132539-06-1 Usage
Uses
Used in Pharmaceutical Industry:
Olanzapine is used as an antipsychotic agent for controlling schizophrenia, bipolar mania, and other diseases. It acts as a serotonin (5-HT2) and dopamine (D1/D2) receptor antagonist with anticholinergic activity, helping in the treatment of various psychiatric disorders.
Used in Chemical Synthesis:
Olanzapine serves as an intermediate for the synthesis of various compounds such as Imidacloprid, Indobufen, Nitroguanidine, Nalorphine, Tazarotene, and Trovafloxacin.
Used in Gastrointestinal Treatment:
Olanzapine is used as an anti-ulcer and gastrointestinal-emptying agent, enhancing motility in the upper gastrointestinal tract.
Used in Antidepressant Combination Therapy:
Olanzapine is combined with fluoxetine (Symbyax) for use in depression that is associated with bipolar I disorder. This combination helps in mood stabilization and produces antidepressant effects through 5-HT2A receptor blockade and increased cortical dopamine and norepinephrine concentrations.
Brand Name:
Zyprexa (Lilly) is the brand name under which Olanzapine is marketed.
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.
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.
Originator
Lilly (USA)
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
Therapeutic Function
Antipsychotic
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
132539-06-1Relevant 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.
A synthesis of tritium-labeled olanzapine
Shevchenko,Nagaev,Kuznetsov,Polunin,Zozulya,Myasoedov
, p. 378 - 382 (2005)
A synthesis of olanzapine, 2-methyl-10-(4-methyl-1-piperazinyl)-4H- thieno[2,3-b][1,5]benzodiazepine, was carried out and the conditions for its tritium labeling were optimized to obtain a tritium-labeled olanzapine preparation with a specific radioactivity of 12 Ci/mmol.
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.
A method of improving the crystal form II olanzapine and method
-
Paragraph 0050-0051; 0053; 0055, (2018/03/01)
The invention discloses an improved method for preparation of olanzapine. The method comprises the step as follows: in a single solvent, a compound shown in a formula (II) reacts with N-methyl piperazine at the temperature greater than or equal to 111 DEG C. By adopting the method disclosed by the invention, the productivity is about over 85%, and the purity of high performance liquid chromatography is about 99% or about 99.5%, or over about 99.9%. The used solvent and reagent can be recycled, are economical and environment-friendly, and accord with the requirements of green chemistry.
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.
Design and Performance Validation of a Conductively Heated Sealed-Vessel Reactor for Organic Synthesis
Obermayer, David,Znidar, Desiree,Glotz, Gabriel,Stadler, Alexander,Dallinger, Doris,Oliver Kappe
, p. 11788 - 11801 (2016/12/09)
A newly designed robust and safe laboratory scale reactor for syntheses under sealed-vessel conditions at 250 °C maximum temperature and 20 bar maximum pressure is presented. The reactor employs conductive heating of a sealed glass vessel via a stainless steel heating jacket and implements both online temperature and pressure monitoring in addition to magnetic stirring. Reactions are performed in 10 mL borosilicate vials that are sealed with a silicone cap and Teflon septum and allow syntheses to be performed on a 2-6 mL scale. This conductively heated reactor is compared to a standard single-mode sealed-vessel microwave instrument with respect to heating and cooling performance, stirring efficiency, and temperature and pressure control. Importantly, comparison of the reaction outcome for a number of different synthetic transformations performed side by side in the new device and a standard microwave reactor suggest that results obtained using microwave conditions can be readily mimicked in the operationally much simpler and smaller conventionally heated device.
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.
Production of [...]
-
Paragraph 0040-0056, (2020/10/21)
PROBLEM TO BE SOLVED: To provide olanzapine which is useful as an antipsychotic drug and has high purity.SOLUTION: A method for producing olanzapine comprises the steps of: reacting 4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine hydrochloride with N-methylpiperazine in the absence of a solvent at 80-120°C to produce the olanzapine; cooling a reaction mixture obtained at the reaction step to 60-80°C; mixing acetonitrile of, for example, the weight equivalent to 1.18 times of the weight of the 4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine hydrochloride, in the cooled reaction mixture; keeping the acetonitrile-mixed reaction mixture at 60-80°C; and adding water of, for example, the weight equivalent to 3 times of the weight of the 4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine hydrochloride, to the mixture of 60-80°C to precipitate the olanzapine.
Method for producing intermediate olanzapine
-
Paragraph 0035, (2020/10/19)
PROBLEM TO BE SOLVED: To provide a method for producing an intermediate of olanzapine by a safe and simplified method without using tin chloride.SOLUTION: A method for producing a compound of formula 1 or its acid adduct is characterized by preparing a suspension containing a compound of formula 2, iron powder or zinc powder and a water-soluble alcohol and then adding an acid to the suspension to react them.
PROCESS FOR THE PREPARATION OF HIGH PURITY OLANZAPINE AND CRYSTALLINE FORM II THEREOF
-
Paragraph 61-65, (2014/10/15)
The present invention provides a process for the preparation of high-purity olanzapine with high yield and a process for the preparation of olanzapine crystalline Form II, which are industrially applicable. The preparation processes according to the present invention are useful for the preparation of high-purity olanzapine and olanzapine crystalline Form II with high yield and thus can be effectively used for mass production.
