [M+H]+; Rt = 0.97 min} and 6- chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-3-(trifluoromethyl)pyridin-2-amine (80 mg) {LCMS (m/z): 295.1 [M+H]+; Rt = 1.03 min}.

Reference： [1]Patent: US2011/28492,2011,A1 .Location in patent: Page/Page column 25-26
[2]Patent: WO2012/101063,2012,A1 .Location in patent: Page/Page column 79
[3]Patent: WO2012/101065,2012,A2 .Location in patent: Page/Page column 135-136
[4]Patent: WO2012/101066,2012,A1 .Location in patent: Page/Page column 76-77
[5]Patent: WO2012/101064,2012,A1 .Location in patent: Page/Page column 118

70
[ 98-10-2 ]
[ 55304-75-1 ]
N-(6-chloro-5-trifluoromethyl-2-pyridinyl)benzenesulfonamide [ No CAS ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2011,vol. 59,p. 783 - 786

71
[ 55304-75-1 ]
[ 1520-70-3 ]
[ 163238-02-6 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2011,vol. 59,p. 783 - 786

72
1-(2,3-dichlorobenzyl)piperazine [ No CAS ]
[ 55304-75-1 ]
[ 1135438-50-4 ]

Reference： [1]Journal of Agricultural and Food Chemistry,2010,vol. 58,p. 2624 - 2629

73
1-(2-chloro-6-fluorobenzyl)piperazine [ No CAS ]
[ 55304-75-1 ]
[ 1135438-49-1 ]

Reference： [1]Journal of Agricultural and Food Chemistry,2010,vol. 58,p. 2624 - 2629

74
[ 55304-75-1 ]
[ 1135439-04-1 ]
[ 1203719-14-5 ]

Reference： [1]Journal of Agricultural and Food Chemistry,2010,vol. 58,p. 2624 - 2629

75
[ 55304-75-1 ]
[ 1135439-05-2 ]
[ 1135438-41-3 ]

Reference： [1]Journal of Agricultural and Food Chemistry,2010,vol. 58,p. 2624 - 2629

76
[ 55304-75-1 ]
[ 874774-61-5 ]
[ 1203719-15-6 ]

Reference： [1]Journal of Agricultural and Food Chemistry,2010,vol. 58,p. 2624 - 2629

77
[ 55304-75-1 ]
[ 523981-01-3 ]
[ 1135438-82-2 ]

Reference： [1]Journal of Agricultural and Food Chemistry,2010,vol. 58,p. 2624 - 2629

78
[ 17532-19-3 ]
[ 55304-75-1 ]
[ 1135438-47-9 ]

Reference： [1]Journal of Agricultural and Food Chemistry,2010,vol. 58,p. 2624 - 2629

79
[ 23145-88-2 ]
[ 55304-75-1 ]
[ 1135438-43-5 ]

Reference： [1]Journal of Agricultural and Food Chemistry,2010,vol. 58,p. 2624 - 2629

80
[ 55304-75-1 ]
[ 956-61-6 ]
[ 1203719-16-7 ]

Reference： [1]Journal of Agricultural and Food Chemistry,2010,vol. 58,p. 2624 - 2629

81
[ 130290-79-8 ]
[ 55304-75-1 ]
[ 1263374-34-0 ]

Reference： [1]Patent: WO2012/101065,2012,A2
[2]Patent: WO2012/101066,2012,A1

82
[ 55304-75-1 ]
[ 1263374-34-0 ]

Reference： [1]Patent: WO2012/101064,2012,A1

83
[ 55304-75-1 ]
[ 1270076-15-7 ]

Reference： [1]Patent: WO2012/101064,2012,A1

84
[ 100-82-3 ]
[ 55304-75-1 ]
6-chloro-N-(3-fluorobenzyl)-4-(trifluoromethyl)pyridin-2-amine trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dimethyl sulfoxide; at 90℃; for 1h;	Example 11 (Compound 1 1)N2'-(frans-4-aminocyclohexyl)-N6-(3-fluorobenzyl)-4-(trifluoromethyl)-2,4'-bipyridine-2',6- diamineStep 1. Preparation of 6-chloro-N-(3-fluorobenzyl)-4-(trifluoromethyl)pyridin-2-amine:To 2,6-dichloro-4-(trifluoromethyl)pyridine (250 mg, 1.157 mmol) was added DMSO (2 ml), TEA (0.194 ml, 1.389 mmol), and (3-fluorophenyl)methanamine (290 mg, 2.315 mmol). The reaction mixture was stirred at 90 C until completion as indicated by LCMS, about 1 hour. To the crude reaction mixture was added 1.5 ml of DMSO, filtered and purified by prep LC. After lyophilization, 158 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 305.1 (MH+), rt= 1.21 min.

Reference： [1]Patent: WO2012/101066,2012,A1 .Location in patent: Page/Page column 144

85
[ 109-01-3 ]
[ 55304-75-1 ]
[ 1418153-26-0 ]

Reference： [1]European Journal of Organic Chemistry,2012,p. 6940 - 6952

86
[ 55304-75-1 ]
[ 5720-07-0 ]
[ 1426922-09-9 ]

Yield	Reaction Conditions	Operation in experiment
61%	With potassium phosphate; palladium diacetate; In water; N,N-dimethyl-formamide; at 20℃; for 12h;	A DMF/water solution (1:1, 2 mL per 1 mmol of 1) of K3 PO4 (1.5 mmol),Pd(OAc)2 (2 mol %), and arylboronic acid 2a-n (0.9 mmol) was stirred atroom temperature for 8-12 h (tlc control). After completion of the reaction, themixture was extracted with CH2Cl2 and the combined organic layers weredried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residuewas purified by column chromatography (silica gel, EtOAc/heptane = 1:4).Starting with 1 (216 mg, 1.00 mmol), K3PO4 (165 mg, 1.50 mmol), Pd(OAc)2(2 mol %), arylboronic acid (149 mg, 0.90 mmol), and a solution ofDMF and water (1:1, 5 mL), 3a-3n was isolated

Reference： [1]Tetrahedron Letters,2013,vol. 54,p. 1669 - 1672

87
[ 55304-75-1 ]
[ 5720-07-0 ]
[ 1426922-18-0 ]

Yield	Reaction Conditions	Operation in experiment
63%	With potassium phosphate; palladium diacetate; In water; N,N-dimethyl-formamide; at 20℃;	A DMF/water solution (1:1, 2 mL per 1 mmol of 1) of K3PO4 (1.5 mmol), Pd(OAc)2(2 mol %), and arylboronic acid 2 (2.2 mmol) was stirred at room temperaturefor 8-12 h (tlc control). After completion of the reaction, the mixture wasextracted with CH2Cl2 and the combined organic layers were dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified bycolumn chromatography (silica gel, EtOAc/heptane = 1:4). Starting with 1(216 mg, 1.0 mmol), K3PO4 (345 mg, 2.5 mmol), Pd(OAc)2 (2 mol %), 4-methoxyphenylboronic acid (334 mg, 2.20 mmol), and solution of DMF andwater (1:1) (2 mL), 4e was isolated as a colorless solid (226 mg, 63%),mp = 104-105 C. 1H NMR (300 MHz, CDCl3): d = 3.87 (s, 3H, CH3), 3.88 (s,3H, CH3), 6.98 (d, J = 1.70, Hz, 2H, ArH), 7.01 (d, J = 1.70 Hz, 2H, ArH), 7.58 (d,J = 8.60, 2H, ArH), 7.71 (d, J = 8.60, Hz, 1H, ArH), 8.03-8.10 (m, 3H, ArH). 13CNMR (75.46 MHz, CDCl3): d = 55.3 (OCH3), 55.3 (OCH3), 113.4 (2CH), 114.2(2CH), 116.6 (CH), 124.1 (d, 1JCF = 273.1 Hz, CF3), 128.8 (2CH), 130.4 (d,JCF = 2.11 Hz, 2CH), 130.5 (CH), 132.4 (C), 135.7 (q, 3JCF = 4.85, Hz, C), 157.6 (C),158.7 (2C), 160.1 (C), 161.3 (C). 19F NMR (282.4 MHz, CDCl3): d = 57.04 (CF).IR (ATR, cm 1): m = 3075 (w), 2969 (w), 2846 (w), 1605 (m), 1581 (m), 1510(m), 1249 (s), 1124 (s), 1019 (s), 828 (s). MS (EI, 70 eV): m/z (%) 359 (100) [M+],316 (8). HRMS (EI) calcd for C20H16F3NO2 [M+]: 359.11276, found 359.11258

Reference： [1]Tetrahedron Letters,2013,vol. 54,p. 1669 - 1672

88
[ 55304-75-1 ]
[ 1765-93-1 ]
[ 1426922-10-2 ]

Yield	Reaction Conditions	Operation in experiment
68%	With potassium phosphate; palladium diacetate; In water; N,N-dimethyl-formamide; at 20℃; for 12h;	General procedure: A DMF/water solution (1:1, 2 mL per 1 mmol of 1) of K3 PO4 (1.5 mmol),Pd(OAc)2 (2 mol %), and arylboronic acid 2a-n (0.9 mmol) was stirred atroom temperature for 8-12 h (tlc control). After completion of the reaction, themixture was extracted with CH2Cl2 and the combined organic layers weredried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residuewas purified by column chromatography (silica gel, EtOAc/heptane = 1:4).Starting with 1 (216 mg, 1.00 mmol), K3PO4 (165 mg, 1.50 mmol), Pd(OAc)2(2 mol %), arylboronic acid (149 mg, 0.90 mmol), and a solution ofDMF and water (1:1, 5 mL), 3a-3n was isolated

Reference： [1]Tetrahedron Letters,2013,vol. 54,p. 1669 - 1672

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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