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132539-06-1

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  • High Quality 99% 10H-Thieno[2,3-b][1,5]benzodiazepine, 2-methyl-4-(4-methyl-1-piperazinyl)- 132539-06-1 ISO Producer

    Cas No: 132539-06-1

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132539-06-1 Usage

Antipsychotics

Olanzapine also known as olanzapine, olanzapine Oran, is a common antipsychotic drugs, clinically used to control schizophrenia, bipolar mania and agitation symptoms of dementia, it can significantly improve schizophrenia negative (for example: apathy, emotional and social withdrawal, poverty of speech), positive symptoms (such as: delusions, hallucinations, thought disorder, hostility and suspicion), and it may also relieve common secondary schizophrenia and related disorders affective symptoms. Good oral absorption, it needs 5-8 hours to reach the peak plasma concentration, and it is not affected by eating, it is metabolized in the liver through a combination of oxidation ; the major circulating metabolite is the 10-N-glucuronide. Animal experiments show that olanzapine displays affinity on multiple receptors 5-HT, dopamine D, α-adrenergic, histamine H et , the affinity with 5-HT2 receptor in vitro and in vivo is greater than its affinity for dopamine D2 receptors. Animal behavior studies show that olanzapine has a 5-HT, dopamine, and cholinergic antagonism effect, and it is consistent with its receptor binding situation. Electrophysiological studies show that olanzapine selectively reduces the limbic system (A10) dopaminergic neurons discharge, while the effect on the striatal (A9) motor path function is very small. In the reaction below to produce froze dosage levels, it can reduce the conditioned avoidance response. Different with other antipsychotics, olanzapine increases the anxiolytic response in test . The above information is edited by the lookchem of Tian Ye.

Chemical properties

Crystallization from acetonitrile, melting point of 195 ℃.

Uses

Different sources of media describe the Uses of 132539-06-1 differently. You can refer to the following data:
1. Used to control schizophrenia, bipolar mania and other diseases
2. A serotonin (5-HT2) and dopamine (D1/D2) receptor antagonist with anticholinergic activity. Antipsychotic.
3. intermediate for Imidacloprid, Indobufen, Nitroguanidine, Nalorphine, Tazarotene, Trovafloxacin
4. anti-ulcer, gastrointestinal-emptying agent enhances motility in the upper gastrointestinal tract

Production method

4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzo-diazepin-hydrochloride and N-methylpiperazine in toluene and dimethylsulfoxide , reflux under nitrogen for 20h, to obtain olanzapine.

Description

Different sources of media describe the Description of 132539-06-1 differently. You can refer to the following data:
1. O lanzapine is classed as an atypical antipsychotic and is considered a firstline agent in the management of newly diagnosed psychosis. It has a similar mechanism of action to classical antipsychotics but with a lower incidence of adverse events. O lanzapine rarely produces hypotension and has less potential for QT prolongation. It is used in the management of delirium in ICU.
2. Zyprexa was launched in Canada, Germany, the UK and US as an antipsychotic agent. Prepared in three steps via the intermediate diazepinone, it is an atypical antipsychotic with a high affinity for dopaminergic and serotonergic receptors. Specifically, olazapine is a potent 5-HT2/D2 antagonist with anticholinergic activity. It has a greater antagonistic effect at 5-HT2a than at dopamine D2 receptors and in vivo is clozapine-like. Thus it is less likely to produce extrapyramidal side effects and does not produce any granulocytopenia. Its 10 metabolic products are all inactive.

Chemical Properties

Yellow Crystalline Powder

Originator

Lilly (USA)

Definition

ChEBI: A benzodiazepine that is 10H-thieno[2,3-b][1,5]benzodiazepine substituted by a methyl group at position 2 and a 4-methylpiperazin-1-yl group at position 4.

Manufacturing Process

1. 2-Amino-5-methylthiophene-3-carbonitrile A mixture of sulphur (217.8 g, 6.79 mol), propionaldehyde (472.5 g, 587 mL, 8.13 mol) and dimethylformamide (1350 m) was placed in a 5 liter flangenecked flask fitted with air stirrer, air condenser, thermometer and dropping funnel. Triethylamine (576 mL, 4.13 mol) was added dropwise over 30 minutes to the cooled stirred reaction mixture whilst maintaining the pot temperature between 5°-10°C with an ice-bath. After addition was complete the pot was allowed to warm up to 18°C over 50 minutes, keeping the mixture well stirred. Then a solution of malononitrile (450 g, 6.8 mol) in dimethylformamide (900 mL) was added dropwise over 70 minutes keeping the pot temperature around 20°C throughout the addition. After addition was complete the mixture was stirred at 15°-20°C for a further 45 minutes then sampled for TLC. The mixture was then poured onto ice (4 liters)/water (8 liters) with stirring and this caused the required product to precipitate. After 10 minutes the stirrer was switched off and the solid allowed to settle. The aqueous liquor was decanted away and the solid isolated by filtration. The isolated solid was well washed with water (de-ionised, 4 liters), then dried over night in vacuo at 70°-75°C to give the title compound (585 g), m.p. 100°C.2. 2-(2-Nitroanilino)-5-methylthiophene-3-carbonitrile To a stirred slurry of sodium hydride (14.4 g, 50% dispersion in oil, 0.3 mol) in dry tetrahydrofuran (50 mL) under nitrogen was added, dropwise, a solution of 2-fluoronitrobenzene (28.2 g, 0.2 mol) and 2-amino-5methylthiophene3-carbonitrile (27.6 g, 0.2 mol) in dry tetrahydrofuran (250 mL). The mixture was stirred at 25°C for 24 hours, poured onto cracked ice and extracted into dichloromethane (3 times 500 mL). The combined extracts were washed with 2 N hydrochloric acid (2 times 200 mL), water (2 times 200 mL), dried over magnesium sulphate and the solvent removed under reduced pressure. The residue was crystallised from ethanol to give the title compound, (35.2 g), m.p. 99°-102°C. 3. 4-Amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine, hydrochloride To a stirred slurry of 2-(2-nitroanilino)-5-methylthiophene-3-carbonitrile (3 g, 0.011 mol) in ethanol (35 mL) at 50°C was added, over 10 minutes, a solution of anhydrous stannous chloride (6.95 g, 0.037 mol) in hydrochloric acid (26 mL, 5 M). The mixture was stirred under reflux for 1 hour, concentrated under reduced pressure and allowed to crystallise over night at 5°C. The salt was filtered, washed with a small amount of water, dried (4.3 g) m.p. >250°C, and used without further purification in the next stage. 4. 2-Methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine Crude 4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine, hydrochloride (4.3 g) was refluxed in a mixture of N-methylpiperazine (15 mL), dimethylsulfoxide (20 mL) and toluene (20 mL) under a nitrogen atmosphere for 20 hours. The mixture was cooled to ca. 50°C, water (20 mL) added, and the product allowed to crystallise at 5°C over night. The product was filtered and crystallised from acetonitrile (30 mL) to give the title compound (1.65 g) m.p. 195°C. The structure of the compound was confirmed spectroscopically

Brand name

Zyprexa (Lilly).

Therapeutic Function

Antipsychotic

General Description

Olanzapine, 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5] benzodiazepine (Zyprexa), isa yellow crystalline solid that is essentially insoluble in water.Olanzapine orally disintegrating tablets (Zyprexa Zydis) is asolid dosage form that immediately disintegrates when exposedto saliva. This product is useful for elderly patients whohave difficulty in swallowing. An injectable form, olanzapinefor injection (Zyprexa IM), is indicated for agitation associatedwith schizophrenia or bipolar I mania. Olanzapine iscombined with fluoxetine (Symbyax) for use in depressionthat is associated with bipolar I disorder. Peak concentrationsof oral olanzapine are reached at 6 hours after oral administration,and absorption of the compound is not affected byfood.Olanzapine binds with high affinity at DA D2, 5-HT2A,5-HT2C, 5-HT6,α1, and H1 histamine receptors. The effectsof olanzapine for the treatment of schizophrenia are presumablymediated through antagonism at D2 and 5-HT2Areceptors.The use of olanzapine in acute maniathat is associated with bipolar I disorder is thought to bemediated by antagonism at D2 and other monamine receptors.Additionally, olanzapine is postulated to produce itsmood stabilizing and antidepressant effects through 5-HT2Areceptor blockade and increased cortical DA and NE concentrations.Several studies have investigated the effectof olanzapine-induced weight gain and new-onset type 2diabetes.In a comparison study with risperidone,olanzapine was shown to have a greater risk of producingdyslipidemia and type 2 diabetes.

Biochem/physiol Actions

Olanzapine is a 5-HT2 serotonin and D1/D2 dopamine receptor antagonist.

Clinical Use

The thienobenzodiazepine olanzapine is an effective atypical antipsychotic agent that is close in structure to clozapine but has a somewhat different neuropharmacological profile, in that it is a more potent antagonist at dopamine D2 and, especially, serotonin 5-HT2A receptors. Olanzapine is well absorbed after oral administration and is metabolized mainly by CYP1A2 to inactive metabolites, with a variable half-life of approximately 20 to 50 hours.

in vitro

binding studies showed that olanzapine interacted with keyreceptorsof interest in schizophrenia, exihibiting a nanomolar affinity for dopaminergic, serotonergic, alpha 1-adrenergic, and muscarinic receptors [1].

in vivo

olanzapine was a potent antagonist at dareceptorsand 5-ht receptors, but showed weaker activity at alpha-adrenergic and muscarinic receptors [1].administration of olanzapine at 0.5, 3 and 10 mg/kg (s.c.) increased the extracellulardopamine(da) and norepinephrine (ne) levels in all three brain areas in a dose-dependent manner.the increases reached peaks 60-90 min after olanzapine administration and lasted for at least 2 h. the highest da increases in the acb and cpu were induced by olanzapine at 3 mg/kg but at 10 mg/kg in the pfc while the highest ne increase in the pfc (414% ± 40) induced by 10 mg/kg olanzapine [2].in macaque monkeys, olanzapine treatment resulted in an 8-11% reduction in mean fresh brain weights as well as left cerebrum fresh weights and volumes [3].

Drug interactions

Potentially hazardous interactions with other drugs Anaesthetics: enhanced hypotensive effect. Analgesics: increased risk of convulsions with tramadol; enhanced hypotensive and sedative effects with opioids; increased risk of ventricular arrhythmias with methadone. Anti-arrhythmics: increased risk of ventricular arrhythmias. Antibacterials: concentration possibly increased by ciprofloxacin. Antidepressants: fluvoxamine increases concentration of olanzapine; increased concentration of tricyclics. Antiepileptics: antagonism (convulsive threshold lowered); carbamazepine increases metabolism of olanzapine; increased risk of neutropenia with valproate. Antimalarials: avoid with artemether/lumefantrine. Antipsychotics: increased risk of ventricular arrhythmias with risperidone. Antivirals: concentration reduced by ritonavir - consider increasing olanzapine dose. Anxiolytics and hypnotics: increased sedative effects; increased risk of hypotension, bradycardia and respiratory depression with IM olanzapine and parenteral benzodiazepines. Atomoxetine: increased risk of ventricular arrhythmias. Cytotoxics: increased risk of ventricular arrhythmias with arsenic trioxide.

Metabolism

Olanzapine is extensively metabolised in the liver, mainly by direct glucuronidation and by oxidation mediated through the cytochrome P450 isoenzymes CYP1A2, and, to a lesser extent, CYP2D6. The 2 major metabolites, 10-N-glucuronide and 4′-N-desmethyl olanzapine, appear to be inactive. About 57% of a dose is excreted in the urine, mainly as metabolites, and about 30% appears in the faeces.

references

[1]. bymaster fp1,rasmussen k,calligaro do,nelson dl,delapp nw,wong dt,moore na. in vitro and in vivo biochemistry of olanzapine: a novel, atypical antipsychotic drug.j clin psychiatry.1997;58suppl 10:28-36.[2]. li xm1,perry kw,wong dt,bymaster fp. olanzapine increases in vivodopamineand norepinephrine release in rat prefrontal cortex, nucleus accumbens and striatum.psychopharmacology (berl).1998 mar;136(2):153-61.[3]. dorph-petersen ka1,pierri jn,perel jm,sun z,sampson ar,lewis da. the influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys.neuropsychopharmacology.2005 sep;30(9):1649-61.

Check Digit Verification of cas no

The CAS Registry Mumber 132539-06-1 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,3,2,5,3 and 9 respectively; the second part has 2 digits, 0 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 132539-06:
(8*1)+(7*3)+(6*2)+(5*5)+(4*3)+(3*9)+(2*0)+(1*6)=111
111 % 10 = 1
So 132539-06-1 is a valid CAS Registry Number.
InChI:InChI=1/C17H20N4S/c1-12-11-13-16(21-9-7-20(2)8-10-21)18-14-5-3-4-6-15(14)19-17(13)22-12/h3-6,11,19H,7-10H2,1-2H3

132539-06-1 Well-known Company Product Price

  • Brand
  • (Code)Product description
  • CAS number
  • Packaging
  • Price
  • Detail
  • TCI America

  • (O0393)  Olanzapine  >98.0%(GC)(T)

  • 132539-06-1

  • 1g

  • 770.00CNY

  • Detail
  • TCI America

  • (O0393)  Olanzapine  >98.0%(GC)(T)

  • 132539-06-1

  • 5g

  • 1,990.00CNY

  • Detail
  • Sigma-Aldrich

  • (Y0001380)  Olanzapine for system suitability  European Pharmacopoeia (EP) Reference Standard

  • 132539-06-1

  • Y0001380

  • 1,880.19CNY

  • Detail
  • Cerilliant

  • (O-024)  Olanzapine solution  1.0 mg/mL in acetonitrile, ampule of 1 mL, certified reference material

  • 132539-06-1

  • O-024-1ML

  • 950.04CNY

  • Detail

132539-06-1SDS

SAFETY DATA SHEETS

According to Globally Harmonized System of Classification and Labelling of Chemicals (GHS) - Sixth revised edition

Version: 1.0

Creation Date: Aug 10, 2017

Revision Date: Aug 10, 2017

1.Identification

1.1 GHS Product identifier

Product name olanzapine

1.2 Other means of identification

Product number -
Other names Oliza

1.3 Recommended use of the chemical and restrictions on use

Identified uses For industry use only.
Uses advised against no data available

1.4 Supplier's details

1.5 Emergency phone number

Emergency phone number -
Service hours Monday to Friday, 9am-5pm (Standard time zone: UTC/GMT +8 hours).

More Details:132539-06-1 SDS

132539-06-1Synthetic route

2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine acetic acid monosolvate

2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine acetic acid monosolvate

zyprexa
132539-06-1

zyprexa

Conditions
ConditionsYield
at 65 - 70℃; for 18h; Vacuo;100%
N-desmethyl olanzapine
161696-76-0

N-desmethyl olanzapine

methyl iodide
74-88-4

methyl iodide

zyprexa
132539-06-1

zyprexa

Conditions
ConditionsYield
With potassium tert-butylate In tetrahydrofuran at 0℃; for 2h; Product distribution / selectivity;99%
With sodium hydride In tetrahydrofuran at -10℃; for 3h; Product distribution / selectivity;98%
With sodium hydroxide In tetrahydrofuran at -15℃; for 4h; Product distribution / selectivity;98%
With triethylamine In tetrahydrofuran at -10℃; for 4h; Product distribution / selectivity;82%
1-methyl-piperazine
109-01-3

1-methyl-piperazine

4-amino-2-methyl-10H-thiene [2,3-b][1,5]-benzodiazepine hydrochloride

4-amino-2-methyl-10H-thiene [2,3-b][1,5]-benzodiazepine hydrochloride

zyprexa
132539-06-1

zyprexa

Conditions
ConditionsYield
In ethanol; dimethyl sulfoxide at 100 - 130℃; Solvent; Temperature;92.5%
In dimethyl sulfoxide at 100 - 120℃; for 8h;84.2%
1-methyl-piperazine
109-01-3

1-methyl-piperazine

2-methyl-10H-benzo[b]thieno[2,3-e][1,4]diazepin-4-amine
612503-08-9

2-methyl-10H-benzo[b]thieno[2,3-e][1,4]diazepin-4-amine

zyprexa
132539-06-1

zyprexa

Conditions
ConditionsYield
In propan-1-ol at 110℃; Product distribution / selectivity; Heating / reflux;89%
In iso-butanol at 118℃; Product distribution / selectivity; Heating / reflux;84%
In isopropyl alcohol at 100 - 102℃; Product distribution / selectivity; Heating / reflux;80%
1-methyl-piperazine
109-01-3

1-methyl-piperazine

4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine hydrochloride

4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine hydrochloride

zyprexa
132539-06-1

zyprexa

Conditions
ConditionsYield
at 125 - 145℃; for 5 - 12h; Product distribution / selectivity; Neat (no solvent);84%
at 120℃; for 5h;83.8%
In dimethyl sulfoxide at 112 - 115℃; for 16h;82%
olanzapinium oxalate

olanzapinium oxalate

zyprexa
132539-06-1

zyprexa

Conditions
ConditionsYield
With sodium hydroxide In water pH=9;72.6%
With sodium hydroxide In water pH=8 - 10;
With sodium hydroxide In water pH=9 - 10; Product distribution / selectivity;
2,4-bis(4-methyl-1-piperazinyl)-3-propylidene-3H-[1,5]benzodiazepine

2,4-bis(4-methyl-1-piperazinyl)-3-propylidene-3H-[1,5]benzodiazepine

zyprexa
132539-06-1

zyprexa

Conditions
ConditionsYield
With quinoline p-toluenesulfonate; sulfur In benzonitrile at 140℃; for 13.5h;69.5%
With pyridinium p-toluenesulfonate; sulfur In benzonitrile at 140℃; for 13.5h;66.6%
With sulfur; 1-methyl-imidazolium p-toluenesulfonic acid In benzonitrile at 140℃; for 10h;54.2%
With toluene-4-sulfonic acid; sulfur In benzonitrile at 140℃; for 9h;51.7%
With sulfur; triethylamine In propan-1-ol; dimethyl sulfoxide at 100℃; for 120h;12%
dimethyl sulfate
77-78-1

dimethyl sulfate

N-desmethyl olanzapine
161696-76-0

N-desmethyl olanzapine

zyprexa
132539-06-1

zyprexa

Conditions
ConditionsYield
With potassium carbonate In methanol at 25℃; for 2h; Product distribution / selectivity;60%
With potassium carbonate In acetone at -10℃; for 4h; Product distribution / selectivity;46%
Stage #1: dimethyl sulfate; N-desmethyl olanzapine With sodium hydroxide In methanol at 0 - 5℃;
Stage #2: With water In methanol Product distribution / selectivity;
Stage #1: dimethyl sulfate; N-desmethyl olanzapine With sodium hydroxide In methanol; dichloromethane at 0 - 5℃;
Stage #2: With water In methanol; dichloromethane Product distribution / selectivity;
Stage #1: dimethyl sulfate; N-desmethyl olanzapine With sodium hydroxide; potassium carbonate In tetrahydrofuran; water at 10 - 30℃; for 7.5 - 8.5h;
Stage #2: With hydrogenchloride In tetrahydrofuran; water at 50℃;
1-methyl-piperazine
109-01-3

1-methyl-piperazine

2-(2-nitroanilino)-5-methylthiophene-3-carbonitrile
138564-59-7

2-(2-nitroanilino)-5-methylthiophene-3-carbonitrile

zyprexa
132539-06-1

zyprexa

Conditions
ConditionsYield
With hydrogen In mesytilene at 160℃; for 48h; chemoselective reaction;54%
N-{5-methyl-3-[(4-methylpiperazin-1-yl)carbonyl]thien-2-yl}-N-(2-nitrophenyl)amine

N-{5-methyl-3-[(4-methylpiperazin-1-yl)carbonyl]thien-2-yl}-N-(2-nitrophenyl)amine

zyprexa
132539-06-1

zyprexa

Conditions
ConditionsYield
With tributylphosphine at 220℃; for 48h;41%
Olanzapine N-Oxide

Olanzapine N-Oxide

zyprexa
132539-06-1

zyprexa

Conditions
ConditionsYield
With osmium(VIII) oxide; (2E)-3-phenyl-2-propen-1-ol In water; tert-butyl alcohol at 20℃; for 19h; Inert atmosphere;30%
10-Benzyl-2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine
765244-26-6

10-Benzyl-2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine

zyprexa
132539-06-1

zyprexa

Conditions
ConditionsYield
With hydrogenchloride; acetic acid In water at 60℃; for 6 - 6.5h;20%
1-methyl-piperazine
109-01-3

1-methyl-piperazine

2-(2-nitroanilino)-5-methylthiophene-3-carbonitrile
138564-59-7

2-(2-nitroanilino)-5-methylthiophene-3-carbonitrile

A

zyprexa
132539-06-1

zyprexa

B

2-methyl-5,10-dihydro-4H-benzo[b]thieno[2,3-e][1,4]diazepin-4-one

2-methyl-5,10-dihydro-4H-benzo[b]thieno[2,3-e][1,4]diazepin-4-one

Conditions
ConditionsYield
With hydrogen In mesytilene at 160℃; for 24h; chemoselective reaction;A 20%
B 25 %Chromat.
ortho-nitrofluorobenzene
1493-27-2

ortho-nitrofluorobenzene

zyprexa
132539-06-1

zyprexa

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: 23 percent / NaH / tetrahydrofuran; various solvent(s) / 24 h / 25 °C
2: 65 percent / SnCl2; conc. HCl / ethanol / 1.5 h / Heating
3: 65 percent / dimethylsulfoxide; toluene / 24 h / Heating
View Scheme
Multi-step reaction with 3 steps
1: LiOH / dimethylsulfoxide
2: SnCl2 / ethanol
3: toluene; dimethylsulfoxide
View Scheme
2-(2-nitroanilino)-5-methylthiophene-3-carbonitrile
138564-59-7

2-(2-nitroanilino)-5-methylthiophene-3-carbonitrile

zyprexa
132539-06-1

zyprexa

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: 65 percent / SnCl2; conc. HCl / ethanol / 1.5 h / Heating
2: 65 percent / dimethylsulfoxide; toluene / 24 h / Heating
View Scheme
Multi-step reaction with 2 steps
1: SnCl2 / ethanol
2: toluene; dimethylsulfoxide
View Scheme
Multi-step reaction with 2 steps
1: tin(II) chloride dihdyrate; hydrogenchloride / ethanol; water / 1 h / Reflux
2: dimethyl sulfoxide; toluene / 20 h / Reflux; Inert atmosphere
View Scheme
Multi-step reaction with 3 steps
1: iron(III)-acetylacetonate; hydrazine hydrate / ethanol / 0.08 h / 150 °C / Sealed tube
2: hydrogenchloride / ethanol; water; ethyl acetate / 0.17 h / 120 °C / Sealed tube
3: 0.5 h / 160 °C / Sealed tube
View Scheme
2-amino-5-methylthiophene-3-carbonitrile
138564-58-6

2-amino-5-methylthiophene-3-carbonitrile

zyprexa
132539-06-1

zyprexa

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: 23 percent / NaH / tetrahydrofuran; various solvent(s) / 24 h / 25 °C
2: 65 percent / SnCl2; conc. HCl / ethanol / 1.5 h / Heating
3: 65 percent / dimethylsulfoxide; toluene / 24 h / Heating
View Scheme
Multi-step reaction with 3 steps
1: LiOH / dimethylsulfoxide
2: SnCl2 / ethanol
3: toluene; dimethylsulfoxide
View Scheme
Multi-step reaction with 3 steps
1: sodium hydride / tetrahydrofuran; mineral oil / 18 h / 20 °C / Inert atmosphere; Cooling with ice
2: tin(II) chloride dihdyrate; hydrogenchloride / ethanol; water / 1 h / Reflux
3: dimethyl sulfoxide; toluene / 20 h / Reflux; Inert atmosphere
View Scheme
Multi-step reaction with 4 steps
1: palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; 1,8-diazabicyclo[5.4.0]undec-7-ene / toluene; ethyl acetate / 0.17 h / 130 °C / Sealed tube
2: iron(III)-acetylacetonate; hydrazine hydrate / ethanol / 0.08 h / 150 °C / Sealed tube
3: hydrogenchloride / ethanol; water; ethyl acetate / 0.17 h / 120 °C / Sealed tube
4: 0.5 h / 160 °C / Sealed tube
View Scheme
2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine dihydrate

2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine dihydrate

zyprexa
132539-06-1

zyprexa

Reaxys ID: 12045368

Reaxys ID: 12045368

zyprexa
132539-06-1

zyprexa

Conditions
ConditionsYield
With silica gel In dichloromethane at 0℃; for 0.0833333h; Purification / work up;
C4H10O*2C17H20N4S

C4H10O*2C17H20N4S

zyprexa
132539-06-1

zyprexa

Conditions
ConditionsYield
at 65℃; for 2.5h;
olanzapine monohydrate
402586-77-0

olanzapine monohydrate

zyprexa
132539-06-1

zyprexa

olanzapine methylene chloride hemisolvate

olanzapine methylene chloride hemisolvate

zyprexa
132539-06-1

zyprexa

Conditions
ConditionsYield
In isopropyl alcohol at 20℃; for 0.5 - 1h; Product distribution / selectivity;
Stage #1: olanzapine methylene chloride hemisolvate at 50℃; for 12h;
Stage #2: In isopropyl alcohol at 20℃; for 0.333333h; Product distribution / selectivity;
2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine propan-2-ol hemisolvate monohydrate

2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine propan-2-ol hemisolvate monohydrate

zyprexa
132539-06-1

zyprexa

Conditions
ConditionsYield
Stage #1: 2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine propan-2-ol hemisolvate monohydrate at 50℃; for 16h;
Stage #2: In isopropyl alcohol at 20℃; for 0.25h; Product distribution / selectivity;
olanzapine-CH2Cl2-water

olanzapine-CH2Cl2-water

zyprexa
132539-06-1

zyprexa

Conditions
ConditionsYield
In dichloromethane Product distribution / selectivity;
olanzapine-DMSO-water

olanzapine-DMSO-water

zyprexa
132539-06-1

zyprexa

Conditions
ConditionsYield
In dichloromethane Product distribution / selectivity;
1-methyl-piperazine
109-01-3

1-methyl-piperazine

2-((2-aminophenyl)amino)-5-methylthiophene-3-carbonitrile
873895-41-1

2-((2-aminophenyl)amino)-5-methylthiophene-3-carbonitrile

zyprexa
132539-06-1

zyprexa

Conditions
ConditionsYield
With acetic acid at 120℃; Product distribution / selectivity;
With acetic acid at 120℃; Product distribution / selectivity;
With platinum doped titanium oxide; hydrogen In mesytilene at 140℃; for 24h;24 %Chromat.
1-methyl-piperazine
109-01-3

1-methyl-piperazine

2-((2-aminophenyl)amino)-5-methylthiophene-3-carbonitrile
873895-41-1

2-((2-aminophenyl)amino)-5-methylthiophene-3-carbonitrile

1-methylpiperazine hydrochloride
34352-59-5, 50398-09-9, 51545-09-6

1-methylpiperazine hydrochloride

zyprexa
132539-06-1

zyprexa

Conditions
ConditionsYield
at 120℃; Product distribution / selectivity;
at 120℃; Product distribution / selectivity;
at 120℃; Product distribution / selectivity;
at 120℃; Product distribution / selectivity;
olanzapine tetrahydrofuran water solvate

olanzapine tetrahydrofuran water solvate

zyprexa
132539-06-1

zyprexa

Conditions
ConditionsYield
at 40℃; under 1 - 20 Torr; for 4 - 10h; Product distribution / selectivity; vacuum drying;
1-methyl-piperazine
109-01-3

1-methyl-piperazine

dimethyl sulfoxide
67-68-5

dimethyl sulfoxide

4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine hydrochloride

4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine hydrochloride

zyprexa
132539-06-1

zyprexa

Conditions
ConditionsYield
In water; toluene
In water; toluene
In water; toluene
In water; toluene
In water; toluene
5-methyl-2-(2-nitro-anilino)-thiophene-3-carboxylic acid methyl ester
72242-31-0

5-methyl-2-(2-nitro-anilino)-thiophene-3-carboxylic acid methyl ester

zyprexa
132539-06-1

zyprexa

Conditions
ConditionsYield
With ammonia; palladium on charcoal catalyst; titanium tetrachloride In 1-methyl-piperazine; ethanol ethyl acetate; ethyl acetate; methoxybenzene; isopropyl alcohol
With ammonia; palladium on charcoal catalyst; titanium tetrachloride In 1-methyl-piperazine; ethanol ethyl acetate; ethyl acetate; methoxybenzene; isopropyl alcohol
zyprexa
132539-06-1

zyprexa

2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine dihydrate

2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine dihydrate

Conditions
ConditionsYield
With water In dimethyl sulfoxide at 0 - 80℃; for 48h;100%
With water In 1,3-dioxane at 0 - 80℃;93.5%
With water In acetone at 0 - 80℃;87.5%
With water In ethyl acetate; toluene at 20 - 60℃; for 1.5h;63.3%
In water at 30 - 35℃; for 0.5h;
zyprexa
132539-06-1

zyprexa

olanzapine sesquihydrate

olanzapine sesquihydrate

Conditions
ConditionsYield
Stage #1: zyprexa With hydrogenchloride; water
Stage #2: With sodium hydroxide; water at 0℃; for 0.5h; pH=8.5;
100%
zyprexa
132539-06-1

zyprexa

aspirin
50-78-2

aspirin

C7H6O3*C17H20N4S
929209-00-7

C7H6O3*C17H20N4S

Conditions
ConditionsYield
In methanol for 24h; Product distribution / selectivity;99%
zyprexa
132539-06-1

zyprexa

2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]-benzodiazepine monohydrochloride

2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]-benzodiazepine monohydrochloride

Conditions
ConditionsYield
With hydrogenchloride In water; acetonitrile Heating / reflux;98.5%
With hydrogenchloride In Isopropyl acetate; water
zyprexa
132539-06-1

zyprexa

2-methyl-4-(4-methyl-piperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine dihydrochloride

2-methyl-4-(4-methyl-piperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine dihydrochloride

Conditions
ConditionsYield
With hydrogenchloride In 1,4-dioxane at 0℃; for 0.166667h;97%
With hydrogenchloride In ethyl acetate at 0℃; for 0.166667h;97%
With hydrogenchloride In isopropyl alcohol at 0℃; for 0.166667h;97%
zyprexa
132539-06-1

zyprexa

Pamoic acid
130-85-8

Pamoic acid

olanzapine pamoate monohydrate

olanzapine pamoate monohydrate

Conditions
ConditionsYield
Stage #1: Pamoic acid With ammonium hydroxide In water
Stage #2: zyprexa With hydrogenchloride; water at 25 - 30℃; Reagent/catalyst;
97%
Stage #1: zyprexa; Pamoic acid In dimethyl sulfoxide at 20 - 25℃; for 0.333333h;
Stage #2: With water In dimethyl sulfoxide at 20 - 40℃; for 1.16667h;
maleic acid
110-16-7

maleic acid

zyprexa
132539-06-1

zyprexa

olanzapinium monomaleate
861390-74-1

olanzapinium monomaleate

Conditions
ConditionsYield
In ethanol for 24h; Product distribution / selectivity;88%
In hexane for 24h; Product distribution / selectivity;83%
In 1,4-dioxane for 24h; Product distribution / selectivity;75%
In acetonitrile for 0.25h;
maleic acid
110-16-7

maleic acid

zyprexa
132539-06-1

zyprexa

olanzapinium dimaleate

olanzapinium dimaleate

Conditions
ConditionsYield
In methanol for 24h; Product distribution / selectivity;88%
In methanol for 24h; Product distribution / selectivity;44%
In acetonitrile for 0.25h;
(2E)-but-2-enedioic acid
110-17-8

(2E)-but-2-enedioic acid

zyprexa
132539-06-1

zyprexa

olanzapine fumarate

olanzapine fumarate

Conditions
ConditionsYield
In dimethyl sulfoxide at 0 - 30℃; for 3h; Product distribution / selectivity;85.2%
In methanol; dichloromethane; water at 0 - 25℃; for 3h; Product distribution / selectivity;65.7%
In isopropyl alcohol at 0 - 25℃; for 2h; Product distribution / selectivity;
tetrahydrofuran
109-99-9

tetrahydrofuran

zyprexa
132539-06-1

zyprexa

olanzapine tetrahydrofuran water solvate

olanzapine tetrahydrofuran water solvate

Conditions
ConditionsYield
With water at 0 - 50℃; for 2.5h; Product distribution / selectivity;85%
With water at 5℃; Heating / reflux;
(2E)-but-2-enedioic acid
110-17-8

(2E)-but-2-enedioic acid

zyprexa
132539-06-1

zyprexa

3C4H4O4*C17H20N4S

3C4H4O4*C17H20N4S

Conditions
ConditionsYield
In methanol for 4h;84%
acetonitrile
75-05-8

acetonitrile

zyprexa
132539-06-1

zyprexa

2,10-Dimethyl-4-(4-methyl-1-piperazinyl)-10H-thieno-[2,3-b][1,5]benzodiazepine
155817-84-8

2,10-Dimethyl-4-(4-methyl-1-piperazinyl)-10H-thieno-[2,3-b][1,5]benzodiazepine

Conditions
ConditionsYield
With 18-crown-6 ether; carbon dioxide at 80℃; under 750.075 Torr; for 72h; Inert atmosphere; Schlenk technique; Glovebox;83%
zyprexa
132539-06-1

zyprexa

salicylic acid
69-72-7

salicylic acid

C7H6O3*C17H20N4S
929209-00-7

C7H6O3*C17H20N4S

Conditions
ConditionsYield
In methanol for 24h; Product distribution / selectivity;82%
zyprexa
132539-06-1

zyprexa

Olanzapine N-Oxide

Olanzapine N-Oxide

Conditions
ConditionsYield
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 12℃; for 12h;79.1%
With 3-chloro-benzenecarboperoxoic acid In dichloromethane
With α-D-glucose 6-phosphate; glucose phosphate dehydrogenase; human cytochrome P450 (CYP) 2D6.10, recombinant; NADP In aq. phosphate buffer at 37℃; for 0.75h; Kinetics; Reagent/catalyst; Enzymatic reaction;
acetic acid
64-19-7

acetic acid

zyprexa
132539-06-1

zyprexa

2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine acetic acid monosolvate

2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine acetic acid monosolvate

Conditions
ConditionsYield
In ethyl acetate at 4 - 20℃; Product distribution / selectivity;79%
In acetone at 4 - 20℃; Product distribution / selectivity;56%
In dimethyl sulfoxide at 4℃; for 4h; Product distribution / selectivity;
In isopropyl alcohol Product distribution / selectivity;
3-chloro-benzenecarboperoxoic acid
937-14-4

3-chloro-benzenecarboperoxoic acid

zyprexa
132539-06-1

zyprexa

olanzapine N-oxide-m-chlorobenzoate

olanzapine N-oxide-m-chlorobenzoate

Conditions
ConditionsYield
In chloroform at 23℃; for 0.166667h; Inert atmosphere;78%
(2E)-but-2-enedioic acid
110-17-8

(2E)-but-2-enedioic acid

zyprexa
132539-06-1

zyprexa

2C4H4O4*C17H20N4S

2C4H4O4*C17H20N4S

Conditions
ConditionsYield
In methanol for 22h;74%
carbonochloridic acid, chloromethyl ester
22128-62-7

carbonochloridic acid, chloromethyl ester

zyprexa
132539-06-1

zyprexa

chloromethyl 2-methyl-4-(4-methyl(y)pi(y)perazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diaze(y)pine-5-carboxylate
1443629-16-0

chloromethyl 2-methyl-4-(4-methyl(y)pi(y)perazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diaze(y)pine-5-carboxylate

Conditions
ConditionsYield
Stage #1: zyprexa With triethylamine In dichloromethane at 5 - 35℃;
Stage #2: carbonochloridic acid, chloromethyl ester In dichloromethane at 5 - 25℃; for 1.08333h; regioselective reaction;
73%
With triethylamine In dichloromethane at 5 - 35℃; for 0.833333h;73%
Stage #1: zyprexa With triethylamine In dichloromethane at 35℃;
Stage #2: carbonochloridic acid, chloromethyl ester at 5 - 20℃; for 1.08333h;
73%
With triethylamine In dichloromethane at 20℃; for 0.75h;73%
With triethylamine In dichloromethane at 5 - 35℃; for 1.08333h;73%
zyprexa
132539-06-1

zyprexa

olanzapine trihydrate

olanzapine trihydrate

Conditions
ConditionsYield
Stage #1: zyprexa With water; acetic acid at 20℃;
Stage #2: With ammonia; water at 20℃; pH=9.75;
68.5%

132539-06-1Relevant articles and documents

[11C]Olanzapine, radiosynthesis and lipophilicity of a new potential PET 5-HT2 and D2 receptor radioligand

Gao, Mingzhang,Shi, Zenas,Wang, Min,Zheng, Qi-Huang

, p. 1953 - 1956 (2013)

Olanzapine and its precursor desmethyl-Olanzapine were synthesized from malononitrile, propionaldehyde, 1-fluoro-2-nitrobenzene, and substituted piperazine in 4, 4, 5, and 5 steps with 35%, 32%, 26%, and 32% overall chemical yield, respectively. [11C]Olanzapine was prepared from desmethyl-Olanzapine with [11C]CH3OTf through N-[ 11C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 40-50% radiochemical yield based on [11C]CO 2 and decay corrected to end of bombardment (EOB), with 370-740 GBq/μmol specific activity at EOB. The calculated Log P (C Log P) value of [11C]Olanzapine is 3.39.

Direct Reductive Cyclocondensation of the Nitro Group with the Amido Group: Key Role of the Iminophosphorane Intermediate in the Synthesis of 1,4-Dibenzodiazepine Derivatives

Tryniszewski, Micha?,Bujok, Robert,Cmoch, Piotr,Gańczarczyk, Roman,Kulszewicz-Bajer, Irena,Wróbel, Zbigniew

, p. 2277 - 2286 (2019/05/16)

A class of dialkylamino-substituted dibenzodiazepines and their hetero analogues was synthesized by the intramolecular aza-Wittig condensation of the amido group with iminophosphoranes. The one-pot, two-step procedure includes reductive synthesis of the intermediate iminophosphoranes from the corresponding nitroamides and tributylphosphine.

Production of [oranzapin[oranzapin]

-

Paragraph 0025-0028, (2017/10/20)

PROBLEM TO BE SOLVED: To provide a method for producing an antipsychotic agent, olanzapine, having a desired appearance as a medicine.SOLUTION: A method for producing type II olanzapine is characterized by adding activated clay to an olanzapine solution prepared by dissolving the olanzapine in an organic solvent to purify the olanzapine.

Method of manufacturing olanzapine II type

-

Paragraph 0045-0050, (2018/10/16)

PROBLEM TO BE SOLVED: To provide a method for obtaining a II type crystal of 2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine (general name:olanzapine) at a high recovery rate, which crystal is useful as an antipsychotic drug.SOLUTION: A method for producing the olanzapine II type crystal comprises the steps of: using water-containing ethyl acetate as a recrystallization solvent when a crude material of the olanzapine is re-crystallized; dissolving the crude material of the olanzapine in the water-containing ethyl acetate; adjusting the amount of the water within 1.5-4.5 moles based on 1 mole of the dissolved olanzapine; precipitating crystals to obtain a new olanzapine hydrate crystal having characteristic peaks at such positions that 2θ is 8.9±0.2°, 9.4±0.2°, 17.1±0.2°, 18.2±0.2°, 18.6±0.2°, 20.2±0.2°, 20.5±0.2°, 20.8±0.2°, 21.7±0.2°, and 26.4±0.2° when X-ray diffraction measurement is performed by using a Cu-Kα ray; and drying the obtained olanzapine hydrate crystal.

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