183321-74-6

Basic information

• Product Name: Erlotinib
• Synonyms: ERLOTINIB;ERLOTINIB HCL;ERLOTINIB HCL SALT;4-[(3-ethynylphenyl)amino]-6,7-bis(2-methoxyethoxy)quinazoline;n-(3-ethynylphenyl)[6,7-bis(2-methoxyethoxy)quinazolin-4-yl]amine;Erlotinib Hydrochloirde;4-Quinazolinamine, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-;Tarceva
• CAS NO: 183321-74-6
• Molecular Formula: C₂₂H₂₃N₃O₄
• Molecular Weight: 393.44
• EINECS: 1312995-182-4
• Product Categories: Erlotinib;Pharmaceutical intermediate;APIs;Isotope;Tarceva;Antineoplastic;Anti-cancer&immunity;API;Inhibitors
• Mol File: 183321-74-6.mol

Chemical Properties

• Melting Point: 159-160 °C
• Boiling Point: 553.6 °C at 760 mmHg
• Flash Point: 288.6 °C
• Appearance: white to off-white powder
• Density: 1.24
• Storage Temp.: Keep in dark place,Sealed in dry,Store in freezer, under -20°C
• Solubility: Chloroform (Slightly), DMSO (Slightly), Methanol (Slightly)
• PKA: 5.32±0.30(Predicted)
• CAS DataBase Reference: Erlotinib(CAS DataBase Reference)
• NIST Chemistry Reference: Erlotinib(183321-74-6)
• EPA Substance Registry System: Erlotinib(183321-74-6)

Safety Data

• Safety Statements: 24/25
• Hazardous Substances Data: 183321-74-6(Hazardous Substances Data)

Usage

Uses

Used in Anticancer Applications:
Erlotinib is used as an antineoplastic agent for inhibiting tumor growth in various types of cancer. It has been particularly effective in treating human head and neck carcinoma HN5 tumor xenografts in mice, as well as suppressing cyclin-dependent kinase 2 (Cdk2) activity in breast cancer cells and JAK2 mutant JAK2V617F positive hematopoietic progenitor cells, which are associated with polycythemia vera, idiopathic myelofibrosis, and essential thrombocythemia.
Used in Non-Small Cell Lung Cancer Treatment:
Erlotinib is used as a tyrosine kinase inhibitor for treating certain forms of non-small cell lung cancer. Formulations containing erlotinib have been developed to enhance its therapeutic outcomes in patients with this type of cancer.
Used in Pharmaceutical Industry:
In the pharmaceutical industry, erlotinib is used as a key component in the development of targeted cancer therapies. Its ability to inhibit EGFR-associated kinase activity makes it a valuable asset in the fight against various types of cancer, including non-small cell lung cancer and other solid malignancies.

Molecular targeted therapy

The small molecule compound, Erlotinib is a receptor tyrosine kinase inhibitor (EGFR antagonist) and belongs to molecular targeted therapy Drugs. It can inhibit the phosphorylation reaction through competing with adenosine triphosphate to bind to the catalytic region of the receptor tyrosine kinase, thereby blocking the down-proliferation signaling and inhibiting the activity of the tumor cell ligand-dependent HER-1/EGFR, thus achieving the inhibition of the proliferation of tumor cells. Clinically, it is mainly used in the treatment of incurable locally advanced or metastatic non-small cell lung cancer (NSCLC) and being used in combination with gemcitabine for first-line treatment of locally advanced unresectable or metastatic pancreatic cancer. In November 2004, the product was first approved in the United States for the treatment of local advanced or metastatic non-small cell lung cancer (NSCLC) which has been undergone at least one time of chemotherapy failure. In 2005, the results of a Phase III trial of the NCI Canadian Clinical Trials Group suggested that gemcitabine, in combination with erlotinib (EGFR blocker) can increase the median survival of patients with advanced pancreatic cancer from 5.9 months to 6.4 months and 1-year survival from 17% to 24%. In November 2005, Genentech and OSI jointly announced that the US Food and Drug Administration (FDA) had approved the combination of erlotinib (Tarceva) and gemcitabine as first-line treatment for advanced pancreatic cancer.

Gefitinib

Gefitinib is an aniline quinazoline derivative and is also a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that inhibits the growth, metastasis and angiogenesis of tumors and increases tumor cell apoptosis; Gefitinib is a kind of highly-specific anti-tumor targeted therapy drugs developed by the United Kingdom AstraZeneca, being the first molecular targeted drug for the treatment of non-small cell lung cancer. It takes effects through selectively inhibiting the signal transduction pathway of the epidermal growth factor receptor tyrosine kinase (EGFR-TK). Epidermal growth factor (EGF) is a polypeptide with a relative molecular mass of 6.45 × 103 that binds to the epidermal growth factor receptor (EGFR) on the target cell membrane to produces biological effects. EGFR is a tyrosine kinase (TK) receptor that, when conjugated to EGF, being capable of promoting the TK activation in the receptor, leading to auto-phosphorylation of the receptor tyrosine residue, providing a continuous signal splitting into the cell, further causing cell proliferation and differentiation. EGFR is abundant in human tissues and highly expressed in malignant tumors. Gefitinib, through interfering with the EGFR signaling transduction pathways on the cell surface, inhibits the tumor growth, metastasis and angiogenesis and induces tumor cell apoptosis. In August 2002, gefitinib, as a first-line treatment of non-small cell lung cancer drugs, was first listed in Japan under the trade name of Iressa. In May 2003, the US Food and Drug Administration approved gefitinib as the three-line monotherapy drug for patients with advanced non-small cell lung cancer that can’t be cured by platinum-based anti-cancer drugs and docetaxel chemotherapy. Now, it has been also approved by Australia, Japan, Argentina, Singapore and South Korea and other countries for the treatment of advanced non-small cell lung cancer. On February 28, 2005, the Chinese Food and Drug Administration approved gefitinib for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) previously subjecting to chemotherapy treatment. It has not yet been approved as a first-line treatment for advanced NSCLC. On July 1, 2009, the European Union Drug Administration has formally approved gefitinib for the first, second and third line treatment of adult EGFR mutations locally advanced or metastatic non-small cell lung cancer.

Dosage and Usage

Non-small cell lung cancer: 150mg/d; administrate at least1h before meals or 2h after meal; continue taking the drug until the disease get progression or the emergence of intolerable toxicity response when the patients should withdraw the drug. Pancreatic cancer: combine with gemcitabine for 100mg /d at least 1h before meals or 2h after meals; continue taking the drug until the disease get progression or the emergence of intolerable toxicity response when the patients should withdraw the drug. Upon severe liver insufficiency, the drug dosage should be reduced or temporarily discontinued, elderly patients do not have to adjust the dose.

Clinical evaluation

Erlotinib is another tyrosine kinase inhibitor for the treatment of NSCLC after imatinib. The phase I clinical trial results have shown that its main toxicity and side effects are dose-dependent rash and diarrhea. Other rare side effects also include headache, nausea and vomiting. Phase II trial takes erlotinib as a second line antineoplastic drugs with the efficacy being comparable as the second-line chemotherapy drug docetaxel. The Phase III randomized controlled trial (BR21) was performed in patients with NSCLC who had failed in the primary or secondary chemotherapy (locally advanced and distant metastases). Study group applied erlotinib in a dosage of 150mg daily for treatment of a total of 488 cases. A total of 243 cases were treated with placebo in the control group. The result: the median overall survival rate was 6.7 months in the treatment group and 4.7 months in the control group (P <0.001, HR = 0.73). The 1-year survival rate was 31.2% in the treatment group and 21.5% in the control group; the time of progression was 9.9 weeks in treatment group and 7.9 weeks in control group while the improvement of symptoms in patients with erlotinib was more obvious. Based on the results of BR21 research, a number of phase Ⅲ clinical studies have been carried out successively. TRIBUTE clinical trial combined the Erlotinib with chemotherapy in an attempt to compare whether the efficacy of its combination with chemotherapy is better than chemotherapy alone. For the treatment group, chemotherapy (carboplatin plus paclitaxel) + erlotinib were combined; for the control group, the same chemotherapy was used alone. A total of 1059 patients with advanced NSCLC were included in the study. The efficacy in the research result: 21.5% for research group; 19.3% for the control group. The median survival time was 10.8 months in the study group and 10.6 months in the control group. The time to tumor progression (TTP) was 5.1 months in the study group and 5.0 months in the control group. Another TALENT study also focused on whether the combination of erlotinib and chemotherapy (gemcitabine + cisplatin) can improve the efficacy of chemotherapy and have included a total of 1172 cases of NSCLC patients. The results also did not show that erlotinib can significantly improve the efficacy of chemotherapy.

Adverse reactions and precautions

Common adverse reactions include rash, fever, anorexia, indigestion, nausea, vomiting, diarrhea, constipation and abdominal pain, fatigue, weight loss and edema, bone pain and muscle pain, dyspnea, elevated transaminases. In rare cases, it was observed of bone marrow suppression. Oral administration of warfarin may lead to unexpectedly increased international standardization ratio. There are occasionally chills, cough, stomatitis, keratoconjunctivitis, anxiety and neurological diseases, elevated bilirubin. In rare cases, there are microangiopathies hemolytic anemia and thrombocytopenia. Cough and fever may be associated with interstitial lung disease, if it occurs, the drugs should be discontinued. Cytochrome P450 enzymes affect the metabolism of the product. Its inhibitor ketoconazole or agonist rifampicin can change the plasma concentration of this product, resulting in increased toxicity or reduced toxicity. Patients of co-administration of warfarin should subject to closely monitoring of the international normalized ratio.

What is molecular targeted therapy?

Molecular targeted therapy is no longer a new term. Scientists are constantly exploring the pathogenesis of cancer molecular biology, realizing that if specific changes in cancer can be given by a powerful blow, it will greatly improve the treatment effect, triggering changes in anti-cancer treatment concept. In recent years, new molecular targeted drugs in clinical practice have achieved remarkable results. The practice has shown that the correctness and feasibility of the molecular targeted therapy theory, putting the cancer treatment to an unprecedented new stage. Depending on the target and nature of the drug, the drugs of the major target molecule therapy can be divided into the following categories: (1) Small molecule tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR): such as gefitinib (Iressa), Erlotinib (Tarceva); (2) anti-EGFR monoclonal antibody: such as cetuximab (); (3) Anti-HER-2 monoclonal antibody: such as Herceptin (Trastuzumab); (4) Bcr-Abl tyrosine kinase inhibitors: such as imatinib; (5) Vascular endothelial growth factor receptor inhibitors: such as Bevacizumab (Avastin); (6) anti-CD20 monoclonal antibody: such as rituximab (Rituximab); (7) IGFR-1 kinase inhibitors such as NVP-AEW541; (8) mTOR kinase inhibitors: such as CCI-779; (9) Ubiquitin-proteasome inhibitors: such as Bortezomib; (10) Other: such as Aurora kinase inhibitors, histone deacetylase (HDACs) inhibitors.

Clinical Use

ErlotinibTreatment of locally advanced or metastatic nonsmall cell lung cancer after failure of at least 1 other regimePancreatic cancer

Side effects

Burning, tingling, numbness or pain in the hands, arms, feet, or legs.cough or hoarseness.diarrhea (severe)difficult or labored breathing.fever or chills.rash (severe)sensation of pins and needles.stabbing chest pain.

Synthesis

The synthesis of?Erlotinib is as follows:N-dimethylformamidine, 0.72 g (6.15 mmol) of N '- [2-cyano-4,5-bis (2-methoxyethoxy) phenyl] ) Of 3-aminophenylacetylene and 8 mL of acetic acid were reacted in a 50 mL reaction flask at 125 ° C for 1 hour and cooled to room temperature.20 mL of ice water was added to the mixture, the pH was adjusted to 10 with aqueous ammonia, and the mixture was stirred for 1 hour, suction filtered and the filter cake washed with water until neutral.The filter cake was dried to obtain 2.15 g of erlotinib in a yield of 91.5%.

Drug interactions

Potentially hazardous interactions with other drugs Analgesics: increased risk of bleeding with NSAIDs.Antacids: concentration possibly reduced by antacids, give at least 4 hours before or 2 hours after erlotinib. Anticoagulants: increased risk of bleeding with coumarinsAntipsychotics: avoid concomitant use with clozapine, increased risk of agranulocytosis.Antivirals: avoid with boceprevir.Ulcer-healing drugs: avoid with cimetidine, esomeprazole, famotidine, lansoprazole, nizatidine, pantoprazole and rabeprazole; concentration reduced by ranitidine, give at least 2 hours before or 10 hours after ranitidine; concentration reduced by omeprazole - avoid.

Metabolism

Erlotinib is metabolised mainly by the cytochrome P450 isoenzyme CYP3A4, and to a lesser extent by CYP1A2. Extrahepatic metabolism by CYP3A4 in intestine, CYP1A1 in lung, and 1B1 in tumour tissue potentially contribute to the metabolic clearance of erlotinib.Metabolic pathways include demethylation, to metabolites OSI-420 and OSI-413, oxidation, and aromatic hydroxylation. The metabolites OSI-420 and OSI-413 have comparable potency to erlotinib in non-clinical in vitro assays and in vivo tumour models. They are present in plasma at levels that are <10 % of erlotinib and display similar pharmacokinetics as erlotinib. Erlotinib is excreted predominantly as metabolites via the faeces (>90%) with renal elimination accounting for only a small amount (approximately 9%) of an oral dose. Less than 2% of the orally administered dose is excreted as parent substance

InChI:InChI=1/C22H23N3O4/c1-4-16-6-5-7-17(12-16)25-22-18-13-20(28-10-8-26-2)21(29-11-9-27-3)14-19(18)23-15-24-22/h1,5-7,12-15H,8-11H2,2-3H3,(H,23,24,25)

Synthetic route

3-acetylenephenylamine (54060-30-9) + 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1) → erlotinib (183321-74-6)

Conditions	Yield
In isopropyl alcohol Concentration; Reflux;	96.6%
In isopropyl alcohol Temperature; Reflux;	96.6%
In isopropyl alcohol at 20℃; Concentration; Temperature; Reflux;	96.6%

erlotinib hydrochloride (183319-69-9) → erlotinib (183321-74-6)

Conditions	Yield
With sodium hydroxide In water pH=5 - 12; Product distribution / selectivity;	96.3%
With ammonia In water for 2h; pH=9.4; Product distribution / selectivity;	94.3%
With sodium hydroxide In water; ethyl acetate at 20℃; Product distribution / selectivity;

N′-[2-cyano-4,5-{bis(2-methoxyethoxy)phenyl}]-N,N-dimethylformamidine (950596-59-5) + 3-acetylenephenylamine (54060-30-9) → erlotinib (183321-74-6)

Conditions	Yield
With acetic acid In N,N-dimethyl-formamide at 125℃; for 1h;	91.5%
With acetic acid In toluene at 125 - 130℃;	66%
With acetic acid at 125 - 130℃; for 3h;	66%
Stage #1: N′-[2-cyano-4,5-{bis(2-methoxyethoxy)phenyl}]-N,N-dimethylformamidine; 3-acetylenephenylamine With acetic acid at 125℃; for 3h; Stage #2: With sodium hydrogencarbonate In water at 0℃;

2-amino-4,5-bis-(2-methoxyethoxy)-benzonitrile (950596-58-4) + (E)-N,N'-bis(3-ethynylphenyl)methyl ether → erlotinib (183321-74-6)

Conditions	Yield
With toluene-4-sulfonic acid In toluene at 110℃; for 5h; Temperature; Solvent;	88.2%

6,7-bis(2-methoxyethoxy)-3,4-dihydroquinazolin-4-one (179688-29-0) + 3-acetylenephenylamine (54060-30-9) → erlotinib (183321-74-6)

Conditions	Yield
With titanium tetrachloride; methoxybenzene In 1,4-dioxane for 4h; Inert atmosphere; Reflux;	82%
Stage #1: 6,7-bis(2-methoxyethoxy)-3,4-dihydroquinazolin-4-one With triethylamine; trichlorophosphate In toluene at 20 - 65℃; Inert atmosphere; Stage #2: 3-acetylenephenylamine In isopropyl alcohol; toluene for 2.5h; Inert atmosphere;	64%

6,7-bis(2-methoxyethoxy)-4-methoxyquinazoline (1312937-41-9) + 3-acetylenephenylamine (54060-30-9) → erlotinib (183321-74-6)

Conditions	Yield
Stage #1: 3-acetylenephenylamine In tetrahydrofuran; toluene at 0℃; for 0.5h; Inert atmosphere; Stage #2: 6,7-bis(2-methoxyethoxy)-4-methoxyquinazoline In tetrahydrofuran; toluene at 20℃; for 4h; Product distribution / selectivity;	70%
Stage #1: 3-acetylenephenylamine With n-butyllithium In tetrahydrofuran; toluene at 0℃; Inert atmosphere; Stage #2: 6,7-bis(2-methoxyethoxy)-4-methoxyquinazoline In tetrahydrofuran; toluene at 0 - 20℃; for 4.16667h; Product distribution / selectivity;	70%

3,4-bis(2-methoxyethoxy) benzonitrile (80407-68-7) → erlotinib (183321-74-6)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: nitric acid / acetic acid / 4 h / 0 °C 2.1: sodium dithionite / water / 3 h / 50 °C 2.2: 0.5 h / 65 °C 3.1: acetic acid; N,N-dimethyl-formamide dimethyl acetal / toluene / 4 h / 105 °C 4.1: acetic acid / toluene / 5 h / 60 °C 5.1: toluene / 5 h / 125 °C View Scheme
Multi-step reaction with 4 steps 1.1: nitric acid / acetic acid / 4 h / 0 °C 2.1: sodium dithionite / water / 3 h / 50 °C 2.2: 0.5 h / 65 °C 3.1: acetic acid; N,N-dimethyl-formamide dimethyl acetal / toluene / 4 h / 105 °C 4.1: acetic acid / toluene / 125 - 130 °C View Scheme
Multi-step reaction with 4 steps 1.1: acetic acid / 20 °C 1.2: 5 - 55 °C 2.1: palladium on activated charcoal; hydrogen / ethanol / 2.5 h / 20 °C / 2585.81 Torr 3.1: 3 h / 20 °C / Reflux 4.1: acetic acid / 2 h / Reflux View Scheme

2-nitro-4,5-bis(2-methoxyethoxy)benzonitrile (236750-65-5) → erlotinib (183321-74-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium dithionite / water / 3 h / 50 °C 1.2: 0.5 h / 65 °C 2.1: acetic acid; N,N-dimethyl-formamide dimethyl acetal / toluene / 4 h / 105 °C 3.1: acetic acid / toluene / 5 h / 60 °C 4.1: toluene / 5 h / 125 °C View Scheme
Multi-step reaction with 3 steps 1.1: sodium dithionite / water / 3 h / 50 °C 1.2: 0.5 h / 65 °C 2.1: acetic acid; N,N-dimethyl-formamide dimethyl acetal / toluene / 4 h / 105 °C 3.1: acetic acid / toluene / 125 - 130 °C View Scheme
Multi-step reaction with 3 steps 1: sodium dithionite / water / 2.5 h / 50 °C 2: acetic acid / toluene / 3 h / 105 °C / Dean-Stark 3: acetic acid / 3 h / 125 - 130 °C View Scheme
Multi-step reaction with 4 steps 1: hydrazine hydrate / water / 3 h / 20 - 30 °C 2: trifluoroacetic acid / ethyl acetate / 4 h / Reflux 3: trichlorophosphate; N,N-dimethyl-formamide / ethyl acetate / 2 h / 70 °C / Inert atmosphere 4: ethanol / 3 h / 40 - 70 °C View Scheme
Multi-step reaction with 3 steps 1: palladium on activated charcoal; hydrogen / ethanol / 2.5 h / 20 °C / 2585.81 Torr 2: 3 h / 20 °C / Reflux 3: acetic acid / 2 h / Reflux View Scheme

C24H30N4O4 → erlotinib (183321-74-6)

Conditions	Yield
In toluene at 125℃; for 5h;	47 g

methoxyethoxy 3,4-bis(2-methoxyethoxy)-benzoate → erlotinib (183321-74-6)

Conditions	Yield
Multi-step reaction with 8 steps 1.1: water; potassium hydroxide / methanol / 4 h / 20 °C 2.1: urea / 0.5 h / 220 °C 3.1: phosphorus pentoxide / 5,5-dimethyl-1,3-cyclohexadiene / 18 h / Reflux 4.1: nitric acid / acetic acid / 4 h / 0 °C 5.1: sodium dithionite / water / 3 h / 50 °C 5.2: 0.5 h / 65 °C 6.1: acetic acid; N,N-dimethyl-formamide dimethyl acetal / toluene / 4 h / 105 °C 7.1: acetic acid / toluene / 5 h / 60 °C 8.1: toluene / 5 h / 125 °C View Scheme
Multi-step reaction with 7 steps 1.1: water; potassium hydroxide / methanol / 4 h / 20 °C 2.1: urea / 0.5 h / 220 °C 3.1: phosphorus pentoxide / 5,5-dimethyl-1,3-cyclohexadiene / 18 h / Reflux 4.1: nitric acid / acetic acid / 4 h / 0 °C 5.1: sodium dithionite / water / 3 h / 50 °C 5.2: 0.5 h / 65 °C 6.1: acetic acid; N,N-dimethyl-formamide dimethyl acetal / toluene / 4 h / 105 °C 7.1: acetic acid / toluene / 125 - 130 °C View Scheme

3,4-bis(2-methoxyethoxy)-benzamide (1418289-91-4) → erlotinib (183321-74-6)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: phosphorus pentoxide / 5,5-dimethyl-1,3-cyclohexadiene / 18 h / Reflux 2.1: nitric acid / acetic acid / 4 h / 0 °C 3.1: sodium dithionite / water / 3 h / 50 °C 3.2: 0.5 h / 65 °C 4.1: acetic acid; N,N-dimethyl-formamide dimethyl acetal / toluene / 4 h / 105 °C 5.1: acetic acid / toluene / 5 h / 60 °C 6.1: toluene / 5 h / 125 °C View Scheme
Multi-step reaction with 5 steps 1.1: phosphorus pentoxide / 5,5-dimethyl-1,3-cyclohexadiene / 18 h / Reflux 2.1: nitric acid / acetic acid / 4 h / 0 °C 3.1: sodium dithionite / water / 3 h / 50 °C 3.2: 0.5 h / 65 °C 4.1: acetic acid; N,N-dimethyl-formamide dimethyl acetal / toluene / 4 h / 105 °C 5.1: acetic acid / toluene / 125 - 130 °C View Scheme

3,4-bis(2-methoxyethoxy)-benzoic acid (819813-71-3) → erlotinib (183321-74-6)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: urea / 0.5 h / 220 °C 2.1: phosphorus pentoxide / 5,5-dimethyl-1,3-cyclohexadiene / 18 h / Reflux 3.1: nitric acid / acetic acid / 4 h / 0 °C 4.1: sodium dithionite / water / 3 h / 50 °C 4.2: 0.5 h / 65 °C 5.1: acetic acid; N,N-dimethyl-formamide dimethyl acetal / toluene / 4 h / 105 °C 6.1: acetic acid / toluene / 5 h / 60 °C 7.1: toluene / 5 h / 125 °C View Scheme
Multi-step reaction with 6 steps 1.1: urea / 0.5 h / 220 °C 2.1: phosphorus pentoxide / 5,5-dimethyl-1,3-cyclohexadiene / 18 h / Reflux 3.1: nitric acid / acetic acid / 4 h / 0 °C 4.1: sodium dithionite / water / 3 h / 50 °C 4.2: 0.5 h / 65 °C 5.1: acetic acid; N,N-dimethyl-formamide dimethyl acetal / toluene / 4 h / 105 °C 6.1: acetic acid / toluene / 125 - 130 °C View Scheme
Multi-step reaction with 10 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 3 h / 0 - 20 °C 2: triethylamine / dichloromethane / 0 - 20 °C 3: triethylamine; dmap / dichloromethane / 24 h / 20 °C 4: sodium hydroxide / methanol / 2 h / 20 °C 5: dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; silver hexafluoroantimonate; [bis(acetoxy)iodo]benzene / dichloromethane / 16 h / 40 °C / Inert atmosphere 6: sodium hydroxide / ethanol / 20 °C 7: ethanol / 1 h / Reflux 8: hydrogenchloride / water / 2 h / 100 - 105 °C 9: trichlorophosphate / toluene / 4 h / Reflux 10: pyridine / isopropyl alcohol / 4 h / Reflux View Scheme

2-amino-4,5-bis-(2-methoxyethoxy)-benzonitrile (950596-58-4) → erlotinib (183321-74-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: acetic acid; N,N-dimethyl-formamide dimethyl acetal / toluene / 4 h / 105 °C 2: acetic acid / toluene / 5 h / 60 °C 3: toluene / 5 h / 125 °C View Scheme
Multi-step reaction with 2 steps 1: acetic acid / toluene / 3 h / 105 °C / Dean-Stark 2: acetic acid / 3 h / 125 - 130 °C View Scheme

N′-[2-cyano-4,5-{bis(2-methoxyethoxy)phenyl}]-N,N-dimethylformamidine (950596-59-5) → erlotinib (183321-74-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: acetic acid / toluene / 5 h / 60 °C 2: toluene / 5 h / 125 °C View Scheme

3,4-Dihydroxybenzoic acid (99-50-3) → erlotinib (183321-74-6)

Conditions	Yield
Multi-step reaction with 9 steps 1.1: tetra-(n-butyl)ammonium iodide; potassium carbonate / N,N-dimethyl-formamide / 1 h / 100 °C 1.2: 50 - 85 °C 2.1: water; potassium hydroxide / methanol / 4 h / 20 °C 3.1: urea / 0.5 h / 220 °C 4.1: phosphorus pentoxide / 5,5-dimethyl-1,3-cyclohexadiene / 18 h / Reflux 5.1: nitric acid / acetic acid / 4 h / 0 °C 6.1: sodium dithionite / water / 3 h / 50 °C 6.2: 0.5 h / 65 °C 7.1: acetic acid; N,N-dimethyl-formamide dimethyl acetal / toluene / 4 h / 105 °C 8.1: acetic acid / toluene / 5 h / 60 °C 9.1: toluene / 5 h / 125 °C View Scheme
Multi-step reaction with 8 steps 1.1: tetra-(n-butyl)ammonium iodide; potassium carbonate / N,N-dimethyl-formamide / 1 h / 100 °C 1.2: 50 - 85 °C 2.1: water; potassium hydroxide / methanol / 4 h / 20 °C 3.1: urea / 0.5 h / 220 °C 4.1: phosphorus pentoxide / 5,5-dimethyl-1,3-cyclohexadiene / 18 h / Reflux 5.1: nitric acid / acetic acid / 4 h / 0 °C 6.1: sodium dithionite / water / 3 h / 50 °C 6.2: 0.5 h / 65 °C 7.1: acetic acid; N,N-dimethyl-formamide dimethyl acetal / toluene / 4 h / 105 °C 8.1: acetic acid / toluene / 125 - 130 °C View Scheme
Multi-step reaction with 7 steps 1.1: sulfuric acid / 10 h / 40 - 80 °C 2.1: potassium tert-butylate; potassium iodide / N,N-dimethyl-formamide / 12 h / 100 °C 3.1: sulfuric acid; nitric acid / 1 h / 20 °C / Darkness 4.1: palladium 10% on activated carbon / ethanol / 10 h / 20 °C 4.2: 20 °C 5.1: ammonium formate; triethylamine / 6 h / 160 °C 6.1: oxalyl dichloride / N,N-dimethyl-formamide; dichloromethane / 3 h / 50 °C 7.1: methanol / 3 h / 20 - 30 °C 7.2: 3 h / 50 °C View Scheme

Ethyl protocatechuate (3943-89-3) → erlotinib (183321-74-6)

Conditions	Yield
Multi-step reaction with 12 steps 1: potassium carbonate / N,N-dimethyl-formamide / 5 h / 50 °C 2: potassium hydroxide / ethanol; water / 3 h / 20 °C 3: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 3 h / 0 - 20 °C 4: triethylamine / dichloromethane / 0 - 20 °C 5: triethylamine; dmap / dichloromethane / 24 h / 20 °C 6: sodium hydroxide / methanol / 2 h / 20 °C 7: dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; silver hexafluoroantimonate; [bis(acetoxy)iodo]benzene / dichloromethane / 16 h / 40 °C / Inert atmosphere 8: sodium hydroxide / ethanol / 20 °C 9: ethanol / 1 h / Reflux 10: hydrogenchloride / water / 2 h / 100 - 105 °C 11: trichlorophosphate / toluene / 4 h / Reflux 12: pyridine / isopropyl alcohol / 4 h / Reflux View Scheme
Multi-step reaction with 6 steps 1: potassium carbonate; tetra-(n-butyl)ammonium iodide / acetone / 64 h / Inert atmosphere; Reflux 2: acetic acid; nitric acid / 24 h / 5 °C 3: hydrogenchloride; hydrogen; platinum(IV) oxide hydrate / water; ethanol / 6 h / 2327.23 Torr 4: ammonium formate / 3 h / 160 - 165 °C / Inert atmosphere 5: pyridine; trichlorophosphate / 2.5 h / Inert atmosphere 6: pyridine / isopropyl alcohol / 4 h / Reflux; Inert atmosphere View Scheme
Multi-step reaction with 6 steps 1: potassium carbonate; tetra-(n-butyl)ammonium iodide / acetone / 64 h / Inert atmosphere; Reflux 2: acetic acid; nitric acid / 24 h / 5 °C 3: hydrogenchloride; hydrogen; platinum(IV) oxide hydrate / water; ethanol / 6 h / 2327.23 Torr 4: ammonium formate / 3 h / 160 - 165 °C / Inert atmosphere 5: oxalyl dichloride; N,N-dimethyl-formamide / methanol / 1.5 h / Reflux 6: pyridine / isopropyl alcohol / 4 h / Reflux; Inert atmosphere View Scheme
Multi-step reaction with 6 steps 1.1: potassium tert-butylate; potassium iodide / N,N-dimethyl-formamide / 12 h / 100 °C 2.1: sulfuric acid; nitric acid / 1 h / 20 °C / Darkness 3.1: palladium 10% on activated carbon / ethanol / 10 h / 20 °C 3.2: 20 °C 4.1: ammonium formate; triethylamine / 6 h / 160 °C 5.1: oxalyl dichloride / N,N-dimethyl-formamide; dichloromethane / 3 h / 50 °C 6.1: methanol / 3 h / 20 - 30 °C 6.2: 3 h / 50 °C View Scheme

3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (183322-16-9) → erlotinib (183321-74-6)

Conditions	Yield
Multi-step reaction with 11 steps 1: potassium hydroxide / ethanol; water / 3 h / 20 °C 2: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 3 h / 0 - 20 °C 3: triethylamine / dichloromethane / 0 - 20 °C 4: triethylamine; dmap / dichloromethane / 24 h / 20 °C 5: sodium hydroxide / methanol / 2 h / 20 °C 6: dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; silver hexafluoroantimonate; [bis(acetoxy)iodo]benzene / dichloromethane / 16 h / 40 °C / Inert atmosphere 7: sodium hydroxide / ethanol / 20 °C 8: ethanol / 1 h / Reflux 9: hydrogenchloride / water / 2 h / 100 - 105 °C 10: trichlorophosphate / toluene / 4 h / Reflux 11: pyridine / isopropyl alcohol / 4 h / Reflux View Scheme
Multi-step reaction with 5 steps 1: acetic acid; nitric acid / 24 h / 5 °C 2: hydrogenchloride; hydrogen; platinum(IV) oxide hydrate / water; ethanol / 6 h / 2327.23 Torr 3: ammonium formate / 3 h / 160 - 165 °C / Inert atmosphere 4: pyridine; trichlorophosphate / 2.5 h / Inert atmosphere 5: pyridine / isopropyl alcohol / 4 h / Reflux; Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1: acetic acid; nitric acid / 24 h / 5 °C 2: hydrogenchloride; hydrogen; platinum(IV) oxide hydrate / water; ethanol / 6 h / 2327.23 Torr 3: ammonium formate / 3 h / 160 - 165 °C / Inert atmosphere 4: oxalyl dichloride; N,N-dimethyl-formamide / methanol / 1.5 h / Reflux 5: pyridine / isopropyl alcohol / 4 h / Reflux; Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1.1: sulfuric acid; nitric acid / 1 h / 20 °C / Darkness 2.1: palladium 10% on activated carbon / ethanol / 10 h / 20 °C 2.2: 20 °C 3.1: ammonium formate; triethylamine / 6 h / 160 °C 4.1: oxalyl dichloride / N,N-dimethyl-formamide; dichloromethane / 3 h / 50 °C 5.1: methanol / 3 h / 20 - 30 °C 5.2: 3 h / 50 °C View Scheme

C13H17ClO5 → erlotinib (183321-74-6)

Conditions

Yield

Multi-step reaction with 9 steps 1: triethylamine / dichloromethane / 0 - 20 °C 2: triethylamine; dmap / dichloromethane / 24 h / 20 °C 3: sodium hydroxide / methanol / 2 h / 20 °C 4: dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; silver hexafluoroantimonate; [bis(acetoxy)iodo]benzene / dichloromethane / 16 h / 40 °C / Inert atmosphere 5: sodium hydroxide / ethanol / 20 °C 6: ethanol / 1 h / Reflux 7: hydrogenchloride / water / 2 h / 100 - 105 °C 8: trichlorophosphate / toluene / 4 h / Reflux 9: pyridine / isopropyl alcohol / 4 h / Reflux View Scheme

C15H23NO6 → erlotinib (183321-74-6)

Conditions

Yield

Multi-step reaction with 8 steps 1: triethylamine; dmap / dichloromethane / 24 h / 20 °C 2: sodium hydroxide / methanol / 2 h / 20 °C 3: dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; silver hexafluoroantimonate; [bis(acetoxy)iodo]benzene / dichloromethane / 16 h / 40 °C / Inert atmosphere 4: sodium hydroxide / ethanol / 20 °C 5: ethanol / 1 h / Reflux 6: hydrogenchloride / water / 2 h / 100 - 105 °C 7: trichlorophosphate / toluene / 4 h / Reflux 8: pyridine / isopropyl alcohol / 4 h / Reflux View Scheme

2-(3,4-bis(2-methoxyethoxy)phenyl)-4,5-dihydro-oxazole → erlotinib (183321-74-6)

Conditions

Yield

Multi-step reaction with 6 steps 1: dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; silver hexafluoroantimonate; [bis(acetoxy)iodo]benzene / dichloromethane / 16 h / 40 °C / Inert atmosphere 2: sodium hydroxide / ethanol / 20 °C 3: ethanol / 1 h / Reflux 4: hydrogenchloride / water / 2 h / 100 - 105 °C 5: trichlorophosphate / toluene / 4 h / Reflux 6: pyridine / isopropyl alcohol / 4 h / Reflux View Scheme

C17H21F3N2O6 → erlotinib (183321-74-6)

Conditions	Yield
Multi-step reaction with 5 steps 1: sodium hydroxide / ethanol / 20 °C 2: ethanol / 1 h / Reflux 3: hydrogenchloride / water / 2 h / 100 - 105 °C 4: trichlorophosphate / toluene / 4 h / Reflux 5: pyridine / isopropyl alcohol / 4 h / Reflux View Scheme

erlotinib (183321-74-6) → erlotinib hydrochloride (183319-69-9)

Conditions	Yield
With hydrogenchloride In isopropyl alcohol at 0℃; for 1h; Product distribution / selectivity; Inert atmosphere;	100%
With hydrogenchloride In ethanol; water at 72℃; for 0.333333h; Solvent; Temperature;	99%
With hydrogenchloride In water; acetone at 10℃; for 2.5h; Solvent; Temperature;	98.7%

erlotinib (183321-74-6) → N‐(3‐ethynylphenyl)‐6,7‐bis(2‐methoxyethoxy)quinazolin‐4‐amine hydrochloride

Conditions	Yield
With hydrogenchloride In diethyl ether; dichloromethane at 15 - 30℃; for 3.08333h; Product distribution / selectivity;	100%
With hydrogenchloride In 1,4-dioxane; isopropyl alcohol at 0 - 70℃; for 1.5h; Solvent; Temperature;	97.2%
With hydrogenchloride In water; butanone at 30 - 35℃;	93.13%
With hydrogenchloride In isopropyl alcohol at 20 - 65℃; for 1h; Time; Concentration;	30.0 g
With hydrogenchloride In diethyl ether; chloroform	90 mg

dichloro-acetic acid (79-43-6) + erlotinib (183321-74-6) → erlotinib dichloroacetate (1355242-84-0)

Conditions	Yield
In isopropyl alcohol at 20 - 25℃; for 0.0416667h; Product distribution / selectivity;	95.43%

3,3-difluoro-2-iododec-1-ene + erlotinib (183321-74-6) → N-(3-(4,4-difluoro-3-methyleneundec-1-yn-1-yl)phenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine

Conditions	Yield
With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl-formamide at 40℃; for 48h; Inert atmosphere;	95%

2-[2-(2-azidoethoxy)ethoxy]ethanol (86520-52-7) + erlotinib (183321-74-6) → C28H36N6O7 (1454772-95-2)

Conditions	Yield
With copper(ll) sulfate pentahydrate; sodium L-ascorbate In ethanol; water at 20℃; for 24h;	93%
With copper(ll) sulfate pentahydrate; sodium L-ascorbate In tetrahydrofuran; ethanol; water at 20℃; for 24h;	93%
With copper(ll) sulfate pentahydrate; sodium L-ascorbate In tetrahydrofuran; water; tert-butyl alcohol at 40℃; for 5h; Inert atmosphere;	54%
With copper(ll) sulfate pentahydrate; sodium L-ascorbate In tetrahydrofuran; water; tert-butyl alcohol at 60℃; for 3h; Inert atmosphere;

2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethanol (86770-67-4) + erlotinib (183321-74-6) → C30H40N6O8

Conditions	Yield
With copper(ll) sulfate pentahydrate; sodium L-ascorbate In tetrahydrofuran; water; tert-butyl alcohol at 60℃; for 3h; Inert atmosphere;	91%

tert-butyl N-(3-azidopropyl)carbamate (129392-84-3) + erlotinib (183321-74-6) → tert-butyl-3-(4-(3-(6,7-bis(2-methoxyethoxy)quinazolin-4-ylamino)phenyl)-1H-1,2,3-triazol-1-yl)propylcarbamate

Conditions	Yield
With copper(ll) sulfate pentahydrate; sodium L-ascorbate In water; tert-butyl alcohol at 60℃; Inert atmosphere;	90%

2-azidoethanesulfonyl fluoride + erlotinib (183321-74-6) → 2-(4-(3-((6,7-bis(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)-1H-1,2,3-triazol-1-yl)ethane-1-sulfonyl fluoride

Conditions	Yield
With copper(ll) sulfate pentahydrate; sodium L-ascorbate In dimethyl sulfoxide at 20℃; for 12h;	90%

C54H55BF2I2N8O7 + erlotinib (183321-74-6) → C76H78BF2I2N11O11

Conditions	Yield
With copper(ll) sulfate pentahydrate; sodium L-ascorbate In ethanol; chloroform; water for 24h; Darkness;	89%

benzyl azide (622-79-7) + erlotinib (183321-74-6) → N-(3-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine

Conditions	Yield
With [(1-phenylisoquinoline)2Ir(acetylacetonate)] In dichloromethane at 20℃; Irradiation; regioselective reaction;	87%
With copper(ll) sulfate pentahydrate; sodium L-ascorbate In tetrahydrofuran; water; tert-butyl alcohol at 70℃;	0.41 g

carbon monoxide (201230-82-2) + 2-(2-(1-phenylethylidene)hydrazinyl)pyridine + erlotinib (183321-74-6) → 2-{3-[6,7-bis(2-methoxyethoxy)quinazolin-4-ylamino]phenyl}-4H-pyrido[1,2-a]pyrimidin-4-one

Conditions	Yield
With dimanganese decacarbonyl In toluene at 100℃; under 760.051 Torr; for 16h; Schlenk technique; Sealed tube;	86%

N′-methyl-N′-(pyridin-2-yl)benzohydrazide + erlotinib (183321-74-6) → 3-{3-([6,7-bis(2-methoxyethoxy)quinazolin-4-yl]amino)phenyl}-2-(methyl(pyridin-2-yl)amino)isoquinolin-1(2H)-one

Conditions	Yield
With cobalt(II) acetate; sodium pivalate at 23℃; for 16h; Inert atmosphere; Electrolysis;	85%

erlotinib (183321-74-6) + 1-azido-1-deoxy-β-D-glucopyranoside tetraacetate (13992-25-1) → N-(3-(1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-1H-1,2,3-triazol-4-yl)phenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine

Conditions	Yield
With copper(ll) sulfate pentahydrate; sodium L-ascorbate In water; tert-butyl alcohol for 24h;	83%

C46H49BF2I2N8O7 + erlotinib (183321-74-6) → C90H95BF2I2N14O15

Conditions	Yield
With copper(ll) sulfate pentahydrate; sodium L-ascorbate In ethanol; chloroform; water for 24h; Darkness;	82%

Upstream product

• 183319-69-9 erlotinib hydrochloride 
• 54060-30-9 3-acetylenephenylamine 
• 183322-18-1 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline 
• 938185-06-9 N-(3-ethynylphenyl)-6,7-dihydroxy-4-quinazolinamine 
• 4296-15-5 2-iodo-1-methoxyethane 
• 179688-29-0 6,7-bis(2-methoxyethoxy)-3,4-dihydroquinazolin-4-one 
• 80407-68-7 3,4-bis(2-methoxyethoxy)-benzonitrile 
• 236750-65-5 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile 
• 1418289-91-4 3,4-bis(2-methoxyethoxy)-benzamide 
• 819813-71-3 3,4-bis(2-methoxyethoxy)-benzoic acid 
• 950596-58-4 2-amino-4,5-bis-(2-methoxyethoxy)-benzonitrile 
• 950596-59-5 N′-[2-cyano-4,5-{bis(2-methoxyethoxy)phenyl}]-N,N-dimethylformamidine 
• 99-50-3 3,4-Dihydroxybenzoic acid 
• 3943-89-3 Ethyl protocatechuate 

Downstream Products

• 183319-69-9 erlotinib hydrochloride 
• 1415223-74-3 C₂₂H₂₂ClN₃O₄ 
• 1415223-75-4 C₂₂H₂₂FN₃O₄ 
• 1415223-76-5 C₂₂H₂₃F₄N₃O₄ 
• 1415223-77-6 C₂₂H₂₁F₂N₃O₄ 
• 1415223-78-7 C₂₂H₂₁ClFN₃O₄ 
• 1415223-79-8 C₂₂H₂₁F₂N₃O₄ 
• 776274-03-4 C₂₂H₂₂FN₃O₄ 
• 1415223-68-5 C₂₂H₂₂FN₃O₄ 
• 1415223-69-6 C₂₂H₂₂ClN₃O₄ 
• 1415223-70-9 C₂₂H₂₂ClN₃O₄ 
• 1415223-71-0 C₂₂H₂₁F₂N₃O₄ 
• 1415223-72-1 C₂₂H₂₃F₂N₃O₄ 
• 1415223-73-2 C₂₂H₂₂FN₃O₄ 

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Novel method for preparing Erlotinib and intermediates thereof

The invention discloses a novel method for preparing Erlotinib and intermediates thereof and belongs to the field of drug synthesis. The method comprises the following steps: enabling triacetenyl aniline to react with trimethyl orthoformate or triethyl orthoformate in a proper solvent, so as to obtain a compound B; enabling the compound B and a compound C to subject to ring closing in the presenceof a proper catalyst, thereby obtaining the Erlotinib or intermediates thereof. According to the method provided by the invention, the synthesis route is short, the two-step synthesis of the target product, i.e., the Erlotinib is achieved, the consumption of high-pollution raw materials is avoided, the yield is high, the product purity is high, and thus, the method is applicable to industrial production.

Erlotinib preparation method

The invention relates to an erlotinib preparation method. The method for synthesizing erlotinib includes the steps: (1) reacting a compound 1 and paraformaldehyde under the condition of catalytic amount of boron trifluoride diethyl etherate to generate a compound 2; (2) reacting the compound 2 and ammonium hydroxide under the condition of catalytic amount of tetrabutylammonium bromide and ultrasound to generate a compound 3; (3) reacting the compound 3 and sulfoxide chloride to generate a compound 4; (4) reacting the compound 4 and aminophenylacetylene to generate erlotinib.

Intermediate for preparing erlotinib

The invention relates an intermediate for preparing an erlotinib. The intermediate is of a structure which is shown as the compound 2 in the description.

Preparation method of erlotinib intermediate

The invention relates to a preparation method of an erlotinib intermediate. The preparation method concretely comprises the following steps: implanting a synthesis route described in the description; adding a compound 2 into ammonia water, adding a catalytic amount of tetrabutyl ammonium bromide at the room temperature, and carrying out ultrasonic treatment for 5-30min to generate a compound 3, wherein the ultrasonic frequency is 30-50kHz.