[ CAS No. 1668-84-4 ] {[proInfo.proName]}

Name: 1668-84-4|Benzo[d][1,3]dioxol-4-amine|97%
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SKU: A118425
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Quality Control of [ 1668-84-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 1668-84-4 ]

CAS No. :	1668-84-4	MDL No. :	MFCD09038121
Formula :	C₇H₇NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KQMXPHISFRKBJP-UHFFFAOYSA-N
M.W :	137.14	Pubchem ID :	10313165
Synonyms :

Calculated chemistry of [ 1668-84-4 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	36.91
TPSA :	44.48 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.39 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.53
Log Po/w (XLOGP3) :	1.05
Log Po/w (WLOGP) :	1.01
Log Po/w (MLOGP) :	0.55
Log Po/w (SILICOS-IT) :	1.24
Consensus Log Po/w :	1.08

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.8
Solubility :	2.19 mg/ml ; 0.016 mol/l
Class :	Very soluble
Log S (Ali) :	-1.57
Solubility :	3.65 mg/ml ; 0.0266 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.76
Solubility :	2.38 mg/ml ; 0.0173 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.12

Safety of [ 1668-84-4 ]

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 [ 1668-84-4 ]

* 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 [ 1668-84-4 ]
Downstream synthetic route of [ 1668-84-4 ]

[ 1668-84-4 ] Synthesis Path-Upstream 1~14

1
[ 111081-10-8 ]
[ 1668-84-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogenchloride In 1,4-dioxane at 18 - 22℃; for 1 h;	The Boc starting material G2 (257 mg; 1.08 MMOL) was dissolved in 4M HCI/DIOXANE (5.0 mL) and stirred at room temperature for 1 hr. The solvent was evaporated and the residue diluted with saturated sodium bicarbonate (few mL) and 1 M NAOH (1 ML), extracted with EtOAc (2x), dried (MGS04), filtered and evaporated to dryness to provide the crude 2, 3-methylene DIOXYANILINE G3 (158 mg; 106percent).

Reference： [1] Patent: WO2004/103996, 2004, A1, . Location in patent: Page 50
[2] Journal of Medicinal Chemistry, 2004, vol. 47, # 4, p. 871 - 887
[3] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1991, # 2, p. 259 - 262
[4] Patent: US2004/34046, 2004, A1,
[5] Patent: WO2004/4732, 2004, A1, . Location in patent: Page/Page column 66
[6] Patent: WO2004/5284, 2004, A1, . Location in patent: Page 69

2
[ 72744-45-7 ]
[ 1668-84-4 ]

Yield	Reaction Conditions	Operation in experiment
63%	With hydrogen In ethanol for 4 h;	[d][1 ,3]dioxol-4-amine To a solution of 4-nitrobenzo[d][1 ,3]dioxoie (2.0 g, 12 mmol) in ethanol (80 mL) was added Raney Ni (ca. 0.5 g). The mixture was stirred under an atmosphere of hydrogen for 4 hours. The catalyst was removed by filtration and the filtrate was concentrated. The residue was purified by silica gel chromatography (dich.oromethane) to afford the product benzo[d][1.3]dioxol-4-amine (1 .04 g, yield 63 percent). H NMR (400 MHz, CDCI₃) δ ppm 6.64-6.68 (t, 1 H, J = 8.0 Hz), 6.29-6.35 (dt, 2H, J = 0.8 Hz, 6.4 Hz), 5.90 (s, 2H), 3.52 (br, 2H).

Reference： [1] Journal of Medicinal Chemistry, 2002, vol. 45, # 19, p. 4128 - 4139
[2] Patent: WO2012/92880, 2012, A1, . Location in patent: Page/Page column 62
[3] Journal of the American Chemical Society, 1957, vol. 79, p. 6328,6333

3
[ 1137558-08-7 ]
[ 1668-84-4 ]

Reference： [1] Journal of Medicinal Chemistry, 2009, vol. 52, # 7, p. 1873 - 1884

4
[ 274-09-9 ]
[ 1668-84-4 ]
[ 14268-66-7 ]

Reference： [1] Journal of Organic Chemistry, 1984, vol. 49, # 23, p. 4479 - 4482

5
[ 6665-98-1 ]
[ 1668-84-4 ]

Reference： [1] Journal of Medicinal Chemistry, 2002, vol. 45, # 19, p. 4128 - 4139
[2] Journal of the American Chemical Society, 1957, vol. 79, p. 6328,6333
[3] Patent: WO2012/92880, 2012, A1,

6
[ 5768-39-8 ]
[ 1668-84-4 ]

Reference： [1] Journal of Medicinal Chemistry, 2004, vol. 47, # 4, p. 871 - 887
[2] Agricultural and Biological Chemistry, 1980, vol. 44, # 2, p. 235 - 243

7
[ 33842-16-9 ]
[ 1668-84-4 ]

Reference： [1] Journal of Medicinal Chemistry, 2004, vol. 47, # 4, p. 871 - 887

8
[ 2411-83-8 ]
[ 1668-84-4 ]

Reference： [1] Journal of Medicinal Chemistry, 2004, vol. 47, # 4, p. 871 - 887

9
[ 303-38-8 ]
[ 1668-84-4 ]

Reference： [1] Journal of Medicinal Chemistry, 2004, vol. 47, # 4, p. 871 - 887

10
[ 120-80-9 ]
[ 1668-84-4 ]

Reference： [1] Patent: WO2012/92880, 2012, A1,

11
[ 69151-39-9 ]
[ 1668-84-4 ]

Reference： [1] Agricultural and Biological Chemistry, 1980, vol. 44, # 2, p. 235 - 243

12
[ 24677-78-9 ]
[ 1668-84-4 ]

Reference： [1] Agricultural and Biological Chemistry, 1980, vol. 44, # 2, p. 235 - 243

13
[ 148-53-8 ]
[ 1668-84-4 ]

Reference： [1] Agricultural and Biological Chemistry, 1980, vol. 44, # 2, p. 235 - 243

14
[ 7797-83-3 ]
[ 1668-84-4 ]

Reference： [1] Agricultural and Biological Chemistry, 1980, vol. 44, # 2, p. 235 - 243

[ 1668-84-4 ] Synthesis Path-Downstream 1~87

1
[ 1668-84-4 ]
[ 77-78-1 ]
[ 116532-63-9 ]

Reference： [1]Journal of the American Chemical Society,1957,vol. 79,p. 6328,6333

2
[ 72744-45-7 ]
[ 1668-84-4 ]

Yield	Reaction Conditions	Operation in experiment
63%	With hydrogen;Raney Ni; In ethanol; for 4h;	[d][1 ,3]dioxol-4-amine To a solution of 4-nitrobenzo[d][1 ,3]dioxoie (2.0 g, 12 mmol) in ethanol (80 mL) was added Raney Ni (ca. 0.5 g). The mixture was stirred under an atmosphere of hydrogen for 4 hours. The catalyst was removed by filtration and the filtrate was concentrated. The residue was purified by silica gel chromatography (dich.oromethane) to afford the product benzo[d][1.3]dioxol-4-amine (1 .04 g, yield 63 %). H NMR (400 MHz, CDCI3) delta ppm 6.64-6.68 (t, 1 H, J = 8.0 Hz), 6.29-6.35 (dt, 2H, J = 0.8 Hz, 6.4 Hz), 5.90 (s, 2H), 3.52 (br, 2H).

Reference： [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 4128 - 4139
[2]Patent: WO2012/92880,2012,A1 .Location in patent: Page/Page column 62
[3]Journal of the American Chemical Society,1957,vol. 79,p. 6328,6333

3
[ 1668-84-4 ]
[ 22539-80-6 ]
[ 17232-46-1 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1967,vol. 22,p. 2368 - 2371

4
[ 1668-84-4 ]
[ 13487-89-3 ]
[ 1936-74-9 ]

Reference： [1]Indian Journal of Chemistry,1964,vol. 2,p. 449 - 450

5
[ 274-09-9 ]
[ 1668-84-4 ]
[ 14268-66-7 ]

Reference： [1]Journal of Organic Chemistry,1984,vol. 49,p. 4479 - 4482

6
[ 1668-84-4 ]
[ 79-04-9 ]
[ 105-53-3 ]
[ 74120-83-5 ]

Reference： [1]Agricultural and Biological Chemistry,1980,vol. 44,p. 235 - 243

7
[ 69151-39-9 ]
[ 1668-84-4 ]

Reference： [1]Agricultural and Biological Chemistry,1980,vol. 44,p. 235 - 243

8
[ 111081-10-8 ]
[ 1668-84-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogenchloride; In 1,4-dioxane; at 18 - 22℃; for 1h;	The Boc starting material G2 (257 mg; 1.08 MMOL) was dissolved in 4M HCI/DIOXANE (5.0 mL) and stirred at room temperature for 1 hr. The solvent was evaporated and the residue diluted with saturated sodium bicarbonate (few mL) and 1 M NAOH (1 ML), extracted with EtOAc (2x), dried (MGS04), filtered and evaporated to dryness to provide the crude 2, 3-methylene DIOXYANILINE G3 (158 mg; 106%).
	With potassium hydroxide; aqueous hydrochloric acid; In ethanol;	A 5N aqueous hydrochloric acid solution (30 ml) was added to a solution of tert-butyl 2,3-methylenedioxyphenylcarbamate (1.9 g) in ethanol (38 ml) and the reaction mixture was stirred at ambient temperature for 20 hours. The ethanol was evaporated and the residual aqueous phase was washed with diethyl ether and neutralised to pH7 by the addition of solid potassium hydroxide. The resultant mixture was filtered and the aqueous phase was extracted with diethyl ether. The organic phase was washed with brine, dried over magnesium sulphate and evaporated. There was thus obtained 2,3-methylenedioxyaniline (1.0 g) as an oil; NMR Spectrum: (CDCl3) 3.0 (br s, 2H), 5.9 (s, 2H), 6.3 (m, 2H), 7.25 (t, 1H).
		A 5N aqueous hydrochloric acid solution (30 ml) was added to a solution of tert-butyl 2,3-methylenedioxyphenylcarbamate (1.9 g) in ethanol (38 ml) and the reaction mixture was stirred at ambient temperature for 20 hours. The ethanol was evaporated and the residual aqueous phase was washed with diethyl ether and neutralised to pH7 by the addition of solid potassium hydroxide. The resultant mixture was filtered and the aqueous phase was extracted with diethyl ether. The organic phase was washed with brine, dried over magnesium sulphate and evaporated. There was thus obtained 1, 3-benzodioxol-4-amine (1.0 g) as an oil; NMR Spectrum : (CDC13) 3.0 (br s, 2H), 5.9 (s, 2H), 6.3 (m, 2H), 7.25 (t, 1H).

A 5N aqueous hydrochloric acid solution (30 ml) was added to a solution of tert-butyl [N- (2, 3-METLIYLENEDIOXYPHEENYL) CARBAMATE] (1.9 g) in ethanol (38 ml) and the reaction mixture was stirred at ambient temperature for 20 hours. The ethanol was evaporated and the residual aqueous phase was washed with diethyl ether and neutralised to pH7 by the addition of solid potassium hydroxide. The resultant mixture was filtered and the aqueous phase was extracted with diethyl ether. The organic phase was washed [WITH A] saturated brine solution, dried over magnesium sulphate and evaporated. There was thus obtained 2, 3-methylenedioxyaniline (1.0 g) as an oil; NMR Spectrum : (CDC13) 3.0 (br s, 2H), 5.9 (s, 2H), 6.3 (m, 2H), 7.25 (t, 1H).

Reference： [1]Patent: WO2004/103996,2004,A1 .Location in patent: Page 50
[2]Journal of Medicinal Chemistry,2004,vol. 47,p. 871 - 887
[3]Journal of the Chemical Society. Perkin transactions I,1991,p. 259 - 262
[4]Patent: US2004/34046,2004,A1
[5]Patent: WO2004/4732,2004,A1 .Location in patent: Page/Page column 66
[6]Patent: WO2004/5284,2004,A1 .Location in patent: Page 69

10
[ 1668-84-4 ]
[ 821-48-7 ]
[ 98224-27-2 ]

Reference： [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 4128 - 4139

11
[ 1668-84-4 ]
[ 196195-13-8 ]
N-(1,3-benzodioxol-4-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-amine dihydrochloride [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 871 - 887

12
[ 379228-48-5 ]
[ 1668-84-4 ]
benzo[1,3]dioxol-4-yl-[7-methoxy-5-(1-methyl-piperidin-4-yloxy)-quinazolin-4-yl]-amine; compound with GENERIC INORGANIC NEUTRAL COMPONENT [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 6465 - 6488

13
[ 379229-95-5 ]
[ 1668-84-4 ]
[ 536740-59-7 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 6465 - 6488

14
[ 5768-39-8 ]
[ 1668-84-4 ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 871 - 887
[2]Agricultural and Biological Chemistry,1980,vol. 44,p. 235 - 243

15
[ 33842-16-9 ]
[ 1668-84-4 ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 871 - 887

16
[ 2411-83-8 ]
[ 1668-84-4 ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 871 - 887

17
[ 303-38-8 ]
[ 1668-84-4 ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 871 - 887

18
[ 1668-84-4 ]
3-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-1-(5-fluoro-benzo[<i>b</i>]thiophen-3-yl)-propan-1-ol [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 4128 - 4139

19
[ 1668-84-4 ]
[ 433303-00-5 ]

Reference： [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 4128 - 4139

20
[ 6665-98-1 ]
[ 1668-84-4 ]

Reference： [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 4128 - 4139
[2]Journal of the American Chemical Society,1957,vol. 79,p. 6328,6333
[3]Patent: WO2012/92880,2012,A1

21
[ 1668-84-4 ]
[ 482-32-6 ]

Reference： [1]Agricultural and Biological Chemistry,1980,vol. 44,p. 235 - 243
[2]Indian Journal of Chemistry,1964,vol. 2,p. 449 - 450

22
[ 1668-84-4 ]
[ 74120-88-0 ]

Reference： [1]Agricultural and Biological Chemistry,1980,vol. 44,p. 235 - 243

23
[ 1668-84-4 ]
[ 74120-89-1 ]

Reference： [1]Agricultural and Biological Chemistry,1980,vol. 44,p. 235 - 243

24
[ 1668-84-4 ]
[ 74120-90-4 ]

Reference： [1]Agricultural and Biological Chemistry,1980,vol. 44,p. 235 - 243

25
[ 7797-83-3 ]
[ 1668-84-4 ]

Reference： [1]Agricultural and Biological Chemistry,1980,vol. 44,p. 235 - 243

26
[ 24677-78-9 ]
[ 1668-84-4 ]

Reference： [1]Agricultural and Biological Chemistry,1980,vol. 44,p. 235 - 243

27
[ 148-53-8 ]
[ 1668-84-4 ]

Reference： [1]Agricultural and Biological Chemistry,1980,vol. 44,p. 235 - 243

28
[ 1668-84-4 ]
[ 2278-39-9 ]

Reference： [1]Indian Journal of Chemistry,1964,vol. 2,p. 449 - 450

29
[ 1668-84-4 ]
[ 1936-76-1 ]

Reference： [1]Indian Journal of Chemistry,1964,vol. 2,p. 449 - 450

30
[ 1668-84-4 ]
[ 1936-77-2 ]

Reference： [1]Indian Journal of Chemistry,1964,vol. 2,p. 449 - 450

31
[ 1668-84-4 ]
[ 1936-75-0 ]

Reference： [1]Indian Journal of Chemistry,1964,vol. 2,p. 449 - 450

32
[ 1668-84-4 ]
[ 196308-33-5 ]

Yield	Reaction Conditions	Operation in experiment
	With phenyltrimethylammonium dichloroiodate; calcium carbonate; In methanol; dichloromethane; at 20℃; for 1.5h;	Benzyltrimethylammonium dichloroiodate (2.8 g) was added portionwise over 10 minutes to a stirred mixture of 1, 3-benzodioxol-4-amine (1 g), calcium carbonate (0.95 g) in methanol (5 ml) and dichloromethane (10 ml). The reaction mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The organics were washed with water saturated brine and dried over magnesium sulfate. The residue was purified by column chromatography on silica using a gradient of an 8: 1 mixture of dichloromethane/isohexane to Dichloromethane as eluent. There was thus obtained 7-iodo-1, 3-benzodioxol-4-amine as a beige crystalline solid (1.1 g); NMR Spectrum: (DMSOd6) 5.04 (bs, 2H); 5.94 (s, 2H) ; 6.13 (d, 1H), 6.80 (d, 1H).
	With N,N,N-trimethylbenzenemethanaminium dichloroiodate; calcium carbonate; In methanol; dichloromethane; at 20℃; for 1.66667h;	Benzyltrimethylammonium dichloroiodate (2.8 g) was added portionwise during 10 minutes to a stirred mixture of 2,3-methylenedioxyaniline (1 g), calcium carbonate (0.95 g), methanol (5 ml) and methylene chloride (10 ml). The reaction mixture was stirred at ambient temperature for 1.5 hours. The resultant mixture was diluted with water and extracted with methylene chloride. The organic phase was washed with water and with a saturated brine solution, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of isohexane and methylene chloride as eluent. There was thus obtained 4-iodo-2, [3-METL1YLENEDIOXYANILINE] as a solid [(1.] [1] g); NMR Spectrum: [(DMSOD6)] 5.04 (br s, 2H), 5.94 (s, 2H), 6.13 (d, [1H),] 6. [8] (d, [1H).]

Reference： [1]Patent: WO2004/4732,2004,A1 .Location in patent: Page/Page column 66-67
[2]Patent: WO2004/5284,2004,A1 .Location in patent: Page 69

33
[ 1668-84-4 ]
[ 762-42-5 ]
C₁₃H₁₃NO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	In methanol; for 3h;Heating / reflux;	Dimethyl acetylene dicarboxylate A3 (130 pL, 1.06 MMOL) was added dropwise to a solution of crude 2, 3-methylene DIOXYANILINE G3 (148 mg, 1. 08 MMOL) in MEOH (2.5 mL). Caution the reaction is exothermic. The mixture was heated at A gentle reflux for 3 hours, cooled and concentrated under vacuum. The crude material was purified by flash column chromatography on silica gel with hexane: EtOAc (9: 1) to provide, after evaporation of the pure fractions, the diester adduct G4 (185 mg; 0.662 mmol ; 61% yield).

Reference： [1]Patent: WO2004/103996,2004,A1 .Location in patent: Page 50

34
[ 1668-84-4 ]
N,N,N-trimethyl benzenemethanaminium dichloroiodate [ No CAS ]
[ 196308-33-5 ]

Yield	Reaction Conditions	Operation in experiment
3.5 g (46.9%)	With calcium carbonate; In methanol; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran;	a) CaCO3 (3.9 g) was added to a mixture of <strong>[1668-84-4]1,3-benzodioxol-4-amine</strong> (4.11 g) in DCM (40 ml) and CH3OH (20 ml). This mixture was stirred at room temperature. N,N,N-trimethyl benzenemethanaminium dichloroiodate (11.5 g) was added portionwise at room temperature. The resulting reaction mixture was stirred for 15 minutes at room temperature. The mixture was diluted with water. The layers were separated. The aqueous phase was extracted with DCM. The combined organic layers were washed with water, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/hexane 80/20). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE. The precipitate was filtered off and dried, yielding 3.5 g (46.9%) of 7-iodo-<strong>[1668-84-4]1,3-benzodioxol-4-amine</strong> (intermediate 2-a).
3.5 g (46.9%)	With calcium carbonate; In methanol; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran;	a) CaCO3 (3.9 g) was added to a mixture of <strong>[1668-84-4]1,3-benzodioxol-4-amine</strong> (4.11 g) in DCM (40 ml) and CH3OH (20 ml). This mixture was stirred at room temperature. N,N,N-trimethyl benzenemethanaminium dichloroiodate (11.5 g) was added portionwise at room temperature. The resulting reaction mixture was stirred for 15 minutes at room temperature. The mixture was diluted with water. The layers were separated. The aqueous phase was extracted with DCM. The combined organic layers were washed with water, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/hexane 80/20). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE. The precipitate was filtered off and dried, yielding 3.5 g (46.9%) of 7-iodo-<strong>[1668-84-4]1,3-benzodioxol-4-amine</strong> (intermediate 18).

Reference： [1]Patent: US2002/86879,2002,A1
[2]Patent: US6291481,2001,B1

35
[ 1668-84-4 ]
[ 883985-83-9 ]
C₂₇H₂₅N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 2-hydroxy-pyridine N-oxide; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 17 - 25℃; for 16h;	Example 9; Using an analogous procedure to that described in Example 6, the appropriate 2-phenylacetic acid was reacted with the appropriate aniline, heterocyclylamine or heteroarylamine to give the compounds described in Table IV. For the Compounds [1] to [23], [26] to [28], [31] to [33], [35] to [55] and [57] to [81] below, DMA was used in place of DMF as the reaction solvent. Unless otherwise stated, each aniline, heterocyclylamine and heteroarylamine was a commercially available material.; Notes The products gave the characterising data shown below., [1] 1H NMR: (DMSOd6) 1.44 (t, 3H), 3.74 (s,lH), 4.26 (q, 2H), 6.05 (s, 2H) 6.72 (d, IH),6.79 (t, IH), 7.27 (m, 3H), 7.37 (s, IH), 7.43 (d, 2H), 7.56 (s, IH), 8.53 (s, IH), 9.96 (s,lH); 5 Mass Spectrum: M+H* 474.<strong>[1668-84-4]2,3-Methylenedioxyaniline</strong> is described in J. Med. Chem.. 1979, 22, 1354.

Reference： [1]Patent: WO2006/40520,2006,A1 .Location in patent: Page/Page column 110-114

36
[ 1668-84-4 ]
[ 884344-14-3 ]
C₂₇H₂₈N₆O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;	Example 37 .; Using a similar procedure to that described in Example 8, the appropriate2-(pyrazol-l-yl)acetic acid was reacted with the appropriate aniline to give the compounds described in Table X. Unless otherwise stated, each aniline or heterocyclyl amine starting material was commercially available.For each of the Compounds [1] to [14] below, 2-(benzotriazol-l-yl)- 1,1,3,3-tetramethyluronium tetrafluoroborate was used in place of 2-(7-azabenzotriazol-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate(V), the reaction mixture was stirred at ambient temperature for 16 hours, water was added and the precipitate was recovered by filtration and purified by preparative HPLC using a Waters 'Symmetry' C18 re versed-phase EPO <DP n="169"/>column (5 microns silica, 19 mm diameter, 100 mm length) and decreasingly polar mixtures of water (containing 2% acetic acid) and acetonitrile as eluent.Unless otherwise stated, for the Compounds [15] to [27] below, the reaction mixture was stirred at ambient temperature for 1 hour and the resultant reaction mixture was injected into a Waters 'beta Basic Hypersil' reversed-phase column (5 microns silica, 30 mm diameter, 250 mm length) which was eluted with decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile.

Reference： [1]Patent: WO2006/40526,2006,A1 .Location in patent: Page/Page column 167-168

37
[ 1668-84-4 ]
[ 884344-86-9 ]
N-(2,3-methylenedioxyphenyl)-2-(4-[6-(2-chloroethoxy)-7-methoxyquinazolin-4-yloxy]pyrazol-1-yl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 2-hydroxy-pyridine N-oxide; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 100℃; for 0.05h;Microwave irradiation;	Using a similar procedure to that described in Example 32 except that the reaction mixture was stirred in a microwave oven at 100C for 3 minutes, 2-{4-[6-(2-chloroethoxy)- 7-methoxyquinazolin-4-yloxy]pyrazol- 1-yl} acetic acid (1 g) was reacted with2,3-methylenedioxyaniline (0.435 g). On completion of the reaction, water was added and the resultant solid was isolated and washed with diethyl ether. The solid was dissolved in a mixture of methylene chloride and toluene and the solution was evaporated. The solid so obtained was dried under vacuum. There was thus obtained the required starting material (0.8 g); 1H NMR: (DMSOd6) 4.0 (s, 3H), 4.05 (m, 2H), 4.5 (m, 2H), 5.1 (s, 2H), 6.05 (s, 2H), 6.75 (d, IH), 6.8 (t, IH), 7.3 (d, IH), 7.4 (s, IH), 7.6 (s, IH), 7.65 (s, IH), 8.1 (s, IH), 8.65 (s, IH); Mass Spectrum: M+H4498 and 500.

Reference： [1]Patent: WO2006/40526,2006,A1 .Location in patent: Page/Page column 193

38
[ 1668-84-4 ]
copper (II) chloride monohydrate [ No CAS ]
benzo[d][1,3]dioxole-4-sulfonyl chloride [ No CAS ]
1,3-benzodioxol-4-sulfochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sulfur dioxide; sodium nitrite; In hydrogenchloride; water; acetic acid;	(a) 1,3-Benzodioxol-4-sulfonyl chloride 7.5 g of 4-amino-1,3-benzodioxol are suspended in 23 ml of 36% hydrochloric acid. While cooling with ice, diazotisation is effected with a solution of 4.06 g of sodium nitrite in 8 ml of water. To the solution of the diazonium salt is added dropwise a mixture of 50 ml of glacial acetic acid, 5 ml of water, 15 g of sulfur dioxide and 2.3 g of copper (II) chloride hydrate. The temperature is kept constant at 40 C. until the addition to the solution of the diazonium salt is complete. The reaction mixture is then cooled and diluted with 500 ml of ice/water. The crude 1,3-benzodioxol-4-sulfochloride is isolated and dried. Melting point: 121-124 C.

Reference： [1]Patent: US4634465,1987,A

Yield	Reaction Conditions	Operation in experiment
		(2) t-Butyl [(2,3-methylenedioxyphenylamino)carbothioyl]amino}propylcarbamate A mixture of 2,3-methylenedioxyphenylamine (698 mg) obtained by the method disclosed in Neville, et al., (Neville, C. F. et al., J. Chem. Soc. Perkin Trans. 1, 1991, 259-262), t-butyl 3-isothiocyanatepropylcarbamate (1.1 g) and dioxane (10 ml) was heated with reflux under nitrogen atmosphere. Four hours thereafter, the reaction mixture was concentrated under reduced pressure. The residue was crystallized from diethyl ether-n-hexane to give the title compound (803 mg). 1H-NMR (CDCl3): 6 1.37 (9H, s), 1.73 (2H, m), 3.14 (2H, m), 3.71 (2H, m), 4.79 (1H, m), 6.03 (2H, s), 6.71-6.88 (3H, m), 7.12 (1H, m), 7.35 (1H, brs)

40
[ 1668-84-4 ]
[ 6032-29-7 ]
[ 196195-13-8 ]
6-methoxy-4-(2,3-methylenedioxyanilino)-7-(3-morpholinopropoxy)quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In isopropyl alcohol;	EXAMPLE 1 6-methoxy-4-(2,3-methylenedioxyanilino)-7-(3-morpholinopropoxy)quinazoline A mixture of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (0.1 g), 2,3-methylenedioxyaniline (0.048 g), pentan-2-ol (5 ml) and a solution of hydrogen chloride in isopropanol (6M, 4 drops) was stirred and heated to 100 C. for 5 hours. The resultant mixture was cooled to ambient temperature and the precipitate was isolated by filtration, washed with pentan-2-ol and dried under vacuum. There was thus obtained the title compound (0.138 g) as a dihydrochloride salt; NMR Spectrum: (DMSOd6 and CF3COOD) 2.35 (m, 2H), 2.5 (m, 2H), 3.15 (m, 2H), 3.3 (m, 21), 3.55 (d, 2H), 3.8 (t, 2H), 4.05 (s, 3H), 4.35 (t, 2H), 6.1 (s, 2H), 7.0 (m, 3H), 7.4 (s, 1H), 8.2 (s, 1H), 8.85 (s, 1H); Mass Spectrum: M+H+ 439; Elemental Analysis: Found C, 52.8; H, 5.56; N, 10.68; C23H26N4O5 2HCl 0.5H2O requires C, 53.08; H, 5.62; N, 10.77%.

Reference： [1]Patent: US2004/34046,2004,A1

41
C₇H₅N₃O₂ [ No CAS ]
[ 1668-84-4 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of the compound of the previous step (13 g) in acetone (200 ml) were added triethylamine (12 ml) and ethyl chlorocarbonate (8.0 ml) under ice-cooling, and the mixture was stirred for 30 min. Then, sodium azide (5.5 g) was added to the solution under ice-cooling, and the mixture was stirred for 1 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. Toluene (160 ml) was added to the residue, and the mixture was heated under reflux for 1 hr. tert-Butanol (40 ml) was added, and the mixture was further heated under reflux for 3.5 hr. The reaction solution was concentrated, ethyl acetate was added, and the precipitate was removed by filtration. The solvent was evaporated under reduced pressure. The residue was dissolved in CHCl3 (50 ml), trifluoroacetic acid (30 ml) was added, and the mixture was stirred at room temperature for 8 hr. The reaction solution was poured into aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (13 g, 100%). NMR(300MHz, CDCl3)delta:3.57(2H, br), 5.92(2H, s), 6.30-6.36(2H, m), 6.67(1H, dd, J=7.8, 0.3Hz).

Reference： [1]Patent: EP2116538,2009,A1 .Location in patent: Page/Page column 49

42
[ 1668-84-4 ]
[ 691-45-2 ]
[ 1137557-40-4 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 1873 - 1884

43
[ 1137558-08-7 ]
[ 1668-84-4 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 1873 - 1884

44
[ 3934-20-1 ]
[ 1668-84-4 ]
[ 945396-82-7 ]

Yield	Reaction Conditions	Operation in experiment
50%	With N,N-diethyl-N-isopropylamine; In N,N-dimethyl-formamide; at 50 - 80℃; for 27h;	A mixture of 2,4-dichloropyrimidine (4.0 g, 27 mmol), 4-aminobenzodioxole (3.7 g, 27 mmol) and diethylisopropylamine (5.1 ml, 29.7 mmol) in DMF (25 ml) was stirred at 50 C. for 18 hours, then at 80 C. for 9 hours. After concentration under vacuum, the residue was partitioned between water and ethyl acetate and the precipitate was filtered, washed with water then ether and dried under vacuum. The organic layer from the filtrate was dried, evaporated and the residue purified on silica gel (10 to 50% EtOAc in petroleum ether) to give a solid, which was combined with the precipitate to provide 3.35 g of the title compound (50% yield); NMR Spectrum 6.05 (s, 2H), 6.68 (br s, 1H), 6.81 (d, 1H), 6.87 (t, 1H), 7.05 (br s, 1H), 8.15 (d, 1H), 9.83 (br s, 1H); Mass Spectrum MH+ 250.

Reference： [1]Patent: US2011/46108,2011,A1 .Location in patent: Page/Page column 76

45
[ 1668-84-4 ]
C₁₅H₁₆N₄O₄S₄ [ No CAS ]

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 6719 - 6722

46
[ 1668-84-4 ]
[ 1351624-80-0 ]

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 6719 - 6722

47
[ 1668-84-4 ]
[ 463-71-8 ]
[ 203201-49-4 ]

Yield	Reaction Conditions	Operation in experiment
91%	With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 2.5h;Inert atmosphere;	General procedure: Thiophosgene (1.2 eq.) was added dropwise to a stirred suspension of the aromatic amine (1.0 eq.) and triethylamine (2.4 eq.) in THF (35 mL / g of amine) at 0 C over a period of 30 minutes under argon. The resulting solution was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was concentrated to dryness and the residue was dissolved in EtOAc and washed with a saturated aqueous solution of NaHCO3 and dried over MgSO4. Activated charcoal was added to the reaction mixture and the suspension was filtered and concentrated to afford the isothiocyanates usually as solids which could be used without further purification or purifed by silica gel chromatography eluting with a gradient of petroleum ether and ethyl acetate.

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 6719 - 6722

48
[ 120-80-9 ]
[ 1668-84-4 ]

Reference： [1]Patent: WO2012/92880,2012,A1

49
[ 1668-84-4 ]
[ 302-17-0 ]
[ 1312163-25-9 ]

Yield	Reaction Conditions	Operation in experiment
53%	With hydrogenchloride; hydroxylamine sulfate; sodium sulfate; In water; at 60℃; for 1.5h;	oxo.o[4',5':5,6]benzo[1 ,2-bjazet-6(7H)-one To a slurry of chloral hydrate (1 .39 g, 8.4 mmol) and sodium sulfate (6.91 g, 48.7 mmol) in water (23.1 mL) was added benzo[d][1 ,3]dioxo.-4-amine (1 .0 g, 7.3 mmol), hydroxylamine sulfate (6.24 g, 38 mmol) and diluted hydrochloric acid (1 .2 N, 7.7 mL). After stirring at 60 C for 1.5 hours, the reaction mixture was kept at 25 C overnight. The brown solid was collected by filtration and washed with water. After drying under vacuum, the solid was taken up in methane sulfonic acid and the solution was heated at 45 C for 30 minutes. The mixture was cooled to 0 CC and then poured into ice (200 g). A dark red solid was precipitated and collected by filtration, dried to afford the product (635 mg, yield 53 %). H NMR (400 MHz, CDCI3) delta ppm 7.68 (br s, 1 H), 7.35-7.37 (d, 1 H, J = 8.0 Hz), 6.59-6.61 (d, 1 H. J = 8.0 Hz), 6.13 (s, 2H).

Reference： [1]Patent: WO2012/92880,2012,A1 .Location in patent: Page/Page column 62

50
[ 1668-84-4 ]
[ 4720-76-7 ]

Reference： [1]Patent: WO2012/92880,2012,A1

51
[ 1668-84-4 ]
[ 1022948-50-0 ]

Reference： [1]Patent: WO2012/92880,2012,A1

52
[ 27605-74-9 ]
[ 1668-84-4 ]
[ 1610613-56-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; at 20℃;	General procedure: To a stirred solution of 3-chloro-6-nitrobenzo[d]isothiazole 1,1-dioxide (2) 1 mmol) in THF (15 mL), triethylamine (3 mmol) and aromatic amine (1 mmol) were added. The mixture was stirred at room temperature for 4~6 h. The solvent was eliminated in vacuo and the resulting residual was recrystallised from ethyl acetate/hexane to give the title compounds in mediate to high over yield.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 2764 - 2767

53
[ 1668-84-4 ]
C₂₃H₂₈N₂O₆S [ No CAS ]

Reference： [1]Patent: WO2014/139325,2014,A1

54
[ 1668-84-4 ]
benzo[d][1,3]dioxole-4-sulfonyl chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a suspension of benzo[d][l ,3]dioxol-4-amine (800 mg, 5.84 mmol) in HC1 (30 mL) was added dropwise NaN02 (604.4 mg, 8.76 mmol) in water (2 mL) at 0C. After the the addition, the reaction mixture was stirred at 0C for 2 h. To a solution of CuCl (867.2 mg, 8.76 mmol) in CH3COOH (30 mL) was pumped S02 for 3h at 20C, and the resulting reaction mixture was added to the previous solution at r.t. Then the reaction mixture was stirred at 40C overnight. The reaction mixture was quenched by sat. NH4CI solution, and the reslting mixture was extracted with EtOAc (50 mL, twice). The combined organic phase was washed with brine, dried over anhy. Na2S04 and concentrated in vacuo to give 51B. LC-MS: m/z 221.6 (M+H)+.

Reference： [1]Patent: WO2014/139325,2014,A1 .Location in patent: Page/Page column 243

55
[ 98-98-6 ]
[ 1668-84-4 ]
C₁₃H₁₀N₂O₃ [ No CAS ]

Reference： [1]Journal of Chemical Sciences,2014,vol. 126,p. 1091 - 1105

56
[ 1668-84-4 ]
[ 499-83-2 ]
C₂₁H₁₅N₃O₆ [ No CAS ]

Reference： [1]Journal of Chemical Sciences,2014,vol. 126,p. 1091 - 1105

57
[ 1668-84-4 ]
[ 499-83-2 ]
2,6-bis((2,3-dihydroxybenzene)carbamoyl)pyridine [ No CAS ]

Reference： [1]Journal of Chemical Sciences,2014,vol. 126,p. 1091 - 1105

58
[ 1668-84-4 ]
2-hydroxy-3-(morpholinomethyl)benzaldehyde [ No CAS ]
2-((benzo[d][1,3]dioxol-4-ylimino)methyl)-6-(morpholinomethyl)phenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	In ethanol;Reflux;	General procedure: A mixture of 2-hydroxy-3-(morpholinomethyl)benzaldehyde(0.5 mmol) and mono-aromatic amines (0.5 mmol)and aromatic diamines (0.25 mmol) was refluxed in ethanol(20 mL) for 3-5 h. Then, the solvent was evaporatedunder vacuum and crude oily Schiff bases 3b-c, 5, 7, 9, 13,17a-f and solid Schiff bases were obtained. Compounds3a, 3d, 11a-b, 15a-b were filtered and washed withethanol to afford pure solid Schiff bases.

Reference： [1]Medicinal Chemistry Research,2015,vol. 24,p. 4105 - 4112

59
[ 1668-84-4 ]
[ 105-45-3 ]
[ 1137557-40-4 ]

Yield	Reaction Conditions	Operation in experiment
13%	In toluene;Reflux;	A mixture of the compound represented by the structural formula (B-1) (5.0 g, 36.5 mmol) and the compound represented by the structural formula (B-1A) (4.66 g, 40.1 mmol) in toluene (50 mL) was heated to reflux, and stirred overnight. Then, the mixture was cooled to room temperature, and toluene was removed. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate (henceforth also referred to as "EA") = 100:0 to 2:1) to give the compound represented by the structural formula (B-2), N-(2H-benzo[d]1,3-dioxolen-4-yl)-3-oxobutanamide (1.08 g, yield 13%), as red solid. 1H-NMR Spectrum (300MHz, CDCl3):delta (ppm): 9.08 (brs, 1H), 7.57-7.60 (m, 1H), 6.78-6.84 (m, 1H), 6.63-6.66 (m, 1H), 6.01 (s, 2H), 3.61 (s, 2H), 2.33 (s, 3H)

Reference： [1]Patent: EP2987787,2016,A1 .Location in patent: Paragraph 0077-0078

60
[ 1668-84-4 ]
6-(hydroxymethyl)-9-methyl-9-hydro-2H-1,3-dioxoleno[4,5-h]quinolin-8-one [ No CAS ]

Reference： [1]Patent: EP2987787,2016,A1

61
[ 1668-84-4 ]
[ 1137557-67-5 ]

Reference： [1]Patent: EP2987787,2016,A1

62
[ 1668-84-4 ]
[ 1137557-69-7 ]

Reference： [1]Patent: EP2987787,2016,A1

63
[ 1668-84-4 ]
9-methyl-8-oxo-9-hydro-2H-1,3-dioxoleno[4,5-H]quinoline-6-carboaldehyde [ No CAS ]

Reference： [1]Patent: EP2987787,2016,A1

64
[ 1668-84-4 ]
N-(4-chloropyridin-2-yl)cyclopropanecarboxamide [ No CAS ]
N-(4-((benzo[d][1,3]dioxol-4-yl)amino)pyridin-2-yl)cyclopropanecarboxamide [ No CAS ]

Reference： [1]MedChemComm,2016,vol. 7,p. 1204 - 1208

65
[ 1668-84-4 ]
12-N-p-chlorobenzylsophoridinealdehyde [ No CAS ]
N'-2,3-methylenedioxyphenyl-12N-p-chlorobenzyl sophoridinamine [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 245 - 250

66
[ 1668-84-4 ]
N-(5-nitrobenzo[d][1,3]dioxol-4-yl)acetamide [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2018,vol. 16,p. 3881 - 3884

67
[ 1668-84-4 ]
[ 108-24-7 ]
[ 1936-72-7 ]

Reference： [1]Organic and Biomolecular Chemistry,2018,vol. 16,p. 3881 - 3884

68
[ 1668-84-4 ]
[ 20035-41-0 ]
2-[(1,3-benzodioxole-4-ylimino)methyl]-3-bromo-6-methoxyphenol [ No CAS ]