[ CAS No. 934660-93-2 ] {[proInfo.proName]}

Name: 934660-93-2|(S)-(3,4-Difluoro-2-((2-fluoro-4-iodophenyl)amino)phenyl)(3-hydroxy-3-(piperidin-2-yl)azetidin-1-yl)methanone|98%
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Quality Control of [ 934660-93-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 934660-93-2 ]

CAS No. :	934660-93-2	MDL No. :	MFCD22124461
Formula :	C₂₁H₂₁F₃IN₃O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	531.31	Pubchem ID :	-
Synonyms :	XL518;GDC-0973;RG-7420	Chemical Name :	(S)-(3,4-Difluoro-2-((2-fluoro-4-iodophenyl)amino)phenyl)(3-hydroxy-3-(piperidin-2-yl)azetidin-1-yl)methanone

Calculated chemistry of [ 934660-93-2 ]

Physicochemical Properties

Num. heavy atoms :	30
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.38
Num. rotatable bonds :	5
Num. H-bond acceptors :	6.0
Num. H-bond donors :	3.0
Molar Refractivity :	122.92
TPSA :	64.6 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-6.79 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.39
Log Po/w (XLOGP3) :	3.88
Log Po/w (WLOGP) :	4.28
Log Po/w (MLOGP) :	4.08
Log Po/w (SILICOS-IT) :	4.71
Consensus Log Po/w :	4.07

Druglikeness

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

Water Solubility

Log S (ESOL) :	-5.54
Solubility :	0.00152 mg/ml ; 0.00000285 mol/l
Class :	Moderately soluble
Log S (Ali) :	-4.93
Solubility :	0.00618 mg/ml ; 0.0000116 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-7.28
Solubility :	0.0000281 mg/ml ; 0.0000000528 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	3.92

Safety of [ 934660-93-2 ]

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 [ 934660-93-2 ]

* 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.

Downstream synthetic route of [ 934660-93-2 ]

[ 934660-93-2 ] Synthesis Path-Downstream 1~35

2
[ 391211-97-5 ]
[14C]-GDC-0973 [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2012,vol. 3,p. 416 - 421
[2]Patent: CN106866624,2017,B

3
[ 934665-55-1 ]
[ 934660-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: palladium 10% on activated carbon; hydrogen / methanol / 1 h / 760.05 Torr 2: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 20 °C 3: hydrogenchloride / 1,4-dioxane; methanol / 55 °C
	Multi-step reaction with 3 steps 1: palladium on activated charcoal; hydrogen / methanol / 3 h / 35 °C 2: triethylamine / chloroform / 9 h / 45 °C 3: N-ethyl-N,N-diisopropylamine; hydrogenchloride / tetrahydrofuran / 8 h / 50 °C

Reference： [1]Rice, Kenneth D.; Aay, Naing; Anand, Neel K.; Blazey, Charles M.; Bowles, Owen J.; Bussenius, Joerg; Costanzo, Simona; Curtis, Jeffry K.; Defina, Steven C.; Dubenko, Larisa; Engst, Stefan; Joshi, Anagha A.; Kennedy, Abigail R.; Kim, Angie I.; Koltun, Elena S.; Lougheed, Julie C.; Manalo, Jean-Claire L.; Martini, Jean-Francois; Nuss, John M.; Peto, Csaba J.; Tsang, Tsze H.; Yu, Peiwen; Johnston, Stuart [ACS Medicinal Chemistry Letters, 2012, vol. 3, # 5, p. 416 - 421]
[2]Current Patent Assignee: HUNAN OUYA BIOLOGICAL - CN106045969, 2016, A

4
[ 934666-39-4 ]
[ 934664-19-4 ]
[ 934660-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 20 °C 2: hydrogenchloride / 1,4-dioxane; methanol / 55 °C

5
[ 934664-27-4 ]
[ 934660-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: dmap / dichloromethane / 0 - 60 °C 2: sodium hydroxide / methanol; water / 1 h / 20 °C 3: palladium 10% on activated carbon; hydrogen / methanol / 1 h / 760.05 Torr 4: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 20 °C 5: hydrogenchloride / 1,4-dioxane; methanol / 55 °C
	Multi-step reaction with 4 steps 1.1: palladium on activated charcoal; hydrogen / ethanol / 2 h / 2625.26 Torr 2.1: tetrahydrofuran; methanol / 17 h / 20 °C 3.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / acetonitrile / 1 h / 20 °C / Inert atmosphere 3.2: 5 - 20 °C 4.1: hydrogenchloride / water; methanol / 24 h

6
[ CAS Unavailable ]
[ 934660-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: sodium hydroxide / methanol; water / 1 h / 20 °C 2: palladium 10% on activated carbon; hydrogen / methanol / 1 h / 760.05 Torr 3: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 20 °C 4: hydrogenchloride / 1,4-dioxane; methanol / 55 °C

7
[ 934663-52-2 ]
[ 934660-93-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	With triethylsilane; trifluoroacetic acid In dichloromethane at 0℃; for 3h;
73%	With hydrogenchloride In methanol at 20 - 35℃; for 4h;	13 A 10 L three-necked flask was charged with Compound J-2 (167 g, 0.265 mol)And 2.2 L of methanol,2.2 L 4N HCl / MeOH solution was added dropwise to the reaction,Stir at room temperature for 4h.The reaction solution was concentrated,Then add 2 L of water,The aqueous phase is extracted once with MTBE (3 L)The pH of the aqueous phase was adjusted to 8-9 with saturated sodium bicarbonate solution,The aqueous phase was extracted with DCM (1.5 L * 3)The combined organic phase,dry,concentrate,Obtained as an off-white solid (119.5 g, yield: 85%).The solid and 300mL DCM was added to the three-necked flask,Stir 4h,filter,The filter cake is rinsed once with DCM.Solid drying,The compound Cobimetinib (102.6 g, yield: 73%, purity: 99.1%) was obtained.
	With hydrogenchloride In 1,4-dioxane; methanol at 55℃;

45.6 g	With hydrogenchloride In methanol; water at 20℃; for 1h;	Experimental Example: The above crude compound was dissolved in methanol (300 mL)Concentrated hydrochloric acid (150 mL) was added dropwise at room temperature.After the addition was completed at room temperature for 1 hour, the reaction was completed,The reaction mixture was concentrated, adjusted to pH 8-9 with saturated potassium carbonate solution,Extract with ethyl acetate (300 ml * 2), dry over anhydrous sodium sulfate,After concentration, the crude compound was obtained, the crude product was recrystallized from chloroform methanol,The title compound was obtained after drying in vacuocobimetinib (45.6 g, yield 86%, purity 99.29%,
0.1 g	Stage #1: tert-butyl (S)-2-{1-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzoyl]-3-hydroxy-3-azetidinyl}perhydropyridine-1-carboxylate With hydrogenchloride In methanol; water for 24h; Stage #2: With sodium hydrogencarbonate In methanol	To a solution of 0.29 g (leq.) tert-Butyl (lS)-2-{ l-[3,4-difluoro-2-(2-fluoro-4- iodophenylamino)benzoyl]-3-hydroxy-3-azetidinyl}perhydropyridine-l-carboxylate, prepared by the above procedure, in 10 mL methanol 0.38 mL of 36% aqueous HC1 (lOeq.) was added and stirred for 24h. The solvent was evaporated and a yellowish solid residue triturated with diethyl ether to result in 0.2 g of the title product as beige powder with 85,4% HPLC peak area (yield 65,6%); To a mixture of 0,2g of Cobimetinib hydrochloride (leq.), prepared by the above procedure, and 0,06g of sodium bicarbonate (2eq.) 10 mL of methanol were added with stirring to form a light-pink turbid solution. Reaction mixture stirred for 15min and evaporated to dryness. To the residue lOmL of water added and extracted three times with overall 30mL of ethyl acetate. Combined organic washings dried over magnesium sulfate, filtered and evaporated to dryness to give 0,18 g of a crude product. Recrystallisation from 2mL DCM/acetonitrile 1 :3 mixture afforded 0, lg of pure product (HPLC peak area of the title compound 98,73%, EE 99,5%).

Reference： [1]Fawcett, Alexander; Murtaza, Amna; Gregson, Charlotte H. U.; Aggarwal, Varinder K. [Journal of the American Chemical Society, 2019]
[2]Current Patent Assignee: MEDCHEMEXPRESS CHINA; HAOYUAN CHEMEXPRESS - CN104725352, 2017, B Location in patent: Paragraph 0109-0111
[3]Rice, Kenneth D.; Aay, Naing; Anand, Neel K.; Blazey, Charles M.; Bowles, Owen J.; Bussenius, Joerg; Costanzo, Simona; Curtis, Jeffry K.; Defina, Steven C.; Dubenko, Larisa; Engst, Stefan; Joshi, Anagha A.; Kennedy, Abigail R.; Kim, Angie I.; Koltun, Elena S.; Lougheed, Julie C.; Manalo, Jean-Claire L.; Martini, Jean-Francois; Nuss, John M.; Peto, Csaba J.; Tsang, Tsze H.; Yu, Peiwen; Johnston, Stuart [ACS Medicinal Chemistry Letters, 2012, vol. 3, # 5, p. 416 - 421]
[4]Current Patent Assignee: CHENGDU BAISHIXING SCIENCE AND TECH - CN106220607, 2016, A Location in patent: Paragraph 0090; 0091
[5]Current Patent Assignee: AZAD PHARMA AG - WO2019/86469, 2019, A1 Location in patent: Page/Page column 32

8
[ 29632-74-4 ]
[ 2065147-70-6 ]
[ 934660-93-2 ]

Yield	Reaction Conditions	Operation in experiment
20.66 g	With lithium hexamethyldisilazane In tetrahydrofuran at 20 - 30℃; for 3.46667h;	6 Example6Synthesis of [3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-phenyl]-((S)-3-hydroxy-3-piperidin-2-yl-azetidin-1-yl)-methanone To a solution of ((S)-3-hydroxy-3-piperidin-2-yl-azetidin-1-yl)-(2,3,4-trifluorophenyl)-methanone hydrochloride (15.0 g,42.8 mmol, 1.0 eq.) and 2-flouro-4-iodo-anilin (11.1 g,47 mmol, 1.1 eq.) in THF (90 ml), a solution ofLiHMDS in THF (149 g, 20.7% w/w, 184 mmol,4.3 eq.) was dosed over 88 min at 20 to 30 °C. Stirring was continued for 2 h. After completeconversion, the mixture was dosed to a mixture of sulfuric acid (12.0 g, 96%-w/w, 118 mmol,2.75 eq.) in water (75 mL) over 25 min and kept stirring for 1 h. The layers were allowed toseparate, and the organic phase was washed with a mixture of water ( 60 mL) and toluene (96mL ). The organic phase was concentrated under vacuum to a volume of approximately 150 mL.Toluene (250 mL) was added and residual THF was removed by distillation at 55 oc jackettemperature and at a pressure of 84 mbar while keeping the batch volume constant by continuousdosing of toluene ( 400 mL ), resulting in slow precipitation of the product. The batchtemperature was then lowered to 10 oc within 2 h, and the suspension was kept stirring overnightat 10 °C. The product was filtered off, and the cake was rinsed with cold toluene (150 mL).Drying overnight under vacuum at 35 °C until weight constancy yielded the title compound(20.66 g) as a colorless product. HPLC purity: 99.7%-area. M.p (DSC): Tonset: 166.7°C,extrapolated peak: 168.2°C (91.5 J/g). 1H NMR (600 MHz, CDCh): o 8.28- 8.48 (br, 1 H), 7.39(dd, 1 H), 7.32 (ddd, 1 H), 7.09-7.14 (m, 1 H), 6.75-6.86 (br, 1 H), 6.60 (ddd, 1 H), 4.10 (d, 2H), 4.05-4.20 (br, 1 H), 3.93- 4.04 (br, 1 H), 3.09 (d, 1 H), 2.70 (d, 1 H), 2.56- 2.67 (br, 1 H),1.68 - 1.87 (m, 1 H), 1.50 - 1.64 (m, 2 H), 1.25 - 1.38 (m, 2 H), 1.07 - 1.24 (m, 1 H). MS (EI): mlz = 532 ([M+Ht, 100%). EA for C21H21F3IN203: calcd: C 47.47, H 3.98, N 7.91, F 10.73;found C 47.68, H 4.00, N 7.66, F 10.80.
20.66 g	With lithium hexamethyldisilazane In tetrahydrofuran at 20 - 30℃; for 3.46667h;	6 Example 6 Synthesis of (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl][3-hydroxy-3-(piperidin-2-yl)azetidin-1-yl]methanone (Compound I) To a solution of ((S)-3-hydroxy-3-piperidin-2-yl-azetidin-l-yl)-(2,3,4-trifluoro- phenyl)-methanone hydrochloride (15.0 g,42.8 mmol, 1.0 eq.) and 2-flouro-4-iodo-anilin (11.1 g, 47 mmol, 1.1 eq.) in THF (90 ml), a solution of LiHMDS in THF (149 g, 20.7% w/w, 184 mmol, 4.3 eq.) was dosed over 88 min at 20 to 30 °C. Stirring was continued for 2 h. After complete conversion, the mixture was dosed to a mixture of sulfuric acid (12.0 g, 96%-w/w, 118 mmol, 2.75 eq.) in water (75 mL) over 25 min and kept stirring for 1 h. The layers were allowed to separate, and the organic phase was washed with a mixture of water (60 mL) and toluene (96 mL). The organic phase was concentrated under vacuum to a volume of approximately 150 mL. Toluene (250 mL) was added and residual THF was removed by distillation at 55 °C jacket temperature and at a pressure of 84 mbar while keeping the batch volume constant by continuous dosing of toluene (400 mL), resulting in slow precipitation of the product. The batch temperature was then lowered to 10 °C within 2 h, and the suspension was kept stirring overnight at 10 °C. The product was filtered off, and the cake was rinsed with cold toluene (150 mL). Drying overnight under vacuum at 35 °C until weight constancy yielded the title compound (20.66 g) as a colorless product. HPLC purity: 99.7%-area. M.p (DSC): TonSet: 166.7°C, extrapolated peak: 168.2°C (91.5 J/g). NMR (600 MHz, CDC13): δ 8.28 - 8.48 (br, 1 H), 7.39 (dd, 1 H), 7.32 (ddd, 1 H), 7.09 - 7.14 (m, 1 H), 6.75 - 6.86 (br, 1 H), 6.60 (ddd, 1 H), 4.10 (d, 2 H), 4.05 - 4.20 (br, 1 H), 3.93 - 4.04 (br, 1 H), 3.09 (d, 1 H), 2.70 (d, 1 H), 2.56 - 2.67 (br, 1 H), 1.68 - 1.87 (m, 1 H), 1.50 - 1.64 (m, 2 H), 1.25 - 1.38 (m, 2 H), 1.07 - 1.24 (m, 1 H). MS (EI): m/z = 532 ([M+H]+, 100%). EA for C2,H2iF3rN203: calcd: C 47.47, H 3.98, N 7.91, F 10.73; found C 47.68, H 4.00, N 7.66, F 10.80.

Reference： [1]Current Patent Assignee: EXELIXIS INC - WO2014/59422, 2014, A1 Location in patent: Paragraph 000143
[2]Current Patent Assignee: EXELIXIS INC; JOHNSON MATTHEY PLC - WO2017/4393, 2017, A1 Location in patent: Paragraph 00130

9
[ 1882059-84-8 ]
[ 934660-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium tetrahydroborate; methanol / 6 h / 20 - 30 °C 1.2: 35 - 40 °C 2.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 20 °C / Cooling with ice 3.1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate / N,N-dimethyl-formamide / 0.5 h / 20 °C 3.2: 45 - 50 °C

Reference： [1]Current Patent Assignee: SUZHOU MIRACPHARMA TECHNOLOGY CO LTD - CN105330643, 2016, A

10
[ 1882059-83-7 ]
[ 934660-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: lithium aluminium tetrahydride / tetrahydrofuran / 20 °C 2.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 20 °C / Cooling with ice 3.1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate / N,N-dimethyl-formamide / 0.5 h / 20 °C 3.2: 45 - 50 °C

Reference： [1]Current Patent Assignee: SUZHOU MIRACPHARMA TECHNOLOGY CO LTD - CN105330643, 2016, A

11
[ 3105-95-1 ]
[ 934660-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: thionyl chloride / 3 h / Reflux 1.2: 90 - 100 °C 2.1: sodium methylate / 50 - 60 °C 3.1: sodium tetrahydroborate; methanol / 6 h / 20 - 30 °C 3.2: 35 - 40 °C 4.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 20 °C / Cooling with ice 5.1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate / N,N-dimethyl-formamide / 0.5 h / 20 °C 5.2: 45 - 50 °C

Reference： [1]Current Patent Assignee: SUZHOU MIRACPHARMA TECHNOLOGY CO LTD - CN105330643, 2016, A

12
1,1-dimethylethyl (2S)-2-(3-hydroxyazetidin-3-yl)piperidine-1-carboxylate [ No CAS ]
[ 391211-97-5 ]
[14C]-GDC-0973 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70.1%		The reaction flask was added 3,4-difluoro-2 - [(2-fluoro-4-iodophenyl) amino] benzoic acid (1.96g, 5mmol) and N, N- dimethylformamide 25mL, dropwise at room temperature plusHexafluorophosphate, benzotriazol-1-yl - yloxy tripyrrolidinophosphonium phosphorus (2.6g, 5mmol) in N, N- dimethylformamide 25mL solution dropwise within 30 minutes after. Was added (2S) -1- tert-butoxycarbonyl-2- (3-hydroxy-azetidin-3-yl) piperidine (II) (1.92g, 7.5mmol) and diisopropylethylamine (1.29 g of , 10mmol). Warmed to 45-50 , the reaction was stirred for 3-4 hours, TLC the reaction was complete. To the reaction mixture was added ethyl acetate and 10% sodium hydroxide solution, stirred for 15 minutes and the organic layer was separated. The organic layer was washed with water 3 times, washed once with saturated brine, dried over anhydrous sodium sulfate. Concentrated and the resulting solid was added dioxane 25mL 4N solution of hydrogen chloride, heated to 55-60 , the reaction was stirred for 2-4 hours, cooled to room temperature, concentrated under reduced pressure, the crude product from ethyl acetate / hexane (1/1 ) recrystallized white solid cobimetinib (I) 1.86g, yield 70.1%

Reference： [1]Patent: CN105330643,2016,A .Location in patent: Paragraph 0052; 0053

13
[ 1882059-85-9 ]
[ 934660-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: sodium methylate / 50 - 60 °C 2.1: sodium tetrahydroborate; methanol / 6 h / 20 - 30 °C 2.2: 35 - 40 °C 3.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 20 °C / Cooling with ice 4.1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate / N,N-dimethyl-formamide / 0.5 h / 20 °C 4.2: 45 - 50 °C

Reference： [1]Current Patent Assignee: SUZHOU MIRACPHARMA TECHNOLOGY CO LTD - CN105330643, 2016, A

14
[ 1882059-86-0 ]
[ 934660-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: potassium hydroxide / ethanol / 50 - 60 °C 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 20 °C 3.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 20 °C / Cooling with ice 4.1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate / N,N-dimethyl-formamide / 0.5 h / 20 °C 4.2: 45 - 50 °C

Reference： [1]Current Patent Assignee: SUZHOU MIRACPHARMA TECHNOLOGY CO LTD - CN105330643, 2016, A

15
[ 29632-74-4 ]
[ 2035072-28-5 ]
[ 934660-93-2 ]

Yield	Reaction Conditions	Operation in experiment
88%	With hydrogenchloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 50℃; for 8h;	1.E E) Preparation of cobimetinib [2,3,4-trifluorobenzoyl][3-hydroxy-3-(2S)-N-boc-2-piperidinyl-1-azetidinyl]methanone (11.0 g, 0.027 mol) was dissolved in tetrahydrofuran (40 mL), 2-fluoro-4-iodoaniline (7.9 g, 0.033 mol) was added, N-diisopropylethylamine (17.2 g, 0.133 mol) was added and the reaction mixture was stirred at 50 ° C for 8 hours. The reaction was confirmed by TLC plate. After the reaction solution was concentrated to dryness by rotary evaporation, the mixture was adjusted to neutral with dilute hydrochloric acid, extracted with ethyl acetate, dried over magnesium sulfate,Concentration to dryness, methanol recrystallization, was cobimetinib in a white solid (12.4g), yield 88.0%, the reaction of this step, such as under:

Reference： [1]Current Patent Assignee: HUNAN OUYA BIOLOGICAL - CN106045969, 2016, A Location in patent: Paragraph 0037; 0050; 0051; 0052

16
[ 28697-17-8 ]
[ 934660-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: lithium hydroxide; silver nitrate / dichloromethane / 0.17 h / 25 °C 1.2: 10 h / 90 °C 2.1: magnesium / diethyl ether / 2 h / 20 °C 2.2: 7 h / 0 - 3 °C 3.1: palladium on activated charcoal; hydrogen / methanol / 3 h / 35 °C 4.1: triethylamine / chloroform / 9 h / 45 °C 5.1: N-ethyl-N,N-diisopropylamine; hydrogenchloride / tetrahydrofuran / 8 h / 50 °C

Reference： [1]Current Patent Assignee: HUNAN OUYA BIOLOGICAL - CN106045969, 2016, A

17
[ 2035072-27-4 ]
[ 934660-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: magnesium / diethyl ether / 2 h / 20 °C 1.2: 7 h / 0 - 3 °C 2.1: palladium on activated charcoal; hydrogen / methanol / 3 h / 35 °C 3.1: triethylamine / chloroform / 9 h / 45 °C 4.1: N-ethyl-N,N-diisopropylamine; hydrogenchloride / tetrahydrofuran / 8 h / 50 °C

Reference： [1]Current Patent Assignee: HUNAN OUYA BIOLOGICAL - CN106045969, 2016, A

18
[ 61079-72-9 ]
[ 934660-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: pyridine; oxalyl dichloride / toluene / 2.77 h / 60 - 70 °C 2.1: potassium phosphate / ethanol; water / 0.48 h / 10 - 20 °C / pH 11.9 2.2: 0.53 h / 10 - 20 °C 3.1: acetic acid; hydrogenchloride; 10% Pd/C; hydrogen / ethanol; water / 12 h / 25 °C / 1500.15 Torr / Inert atmosphere; Autoclave 4.1: lithium hexamethyldisilazane / tetrahydrofuran / 3.47 h / 20 - 30 °C

Reference： [1]Current Patent Assignee: EXELIXIS INC; JOHNSON MATTHEY PLC - WO2017/4393, 2017, A1

19
[ 157373-08-5 ]
[14C]-GDC-0973 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: potassium phosphate / ethanol; water / 0.48 h / 10 - 20 °C / pH 11.9 1.2: 0.53 h / 10 - 20 °C 2.1: acetic acid; hydrogenchloride; palladium 10% on activated carbon; hydrogen / ethanol; water / 12 h / 25 °C / 1500.15 Torr / Inert atmosphere; Autoclave 3.1: lithium hexamethyldisilazane / tetrahydrofuran / 3.47 h / 20 - 30 °C

Reference： [1]Current Patent Assignee: JOHNSON MATTHEY PLC; EXELIXIS INC - WO2017/4393, 2017, A1

20
[ 934660-93-2 ]
[ 110-17-8 ]
[ 1369665-02-0 ]

Yield	Reaction Conditions	Operation in experiment
	In water; isopropyl alcohol at 77℃; Large scale;	7 Example 7 Preparation of the Crystalline Fumarate Salt of (S)-[3,4-difluoro-2-(2-fluoro-4- iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl) azetidin-l-yl]-methanone (Compound I) Designated as Form A (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl][3-hydroxy-3-(piperidin-2-yl)azetidin-1-yl]methanone (80 kg) was dissolved in a mixture of 2- propanol/water 88:12 w/w (9 weight equivalents (weq)) at 77°C and filtered over activated carbon. Fumaric acid (0.52 eq.) was dissolved in a mixture of 2-propanol/water 88: 12 w/w (2.6 weq). An initial amount of the fumaric acid solution (8% of the overall amount) was added to the filtered solution of (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3- hydroxy-3-(piperidin-2-yl) azetidin-l-yl]-methanone at 77°C. Seeding crystals (0.023 weq) were added as a suspension in a mixture of 2-propanol/water 88:12 w/w(0.2 weq) at 77°C. The remaining amount of the fumaric acid solution was added within 6 hours at the same temperature. To complete crystallization, the suspension was cooled to 20°C within 7 hours. The fumarate salt crystalline Compound I Form A was isolated by centrifugation, washed with 2-propanol (e.g., 0.6 weq.), dried under reduced pressure at max. 55°C and delumped.
120.3 mg	In ethanol for 0.5h;	Preparation of amorphous Cobimetinib hemifumarate Amorphous Cobimetinib hemifumarate was obtained by dissolving Cobimetinib free base (500.3 mg) in ethanol (28 ml) to form a solution I. Fumaric acid (54,826 mg, resulting in a molar ratio Cobimetinib: fumaric acid of 2: 1) was completely dissolved in ethanol (4 ml) to form a solution II. Solution II was combined with solution I and in order to assure the complete transfer of solution II the vial was rinsed with further 1 ml ethanol. No precipitation was visible. The combined solution was stirred for 30 minutes and the solvent was removed at reduced pressure and higher temperature using a rotary evaporator. A precipitate was obtained and dried at 20 h at 50°C in vacuo. 206.5 mg of the white solid were treated in a mill (3x10 minutes) and at the end of the procedure 120.3 mg of a white, amorphous solid were obtained.

Reference： [1]Current Patent Assignee: EXELIXIS INC; JOHNSON MATTHEY PLC - WO2017/4393, 2017, A1 Location in patent: Paragraph 00131
[2]Current Patent Assignee: AZAD PHARMA AG - WO2019/86469, 2019, A1 Location in patent: Page/Page column 34

21
[ 106565-71-3 ]
[ 934660-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon; lithium diisopropyl amide / tetrahydrofuran; n-heptane; ethylbenzene / 2.5 h / -80 - -70 °C 1.2: 1.5 h / -80 - -70 °C 2.1: sodium cyanoborohydride; acetic acid / ethanol / 5 h / 30 - 75 °C 3.1: hydrogenchloride / toluene; water / 4.2 h / 23 - 50 °C 4.1: potassium phosphate / ethanol; water / 0.48 h / 10 - 20 °C / pH 11.9 4.2: 0.53 h / 10 - 20 °C 5.1: acetic acid; hydrogenchloride; 10% Pd/C; hydrogen / ethanol; water / 12 h / 25 °C / 1500.15 Torr / Inert atmosphere; Autoclave 6.1: lithium hexamethyldisilazane / tetrahydrofuran / 3.47 h / 20 - 30 °C

Reference： [1]Current Patent Assignee: EXELIXIS INC; JOHNSON MATTHEY PLC - WO2017/4393, 2017, A1

22
[ 1597407-55-0 ]
[ 934660-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: sodium cyanoborohydride; acetic acid / ethanol / 5 h / 30 - 75 °C 2.1: hydrogenchloride / toluene; water / 4.2 h / 23 - 50 °C 3.1: potassium phosphate / ethanol; water / 0.48 h / 10 - 20 °C / pH 11.9 3.2: 0.53 h / 10 - 20 °C 4.1: acetic acid; hydrogenchloride; 10% Pd/C; hydrogen / ethanol; water / 12 h / 25 °C / 1500.15 Torr / Inert atmosphere; Autoclave 5.1: lithium hexamethyldisilazane / tetrahydrofuran / 3.47 h / 20 - 30 °C

Reference： [1]Current Patent Assignee: EXELIXIS INC; JOHNSON MATTHEY PLC - WO2017/4393, 2017, A1

23
[ 1597407-56-1 ]
[ 934660-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: hydrogenchloride / toluene; water / 4.2 h / 23 - 50 °C 2.1: potassium phosphate / ethanol; water / 0.48 h / 10 - 20 °C / pH 11.9 2.2: 0.53 h / 10 - 20 °C 3.1: acetic acid; hydrogenchloride; 10% Pd/C; hydrogen / ethanol; water / 12 h / 25 °C / 1500.15 Torr / Inert atmosphere; Autoclave 4.1: lithium hexamethyldisilazane / tetrahydrofuran / 3.47 h / 20 - 30 °C

Reference： [1]Current Patent Assignee: EXELIXIS INC; JOHNSON MATTHEY PLC - WO2017/4393, 2017, A1

24
[ 2058310-62-4 ]
[ 934660-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: potassium phosphate / ethanol; water / 0.48 h / 10 - 20 °C / pH 11.9 1.2: 0.53 h / 10 - 20 °C 2.1: acetic acid; hydrogenchloride; 10% Pd/C; hydrogen / ethanol; water / 12 h / 25 °C / 1500.15 Torr / Inert atmosphere; Autoclave 3.1: lithium hexamethyldisilazane / tetrahydrofuran / 3.47 h / 20 - 30 °C

Reference： [1]Current Patent Assignee: EXELIXIS INC; JOHNSON MATTHEY PLC - WO2017/4393, 2017, A1

25
[ 1597407-58-3 ]
[ 934660-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: acetic acid; hydrogenchloride; 10% Pd/C; hydrogen / ethanol; water / 12 h / 25 °C / 1500.15 Torr / Inert atmosphere; Autoclave 2: lithium hexamethyldisilazane / tetrahydrofuran / 3.47 h / 20 - 30 °C

Reference： [1]Current Patent Assignee: EXELIXIS INC; JOHNSON MATTHEY PLC - WO2017/4393, 2017, A1

26
[ 2055732-90-4 ]
[ 934660-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: hydrogen / ethanol / 6 h / 20 °C / Autoclave 2: triethylamine / dichloromethane / 2 h / 10 - 20 °C / Cooling with ice 3: hydrogenchloride / methanol; water / 1 h / 20 °C

Reference： [1]Current Patent Assignee: CHENGDU BAISHIXING SCIENCE AND TECH - CN106220607, 2016, A

27
[ 26250-84-0 ]
[ 934660-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: tetrahydrofuran / 20 h / 20 °C 2.1: potassium <i>tert</i>-butylate / dimethyl sulfoxide / 2 h / 20 °C 2.2: 18 h / 20 °C 3.1: isopropylmagnesium chloride / tetrahydrofuran / 3 h / -78 °C / Inert atmosphere 3.2: -78 - 20 °C 4.1: hydrogen / ethanol / 6 h / 20 °C / Autoclave 5.1: triethylamine / dichloromethane / 2 h / 10 - 20 °C / Cooling with ice 6.1: hydrogenchloride / methanol; water / 1 h / 20 °C

Reference： [1]Current Patent Assignee: CHENGDU BAISHIXING SCIENCE AND TECH - CN106220607, 2016, A

28
[ 1470031-47-0 ]
[ 934660-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: potassium <i>tert</i>-butylate / dimethyl sulfoxide / 2 h / 20 °C 1.2: 18 h / 20 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 3 h / -78 °C / Inert atmosphere 2.2: -78 - 20 °C 3.1: hydrogen / ethanol / 6 h / 20 °C / Autoclave 4.1: triethylamine / dichloromethane / 2 h / 10 - 20 °C / Cooling with ice 5.1: hydrogenchloride / methanol; water / 1 h / 20 °C

Reference： [1]Current Patent Assignee: CHENGDU BAISHIXING SCIENCE AND TECH - CN106220607, 2016, A

29
[ 1470031-48-1 ]
[ 934660-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 3 h / -78 °C / Inert atmosphere 1.2: -78 - 20 °C 2.1: hydrogen / ethanol / 6 h / 20 °C / Autoclave 3.1: triethylamine / dichloromethane / 2 h / 10 - 20 °C / Cooling with ice 4.1: hydrogenchloride / methanol; water / 1 h / 20 °C

Reference： [1]Current Patent Assignee: CHENGDU BAISHIXING SCIENCE AND TECH - CN106220607, 2016, A

30
[ 1415560-00-7 ]
[ 934660-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: platinum(IV) oxide; hydrogen / methanol / 760.05 Torr 2: triethylamine; dmap / dichloromethane / 20 - 35 °C 3: ammonium hydroxide / dichloromethane / 20 - 35 °C 4: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1 h / 20 - 35 °C 5: hydrogenchloride / methanol / 4 h / 20 - 35 °C

Reference： [1]Current Patent Assignee: MEDCHEMEXPRESS CHINA; HAOYUAN CHEMEXPRESS - CN104725352, 2017, B

31
[ 1799970-85-6 ]
[ 934660-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: triethylamine; dmap / dichloromethane / 20 - 35 °C 2: ammonium hydroxide / dichloromethane / 20 - 35 °C 3: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1 h / 20 - 35 °C 4: hydrogenchloride / methanol / 4 h / 20 - 35 °C

Reference： [1]Current Patent Assignee: MEDCHEMEXPRESS CHINA; HAOYUAN CHEMEXPRESS - CN104725352, 2017, B

32
[ 1415559-54-4 ]
[ 934660-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: ammonium hydroxide / dichloromethane / 20 - 35 °C 2: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1 h / 20 - 35 °C 3: hydrogenchloride / methanol / 4 h / 20 - 35 °C

Reference： [1]Current Patent Assignee: MEDCHEMEXPRESS CHINA; HAOYUAN CHEMEXPRESS - CN104725352, 2017, B

33
[ 934666-06-5 ]
[ 934660-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1 h / 20 - 35 °C 2: hydrogenchloride / methanol / 4 h / 20 - 35 °C
	Multi-step reaction with 3 steps 1.1: tetrahydrofuran; methanol / 17 h / 20 °C 2.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / acetonitrile / 1 h / 20 °C / Inert atmosphere 2.2: 5 - 20 °C 3.1: hydrogenchloride / water; methanol / 24 h

Reference： [1]Current Patent Assignee: MEDCHEMEXPRESS CHINA; HAOYUAN CHEMEXPRESS - CN104725352, 2017, B
[2]Current Patent Assignee: AZAD PHARMA AG - WO2019/86469, 2019, A1

34
[ 109-04-6 ]
[ 934660-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1: n-butyllithium / tert-butyl methyl ether; hexane / 1 h / -50 - -45 °C 2: hydrogenchloride / methanol / 20 - 35 °C 3: triethylamine / dichloromethane / 0 - 35 °C 4: platinum(IV) oxide; hydrogen / methanol / 760.05 Torr 5: triethylamine; dmap / dichloromethane / 20 - 35 °C 6: ammonium hydroxide / dichloromethane / 20 - 35 °C 7: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1 h / 20 - 35 °C 8: hydrogenchloride / methanol / 4 h / 20 - 35 °C

Reference： [1]Current Patent Assignee: MEDCHEMEXPRESS CHINA; HAOYUAN CHEMEXPRESS - CN104725352, 2017, B

35
[ 1415560-24-5 ]
[ 934660-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: hydrogenchloride / methanol / 20 - 35 °C 2: triethylamine / dichloromethane / 0 - 35 °C 3: platinum(IV) oxide; hydrogen / methanol / 760.05 Torr 4: triethylamine; dmap / dichloromethane / 20 - 35 °C 5: ammonium hydroxide / dichloromethane / 20 - 35 °C 6: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1 h / 20 - 35 °C 7: hydrogenchloride / methanol / 4 h / 20 - 35 °C

Reference： [1]Current Patent Assignee: HAOYUAN CHEMEXPRESS; MEDCHEMEXPRESS CHINA - CN104725352, 2017, B

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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
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Code	Phrase
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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.
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P270	Do not eat, drink or smoke when using this product.
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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.
P281	Use personal protective equipment as required.
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Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
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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
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P321
P322
P330	Rinse mouth.
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P332	IF SKIN irritation occurs:
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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.
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P401
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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

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