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[ CAS No. 1000698-88-3 ] {[proInfo.proName]}

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3d Animation Molecule Structure of 1000698-88-3

Chemical Structure| 1000698-88-3

Chemical Structure| 1000698-88-3

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Quality Control of [ 1000698-88-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 1000698-88-3 ]

Product Details of [ 1000698-88-3 ]

CAS No. :	1000698-88-3	MDL No. :	MFCD12913719
Formula :	C₁₁H₁₄F₂N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	NYKTXVPUGXBLOK-UHFFFAOYSA-N
M.W :	244.24	Pubchem ID :	66619231
Synonyms :

Calculated chemistry of [ 1000698-88-3 ]

Physicochemical Properties

Num. heavy atoms :	17
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.36
Num. rotatable bonds :	4
Num. H-bond acceptors :	4.0
Num. H-bond donors :	2.0
Molar Refractivity :	61.01
TPSA :	64.35 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.36 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.27
Log Po/w (XLOGP3) :	2.01
Log Po/w (WLOGP) :	3.55
Log Po/w (MLOGP) :	2.6
Log Po/w (SILICOS-IT) :	1.85
Consensus Log Po/w :	2.46

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.62
Solubility :	0.589 mg/ml ; 0.00241 mol/l
Class :	Soluble
Log S (Ali) :	-2.99
Solubility :	0.251 mg/ml ; 0.00103 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.56
Solubility :	0.068 mg/ml ; 0.000279 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.28

Safety of [ 1000698-88-3 ]

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

Application In Synthesis of [ 1000698-88-3 ]

* 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 [ 1000698-88-3 ]
Downstream synthetic route of [ 1000698-88-3 ]

[ 1000698-88-3 ] Synthesis Path-Upstream 1~3

1
[ 1000698-90-7 ]
[ 1000698-88-3 ]

Reference： [1] Patent: US2009/163552, 2009, A1, . Location in patent: Page/Page column 17
[2] Patent: WO2010/28981, 2010, A1, . Location in patent: Page/Page column 83-84

2
[ 24424-99-5 ]
[ 76179-40-3 ]
[ 1000698-88-3 ]

Yield	Reaction Conditions	Operation in experiment
74.2%	With iodine In ethanol at 0℃;	Example 54; N-Cyclohexyl-2-[5,6-difluoro-2-(methoxy-phenyl-methyl)-benzoimidazol-1-yl]-2-(4-methoxy-phenyl)-acetamide; Step 1; (2-Amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester [CAS RN 1000698-88-3] (for alternative preparation see also Example 1, Step 1); To a ice-bath cooled mixture of 1,2-diamino-4,5-difluorobenzene (10.00 g, 69 mmol, 1.0 equiv., [CAS RN 76179-40-3]) and di-tert-butyl-dicarbonate (12.87 g, 59 mmol, 0.85 equiv; [CAS RN 24424-99-5]) in absolute ethanol (150 mL) was added iodine (0.18 g, 0.007 mmol, 0.01 equiv; [CAS RN 7553-56-2]). The mixture was maintained overnight in the refrigerator. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (500 g, 1:0-->19:1 dichloromethane/ethyl acetate eluant) to afford, in order of elution, the bis-boc derivative as an orange solid (1.58 g, 6.6percent), and the desired compound as a white solid (12.58 g, 74.2percent).
74%	With iodine In ethanolCooling with ice	To a cooled (ice-bath) mixture of l,2-diamino-4,5-difluorobenzene (10.00 g, 69 mmol, 1.0 equiv., [CAS RN 76179-40-3]) and di-tert-butyl-dicarbonate (12.87 g, 59 mmol, 0.85 equiv; [CAS RN 24424-99-5]) in absolute ethanol (150ml) was added iodine (0.18g, 0.007 mmol, 0.01 equiv. [CAS RN 7553-56-2]). The mixture was maintained overnight in the refrigerator. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (50Og, 1:0 to 19:1 CH2Cl2/AcOEt eluant) to afford, in order of elution, the bis-boc derivative as an orange solid (1.58 g, 6 percent), and the desired compound as a white solid (12.58g, 74⁰Zo)₁¹H NMR (300 MHz, DMSO): <5 1.46 ( s, 9H), 5.03 (br s, 2H), 6.65 (dd, / = 8.2 Hz, / = 12.9 Hz, IH), 7.30 (dd, / = 8.9 Hz, / = 12.3 Hz, IH), 8.38 (br s, IH). MS (ISN): 243.4 [M-H]^".

Reference： [1] Patent: US2009/131482, 2009, A1, . Location in patent: Page/Page column 20
[2] Patent: WO2010/43513, 2010, A1, . Location in patent: Page/Page column 31

3
[ 24424-99-5 ]
[ 78056-39-0 ]
[ 1000698-88-3 ]

Reference： [1] Patent: WO2008/643, 2008, A1, . Location in patent: Page/Page column 118
[2] Patent: US2009/62356, 2009, A1, . Location in patent: Page/Page column 16-17
[3] Patent: US2009/131482, 2009, A1, . Location in patent: Page/Page column 14

[ 1000698-88-3 ] Synthesis Path-Downstream 1~14

1
[ 24424-99-5 ]
[ 78056-39-0 ]
[ 1000698-88-3 ]

Yield	Reaction Conditions	Operation in experiment
		Example 365; (2-Amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester4,5-Difluoro-2-nitro-phenylamine (6.0 g, 34 mmol, 1 equiv.) was added to a solution of di- tert-butyl dicarbonate (14.8 g, 68 mmol, 2 equiv.) and DMAP (211 mg, 0.2 mmol, 0.05 in THF (100 mL) and the mixture was stirred at room temperature for 72 hours. The solvent was evaporated and the crude extracted from ethylacetate and aq. NaHCO3. The residue was taken up in DCM and cooled to 0 C. Trifluoroacetic acid (7.75 g, 68 mmol, 2 equiv) were added slowly and the mixture stirred for 48h at 0 C. 2 N NaOH was added to adjust the pH to 7. The organic layer was separated and evaporated. The residue was taken up in ethyl acetate and the product extracted from aq. NaHCU3. The intermediate was isolated via Kieselgel chromatography. 4.28 g (16mmol, 1 equiv.) were dissolved in DMF (50 ml) and 13 ml of a saturated NH4Cl solution added. Zink powder (5.1 g, 78 mmol, 5 equiv.) was added and the suspension stirred for 30 minutes at 800C and another 2 hours at room temperature. The remaining solid was filtered off and the organic layer evaporated. The product was extracted from ethyl actetate and aq. NaHCtheta3 and further purified via Kieselgel chromatography.
		To a solution of di-tert-butyl dicarbonate (14.8 g, 67.8 mmol, 2.0 equiv; [CAS RN 24424-99-5]) and 4-dimethylaminopyridine (0.21 g, 1.7 mmol, 0.05 equiv; DMAP; [CAS RN 1122-58-3]) in THF (100 mL) was added 4,5-difluoro-2-nitro-phenylamine (5.9 g, 33.9 mmol, 1.0 equiv; [CAS RN 78056-39-0]) and the mixture was stirred at rt for 72 h. The solvent was evaporated under reduced pressure and the crude reaction product extracted from a sat. solution of NaHCO3 with ethyl acetate. The organic phases were dried over Na2SO4, the residue taken up in dichloromethane and cooled to 0 C. Trifluoroacetic acid (7.73 g, 67.8 mmol, 2.0 equiv) was added slowly and the reaction mixture stirred at 0 C. for 48 h. A solution of 2 N NaOH was added to adjust the pH of the solution to 7. The organic layer was separated and evaporated under reduced pressure. The residue was taken up in ethyl acetate and the product extracted from a sat. solution of NaHCO3, the organic phase dried over Na2SO4 and the intermediate isolated via Kieselgel chromatography. The purified product (4.28 g, 15.6 mmol, 1.0 equiv) was dissolved in DMF (50 mL) and a sat. solution of NH4Cl (13 mL) was added. Zinc powder (5.10 g, 78.0 mmol, 5.0 equiv) was added and the suspension stirred for 30 min at 80 C. and for an additional time period of 2 h at rt. The remaining solid was filtered off and the organic layer evaporated. The product was extracted from a sat. solution of NaHCO3 with ethyl actetate, the organic layer dried over Na2SO4 and the crude reaction product purified via Kieselgel chromatography. 1H NMR (300 MHz, DMSO): delta1.46 ( s, 9H), 5.03 (br s, 2H), 6.65 (dd, J=8.2 Hz, J=12.9 Hz, 1H), 7.30 (dd, J=8.9 Hz, J=12.3 Hz, 1H), 8.38 (br s, 1H). MS (ISN): 243.4 [M-H]-.
		Example 1; 2-[2-(3-Chloro-benzyl)-5,6-difluoro-benzoimidazol-1-yl]-2,N-dicyclohexyl-acetamide; Step 1: (2-Amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester; To a solution of di-tert-butyl dicarbonate (14.8 g, 67.8 mmol, 2.0 equiv; [CAS RN 24424-99-5]) and 4-dimethylaminopyridine (0.21 g, 1.7 mmol, 0.05 equiv; DMAP; [CAS RN 1122-58-3]) in THF (100 mL) was added 4,5-difluoro-2-nitro-phenylamine (5.9 g, 33.9 mmol, 1.0 equiv; [CAS RN 78056-39-0]) and the mixture was stirred at rt for 72 h. The solvent was evaporated under reduced pressure and the crude reaction product extracted from a sat. solution of NaHCO3 with ethyl acetate. The organic phases were dried over Na2SO4, the residue taken up in dichloromethane and cooled to 0 C. Trifluoroacetic acid (7.73 g, 67.8 mmol, 2.0 equiv) was added slowly and the reaction mixture stirred at 0 C. for 48 h. A solution of 2 N NaOH was added to adjust the pH of the solution to 7. The organic layer was separated and evaporated under reduced pressure. The residue was taken up in ethyl acetate and the product extracted from a sat. solution of NaHCO3, the organic phase dried over Na2SO4 and the intermediate isolated via Kieselgel chromatography. The purified product (4.28 g, 15.6 mmol, 1.0 equiv) was dissolved in DMF (50 mL) and a sat. solution of NH4Cl (13 mL) was added. Zinc powder (5.10 g, 78.0 mmol, 5.0 equiv) was added and the suspension stirred for 30 min at 80 C. and for an additional time period of 2 h at rt. The remaining solid was filtered off and the organic layer evaporated. The product was extracted from a sat. solution of NaHCO3 with ethyl actetate, the organic layer dried over Na2SO4 and the crude reaction product purified via Kieselgel chromatography. 1H NMR (300 MHz, DMSO): delta1.46 (s, 9H), 5.03 (br s, 2H), 6.65 (dd, J=8.2 Hz, J=12.9 Hz, 1H), 7.30 (dd, J=8.9 Hz, J=12.3 Hz, 1H), 8.38 (br s, 1H). MS (ISN): 243.4 [M-H]-.

Reference： [1]Patent: WO2008/643,2008,A1 .Location in patent: Page/Page column 118
[2]Patent: US2009/62356,2009,A1 .Location in patent: Page/Page column 16-17
[3]Patent: US2009/131482,2009,A1 .Location in patent: Page/Page column 14

2
[ 614-61-9 ]
[ 1000698-88-3 ]
[ 931-53-3 ]
[ 2043-61-0 ]
C₃₃H₄₂ClF₂N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
17.5 mg (34%)		To a solution of <strong>[1000698-88-3](2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester</strong> (24.42 mg, 0.10 mmol, 1.0 equiv; Intermediate C) in MeOH (1.0 mL) was added cyclohexanecarbaldehyde (16.83 mg, 18.05 mul, 0.15 mmol, 1.5 equiv; [2043-61-0]) and the mixture stirred at rt. After 30 min, (2-chloro-phenoxy)-acetic acid (18.66 mg, 0.10 mmol, 1.0 equiv; [CAS RN 614-61-9]) and cyclohexyl isocyanide (10.92 mg, 12.27 pi, 0.10 mmol, 1.0 equiv; [931-53-3]) were added and stirring continued at rt for 2 h. A solution of 4 M HCl in dioxane (0.2 mL) was added and the reaction mixture stirred at rt overnight. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile I water provided 17.5 mg (34%) of the title compound. MS (ISP): 516.2 [M+H]+.

Reference： [1]Patent: US2009/62356,2009,A1 .Location in patent: Page/Page column 17

3
[ 24424-99-5 ]
[ 76179-40-3 ]
[ 1000698-88-3 ]
C₁₆H₂₂F₂N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74.2%; 6.6%	With iodine; In ethanol; at 0℃;Product distribution / selectivity;	Example 54; N-Cyclohexyl-2-[5,6-difluoro-2-(methoxy-phenyl-methyl)-benzoimidazol-1-yl]-2-(4-methoxy-phenyl)-acetamide; Step 1; (2-Amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester [CAS RN 1000698-88-3] (for alternative preparation see also Example 1, Step 1); To a ice-bath cooled mixture of 1,2-diamino-4,5-difluorobenzene (10.00 g, 69 mmol, 1.0 equiv., [CAS RN 76179-40-3]) and di-tert-butyl-dicarbonate (12.87 g, 59 mmol, 0.85 equiv; [CAS RN 24424-99-5]) in absolute ethanol (150 mL) was added iodine (0.18 g, 0.007 mmol, 0.01 equiv; [CAS RN 7553-56-2]). The mixture was maintained overnight in the refrigerator. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (500 g, 1:0?19:1 dichloromethane/ethyl acetate eluant) to afford, in order of elution, the bis-boc derivative as an orange solid (1.58 g, 6.6%), and the desired compound as a white solid (12.58 g, 74.2%).
74%; 6%	With iodine; In ethanol;Cooling with ice;	To a cooled (ice-bath) mixture of l,2-diamino-4,5-difluorobenzene (10.00 g, 69 mmol, 1.0 equiv., [CAS RN 76179-40-3]) and di-tert-butyl-dicarbonate (12.87 g, 59 mmol, 0.85 equiv; [CAS RN 24424-99-5]) in absolute ethanol (150ml) was added iodine (0.18g, 0.007 mmol, 0.01 equiv. [CAS RN 7553-56-2]). The mixture was maintained overnight in the refrigerator. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (50Og, 1:0 to 19:1 CH2Cl2/AcOEt eluant) to afford, in order of elution, the bis-boc derivative as an orange solid (1.58 g, 6 %), and the desired compound as a white solid (12.58g, 740Zo)11H NMR (300 MHz, DMSO): <5 1.46 ( s, 9H), 5.03 (br s, 2H), 6.65 (dd, / = 8.2 Hz, / = 12.9 Hz, IH), 7.30 (dd, / = 8.9 Hz, / = 12.3 Hz, IH), 8.38 (br s, IH). MS (ISN): 243.4 [M-H]".

Reference： [1]Patent: US2009/131482,2009,A1 .Location in patent: Page/Page column 20
[2]Patent: WO2010/43513,2010,A1 .Location in patent: Page/Page column 31

4
[ 1000698-88-3 ]
[ 931-53-3 ]
[ 1878-65-5 ]
[ 2043-61-0 ]
[ 1153859-80-3 ]

Yield	Reaction Conditions	Operation in experiment
21%		Step 2; To a solution of <strong>[1000698-88-3](2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester</strong> (36.64 mg, 0.15 mmol, 1.0 equiv) in methanol (2.0 mL) was added cyclohexanecarbaldehyde (25.80 mg, 27.08 muL, 0.23 mmol, 1.5 equiv; [2043-61-0]) and the mixture stirred at rt. After 30 min, (3-chloro-phenyl)-acetic acid (34.12 mg, 0.20 mmol, 1.33 equiv; [CAS RN 1878-65-5]) and cyclohexyl isocyanide (16.38 mg, 18.41 muL, 0.15 mmol, 1.0 equiv; [931-53-3]) were added and stirring continued at rt for 2 h. A solution of 4 M HCl in dioxane (0.2 mL) was added and the reaction mixture stirred at rt overnight. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 15.7 mg (21%) of the title compound. MS (ISP): 500.2 [M+H]+.

Reference： [1]Patent: US2009/131482,2009,A1 .Location in patent: Page/Page column 14

5
[ 5326-23-8 ]
[ 1000698-88-3 ]
[ 88333-03-3 ]
[ 2043-61-0 ]
C₂₇H₂₅ClF₂N₄O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		a) [2-(6-Chloro-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid; To a solution of <strong>[1000698-88-3](2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester</strong> (1.0 g, 4.1 mmol) in methanol (15 mL) were added cyclohexanecarbaldehyde (0.82 mL, 6.14 mmol, 1.5 equiv.), 6-chloro-nicotinic acid (0.665 g, 4.1 mmol, 1.0 equiv.) and isocyanomethyl-benzene (0.48 mL, 10.24 mmol, 1.0 equiv.) and stirred at rt for 16 h. A solution of 4 M HCl in dioxane (10 mL) was added and the reaction mixture stirred at rt for 3 h. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 9 by addition of a solution of 1 M NaHCO3 and the aqueous layer extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure. The crude material was dissolved in a mixture of acetic anhydride (40 ml) and acetic acid (20 ml) and cooled to 0 C. Sodium nitrite (7.4 g, 107 mmol) were added in portions. After the addition the reaction was warmed to rt and stirred for 3 h. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 9 by addition of a solution of 1 M NaHCO3 and the aqueous layer extracted with ethyl acetate. The resulting brown oil was taken up in a mixture of THF:water (3:1, 20 mL) and a pre-prepared solution of LiOH (2.1 g, 48.7 mmol) in hydrogen peroxide (10 mL, 30% solution in water) was added drop wise. The mixture was stirred at rt for 30 min. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 4 by addition of acetic acid and the aqueous layer extracted with ethyl acetate. The intermediate was not further purified but used as crude material for further modification. MS (ES-): 404 (M-H).

Reference： [1]Patent: US2009/163552,2009,A1 .Location in patent: Page/Page column 17

6
[ 5326-23-8 ]
[ 1000698-88-3 ]
trans-4-isocyano-cyclohexanecarboxylic acid methyl ester [ No CAS ]
[ 2043-61-0 ]
trans-4-{2-[2-(6-chloro-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acetylamino}-cyclohexanecarboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 7 trans-4-{2-[2-(6-Chloro-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acetylamino}-cyclohexanecarboxylic acid; To a solution of <strong>[1000698-88-3](2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester</strong> (0.2 g, 0.82 mmol) in methanol (4 mL) were added cyclohexanecarbaldehyde (0.16 mL, 1.22 mmol, 1.5 equiv.), 6-chloro-nicotinic acid (0.13 g, 0.82 mmol, 1.0 equiv.) and trans-4-Isocyano-cyclohexanecarboxylic acid methyl ester (0.137 mg, 0.82 mmol, 1.0 equiv.) and stirred at rt for 16 h. A solution of 4 M HCl in dioxane (4 mL) was added and the reaction mixture stirred at rt for 3 h. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 9 by addition of a solution of 1 M NaHCO3 and the aqueous layer extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure. The crude material was dissolved in methanol (15 ml) and NaOH (5 ml) and DMF (1 ml) were added and the mixture heated to 50 C. overnight. The pH was adjusted to 4. A light brown solid appeared which was further purified by preparative HPLC. MS (ES+): 532 (M+H).

Reference： [1]Patent: US2009/163552,2009,A1 .Location in patent: Page/Page column 18

7
[ 1000698-88-3 ]
[ 88333-03-3 ]
[ 16727-43-8 ]
[ 2043-61-0 ]
[ 1162675-51-5 ]

Yield	Reaction Conditions	Operation in experiment
72%		f) N-Benzyl-2-cyclohexyl-2-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol- 1 -yll -acetamide; 10.0 g (40.94 mmol) (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester were dissolved in 60 ml methanol, then 5.91 ml (49.13 mmol) cyclohexylcarbaldehyde(commercially available) were added. After stirring for 5 min. at room temperature the solution was treated with 7.50 g (40.94 mmol) <strong>[16727-43-8]2,6-dimethoxynicotinic acid</strong> commercially available), followed by an addition of 5.0 ml (40.94 mmol) benzylisocyanide (commercially available). From the clear, light brown and slightly warm solution a suspension formed within a few minutes. After 3 h another 40 ml methanol were added. After stirring for 20 h, 51.18 ml (205 mmol) of a IM hydrochloric acid solution in dioxane were added dropwise over 5 min. The resulting solution was stirred at room temperature for 29 h, then poured onto 500 ml saturated aqueous sodium bicarbonate solution and the lyers were separated. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated to dryness. The resulting solid was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with n-heptane : tert-butyl methyl ether (1 : 1) as eluant. Off- white foam (72%). MS (Turbo Spray) m/z = 521.5 [M+H].
60%		Intermediatesa) N-Benzyl-2-cyclohexyl-2-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-acetamide; To a solution of (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester (2.50 g, 10.24 mmol, 1.0 equiv; example 1, intermediate b) in methanol (30 mL) was added cyclohexanecarbaldehyde (1.15 g, 1.23 mL, 10.24 mmol, 1.0 equiv; [2043-61-0]) and the mixture stirred at rt. After 30 min, <strong>[16727-43-8]2,6-dimethoxy-nicotinic acid</strong> (1.88 g, 10.24 mmol, 1.0 equiv; [CAS RN 16727-43-8]) and isocyanomethyl-benzene (1.20 g, 1.25 mL, 10.24 mmol, 1.0 equiv; [931-53-3]) were added and stirring continued at rt for 2 h. A solution of 4 M HCl in dioxane (20 mL) was added and the reaction mixture stirred at rt overnight. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 9 by addition of a solution of 1 M NaHCO3 and the aqueous layer extracted with dichloromethane. The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure. The crude material was purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate to give 3.57 g (60%) of the title compound. MS (ES+): 522 (M+H).

Reference： [1]Patent: WO2010/28981,2010,A1 .Location in patent: Page/Page column 83
[2]Patent: US2009/163552,2009,A1 .Location in patent: Page/Page column 18-19

8
[ 1000698-88-3 ]
[ 455-24-3 ]
[ 1983-99-9 ]
[ 2043-61-0 ]
[ 1162676-15-4 ]

Yield	Reaction Conditions	Operation in experiment
7%		Intermediate4-{2-Cyclohexyl-2-[5,6-difluoro-2-(4-trifluoromethyl-phenyl)-benzoimidazol-1-yl]-acetylamino}-benzoic acid ethyl ester; The solution of 0.30 g (1.23 mmol) <strong>[1000698-88-3](2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester</strong> and 0.15 ml (0.14 g, 1.23 mmol) cyclohexanecarboxaldehyde was stirred for 10 min. Then, 0.23 g (1.23 mmol) 4-(trifluoromethyl)benzoic acid and after another 5 min. 0.22 g (1.23 mmol) 4-isocyano-benzoic acid ethyl ester were added. After 21 h 3 ml 4M aqueous hydrochloric acid were added and stirring continued for another 16 h. The solvent is evaporated, the residue dissolved in a mixture of acetonitrile, water and N,N-dimethylformamide and purified by preparative HPLC to give the desired compound as a colorless solid (7%).MS m/e (M+H)+: 586.1.

Reference： [1]Patent: US2009/163552,2009,A1 .Location in patent: Page/Page column 25

9
[ 1000698-90-7 ]
[ 1000698-88-3 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium chloride; zinc; In water; N,N-dimethyl-formamide; at 20 - 80℃; for 2.5h;	b) (2-Amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester; 4,5-Difluoro-2-nitro-phenylamine (6.0 g, 34 mmol, 1 equiv.) was added to a solution of di-tert-butyl dicarbonate (14.8 g, 68 mmol, 2 equiv.) and DMAP (211 mg, 0.2 mmol, 0.05 in THF (100 mL) and the mixture was stirred at room temperature for 72 hours. The solvent was evaporated and the crude extracted from ethylacetate and aq. NaHCO3. The residue was taken up in DCM and cooled to 0 C. Trifluoroacetic acid (7.75 g, 68 mmol, 2 equiv) were added slowly and the mixture stirred for 48 h at 0 C. 2 N NaOH was added to adjust the pH to 7. The organic layer was separated and evaporated. The residue was taken up in ethyl acetate and the product extracted from aq. NaHCO3. The intermediate was isolated via Kieselgel chromatography. 4.28 g (16 mmol, 1 equiv.) were dissolved in DMF (50 ml) and 13 ml of a saturated NH4Cl solution added. Zink powder (5.1 g, 78 mmol, 5 equiv.) was added and the suspension stirred for 30 minutes at 80 C. and another 2 hours at room temperature. The remaining solid was filtered off and the organic layer evaporated. The product was extracted from ethyl actetate and aq. NaHCO3 and further purified via Kieselgel chromatography.
		g) (2-Amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester; To a solution of di-terf-butyl dicarbonate (14.8 g, 67.8 mmol, 2.0 equiv; [CAS RN 24424- 99-5]) and 4-dimethylaminopyridine (0.21 g, 1.7 mmol, 0.05 equiv; DMAP; [CAS RN 1122-58-3]) in tetrahydrofuran (100 mL) was added 4,5-difluoro-2-nitro-phenylamine (5.9 g, 33.9 mmol, 1.0 equiv; [CAS RN 78056-39-0]) and the mixture was stirred at room temperature for 72 h. The solvent was evaporated under reduced pressure and the crude reaction product extracted from a saturated aqueous sodium bicrabonate solution with ethyl acetate. The organic phases were dried over sodium sulfate, the residue taken up in dichloromethane and cooled to 00C. Trifluoroacetic acid (7.73 g, 67.8 mmol, 2.0 equiv) was added slowly and the reaction mixture stirred at 00C for 48 h. A solution of 2M aqueous sodium hydroxide solution was added to adjust the pH of the solution to 7. The organic layer was separated and evaporated under reduced pressure. The residue was taken up in ethyl acetate and the product extracted from an aqueous saturated sodium bicarbonate solution, the organic phase dried over sodium sulfate and the intermediate isolated via silica gel chromatography. The purified product (4.28 g, 15.6 mmol, 1.0 equiv) was dissolved in N,N-dimethylformamide (50 mL) and an aqueous saturated solution of ammonium chloride (13 mL) was added. Zinc powder (5.10 g, 78.0 mmol, 5.0 equiv) was added and the suspension stirred for 30 min at 800C and for an additional 2 h at room temperature. The remaining solid was filtered off and the organic layer evaporated. The product was extracted from an aqueous saturated sodium bicarbonate solution with ethyl actetate, the organic layer dried over sodium sulfate and the crude reaction product purified via silica gel chromatography. 1H NMR (300 MHz, DMSO): 1.46 ( s, 9H), 5.03 (br s, 2H), 6.65 (dd, / = 8.2 Hz, / = 12.9 Hz, IH), 7.30 (dd, / = 8.9 Hz, / = 12.3 Hz, IH), 8.38 (br s, IH). MS (ISN): m/z = 243.4 [M-H].

Reference： [1]Patent: US2009/163552,2009,A1 .Location in patent: Page/Page column 17
[2]Patent: WO2010/28981,2010,A1 .Location in patent: Page/Page column 83-84

10
[ 1000698-88-3 ]
[ 88333-03-3 ]
[ 1489-69-6 ]
[ 74-11-3 ]
[ 1265885-23-1 ]

Yield	Reaction Conditions	Operation in experiment
99%		e) N-Benzyl-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-l-yl]-2-cyclopropyl- acetamide; To a solution of 7.2 g (29.48 mmol) (2-amino-4,5-difluoro-phenyl)-carbamic acid tert- butyl ester (Example 73, intermediate g) in 75 ml methanole, 2.48 g (35.37 mmol) cyclopropanecarbaldehyde (commercially available) were added. After stirring for 5 min. at room temperature the solution was treated with 4.62 g (29.5 mmol) 4-chlorobenzoic acid (comemrcially available), followed by an addition of 3.6 ml (29.47 mmol) benzylisocyanide (commercially available). The formed solution was stirred at room temperature for 23 h, then 36.85 ml (147 mmol) 4 M hydrochloric acid in dioxane were added dropwise over 5 min. The resulting suspension was stirred for 23 h, then poured onto 500 ml saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and evaporated. The residue was purified by silica gel column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane : ethyl acetate (100 : 0 to 50 : 50). Light yellow solid (99%). MS (Turbo Spray): m/z = 452.1 [M+H].

Reference： [1]Patent: WO2010/28981,2010,A1 .Location in patent: Page/Page column 117-118

11
[ 872-53-7 ]
[ 1000698-88-3 ]
[ 88333-03-3 ]
[ 74-11-3 ]
[ 1265885-28-6 ]

Yield	Reaction Conditions	Operation in experiment
97%		e) N-Benzyl-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-l-yll-2-cyclopentyl- acetamide; To a solution of 5.0 g (20.47 mmol) (2-amino-4,5-difluoro-phenyl)-carbamic acid tert- butyl ester (Example 73, intermediate g) in 50 ml methanol, 2.21 g (22.57 mmol) cyclopentanecarbaldehyde (commercially available) were added. After stirring for 5 min. at room temperature, 3.2 g (20.5 mmol) p-chlorobenzoic acid and 2.5 ml (20.47 mmol) benzyl isocyanide (commercially available) were added. After stirring for 19 h, 38.38 ml (153.52 mmol) 4 M hydrochloric acid in dioxane were added dropwise over 5 min. After 5 h the solution was poured on 500 ml saturated aqueous sodium bicarbonate solution and the phases were separated. The organic layer was extracted three times with ethyl acetate and the combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and evaporated. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n- heptane : ethyl acetate (100 : 0 to 50 : 50). Light yellow foam (97%). MS (Turbo Spray): m/z = 480.1 [M+H].

Reference： [1]Patent: WO2010/28981,2010,A1 .Location in patent: Page/Page column 115-116

12
[ 265108-36-9 ]
[ 1000698-88-3 ]
[ 88333-03-3 ]
[ 74-11-3 ]
[ 1265885-42-4 ]

Yield	Reaction Conditions	Operation in experiment
76%		e) N-Benzyl-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-l-yll-2-(4,4-difluoro- cyclohexyl) -acetamide; To a solution of 3.8 g (15.56 mmol) (2-amino-4,5-difluoro-phenyl)-carbamic acid tert- butyl ester (Example 73, intermediate g) in 38 ml methanol, 2.54 g (17.12 mmol) 4,4- difluorocyclohexanone (commercially available) were added. After stirring for 5 min. at room temperature the solution was treated with 2.44 g (15.58 mmol) p-chlorobenzoic acid, followed by an addition of 1.9 ml (15.56 mmol) benzyl isocyanide (commercially available). To the viscous slurry 12 ml methanol were added and the reaction for 22.5 h. Then 19.45 ml (77.80 mmol) 4M hydrochloric acid in dioxane were added dropwise over 5 min. After 4.5 h another 19.45 ml (77.80 mmol) 4M hydrochloric acid in dioxane were added. After 24 h, the suspension was poured onto 300 ml aqueous saturated sodium bicarbonate solution and the phases were separated. The aqueous layer was extracted three times with ethyl acetate and the organic layers were washed with brine, dried over magnesium sulfate, filtered, and evaporated. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane : ethyl acetate (100 : 0 to 50 : 50). Light yellow solid (76%). MS (Turbo Spray): m/z = 530.2 [M+H].).

Reference： [1]Patent: WO2010/28981,2010,A1 .Location in patent: Page/Page column 113

13
[ 1000698-88-3 ]
[ 88333-03-3 ]
[ 7499-07-2 ]
[ 2043-61-0 ]
[ 1265885-62-8 ]

Yield	Reaction Conditions	Operation in experiment
		c) N-Benzyl-2-[2-(4-chloro-2-methyl-phenyl)-5,6-difluoro-benzoimidazol-l-yll-2- cyclohexyl-acetamide; To the solution of 1.5 g (6.145 mmol) 2-amino-4,5-difluoro-phenyl)-carbamic acid tert- butyl ester (Example 73, intermediate g), 1.080 g (6.145 mmol) 4-chlor-2-methyl-benzoic acid (commercially available), 985.5 ul (7.375 mmol) cyclohexanecarbaldehyde (commercially available) and 763.5 ul (6.145 mmol) benzyl isocyanide (commercially available) were dissolved in 15 ml methanol and the light brown solution was stirred at room temperature overnight. Then 15.00 ml (60.0 mmol) 4M hydrochloric acid in dioxane (commercially available) were added and the reaction mixture was stirred at room tempaerature for 4.5 h and then evaporated. The residue was taken up in ethyl acetate and aqueous saturated sodium bicarbonate solution, the phases were separated, the organic phase extracted a second time with ethyl acetate and the combined organic layers washed with water and brine to give, after evaporation, the compound as yellow foam which was pure enough for the next step without further purification. MS (ESI): m/z = 508.02 (M+).

Reference： [1]Patent: WO2010/28981,2010,A1 .Location in patent: Page/Page column 105-106

14
[ 1000698-88-3 ]
[ 88333-03-3 ]
[ 26164-26-1 ]
[ 2043-61-0 ]
C₃₅H₄₁F₂N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 20℃;	To a mixture of (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butgamma ester (1.00 g, 4 mmol, 1.0 equiv) and (S)-alpha-methoxyphenylacetic acid (0.68 g, 1.0 equiv., [CAS RN 26164-26-1]) in methanol (25 mL) were added cyclohexanecarbaldehyde (0.459 g, 4 mmol, 1.0 equiv; [2043-61-0]) and benzyl isonitrile (0.48 g, l.Oequiv., 4 mmol, CAS RN 10340-91- 7). The mixture was stirred overnight at room temperature. A solution of 4 M HCl in dioxane (3 mL) was added, and the reaction mixture stirred at room temperature overnight. The mixture was partitioned between water (100ml) and ethyl acetate (100ml). The phases were separated and the aqueous phase extracted with ethyl acetate (2x50ml), the combined organic phases washed with brine, dried over sodium sulfate and evaporated under reduced pressure to afford the title compound as an orange gum (2.16g, quant., mixture of diastereomers) that was used without further purification. MS (ISP): 504.1 [M+H]+.

Reference： [1]Patent: WO2010/43513,2010,A1 .Location in patent: Page/Page column 31-32

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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.
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P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
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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.
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P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
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P251	Pressurized container: Do not pierce or burn, even after use.
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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.
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P280	Wear protective gloves/protective clothing/eye protection/face protection.
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P285	In case of inadequate ventilation wear respiratory protection.
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Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
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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.
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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
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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.
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P405	Store locked up.
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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