127168-88-1

Basic information

• Product Name: 5-METHOXY-2,3-DIHYDRO-1H-ISOINDOLE
• Synonyms: 5-METHOXY-2,3-DIHYDRO-1H-ISOINDOLE;5-METHOXYISOINDOLINE;5-METHOXY-2,3-DIHYDRO-1H-ISOINDOL;m90100;5-METHOXYISOINDOLINE HCL;1H-Isoindole,2,3-dihydro-5-Methoxy-;5-methoxyisoindoline 5-methoxy-2,3-dihydro-1h-isoindole;2,3-Dihydro-5-methoxy-1H-isoindole
• CAS NO: 127168-88-1
• Molecular Formula: C₉H₁₁NO
• Molecular Weight: 149.19
• Product Categories: Heterocycles series
• Mol File: 127168-88-1.mol
• Article Data: 12

Chemical Properties

• Boiling Point: 254℃
• Flash Point: 95℃
• Appearance: /
• Density: 1.076
• Vapor Pressure: 0.018mmHg at 25°C
• Refractive Index: 1.546
• Storage Temp.: 2-8°C(protect from light)
• PKA: 9.56±0.20(Predicted)
• CAS DataBase Reference: 5-METHOXY-2,3-DIHYDRO-1H-ISOINDOLE(CAS DataBase Reference)
• NIST Chemistry Reference: 5-METHOXY-2,3-DIHYDRO-1H-ISOINDOLE(127168-88-1)
• EPA Substance Registry System: 5-METHOXY-2,3-DIHYDRO-1H-ISOINDOLE(127168-88-1)

Safety Data

• Hazardous Substances Data: 127168-88-1(Hazardous Substances Data)

Usage

Uses

5-Methoxyisoindoline is a reagent used in the sysnthesis of PDK inhibitors for used in targetting glucose and fat levels in type 2 diabetes. Also used in the preparation of C20’ ureas based on 20’amino-vinblastine for use against vinblastine-resistant cancer cell lines.

InChI:InChI=1/C9H11NO/c1-11-9-3-2-7-5-10-6-8(7)4-9/h2-4,10H,5-6H2,1H3

Synthetic route

4-methoxyphthalimide (50727-04-3) → 5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1)

Conditions	Yield
Stage #1: 4-methoxyphthalimide With borane-THF In tetrahydrofuran at 0℃; for 16h; Heating / reflux; Stage #2: With hydrogenchloride In tetrahydrofuran; methanol; water for 3h; Heating / reflux;	47%
Stage #1: 4-methoxyphthalimide With borane-THF In tetrahydrofuran at 0℃; for 16h; Heating / reflux; Stage #2: With hydrogenchloride In tetrahydrofuran; methanol at 0℃; for 3h; Heating / reflux;	47%
With borane In tetrahydrofuran at 0℃; for 16h; Heating / reflux;	47%

N-benzylisoindolin-5-yl methyl ether (127168-89-2) → 5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1)

Conditions	Yield
With Pd(OH)2/C; ammonium formate In methanol Reflux;
Stage #1: N-benzylisoindolin-5-yl methyl ether With hydrogen; acetic acid; palladium on carbon In methanol under 2327.23 Torr; for 23h; Stage #2: With sodium hydroxide; water In methanol

5-methoxy-2-[(4-methylphenyl)sulfonyl]isoindoline (1025424-06-9) → 5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1)

Conditions	Yield
With hydrogen bromide; phenol In propan-1-ol; water at 100℃; for 2h;

3,4-dimethylanisole (4685-47-6) → 5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1)

5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1) → 5-hydroxy-isoindoline hydrobromide

Conditions	Yield
With hydrogen bromide In water at 100℃;	95%
With hydrogen bromide In water for 16h; Heating / reflux;	93%
With hydrogen bromide In water for 16h; Heating / reflux;	93%

5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1) → 5-hydroxyisoindoline (54544-67-1)

Conditions	Yield
With hydrogen bromide at 100℃; for 2h;	80%

4-bromophenyl chloroformate (7693-44-9) + 5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1) → 4-bromophenyl 5-methoxyisoindoline-2-carboxylate (1620228-48-9)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 1h;	63%

2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)acetic acid (1620226-65-4) + 5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1) → 4-(4-(2-(5-methoxyisoindolin-2-yl)-2-oxoethyl)phenyl)phthalazin-1(2H)-one (1620222-40-3)

Conditions	Yield
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h;	59%

tert-butyl 4-((1H-indazol-5-yl)amino)-2-chloro-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate + 5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1) → tert-butyl 4-((1H-indazol-5-yl)amino)-2-(5-methoxyisoindolin-2-yl)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate

Conditions	Yield
With triethylamine In 1-methyl-pyrrolidin-2-one at 150℃; for 1h;	48.9%

2,6-Dichloropyrimidine (3934-20-1) + 5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1) → 2-(2-chloropyrimidin-4-yl)-5-methoxyisoindoline

Conditions	Yield
With sodium carbonate In ethanol at 90℃; for 12h;	47.8%

(4-bromophenyl)(2-chloropyrimidin-4-yl)amine (260046-09-1) + 5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1) → N-(4-bromophenyl)-2-(5-methoxyisoindolin-2-yl)pyrimidin-4-amine

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 90℃; for 17h;	42.9%
With N-ethyl-N,N-diisopropylamine In acetonitrile at 90℃; for 17h;	42.9%

2-chloropyrimidin-4-amine (7461-50-9) + 5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1) → 2-(5-methoxyisoindolin-2-yl)pyrimidin-4-amine

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 90℃; for 16h;	35.4%
With N-ethyl-N,N-diisopropylamine In acetonitrile at 90℃; for 16h;	35.4%

N-(2-chloro-5,6-dimethylpyrimidin-4-yl)-1H-indazol-5-amine + 5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1) → N-(2-(5-methoxyisoindolin-2-yl)-5,6-dimethylpyrimidin-4-yl)-1H-indazol-5-amine

Conditions	Yield
With potassium carbonate In acetonitrile at 90℃; for 72h;	30%
With potassium carbonate In acetonitrile at 90℃; for 72h;	30%

tert-butyl 4-((1H-indazol-5-yl)amino)-2-chloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate + 5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1) → tert-butyl 4-((1H-indazol-5-yl)amino)-2-(5-methoxyisoindolin-2-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate

Conditions	Yield
With triethylamine In 1-methyl-pyrrolidin-2-one at 150℃; for 1h;	29.6%

N-(2,5-dichloropyrimidin-4-yl)-1H-indazol-5-amine (1257302-89-8) + 5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1) → N-(5-chloro-2-(5-methoxyisoindolin-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 90℃; for 12h;	29.1%

N-(2-chloro-5-methylpyrimidin-4-yl)-1H-indazol-5-amine (1257302-90-1) + 5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1) → N-(2-(5-methoxyisoindolin-2-yl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 110℃; for 12h;	27%

N-(2-chloro-6-methylpyrimidin-4-yl)-1H-indazol-5-amine + 5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1) → N-(2-(5-methoxyisoindolin-2-yl)-6-methylpyrimidin-4-yl)-1H-indazol-5-amine

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 110℃; for 12h;	21.4%

2-chloro-N-(1H-indazol-5-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine + 5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1) → N-(1H-indazol-5-yl)-2-(5-methoxyisoindolin-2-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 90℃; for 20h;	17.2%

2-chloro-5-fluoro-N-(indazoline-5-yl)-4-pyrimidineamine (575474-16-7) + 5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1) → N-(5-fluoro-2-(5-methoxyisoindolin-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 90℃; for 12h;	12.1%

N-(1H-indazol-5-yl)-2-(methylsulfonyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine + 5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1) → N-(1H-indazol-5-yl)-2-(5-methoxyisoindolin-2-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine

Conditions	Yield
With triethylamine In 1,4-dioxane at 150℃; for 2h; Microwave irradiation; Sealed tube;	7.23%

trans-2-(1-(4-(N-tert-butoxycarbonyl)amino)cyclohexyl)acetaldehyde (215790-29-7) + 5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1) → {4-[2-(5-methoxy-1,3-dihydro-isoindol-2-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester (437650-81-2)

Conditions	Yield
With NaBH(OAc)2 In 1,2-dichloro-ethane at 20℃; for 16h;

5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1) → 5-cyano-2,3-dihydro-1H-isoindole (263888-58-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: 80 percent / aq. HBr / 2 h / 100 °C 2: 40 percent / Et3N / CH2Cl2 / 16 h / 20 °C 3: 70 percent / Et3N / CH2Cl2 / 6 h / -20 - 20 °C 4: 90 percent / Pd(PPh3)4 / dimethylformamide / 4 h / 100 °C 5: 90 percent / TFA / CH2Cl2 / 0.5 h / 40 °C View Scheme

5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1) → 5-methanesulfonyloxy-2,3-dihydro-1H-isoindole (263888-60-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: 80 percent / aq. HBr / 2 h / 100 °C 2: 40 percent / Et3N / CH2Cl2 / 16 h / 20 °C 3: 70 percent / Et3N / CH2Cl2 / 16 h / 20 °C 4: 90 percent / TFA / CH2Cl2 / 0.5 h / 40 °C View Scheme

5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1) → tert-butyl 5-hydroxyisoindoline-2-carboxylate (226070-47-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 80 percent / aq. HBr / 2 h / 100 °C 2: 40 percent / Et3N / CH2Cl2 / 16 h / 20 °C View Scheme

5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1) → tert-butyl 5-cyanoisoindoline-2-carboxylate (263888-56-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: 80 percent / aq. HBr / 2 h / 100 °C 2: 40 percent / Et3N / CH2Cl2 / 16 h / 20 °C 3: 70 percent / Et3N / CH2Cl2 / 6 h / -20 - 20 °C 4: 90 percent / Pd(PPh3)4 / dimethylformamide / 4 h / 100 °C View Scheme

5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1) → 5-methanesulfonyloxy-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (263888-59-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: 80 percent / aq. HBr / 2 h / 100 °C 2: 40 percent / Et3N / CH2Cl2 / 16 h / 20 °C 3: 70 percent / Et3N / CH2Cl2 / 16 h / 20 °C View Scheme

5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1) → 4-[2-(5-methoxy-1,3-dihydro-isoindol-2-yl)-ethyl]-cyclohexylamine (437651-98-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: NaBH(OAc)2 / 1,2-dichloro-ethane / 16 h / 20 °C 2: 90 percent / TFA / CH2Cl2 / 0.5 h / 40 °C View Scheme

5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1) → 5-trifluoromethanesulfonyloxy-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (263888-57-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: 80 percent / aq. HBr / 2 h / 100 °C 2: 40 percent / Et3N / CH2Cl2 / 16 h / 20 °C 3: 70 percent / Et3N / CH2Cl2 / 6 h / -20 - 20 °C View Scheme

5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1) → 2-[2-(4-amino-cyclohexyl)-ethyl]-2,3-dihydro-1H-isoindole-5-carbonitrile (437652-04-5)

Conditions	Yield
Multi-step reaction with 7 steps 1: 80 percent / aq. HBr / 2 h / 100 °C 2: 40 percent / Et3N / CH2Cl2 / 16 h / 20 °C 3: 70 percent / Et3N / CH2Cl2 / 6 h / -20 - 20 °C 4: 90 percent / Pd(PPh3)4 / dimethylformamide / 4 h / 100 °C 5: 90 percent / TFA / CH2Cl2 / 0.5 h / 40 °C 6: NaBH(OAc)2 / 1,2-dichloro-ethane / 16 h / 20 °C 7: 90 percent / TFA / CH2Cl2 / 0.5 h / 40 °C View Scheme

5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1) → methanesulfonic acid 2-[2-(4-amino-cyclohexyl)-ethyl]-2,3-dihydro-1H-isoindol-5-yl ester (437652-01-2)

Conditions	Yield
Multi-step reaction with 6 steps 1: 80 percent / aq. HBr / 2 h / 100 °C 2: 40 percent / Et3N / CH2Cl2 / 16 h / 20 °C 3: 70 percent / Et3N / CH2Cl2 / 16 h / 20 °C 4: 90 percent / TFA / CH2Cl2 / 0.5 h / 40 °C 5: NaBH(OAc)2 / 1,2-dichloro-ethane / 16 h / 20 °C 6: 90 percent / TFA / CH2Cl2 / 0.5 h / 40 °C View Scheme

5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1) → {4-[2-(5-cyano-1,3-dihydro-isoindol-2-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester (437651-10-0)

Conditions	Yield
Multi-step reaction with 6 steps 1: 80 percent / aq. HBr / 2 h / 100 °C 2: 40 percent / Et3N / CH2Cl2 / 16 h / 20 °C 3: 70 percent / Et3N / CH2Cl2 / 6 h / -20 - 20 °C 4: 90 percent / Pd(PPh3)4 / dimethylformamide / 4 h / 100 °C 5: 90 percent / TFA / CH2Cl2 / 0.5 h / 40 °C 6: NaBH(OAc)2 / 1,2-dichloro-ethane / 16 h / 20 °C View Scheme

5-methoxy-2,3-dihydro-1H-isoindole (127168-88-1) → methanesulfonic acid 2-[2-(4-tert-butoxycarbonylamino-cyclohexyl)-ethyl]-2,3-dihydro-1H-isoindol-5-yl ester (437650-82-3)

Conditions	Yield
Multi-step reaction with 5 steps 1: 80 percent / aq. HBr / 2 h / 100 °C 2: 40 percent / Et3N / CH2Cl2 / 16 h / 20 °C 3: 70 percent / Et3N / CH2Cl2 / 16 h / 20 °C 4: 90 percent / TFA / CH2Cl2 / 0.5 h / 40 °C 5: NaBH(OAc)2 / 1,2-dichloro-ethane / 16 h / 20 °C View Scheme

Upstream product

• 4685-47-6 3,4-dimethylanisole 
• 1025424-06-9 5-methoxy-2-[(4-methylphenyl)sulfonyl]isoindoline 
• 50727-04-3 4-methoxyphthalimide 
• 127168-89-2 N-benzylisoindolin-5-yl methyl ether 

Downstream Products

• 1233145-41-9 6-methoxy-2-methylisoindolin-5-amine 
• 1620228-48-9 4-bromophenyl 5-methoxyisoindoline-2-carboxylate 
• 1620228-49-0 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl 5-methoxyisoindoline-2-carboxylate 
• 905269-98-9 C₂₀H₂₀F₃NO₅S 
• 888724-82-1 1-(5-methoxyisoindolin-2-yl)-6-[4-(3-trifluoromethylphenyl)piperazin-1-yl]hexan-1-one 
• 508237-23-8 5-(3,4-Dimethoxybenzylamino)-2-(2-furyl)-8-(5-methoxyisoindolin-2-ylmethyl)[1,2,4]triazolo[1,5-c]pyrimidine 
• 630407-39-5 5-methoxy-2-methylisoindoline 
• 437650-82-3 methanesulfonic acid 2-[2-(4-tert-butoxycarbonylamino-cyclohexyl)-ethyl]-2,3-dihydro-1H-isoindol-5-yl ester 
• 437651-10-0 {4-[2-(5-cyano-1,3-dihydro-isoindol-2-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester 
• 437652-01-2 methanesulfonic acid 2-[2-(4-amino-cyclohexyl)-ethyl]-2,3-dihydro-1H-isoindol-5-yl ester 

Relevant articles and documents

PHARMACEUTICAL COMPOUNDS

The invention provides a compound for use in medicine, the compound being a compound of the formula (VI0) or a salt, solvate, tautomer or N-oxide thereof: wherein the bicyclic group: is selected from the structures C1, C5 and C6: wherein n is 0, 1, 2 or 3; R1 is hydrogen, hydroxy, or O—Rz; R2a is hydroxy, methoxy or O—Rz; provided that at least one of R1 and R2a is O—Rz; Rz is Lp-Rp1; SO3H; a glucuronide residue; a mono-, di- or tripeptide residue; or Lp is a bond, C═O, (C═O)O, (C═O)NRp1 or S(O)xNRp1; x is 1 or 2; Rp1 is hydrogen or a an optionally substituted C1-25 hydrocarbyl group containing 0, 1 or 2 carbocyclic rings and 0, 1, 2, 3, 4, 5 or 6 carbon-carbon multiple bonds, provided that Rp1 is not hydrogen when Lp is a bond, C═O or (C═O)O; and provided also that O—Rz does not contain an O—O moiety; and excluding compounds wherein R1 is hydroxy and R2a is methoxy; Rp2 and Rp3 are the same or different and each is a group Rp1; and R3, R4a, R8 and R10 are defined in the claims. The compounds of formula (VI0) are pro-drugs of parent compounds wherein R1 and/or R2a are hydroxy, wherein the parent compounds have Hsp90 inhibiting activity.

Arylpiperazine Derivatives and their Use as Selective Dopamine D3 Receptor Ligands

The invention concerns compounds of general formula (I), a method for preparing same, as well as their use as therapeutic agent.

PHARMACEUTICAL COMBINATIONS

The invention provides combinations comprising (or consisting essentially of) one or more ancillary compound(s) and a compound of the formula (I): or salts, tautomers, solvates and N-oxides thereof; wherein R1 is hydroxy or hydrogen; R2 is hydroxy; methoxy or hydrogen; provided that at least one of R1 and R2 is hydroxy; R3 is selected from hydrogen; halogen; cyano; optionally substituted C1-5 hydrocarbyl and optionally substituted C1-5 hydrocarbyloxy; R4 is selected from hydrogen; a group -(O)n-R7 where n is 0 or 1 and R7 is an optionally substituted acyclic C1-5 hydrocarbyl group or a monocyclic carbocyclic or heterocyclic group having 3 to 7 ring members; halogen; cyano; hydroxy; amino; and optionally substituted mono- or di-C1-5 hydrocarbyl-amino; or R3 and R4 together form a monocyclic carbocyclic or heterocyclic ring of 5 to 7 ring members; and NR5R6 forms an optionally substituted bicyclic heterocyclic group having 8 to 12 ring members of which up to 5 ring members are heteroatoms selected from oxygen, nitrogen and sulphur. The combinations have activity as Hsp90 and/or glycogen synthase kinase-3 and/or cyclin dependent kinase inhibitors.