Brexpiprazole

ブレクスピプラゾール

NDA is considered filed as of September 9, 2014 (60 days after submission). The PDUFA date is July 11, 2015.

Brexpiprazole (/brɛksˈpɪprəzoʊl/ breks-pip-rə-zohl; also called OPC-34712) is a novel D2 dopamine partial agonist investigational product currently in clinical trials for the treatment of depression, schizophrenia, and attention deficit hyperactivity disorder(ADHD).^[1]Although it failed Stage 2 trials for ADHD, it has been designed to provide improved efficacy and tolerability (e.g., lessakathisia, restlessness and/or insomnia) over established adjunctive treatments for major depressive disorder (MDD).^[2]

OPC-34712 is an antidepressant and antipsychotic drug candidate awaiting approval in the U.S. for the treatment of schizophrenia and also as adjunctive treatment of major depressive disorder (MDD). The product is in phase III clinical trials for the treatment of agitation associated with Alzheimer’s disease. Phase III clinical trials are also underway for the treatment of post-traumatic stress disorder (PTSD).

brexpiprazole (pre-registration, as of April 2015), which is being developed by Otsuka and Lundbeck, useful for treating schizophrenia, agitation associated with Alzheimer’s disease, major depressive disorder and attention deficit hyperactivity disorder. Family members of the product case, WO2006112464, hold protection in EU states until 2026 and its US equivalent, US7888362, has US154 extension, expiring in 2027. Suzhou Vigonvita Life Sciences appears to be new to patenting and is the first collaborative filing from the three assignees.

Phase II clinical trials are also ongoing for use as adjunctive therapy in adults with attention deficit hyperactivity disorder (ADHD). The compound is being developed by Otsuka Pharmaceutical. In 2011, a codevelopment and commercialization agreement was signed by Lundbeck and Otsuka Pharmaceutical in Latin and North America, Australia and Europe for the treatment of psychiatric disorders.

The drug is being developed by Otsuka, and is considered to be a successor^[3] of its top-selling antipsychotic agent aripiprazole(brand names: Abilify, Aripiprex). Otsuka’s US patent on aripiprazole expired on October 20, 2014;^[4] however, due to a pediatric extension, a generic will not become available until at least April 20, 2015.^[5]

Brexpiprazole (1) , a serotonin–dopamine activity modulator, is an investigational new drug currently in phase-III clinical trials for the treatment of depression, schizophrenia, and attention deficit hyperactivity disorder.(1A) Brexpiprazole is also considered to be a possible successor to the top-selling antipsychotic agent aripiprazole.(2A)

1. 1A……….Phase II and Phase III Drugs in U.S. Development for Depression, Anxiety, Sleep Disorders, Psychosis & ADHD, 2011. http://www.neurotransmitter.net/newdrugs.html(accessed Jan 27, 2015).
2. 2A…………FDA accepts new schizophrenia drug filing, 2014.http://www.pharmafile.com/news/194878/fda-accepts-new-schizophrenia-drug-filing(accessed Jan 27, 2015).

   

   Brexpiprazole

   In the clinical program, brexpiprazole demonstrated improvement in symptoms in both schizophrenia and as adjunctive therapy in major depressive disorder (MDD)

   July 2015 is the anticipated completion timing of the FDA’s review (based on PDUFA timeline)Otsuka Pharmaceutical Co., Ltd. (Otsuka) and H. Lundbeck A/S (Lundbeck) today announced that the U.S. Food and Drug Administration (FDA) has determined that the New Drug Application (NDA) for brexpiprazole for monotherapy in adult patients with schizophrenia and for adjunctive treatment of major depressive disorder (MDD) in adult patients is sufficiently complete to allow for a substantive review, and the NDA is considered filed as of September 9, 2014 (60 days after submission). The PDUFA date is July 11, 2015.The NDA is supported by seven completed placebo-controlled clinical phase II or III studies in the proposed indications – three studies in schizophrenia and four studies with brexpiprazole as adjunctive therapy in MDD. The dossier included data from more than 6,000 participants of whom more than 5,000 received brexpiprazole.

   Brexpiprazole in adult patients with schizophreniaOne clinical phase II and two clinical phase III placebo-controlled studies have been completed using brexpiprazole in adult patients suffering from schizophrenia. Across the three studies more than 1,700 patients have been randomized.In the first pivotal phase III study randomizing approximately 625 patients, brexpiprazole 2mg/day and 4 mg/day both demonstrated greater improvement of symptoms relative to placebo as measured by change from baseline in the Positive and Negative Syndrome Scale (PANSS) Total Score at week 6 (p<0.05). Results of the key secondary endpoint supported primary results.In the second pivotal phase III study randomizing approximately 650 patients, brexpiprazole 4 mg/day again demonstrated greater improvement of symptoms relative to placebo (p<0.05) in change from baseline in the PANSS Total Score at Week 6. Brexpiprazole 2 mg/day showed numerical improvement (p>0.05) over placebo at Week 6.The results from the clinical phase II studyi were presented at the 24th Annual US Psychiatric and Mental Health Congress in November 2011. The study showed a clinically meaningful improvement from baseline measured by PANSS total score at week 6, although it did not achieve statistical separation from placeboii.In the placebo-controlled phase II and III studies, the rates of discontinuation due to adverse events were 8.1% for patients receiving brexpiprazole compared to 12.7% of patients receiving placebo; the only adverse event that occurred in more than 5% of brexpiprazole patients and more frequently than placebo was akathisia (5.8% vs. 4.5%).

   Brexpiprazole as adjunctive therapy in major depressive disorder (MDD) Four studies have been included in the dossier using brexpiprazole as adjunctive therapy for adult patients suffering from MDD who had demonstrated a consistent, inadequate response to at least two regimens of prior antidepressant treatment. Patients with MDD and an inadequate response to one to three antidepressants were enrolled and received antidepressants for 8 weeks, single blinded, in the two phase III studies. Patients with an inadequate response during this prospective phase were provided antidepressant therapy and randomized adjunctive treatment with either brexpiprazole or placebo for 6 weeks. The primary efficacy endpoint was the change in MADRS (Montgomery–Åsberg Depression Rating Scale) Total Score from baseline at week 6. MADRS is a commonly used scale to assess the range of symptoms in patients with MDD. Across the four studies, more than 3,900 patients entered the prospective phase and more than 1,800 patients were included in the randomized phase of the studies.The first pivotal phase III results were presented in a poster session at the 22nd European Psychiatry Association Congress (EPA) in March 2014. This two-arm phase III study randomized approximately 380 patients and demonstrated an improvement of symptoms with an antidepressant plus 2 mg brexpiprazole that was greater than an antidepressant plus placebo (p<0.001)The second pivotal phase III study was a three-arm study in which approximately 675 patients were randomized to treatment with an antidepressant plus either placebo, 1 mg brexpiprazole or 3 mg brexpiprazole.v Patients in both brexpiprazole treatment groups showed greater improvement in symptoms as measured by the MADRS compared to placebo (1 mg p>0.05, 3 mg p<0.05). Results of the second pivotal phase III study in MDD have not yet been published.

   The first clinical phase IIvi study randomized approximately 425 patients in four arms and was presented at the 164th Annual Meeting of the American Psychiatric Association in May 2011. Patients exhibited greater improvements than adjunctive placebo in MADRS Total score with the 1.5 (±0.5) mg/day dose of brexpiprazole after six weeks of treatment (p

   About brexpiprazole (OPC-34712)Brexpiprazole is a novel investigational psychotropic compound discovered by Otsuka and under co-development with Lundbeck. Brexpiprazole is a serotonin-dopamine activity modulator (SDAM) that acts as a partial agonist at 5-HT1A and dopamine D2 receptors at similar potency, and an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors.

Partnership with Lundbeck

In November 2011, Otsuka and Lundbeck have announced a global alliance.^[6] Lundbeck has given Otsuka an upfront payment of $200 million, and the deal includes development, regulatory and sales payments, for a potential total of $1.8 billion. Specifically for OPC-34712, Lundbeck will obtain 50% of net sales in Europe and Canada and 45% of net sales in the US from Otsuka.

The partnership has been presented by Otsuka to its investors as a good fit for several reasons:^[7]

• Geographic strategy: Otsuka in Japan, Asia, US; Lundbeck in Europe, South America and emerging markets
• Research strategy: Otsuka has knowledge in antipsychotics, Lundbeck in anti-depressant and anxiolytic.
• CNS strategy: Otsuka has a robust portfolio in next-generation CNS drugs, while Lundbeck covers a wide range of CNS conditions from Alzheimer’s to schizophrenia.
• Similar corporate culture

Clinical trials

OPC-34712 is currently in clinical trials for adjunctive treatment of MDD, adjunctive treatment of adult ADHD and schizophrenia.^[8]

Major depression

Phase II

The Phase 2 multicenter, double-blind, placebo-controlled study randomized 429 adult MDD patients who exhibited an inadequate response to one to three ADTs in the current episode. The study was designed to assess the efficacy and safety of OPC-34712 as an adjunctive treatment to standard ADT. The ADTs included in the study were desvenlafaxine, escitalopram, fluoxetine, paroxetine, sertraline, and venlafaxine.^[9]

Phase III

A new Phase III study is currently in the recruiting stage: “Study of the Safety and Efficacy of Two Fixed Doses of OPC-34712 as Adjunctive Therapy in the Treatment of Adults With Major Depressive Disorder (the Polaris Trial)”.^[10] Its goal is “to compare the effect of OPC-34712 to the effect of placebo (an inactive substance) as add on treatment to an assigned FDA approved antidepressant treatment (ADT) in patients with Major Depressive Disorder who demonstrate an incomplete response to a prospective trial of the same assigned FDA approved ADT”. Estimated enrollment is 1250 volunteers.

Brexpiprazole, code: OPC-34712) is Otsuka Pharmaceutical Co., Ltd. developed a new generation of anti-psychotic drug candidates, and its role in multiple receptors, dopamine D2 receptor partial agonist (improving positive and negative symptoms, cognitive impairment and depressive symptoms), 5-HT2A receptor antagonist (improving negative symptoms, cognitive dysfunction, symptoms of depression, insomnia), α1 adrenoceptor antagonists (improving positive symptoms of schizophrenia), 5 – serotonin uptake / reuptake inhibitors (improve depressive symptoms); at the same time, but also a 5-HT1A partial agonist (anxiolytic and antidepressant activity) and 5-HT7 antagonist (temperature, circadian rhythms, learning and memory, sleep) . Currently, in the United States and Europe as adjuvant treatment of severe depression (MDD) Phase III clinical trial; III clinical trial for the treatment of schizophrenia in the United States, Europe and Japan, meanwhile, is still the United States Phase II adult ADHD Clinical Trials.

Adult ADHD

Phase II

• Study of the Safety and Efficacy of OPC-34712 as a Complementary Therapy in the Treatment of Adult Attention Deficit/Hyperactivity Disorder (STEP-A)^[11] The company did not move the product to Phase III, and it is presumed this drug failed Phase II trials for the disorder.

Schizophrenia

Phase I

• Trial to Evaluate the Effects of OPC-34712 on QT/QTc in Subjects With Schizophrenia or Schizoaffective Disorder^[12]

Phase II

• A Dose-finding Trial of OPC-34712 in Patients With Schizophrenia^[13]

Phase III

• Efficacy Study of OPC-34712 in Adults With Acute Schizophrenia (BEACON)^[14]
• Safety and Tolerability Study of Oral OPC-34712 as Maintenance Treatment in Adults With Schizophrenia (ZENITH)^[15]
• Study of the Effectiveness of Three Different Doses of OPC-34712 in the Treatment of Adults With Acute Schizophrenia (VECTOR)^[16]
• A Long-term Trial of OPC-34712 in Patients With Schizophrenia^[17]

Conferences

• Phase II results were presented at the American Psychiatric Association’s 2011 annual meeting in May 2011.^[18]

• The drug has been presented at the 2nd Congress of Asian College of Neuropsychopharmacology^[19] in September 2011.

• At the US Psychiatric and Mental Health Congress in November 2011 in Vegas, Robert McQuade presented the Phase II Trial results for Schizophrenia^[20]

 Pharmacology

Brexpiprazole acts as a partial agonist of the 5-HT_1A, D₂, and D₃ receptors, and as an antagonist of the 5-HT_2A, 5-HT_2B, 5-HT₇, α_1A–, α_1B–, α_1D–, and α_2C-adrenergic, and H₁receptors.^[22] It has negligible affinity for the mACh receptors.^[22]

Patents

• U.S. Patent 8,071,600
• WIPO PCT/JP2006/317704
• Canadian patent: 2620688^[24]
• WO 2013162046
• WO 2013161830
•  WO 2013162048
• WO 2013015456
• JP 2008115172
• WO 2006112464
• WO2015054976 NEW

Reaction Scheme 2:

Synthesis

WO 2013015456

IN THIS BELOW PIC WE SEE

click on pics below to view

Synthesis of A

1 BROMO 4 CHLORO BUTANE WAS REACTED WITH 7 HYDROXY 1H QUINOLINE -2-ONE TO GIVE A

7 ( 4 CHLORO BUTOXY)-1H -QUINOLINE-2-ONE, WHICH WILL BE USED FOR COUPLING AT LAST STAGE

1 BROMO 4 CHLORO BUTANE

IN THE BELOW PIC  2,6-Dichlorobenzaldehyde AND RHODANINE WERE REACTED TO GIVE 2,6-dichlorobenzylidenerhodanine.

2,6-Dichlorobenzaldehyde

RHODANINE

NEXT WAS
2,6-dichlorobenzylidenerhodanine, GAVE (Z)-3-(2,6-dichlorophenyl)-2-mercapto-2-propenoic acid.

1H-NMR (DMSO-d6) d
ppm; 7.23-7.67 (4H, m), 3.5-5.7 (1H, br.), 11.7-14.5 (1H, br.).

Next was prepration of K salt

(Z)-3-(2,6-dichlorophenyl-2-mercapto-2-propenoic acid and  potassium hydroxide gave ((Z)-3-(2,6-dichlorophenyl-2-mercapto-2-propenoic acid potassium salt).

Next stage

((Z)-3-(2,6-dichlorophenyl-2-mercapto-2-propenoic acid potassium
salt) GAVE  2-carboxy-4-chlorobenzo[b]thiophene.
Yield: 48.8 g. 1H-NMR (DMSO-d6) d ppm; 7.53 (1H, t, J = 7.7 Hz), 7.58 (1H, dd, J = 7.7, 1.3
Hz), 8.03 (1H, d, J = 0.5 Hz), 8.07 (1H, d, J = 7.6 Hz).

NEXT IS DECARBOXYLATION

A mixture of 2-carboxy-4-chlorobenzo[b]thiophene, 1,3-dimethyl-2-imidazolidinone, and 1,8-
diazabicyclo[5.4.0]-undec-7-ene GAVE  compound. 4-chlorobenzo[b]thiophene.  1H-NMR (DMSO-d6) d ppm; 7.38 (1H, t, J = 8.4
Hz), 7.51 (1H, dd, J = 5.5, 0.8 Hz), 7.48 (1H, dd, J = 7.7, 0.9 Hz), 7.94 (1H, dd, J = 5.5, 0.4
Hz), 8.02 (1H, dt, J = 8.0, 0.9 Hz).

BETTER REPRESENTATION OF ABOVE PIC

CLIPS FROM PATENT

Synthesis of 2,6-dichlorobenzylidenerhodanine

2,6-Dichlorobenzaldehyde (77.0 g) , rhodanine (58.6 g) , and acetic acid (539 ml) were suspended with stirring at room temperature. Anhydrous sodium acetate (116 g) was added to the suspension, and the resulting mixture was heated under reflux for 3 hours. The reaction mixture was cooled to 45°C, and ice water (700 ml) was added. After the mixture was stirred for 0.2 hours, the precipitated crystals were collected by filtration, washed with water, and then dried to obtain 2,6- dichlorobenzylidenerhodanine. Even in non-dried form, this product could be subjected to the subsequent step.

Yield: 125.4 g^- MR (CDC1₃) 6ppm;7.30-7.44 (3H, m) , 7.70 (1H. s), 9.6 (1H, br.).

Reference Example 3

• Synthesis of (Z)-3-(2,6-dichlorophenyl)-2-mercapto-2-propenoic acid

A suspension of 2,6- dichlorobenzylidenerhodanine (160.4 g) and water (800 ml) was stirred at room temperature, and sodium hydroxide (83.0 g) was added over a period of 1 hour. The resulting mixture was heated with stirring for another 0.5 hours. The reaction mixture was cooled with ice (10°C), and concentrated hydrochloric acid (192 ml) was added. After the mixture was stirred while cooling with ice for 0.5 hours, the precipitated crystals were collected by filtration. The crystals obtained by filtration were washed with water and then dried to obtain an equivalent amount of (Z)-3-(2,6-dichlorophenyl)-2-mercapto-2- propenoic acid.

Yield: 138.9 g l-NMR (DMSO-de) δρρπΐ;7.23-7.67 (4H, m) , 3.5-5.7 (1H, br.), 11.7-14.5 (1H, br.).

Reference Example 4

• Synthesis of 2-carboxy-4-chlorobenzo[b] thiophene

A suspension of (Z)-3-(2,6-dichlorophenyl-2-mercapto-2- propenoic acid (72.4 g) and water (362 ml) was stirred at room temperature. Further, potassium hydroxide (40.8 g) was added, and the mixture was heated under reflux for 4 hours . After the mixture was allowed to cool, the mixture was stirred for 1 hour while cooling with ice. The precipitated crystals ((Z)-3-(2,6- dichlorophenyl-2-mercapto-2-propenoic acid potassium salt) were collected by filtration and washed with cold water. After the crystals were suspended in water, 35% concentrated hydrochloric acid (32 ml) was added (pH = 1), and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration and dried to obtain 2-carboxy-4- chlorobenzo[b] thiophene.

Yield of 48.8 g ^- MRiDMSO-de) 6ppm; 7.53 (1H, t, J = 7.7 Hz), 7.58 (1H, dd, J = 7.7, 1.3 Hz), 8.03 (1H, d, J = 0.5 Hz), 8.07 (1H, d, J = 7.6 Hz).

Reference Example 5

• Synthesis of K salt  4-chlorobenzo[b] thiophen-2-carboxylate

Reference Example 6

· Synthesis of 2-carboxy-4-chlorobenzo[b]thiophene

Sodium 4-chlorobenzo[b] thiophen-2-carboxylate (2.40 g) was dissolved in water (33 ml) at 60°C. Concentrated hydrochloric acid (1.3 ml) was added to the solution at the same temperature, and the resulting mixture was stirred. The precipitated crystals were collected by filtration, washed with water, and then dried to obtain 2-carboxy-4-chlorobenzo[b] thiophene.

Yield: 1.61 g ^- MR (DMS0-d₆);7.53 (1H, t, J = 7.7 Hz), 7.58 (1H, dd, J = 7.7, 1.3 Hz), 8.03 (1H, d, J = 0.5 Hz), 8.07 (1H, d, J = 7.6 Hz).

Elaborate description

IN THIS BELOW PIC WE SEE

Synthesis of 4-(1-piperazinyl)benzo[b]thiophene

4-Chlorobenzo[b]thiophene and xylene , Subsequently, piperazine, sodium tert-butoxide, palladium acetate (II), and 2-dicyclohexylphosphino-2′,6′-di-iso-propoxy-1,1′-biphenyl (RuPhos) …… producing 4-(1-piperazinyl)benzo[b]thiophene.

NEXT IS PREPARATION OF HYDROCHLORIDE

4-(1-piperazinyl)benzo[b]thiophene hydrochloride. 1H-NMR (DMSO-d6) d ppm;
3.30 (4H, br.s), 3.61 (4H, br.s), 6.97 (1H, d, J = 7.8 Hz), 7.32 (1H, br. dd, J = 8.4, 7.8 Hz),
7.53 (1H, d, J = 5.6 Hz), 7.70 (1H, d, J = 8.4 Hz), 7.76 (1H, d, J = 5.6 Hz), 9.37 (1H, br.s).

NEXT  IS REACTION WITH A TO GIVE BREXPIPRAZOLE

1-benzo[b]thiophen-4-yl-piperazine hydrochloride, potassium carbonate
and DMF  and  7-(4-chlorobutoxy)-1H-quinolin-2-one A  FROM PIC 1 and potassium iodide  GAVE BREXPIPRAZOLE, ie 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one.

1H-NMR (DMSO-d6) d ppm; 1.6-1.75 (2H, m), 1.75-1.9 (2H, m), 2.44
(2H, t, J = 7.0 Hz), 2.55-2.70 (4H, m), 3.00-3.15 (4H, m), 4.06 (2H, t, J = 6.3 Hz), 6.30 (1H,
d, J = 9.5 Hz), 6.75-6.85 (2H, m), 6.88 (1H, d, J = 7.5 Hz), 7.27 (1H, dd, J = 8 Hz, 8 Hz),
7.40 (1H, d, J = 5.5 Hz), 7.55 (1H, d, J = 9.5 Hz), 7.61 (1H, d, J = 8 Hz), 7.69 (1H, d, J = 5.5
Hz), 7.80 (1H, d, J = 9.5 Hz), 11.58 (1H, bs).

BETTER REPRESENTATION OF  PIC

Example 2

• Synthesis of 4- (l-piperazinyl)benzo[b]thiophene hydrochloride

4-Chlorobenzo[b] thiophene (5.00 g), piperazine (5.11 g) , palladium acetate (II) (2.7 mg), tri-tert-butylphosphonium

tetraphenylborate (6.2 mg), sodium tert-butoxide (8.548 g), and xylene (70 ml) were stirred at 120 to 130°C for 5 hours. After the reaction mixture was cooled to room temperature, water was added thereto, and the layers were separated. The xylene layer was washed with water, and then with saline. After addition of activated carbon, the mixture was stirred at room temperature for 30 minutes. After filtration of the mixture, concentrated

hydrochloric acid was added to the filtrate, and the resulting mixture was stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration and dried to obtain 4- ( l-piperazinyl)benzo[b] thiophene hydrochloride.

Yield: 6.94 g !H-NMRiDMSO-de) 6ppm; 3.30 (4H, br.s), 3.61 (4H, br.s), 6.97 (1H, d, J= 7.8 Hz), 7.32 (1H, br.dd, J= 8.4. 7.8 Hz), 7.53 (1H, d, J= 5.6 Hz), 7.70 (1H, d, J= 8.4 Hz), 7.76 (1H, d, J= 5.6 Hz), 9.37 (1H, br.s).

Example 3

• Synthesis of 4- ( 1-piperazinyl)benzo[b] thiophene hydrochloride

4-Chlorobenzo[b] thiophene (10.0 g) and xylene (100 ml) were placed in a reaction vessel. The reaction vessel was

evacuated and then purged with argon. Subsequently, piperazine (15.3 g) , sodium tert-butoxide (17.1 g) , palladium acetate (II) (13.0 mg) , and 2-dicyclohexylphosphino-2′,6′-di-iso-propoxy-1,1′- biphenyl (RuPhos) (69.0 mg) were added. After evacuation and purging with argon, the mixture was refluxed for 2 hours. After the reaction mixture was cooled to about 80°C, water (50 ml) and silica #600H (0.65 g) were added. The mixture was stirred at approximately 60°C for about 10 minutes, and then filtered. After the filtrate was separated into layers, the xylene layer was washed with water. Subsequently, the xylene layer was placed into the reaction vessel again. After addition of water (200 ml) and concentrated hydrochloric acid (8.0 ml) , the mixture was heated with stirring for dissolution. The layers were separated at 75°C or more. After the aqueous layer was collected, toluene (150 ml) and 25% aqueous sodium hydroxide solution (16 ml) were added, and the mixture was stirred. The layers were separated, and the organic layer was collected. The organic layer was washed with water and concentrated with an evaporator. Methanol (150 ml) was added to the concentrated oil to dissolve the oil, thus producing a methanol solution. 2-Propanol (150 ml) and concentrated

hydrochloric acid (7 ml) were placed into another reaction vessel, and the methanol solution was added dropwise over a period of 15 minutes or more. After completion of the dropwise addition, the mixture was cooled and stirred at 10°C or less for about 30 minutes, and then filtered (washed with a mixture of 5 ml of methanol and 5 ml of 2-propanol) . The crystals were collected, and then dried to obtain 4-(l-piperazinyl)benzo[b]thiophene hydrochloride.

Yield: 11.61 g

^-NMRfDMSO-de) oppm;

3.25-3.40 (8H, br.s), 6.96 (1H, d, J = 7.5 Hz), 7.32 (1H, dd, J = 8.0, 7.5 Hz), 7.52 (1H, d, J = 5.5 Hz ) . 7.70 (1H, d, J = 8.0 Hz), 7.75 (1H, d, J = 5.5 Hz), 9.35 (1H, br.s).

Reference Example 9

· Synthesis of 7- ( 4-chlorobutoxy) -lH-quinolin-2-one

After 7-hydroxy-lH-quinolin-2-one (10 g) and DMF (50 ml) were heated to approximately 30°C, an aqueous potassium carbonate solution (potassium carbonate: 8.6 g, water: 10 ml) was added. After the mixture was stirred at 30 to 40°C for about 15 minutes, l-bromo-4-chlorobutane (14.3 ml) was added and stirred at approximately 40°C for 5 hours. Water (100 ml) was added dropwise over a period of 30 minutes or more while the

temperature was maintained at 30°C or more. After the mixture was stirred at approximately 30°C for 30 minutes, stirring was continued at 10°C or less for 1 hour, after which the precipitated crystals were collected by filtration. After methanol (100 ml) was added to the precipitated crystals, the mixture was stirred under reflux to ensure dissolution. This solution was cooled and stirred at 30 to 40°C for 30 minutes and then at 5°C or less for about 1 hour, after which the precipitated crystals were

collected by filtration. The crystals were dried at 60°C to obtain 7- (4-chlorobutoxy) -lH-quinolin-2-one as white powder.

Yield: 12.3 g

^I-NMR (300 MHz; CDC1₃) oppm; 1.95-2.05 (4H, m) , 3.64 (2H, t, J = 6.0Hz), 4.10 (2H, t. J = 5.5 Hz), 6.56 (1H, d, J = 9.5 Hz), 6.80 (1H. dd, J = 9.0 Hz, 2.5 Hz), 6.84 (1H, d, J = 2.5 Hz), 7.45 (1H, d, J = 9.0 Hz), 7.73 (1H, d, J = 9.5 Hz), 12.45 (1H, brs).

Example 4

· Synthesis of 7- [4- (4-benzo[b]thiophen-4-yl-piperazin-l- yl)butoxy] -lH-quinolin-2-one

After 1-benzo[b] thiophen-4-yl-piperazine hydrochloride (10.6 g), potassium carbonate (5.8 g) , and DMF (50 ml) were stirred at 30 to 40°C for about 30 minutes, 7-(4-chlorobutoxy) -1H- quinolin-2-one (10.0 g) and potassium iodide (6.9 g) were added. The mixture was stirred at 90 to 100°C for 2 hours. While the temperature of the mixture was maintained at 60°C or more, water (150 ml) was added dropwise over a period of 10 minutes or more.

After the mixture was cooled to 10°C or less, the precipitated crystals were collected by filtration, and washed with water and then with ethanol.

After ethanol (325 ml) and acetic acid (25 ml) were added to the precipitated crystals, the mixture was stirred under reflux for dissolution. Concentrated hydrochloric acid (3.6 ml) was added at around 70°C, and the mixture was cooled. After confirming the precipitation of crystals, the mixture was heated again and stirred under reflux for 1 hour. After the mixture was cooled to 10°C or less, the precipitated crystals were collected by filtration and washed with ethanol.

After ethanol (191 ml) and water (127 ml) were added to the precipitated crystals, the mixture was stirred under reflux for dissolution. After activated carbon (0.89 g) was added, the mixture was stirred under reflux for 30 minutes and then hot filtered. After activated carbon was removed, the mixture was heated again for dissolution. After 25% aqueous sodium hydroxide solution (5.8 ml) was added at approximately 70°C, the mixture was stirred under reflux for 30 minutes, after which water (64 ml) was added at approximately 70°C. After the mixture was stirred at 40°C for 30 minutes, the precipitated crystals were collected by filtration at 40°C or less, then washed with water, and dried to obtain 7- [4-(4-benzo[b]thiophen-4-yl-piperazin-l-yl)butoxy] -1H- quinolin-2-one as white crystals.

Yield: 14.30 g ^-NMRfDMSO-de) 6ppm; 1.6-1.75 (2H, m) . 1.75-1.9 (2H, m) , 2.44 (2H, t, J = 7.0 Hz),2.55-2.70 (4H, m) , 3.00-3.15 (4H, m) , 4.06 (2H, t, J = 6.3 Hz), 6.30 (1H, d, J = 9.5 Hz), 6.75-6.85 (2H, m) , 6.88 (1H, d, J = 7.5 Hz), 7.27 (1H, dd, J = 8 Hz, 8 Hz), 7.40 (1H, d, J = 5.5 Hz), 7.55 (1H, d, J = 9.5 Hz), 7.61 (1H, d, J = 8 Hz), 7.69 (1H, d, J = 5.5 Hz), 7.80 (1H, d, J = 9.5 Hz), 11.58 (1H, bs) .

SEE  http://www.molbase.com/en/index.html

IH NMR PREDICT

13 C NMR PREDICT

Patent

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=D842B4D68D66F641E505E9690CF876D0.wapp2nB?docId=WO2015054976&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

Wherein, X is fluorine, chlorine, bromine or iodine; R ₁ as defined above, with a compound of formula I as defined for the same;

Reaction Scheme 5:

Wherein, X is fluorine, chlorine, bromine or iodine; R ₁ is the same as defined in the compounds shown above, and R are as defined for formula I. The present invention also provides processes for preparing key intermediates Bray prazosin/  Brexpiprazole or a salt thereof, the method as shown in Scheme 6:

Scheme 6:

PAPER

Figure 1. Brexpiprazole (1) and intermediate 18.

2-Chloro-6-fluorobenzaldehyde was converted to 4-(1-piperazinyl)benzo[b]thiophene dihydrochloride (18), an intermediate in the synthesis of brexpiprazole, via a five-step sequence in 54% overall yield. This procedure requires no expensive catalyst and avoids the side products produced in the coupling step in the reported process. Several kilograms of compound 18 were prepared using this economical and scalable process.

1-(Benzo[b]thiophen-4-yl)piperazine Dihydrochloride (18)

Compound 10 (1.5 kg, 4.71 mol) was dissolved in ………………..DELETED…………………, and then dried to give compound 18 (1.17 kg, 85% yield). HPLC for compound 18 (t_R = 6.3 min, identical to authentic sample) 99.8% purity; HPLC method B.

18:

¹H NMR (400 MHz, DMSO-d₆) δ 11.86 (s, 1H), 9.65 (s, 2H), 7.75 (d, J = 5.5 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 5.5 Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 3.30 (s, 8H).

¹³C NMR (100 MHz, DMSO-d₆): δ 146.92, 140.62, 133.40, 126.50, 125.06, 121.91, 117.73, 112.56, 48.52, 43.00.

MS (ESI, eV): m/z = 219.1 [M + H]⁺.

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PATENT

http://www.google.com/patents/US20140187782

A 4-(1-piperazinyl)benzo[b]thiophene compound represented by Formula (1):

is useful for various medicines such as antipsychotic drugs. Moreover, a 4-(1-piperazinyl)benzo[b]thiophene compound represented by Formula (4):

wherein R¹ is a hydrogen atom or a protecting group, is useful as an intermediate for synthesizing the compound represented by Formula (1).

Reference Example 30 and Example 1 of PTL 1 specifically disclose a method for producing a benzo[b]thiophene compound (the reaction scheme shown below). In Reference Example 30, 4-(1-piperazinyl)benzo[b]thiophene is produced by heating under reflux a mixture comprising 14.4 g of 4-bromobenzo[b]thiophene, 29.8 g of anhydrous piperazine, 9.3 g of sodium tert-butoxide, 0.65 g of (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), 0.63 g of tris(dibenzylideneacetone)dipalladium (0), and 250 ml of toluene (step X).

However, the reaction of the step X produces a relatively large amount of by-products that can hardly be separated, and the purity of the compound (4a) is thus inevitably reduced. Moreover, although column purification is performed to increase the purity of the compound (4a), it is very difficult to completely remove by-products, even by column chromatography purification. For this reason, there is a demand for the development of a novel method for producing the compound (4a) with high yield and high purity.

Furthermore, by-products contained in the compound (4a) inevitably reduce the purity of the compound (1) in the subsequent step Y. Since the method described in PTL 1 requires purification by column chromatography to obtain the target compound (1) with high purity, the method is not suitable for the industrial process of mass production. In addition, according to the method, incorporation of by-products that can hardly be separated is inevitable, and high-purity products usable as active pharmaceutical ingredients cannot be produced without purification by column chromatography.

CITATION LISTPatent Literature

• PTL 1: Japanese Unexamined Patent Publication No. 2006-316052 Non Patent Literature
• NPL 1: Tetrahedron Lett., 2004, 45, 9645

Example 4

Synthesis of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one

After 1-benzo[b]thiophen-4-yl-piperazine hydrochloride (10.6 g), potassium carbonate (5.8 g), and DMF (50 ml) were stirred at 30 to 40° C. for about 30 minutes, 7-(4-chlorobutoxy)-1H-quinolin-2-one (10.0 g) and potassium iodide (6.9 g) were added. The mixture was stirred at 90 to 100° C. for 2 hours. While the temperature of the mixture was maintained at 60° C. or more, water (150 ml) was added dropwise over a period of 10 minutes or more. After the mixture was cooled to 10° C. or less, the precipitated crystals were collected by filtration, and washed with water and then with ethanol.

After ethanol (325 ml) and acetic acid (25 ml) were added to the precipitated crystals, the mixture was stirred under reflux for dissolution. Concentrated hydrochloric acid (3.6 ml) was added at around 70° C., and the mixture was cooled. After confirming the precipitation of crystals, the mixture was heated again and stirred under reflux for 1 hour. After the mixture was cooled to 10° C. or less, the precipitated crystals were collected by filtration and washed with ethanol.

After ethanol (191 ml) and water (127 ml) were added to the precipitated crystals, the mixture was stirred under reflux for dissolution. After activated carbon (0.89 g) was added, the mixture was stirred under reflux for 30 minutes and then hot filtered. After activated carbon was removed, the mixture was heated again for dissolution. After 25% aqueous sodium hydroxide solution (5.8 ml) was added at approximately 70° C., the mixture was stirred under reflux for 30 minutes, after which water (64 ml) was added at approximately 70° C. After the mixture was stirred at 40° C. for 30 minutes, the precipitated crystals were collected by filtration at 40° C. or less, then washed with water, and dried to obtain 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one as white crystals.

Yield: 14.30 g

¹H-NMR (DMSO-d₆) δ ppm;

1.6-1.75 (2H, m), 1.75-1.9 (2H, m), 2.44 (2H, t, J=7.0 Hz), 2.55-2.70 (4H, m), 3.00-3.15 (4H, m), 4.06 (2H, t, J=6.3 Hz), 6.30 (1H, d, J=9.5 Hz), 6.75-6.85 (2H, m), 6.88 (1H, d, J=7.5 Hz), 7.27 (1H, dd, J=8 Hz, 8 Hz), 7.40 (1H, d, J=5.5 Hz), 7.55 (1H, d, J=9.5 Hz), 7.61 (1H, d, J=8 Hz), 7.69 (1H, d, J=5.5 Hz), 7.80 (1H, d, J=9.5 Hz), 11.58 (1H, bs).

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PATENT

http://www.google.com/patents/WO2006112464A1?cl=en

Example 1

Preparation of 7- [4- (4-benzo [b] thiophen-4-yl- piperazin-1-yl) butoxy] -lH-quinolin-2-one

A mixture of 9.0 g of 7- ( 4-chlorobutoxy) -IH- quinolin-2-one, 10 g of 1-benzo [b] thiophene-4-yl- piperazine hydrochloride, 14 g of potassium carbonate, 6 g of sodium iodide and 90 ml of dimethylformamide was stirred for 2 hours at 😯⁰C. Water was added to the reaction solution and precipitated crystals were separated by filtration. The crystals were dissolved in a mixed solvent of dichloromethane and methanol, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane .-methanol = 100:3). Recrystallized from ethanol, 13.6 g of 7- [4- (4-benzo [b] thiophen-4-yl- piperazin-1-yl) butoxy] -lH-quinolin-2-one in the form of a white powder was obtained.

Melting point 183.5-184.5⁰C

¹H-NMR ( DMSO-dg) δppm:

1.6-1.75 (2H, m) , 1.75-1.9(2H, m) , 2.44(2H, t, J=7Hz) , 2.5-2.8(4H, m) , 2.9-3.2(4H, m) , 4.06(2H, t, J=6.5Hz), 6.3O(1H, d, J=9.5Hz), 6.75-6.85 (2H, m) , 6.88(1H, d, J=7.5Hz), 7.27 (IH, dd, J=8Hz, 8Hz), 7.40 (IH, d, J=5.5Hz), 7.55 (IH, d, J=9.5Hz), 7.61(1H, d, J=8Hz) , 7.69(1H, d, J=5.5Hz), 7.8O(1H, d, J=9.5Hz), 11.59(1H, bs) .

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PATENT

7- [ 4- ( 4-benzo[b]thiophen-4- yl-piperazin-l-yl)butoxy] -lH-quinolin-2-one

The dihydrate of the benzothiophene compound represented by Formula (I) or of a salt thereof according to the present invention can be produced from an anhydride of the benzothiophene compound or of a salt thereof.

The benzothiophene compound (in the form of an

anhydride) of Formula (I), from which the dihydrate of the present invention is produced, is a known compound, and can be obtained by the production method disclosed in Example 1 of

JP2006-316052A or according to Reference Examples 1 and 2

Fig. 1 shows the ^-NMR spectrum of the dihydrate of the benzothiophene compound represented by Formula (I) prepared in Example 1.

Fig. 2 shows the X-ray powder diffraction pattern of the dihydrate of the benzothiophene compound represented by

Formula (I) prepared in Example 1.

Fig. 3 shows the infrared absorption spectrum of the dihydrate of the benzothiophene compound represented by Formula (I) prepared in Example 1.

Fig. 4 shows the Raman spectrum of the dihydrate of the benzothiophene compound represented by Formula (I) prepared in Example 1.

Fig. 5 shows the ^XH- MR spectrum of the benzothiophene compound represented by Formula (I) prepared in Example 2.

Reference Example 1: Synthesis of 7-(4-chlorobutoxy)-lH-quinolin- 2-one Methanol (149 L) , 7-hydroxy-lH-quinolin-2-one (14.87 kg), and potassium hydroxide (6.21 kg) were mixed and stirred. After dissolution, l-bromo-4-chlorobutane (47.46 kg) was further added thereto and the resulting mixture was stirred under reflux for seven hours. Thereafter, the mixture was stirred at 10° C for one hour. The precipitated crystal was centrifuged and washed with methanol (15 L). The wet crystal was collected and placed in a tank. Water (149 L) was added thereto, followed by stirring at room temperature. After centrifugation, the resulting solid was washed with water (30 L). The wet crystal was collected and placed in a tank. After adding methanol (74 L), the mixture was stirred under reflux for one hour, cooled to 10° C, and then stirred. The precipitated crystal was centrifuged and washed with methanol (15 L). The separated crystal was dried at 60° C to obtain 7- (4-chlorobutoxy) -lH-quinolin-2-one (15.07 kg).

Reference Example 2: Synthesis of 7- [ 4- ( 4-benzo[b] thiophen-4-yl- piperazin-l-yl)butoxy] -lH-quinolin-2-one

Water (20 L), potassium carbonate (1.84 kg), 1- benzo[b] thiophen-4-yl-piperazine hydrochloride (3.12 kg), and ethanol (8 L) were mixed and stirred at 50° C. 7- ( 4-Chlorobutoxy) – lH-quinolin-2-one (2.80 kg) obtained in Reference Example 1 was added to the mixture and stirred under reflux for nine hours.

After concentrating the solvent (8 L) under ordinary pressure, the mixture was stirred at 90° C for one hour and then cooled to 9° C . The precipitated crystal was centrifuged and then

sequentially washed with water (8 L) and ethanol (6 L). The separated crystal was dried at 60° C to obtain a crude product. The crude product (4.82 kg) and ethanol (96 L) were mixed in a reaction vessel, and acetic acid (4.8 L) was introduced into the reaction vessel. The mixture was stirred under reflux for one hour to dissolve the crude product. After introducing

hydrochloric acid (1.29 kg), the mixture was cooled to 10° C. The mixture was heated again, refluxed for one hour, and cooled to 7° C. The precipitated crystal was centrifuged and washed with ethanol (4.8 L). The separated crystal was dried at 60° C to obtain 7- [4- (4-benzo[b] thiophen-4-yl-piperazin-l-yl)butoxy] -1H- quinolin-2-one hydrochloride (5.09 kg). The resulting 7- [4- (4- benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy] -lH-quinolin-2-one hydrochloride (5.00 kg), ethanol (45 L), and water (30 L) were mixed in a reaction vessel. The mixture was stirred under reflux to dissolve the 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-l- yl)butoxy] -lH-quinolin-2-one hydrochloride. Activated carbon (500 g) and water (5 L) were added thereto, and an activated carbon treatment was conducted under reflux for 30 minutes. After performing hot filtration, a solution containing sodium hydroxide (511 g) dissolved in water (1.5 L) was flowed into the reaction vessel while stirring the filtrate under reflux. After stirring under reflux for 30 minutes, water (10 L) was introduced thereto and the mixture was cooled to approximately 40° C. The

precipitated crystal was centrifuged and washed with water (125 L). The separated crystal was dried at 80° C to obtain 7- [4- (4- benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy] – lH-quinolin-2-one (3.76 kg).

Example 1: Preparation of 7- [ 4- ( 4-benzo[b]thiophen-4-yl- piperazin-l-yl)butoxy] -lH-quinolin-2-one dihydrate

The 7- [4- (4-benzo[b] thiophen-4-yl-piperazin-1- yl)butoxy] -lH-quinolin-2-one (3.2 kg) obtained in Reference

Example 2, ethanol (64 L) , water (74 L) , and acetic acid (1.77 kg) were mixed in a reaction vessel to prepare an acidic liquid mixture. The mixture was stirred under reflux to dissolve the 7- [ 4- ( 4-benzo[b] thiophen-4-yl-piperazin-1-yl)butoxy] -1H-quinolin-2- one (reflux temperature: 84° C). After cooling to -5°C, the solution obtained above was introduced, over a period of 30 minutes, into a solution containing 25% sodium hydroxide (5.9 kg) and water (54 L) that was cooled to 0°C, to prepare a liquid mixture with pHlO. After being stirred at 5° C or below for one hour, the mixture was heated to 20 to 30° C and further stirred for-seven hours . The precipitated crystal was filtered and washing with water (320 L) was performed, until alkali in the solid component disappeared (i.e.. until the pH value of the filtrate became 7 ) . The solid component was then air-dried until its weight became constant to obtain a white solid 7-[4-(4- benzofb] thiophen-4-yl-piperazin-l-yl)butoxy] -lH-quinolin-2-one dihydrate (unground, 3.21 kg).

Fig. 1 shows the ^XH-NMR spectrum (D SO-d₆, TMS) of the dihydrate prepared by the aforesaid method. As shown in Fig. 1, in the ^- MR spectrum (DMSO-d₆, TMS) , peaks were observed at 1.64 ppm (tt, J = 7.4 Hz, J = 7.4 Hz, 2H) , 1.80 ppm (tt, J = 7.0 Hz, J = 7.0 Hz, 2H), 2.44 ppm (t, J = 7.5 Hz, 2H) , 2.62 ppm (br, 4H) , 3.06 ppm (br, 4H) , 3.32 ppm (s, 4H + H₂0) , 4.06 ppm (t, J = 6.5 Hz, 2H), 6.29 ppm (d, J = 9.5 Hz, 1H), 6.80 ppm (d, J = 2.5 Hz, 1H) , 6.80 ppm (dd, J = 2.5 Hz, J = 9.0 Hz, 1H) , 6.88 ppm (d, J = 7.5 Hz, 1H), 7.27 ppm (dd, J = 7.8 Hz, J = 7.8 Hz, 1H) , 7.40 ppm (dd, J = 0.5 Hz, J = 5.5 Hz, 1H), 7.55 ppm (d, J = 9.0 Hz, 1H) , 7.61 ppm (d, J = 8.0 Hz, 1H) , 7.69 ppm (d, J = 5.5 Hz, 1H) , 7.80 ppm (d, J = 9.5 Hz, 1H), and 11.57 ppm (s, 1H) .

The X-ray powder diffraction spectrum of the dihydrate prepared by the aforesaid method was measured using an X-ray diffractometer (D8 ADVANCE, available from Bruker AXS). Fig. 2 shows the X-ray powder diffraction spectrum. As shown in Fig. 2, in the X-ray powder diffraction spectrum, diffraction peaks were observed at 2Θ = 8.1° , 8.9° , 15.1° , 15.6° , and 24.4° . Other than those mentioned above, the diffraction peaks were also observed at 2Θ = 11.6°.. 12.2°, 14.0°, 16.3°, 18.1°, 18.4°, 18.9°, 19.5°, 20.5°, 21.5°, 22.6°, 23.3°, 25.0°, 26.1°, 26.4°, 27.1°. 28.1°, 28.5°, 28.9°, 29.8°, 30.4°, 30.7°, 31.6°, 32.9°, 33.9°, 34.4°, 35.2°, 36.0°, 36.7°, 37.4° , and 38.3°.

The IR (KBr) spectrum of the dihydrate prepared by the aforesaid method was measured. Fig. 3 shows the IR (KBr) spectrum. As shown in Fig. 3, in the IR (KBr) spectrum, absorption bands were observed in the vicinity of wavenumbers 3509 cm^“1, 2934 cm^“1, 2812 cm^“1, 1651 cm^“1, 1626 cm^“1, 1447 cm^“1, 1223 cm^“1 and 839 cm^“1.

The Raman spectrum of the dihydrate prepared by the aforesaid method was measured. Fig. 4 shows the Raman spectrum. As shown in Fig. 4, in the Raman spectrum, absorption bands were observed in the vicinity of wavenumbers 1497 cm^“1, 1376 cm^“1, 1323 cm^“1, 1311 cm^“1, 1287 cm^“1, 1223 cm^“1, and 781 cm^“1.

Other than those mentioned above, absorption was also observed in the vicinity of wavenumbers 1656 cm^“1, 1613 cm^“1, 1563 cm^“1, 1512 cm^“1, 1468 cm^“1, 1446 cm^“1, 1241 cm^“1, 1203 cm^“1, 1145 cm^“1, 1096 cm^“1, 1070 cm^“1, 971 cm^“1, and 822 cm^“1.

The water content of the dihydrate prepared by the aforesaid method was measured using a moisture meter (CA-100, available from Mitsubishi Chemical Analytech Co., Ltd.) by the Karl Fischer method. As a result, the dihydrate had a water content of 7.79% by weight.

Example 2; Preparation of finely ground dihydrate

Dihydrate crystal (2.73 kg) obtained in Example 1 was ground using a jet mill. Here, the air pressure was set at 5 kgf/cm², and the rotational speed of the feeder was set at 20 rpm. As a result, finely ground 7-[4-(4-benzo[b]thiophen-4-yl- piperazin-1-yl)butoxy] -1H-quinoli -2-one dihydrate (2.61 kg,

95.6%) was obtained.

The dihydrate (finely ground product) thus obtained had a mean particle diameter of 5.5 um. The mean particle diameter was measured using a Microtrack HRA, manufactured by Nikkiso Co., Ltd.

Fig. 5 shows the ^-NMR spectrum (DMSO-d₆, TMS) of the dihydrate prepared by the above method. As shown in Fig. 5, in the ^- MR spectrum (DMSO-d₆, TMS), peaks were observed at 1.64 ppm (tt, J = 7.3 Hz, J = 7.3 Hz, 2H), 1.80 ppm (tt, J = 6.9 Hz, J = 6.9 Hz, 2H), 2.44 ppm (t, J = 7.3 Hz, 2H) , 2.62 ppm (br, 4H) , 3.06 ppm (br, 4H) , 3.32 ppm (s, 4H + H₂0) , 4.06 ppm (t, J = 6.5 Hz, 2H), 6.29 ppm (d, J = 9.5 Hz, 1H) , 6.80 ppm (d, J = 2.5 Hz , 1H) , 6.80 ppm (dd, J = 2.3 Hz, J = 9.3 Hz, 1H) , 6.88 ppm (d, J = 7.5 Hz, 1H), 7.27 ppm (dd, J = 8.0 Hz, J = 8.0 Hz, 1H) , 7.40 ppm (d, J = 5.5 Hz, 1H), 7.55 ppm (d, J = 9.5 Hz , 1H) , 7.61 ppm (d, J = 8.0 Hz, 1H), 7.69 ppm (d, J = 5.5 Hz, 1H) , 7.80 ppm (d, J = 9.5

Hz, 1H), and 11.57 ppm (s, 1H) .

The X-ray powder diffraction spectrum of the dihydrate prepared by the aforesaid method was measured in the same manner as in Example 1. Fig. 6 shows the X-ray powder diffraction spectrum. As shown in Fig. 6, in the X-ray powder diffraction spectrum, diffraction peaks were observed at 2Θ = 8.2° , 8.9° ,

15.2° , 15.7° and 24.4° .

Other than those mentioned above, the diffraction peaks were also observed at 2Θ = 6.8°, 12.2°, 14.0°, 14.5″, 17.4°,

18.1°, 18.5°, 19.0°, 19.2°, 19.6°, 20.3°, 20.6°, 21.5°, 22.7°,

23.4°, 25.0°, 26.1°, 27.1°, 28.6°, 29.0°, 30.4°, 34.0°, 34.5°,

35.3° , and 36.7° .

The IR (KBr) spectrum of the dihydrate prepared by the aforesaid method was measured in the same manner as in Example 1.

Fig. 7 shows the IR (KBr) spectrum. As shown in Fig. 7, in the IR

(KBr) spectrum, absorption bands were observed in the vicinity of wavenumbers 3507 cm^“1, 2936 cm^“1, 2812 cm^“1, 1651 cm^“1, 1626 cm^“1,

1447 cm^“1, 1223 cm^“1 and 839 cm^“1.

The Raman spectrum of the dihydrate prepared by the aforesaid method was measured. Fig. 8 shows the Raman spectrum.

As shown in Fig. 8, in the Raman spectrum, absorption bands were observed in the vicinity of wavenumbers 1496 cm^‘1, 1376 cm^“1, 1323 cm^‘1, 1311 cm^“1, 1286 cm^“1, 1223 cm^“1, and 781cm^“1.

Other than those mentioned above, absorption was also observed in the vicinity of wavenumbers 1656 cm^“1, 1614 cm^“1, 1563 cm^“1, 1512 cm^“1, 1467 cm^“1, 1446 cm^“1, 1241 cm^“1, 1203 cm^“1, 1145 cm^“1,

1095 cm^“1, 1069 cm^“1, 971 cm^“1, and 822 cm^“1.

The water content of the dihydrate prepared by the aforesaid method was measured using a moisture meter (CA-100, available from Mitsubishi Chemical Analytech Co., Ltd.) by the

Karl Fischer method. As a result, the dihydrate had a water content of 6.74% by weight . Example 3 : Preparation of 7- [ 4- ( 4-benzo[b] thiophen-4-yl- piperazin-l-yl)butoxy] -lH-quinolin-2-one dihydrate

7- [ 4- ( 4-Benzo[ ] thiophen-4-yl-piperazin-1-yl)butoxy] – lH-quinolin-2-one (5.0 kg), ethanol (100 L), water (115 L), and DL-lactic acid (2.29 kg) were mixed to prepare an acidic liquid mixture. The liquid mixture was stirred under reflux to dissolve the 7- [4- (4-benzo[b] thiophen-4-yl-piperazin-l-yl)butoxy] -1H- quinolin-2-one (reflux temperature: 82° C). After cooling to -5°C, the solution obtained above was introduced, over a period of about 15 minutes, into a solution containing sodium hydroxide (1.48 kg) and water (135 L) that was cooled to 1°C, to prepare a liquid mixture with pHll. After being stirred at approximately 2 to 5° C for three hours, the mixture was heated to 45° C and

further stirred at 45 to 50° C for two hours. The precipitated crystal was filtered and washing with water (200 L) was performed until alkali in the solid component disappeared (i.e., until the pH value of the filtrate became 7). The solid component was further washed with a liquid mixture of ethanol (15 L) and water (20 L). The solid component was then dried at room temperature until its weight became constant to obtain a white solid 7- [4- (4- benzo[b] thiophen-4-yl-piperazin-1-yl)butoxy] -1H-quinolin-2-one dihydrate (unground, 5.11 kg).

The dihydrate thus obtained was the same as that obtained in Example 1.

The Raman spectrum of the dihydrate prepared by the aforesaid method was measured. Fig. 9 shows the Raman spectrum. As shown in Fig. 9, in the Raman spectrum, absorption bands were observed in the vicinity of wavenumbers 1497 cm^“1, 1376 cm^“1, 1323 cm^“1, 1311 cm^“1, 1287 cm^“1, 1223 cm^“1, and 782 cm^“1.

Other than those mentioned above, absorption was also observed in the vicinity of wavenumbers 1656 cm^“1, 1614 cm^“1, 1563 cm^“1, 1512 cm^“1, 1468 cm^“1, 1446 cm^“1, 1241 cm^“1, 1203 cm^“1, 1145 cm^“1, 1126 cm^“1, 1096 cm^“1, 1070 cm^“1, 972 cm^“1, and 822 cm^“1.

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PATENT

http://www.google.com/patents/WO2006112464A1?cl=en

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PATENT

http://www.google.com/patents/US20110152286

References

 ………

Bray prazosin (Brexpiprazole, code: OPC-34712) is Otsuka Pharmaceutical Co., Ltd. developed a new generation of anti-psychotic drug candidates that act on more than one receptor, dopamine D2 receptor partial agonist (improving positive and negative symptoms, cognitive impairment and depressive symptoms), 5-HT2A receptor antagonist (improving negative symptoms, cognitive dysfunction, symptoms of depression, insomnia), α1 adrenoceptor antagonists (improving positive symptoms of schizophrenia), 5 – serotonin uptake / reuptake inhibitors (symptoms of depression); at the same time, but also a 5-HT1A partial agonist (anxiolytic and antidepressant activity) and 5-HT7 antagonist (temperature, circadian rhythms, learning and memory, sleep) . Currently, in the United States and Europe as an adjunctive treatment of severe depression (MDD) Phase III clinical trials; III clinical trials the treatment of schizophrenia in the United States, Europe and Japan, meanwhile, is still the United States II Adult ADHD clinical trials.

Otsuka Pharmaceutical Co., Ltd. are disclosed in PCT Application WO2006112464A1 in the preparation route Bray prazosin, see Scheme 1, the difficulty of the route is the first step in the reaction by-products easily separated by column chromatography is not easy to obtain high-purity intermediates, thus affecting the final product Bray prazosin purity and yield.

Scheme 1:

Subsequently, Otsuka Pharmaceutical Co., Ltd. are disclosed in PCT Application WO2013015456A1 in the alternative method of preparing the reaction of this step, see Scheme 2, along the route of the reagents are more expensive, high-cost, environmentally unfriendly and not suitable for industrial production.

Reaction Scheme 2:

Due to the above production process there is a high cost, and difficult to separate impurities and other shortcomings, it is necessary to find an economical, practical, environmental protection, new routes to improve process stability, reduce costs, improve product quality.

DISCLOSURE

In response to these deficiencies, an object of the present invention is to provide a new, simple operation, high yield, low cost, environmentally friendly and suitable for industrial mass production Bray prazosin and the like, key intermediates and preparing a salt thereof.

Another object of the present invention is to provide novel compounds and salts thereof of the manufacturing process.

To achieve the above objects, the present invention provides compounds of formula I, the structure is as follows:

Wherein, R is C1 ~ C6 straight or branched chain alkyl, benzyl; preferably, R is C1 ~ C4 straight or branched chain alkyl group; most preferably, R is methyl, ethyl, t-butyl group;

R ₁ is acyl amino-protecting groups (e.g. formyl ( ), an acetyl group, a propionyl group, a benzoyl group, haloacetyl group, phthaloyl) or class alkoxycarbonyl amino-protecting group (e.g. t-butoxycarbonyl , benzyloxycarbonyl, 9-fluorenyl methoxy carbonyl); said haloacetyl group is a fluorinated acetyl, bromoacetyl, chloroacetyl or iodoacetyl group; preferably, R ₁ is formyl, acetyl and tert-butoxycarbonyl groups;

The present invention also provides a method for preparing a compound of formula I, the compound of formula II with a thioglycolate as shown in the reaction, the compound, the method shown in Formula I as shown in Scheme 3,

Reaction Scheme 3:

Wherein, X is halogen, such as fluorine, chlorine, bromine, iodine; R and R ₁ are as defined above, the compound of formula I as defined the same;

The above reaction in the presence of a base, in particular, is an inorganic base (e.g. sodium hydroxide, potassium hydroxide, strontium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, cesium hydroxide, sodium hydrogen carbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, strontium carbonate, cesium carbonate, sodium sulfide, sodium hydroxide, etc.) or an organic base (e.g. sodium alkoxide, potassium alkoxide, butyl lithium, 1,8-diazabicyclo [5,4 0] undecene -7 (DBU), pyridine, quinoline, 4-dimethylaminopyridine (DMAP) or an organic amine, etc.) performed in the presence of, wherein the sodium alkoxide may be sodium methoxide, sodium ethoxide, propoxy sodium alkoxide, sodium isopropoxide, n-butoxide, sodium tert-butoxide and the like; may be the potassium alkoxide, potassium methoxide, potassium ethoxide, potassium-propanol, potassium isopropoxide, n-butoxide, potassium tert-butoxide , the organic amine may be triethylamine, diethylamine, n-butylamine, tripropylamine, diisopropylamine, diisopropylethylamine, etc., preferably, the base may be an inorganic alkali sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium carbonate, sodium carbonate, strontium carbonate, sodium sulfide, sodium hydroxide, or organic bases as sodium methoxide, sodium ethoxide, tert-butoxide potassium, triethylamine, diethylamine, diisopropylamine or diisopropylethylamine;

The above reaction is carried out in a suitable solvent, the solvent is water, C ₁ ~ C ₅ lower alcohol (such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, n-amyl alcohol, amyl alcohol, ethylene glycol, propylene glycol, glycerol), N, N- dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, dioxane, N- methylpyrrolidone, methylene chloride, chloroform, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether or ethylene glycol monomethyl ether, and the like, one or more, preferably, the solvent is water , methanol, ethanol, N, N- dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, dioxane or ethylene glycol dimethyl ether or a species; the reaction time from 1 hour to 24 hours, preferably 2 hours to 12 hours. The reaction temperature is 0 ℃ ~ 150 ℃, preferably room temperature ~ 100 ℃.

To achieve the above object, the present invention also provides a compound of formula III, is structured as follows:

Wherein, R ₁ is acyl amino protecting groups (e.g. formyl, acetyl, propionyl, benzoyl, halo acetyl, phthaloyl) or class alkoxycarbonyl amino-protecting group (e.g. t-butoxycarbonyl , benzyloxycarbonyl, 9-fluorenyl methoxycarbonyl), said haloacetyl group is a fluorinated acetyl, bromoacetyl, chloroacetyl or iodoacetyl;

Preferably, R ₁ is formyl, acetyl or t-butoxycarbonyl;

The present invention also provides a method of preparing compounds of Formula III are shown, thioglycolic acid compound and reacting compound of formula III as shown in the method shown by the formula II as shown in Scheme 4,

Scheme 4:

Wherein, X is fluorine, chlorine, bromine or iodine; R ₁ as defined above, with a compound of formula I as defined the same;

Example 71- formyl-4- (2-carboxy-benzothiophen-4-yl) – piperazine

The product of (500mg, 1.38mmol) of Example 2 was dissolved in quinoline (3mL) the addition of cuprous oxide (20mg), the reaction temperature was raised to 140 ℃ After 2h, the reaction continues to heat up to 240 ℃ 3h, cooled to room temperature, filtered , water was added, extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, silica gel column chromatography, and concentrated to give the desired product. ¹ HNMR (300 MHz, DMSO-d ₆ ): [delta] 8.74 (bs, 1H), 7.75 (d, 1H), 7.69 (d, 1H), 7.51 (d, 1H), 7.31 (t, 1H), 6.95 ( d, 1H), 3.24 (m, 8H) ESI: [M + 1] ⁺ = 219.2.

Example 15 7- [4- (2-carboxy-4-yl-benzothiophene-1-piperazinyl) butoxy] -3,4-dihydro -2 (1H) – quinolinone Preparation of

7- [4- (2-ethoxycarbonyl-4-phenyl and thienyl-1-piperazinyl) butoxy] -3,4-dihydro -2 (1H) – quinolinone (300mg, 0.59 mmol) was dissolved in methanol (3mL) and water (1mL) was added lithium hydroxide (76mg, 1.8mmol), stirred at rt for 3h, ethyl acetate was added, the aqueous phase was adjusted with 1N dilute hydrochloric acid to about pH 4.0, using bis dichloromethane: methanol (10: 1) extraction, concentration did a white solid (210mg, 46% yield).

¹ HNMR (400 MHz, DMSO-d ₆ ): [delta] 10.01 (s, 1H), 7.88 (s, 1H), 7.61 (d, 1H), 7.38 (t, 1H), 7.03 (q, 1H), 6.93 ( d, 1H), 6.48 (m, 2H), 3.92 (m, 4H), 3.35 (s, 4H), 2.84 (s, 4H), 2.77 (s, 2H), 2.62 (s, 2H), 1.72 (m , 4H), ESI: [M-1] ^– = 478.3.

The product (500mg, 1.04mmol) of Example 15 will be implemented, cuprous oxide (50mg) was dissolved in quinoline (5mL) inside, heated to 140 ℃ overnight. After cooling and filtration, water was added, extracted with ethyl acetate, washed with 1N HCl solution was added until pH = 4.0, dichloromethane: methanol (10: 1) extracted, dried over anhydrous sodium sulfate, and silica gel column chromatography to give a solid (320mg , yield 70%).

¹ HNMR (400 MHz, DMSO-d ₆ ): δ10.00 (s, 1H), 7.69 (d, 1H), 7.61 (d, 1H), 7.40 (d, 1H), 7.27 (t, 1H), 7.04 ( d, 1H), 6.89 (d, 1H), 6.50 (dd, 1H), 6.45 (d, 1H), 3.93 (t, 2H), 3.06 (br, 4H), 2.78 (t, 2H), 2.60 (br , 4H), 2.41 (t, 4H), 1.74 (t, 2H), 1.60 (t, 2H) ESI: [M + 1]⁺ = 436.3.

Preparation of piperazine-1-carboxylic acid tert-butyl ester – Example 17 4- (2-ethoxycarbonyl phenyl and thien-4-yl)

Under nitrogen at room temperature was added the product of Reference Example 1 to ethanol (5mL) inside (200mg, 0.62mmol), ethyl mercaptoacetate (0.081ml, 0.74mmol), sodium hydroxide (100mg, 2.48mmol), the mixture 85 ℃ stirred for 6 hours, concentrated to column chromatography to obtain the target substance (70mg, 30% yield).

ESI: [M + 1] ⁺ = 478.0.

update………….

4-Chlorobenzo[b]thiophene a key intermediate in brexpiprazole synthesis

We established an improved synthetic route to 4-chlorobenzo[b]thiophene, a key intermediate in brexpiprazole synthesis, via a practical decarboxylation process in three steps. Thermal analysis demonstrated that the coexistence of the decarboxylated product with DBU should be avoided and that removal of the product outside the reactor was vital. Our process yields the target compound by distillation under reduced pressure and is safe, highly batch efficient, cost-effective, and high yielding. Furthermore, manufacturing on a pilot scale was also accomplished through our approach.

4-Chlorobenzo[b]thiophene-2-carboxylic Acid (4)

 4 as a white solid

mp 260 °C.

1H NMR (300 MHz, DMSO-d6) δ 7.54 (d, 1H, J = 11.6, 7.7 Hz), 7.56 (dd, 1H, J = 17.8, 7.7 Hz), 8.03 (d, 1H, J = 0.7 Hz), 8.07 (td, 1H, J = 7.6, 0.9 Hz), 13.19 (brs, 1H).

13C NMR (75 MHz, DMSO-d6) δ 122.21, 125.01, 126.84, 127.99, 128.96, 136.50, 136.57, 142.55, 163.10.

Elemental analysis calcd for C: 50.83%, H: 2.37%, found C: 50.84%, H: 2.21%.

2,3,4,6,7,8,9,10-Octahydropyrimido[1,2-a]azepin-1-ium 4-Chlorobenzo[b]thiophene-2-carboxylate 5

5 as a white solid

Mp 182.5 °C.

1H NMR (300 MHz, CDCl3) δ 1.66 (m, 6H), 1.80–1.75 (m, 2H), 2.98–2.94 (m, 2H), 3.45–3.39 (m, 4H), 3.55–3.51 (m, 2H), 7.31–7.20 (m, 2H), 7.69 (dd, 1H, J = 3.9, 0.6 Hz), 7.97 (s, 1H), 13.19 (brs, 1H).

13C NMR (75 MHz, CDCl3) δ 19.51, 24.03, 26.70, 28.88, 31.99, 38.01, 48.36, 53.94, 121.04, 123.00, 125.17, 126.61, 128.98, 138.21, 142.43, 146.85, 165.91, 167.20.

Elemental analysis calcd for C: 59.25%, H: 5.80%, N: 7.68%, found C: 59.10%, H: 5.44%, N: 7.53%.

4-Chlorobenzo[b]thiophene (2)

1H NMR (300 MHz, CDCl3) δ 7.26 (t, 1H, J = 7.8 Hz), 7.36 (dd, 1H, J = 7.8, 0.9 Hz), 7.50 (d, 1H, J = 5.7 Hz), 7.52 (d, 1H, J = 5.7 Hz), 7.76 (d, 1H, J = 7.8 Hz).

13C NMR (75 MHz, CDCl3) δ 121.12, 122.40, 125.02, 127.43, 128.93, 138.06, 141.07.

Elemental analysis calcd for C: 56.98%, H: 2.99%, found C: 56.76%, H: 2.94%.

SEE

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00340

http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.5b00340/suppl_file/op5b00340_si_001.pdf

Safe and Efficient Decarboxylation Process: A Practical Synthetic Route to 4-Chlorobenzo[b]thiophene

Masahiro Miyake^*, Masamichi Shimizu, Koichi Tsuji, and Keiichi Ikeda

Bulk Pharmaceutical Chemicals Department, Second Tokushima Factory, Production Headquarters, Otsuka Pharmaceutical Co., Ltd., 224-18, Hiraishi Ebisuno, Kawauchi-cho, Tokushima 771-0182, Japan

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.5b00340