913611-97-9

Basic information

• Product Name: Brexpiprazole
• Synonyms: 7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one;Brexpiprazole;OPC-34712;7-[4-(4-benzo[b]thien-4-yl-1-piperazinyl)butoxy]- 2(1H)-Quinolinone;7-[4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy]-1H-quinolin-2-one;7-[4-(4-(Benzo[b]thien-4-yl)-piperazin-1-yl)butoxy]-1H-quinolin-2-one;7-(4-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)butoxy)quinolin-2(1H)-one;Brexpiprazole impurity a
• CAS NO: 913611-97-9
• Molecular Formula: C₂₅H₂₇N₃O₂S
• Molecular Weight: 433.57
• EINECS: 1592732-453-0
• Product Categories: Inhibitors;Dopamine D2 receptor partial agonist;API
• Mol File: 913611-97-9.mol

Chemical Properties

• Boiling Point: 675.2±55.0 °C(Predicted)
• Appearance: /
• Density: 1.245±0.06 g/cm3(Predicted)
• Storage Temp.: Refrigerator
• Solubility: Dichloromethane (Slightly), Chloroform (Slightly), Methanol (Slightly)
• PKA: 11.22±0.70(Predicted)
• CAS DataBase Reference: Brexpiprazole(CAS DataBase Reference)
• NIST Chemistry Reference: Brexpiprazole(913611-97-9)
• EPA Substance Registry System: Brexpiprazole(913611-97-9)

Safety Data

• Hazardous Substances Data: 913611-97-9(Hazardous Substances Data)

Usage

Uses

Used in Psychiatry:
Brexpiprazole is used as an atypical antipsychotic for the treatment of schizophrenia, a chronic mental disorder characterized by delusions, hallucinations, and disorganized thinking. Its unique pharmacological profile allows for efficacy and tolerability over established treatments.
Used in Depression Treatment:
Brexpiprazole is used as an adjunctive treatment for major depressive disorder (MDD), a mood disorder characterized by persistent feelings of sadness, hopelessness, and a lack of interest in activities. It has demonstrated efficacy in improving symptoms and providing an alternative to conventional treatments.
Used in CNS Disorders:
Brexpiprazole is used as a drug candidate for the treatment and prevention of mental disorders, including central nervous system (CNS) disorders. Its multi-receptor pharmacology offers potential benefits in managing various psychiatric conditions.
Used in Cognitive Deficit Amelioration:
Brexpiprazole has shown potential in preclinical studies as a treatment to ameliorate cognitive deficits induced by phencyclidine (PCP) in mice, suggesting a possible application in improving cognitive function in certain conditions via 5-HT1A receptors.

References

https://en.wikipedia.org/wiki/Brexpiprazole https://www.drugbank.ca/drugs/DB09128 Maeda, K, et al. "Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator." Journal of Pharmacology & Experimental Therapeutics 350.3(2014):589-604. Maeda, K, et al. "Brexpiprazole II: antipsychotic-like and procognitive effects of a novel serotonin-dopamine activity modulator." Journal of Pharmacology & Experimental Therapeutics 350.3(2014):605. Yoshimi, N, et al. "Effects of brexpiprazole, a novel serotonin-dopamine activity modulator, on phencyclidine-induced cognitive deficits in mice: a role for serotonin 5-HT1A receptors. " Pharmacology Biochemistry & Behavior 124(2014):245.

Synthesis

Commercially available fluorobenzaldehyde (60) underwent a substitution reaction with commercial tert-butyl piperazine-1- carboxylate (61) under basic conditions to afford the piperazinyl benzaldehyde 62 in excellent yield. Next, the construction of the benzothiophene was affected by initial condensation of thioglycolic acid ethyl ester 63 with ochlorobenzaldehyde 62 under mildly basic conditions at elevated temperatures. Treatment with aqueous base and adjustment of pH to roughly 5 through the use of 4 N HCl furnished the 2-carboxylic acid benzothiophene 64 in 80% yield across the three-step operation. Next, decarboxylation through the use of cuprous oxide using conditions slightly modified from those originally described by Goosen followed by acidic removal of the Boc protecting group on the terminal piperazine nitrogen secured the key piperazinyl benzothiophene subunit 65 as the corresponding hydrochloride salt. The hydroxyquinolone and linker component synthesis began with alkylation of commercially available quinolone 66 with 1,4-bromochlorobutane (67) under basic conditions to furnish chloroalkoxyquinolone 68. A subsequent alkylation with hydrochloride salt 65 using potassium carbonate and warm aqueous ethanol followed by recrystallizative workup resulted in clean conversion to brexpiprazole (VIII) in 78% yield from 68.

Enzyme inhibitor

This serotonin-dopamine activity modulator, or SDAM (FW = 433.60 g/mol; CAS 913611-97-9), also known as OPC-34712, Rexulti?, 7-{4-[4-(1- benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one, is an atypical antipsychotic drug that acts as a dopamine D2L (Ki = 1.1 nM) and D3 (Ki = 0.3 nM) receptor partial agonist and a partial agonist of 5-HT1A receptors (Ki = 0.12 nM). Brexpiprazole is also an antagonist of the 5-HT2A (Ki = 0.47 nM), 5-HT2B (Ki = 1.9 nM), 5-HT7 (Ki = nM), α1B-adrenergic (Ki = 0.17 nM), α2C-adrenergic (Ki = 0.59 nM), and histamine H1 receptors (Ki = 19 nM). It has negligible affinity for the mACh receptors. Rexulti is an FDA-approved add-on medication for major depressive disorder in adults. See Aripiprazole

Synthetic route

brexpiprazole hydrochloride → Brexpiprazole (913611-97-9)

Conditions	Yield
With sodium hydroxide In ethanol; water at 20 - 80℃; for 2h;	96.1%

7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one hydrochloride → Brexpiprazole (913611-97-9)

Conditions	Yield
With potassium carbonate In dichloromethane; water for 2h;	96%
Stage #1: 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one hydrochloride In ethanol; water Reflux; Stage #2: With pyrographite In ethanol; water for 0.5h; Reflux; Stage #3: With sodium hydride In ethanol; water for 0.5h; Reflux;	3.76 kg
With pyrographite In ethanol; water for 0.5h; Reflux; Large scale;	3.76 kg

7-(4-chlorobutoxy)quinoline-2(1H)-one + 1-(benzo[b]thiophen-4-yl)piperazine hydrochloride → Brexpiprazole (913611-97-9)

Conditions	Yield
Stage #1: 1-(benzo[b]thiophen-4-yl)piperazine hydrochloride With sodium carbonate In methanol; water at 50℃; for 0.5h; Stage #2: 7-(4-chlorobutoxy)quinoline-2(1H)-one In methanol; water at 70℃; for 16h;	95.5%
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 70℃; for 10h;	84%
With potassium carbonate In ethanol; water at 40 - 50℃;	82.3%

4-chlorobenzothiophene (66490-33-3) + 7-(4-(piperazin-1-yl)butoxy)quinolin-2(1H)-one → Brexpiprazole (913611-97-9)

Conditions	Yield
With C48H55ClN2Pd; sodium t-butanolate In 1,2-dimethoxyethane at 20℃; for 16h; Inert atmosphere; Sealed tube;	95%

4-bromo-1,3-benzothiazole (767-68-0) + 7-(4-(piperazin-1-yl)butoxy)quinolin-2(1H)-one dihydrochloride → Brexpiprazole (913611-97-9)

Conditions	Yield
Stage #1: 4-bromobenzo[d]thiazole With isopropylmagnesium chloride In tetrahydrofuran at -5℃; for 2h; Stage #2: 7-(4-(piperazin-1-yl)butoxy)quinolin-2(1H)-one dihydrochloride In tetrahydrofuran for 3h;	91.5%

4-chlorobenzothiophene (66490-33-3) + 7-((4-piperazine-1-yl)butoxy)-1H-quinolin-2-one hydrochloride → Brexpiprazole (913611-97-9)

Conditions	Yield
With palladium diacetate; potassium carbonate; triphenylphosphine In 5,5-dimethyl-1,3-cyclohexadiene for 5h; Solvent; Reagent/catalyst; Inert atmosphere; Reflux;	90%

benzo[B]thiophen-4-ylamine (17402-83-4) + 7-(4-(bis-(2-chloroethyl)amino)butoxy)quinolin-2(1H)-one → Brexpiprazole (913611-97-9)

Conditions	Yield
In butan-1-ol at 25 - 125℃;	90%
With potassium carbonate; potassium iodide In 5,5-dimethyl-1,3-cyclohexadiene at 130 - 140℃;	78.5%

1-(benzo[b]thiophen-4-yl)piperazine hydrochloride + C14H17NO3 → Brexpiprazole (913611-97-9)

Conditions	Yield
With sodium carbonate In acetonitrile for 23h; Reflux;	88.3%

1-(benzo[b]thiophen-4-yl)piperazine dihydrochloride + 7–(4-bromobutoxy)quinolin-2(1H)-one (203395-59-9) → Brexpiprazole (913611-97-9)

Conditions	Yield
Stage #1: 1-(benzo[b]thiophen-4-yl)piperazine dihydrochloride With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h; Inert atmosphere; Stage #2: 7–(4-bromobutoxy)quinolin-2(1H)-one With potassium iodide In N,N-dimethyl-formamide at 100℃; for 4h; Inert atmosphere;	85%

benzo[b]thiophen-4-ylboronic acid (177735-30-7) + 7-(4-(piperazin-1-yl)butoxy)quinolin-2(1H)-one → Brexpiprazole (913611-97-9)

Conditions	Yield
With copper diacetate; triethylamine In dichloromethane at 0 - 35℃; Reagent/catalyst; Solvent; Temperature;	83.3%

C12H13Cl2NS + 7-(4-aminobutoxy)quinolin-2(1H)-one → Brexpiprazole (913611-97-9)

Conditions	Yield
With potassium carbonate; sodium iodide In N,N-dimethyl-formamide at 80℃; for 1.5h; Temperature;	83.1%

C16H21N2S(1+)*Br(1-) + 7-hydroxy-1H-quinolin-2-one (70500-72-0) → Brexpiprazole (913611-97-9)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 130 - 135℃; Reagent/catalyst; Temperature;	82%

benzo[B]thiophen-4-ylamine (17402-83-4) + ((4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)azanediyl)bis(ethane-2,1-diyl) dimethanesulfonate → Brexpiprazole (913611-97-9)

Conditions	Yield
With potassium tert-butylate In toluene at 25 - 35℃;	78.5%

4-bromobenzo[b]thiophene (5118-13-8) + 7-(4-(piperazin-1-yl)butoxy)quinolin-2(1H)-one → Brexpiprazole (913611-97-9)

Conditions	Yield
Stage #1: 7-[4-(piperazin-1-yl)butoxy]-2(1H)-quinolinone With trans-di(μ-acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II) In dichloromethane; dimethyl sulfoxide at 25 - 35℃; for 0.25h; Inert atmosphere; Stage #2: 4-bromobenzo[b]thiophene In dichloromethane; dimethyl sulfoxide at 140 - 150℃;	77.8%
With palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In 1,4-dioxane at 25 - 115℃; for 15h; Temperature; Inert atmosphere;	40 g

N-(3-{4-[4-(1-benzo[b]thiophen-4-yl)piperazin-1-yl]butoxy}phenyl)-3-phenylprop-2-enamide → Brexpiprazole (913611-97-9)

Conditions	Yield
With aluminum (III) chloride In chlorobenzene at 0 - 135℃;	70.8%
With aluminum (III) chloride In chlorobenzene at 125 - 135℃;	70.8%

7-(4-chlorobutoxy)quinoline-2(1H)-one + 1-benzo[b]thiophen-4-ylpiperazine hydrochloride → Brexpiprazole (913611-97-9)

Conditions	Yield
With 4-methyl-morpholine In ethanol; water for 10h; Reagent/catalyst; Reflux;	70.4%
Stage #1: 1-benzo[b]thiophen-4-ylpiperazine hydrochloride With potassium carbonate In N,N-dimethyl-formamide at 25 - 50℃; for 0.5h; Stage #2: 7-(4-chlorobutoxy)quinoline-2(1H)-one With potassium iodide In N,N-dimethyl-formamide at 10 - 95℃; Temperature;	63.98%
With potassium carbonate; sodium iodide In N,N-dimethyl-formamide
With potassium carbonate In ethanol; water at 80 - 85℃; for 15h; Solvent; Inert atmosphere;	987 g
With sodium carbonate In ethanol for 12h; Solvent; Reflux;

1-(benzo[b]thiophen-4-yl)piperazine hydrochloride + 4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butanal → Brexpiprazole (913611-97-9)

Conditions	Yield
With sodium acetate; sodium tris(acetoxy)borohydride In isopropyl alcohol at 65 - 68℃; for 0.666667h; Reagent/catalyst; Solvent; Temperature;	51%
Stage #1: 1-(benzo[b]thiophen-4-yl)piperazine hydrochloride; 4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butanal With sodium tris(acetoxy)borohydride In dimethyl sulfoxide at 20 - 40℃; for 1h; Stage #2: With sodium hydroxide In water; dimethyl sulfoxide at 20 - 65℃; for 2h; pH=> 10;

C25H29N3O2S*2ClH → Brexpiprazole (913611-97-9)

Conditions	Yield
With sodium persulfate; iron(III) chloride hexahydrate In water; acetonitrile at 80℃; for 24h;	35%

7-hydroxy-1H-quinolin-2-one (70500-72-0) → Brexpiprazole (913611-97-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: potassium carbonate / water; N,N-dimethyl-formamide / 0.25 h / 30 - 40 °C 1.2: 5 h / 40 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 0.5 h / 30 - 40 °C 2.2: 2 h / 90 - 100 °C View Scheme
Multi-step reaction with 3 steps 1.1: potassium hydroxide / methanol / 8 h / 10 °C / Reflux 2.1: potassium carbonate / water; ethanol / 9 h / 50 °C / Reflux 2.2: 1 h / Reflux 2.3: 1 h / 7 °C / Reflux 3.1: water; ethanol / Reflux 3.2: 0.5 h / Reflux 3.3: 0.5 h / Reflux View Scheme
Multi-step reaction with 3 steps 1.1: sodium hydroxide / ethanol / 5 h / Reflux 2.1: hydrogenchloride / methanol; water / 0.5 h / 30 °C / Cooling with ice; Large scale 2.2: 20 - 65 °C / Large scale 3.1: palladium diacetate; triphenylphosphine; potassium carbonate / 5,5-dimethyl-1,3-cyclohexadiene / 5 h / Inert atmosphere; Reflux View Scheme

4-hydroxybenzothiophene (3610-02-4) → Brexpiprazole (913611-97-9)

Conditions	Yield
Multi-step reaction with 5 steps 1: sodium hydride / toluene / 6 h / 90 - 100 °C 2: sodium hydride; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone / toluene / 3 h / 90 - 100 °C 3: hydrogenchloride / water / 3 h / 90 - 100 °C / Reflux 4: potassium carbonate / butan-1-ol / 24 h / Reflux 5: sodium carbonate / acetonitrile / 23 h / Reflux View Scheme
Multi-step reaction with 4 steps 1.1: triethylamine / dichloromethane / 1 h / 0 °C / Inert atmosphere 2.1: tris(dibenzylideneacetone)dipalladium(0) chloroform complex; XPhos; caesium carbonate / toluene / 8 h / 100 °C / Inert atmosphere 3.1: hydrogenchloride / tetrahydrofuran; water / 0 - 20 °C / Inert atmosphere 4.1: potassium carbonate / N,N-dimethyl-formamide / 0.5 h / 20 °C / Inert atmosphere 4.2: 4 h / 100 °C / Inert atmosphere View Scheme

2-(1-benzo[b]thiophen-4-yloxy)-2-methylpropanamide (62100-45-2) → Brexpiprazole (913611-97-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium hydride; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone / toluene / 3 h / 90 - 100 °C 2: hydrogenchloride / water / 3 h / 90 - 100 °C / Reflux 3: potassium carbonate / butan-1-ol / 24 h / Reflux 4: sodium carbonate / acetonitrile / 23 h / Reflux View Scheme

N-(1-benzo[b]thiophen-4-yl)-2-hydroxy-2-methylpropanamide (62100-46-3) → Brexpiprazole (913611-97-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride / water / 3 h / 90 - 100 °C / Reflux 2: potassium carbonate / butan-1-ol / 24 h / Reflux 3: sodium carbonate / acetonitrile / 23 h / Reflux View Scheme

benzo[B]thiophen-4-ylamine (17402-83-4) → Brexpiprazole (913611-97-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate / butan-1-ol / 24 h / Reflux 2: sodium carbonate / acetonitrile / 23 h / Reflux View Scheme
Multi-step reaction with 2 steps 1.1: toluene-4-sulfonamide / 5,5-dimethyl-1,3-cyclohexadiene / 16 h / 120 - 150 °C 2.1: sodium carbonate / water; methanol / 0.5 h / 50 °C 2.2: 16 h / 70 °C View Scheme
Multi-step reaction with 2 steps 1.1: sodium carbonate / butan-1-ol / 6 h / Reflux 1.2: pH 12 2.1: sodium carbonate / ethanol / 12 h / Reflux View Scheme

C13H13Cl2NO2S → Brexpiprazole (913611-97-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: copper(I) oxide / N,N-dimethyl-formamide / 2 h / 120 °C 2: sodium iodide; potassium carbonate / N,N-dimethyl-formamide / 1.5 h / 80 °C View Scheme

2-bromo-6-fluorobenzaldehyde (360575-28-6) → Brexpiprazole (913611-97-9)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: potassium carbonate / toluene / 4 h / 110 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 4 h / 20 - 100 °C 2.2: 1 h / 40 °C 3.1: lithium hydroxide monohydrate; water / methanol / 3 h / 0 - 50 °C 4.1: copper(I) oxide / N,N-dimethyl-formamide / 2 h / 120 °C 5.1: sodium iodide; potassium carbonate / N,N-dimethyl-formamide / 1.5 h / 80 °C View Scheme

C11H12BrCl2NO → Brexpiprazole (913611-97-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 4 h / 20 - 100 °C 1.2: 1 h / 40 °C 2.1: lithium hydroxide monohydrate; water / methanol / 3 h / 0 - 50 °C 3.1: copper(I) oxide / N,N-dimethyl-formamide / 2 h / 120 °C 4.1: sodium iodide; potassium carbonate / N,N-dimethyl-formamide / 1.5 h / 80 °C View Scheme

C15H17Cl2NO2S → Brexpiprazole (913611-97-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: lithium hydroxide monohydrate; water / methanol / 3 h / 0 - 50 °C 2: copper(I) oxide / N,N-dimethyl-formamide / 2 h / 120 °C 3: sodium iodide; potassium carbonate / N,N-dimethyl-formamide / 1.5 h / 80 °C View Scheme

1-benzo[b]thiophen-4-ylpiperazine hydrochloride + 7–(4-bromobutoxy)quinolin-2(1H)-one (203395-59-9) → Brexpiprazole (913611-97-9)

Conditions	Yield
With potassium carbonate; sodium iodide In acetonitrile Reflux;	21 g

7-chlorobutoxycoumarin → Brexpiprazole (913611-97-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium iodide; potassium carbonate / acetonitrile / 24 h / Reflux 2.1: ammonia / methanol / 2 h / 150 °C 2.2: 24 h / 20 °C / Inert atmosphere 3.1: bromine; sodium acetate / acetic acid; water / 24 h / 80 °C View Scheme

7-(4-(4-(benzothiophen-4-yl)piperazin-1-yl)butoxy)chroman-2-one → Brexpiprazole (913611-97-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: ammonia / methanol / 2 h / 150 °C 1.2: 24 h / 20 °C / Inert atmosphere 2.1: bromine; sodium acetate / acetic acid; water / 24 h / 80 °C View Scheme

Brexpiprazole (913611-97-9) → 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one hydrochloride

Conditions	Yield
With hydrogenchloride In ethanol; water for 1h; Reflux;	90%
With hydrogenchloride In ethanol; acetic acid at 10 - 76℃; for 1h;	800 g
With boron tribromide In methanol; dichloromethane; water
With hydrogenchloride; acetic acid In ethanol at 10℃; for 1h; Reflux;

methanol (67-56-1) + Brexpiprazole (913611-97-9) → brexpiprazole methanol

Conditions	Yield
In dichloromethane at 0 - 10℃; for 2h;	88.5%

Brexpiprazole (913611-97-9) → C16H21N2S(1+)*HO(1-)

Conditions	Yield
In water; N,N-dimethyl-formamide at 120℃; for 6h; Temperature;	84.35%

Brexpiprazole (913611-97-9) + cinnamyl methyl carbonate (85217-69-2, 87802-71-9) → C34H35N3O2S

Conditions	Yield
With bis(1,5-cyclooctadiene)diiridium(I) dichloride; O,O'-(R)-(1,1'-dinaphthyl-2,2'-diyl)-N,N'-di-(R,R)-[phenylethylphosphoramidite]; 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20℃; enantioselective reaction;	75%

Brexpiprazole (913611-97-9) + chloromethyl cyclohexyl carbonate (40510-86-9) → carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester cyclohexyl ester hydrochloride (1427049-18-0)

Conditions	Yield
Stage #1: Brexpiprazole With sodium hydride In tetrahydrofuran; mineral oil at 50℃; for 1h; Stage #2: chloromethyl cyclohexyl carbonate In tetrahydrofuran; mineral oil at 0 - 20℃; Stage #3: With hydrogenchloride In tetrahydrofuran; water; mineral oil	42%
Stage #1: Brexpiprazole With sodium hydride In tetrahydrofuran at 50℃; for 1h; Stage #2: chloromethyl cyclohexyl carbonate In tetrahydrofuran at 0 - 20℃;	42%

Brexpiprazole (913611-97-9) → 4-(1-benzothiophen-4-yl)-1-{4-[(2-oxo-1,2-dihydroquinolin-7-yl)oxy]butyl}piperazin-1-ium-1-olate + 1-(1-benzothiophen-4-yl)-4-{4-[(2-oxo-1,2-dihydroquinolin-7-yl)oxy]butyl}piperazine-1,4-diium-1,4-bis(olate)

Conditions	Yield
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 1h;	A 30% B 37%

Brexpiprazole (913611-97-9) + 2-(benzyloxy)-7-(4-chlorobutoxy)quinoline → 7-{4-[(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2-yl)oxy]butoxy}-1,2-dihydroquinolin-2-one + 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-1-{4-[(2-oxo-1,2-dihydroquinolin-7-yl)oxy]butyl}-1,2-dihydroquinolin-2-one

Conditions	Yield
Stage #1: Brexpiprazole; 2-(benzyloxy)-7-(4-chlorobutoxy)quinoline With caesium carbonate In N,N-dimethyl-formamide at 110℃; for 6h; Stage #2: With hydrogen bromide In water at 60℃; for 5h;	A 19% B 14%

Brexpiprazole (913611-97-9) + toluene-4-sulfonic acid (104-15-4) → 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one p-toluenesulphonate salt

Conditions	Yield
In methanol; dichloromethane

Brexpiprazole (913611-97-9) + maleic acid (110-16-7) → 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one maleate

Conditions	Yield
In methanol; dichloromethane

Brexpiprazole (913611-97-9) + (2E)-but-2-enedioic acid (110-17-8) → 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one fumarate

Conditions	Yield
In methanol; dichloromethane

Brexpiprazole (913611-97-9) + citric acid (77-92-9) → 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one citrate

Conditions	Yield
In methanol; dichloromethane

Brexpiprazole (913611-97-9) → 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one sulfate

Conditions	Yield
With sulfuric acid In methanol; dichloromethane

Upstream product

• 554-84-7 meta-nitrophenol 
• 31191-44-3 1-(4-bromobutyloxy)-3-nitrobenzene 
• 1677681-05-8 1-(benzo[b]thiophen-4-yl)piperazine hydrochloride 
• 1886188-97-1 7-(4-hydroxybutoxy)quinoline-2-(1H)-one 
• 5118-13-8 4-bromobenzo[b]thiophene 
• 913613-82-8 7-(4-chlorobutoxy)quinoline-2(1H)-one 
• 846038-18-4 1-benzo[b]thiophen-4-ylpiperazine hydrochloride 
• 93-35-6 7-hydroxy-2H-chromen-2-one 
• 203395-59-9 7–(4-bromobutoxy)quinolin-2(1H)-one 
• 360575-28-6 2-bromo-6-fluorobenzaldehyde 

Downstream Products

• 1427044-88-9 7-[4-(4-benzo[b]thiophene-4-ylpiperazin-1-yl)butoxy]-2-benzyloxymethoxyquinoline 
• 2094559-58-5 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butoxy)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)quinoline-2(1H)-one 
• 1427049-09-9 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2-yl cyclohexanecarboxylate 
• 1427049-06-6 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butoxy)-1-(cyclohexanecarbonyl)-3,4-dihydroquinolin-2(1H)-one 
• 1427049-03-3 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]quinolin-2-yloxymethyl phenyl carbonate 
• 1427049-18-0 carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester cyclohexyl ester hydrochloride 
• 1427049-01-1 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]quinolin-2-yloxymethyl cyclohexyl carbonate 
• 1427046-45-4 carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester 4-nitrophenyl ester 

Relevant articles and documents

Method for preparing

The invention relates to a preparation method of brexpiprazole and an intermediate thereof; the method includes the steps of carrying out a reaction of a compound represented by the formula II with 1-bromo-4-chlorobutane in a reaction solvent to obtain a compound represented by the formula III, in the presence of 2,3-dicyano-5,6-dichlorobenzoquinone, oxidizing the compound represented by the formula III into a compound represented by the formula IV, carrying out a reaction of the compound represented by the formula IV with a compound represented by the formula V to obtain brexpiprazole, then carrying out hydrochloride formation and refining, adding an alkali, and allowing brexpiprazole to drift away. The purity of brexpiprazole obtained by the method is more than 99.5%, the total yield is more than 80%, the process is simple and the cost is low.

Preparation method of brexpiprazole intermediate 7-hydroxy-1H-quinoline-2-ketone

The invention belongs to the field of chemical engineering, and particularly relates to a preparation method of a brexpiprazole intermediate 7-hydroxy-1H-quinoline-2-ketone. According to the novel method for preparing the 7-hydroxy-1H-quinoline-2-ketone, DDQ is replaced with palladium on carbon, the obtained product is high in yield, few in impurity and easy to operate, the catalyst can be recycled, a target compound is synthesized through direct catalytic dehydrogenation, and the method has green atom economy and is suitable for industrial production.

Large-steric-hindrance N-heterocyclic carbene palladium complex, preparation method and application thereof, and synthesis method of sonidegib based on large-steric-hindrance N-heterocyclic carbene palladium complex

The invention belongs to the technical field of organic synthesis and chemical catalysis, and discloses a large-steric-hindrance N-heterocyclic carbene palladium complex, a preparation method thereof,an application of the complex in efficient catalysis of a C-N coupling reaction under a room-temperature air condition, and a synthesis method of sonidegib based on the complex. According to the large-steric-hindrance N-heterocyclic carbene palladium complex, diphenyl imidazole serves as a main ligand framework, functionalized allyl serves as an auxiliary ligand, the functionalized allyl is introduced beside a metal center of a catalyst to serve as an auxiliary ligand, the catalytic activity and stability are remarkably improved, the large-steric-hindrance N-heterocyclic carbene palladium complex can be applied to efficient catalysis of a CN coupling reaction, particularly, the CN coupling reaction can be efficiently catalyzed under the room temperature condition, and the yield can reachup to 99%. The invention also provides a method for synthesizing sonidegib by taking aryl/aliphatic amine and aryl chloride as reactants and a three-step method at room temperature under the catalysisof a palladium catalytic system, the synthetic method has few steps, and the total yield can reach 74.5%.

Novel method for preparing new antipsychotic drug brexpiprazole

The invention discloses a new electrochemical preparation method of a new antipsychotic drug brexpiprazole. The preparation method specifically comprises the following steps of: preparing a key intermediate, namely -1-(benzo [b] thiophene-4-yl)-4-(4-(-3nitrophenoxy) butyl) piperazine, and carrying out electric reduction on the key intermediate to prepare 3-[4-[4-(benzo [b] thiophene-4-yl) piperazine-1y-l] butoxy] aniline; and carrying out acylation reaction with cinnamyl chloride and intramolecular Friedel-Crafts acylation reaction to prepare brexpiprazole.

Oxidative Aromatization of 3,4-Dihydroquinolin-2(1 H)-ones to Quinolin-2(1 H)-ones Using Transition-Metal-Activated Persulfate Salts

Inorganic persulfate salts were identified as efficient reagents for the oxidative aromatization of 3,4-dihydroquinolin-2(1H)-ones through the activation of readily available transition metals, such as iron and copper. The feasible protocol conforming to the requirement of green chemistry was utilized in the preparation of the key intermediate (7-(4-chlorobutoxy)quinolin-2(1H)-one 2) of brexpiprazole in 80% isolated yield on a 100 g scale, and different quinolin-2(1H)-one derivatives with various functional groups were demonstrated in 52-89% yields.

Industry-Oriented Route Evaluation and Process Optimization for the Preparation of Brexpiprazole

Efforts toward route evaluation and process optimization for the preparation of brexpiprazole (1) are described. Starting from commercially available dihydroquinolinone 11, a three-step synthesis route composed of O-alkylation, oxidation, and N-alkylation was selected for industry-oriented process development aiming to reduce side reactions and achieve better impurity profiles. The reaction conditions of the three steps were investigated, and the control strategy for the process-related impurities was established. The optimized process was validated on the kilogram scale and now is viable for commercialization, with the results of not less than 99.90% purity of 1 (by HPLC) and not more than 0.05% of persistent impurities 15 and 16.

Brexpiprazole derivative and preparation method thereof

The invention provides a brexpiprazole derivative, and a preparation method thereof. According to the chemical structure of the brexpiprazole derivative, the brexpiprazole derivative is prepared through following steps: brexpiprazole, and (HCHO) are reacted in the presence of a first alkaline catalyst to prepare N-hydroxymethyl brexpiprazole; and then N-hydroxymethyl brexpiprazole and an alkylformyl chloride compound are reacted in the presence of a second alkaline catalyst to obtain the brexpiprazole derivative. The brexpiprazole derivative is long in half life, and is capable of reducingmedicine administration frequency; and the brexpiprazole derivative prepared using the preparation method is low in impurity content and cost.

PROCESS FOR THE PREPARATION OF BREXPIPRAZOLE AND ITS INTERMEDIATES

The present invention discloses to a process for the preparation of brexpiprazole and its pharmaceutically acceptable salt. The present invention further discloses novel intermediates and process for the preparation of the novel intermediates of brexpiprazole. The invention also discloses a process for purification of brexpiprazole to reduce or eliminate impurities.

Process for preparing Brexpiprazole

The invention relates to a method for preparing Brexpiprazole with a one-pot process. 7-hydroxyl-2-quinolone reacts with added 1-bromine-4-chlorobutane in the presence of alcohol and alkali, 1-(benzo[B]thiophen-4-yl) piperazine hydrochloride and water are added for a further reaction, finally, filtration, separation and drying are performed, and Brexpiprazole is obtained. Compared with the prior art, the method has the benefits as follows: 1, the problems of insufficient reaction and difficulty in purification in the prior art are solved; 2, the operation process is simplified, and the production efficiency is greatly improved; 3, used solvents are safe, and less environment pollution is caused.

Preparation method and application of substituted quinoline-2(1H)-one compound

The invention belongs to the field of pharmaceutical chemistry and chemical synthesis, and concretely relates to a preparation method of a substituted quinoline-2(1H)-one compound. The invention provides a preparation method of the substituted quinoline-2(1H)-one compound. The preparation method performs an oxidation reaction on a compound represented by a formula I and an oxidant in a solvent toobtain a compound represented by a formula II. The preparation method has the advantages of simple method, high yield and low cost and is suitable for industrial production. The substituted quinoline-2(1H)-one represented by the formula II is an important intermediate of a variety of pharmaceutical active ingredients.