[ CAS No. 1809036-19-8 ] {[proInfo.proName]}

Name: 1809036-19-8|7-Methyl-5-nitro-2,3-dihydrobenzo[b][1,4]dioxine|98%
Brand: Ambeed
SKU: A1384700
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Quality Control of [ 1809036-19-8 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1809036-19-8 ]

SDS Specification

Alternatived Products of [ 1809036-19-8 ]

Product Details of [ 1809036-19-8 ]

CAS No. :	1809036-19-8	MDL No. :	MFCD00800933
Formula :	C₉H₉NO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GULHJQHAMGELCN-UHFFFAOYSA-N
M.W :	195.17	Pubchem ID :	116987833
Synonyms :

Calculated chemistry of [ 1809036-19-8 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.33
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	51.1
TPSA :	64.28 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) :	-6.19 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.89
Log Po/w (XLOGP3) :	1.83
Log Po/w (WLOGP) :	1.67
Log Po/w (MLOGP) :	1.12
Log Po/w (SILICOS-IT) :	0.38
Consensus Log Po/w :	1.38

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.45
Solubility :	0.686 mg/ml ; 0.00351 mol/l
Class :	Soluble
Log S (Ali) :	-2.8
Solubility :	0.309 mg/ml ; 0.00158 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.2
Solubility :	1.23 mg/ml ; 0.0063 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.64

Safety of [ 1809036-19-8 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313	UN#:
Hazard Statements:	H315-H319	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 1809036-19-8 ]

* 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 [ 1809036-19-8 ]

[ 1809036-19-8 ] Synthesis Path-Downstream 1~25

1
[ 1809036-19-8 ]
[ 1809036-20-1 ]

Yield	Reaction Conditions	Operation in experiment
67.7%	With N-Bromosuccinimide In N,N-dimethyl-formamide at 60℃;	1.4 Preparation of 6-bromo-7-methyl-5-nitro-2,3-dihydrobenzo [b] [1,4] dioxin Dihydrobenzo [b] [1,4] dioxin (19 g, 0.097 mol) was dissolved in 200 mL of N, N-dimethylformamide,Bromosuccinimide (34.5 g, 0.194 mol) was added portionwise.The reaction was heated to 60 ° C overnight. The reaction was completed, 300 mL of water was added and the mixture was extracted with ethyl acetate (3 x 200 mL). The organic phases were combined and the solvent was removed by rotary evaporation.The residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to give the product (18 g, yield 67.7%).
66%	With N-Bromosuccinimide In N,N-dimethyl-formamide at 60℃;	6.6 (4)Preparation of 6-bromo-7-methyl-5-nitro-2,3-dihydrobenzo[b][1,4]dioxin 7-Methyl-5-nitro-2,3-dihydrobenzo[b][1,4]dioxin (13 g, 66.61 mmol)was dissolved in 200mL N,N-dimethyl formamide,and N-bromosuccinimide (23.7g, 133.2 mmol)was added in batch. The resultant mixture was heated to 60°C,and the reaction was carried out overnight. After the reaction, 200mL water was added, and the resultant mixture wasextracted with ethyl acetate (33200mL). The organic phases were combined, the solvent was removed by rotary evaporation,and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate=5:1) toobtain the product (12 g, yield: 66%).
62%	With N-Bromosuccinimide In N,N-dimethyl-formamide at 55℃; Inert atmosphere;	15.4 (4) Preparation of 6-bromo-7-methyl-5-nitro-2,3-dihydrobenzo[b][1,4]dioxin Under nitrogen protection,7-Methyl-5-nitro-2,3-dihydrobenzo[b][1,4]dioxin (4 g, 20.49 mmol) was dissolved in N,N-dimethylformamide (160 mL) ,Add NBS (7.3g, 41.02mmol),Stir at 55 ° C overnight.Cool to room temperature,Quenched with water,Extracted with ethyl acetate (3 x 200 mL),The organic phase was washed with a saturated aqueous solution of sodium chloride (3×300 mL).Dry over anhydrous sodium sulfate,After concentration under reduced pressure,The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1: 5) to give the product (3.5g, 62% yield).

Reference： [1]Current Patent Assignee: SIHUAN PHARMACEUTICAL HOLDINGS GROUP LTD. - CN106146478, 2016, A Location in patent: Paragraph 0172; 0173; 0174
[2]Current Patent Assignee: SIHUAN PHARMACEUTICAL HOLDINGS GROUP LTD. - EP3202765, 2017, A1 Location in patent: Paragraph 0172; 0173; 0195; 0196; 0226; 0227
[3]Current Patent Assignee: SIHUAN PHARMACEUTICAL HOLDINGS GROUP LTD.; BOHAI WATER INDUSTRY CO., LTD. - CN104892585, 2018, B Location in patent: Paragraph 0210; 0221; 0222; 0223

2
[ 1809036-19-8 ]
[ 1809036-21-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-Bromosuccinimide / N,N-dimethyl-formamide / 60 °C 2: acetic acid; iron / ethanol / 70 °C
	Multi-step reaction with 2 steps 1: N-Bromosuccinimide / N,N-dimethyl-formamide / 60 °C 2: acetic acid; iron / ethanol / 3 h / 70 - 80 °C
	Multi-step reaction with 2 steps 1: N-Bromosuccinimide / N,N-dimethyl-formamide / 55 °C / Inert atmosphere 2: iron; acetic acid / ethanol / 3 h / 70 - 80 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: SIHUAN PHARMACEUTICAL HOLDINGS GROUP LTD. - CN106146478, 2016, A
[2]Current Patent Assignee: SIHUAN PHARMACEUTICAL HOLDINGS GROUP LTD. - EP3202765, 2017, A1
[3]Current Patent Assignee: SIHUAN PHARMACEUTICAL HOLDINGS GROUP LTD.; BOHAI WATER INDUSTRY CO., LTD. - CN104892585, 2018, B

3
[ 1809036-19-8 ]
[ 1809036-22-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-Bromosuccinimide / N,N-dimethyl-formamide / 60 °C 2: acetic acid; iron / ethanol / 70 °C 3: acetic acid; N-iodo-succinimide / toluene / 3 h / 20 °C
	Multi-step reaction with 3 steps 1: N-Bromosuccinimide / N,N-dimethyl-formamide / 60 °C 2: acetic acid; iron / ethanol / 3 h / 70 - 80 °C 3: acetic acid; N-iodo-succinimide / toluene / 2 h / 20 °C
	Multi-step reaction with 3 steps 1: N-Bromosuccinimide / N,N-dimethyl-formamide / 55 °C / Inert atmosphere 2: iron; acetic acid / ethanol / 3 h / 70 - 80 °C / Inert atmosphere 3: N-iodo-succinimide; acetic acid / toluene / 2 h / 20 °C / Inert atmosphere

4
[ 1809036-19-8 ]
[ 1809036-23-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: N-Bromosuccinimide / N,N-dimethyl-formamide / 60 °C 2: acetic acid; iron / ethanol / 70 °C 3: acetic acid; N-iodo-succinimide / toluene / 3 h / 20 °C 4: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / 1,4-dioxane; water / 3 h / 80 °C
	Multi-step reaction with 4 steps 1: N-Bromosuccinimide / N,N-dimethyl-formamide / 60 °C 2: acetic acid; iron / ethanol / 3 h / 70 - 80 °C 3: acetic acid; N-iodo-succinimide / toluene / 2 h / 20 °C 4: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / 1,4-dioxane / 16 h / 90 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1: N-Bromosuccinimide / N,N-dimethyl-formamide / 55 °C / Inert atmosphere 2: iron; acetic acid / ethanol / 3 h / 70 - 80 °C / Inert atmosphere 3: N-iodo-succinimide; acetic acid / toluene / 2 h / 20 °C / Inert atmosphere 4: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane; water / 2 h / 83 °C / Inert atmosphere

5
[ 1809036-19-8 ]
[ 1809036-24-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: N-Bromosuccinimide / N,N-dimethyl-formamide / 60 °C 2: acetic acid; iron / ethanol / 70 °C 3: acetic acid; N-iodo-succinimide / toluene / 3 h / 20 °C 4: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / 1,4-dioxane; water / 3 h / 80 °C 5: palladium on activated charcoal; hydrogen / methanol / 20 °C
	Multi-step reaction with 5 steps 1: N-Bromosuccinimide / N,N-dimethyl-formamide / 60 °C 2: acetic acid; iron / ethanol / 3 h / 70 - 80 °C 3: acetic acid; N-iodo-succinimide / toluene / 2 h / 20 °C 4: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / 1,4-dioxane / 16 h / 90 °C / Inert atmosphere 5: palladium on activated charcoal / methanol / 12 h / 20 °C
	Multi-step reaction with 5 steps 1: N-Bromosuccinimide / N,N-dimethyl-formamide / 55 °C / Inert atmosphere 2: iron; acetic acid / ethanol / 3 h / 70 - 80 °C / Inert atmosphere 3: N-iodo-succinimide; acetic acid / toluene / 2 h / 20 °C / Inert atmosphere 4: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane; water / 2 h / 83 °C / Inert atmosphere 5: palladium on activated charcoal; hydrogen / methanol / 20 °C / Inert atmosphere

6
[ 1809036-19-8 ]
[ 2054540-28-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: N-Bromosuccinimide / N,N-dimethyl-formamide / 60 °C 2: acetic acid; iron / ethanol / 70 °C 3: acetic acid; N-iodo-succinimide / toluene / 3 h / 20 °C 4: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / 1,4-dioxane; water / 3 h / 80 °C 5: palladium on activated charcoal; hydrogen / methanol / 20 °C 6: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / 1,4-dioxane / 80 °C

Reference： [1]Current Patent Assignee: SIHUAN PHARMACEUTICAL HOLDINGS GROUP LTD. - CN106146478, 2016, A

7
[ 1809036-19-8 ]
[ 2054540-23-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: N-Bromosuccinimide / N,N-dimethyl-formamide / 60 °C 2: acetic acid; iron / ethanol / 70 °C 3: acetic acid; N-iodo-succinimide / toluene / 3 h / 20 °C 4: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / 1,4-dioxane; water / 3 h / 80 °C 5: palladium on activated charcoal; hydrogen / methanol / 20 °C 6: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / 1,4-dioxane / 80 °C 7: trifluoroacetic acid / dichloromethane / 2 h / 20 °C

Reference： [1]Current Patent Assignee: SIHUAN PHARMACEUTICAL HOLDINGS GROUP LTD. - CN106146478, 2016, A

8
[ 1809036-19-8 ]
[ 2054540-24-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1: N-Bromosuccinimide / N,N-dimethyl-formamide / 60 °C 2: acetic acid; iron / ethanol / 70 °C 3: acetic acid; N-iodo-succinimide / toluene / 3 h / 20 °C 4: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / 1,4-dioxane; water / 3 h / 80 °C 5: palladium on activated charcoal; hydrogen / methanol / 20 °C 6: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / 1,4-dioxane / 80 °C 7: trifluoroacetic acid / dichloromethane / 2 h / 20 °C 8: dichloromethane / 2 h / 20 °C

Reference： [1]Current Patent Assignee: SIHUAN PHARMACEUTICAL HOLDINGS GROUP LTD. - CN106146478, 2016, A

9
[ 53411-80-6 ]
[ 1809036-19-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: water; hydrogen bromide; tetrabutyl ammonium fluoride / 110 °C 2: potassium carbonate / N,N-dimethyl-formamide / 60 °C
	Multi-step reaction with 2 steps 1: hydrogen bromide; tetrabutyl ammonium fluoride / water / 18 h / 110 °C 2: potassium carbonate / N,N-dimethyl-formamide / 12 h / 55 °C
	Multi-step reaction with 2 steps 1: hydrogen bromide; Aliquat 336 / 4 h / 100 °C / Inert atmosphere 2: potassium carbonate / N,N-dimethyl-formamide / 55 °C / Inert atmosphere

10
[ 93-51-6 ]
[ 1809036-19-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: acetic acid; nitric acid / chloroform / 0.5 h / 0 - 20 °C 2: water; hydrogen bromide; tetrabutyl ammonium fluoride / 110 °C 3: potassium carbonate / N,N-dimethyl-formamide / 60 °C
	Multi-step reaction with 3 steps 1: acetic acid; nitric acid / chloroform / 0.5 h / 0 - 20 °C 2: hydrogen bromide; tetrabutyl ammonium fluoride / water / 18 h / 110 °C 3: potassium carbonate / N,N-dimethyl-formamide / 12 h / 55 °C
	Multi-step reaction with 3 steps 1: acetic acid; nitric acid / chloroform / 0.03 h / Inert atmosphere; Cooling with ice 2: hydrogen bromide; Aliquat 336 / 4 h / 100 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 55 °C / Inert atmosphere

11
[ 89791-96-8 ]
[ 106-93-4 ]
7-methyl-5-nitro-2,3-dihydrobenzo[b][1,4]dioxin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82.6%	With potassium carbonate; In N,N-dimethyl-formamide; at 60.0℃;	A solution of <strong>[89791-96-8]5-methyl-3-nitrobenzene-1,2-diol</strong> (20 g, 0.118 mol) was dissolved in 100 mL of N, N-dimethylformamide,1,2-Dibromoethane (44.4 g, 0.236 mol) and potassium carbonate (49.2 g, 0.354 mol) were added.Heated to 60 C,The reaction was over night. The reaction was completed, 300 mL of water was added and the mixture was extracted with ethyl acetate (3 x 200 mL). The organic phases were combined and the solvent was removed by rotary evaporation.The residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to give the product (19 g, yield 82.6%).
78%	With potassium carbonate; In N,N-dimethyl-formamide; at 55.0℃; for 12.0h;	5-Methyl-3-nitrobenzene-1,2-diol (9.5 g, 56.2 mmol) was dissolved in DMF (200 mL), and 1,2-dibromoethane(21 g, 112 mmol)and potassium carbonate (23 g, 167 mmol) were added. The resultant mixture was heated to 55Cand reacted under stirring for 16 h. After the reaction, the resultant mixture was cooled to room temperature, and 300mL water was added. After extraction with ethyl acetate (200 mL 3 3), the organic phases were combined, washed withsaturated NaCl aqueous solution, dried with anhydrous sodium sulphate, filtrated, and concentrated. The crude productwas purified by silica gel column chromatography (petroleum ether: ethyl acetate=30:1) to obtain the product (8.5 g,yield: 78%).
4 g	With potassium carbonate; In N,N-dimethyl-formamide; at 55.0℃;Inert atmosphere;	Under nitrogen protection,5-Methyl-3-nitro-1,2-benzenediol (4.5 g, 26.61 mmol) was dissolved in DMF (180 mL).1,2-Dibromoethane (10 g, 53.23 mmol) and potassium carbonate (11 g, 79.59 mmol) were added to a three-neck bottle.Stir at 55 C overnight.Cool to room temperature,Stir overnight,LC-MS showed complete reaction,Cool to room temperature,Quenched with water,Extracted with ethyl acetate (3 x 200 mL),The organic phase was washed with a saturated aqueous solution of sodium chloride (3×300 mL).Dry over anhydrous sodium sulfate,Concentrated under reduced pressure,The residue was purified by silica gel column chromatography (ethyl acetate 5:: petroleum ether = 1) to give the product (4g, 77% yield).

Reference： [1]Patent: CN106146478,2016,A .Location in patent: Paragraph 0169; 0170; 0171
[2]Patent: EP3202765,2017,A1 .Location in patent: Paragraph 0170; 0171; 0194; 0195; 0224; 0225
[3]Patent: CN104892585,2018,B .Location in patent: Paragraph 0210; 0218; 0219; 0220

12
[ 1809036-19-8 ]
[ 1893419-64-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: N-Bromosuccinimide / N,N-dimethyl-formamide / 60 °C 2: acetic acid; iron / ethanol / 3 h / 70 - 80 °C 3: acetic acid; N-iodo-succinimide / toluene / 2 h / 20 °C 4: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / water; 1,4-dioxane / 2 h / 80 °C / Inert atmosphere