[ CAS No. 61964-08-7 ] {[proInfo.proName]}

Name: 61964-08-7|1,3-Dihydroisobenzofuran-5-amine|97%
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Quality Control of [ 61964-08-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 61964-08-7 ]

Product Details of [ 61964-08-7 ]

CAS No. :	61964-08-7	MDL No. :	MFCD05864561
Formula :	C₈H₉NO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GKULNTLNUHOMGD-UHFFFAOYSA-N
M.W :	135.16	Pubchem ID :	12445339
Synonyms :

Calculated chemistry of [ 61964-08-7 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.25
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	39.75
TPSA :	35.25 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.8 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.49
Log Po/w (XLOGP3) :	0.46
Log Po/w (WLOGP) :	1.0
Log Po/w (MLOGP) :	0.82
Log Po/w (SILICOS-IT) :	1.82
Consensus Log Po/w :	1.12

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.41
Solubility :	5.24 mg/ml ; 0.0387 mol/l
Class :	Very soluble
Log S (Ali) :	-0.77
Solubility :	23.0 mg/ml ; 0.17 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.3
Solubility :	0.682 mg/ml ; 0.00505 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.48

Safety of [ 61964-08-7 ]

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

Application In Synthesis of [ 61964-08-7 ]

* 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 [ 61964-08-7 ]
Downstream synthetic route of [ 61964-08-7 ]

[ 61964-08-7 ] Synthesis Path-Upstream 1~2

1
[ 52771-99-0 ]
[ 61964-08-7 ]

Yield	Reaction Conditions	Operation in experiment
98%	With tin(II) chloride dihdyrate In ethanol at 70℃; for 1 h;	Step 2 The compound 8 (5.63 g, 34.1 mmol) was dissolved in ethanol (56 mL). Tin chloride dihydrate (23.1 g, 102 mmol) was added to the solution. The mixture was stirred at 70°C for 1 hour. After cooled to room temperature, water and 2 mol/L aqueous solution of sodium hydroxide were added to the reaction mixture to adjust the pH to 7. The reaction mixture was extracted with ethyl acetate. The organic layer was washed by brine. The solvent was evaporated under reduced pressure to give the crude product of the compound 9 (4.6 g, yield 98percent). ¹H-NMR (CDCl₃) δ: 3.71 (br s, 2H), 5.02 (s, 4H), 6.57 (s, 1H), 6.60 (dd, J = 7.9, 2.0 Hz, 1H), 7.01 (d, J = 7.9 Hz, 1H).

Reference： [1] Patent: EP3287443, 2018, A1, . Location in patent: Paragraph 0585; 0587
[2] Patent: US4144341, 1979, A,

2
[ 496-14-0 ]
[ 61964-08-7 ]

Reference： [1] Patent: WO2005/37796, 2005, A1, . Location in patent: Page/Page column 174
[2] Patent: WO2006/2342, 2006, A1, . Location in patent: Page/Page column 136-137
[3] Patent: EP3287443, 2018, A1,

[ 61964-08-7 ] Synthesis Path-Downstream 1~51

2
[ 496-14-0 ]
[ 61964-08-7 ]

Yield	Reaction Conditions	Operation in experiment
		Example 207 Synthesis of N- (3, 5-Bis-trifluoromethyl-benzyl)-N- (5-cyclopentylmethyl-3, 5,6, 7,8, 9- hexahydro-lH-2-oxa-5-aza-cyclohepta [f] inden-9-yl)-acetamide Stepl. Preparation of 1, 3-Dihydro-isobenzofuran-5-ylamine To a solution of 1,3-dihydro-isobenzofuran (83.2 mmol) in sulfuric acid (75 mL) cooled in an ice bath, add a solution of potassium nitrate (83.2 mmol) in sulfuric acid (25 mL) dropwise. After stirring for 30 min. pour the reaction mixture over ice and collect the resulting precipitate on a glass frit. Wash the precipitate with water (200 mL) and dry under vacuum. Dissolve the precipitate in ethanol (250 mL) and add tin chloride dihydrate (273.6 mmol). After heating at 70 C for 2 h dilute with water (200 mL), cool to room temperature and neutralize the reaction with 5 N sodium hydroxide. Extract the mixture with ethyl acetate (3 x 200 mL) and dry the organics over sodium sulfate. Remove solvent to afford the title compound as a tan solid. H NMR (CDC13, 400 MHz) 8 3.50 (bs, 2H), 5.02 (s, 4H), 6.56 (d, J = 2.4 Hz, 1H), 6.60 (dd, J = 2.4, 8.0 Hz, 1 H), 7.01 (d, J= 8. 0 Hz, 1 H).
		Example 73; Synthesis of (iSl)-(3,5-Bis-trifluoromethyl-benzyl)-(5-cyclopentylmethyl-3,5,6,7,8,9-hexahydro-lH-2-oxa-5-aza-cyclohepta[fJinden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine; Stepl; Preparation of l,3-Dihydro-isobenzofuran-5-ylamine; To a solution of 1,3-dihydro-isobenzofuran (83.2 mmol) in sulfuric acid (75 mL), cooledin an ice bath, add a solution of potassium nitrate (83.2 mmol) in sulfuric acid (25 mL)dropwise. After stirring for 30 min, pour the reaction mixture over ice and collect theresulting precipitate on a glass frit. Wash the precipitate with water (200 mL) and dryunder vacuum. Dissolve the precipitate in ethanol (250 mL) and add tin chloridedihydrate (273.6 mmol). After heating at 70 C for 2 h, dilute with water (200 mL), coolto room temperature, and neutralize the reaction with 5 N NaOH. Extract the mixturewith ethyl acetate (3 x 200 mL) and dry the organic portion over sodium sulfate. Removethe solvent in vacuo to afford the title compound as a tan solid.

Reference： [1]Patent: WO2005/37796,2005,A1 .Location in patent: Page/Page column 174
[2]Patent: WO2006/2342,2006,A1 .Location in patent: Page/Page column 136-137
[3]Patent: EP3287443,2018,A1

3
[ 61964-08-7 ]
[ 872625-34-8 ]

Yield	Reaction Conditions	Operation in experiment
	With Iodine monochloride; sodium hydrogencarbonate; In methanol; dichloromethane; for 1h;	Step 2; Preparation of 6-Iodo-l,3-dihydro-isobenzofuran-5-ylamine; Dropwise, add a 1.0 M solution of iodine monochloride (64 mmol) to a solution of <strong>[61964-08-7]1,3-dihydro-isobenzofuran-5-ylamine</strong> (64 mmol) in dichloromethane (200 mL), methanol (50mL) and sodium bicarbonate (96 mmol). After stirring for 1 h, quench the reaction withaqueous sodium metabisulfite (100 mL). Separate the organic phase and wash theaqueous with dichloromethane (2 x 100 mL). Combine the organics and dry over sodiumsulfate. Filter the reaction and remove solvent under vacuum. Chromatograph (0 - 20 %ethyl acetate/hexane) the crude mixture over silica gel to give the title compound as a tansolid.

Reference： [1]Patent: WO2006/2342,2006,A1 .Location in patent: Page/Page column 137

4
[ 52771-99-0 ]
[ 61964-08-7 ]

Yield	Reaction Conditions	Operation in experiment
98%	With tin(II) chloride dihdyrate; In ethanol; at 70℃; for 1h;	Step 2 The compound 8 (5.63 g, 34.1 mmol) was dissolved in ethanol (56 mL). Tin chloride dihydrate (23.1 g, 102 mmol) was added to the solution. The mixture was stirred at 70C for 1 hour. After cooled to room temperature, water and 2 mol/L aqueous solution of sodium hydroxide were added to the reaction mixture to adjust the pH to 7. The reaction mixture was extracted with ethyl acetate. The organic layer was washed by brine. The solvent was evaporated under reduced pressure to give the crude product of the compound 9 (4.6 g, yield 98%). 1H-NMR (CDCl3) delta: 3.71 (br s, 2H), 5.02 (s, 4H), 6.57 (s, 1H), 6.60 (dd, J = 7.9, 2.0 Hz, 1H), 7.01 (d, J = 7.9 Hz, 1H).
	palladium; In methanol;	Step B: Preparation of 5-aminophthalan The 5-nitrophthalan (19 g.) from Step A was hydrogenated in 200 ml. of methanol over 1 g. of 5% palladium on carbon for 30 minutes. The catalyst was removed by filtration and the filtrate was evaporated to dryness to give 15.1 g. of product, m.p. 102-104. Recrystallization from benzene-petroleum ether gave 5-aminophthalan, m.p. 104-105 C.

Reference： [1]Patent: EP3287443,2018,A1 .Location in patent: Paragraph 0585; 0587
[2]Patent: US4144341,1979,A

5
[ 61964-08-7 ]
C₁₉H₁₇Cl₂N₅O₅S [ No CAS ]
C₂₆H₂₂Cl₂N₆O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 3; 798 mg of the product from step 2 and 295 mg of <strong>[61964-08-7]1,3-dihydro-2-benzofuran-5-amine</strong> were heated at 65 C. for 6 hours in the presence of 15 ml of EtOH and 0.06 ml of concentrated HCl. The reaction medium was diluted with CHCl3 and water, then the pH of the aqueous phase was brought to 9 by adding a saturated NaHCO3 solution. After decanting, the organic phase was isolated, washed with water and then with a saturated NaCl solution, dried and concentrated under reduced pressure. The product was crystallized in AcOEt. 0.67 g of a yellow solid was obtained.

Reference： [1]Patent: US2007/167469,2007,A1 .Location in patent: Page/Page column 20

6
[ 61964-08-7 ]
[ 185039-48-9 ]
[ 944447-36-3 ]

Yield	Reaction Conditions	Operation in experiment
	In acetic acid; for 0.333333h;Heating / reflux;	A mixture of 0.614 g of compound of formula (II), 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one, and 0.389 g of the compound of formula (III), <strong>[61964-08-7](1,3-dihydro-5-isobenzofuranyl)amine</strong>, is heated in 10 ml of acetic acid at reflux for 20 min; the reaction medium is concentrated by half under vacuum, then taken up in a mixture of ethyl acetate and water and brought to pH 9 with a saturated NaHCO3 solution. After separating by settling, the organic phase is washed with water and then with a saturated NaCl solution, dried over sodium sulfate and then evaporated to dryness. The product is purified by flash chromatography on silica with a gradient of 0 to 50% of ethyl acetate in dichloromethane. 0.140 g of expected product is obtained in the form of a yellow solid.MH+=439.NMR: (DMSO, 200 MHz) 3.65 ppm: s: 3H, 5.00 ppm: d: 4H, 7.25 ppm: d: 1H, 7.35-7.70 ppm: m: 5H, 7.90 ppm: s: 1H, 8.80 ppm: s: 1H, 10.25 ppm: s: 1H

Reference： [1]Patent: US2009/48277,2009,A1 .Location in patent: Page/Page column 7

7
[ 61964-08-7 ]
[ 420-04-2 ]
[ 104-15-4 ]
[ 1391602-23-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	In 1,4-dioxane; for 2h;Reflux;	To a stirred mixture of 2.7 g 5.1 (1 ,3-dihydro-isobenzofuran-5-ylamine) in 40 ml dioxane was added 3.8 g p-toluenesulfonic acid and 1 g cyanamide. The reaction mixture was stirred at reflux for 2 h then at ambient temperature for 3 days. The precipitate was filtered, washed with dioxane and dried to give the compound 6.1.Yield: 6.3 g 6.1 (90% of theory) Analysis: [M+H]+ = 178
90%	In 1,4-dioxane; at 20℃; for 74h;Reflux;	To a stirred mixture of 2.7 g 5.1 (<strong>[61964-08-7]1,3-dihydro-isobenzofuran-5-ylamine</strong>) in 40 ml dioxane was added 3.8 g p-toluenesulfonic acid and 1 g cyanamide. The reaction mixture was stirred at reflux for 2 h then at ambient temperature for 3 days. The precipitate was filtered, washed with dioxane and dried to give the compound 6.1. [0188] Yield: 6.3 g 6.1 (90% of theory) Analysis: [M+H]+=178

Reference： [1]Patent: WO2012/101013,2012,A1 .Location in patent: Page/Page column 81; 82
[2]Patent: US2013/23502,2013,A1 .Location in patent: Paragraph 0186-0188

8
[ 61964-08-7 ]
[ 1403888-69-6 ]
[ 1403886-38-3 ]

Reference： [1]Patent: WO2012/143143,2012,A1

9
[ 61964-08-7 ]
[ 1403888-69-6 ]
C₂₇H₂₄N₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In 1,4-dioxane; methanol; at 140℃; for 0.0833333h;Microwave irradiation;	Example No. 147Preparation of (1, 3 -Dihydro- isobenzofuran- 5 -yl) - ( 8 -methoxy-2H- pyrazolo [3 , 4-c] quinolin-4-yl) -amine4-chloro-8-methoxy-2- (4 -methoxybenzyl) -2H-pyrazolo [3, 4- c]quinoline (0.16 mmol) and 1, 3-dihydroisobenzofuran-5-amine (2 eq.,0.3 mmol) were suspended in MeOH (dry, 3mL) in a microwave vial (2-5mL) , HC1 in dioxane (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at 140 C. The reaction mixture was evaporated and used without further purification. The residue was dissolved in TFA (3mL) . The reaction mixture was irradiated in a microwave reactor for 5 min at 140 C. The reaction mixture was concentrated and purified by semi- preparative HPLC-MS and freeze dried from water/t-BuOH 4/1. exact mass: 332.1493 g/molHPLC-MS: analytical method Brt: 1.806 min - found mass: 333.1 (m/z+H)

Reference： [1]Patent: WO2012/143143,2012,A1 .Location in patent: Page/Page column 255-256

10
[ 61964-08-7 ]
[ 1403819-61-3 ]
[ 1403819-22-6 ]

Yield	Reaction Conditions	Operation in experiment
		Example No. 304Preparation of N- (1, 3-dihydroisobenzofuran-5-yl) -5- (thiophen- 2-yl) -lH-pyrazolo [4 , 3-d] yrimidin-7-amine7-chloro-2- (4-methoxybenzyl) -5- (thiophen-2-yl) -2H- pyrazolo [4 , 3-d] pyrimidine (0.16 mmol) and 1,3- dihydroisobenzofuran-5-amine (0.3 mmol 2 eq. , ) were suspended in MeOH (dry, 3mL) in a microwave vial (2-5mL) , HCl in dioxane (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at 140C. The reaction mixture was evaporated and used without further purification. The residue was dissolved in TFA (3mL) . The reaction mixture was irradiated in a microwave reactor for 5 min at 140C. The reaction mixture was concentrated and purified by semi- preparative HPLC-MS and freeze dried from water/t-BuOH 4/1. exact mass: 335.0999 g/molHPLC-MS: analytical method Lrt: 4.61 min - found mass: 336 (m/z+H)

Reference： [1]Patent: WO2012/143144,2012,A1 .Location in patent: Page/Page column 383

11
[ 61964-08-7 ]
[ 1391598-74-5 ]

Reference： [1]Patent: US2013/23502,2013,A1

12
[ 61964-08-7 ]
[ 1391602-52-0 ]

Reference： [1]Patent: US2013/23502,2013,A1

13
[ 61964-08-7 ]
[ 106-89-8 ]
C₁₀H₁₂ClNO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ZnOTf; In N,N-dimethyl-formamide; at 20℃;	General procedure: Epichlorohydrin (0.19 mL, 2.44 mmol, 1 equiv) was dissolved in DMF (8 mL). The reaction mixture was added ZnOTf (17.7 mg, 0.05 mmol, 0.02 equiv), aromatic amine compounds (2.44 mmol, 1 equiv) and stirred at room temperature for overnight. The reaction mixture was diluted with water and extracted with ethyl acetate (EA). The organic part was washed with water and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel to give pure compounds. To a solution of pure compounds (0.70 mmol, 1 equiv) in 1.4-dioxane (2.5 mL) was added KOH (47.5 mg, 0.85 mmol, 1.2 equiv) and stirred at room temperature for overnight. The reaction mixture was diluted with water and extracted with EA. The organic part was washed with water and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatographyon silica gel to give oxirane compounds. To a solutionof 3,6-dibromo-9H-carbazole (69.5 mg, 0.21 mmol, 1 equiv) in THF(1 mL) was added NaH (9.6 mg, 0.24 mmol, 1.1 equiv) and stirred at0 C. The oxirane compound (0.26 mmol, 1.2 equiv) was added andstirred at room temperature for overnight. Thin layer chromatography(TLC) showed complete consumption of starting material. Thereaction mixture was diluted with water and extracted with EA.The organic part was washed with water and brine. The organiclayer was dried over MgSO4 and concentrated under reduced pressure. The crude was purified by column chromatography on silicagel to afford the desired product.

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 7165 - 7174

14
[ 61964-08-7 ]
C₁₀H₁₁NO₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 7165 - 7174

15
[ 61964-08-7 ]
1-(benzo[d][1,3]dioxol-5-ylamino)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 7165 - 7174

16
[ 61964-08-7 ]
[ 73183-34-3 ]
2-(1,3-dihydroisobenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tert.-butylnitrite; dibenzoyl peroxide; In acetonitrile; at 23℃; for 3h;	Example 1 Methyl 4-amino-3-chloro-6-(1,3-dihydroisobenzofuran-5-yl)-5-fluoropicolinate tert-Butyl nitrite (1.3 mL, 11 mmol, 1.5 equiv) was added to a stirred solution of benzoic peroxyanhydride (36 mg, 0.15 mmol, 0.02 equiv), diboron bis(pinoacol) ester (1.9 g, 7.4 mmol, 1.0 equiv), and <strong>[61964-08-7]1,3-dihydroisobenzofuran-5-amine</strong> (1.0 g, 7.4 mmol, 1.0 equiv) in acetonitrile (25 mL) at 23 C. The resulting homogeneous orange/brown solution was stirred at 23 C. for 3 h. Activated charcoal was added and the black mixture was gravity filtered and concentrated by rotary evaporation to afford 1.9 g dark brown oil, which appeared to be consistent with 2-(1,3-dihydroisobenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane of ?30% purity, by crude 1H NMR analysis. To the crude 2-(1,3-dihydroisobenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (estimated to be 570 mg, 2.3 mmol, 1.1 equiv) was added methyl 4-amino-3,6-dichloro-5-fluoropicolinate (500 mg, 2.1 mmol, 1.0 equiv), dichloro[bis(triphenylphosphino)]-palladium(II) (150 mg, 0.21 mmol, 0.10 equiv), and sodium carbonate (240 mg, 2.3 mmol, 1.1 equiv) followed by a 1:1 mixture of water:acetonitrile (7.0 mL) at 23 C. The resulting dark orange/brown mixture was heated to 85 C. and stirred for 4 h. The cooled reaction mixture was diluted with water (150 mL) and extracted with dichloromethane (4*70 mL). The combined organic layers were dried (magnesium sulfate), gravity filtered, and concentrated by rotary evaporation. The residue was purified by reverse phase column chromatography (5% acetonitrile to 100% acetonitrile gradient) to yield the title compound as an orange powder (150 mg, 22%): mp 153-156 C.; IR (neat film) 3468 (m), 3334 (s), 3205 (m), 2952 (m), 2856 (m), 1735 (s), 1623 (s), 1579 (w) cm-1; 1H NMR (400 MHz, CDCl3) delta 7.81-7.86 (m, 2H), 7.33 (d, J=8 Hz, 1H), 5.16 (br d, J=4 Hz, 1H), 4.89 (br s, 2H), 3.97 (s, 3H); ESIMS m/z 323 [(M+H)+].

Reference： [1]Patent: US2014/274701,2014,A1 .Location in patent: Paragraph 0283

17
[ 61964-08-7 ]
methyl 4-amino-3-chloro-6-(1,3-dihydroisobenzofuran-5-yl)-5-fluoropicolinate [ No CAS ]

Reference： [1]Patent: US2014/274701,2014,A1

18
[ 61964-08-7 ]
[ 13623-94-4 ]
C₁₁H₁₂N₂O₃S [ No CAS ]