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[ CAS No. 125568-73-2 ] {[proInfo.proName]}

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

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3d Animation Molecule Structure of 125568-73-2

Chemical Structure| 125568-73-2

Chemical Structure| 125568-73-2

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Quality Control of [ 125568-73-2 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 125568-73-2 ]

SDS Specification

Alternatived Products of [ 125568-73-2 ]

Product Details of [ 125568-73-2 ]

CAS No. :	125568-73-2	MDL No. :	MFCD09396710
Formula :	C₈H₇F₂NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	HHAREYZKVHGBEP-UHFFFAOYSA-N
M.W :	187.14	Pubchem ID :	22110105
Synonyms :

Calculated chemistry of [ 125568-73-2 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	42.04
TPSA :	52.32 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.53 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.61
Log Po/w (XLOGP3) :	1.29
Log Po/w (WLOGP) :	2.18
Log Po/w (MLOGP) :	2.17
Log Po/w (SILICOS-IT) :	1.84
Consensus Log Po/w :	1.82

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.02
Solubility :	1.78 mg/ml ; 0.00949 mol/l
Class :	Soluble
Log S (Ali) :	-1.99
Solubility :	1.92 mg/ml ; 0.0103 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.67
Solubility :	0.396 mg/ml ; 0.00211 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.55

Safety of [ 125568-73-2 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 125568-73-2 ]

* 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 [ 125568-73-2 ]
Downstream synthetic route of [ 125568-73-2 ]

[ 125568-73-2 ] Synthesis Path-Upstream 1~6

1
[ 125568-71-0 ]
[ 125568-73-2 ]

Yield	Reaction Conditions	Operation in experiment
96%	With iron; acetic acid In water at 40℃; for 1.5 h;	Iron powder (12 3 g, 0 22 mol, 4 equiv) was added to a solution of methyl 2,4-dιfluoro-5- nitrobenzoate intermediate 18 (12 0 g, 0 06 mol, 1 equiv) in acetic acid (150 mL) and water (150 mL) and the reaction was heated to 40 ⁰C for 1 5 h The reaction mixture was filtered thru a pad of celite and the filtered solution extracted with ethyl acetate The organics were washed with satd aq NaCI, dried over Na₂SO₄, filtered and concentrated to give intermediate 19 (10 Og, 96percent yield) as a brown solid 1H NMR (400 MHz, DMSO-cfe) δ ppm 7 27 (dd, J=9 98, 742 Hz, 1 H), 7 14 (t, J=10 99 Hz, 1 H), 5 28 (s, 2 H), 3 77 (s, 3 H) ES-LCMS m/z 189 0 (M+H)
96%	at 40℃; for 1.5 h;	Intermediate 5; methyl 5-amino-2,4-difluorobenzoate; Iron powder (12.3 g, 0.22 mol, 4 equiv) was added to a solution of methyl 2,4- difluoro-5-nitrobeπzoate intermediate 17 (12.0 g, 0.06 mol, 1 equiv) in acetic acid (150 mL) and water (150 mL) and the reaction was heated to 40⁰C for 1.5 h. The reaction mixture was filtered thru a pad of celite and the filtered solution extracted with ethyl acetate. The organics were washed with satd. aq. NaCI, dried over Na- ₂SO₄, filtered and concentrated to give intermediate 5 (10.0g, 96percent yield) as a brown solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.27 (dd, J=9.98, 7.42 Hz, 1 H), 7.14 (t, J=10.99 Hz, 1 H), 5.28 (s, 2 H), 3.77 (s, 3 H). ES-LCMS: m/z 189.0 (M+H).
96%	at 40℃; for 1.5 h;	Intermediate 3; methyl 5-amino-2,4-difluorobenzoate; Iron powder (12.3 g, 0.22 mol, 4 equiv) was added to a solution of methyl 2,4-difluoro-5- nitrobenzoate intermediate 2 (12.0 g, 0.06 mol, 1 equiv) in acetic acid (150 mL) and water (150 mL) and the reaction was heated to 40⁰C for 1.5 h. The reaction mixture was filtered thru a pad of celite and the filtered solution extracted with ethyl acetate. The organics were washed with satd. aq. NaCI, dried over Na₂SO₄, filtered and concentrated to give intermediate 3 (10.Og, 96percent yield) as a brown solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.27 (dd, J=9.98, 7.42 Hz, 1 H), 7.14 (t, J=10.99 Hz, 1 H), 5.28 (s, 2 H), 3.77 (s, 3 H). ES-LCMS: m/z 189.0 (M+H).

Reference： [1] Patent: WO2009/75960, 2009, A1, . Location in patent: Page/Page column 22
[2] Patent: WO2009/58919, 2009, A1, . Location in patent: Page/Page column 23
[3] Patent: WO2009/58923, 2009, A1, . Location in patent: Page/Page column 12
[4] Journal of Organic Chemistry, 1990, vol. 55, # 7, p. 2034 - 2044

2
[ 639858-45-0 ]
[ 67-56-1 ]
[ 125568-73-2 ]

Yield	Reaction Conditions	Operation in experiment
86%	With thionyl chloride In methanol at 80℃; for 1 h; Cooling with ice	To an ice cold solution of 5-amino-2,4-difluoro-benzoic acid (1, 0 g,0.017 mol) in methanol (20.0 mL), thionyl chloride (2.514 mL, 0.035 mol) was added. The resulting mixture was heated at 80°C for lh. Progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. DCM and water was added to the reaction mixture. Combined organic layer was dried over sodium sulphate, concentrated under reduced pressure to afford the product methyl 5-amino-2,4-difluoro-benzoate (2.8 g, 86.0percent). LCMS (ESI positive ion) m/z: calculated: 187.15; Observed; 188.2 (M+l). 1H-NMR (400 MHz, CDC13): δ 7.35-7.39 (m, 1H), 6.82-6.87 (m, 1H), and 3.92 (s, 3H).

Reference： [1] Patent: WO2018/178338, 2018, A1, . Location in patent: Page/Page column 104

3
[ 1583-58-0 ]
[ 125568-73-2 ]

Reference： [1] Journal of Organic Chemistry, 1990, vol. 55, # 7, p. 2034 - 2044

4
[ 125568-78-7 ]
[ 109-89-7 ]
[ 125568-73-2 ]
[ 125569-06-4 ]

Reference： [1] Journal of Organic Chemistry, 1990, vol. 55, # 7, p. 2034 - 2044
[2] Journal of Organic Chemistry, 1990, vol. 55, # 7, p. 2034 - 2044

5
[ 125568-78-7 ]
[ 125568-73-2 ]
[ 125568-90-3 ]

Reference： [1] Journal of Organic Chemistry, 1990, vol. 55, # 7, p. 2034 - 2044

6
[ 563-79-1 ]
[ 125568-78-7 ]
[ 125568-73-2 ]
[ 125568-97-0 ]
[ 125568-90-3 ]

Reference： [1] Journal of Organic Chemistry, 1990, vol. 55, # 7, p. 2034 - 2044

[ 125568-73-2 ] Synthesis Path-Downstream 1~31

1
[ 563-79-1 ]
[ 125568-78-7 ]
[ 125568-73-2 ]
[ 125568-97-0 ]
[ 125568-90-3 ]

Reference： [1]Journal of Organic Chemistry,1990,vol. 55,p. 2034 - 2044

2
[ 125568-73-2 ]
[ 125568-78-7 ]

Reference： [1]Journal of Organic Chemistry,1990,vol. 55,p. 2034 - 2044

3
[ 125568-71-0 ]
[ 125568-73-2 ]

Yield	Reaction Conditions	Operation in experiment
96%	With iron; acetic acid; In water; at 40℃; for 1.5h;	Iron powder (12 3 g, 0 22 mol, 4 equiv) was added to a solution of methyl 2,4-diotafluoro-5- nitrobenzoate intermediate 18 (12 0 g, 0 06 mol, 1 equiv) in acetic acid (150 mL) and water (150 mL) and the reaction was heated to 40 0C for 1 5 h The reaction mixture was filtered thru a pad of celite and the filtered solution extracted with ethyl acetate The organics were washed with satd aq NaCI, dried over Na2SO4, filtered and concentrated to give intermediate 19 (10 Og, 96% yield) as a brown solid 1H NMR (400 MHz, DMSO-cfe) delta ppm 7 27 (dd, J=9 98, 742 Hz, 1 H), 7 14 (t, J=10 99 Hz, 1 H), 5 28 (s, 2 H), 3 77 (s, 3 H) ES-LCMS m/z 189 0 (M+H)
96%	With water; iron; acetic acid; at 40℃; for 1.5h;	Intermediate 5; methyl 5-amino-2,4-difluorobenzoate; Iron powder (12.3 g, 0.22 mol, 4 equiv) was added to a solution of methyl 2,4- difluoro-5-nitrobe?zoate intermediate 17 (12.0 g, 0.06 mol, 1 equiv) in acetic acid (150 mL) and water (150 mL) and the reaction was heated to 400C for 1.5 h. The reaction mixture was filtered thru a pad of celite and the filtered solution extracted with ethyl acetate. The organics were washed with satd. aq. NaCI, dried over Na- 2SO4, filtered and concentrated to give intermediate 5 (10.0g, 96% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6) delta ppm 7.27 (dd, J=9.98, 7.42 Hz, 1 H), 7.14 (t, J=10.99 Hz, 1 H), 5.28 (s, 2 H), 3.77 (s, 3 H). ES-LCMS: m/z 189.0 (M+H).
96%	With water; iron; acetic acid; at 40℃; for 1.5h;	Intermediate 3; methyl 5-amino-2,4-difluorobenzoate; Iron powder (12.3 g, 0.22 mol, 4 equiv) was added to a solution of methyl 2,4-difluoro-5- nitrobenzoate intermediate 2 (12.0 g, 0.06 mol, 1 equiv) in acetic acid (150 mL) and water (150 mL) and the reaction was heated to 400C for 1.5 h. The reaction mixture was filtered thru a pad of celite and the filtered solution extracted with ethyl acetate. The organics were washed with satd. aq. NaCI, dried over Na2SO4, filtered and concentrated to give intermediate 3 (10.Og, 96% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6) delta ppm 7.27 (dd, J=9.98, 7.42 Hz, 1 H), 7.14 (t, J=10.99 Hz, 1 H), 5.28 (s, 2 H), 3.77 (s, 3 H). ES-LCMS: m/z 189.0 (M+H).

Reference： [1]Patent: WO2009/75960,2009,A1 .Location in patent: Page/Page column 22
[2]Patent: WO2009/58919,2009,A1 .Location in patent: Page/Page column 23
[3]Patent: WO2009/58923,2009,A1 .Location in patent: Page/Page column 12
[4]Journal of Organic Chemistry,1990,vol. 55,p. 2034 - 2044

4
[ 125568-78-7 ]
[ 125568-73-2 ]
[ 125568-90-3 ]

Reference： [1]Journal of Organic Chemistry,1990,vol. 55,p. 2034 - 2044

5
[ 125568-73-2 ]
[ 100-52-7 ]
[ 125568-84-5 ]

Reference： [1]Journal of Organic Chemistry,1990,vol. 55,p. 2034 - 2044

6
[ 125568-78-7 ]
[ 109-89-7 ]
[ 125568-73-2 ]
[ 125569-06-4 ]

Reference： [1]Journal of Organic Chemistry,1990,vol. 55,p. 2034 - 2044
[2]Journal of Organic Chemistry,1990,vol. 55,p. 2034 - 2044

7
[ 125568-78-7 ]
[ 108-88-3 ]
[ 125568-73-2 ]
[ 125568-84-5 ]
3,3'-dicarbomethoxy-4,4',6,6'-tetrafluoroazobenzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 11 % Chromat. 2: 3 % Chromat. 3: 4 % Chromat.	at 15℃; for 4h; Irradiation;

Reference： [1]Soundararajan, N.; Platz, Matthew S. [Journal of Organic Chemistry, 1990, vol. 55, # 7, p. 2034 - 2044]

8
[ 125568-78-7 ]
[ 108-88-3 ]
[ 125568-73-2 ]
[ 125568-84-5 ]

Yield	Reaction Conditions	Operation in experiment
1: 9 % Chromat. 2: 45 % Chromat.	at -196℃; for 10h; Irradiation;

Reference： [1]Soundararajan, N.; Platz, Matthew S. [Journal of Organic Chemistry, 1990, vol. 55, # 7, p. 2034 - 2044]

9
[ 125568-73-2 ]
[ 125568-97-0 ]

Reference： [1]Journal of Organic Chemistry,1990,vol. 55,p. 2034 - 2044

10
[ 125568-73-2 ]
[ 125568-90-3 ]

Reference： [1]Journal of Organic Chemistry,1990,vol. 55,p. 2034 - 2044

11
[ 1583-58-0 ]
[ 125568-73-2 ]

Reference： [1]Journal of Organic Chemistry,1990,vol. 55,p. 2034 - 2044

12
[ 75-44-5 ]
[ 125568-73-2 ]
C₉H₅F₂NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In dichloromethane; toluene; at -40℃; for 1.5h;Product distribution / selectivity;	A solution of methyl 5-amiotano-2,4-diotafluorobenzoate intermediate 19 (5 5 g, 29 5 mmol, 1 equiv) in dichloromethane (100 mL) at -40 0C was treated with pyridine (7 16 mL, 88 6 mmol, 3 0 equiv) and 1 9 M phosgene in toluene (23 3 mL, 44 3 mmol, 1 5 equiv) After 1 5 h, a solution of 1 ,1-diotamethylethyl 4-(butylamiotano)-1-piotaperiotadiotanecarboxylate intermediate 20 (9 1 g, 35 4 mmol, 1 2 equiv) in dichloromethane (50 mL) was added and the reaction was allowed to warm to RT for 18 h The reaction was diluted with dichloromethane, washed with satd aq NaHCO3, dried over Na2SO4, filtered and concentrated to give intermediate 21 (13 1 g, 95% yield) a white solid1H NMR (400 MHz, DMSO-cfe) delta ppm 8 09 (s, 1 H), 7 89 - 7 99 (m, 1 H), 7 42 (t, J=10 62 Hz, 1 H), 3 88 - 3 99 (m, 1 H), 3 85 (s, 3 H), 3 11 - 3 22 (m, 2 H), 2 96 (d, J=12 27 Hz, 2 H), <n="25"/>2 41 - 2 53 (m, 3 H), 1 43 - 1 59 (m, 5 H), 1 21 - 1 35 (m, 2 H), 1 20 (s, 9 H), 0 90 (t, J=I 33 Hz, 3 H) ES-LCMS m/z 468 1 (M-H); Intermediate 291 ,1-diotamethylethyl 4-[[({2,4-diotafluoro-5-[(methyloxy)carbonyl]phenyl}amiotano)carbonyl](3- fluorophenyl)amiotano]-1-piotaperiotadiotanecarboxylateA solution of methyl 5-amiotano-2,4-diotafluorobenzoate intermediate 19 (5 O g, 26 5 mmol, 1 equiv) in dichloromethane (150 mL) at -40 0C was treated with pyridine (6 4 mL, 79 7 mmol, 3 0 equiv) and 1 9 M phosgene in toluene (20 1 mL, 39 8 mmol, 1 5 equiv) After 1 5 h, the reaction was concentrated down and dried under vac The residue was taken up <n="30"/>in dichloromethane (150 mL) and 1 ,1-diotamethylethyl 4-[(3-fluorophenyl)amiotano]-1- piperidmecarboxylate intermediate 6 (8 6 g, 29 2 mmol, 1 1 equiv) was added and the reaction was heated to 40 0C 18 h The reaction was diluted with dichloromethane, washed with satd aq NaHCO3, dried over Na2SO4, filtered and concentrated The residue was purified by silica gel flash column chromatography (0 ? 30% ethyl acetate hexanes) to give intermediate 29 (12 6 g, 94% yield) a white solid1H NMR (400 MHz, CHLOROFORM-d) delta ppm 8 65 (dd, J=8 88, 7 78 Hz, 1 H), 744 - 7 55 (m, 1 H), 7 17 - 7 24 (m, 1 H), 7 04 (d, J=I 87 Hz, 1 H), 6 92 - 6 99 (m, 1 H), 6 80 (t, J=10 26 Hz, 1 H), 5 96 (d, J=Z 11 Hz, 1 H), 4 56 - 4 70 (m, 1 H), 4 03 - 4 26 (m, 2 H), 3 80 - 3 92 (m, 3 H), 2 79 (s, 2 H), 1 85 (d, J=13 37 Hz, 2 H), 1 39 (s, 9 H), 1 19 - 1 35 (m, 2 H) ES-LCMS m/z 530 1 (M+Na)

Reference： [1]Patent: WO2009/75960,2009,A1 .Location in patent: Page/Page column 23-24; 28-29

13
[ 75-44-5 ]
[ 125568-73-2 ]
C₉H₆ClF₂NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In dichloromethane; toluene; at -40℃; for 1.5h;Product distribution / selectivity;	Synthesis of Intermediate 15; Intermediate 12 <n="19"/>; 1 , 1 -dimethylethyl 4-[[({2,4-difluoro-5-[(methyloxy)carbo?yl]phenyl}amino)carbonyl](3- fluorophenyl)amino]-1-piperidinecarboxylate; A solution of <strong>[125568-73-2]methyl 5-amino-2,4-difluorobenzoate</strong> intermediate 5 (5,0 g, 26.5 mmol, 1 equiv) in dichloromethane (150 mL) at -400C was treated with pyridine (6.4 mL, 79.7 mmol, 3.0 equiv) and 1.9 M phosgene in toluene (20.1 mL, 39.8 mmol, 1.5 equiv). After 1.5 h, the reaction was concentrated down and dried under vac. The residue was taken up in dichloromethane (150 mL) and 1 ,1 -dimethylethyl 4-[(3- fluorophenyl)amino]-1-piperidi?ecarboxylate intermediate 11 (8.6 g, 29.2 mmol, 1.1 equiv) was added and the reaction was heated to 400C 18 h. The reaction was diluted with dichloromethane, washed with satd. aq. NaHCO3, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column chromatography (0 ? 30% ethyl acetate : hexanes) to give intermediate 12 (12.6 g, 94% yield) a white solid.1H NMR (400 WIHz, CHLOROFORM-d) delta ppm 8.65 (dd, J=8.88, 7.78 Hz, 1 H), 7.44 - 7.55 (m, 1 H), 7.17 - 7.24 (m, 1 H), 7.04 (d, J=7.87 Hz, 1 H), 6.92 - 6.99 (m, 1 H), 6.80 (t, J=10.26 Hz, 1 H), 5.96 (d, J=3.11 Hz, 1 H), 4.56 - 4.70 (m, 1 H), 4.03 - 4.26 (m, 2 H), 3.80 - 3.92 (m, 3 H), 2.79 (s, 2 H), 1.85 (d, J=13.37 Hz, 2 H), 1.39 (s, 9 H), 1.19 - 1.35 (m, 2 H). ES-LCMS: m/z 530.1 (M+Na).; Intermediate 19; 1 ,1-dimethylethyl 4-{butyl[({2,4-difluoro-5-[(methyloxy)carbonyl]phenyl}amino)carbonyl]amino}-1-piperidinecarboxylate; A solution of <strong>[125568-73-2]methyl 5-amino-2,4-difluorobenzoate</strong> intermediate 5 (5.5 g, 29.5 mmol, 1 equiv) in dichloromethane (100 mL) at -400C was treated with pyridine (7.16 mL, 88.6 mmol, 3.0 equiv) and 1.9 M phosgene in toluene (23.3 mL, 44.3 mmol, 1.5 equiv). After 1.5 h, a solution of 1 ,1-dimethylethyl 4-(butylamino)-1- piperidinecarboxylate intermediate 18 (9.1 g, 35.4 mmol, 1.2 equiv) in dichloromethane (50 mL) was added and the reaction was allowed to warm to RT for 18 h. The reaction was diluted with dichloromethane, washed with satd. aq. NaHCO3, dried over Na2Stheta4, filtered and concentrated to give intermediate 19 (13.1 g, 95% yield) a white solid.1H NMR (400 MHz, DMSO-Cf6) delta ppm 8.09 (s, 1 H), 7.89 - 7.99 (m, 1 H), 7.42 (t, J=10.62 Hz, 1 H), 3.88 - 3.99 (m, 1 H), 3.85 (s, 3 H), 3.11 - 3.22 (m, 2 H), 2.96 (d, <n="26"/>J=12.27 Hz, 2 H), 2.41 - 2.53 (m, 3 H), 1.43 - 1.59 (m, 5 H), 1.21 - 1.35 (m, 2 H), 1.20 (s, 9 H), 0.90 (t, J=7.33 Hz, 3 H). ES-LCMS: m/z 468.1 (M-H).
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; toluene; at -40℃; for 1.5h;Product distribution / selectivity;	Intermediate 34; methyl 2,4-difluoro-5-([(3-fluorophenyl)(1 -[2-??ethyl-6-({4-[(methylsulfonyl)amino]phenyl}oxy)-3-pyridinyl]methyl}-4- piperidinyl)amino]carbonyl}amino)benzoate; A solution of <strong>[125568-73-2]methyl 5-amino-2,4-difluorobenzoate</strong> intermediate 5 (400 mg g, 2.1 mmol, 1 equiv) in dichloromethane (30 mL) at -400C was treated with N,N- diisopropylethylamine (0.89 mL, 5.1 mmol, 2.4 equiv) and 1.9 M phosgene in toluene (1.3 mL, 2.5 mmol, 1.2 equiv). After 1.5 h, the reaction was concentrated down and dried under vac. The residue was taken up in dichloromethane (30 mL) and lambda/-(4-[5-({4-[(3-fluorophenyl)amino]-1-piperidinyl}methyl)-6-methyl-2- pyridinyl]oxy}phenyl)methanesulfonamide intermediate 33 (1.0 g, 2.13 mmol, 1 equiv) was added and the reaction was stirred at RT for 18 h. The reaction was <n="38"/>diluted with dichloromethane, washed with satd. aq. NaHCO3, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column chromatography (O ? 5% 2N NH3 in MeOH : CH2CI2) to give intermediate 34 (675 mg, 46% yield) as a white solid.1H NWIR (400 MHz, DMSO-cfe) delta ppm 9.61 (s, 1 H), 7.95 (t, J=8.15 Hz, 1 H), 7.45 - 7.56 (m, 2 H), 7.32 - 7.40 (m, 1 H), 7 24 - 7.31 (m, 2 H), 7.17 (t, J=8.88 Hz, 3 H), 7.09 (d, J=7.87 Hz, 1 H), 6.99 - 7.06 (m, 2 H), 6.64 (d, J=8.24 Hz, 1 H), 4.22 (s, 1 H), 3.80 (s, 3 H), 3.31 (s, 2 H), 2.94 (d, J=0.73 Hz, 3 H), 2.74 (s, 2 H), 2.24 (s, 3 H), 1.92 - 2.09 (m, 2 H), 1.73 (s, 2 H), 1.11 - 1.29 (m, 2 H). ES-LCMS: m/z 698.2 (M+H).
	With pyridine; In dichloromethane; toluene; at -40℃; for 1.5h;Product distribution / selectivity;	Intermediate 5; 1 ,1-dimethylethyl 4-{butyl[({2,4-difluoro-5-[(methyloxyjcarbonyllphenyljaminojcarbonyllaminoj-i-piperidinecarboxylate; A solution of <strong>[125568-73-2]methyl 5-amino-2,4-difluorobenzoate</strong> intermediate 3 (5.5 g, 29.5 mmol, 1 equiv) in dichloromethane (100 mL) at -40 0C was treated with pyridine (7.16 mL, 88.6 mmol, 3.0 equiv) and 1.9 M phosgene in toluene (23.3 mL, 44.3 mmol, 1.5 equiv). After 1.5 h, a solution of 1,1-dimethylethyl 4-(butylamino)-1-piperidi?ecarboxylate intermediate 4 (9.1 g, 35.4 mmol, 1.2 equiv) in dichloromethane (50 mL) was added and the reaction was allowed to warm to RT for 18 h. The reaction was diluted with dichloromethane, washed with satd. aq. NaHCO3, dried over Na2SO4, filtered and concentrated to give intermediate 5 (13.1 g, 95% yield) a white solid.1H NMR (400 MHz, DMSO-d6) delta ppm 8.09 (s, 1 H), 7.89 - 7.99 (m, 1 H), 7.42 (t, J=10.62 Hz, 1 H), 3.88 - 3.99 (m, 1 H), 3.85 (s, 3 H), 3.11 - 3.22 (m, 2 H), 2.96 (d, J=12.27 Hz, 2 <n="15"/>H), 2.41 - 2.53 (m, 3 H), 1.43 - 1.59 (m, 5 H), 1.21 - 1.35 (m, 2 H), 1.20 (s, 9 H), 0.90 (t, J=7.33 Hz, 3 H). ES-LCMS: m/z 468.1 (M-H).; Intermediate 13; 1 , 1 -dimethylethyl 4-[[({2,4-difluoro-5-[(methyloxy)carbonyl]phenyl}amino)carbonyl](3- fluoropheny.)amino]-1-piperidinecarboxylate; <n="22"/>A solution of methyl 5-ami?o-2,4-difluorobenzoate intermediate 3 (5.0 g, 26.5 mmol, 1 equiv) in dichloromethane (150 mL) at -400C was treated with pyridine (6.4 ml_, 79.7 mmol, 3.0 equiv) and 1.9 M phosgene in toluene (20.1 mL, 39.8 mmol, 1.5 equiv). After 1.5 h, the reaction was concentrated down and dried under vac. The residue was taken up in dichloromethane (150 mL) and 1 ,1-dimethylethyl 4-[(3-fluorophenyl)amino]-1- piperidinecarboxylate intermediate 12 (8.6 g, 29.2 mmol, 1.1 equiv) was added and the reaction was heated to 40 0C 18 h. The reaction was diluted with dichloromethane, washed with satd. aq. NaHCO3, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column chromatography (0 ? 30% ethyl acetate : hexanes) to give intermediate 13 (12.6 g, 94% yield) a white solid. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 8.65 (dd, J=8.88, 7.78 Hz, 1 H), 7.44 - 7.55 (m, 1 H), 7.17 - 7.24 (m, 1 H), 7.04 (d, J=7.87 Hz, 1 H), 6.92 - 6.99 (m, 1 H), 6.80 (t, J=10.26 Hz, 1 H), 5.96 (d, J=3.11 Hz, 1 H), 4.56 - 4.70 (m, 1 H), 4.03 - 4.26 (m, 2 H), 3.80 - 3.92 (m, 3 H), 2.79 (s, 2 H), 1.85 (d, J=13.37 Hz, 2 H), 1.39 (s, 9 H), 1.19 - 1.35 (m, 2 H). ES-LCMS: rn/z 530.1 (M+Na).

Reference： [1]Patent: WO2009/58919,2009,A1 .Location in patent: Page/Page column 17-18; 24-25
[2]Patent: WO2009/58919,2009,A1 .Location in patent: Page/Page column 36-37
[3]Patent: WO2009/58923,2009,A1 .Location in patent: Page/Page column 13-14; 20-21

14
[ 125568-73-2 ]
[ 1500113-88-1 ]
C₁₂H₉F₂N₃O₃ [ No CAS ]

Reference： [1]Journal of Heterocyclic Chemistry,2013,vol. 50,p. 863 - 867

15
[ 125568-73-2 ]
[ 1500113-89-2 ]

Reference： [1]Journal of Heterocyclic Chemistry,2013,vol. 50,p. 863 - 867

16
[ 125568-73-2 ]
[ 1500113-90-5 ]

Reference： [1]Journal of Heterocyclic Chemistry,2013,vol. 50,p. 863 - 867

17
[ 125568-73-2 ]
[ 1500113-90-5 ]
[ 1500113-91-6 ]

Reference： [1]Journal of Heterocyclic Chemistry,2013,vol. 50,p. 863 - 867

18
[ 125568-73-2 ]
[ 1500113-92-7 ]

Reference： [1]Journal of Heterocyclic Chemistry,2013,vol. 50,p. 863 - 867
[2]Journal of Heterocyclic Chemistry,2013,vol. 50,p. 863 - 867

19
[ 56875-55-9 ]
[ 125568-73-2 ]
C₁₉H₁₅F₂NO₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In dichloromethane; at 0 - 20℃; for 8.0h;Cooling with ice;	General procedure: To a solution of compound 11a (154 mg, 1.0 mmol) in anhydrous CH2Cl2 (10 mL) was added 3,5-dichlorobenzoyl chloride (209 mg, 1.0 mmol) and pyridine (241 mL 3.0 mmol) under ice bath. After stirring at room temperature for about 8 h, the solvent was removed in vacuum. The resulting residue was dissolved in NaOH (1 M) water solution (3 mL) and CH3OH (3 mL) and stirred for another 2 h. Then the solvent was removed under vacuum, and the residue was acidied to pH 2 or below with HCl (1 M) water solution. The solution was extracted with ethyl acetate twice and the combined organics were dried over anhydrous sodium sulfate and concentrated in vacuum. The resulting residue was puried by silica gel chromatography to give the desired compound as a white solid (234 mg, yield 85.0%)

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 154,p. 44 - 59

20
[ 639858-45-0 ]
[ 67-56-1 ]
[ 125568-73-2 ]

Yield	Reaction Conditions	Operation in experiment
86%	With thionyl chloride; In methanol; at 80℃; for 1.0h;Cooling with ice;	To an ice cold solution of 5-amino-2,4-difluoro-benzoic acid (1, 0 g,0.017 mol) in methanol (20.0 mL), thionyl chloride (2.514 mL, 0.035 mol) was added. The resulting mixture was heated at 80C for lh. Progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. DCM and water was added to the reaction mixture. Combined organic layer was dried over sodium sulphate, concentrated under reduced pressure to afford the product methyl 5-amino-2,4-difluoro-benzoate (2.8 g, 86.0%). LCMS (ESI positive ion) m/z: calculated: 187.15; Observed; 188.2 (M+l). 1H-NMR (400 MHz, CDC13): delta 7.35-7.39 (m, 1H), 6.82-6.87 (m, 1H), and 3.92 (s, 3H).

Reference： [1]Patent: WO2018/178338,2018,A1 .Location in patent: Page/Page column 104

21
[ 125568-73-2 ]
tert-butyl 4-(2,4-difluoro-5-(methoxycarbonyl)phenyl)piperazine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2018/178338,2018,A1

22
[ 125568-73-2 ]
5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2,4-difluorobenzoic acid [ No CAS ]

Reference： [1]Patent: WO2018/178338,2018,A1

23
[ 125568-73-2 ]
tert-butyl 4-(5-((2-(dimethylamino)ethyl)carbamoyl)-2,4- difluorophenyl)piperazine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2018/178338,2018,A1

24
[ 125568-73-2 ]
N-(2-(dimethylamino)ethyl)-2,4-difluoro-5-(piperazin-1-yl)benzamide [ No CAS ]

Reference： [1]Patent: WO2018/178338,2018,A1

25
[ 125568-73-2 ]
5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo-[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-2,4-difluorobenzamide [ No CAS ]

Reference： [1]Patent: WO2018/178338,2018,A1

26
[ 125568-73-2 ]
[ 821-48-7 ]
methyl 2,4-difluoro-5-(piperazin-1-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29.9%	at 170℃; for 2.5h;	A mixture of methyl 5-amino-2,4-difluoro-benzoate (2, 3.0 g, 0.016 mol) and 2-chloro-N-(2- chloroethyl)ethanamine hydrochloride (3.719 g, 0.021 mol) in diethylene glycol monomethyl ether (12 mL) was heated to 170C for 2.5h. Progress of the reaction was monitored by TLC. Water was added to the reaction mixture and extracted with ethyl acetate. The organic part was discarded. Then pH of the aqueous part was adjusted with sodium bicarbonate and extracted with ethyl acetate. Combined organic part was dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product obtained was purified by column chromatography to afford the product (1.5 g, 29.9%). LCMS (ESI positive ion) m/z: calculated: 256.25; Observed; 257.0 (M+l).

Reference： [1]Patent: WO2018/178338,2018,A1 .Location in patent: Page/Page column 104

27
[ 125568-73-2 ]
C₁₈H₁₉Cl₂F₂N₃OSi [ No CAS ]
C₂₆H₂₅ClF₄N₄O₃Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In 1,4-dioxane at 110℃; Inert atmosphere;	6.1 first step: 015041A1 synthesis Intermediate 015039A1 (500mg, 1.163mmol), 2,4-difluoro-5-aminobenzoic acid methyl ester (217.6mg, 1.163mmol), BINAP (289.6mg, 0.465mmol), Pd(OAc)2 (52.2mg , 0.233mmol) and cesium carbonate (1.14g, 3.488mmol) were dissolved in dioxane (30mL), stirred overnight at 110°C under nitrogen protection, spin-dried to remove the solvent, concentrated the residue and passed through silica gel column chromatography (EA/PE = 1/10) Isolation and purification gave a yellow solid compound 015041A1 (350 mg, yield 52%).

Reference： [1]Current Patent Assignee: SUZHOU XINNUOWEI PHARMACEUTICAL TECH - CN111303128, 2020, A Location in patent: Paragraph 0255-0258

28
[ 125568-73-2 ]
C₁₉H₂₁Cl₂F₂N₃OSi [ No CAS ]
C₂₇H₂₇ClF₄N₄O₃Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In 1,4-dioxane at 110℃; Inert atmosphere;	8.2 Step 2: Synthesis of 015048A1 Intermediate 015048A0 (600mg, 1.35mmol), 2,4-difluoroaniline-5-carboxylic acid methyl ester (252.6mg, 1.35mmol), BINAP (336.2mg, 0.54mmol), Pd(OAc)2 (60.6mg, 0.27mmol) and cesium carbonate (879.7mg, 2.7mmol) were dissolved in dioxane (30mL), stirred overnight at 110°C under nitrogen protection, spin-dried to remove the solvent, and the residue was concentrated and passed through silica gel column chromatography (EA/PE= 20/1) Isolation and purification gave yellow solid compound 015048A1 (520 mg, yield 65%).

Reference： [1]Current Patent Assignee: SUZHOU XINNUOWEI PHARMACEUTICAL TECH - CN111303128, 2020, A Location in patent: Paragraph 0307-0308; 0312-0314

29
[ 125568-73-2 ]
C₁₂H₁₄BrF₂NO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: triethylamine; dmap / tetrahydrofuran / 2 h / 30 °C 2: lithium aluminium tetrahydride / tetrahydrofuran / 2 h / 0 °C 3: triphenylphosphine; carbon tetrabromide / dichloromethane / 3 h / 30 °C

Reference： [1]Current Patent Assignee: XIAMEN BIOTIME BIOTECHNOLOGY; ADLAI NORTYE BIOPHARMA; HANGZHOU ADLAI NORTYE BIOMEDICAL TECH - CN112028891, 2020, A

30
[ 125568-73-2 ]
C₁₂H₁₅F₂NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: triethylamine; dmap / tetrahydrofuran / 2 h / 30 °C 2: lithium aluminium tetrahydride / tetrahydrofuran / 2 h / 0 °C

Reference： [1]Current Patent Assignee: XIAMEN BIOTIME BIOTECHNOLOGY; ADLAI NORTYE BIOPHARMA; HANGZHOU ADLAI NORTYE BIOMEDICAL TECH - CN112028891, 2020, A

31
[ 24424-99-5 ]
[ 125568-73-2 ]
C₁₃H₁₅F₂NO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With dmap; triethylamine In tetrahydrofuran at 30℃; for 2h;	28 Compound 28a (500mg, 2.67mmol) was dissolved in tetrahydrofuran (20mL),Immediately add triethylamine (811 mg, 8.02 mmol, 1.11 mL), 4-dimethylaminopyridine (326 mg, 2.67 mmol) and di-tert-butyl dicarbonate (700 mg, 3.21 mmol, 737 μL).The reaction solution was stirred at 30°C for 2 hours. The reaction solution was concentrated under vacuum to obtain a yellow oily crude product. Purified by column chromatography (ethyl acetate/petroleum ether = 1/4) to obtain a white solid 28b(598 mg, yield: 78%).

Reference： [1]Current Patent Assignee: XIAMEN BIOTIME BIOTECHNOLOGY; ADLAI NORTYE BIOPHARMA; HANGZHOU ADLAI NORTYE BIOMEDICAL TECH - CN112028891, 2020, A Location in patent: Paragraph 0270-0272

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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