120511-73-1

Basic information

• Product Name: Anastrozole
• Synonyms: ICI-D-1033;ARIMIDEX;1-[3,5-DI-(1-METHYL-1-CYANO)-ETHYL]-BENZYL-1,2,4-TRIAZOLE;ANASTRAZOLE;ANASTROZOLE;tetramethyl-5-(1h-1,2,4-triazol-1ylmethyl) 1,3-benzenediacetionitrile;ZD-1033;1,3-benzenediacetonitrile,alpha,alpha,alpha’,alpha’-tetramethyl-5-(1h-1,2,4-t
• CAS NO: 120511-73-1
• Molecular Formula: C₁₇H₁₉N₅
• Molecular Weight: 293.36626
• EINECS: 1806241-263-5
• Product Categories: Active Pharmaceutical Ingredients;Antineoplastic;All Inhibitors;anti-neoplastic;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;Anastrozole;API
• Mol File: 120511-73-1.mol
• Article Data: 34

Chemical Properties

• Melting Point: 81-82°C
• Boiling Point: 469.718 °C at 760 mmHg
• Flash Point: 237.877 °C
• Appearance: crystalline solid
• Density: 1.085 g/cm³
• Refractive Index: 1.791
• Storage Temp.: Store at RT
• Solubility: DMSO: soluble40mg/mL
• PKA: 2.62±0.10(Predicted)
• CAS DataBase Reference: Anastrozole(CAS DataBase Reference)
• NIST Chemistry Reference: Anastrozole(120511-73-1)
• EPA Substance Registry System: Anastrozole(120511-73-1)

Safety Data

• Hazard Codes: Xi,Xn
• Statements: 36/37/38-22-61-60
• Safety Statements: 26-37/39
• RIDADR: 3249
• WGK Germany: 3
• RTECS: CZ1465000
• HazardClass: 6.1(b)
• PackingGroup: III
• Hazardous Substances Data: 120511-73-1(Hazardous Substances Data)

Usage

Description

Different sources of media describe the Description of 120511-73-1 differently. You can refer to the following data:
1. Anastrozole, chemically known as 2,2-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]bis(2-methylpropiononitrile) a derivative of benzotriazole with the CAS registry number 120511-73-1, is a non-steroidal, third-generation achiral triazole derivative marketed as ARIMIDEX? by AstraZeneca Pharmaceuticals LP1. It is one of the third-generation aromatase inhibitor which is a highly competitive and selective inhibitor of aromatase, thus blocking the conversion of testosterone into estradiol and androstenedione into estrone. Inhibition of the aromatase enzyme occurs particularly through competitive binding of aromatase to the hemegroup of cytochrome P450, decreasing estrogen biosynthesis in the peripheral tissues of the body and in the breast.
2. Anastrozole entered its first market in the United Kingdom for the treatment of advanced breast cancer in post-menopausal women. Anastrozole is a highly potent and selective aromatase inhibitor. It is extremely potent in lowering circulating estradiol to undetectable levels in treated patients without altering other circulating hormones. The drug is reportedly well absorbed and tolerated following oral administration.

Treatment for Early-stage Breast Cancer

Anastrozole is a generally well tolerated treatment for early-stage breast cancer. Like other aromatase inhibitors, its most important adverse effect was an increased risk of bone fractures, which for anastrozole was restricted to the treatment period. It characteristically has mild toxicity when compared with chemotherapy; however, it have been noticed that more patients treated with anastrozole have complained of joint symptoms than expected, particularly digital stiffness similar to that of rheumatoid arthritis. Some clinical trials of anastrozole for postmenopausal women with breast cancer in Europe and the United states reported musculoskeletal disorders as adverse events.Anastrozole (Arimidex?) is an aromatase inhibitor approved in the EU, the US and in other countries worldwide for use as an adjuvant treatment in postmenopausal women with early-stage, hormone receptor-positive breast cancer. It is also approved in the EU and other countries worldwide for continuing adjuvant treatment in women who have already had 2–3 years of adjuvant tamoxifen treatment for breast cancer.

Uses

Different sources of media describe the Uses of 120511-73-1 differently. You can refer to the following data:
1. Anastrozole has significant effects on breast cancer treatment and, therefore, it is currently used as first-line treatment in estrogen receptor (ER)-positive postmenopausal women, particularly to treat locally advanced or metastatic breast cancer. Furthermore, it is also indicated for early cancer treatment, tumor chemoprevention and postmenopausal women using tamoxifen, especially if the drug is used during a prolonged period of time and has been indicated in the disease’s recurrence, i.e., as another therapeutic endocrine option.
2. Anastrozole is a nonsteroidal inhibitor of aromatase which effectively blocks estrogen synthesis in postmenopausal women and is used as therapy of estrogen receptor positive breast cancer. Anastrozole has been associated with a low rate of serum enzyme elevations during therapy and rare instances of clinically apparent liver injury.

Pharmacokinetics

Different sources of media describe the Pharmacokinetics of 120511-73-1 differently. You can refer to the following data:
1. Anastrozole has linear pharmacokinetics. It is metabolized primarily in the liver, with a plasma elimination half-life of 40–50 hours, indicating that oncedaily administration is adequate. In vitro and clinical studies indicate that drugdrug interactions are unlikely to occur between anastrozole and drugs metabolized by hepatic cytochrome P450 enzymes. In patients with breast cancer, there were no clinically important interactions between anastrozole and tamoxifen or its metabolite, N-desmethyltamoxifen.
2. Anastrozole is well absorbed orally, with biliary elimination as its primary route (85%) and an elimination half-life of approxim ately 50 hours. Approximately 60% of an oral dose is m etabolized in the liver by N-dealkylation, hydroxylation, and glucuronidation to inactive triazole metabolites.

Indications and Usage

Anastrozole is a potent selective triazole aromatase inhibitor that inhibits the aromatase that cytochrome P-450 is dependent on to prevent the biosynthesis of estrogen. Estrogen is the main stimulating factor for breast cancer cell growth. This drug’s half maximal inhibitory concentration (IC50) value to human placental aromatase is 15nmol/L. Compared to the traditional drug tamoxifen, Anastrozole can comprehensively and effectively lower the risks of breast cancer recurrence and metastasis, thus extending patients’ disease-free survival. Anastrozole is suitable for treating postmenopausal advanced breast cancer patients, especially postmenopausal advanced breast cancer patients who experienced recurrence following hormone assisted therapy.

Clinical Research

A series of clinical trials compared the effects of third generation aromatase inhibitor Anastrozole with those of tamoxifen. The trial was a global multicenter trial and includes 381 centers in 21 countries. Since 1996, there have been 9366 patients who have participated, and the follow-up time is 100 months. 25.8% of patients in the Anastrozole group experienced recurrence, while 29.9% of patients in the tamoxifen group did. Thus, Anastrozole’s recurrence rate was 4.1% lower than that of tamoxifen, and its risk of distant metastasis was lower as well. Anastrozole is also safer than tamoxifen.

Chemical Properties

Crystalline Solid. soluble in organic solvents such as ethanol, DMSO, and dimethyl formamide. The solubility of anastrozole in these solvents is approximately 20, 13, and 14 mg/ml.

Originator

Zeneca (United Kingdom)

Definition

ChEBI: Anastrozole is a 1,2,4-triazole compound having a 3,5-bis(2-cyano-2-propyl)benzyl group at the 1-position. It has a role as an antineoplastic agent and an EC 1.14.14.14 (aromatase) inhibitor. It is a member of triazoles and a nitrile.

Preparation

synthesis of anastrozole can be realized in four steps based on 3,5-bis(bromomethyl)toluene. Starting with a S N 2 displacement using potassium nitrile and tetrabutylammonium bromide as a phase transfer catalyst to give bis-nitrile compound. Bis-nitrile compound formed undergoes deprotonation with NaH and methylated afterwards with methyl iodide to give bis-dimethyated product.Product undergoes radical substitution reaction following the Wohl-Ziegler reaction using N-bromosuccinamide and benzoyl peroxide as the radical initiator.In the final step, benzylbromide undergoes SN2 displacement with sodium triazole to give anastrozole.

Application

Anastrozole (aromatase inhibitor) has been used:as a positive control in DNA fragmentation (ladder) assayto investigate its effects along with extra virgin olive oil and its major fatty acid component (omega-9 OA) in estrogen receptor positive mammary adenocarcinoma cellsto study its effects on viability, cell proliferation and apoptosis in Glioblastoma multiforme model in vivo

Brand name

Arimidex (AstraZeneca).

Therapeutic Function

Antitumor

General Description

Anastrozole is a non-steroidal and expensive drug marketed under the trade name Arimidex. It was the first specific aromatase inhibitor approved in theUnited States. It is indicated for first-line treatment of postmenopausalwomen with advanced or metastatic breast cancer,for second-line treatment of postmenopausal patientswith advanced breast cancer who have had disease progressionfollowing tamoxifen therapy, and for adjuvant treatmentof women with early breast cancer. Patients who did not respondto tamoxifen therapy rarely respond to anastrozole.

Biological Activity

Potent and highly selective aromatase (CYP19) inhibitor (IC 50 = 15nM) that has no discernible effect on adrenocorticoid hormone synthesis. Reduces plasma estrogen levels and exhibits antitumor activity in vivo . Orally active.

Biochem/physiol Actions

Anastrozole, which contains a triazole functional group, reversibly binds to the cytochrome P-450 component of aromatase. Binding interferes with the catalytic properties of aromatase, which results in inhibition of estrogen synthesis.

Mechanism of action

Anastrozole, a benzyltriazole derivative, competes with the natural s ubstrate for binding to the active site of the aromatase. The mechanism of enzyme inhibition resides in the coordination of the triazole ring with the hemeiron atom of the aromatase enzyme complex. This coordination ultimately prevents arom atization of androgens into estrogens and, therefore, deprives the tumor of estrogen. This effect is reversible. In the presence of anastrozole, estradiol levels are reduced to undetectable levels, with no adverse effects on levels of any other horm one, including cortisol and aldosterone. Maximal estrogen suppression is produced by a 1mg dose. Estrogen suppression is maintained for up to 6 days after discontinuing anastrozole.

Clinical Use

Anastrozole is a potent and highly selective, nonsteroidal aromatase inhibitor utilized in the treatment of advanced breast cancer that is horm one-responsive. It is considered to be second-line therapy (after tamoxifen) in the treatment of postm enopaus al breast cancer.

Drug interactions

Potentially hazardous interactions with other drugs Oestrogen-containing therapies: avoid concomitant administration as would negate pharmacological action. Tamoxifen: avoid concomitant administration.

Environmental Fate

Anastrozole is classified as readily biodegradable and is moderately mobile in soils. The measured octanol-water partition coefficient is low, therefore anastrozole is not predicted to bioaccumulate in aquatic organisms.

Metabolism

Anastrozole is extensively metabolised by postmenopausal women with less than 10% of the dose excreted in the urine unchanged within 72 hours of dosing. Metabolism of anastrozole occurs by N-dealkylation, hydroxylation and glucuronidation via CYP 3A4 and 3A5, and UGT1A4. The metabolites are excreted primarily via the urine. Triazole, the major metabolite in plasma, does not inhibit aromatase.

references

[1] dukes m1, edwards pn, large m, smith ik, boyle t. the preclinical pharmacology of "arimidex" (anastrozole; zd1033)--a potent, selective aromatase inhibitor. j steroid biochem mol biol. 1996 jul;58(4):439-45.

InChI:InChI=1S/C17H19N5/c1-16(2,9-18)14-5-13(8-22-12-20-11-21-22)6-15(7-14)17(3,4)10-19/h5-7,11-12H,8H2,1-4H3

Synthetic route

1,2,4-Triazole (288-88-0) + 2-[3-bromomethyl-5-(cyanodimethylmethyl)phenyl]-2-methylpropanenitrile (120511-84-4) → anastrozol (120511-73-1)

Conditions	Yield
With potassium tert-butylate In toluene at 9 - 21℃; for 4.5h;	100%
With tetrabutylammomium bromide; potassium hydroxide In water; toluene at 75 - 80℃; for 2h; Solvent; Temperature; Reagent/catalyst;	82%
With tetrabutylammomium bromide; potassium carbonate; potassium hydroxide In toluene at 85 - 90℃; for 5h;	47%

1,2,4-Triazole (288-88-0) + 3,5-bis(2-cyanopropan-2-yl)benzaldehyde (120511-89-9) → anastrozol (120511-73-1)

Conditions	Yield
With sodium tris(acetoxy)borohydride In tetrahydrofuran at 45 - 55℃; for 7h; Reagent/catalyst; Solvent;	90%

4-amino-1-[3,5-bis(1-cyano-1-methylethyl)benzyl]-4H-1,2,4-triazolium bromide → anastrozol (120511-73-1)

Conditions	Yield
With sodium azide; sulfuric acid; copper(II) sulfate In methanol; water for 1h; Solvent; Reflux;	82%
With hydrogenchloride; sodium nitrite In water at 0 - 20℃; for 9 - 9.5h;	81.24%
Stage #1: 4-amino-1-[3,5-bis(1-cyano-1-methylethyl)benzyl]-4H-1,2,4-triazolium bromide With hydrogenchloride; sodium nitrite In water at -5 - 20℃; for 8h; Stage #2: With urea In water Stage #3: With ammonia In water; toluene at 0 - 25℃; for 4h;

2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]-di(2-methylpropionitrile) hydrobromide (876514-43-1) → anastrozol (120511-73-1)

Conditions	Yield
With sodium carbonate In water Product distribution / selectivity;	74.7%

1,3,5-Triazine (290-87-9) + C15H20N4*ClH → anastrozol (120511-73-1)

Conditions	Yield
In ethanol for 2h; Heating / reflux;	72.49%

anastrozole mesylate (1015083-81-4) → anastrozol (120511-73-1)

Conditions	Yield
With ammonia In methanol; water at 18 - 22℃; Product distribution / selectivity;	71.5%

2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]-di(2-methylpropionitrile) hydrochloride → anastrozol (120511-73-1)

Conditions	Yield
With sodium carbonate In water Product distribution / selectivity;	69.5%
With sodium hydrogencarbonate In water Product distribution / selectivity;
In water for 48.5h; Product distribution / selectivity;

α,α,α',α'-tetramethyl-5-chloromethyl-1,3-benzene diacetonitrile (120511-91-3) + sodium triazole (41253-21-8) → anastrozol (120511-73-1)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 18h;	52%
In DMF (N,N-dimethyl-formamide) at 20℃; for 18h;

2-[3-bromomethyl-5-(cyanodimethylmethyl)phenyl]-2-methylpropanenitrile (120511-84-4) + sodium triazole (41253-21-8) → anastrozol (120511-73-1)

Conditions	Yield
Stage #1: 2-[3-bromomethyl-5-(cyanodimethylmethyl)phenyl]-2-methylpropanenitrile; sodium triazole In N,N-dimethyl-formamide at 45 - 50℃; for 4h; Stage #2: With hydrogenchloride; water at 50℃; pH=2; Stage #3: With ammonia In water at 0 - 5℃; pH=8 - 9;	34%
In N,N-dimethyl-formamide at 20℃; for 1h;	34%
In N,N-dimethyl-formamide at 20℃; for 1h;	34%

4-amino-1-[3,5-bis(1-cyano-1-methylethyl)benzyl]-4H-1,2,4-triazolium bromide → 2-[3-(1-cyano-1-methylethyl)-5-(1H-1,2,4-triazol-1-ylmethyl)phenyl]-2-methylpropionamide + 2-[3-(1-carbamoyl-1-methylethyl)-5-[1,2,4]triazol-1-ylmethylphenyl]-isobutyramide (120512-04-1) + anastrozol (120511-73-1)

Conditions	Yield
Stage #1: 4-amino-1-[3,5-bis(1-cyano-1-methylethyl)benzyl]-4H-1,2,4-triazolium bromide With hydrogenchloride; sodium nitrite In water at -5 - 20℃; Stage #2: With ammonia; water at 0 - 25℃; for 4h;	A 0.36% B 0.05% C n/a

α,α,α',α'-tetramethyl-5-chloromethyl-1,3-benzene diacetonitrile (120511-91-3) → anastrozol (120511-73-1)

Conditions	Yield
Stage #1: 1,2,4-Triazole With sodium methylate In methanol at 20 - 30℃; for 0.25h; Stage #2: α,α,α',α'-tetramethyl-5-chloromethyl-1,3-benzene diacetonitrile In N,N-dimethyl acetamide at 15 - 55℃; for 3h; Product distribution / selectivity;

2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]di(2-methyl)propionitrile p-toluenesulfonate salt → anastrozol (120511-73-1)

Conditions	Yield
With ammonia In water; toluene for 0.5h; pH=8.5 - 9.0; Product distribution / selectivity;
With ammonia In water; ethyl acetate for 0.5h; pH=8.5 - 9.0; Product distribution / selectivity;
With ammonia In water at 10 - 20℃; for 0.75h; pH=~ 9.00 - 10.00; Product distribution / selectivity;

2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]di(2-methyl)propionitrile fumarate salt → anastrozol (120511-73-1)

Conditions	Yield
With ammonia In water Product distribution / selectivity;

2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]di(2-methyl)propionitrile oxalate → anastrozol (120511-73-1)

Conditions	Yield
With ammonia In water Product distribution / selectivity;

2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]-di(2-methylpropionitrile) hydrochloride + 2,2'-[5-(4H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]-di(2-methyl-propionitrile) hydrochloride → α,α,α',α'-tetramethyl-5-(4H-1,2,4-triazol-4ylmethyl)-1,3-benzene-diacetonitrile (120511-92-4) + anastrozol (120511-73-1)

Conditions	Yield
With sodium carbonate In water; ethyl acetate for 0.333333h; Product distribution / selectivity;
With sodium carbonate In water; ethyl acetate; toluene for 0.25h; Product distribution / selectivity;

2-[3-bromomethyl-5-(cyanodimethylmethyl)phenyl]-2-methylpropanenitrile (120511-84-4) → anastrozol (120511-73-1)

Conditions	Yield
Stage #1: 1,2,4-Triazole With sodium hydroxide In 1-methyl-pyrrolidin-2-one at 20 - 60℃; for 14 - 55h; Stage #2: 2-[3-bromomethyl-5-(cyanodimethylmethyl)phenyl]-2-methylpropanenitrile In 1-methyl-pyrrolidin-2-one at -26 - -20℃; for 18 - 26h; Stage #3: With acetic acid In 1-methyl-pyrrolidin-2-one pH=6.5 - 7; Product distribution / selectivity;

3,5-bis(2-cyanoprop-2-yl)toluene (120511-72-0) + sodium triazole (41253-21-8) → anastrozol (120511-73-1)

Conditions	Yield
With N-Bromosuccinimide; dibenzoyl peroxide In N-methyl-acetamide; tetrachloromethane; water
Stage #1: 3,5-bis(2-cyanoprop-2-yl)toluene; sodium triazole In N,N-dimethyl-formamide at 45 - 50℃; for 4h; Stage #2: With hydrogenchloride In water at 50℃; pH=1 - 2; Stage #3: With ammonia In water at 0 - 5℃; pH=8 - 9;

1,2,4-Triazole (288-88-0) + α,α,α',α'-tetramethyl-5-chloromethyl-1,3-benzene diacetonitrile (120511-91-3) → α,α,α',α'-tetramethyl-5-(4H-1,2,4-triazol-4ylmethyl)-1,3-benzene-diacetonitrile (120511-92-4) + anastrozol (120511-73-1)

Conditions	Yield
In acetonitrile

Reaxys ID: 12539645 → anastrozol (120511-73-1)

3,5-bis(2-cyanoisopropyl)benzylbromide + sodium triazole (41253-21-8) → α,α,α',α'-tetramethyl-5-(4H-1,2,4-triazol-4ylmethyl)-1,3-benzene-diacetonitrile (120511-92-4) + anastrozol (120511-73-1)

Conditions	Yield
In isopropyl alcohol Product distribution / selectivity; Heating / reflux;
In N,N-dimethyl-formamide at 5 - 35℃; for 0.5 - 4h; Product distribution / selectivity;
In n-heptane Product distribution / selectivity; Heating / reflux;
In acetone Product distribution / selectivity; Heating / reflux;
In methanol Product distribution / selectivity; Heating / reflux;

2-[3-bromomethyl-5-(cyanodimethylmethyl)phenyl]-2-methylpropanenitrile (120511-84-4) + sodium triazole (41253-21-8) → 3,5-bis(2-cyanoprop-2-yl)toluene (120511-72-0) + α,α,α',α'-tetramethyl-5-(4H-1,2,4-triazol-4ylmethyl)-1,3-benzene-diacetonitrile (120511-92-4) + anastrozol (120511-73-1)

Conditions	Yield
In N,N-dimethyl-formamide at -10 - -5℃; for 0.75h; Product distribution / selectivity;

2-[3-(cyano-dimethyl-methyl)-5-hydroxymethyl-phenyl]-2-methyl-propionitrile (120511-88-8) + 1-(4-toluenesulfonyl)-1H-1,2,4-triazole (13578-51-3) → anastrozol (120511-73-1)

Conditions	Yield
Stage #1: 2-[3-(cyano-dimethyl-methyl)-5-hydroxymethyl-phenyl]-2-methyl-propionitrile With sodium hydride In tetrahydrofuran at 70℃; for 0.5h; Stage #2: 1-(4-toluenesulfonyl)-1H-1,2,4-triazole In ISOPROPYLAMIDE at 20℃; for 0.333333h; Product distribution / selectivity;
Stage #1: 2-[3-(cyano-dimethyl-methyl)-5-hydroxymethyl-phenyl]-2-methyl-propionitrile With sodium hydride In 1,4-dioxane at 70 - 85℃; for 0.5 - 0.583333h; Stage #2: 1-(4-toluenesulfonyl)-1H-1,2,4-triazole In 1,4-dioxane at 10 - 125℃; for 3.33333 - 5h; Product distribution / selectivity;
Stage #1: 2-[3-(cyano-dimethyl-methyl)-5-hydroxymethyl-phenyl]-2-methyl-propionitrile With sodium hydride In 1,2-dimethoxyethane at 70℃; for 0.5h; Stage #2: 1-(4-toluenesulfonyl)-1H-1,2,4-triazole In 1,2-dimethoxyethane at 10 - 100℃; for 3.33333h; Product distribution / selectivity;
Stage #1: 2-[3-(cyano-dimethyl-methyl)-5-hydroxymethyl-phenyl]-2-methyl-propionitrile With sodium hydride In tetrahydrofuran at 70℃; for 0.5h; Stage #2: 1-(4-toluenesulfonyl)-1H-1,2,4-triazole In tetrahydrofuran at 10 - 100℃; for 3.33333h; Product distribution / selectivity;

1,2,4-Triazole (288-88-0) + 2-[3-bromomethyl-5-(cyanodimethylmethyl)phenyl]-2-methylpropanenitrile (120511-84-4) → α,α,α',α'-tetramethyl-5-(4H-1,2,4-triazol-4ylmethyl)-1,3-benzene-diacetonitrile (120511-92-4) + anastrozol (120511-73-1)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide for 2h; Product distribution / selectivity; Reflux;
With potassium carbonate In toluene at 9 - 21℃; for 4.5h; Overall yield = 71.8 %; Overall yield = 42.14 g;

3,5-bis(2-cyanoprop-2-yl)toluene (120511-72-0) → anastrozol (120511-73-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione / 2,2'-azobis(isobutyronitrile) / cyclohexane / 4 h / 25 - 85 °C 2.1: isopropyl alcohol / 5 h / 80 - 85 °C 3.1: hydrogenchloride; sodium nitrite / water / 8 h / -5 - 20 °C 3.2: 4 h / 5 - 25 °C View Scheme
Multi-step reaction with 3 steps 1.1: N-Bromosuccinimide; acetic acid; 2,2'-azobis(isobutyronitrile) / acetonitrile / 6.5 h / 65 °C / Reflux; Industrial scale 2.1: 3 h / Reflux; Industrial scale 3.1: hydrogenchloride; sodium nitrite / acetonitrile; water / 4 h / 15 - 22 °C / Industrial scale 3.2: 0.5 h / 20 °C / Industrial scale 3.3: 12 h / 12 °C / Industrial scale View Scheme

dichloro(benzene)ruthenium(II) dimer (37366-09-9) + ammonium tetrafluroborate (13826-83-0) + anastrozol (120511-73-1) → [Ru(η6-C6H6)(η1-anastrozole)2Cl]BF4

Conditions	Yield
In ethanol for 6h; Reflux; Inert atmosphere;	68%

dichloro(benzene)ruthenium(II) dimer (37366-09-9) + sodium tetraphenyl borate (143-66-8) + anastrozol (120511-73-1) → [Ru(η6-C6H6)(η1-anastrozole)2Cl]BPh4

Conditions	Yield
In ethanol for 6h; Reflux; Inert atmosphere;	60%

C63H94ClCoN16O14PPt(1+)*C2F3O2(1-) + anastrozol (120511-73-1) → C80H113CoN21O14PPt(2+)*2C2F3O2(1-)

Conditions	Yield
In water at 40℃; for 24h;	58%

Sodium trans-Bis(dimethhyl sulfoxide) tetrachlororuthenate(III) (131759-88-1, 61779-28-0) + anastrozol (120511-73-1) → Na[trans-RuCl4(anastrozole)(dimethyl sulfoxide)]

Conditions	Yield
In acetone Inert atmosphere; Schlenk technique;	56%

Ru(η6-C6H6)oxalate(H2O) + anastrozol (120511-73-1) → Ru(η6-C6H6)oxalate(η1-anastrozole)

Conditions	Yield
In ethanol for 24h; Inert atmosphere; Reflux;	52%

anastrozol (120511-73-1) → 3,5-bis(2-cyanoprop-2-yl)toluene (120511-72-0) + 2-(3-((1H-1,2,4-triazol-1-yl)methyl)-5-isopropylphenyl)-2-methylpropanenitrile

Conditions	Yield
With tetraethylammonium perchlorate; triethylamine In dimethyl sulfoxide at 20℃; for 9h; Electrolysis; Green chemistry;	A 47% B 26%

silver tetrafluoroborate (14104-20-2) + chloro(cyclopentadienyl)bis(triphenylphosphine)ruthenium (II) (32993-05-8) + anastrozol (120511-73-1) → Ru(cyclopentadienyl)(PPh3)2(anastrozole)BF4

Conditions	Yield
In acetone for 2h; Inert atmosphere; Schlenk technique; Reflux;	36%

(η4-1,5-cyclooctadiene)dichlororuthenium(II) + anastrozol (120511-73-1) → Ru(cyclooctadienyl)(anastrozole)2Cl2

Conditions	Yield
In acetonitrile at 80℃; under 775.743 Torr; for 48h; Microwave irradiation; Inert atmosphere; Schlenk technique;	22%

methanesulfonic acid (75-75-2) + anastrozol (120511-73-1) → anastrozole mesylate (1015083-81-4)

Conditions	Yield
In ethyl acetate Product distribution / selectivity; Acidic conditions;

toluene-4-sulfonic acid (104-15-4) + anastrozol (120511-73-1) → 2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]di(2-methyl)propionitrile p-toluenesulfonate salt

Conditions	Yield
In acetone at 20 - 25℃; for 13h;
In acetone for 1h;
In toluene for 0.5h; Heating / reflux;

anastrozol (120511-73-1) → 2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]-di(2-methylpropionitrile) hydrochloride

Conditions	Yield
With hydrogenchloride In isopropyl alcohol; acetone
With hydrogenchloride In water at 20 - 42℃; for 0.5h; Product distribution / selectivity;

(2E)-but-2-enedioic acid (110-17-8) + anastrozol (120511-73-1) → 2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]di(2-methyl)propionitrile fumarate salt

Conditions	Yield
In acetone at 20℃; for 5h; Heating / reflux;

oxalic acid (144-62-7) + anastrozol (120511-73-1) → 2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]di(2-methyl)propionitrile oxalate

Conditions	Yield
In isopropyl alcohol at 20℃; for 4h;

Upstream product

• 120511-88-8 2-[3-(cyano-dimethyl-methyl)-5-hydroxymethyl-phenyl]-2-methyl-propionitrile 
• 13578-51-3 1-(4-toluenesulfonyl)-1H-1,2,4-triazole 
• 288-88-0 1,2,4-Triazole 
• 120511-84-4 2-[3-bromomethyl-5-(cyanodimethylmethyl)phenyl]-2-methylpropanenitrile 
• 120511-89-9 3,5-bis(2-cyanopropan-2-yl)benzaldehyde 
• 120511-72-0 3,5-bis(2-cyanoprop-2-yl)toluene 
• 41253-21-8 sodium triazole 
• 290-87-9 1,3,5-Triazine 
• 120511-91-3 α,α,α',α'-tetramethyl-5-chloromethyl-1,3-benzene diacetonitrile 
• 876514-43-1 2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]-di(2-methylpropionitrile) hydrobromide 
• 1015083-81-4 anastrozole mesylate 

Downstream Products

• 1015083-81-4 anastrozole mesylate 
• 120511-72-0 3,5-bis(2-cyanoprop-2-yl)toluene 

Relevant articles and documents

How to use the Lasentec FBRM probe on manufacturing scale

A Lasentec FBRM probe was installed in a 450-L production unit and deployed to monitor the final three stages of the manufacturing process. Each step features a different type of crystallization: reactive, pH switch and cooling. In total over 100 batches were monitored. The probe detected 'oiling out' and seeding with agitation but did not detect 'bearding' or seeding without agitation. There was remarkable consistency from batch to batch, except for the first batches in some campaigns, which more closely resembled laboratory experiments. The challenge of interpreting Lasentec FBRM data in a production environment is addressed and compared with the alternative, in process control (IPC).

Preparation method of anastrozole

The invention provides a preparation method of anastrozole. The preparation method comprises the following steps that 1, 5-bromomethyl-a,a,a',a'-tetramethyl-1,3-xylylene cyanide and 4-amino-1,2,4-triazole are taken as raw materials to react in an organic solvent, and crystallization is conducted to obtain an intermediate I, that is, a,a,a',a'-tetramethyl-5-[(4-amino-1,2,4-triazol)-methylene]-1,3-xylylene cyanide bromide; 2, the intermediate I is dissolved into a solvent, a little amount of water, acid and a metal catalyst are added, sodium azide is added in batches in a reflux state, immediate filtration is conducted after a complete reaction, a mother solution is concentrated until the volume of the solution is 0.25-0.75 times of the original volume of the mother solution, cooling crystallization is conducted, solids are filtered and subjected to PH regulation and extraction, and concentration is conducted to obtain a crude anastrozole product; 3, the crude anastrozole product is dissolved into an alcohol solvent, decoloring and cooling crystallization are conducted, and the fine anastrozole product is obtained. According to the preparation method, iso-anastrozole impurities influencing the medicinal efficacy are prevented from being generated from the source, no iso-anastrozole is detected out, the remaining single impurity content is less than 0.05%, and the remaining total impurity content is less than 0.2%.

METHOD FOR PREPARING ANASTROZOLE FOR PHARMACEUTICAL PURPOSES

A method for preparing anastrozole characterised in that it comprises; - a bromination step, wherein 2-2' (5-methyl-1, 3- phenylene) bis (2-methylpropanenitrile) is subject to a bromination reaction in the presence of an ester solvent so as to obtain 2- [3 -bromomethyl-5 - (cyano-dimethyl-methyl) -phenyl] - 2-methyl-propanenitrile; - a nucleophilic substitution step, wherein an organic mixture comprising unreacted 2-2' ( 5-methyl-l, 3 -phenylene) bis (2- methylpropanenitrile), the 2- [3 -bromomethyl-5- (cyano-dimethyl- methyl) -phenyl] -2 -methyl-propanenitrile formed and, if necessary, other reaction by-products is caused to react in dimethylformamide with 1-2-4-triazole or with its sodium salt at a temperature ranging from 0 to 25 °C for the formation of anastrozole; - an anastrozole purification step.