183319-69-9

Basic information

• Product Name: Erlotinib hydrochloride
• Synonyms: ERLOTINIB HCL;ERLOTINIB HCL SALT;ERLOTINIB HCL SALT :TARCEVA;Erlotinib, Hydrochloride Salt;N-(3-Ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, Hydrochloride Salt, OSI 774, Tarceva; N-(3-Ethynylphenyl)-6,7-bis-(2-methoxyethoxy)-quinazolin-4-amine;[6,7-Bis-(2-methoxy-ethoxy)-quinazolin-4yl]-(3-ethynyl-phenyl)-amine;Tarceva Hydrochloride See E625000
• CAS NO: 183319-69-9
• Molecular Formula: C₂₂H₂₃N₃O₄*ClH
• Molecular Weight: 429.9
• EINECS: 1308068-626-2
• Product Categories: API;Molecular Targeted Antineoplastic;Heterocyclic Compounds;anti-neoplastic;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Tarceva;Antineoplastic;Anti-cancer&immunity;Inhibitors
• Mol File: 183319-69-9.mol
• Article Data: 53

Chemical Properties

• Melting Point: 223-225°C
• Boiling Point: 553.6 °C at 760 mmHg
• Flash Point: 288.6 °C
• Appearance: White or off-white powder
• Vapor Pressure: 4.52E-12mmHg at 25°C
• Storage Temp.: -20°C Freezer
• Solubility: Soluble in DMSO (up to 18 mg/ml with warming).
• PKA: pKa (25°): 5.42
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20° for up to 3 months.
• CAS DataBase Reference: Erlotinib hydrochloride(CAS DataBase Reference)
• NIST Chemistry Reference: Erlotinib hydrochloride(183319-69-9)
• EPA Substance Registry System: Erlotinib hydrochloride(183319-69-9)

Safety Data

• Safety Statements: 24/25
• Hazardous Substances Data: 183319-69-9(Hazardous Substances Data)

Usage

Indications and Usage

Erlotinib hydrochlorate is a small molecule tyrosine kinase inhibitor which acts reversibly on epidermal growth factor receptors, a hydrochloride of erlotinib, a molecular-targeted drug. The US Food and Drug Administration (FDA) has approved erlotinib (Tarceva) combined with gemcitabine as a first-line treatment for locally advanced and metastatic pancreatic cancer. It is mainly used as a second- or third-line treatment for locally advanced or metstatic non-small cell lung cancer (NSCLC) and as a treatment for pancreatic cancer. It is used as a tyrosine inhibitor for NSCLC treatment.

Mechanisms of Action

The small molecular compound erlotinib is a tyrosine kinase receptor inhibitor which inhibits the proliferation of tumor cells by inhibiting phosphorylation, binding to the intracellular catalytic domain of tyrosine kinase in competition with ATP, thus blocking downstream signal transduction and inhibiting activity of tumor cell ligand dependent HER-1/EGFR.

Clinical Research

Phase I clinical trials showed that the main toxicities and side effects of erlotinib were dose-dependent rashes and diarrhea. Other rare side effects included headaches, nausea, and vomiting. Phase II trials used erlotinib as a second-line anticancer drug, with efficacy matching second-line chemotherapy drug docetaxel. Phase III randomized control trials (BR21) mainly focused on NSCLC patients (locally advanced and distant metastasis) after the failure of first- or second-line chemotherapy. The treatment group, with 488 cases in total, took 150mg of erlotinib daily. The control group (243 cases) took a placebo. The study showed: Median survival rate: 6.7 months for the treatment group, 4.7 months for the control (P<0.001, hazard ratio HR=0.73) 1 year survival rate: 31.2% for the treatment group, 21.5% for the control Median time of no progression: 9.9 weeks for the treatment group, 7.9 weeks for the control Meanwhile, symptomatic improvement in the treatment group was more pronounced. Based on the results of the BR21 study, several further phase III clinical trials were conducted. The TRIBUTE trial combined erlotinib with chemotherapy. The treatment group used chemotherapy (carboplatin + paclitaxel) + erlotinib, while the control used the same chemotherapy alone, with a total of 1,059 late-stage NSCLC patients. The effectiveness of the treatment group was 21.5%, and the control group 19.3%; median survival times were 10.8 and 10.6 months, respectively, and the times of tumor progression (TTP) were 5.1 and 5.0 months. Meanwhile, TALENT trials, with 1,172 NSCLC patients, also investigated the effects of adding erlotinib to chemotherapy (gemcitabine + cisplatin), and also failed to show that erlotinib significantly increased its effects.

Description

Erlotinib, launched as once daily oral treatment for patients with non-small-cell lung cancer (NSCLC), is an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, and it is the second small-molecule drug to be marketed with this mechanism of action. Both erlotinib and its predecessor, gefitinib, are members of the anilinoquinazoline class of tyrosine kinase inhibitors. They compete with the binding of ATP to the intracellular tyrosine kinase domain of EGFR, thereby inhibiting receptor autophosphorylation and blocking downstream signal transduction. Erlotinib is prepared by the condensation of 3-ethynylaniline with 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline, which is a key intermediate obtained in five synthetic steps starting from ethyl 3,4- dihydroxybenzoate. In vitro, Erlotinib inhibits purified human EGFR tyrosine kinase with an IC50 of 2 nM and blocks EGFR autophosphorylation in cellular assays with an IC50 of 20nM. Treatment of human colon cancer cells with erlotinib was associated with growth inhibition, G1 cell cycle arrest, and apoptosis. Oral administration of erlotinib in athymic mice produced potent antitumor effects with an ED50 of 9.2 mg/kg/day for HN5 head and neck xenografts and 14 mg/ kg/day for A431 epidermoid xenografts. The absorption of Erlotinib following oral dosing is approximately 60%. Food greatly enhances the absorption allowing for almost 100% bioavailability of the dose. The time to reach peak plasma levels of the drug is about 4 hours, and the half-life is approximately 36 hours. Steady-state drug levels are reached in 7 to 8 days. Erlotinib has high protein binding (93%) and has an apparent volume of distribution of 232 L. It is metabolized primarily by CYP3A4 and to a lesser extent by CYP1A2 and CYP1A1. The drug is mainly excreted in the feces with less than 9% of the dose found in the urine. Erlotinib is labeled for the treatment of patients with locally advanced or metastatic NSCLC who have failed one or more previous chemotherapy regimens. The recommended dosage is 150 mg daily until disease progression is detected. In a randomized, double blind, placebo-controlled trial involving 731 patients, 150 mg/day oral dose of erlotinib resulted in a median overall survival of 6.7 months compared with 4.7 months in the placebo group (p＜0.001). Progression-free survival was 9.9 weeks and 7.9 weeks in the erlotinib and placebo groups, respectively (p＜0.001). Survival at one year was 31.2% in the erlotinib group versus 21.5% in the placebo group. The use of erlotinib showed greater benefit in patients with EGFR positive tumors and in those who never smoked. The most common adverse events reported in clinical trials were rash (9%) and diarrhea (6%). Elevations in liver function tests were also seen; however, these effects were mainly transient or associated with liver metastases. As previously noted for gefitinib, erlotinib is also shown to lack any clinical benefit in concurrent administration with platinum-based chemotherapy.

Chemical Properties

Off-White Solid

Originator

Pfizer (US)

Uses

Erlotinib hydrochloride (V), a quinazoline derived small molecule inhibitor of epidermal growth factor receptor (EDGFR) tyrosine kinase, was approved in November, 2004, for the treatment of advanced or metastatic non-smallcell lung cancer. It belongs to the same class as gefitinib,another quinazoline approved for treatment of advanced lung cancer, but with improved pharmacokinetic properties. The molecule was originated by Pfizer and development initiated in collaboration with OSI, which assumed full rights to the drug when Pfizer merged with Warner Lambert. Subsequently, Genentech/Roche went into licensing agreement with OSI to develop and market the drug in the US and Worldwide.

Uses

Selective epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor. Antineoplastic

Uses

Erlotinib HCl is an HER1/EGFR inhibitor with IC50 of 2 nM.

Uses

Erlotinib HCl (OSI-744) is an EGFR inhibitor with IC50 of 2 nM, >1000-fold more sensitive for EGFR than human c-Src or v-Abl. Phase 3.

Definition

ChEBI: A quinazoline hydrochloride compound having a (3-ethynylphenyl)amino group at the 4-position and two 2-methoxyethoxy groups at the 6- and 7-positions.

Brand name

Tarceva (OSI).

General Description

Erlotinib is available as 25-, 100-, and 150-mg tablets fororal administration and is used after failure of first-linetherapy in metastatic NSCLC and as first-line therapy incombination with gemcitabine in the treatment of metastaticpancreatic cancer, and in treating malignant gliomas.The structural similarity to gefitnib imparts similar pharmacokineticbehavior with bioavailability of 60% and proteinbinding of 93%. The agent is extensively metabolizedprimarily by CYP3A4. Three major metabolic pathwayshave been identified, involving oxidative-O-demethylationof the side chains followed by further oxidation to give thecarboxlic acids, oxidation of the acetylene functionalityto give a carboxylic acid, and aromatic hydroxylation ofthe phenyl ring para to the electron-donating nitrogen. Themetabolites are primarily eliminated in the feces, and theterminal half-life is 36 hours.The major toxicities seenwith the agent are dose-limiting skin rash and diarrhea.Other common adverse effects include shortness of breath,fatigue, and nausea.

Synthesis

The synthesis of this agent is based on the original patent and is shown in the Scheme. The 3,4-dihydroxy benzoate 31 was reacted with bromoethyl methyl ether in the presence of potassium carbonate and tetrabutyl ammonium iodide to give 32 in 93% yield. Nitration followed by hydrogenation provided 34 in 88% yield, which was then cyclized in formamide with ammonium formate to provide quinazolone 35. Subsequent reaction with oxalyl chloride gave quinazoline chloride 36, which was then reacted with 3-ethynyl aniline (37) in isopropanol in the presence of pyridine to give the desired product erlotinib, which was isolated as the HCl salt (V). An alternate synthesis, that used protected 3-trimethylsilyl ethynyl aniline to couple to the quinazoline chloride 36, has also been published.

References

1) Moyer et al. (1997), Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor tyrosine kinases; Cancer Res., 57 4838 2) Li et al. (2007), Erlotinib effectively inhibits JAK2V617F activity and polycythemia vera cell growth; J. Biol. Chem., 282 3428 3) Wood et al. (2004), A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells; Cancer Res., 64 6652 4) Greve et al. (2015), The pan-HDAC inhibitor panobinostat acts as a sensitizer for erlotinib activity in EGFR-mutated and –wildtype non-small cell lung cancer cells; BMC Cancer, 15 947 5) Minquet et al. (2016), Targeted therapies for treatment of non-small cell lung cancer-Recent advances and future perspectives; Int. J. Cancer, 138 2549

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

Synthetic route

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%

6,7-bis(2-methoxyethoxy)-4-methoxyquinazoline (1312937-41-9) + hydrochloric salt of m-aminophenylacetylene → erlotinib hydrochloride (183319-69-9)

Conditions	Yield
Stage #1: hydrochloric salt of m-aminophenylacetylene With sec.-butyllithium In tetrahydrofuran; cyclohexane at 0℃; for 0.5h; Inert atmosphere; Stage #2: 6,7-bis(2-methoxyethoxy)-4-methoxyquinazoline In tetrahydrofuran; cyclohexane at 20℃; for 15h; Stage #3: With hydrogenchloride In tetrahydrofuran; cyclohexane; water at 20℃; for 1h; Product distribution / selectivity;	100%
Stage #1: hydrochloric salt of m-aminophenylacetylene With sec.-butyllithium In tetrahydrofuran; cyclohexane at 0℃; Inert atmosphere; Stage #2: 6,7-bis(2-methoxyethoxy)-4-methoxyquinazoline In tetrahydrofuran; cyclohexane at 20℃; Stage #3: With hydrogenchloride In tetrahydrofuran; cyclohexane; water at 20℃;	100%

3-acetylenephenylamine (54060-30-9) + 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1) → erlotinib hydrochloride (183319-69-9)

Conditions	Yield
In isopropyl alcohol for 18h; Heating;	98%
In iso-propanol (IPA) for 0.5h; Product distribution / selectivity; Heating / reflux;	97%
Stage #1: 3-acetylenephenylamine; 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline In N,N-dimethyl-formamide; acetonitrile at 90℃; for 7h; Darkness; Stage #2: With hydrogenchloride In water at 15 - 30℃; Temperature; Solvent;	97.6%

6,7-bis(2-methoxyethoxy)-4-methoxyquinazoline (1312937-41-9) + 3-acetylenephenylamine (54060-30-9) → erlotinib hydrochloride (183319-69-9)

Conditions	Yield
Stage #1: 3-acetylenephenylamine With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at 0℃; for 0.5h; Inert atmosphere; Stage #2: 6,7-bis(2-methoxyethoxy)-4-methoxyquinazoline In tetrahydrofuran; n-heptane; ethylbenzene at 20℃; for 15h; Stage #3: With hydrogenchloride In tetrahydrofuran; n-heptane; ethylbenzene; water at 20℃; for 3h; Product distribution / selectivity;	97%
Stage #1: 3-acetylenephenylamine With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at 0℃; Inert atmosphere; Stage #2: 6,7-bis(2-methoxyethoxy)-4-methoxyquinazoline In tetrahydrofuran; n-heptane; ethylbenzene at 20℃; for 15h; Stage #3: With hydrogenchloride In tetrahydrofuran; n-heptane; ethylbenzene; water at 20℃; Product distribution / selectivity;	97%

N-(3-ethynylphenyl)-6,7-dihydroxy-4-quinazolinamine (938185-06-9) + 2-iodo-1-methoxyethane (4296-15-5) → erlotinib hydrochloride (183319-69-9)

Conditions	Yield
Stage #1: N-(3-ethynylphenyl)-6,7-dihydroxy-4-quinazolinamine; 2-iodo-1-methoxyethane With pyridine; tetrapropylammonium iodide In 1-methyl-pyrrolidin-2-one at 20℃; for 1h; Stage #2: With hydrogenchloride In water	95.29%

6,7-bis(2-methoxyethoxy)-3,4-dihydroquinazolin-4-one (179688-29-0) + 3-acetylenephenylamine (54060-30-9) → erlotinib hydrochloride (183319-69-9)

Conditions	Yield
for 3h; Temperature; Reflux; Large scale;	95.1%

4-(methylthio)-6,7-bis(2-methoxyethoxy)quinazoline (958669-57-3) + hydrochloric salt of m-aminophenylacetylene → erlotinib hydrochloride (183319-69-9)

Conditions	Yield
With 3-ethynylaniline In isopropyl alcohol for 15h; Heating;	90%

N-(3-trimethylsilyl-ethynyl)-6,7-bis(2-methoxyethoxy)-4-quinolyl-amine (766497-25-0) → erlotinib hydrochloride (183319-69-9)

Conditions	Yield
With hydrogenchloride In methanol at 20℃; for 1h;	90%

3-acetylenephenylamine (54060-30-9) → erlotinib hydrochloride (183319-69-9)

Conditions	Yield
Stage #1: 6,7-dimethoxy quinazolin-4-one With triethylamine; trichlorophosphate In toluene at 70 - 80℃; for 3h; Stage #2: 3-acetylenephenylamine In toluene; acetonitrile at 20 - 80℃; for 2h;	88%

3-butyn-2-ol, 4-[3-[[6,7-bis(2-methoxyethoxy)-4-quinazolinyl]amine]phenyl]-2-methyl, hydrochloride (299912-59-7) → erlotinib hydrochloride (183319-69-9)

Conditions	Yield
Stage #1: 3-butyn-2-ol, 4-[3-[[6,7-bis(2-methoxyethoxy)-4-quinazolinyl]amine]phenyl]-2-methyl, hydrochloride With sodium hydroxide In water; butan-1-ol pH=10 - 12; Inert atmosphere; Stage #2: With sodium hydroxide In butan-1-ol at 115 - 120℃; for 24h; Stage #3: With hydrogenchloride In water; butan-1-ol at 20 - 25℃;	74%

2-amino-4,5-bis-(2-methoxyethoxy)-benzonitrile (950596-58-4) + 3-acetylenephenylamine (54060-30-9) + 4-(dimethoxymethylene)morpholine → erlotinib hydrochloride (183319-69-9)

Conditions	Yield
Stage #1: 3-acetylenephenylamine; 4-(dimethoxymethylene)morpholine With acetic acid In toluene Reflux; Stage #2: 2-amino-4,5-bis-(2-methoxyethoxy)-benzonitrile In toluene Reflux; Stage #3: With hydrogenchloride In water; toluene at 15 - 20℃;	63%

6,7-bis(2-methoxyethoxy)-3,4-dihydroquinazolin-4-one (179688-29-0) → erlotinib hydrochloride (183319-69-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 95 percent / P2S5 / pyridine / 24 h / Heating 2.1: aq. NaOH / methanol / 0.5 h / 20 °C 2.2: 86 percent / methanol; H2O / 5 h / 25 °C 3.1: 90 percent / 3-ethynylaniline / propan-2-ol / 15 h / Heating View Scheme
Multi-step reaction with 2 steps 1: 94 percent / thionyl chloride / dimethylformamide / 2 h / Heating 2: 80 percent / dimethylformamide / 1 h / 80 °C View Scheme
Multi-step reaction with 2 steps 1: phosphoryl choride; N,N-diethylaniline / 0.67 h / 70 - 90 °C 2: pyridine / propan-2-ol View Scheme

6,7-bis(2-methoxyethoxy)quinazoline-4(3H)-thione (958669-56-2) → erlotinib hydrochloride (183319-69-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: aq. NaOH / methanol / 0.5 h / 20 °C 1.2: 86 percent / methanol; H2O / 5 h / 25 °C 2.1: 90 percent / 3-ethynylaniline / propan-2-ol / 15 h / Heating View Scheme

C13H19NO5 (1006377-63-4) → erlotinib hydrochloride (183319-69-9)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: acetic anhydride / 110 °C 2.1: 85 percent / aq. nitric acid / acetic acid / 8 h / 45 - 50 °C 3.1: FeCl3; hydrazine hydrate / H2O; methanol / 3 h / Heating 3.2: 81 percent / HCl / H2O / 90 - 130 °C 4.1: 94 percent / thionyl chloride / dimethylformamide / 2 h / Heating 5.1: 80 percent / dimethylformamide / 1 h / 80 °C View Scheme

3,4-bis(2-methoxyethoxy) benzonitrile (80407-68-7) → erlotinib hydrochloride (183319-69-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: 85 percent / aq. nitric acid / acetic acid / 8 h / 45 - 50 °C 2.1: FeCl3; hydrazine hydrate / H2O; methanol / 3 h / Heating 2.2: 81 percent / HCl / H2O / 90 - 130 °C 3.1: 94 percent / thionyl chloride / dimethylformamide / 2 h / Heating 4.1: 80 percent / dimethylformamide / 1 h / 80 °C View Scheme
Multi-step reaction with 6 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 6.1: hydrogenchloride / methanol / 0.05 h / 15 - 20 °C View Scheme
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 / 125 - 130 °C 5.1: hydrogenchloride / methanol / 0.05 h / 15 - 20 °C View Scheme
Multi-step reaction with 5 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 5.1: hydrogenchloride / water; methanol / 20 °C View Scheme
Multi-step reaction with 6 steps 1: nitric acid 2: dihydrogen peroxide 3: palladium on activated charcoal; ammonium formate 4: water / 24 h / 130 °C 5: trichlorophosphate; triethylamine 6: hydrogenchloride / water; N,N-dimethyl-formamide View Scheme

2-nitro-4,5-bis(2-methoxyethoxy)benzonitrile (236750-65-5) → erlotinib hydrochloride (183319-69-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: FeCl3; hydrazine hydrate / H2O; methanol / 3 h / Heating 1.2: 81 percent / HCl / H2O / 90 - 130 °C 2.1: 94 percent / thionyl chloride / dimethylformamide / 2 h / Heating 3.1: 80 percent / dimethylformamide / 1 h / 80 °C View Scheme
Multi-step reaction with 5 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 5.1: hydrogenchloride / methanol / 0.05 h / 15 - 20 °C View Scheme
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 / 125 - 130 °C 4.1: hydrogenchloride / methanol / 0.05 h / 15 - 20 °C View Scheme

3,4-bis(2-methoxyethoxy)benzaldehyde (80407-64-3) → erlotinib hydrochloride (183319-69-9)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: hydroxylamine hydrochloride; pyridine / methanol / Heating 2.1: acetic anhydride / 110 °C 3.1: 85 percent / aq. nitric acid / acetic acid / 8 h / 45 - 50 °C 4.1: FeCl3; hydrazine hydrate / H2O; methanol / 3 h / Heating 4.2: 81 percent / HCl / H2O / 90 - 130 °C 5.1: 94 percent / thionyl chloride / dimethylformamide / 2 h / Heating 6.1: 80 percent / dimethylformamide / 1 h / 80 °C View Scheme
Multi-step reaction with 7 steps 1: hydroxylamine hydrochloride; acetic anhydride 2: nitric acid 3: dihydrogen peroxide 4: palladium on activated charcoal; ammonium formate 5: water / 24 h / 130 °C 6: trichlorophosphate; triethylamine 7: hydrogenchloride / water; N,N-dimethyl-formamide View Scheme

3,4-dihydroxybenzaldehyde (139-85-5) → erlotinib hydrochloride (183319-69-9)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: 98 percent / potassium carbonate / dimethylformamide / 100 °C 2.1: hydroxylamine hydrochloride; pyridine / methanol / Heating 3.1: acetic anhydride / 110 °C 4.1: 85 percent / aq. nitric acid / acetic acid / 8 h / 45 - 50 °C 5.1: FeCl3; hydrazine hydrate / H2O; methanol / 3 h / Heating 5.2: 81 percent / HCl / H2O / 90 - 130 °C 6.1: 94 percent / thionyl chloride / dimethylformamide / 2 h / Heating 7.1: 80 percent / dimethylformamide / 1 h / 80 °C View Scheme

Ethyl protocatechuate (3943-89-3) → erlotinib hydrochloride (183319-69-9)

Conditions	Yield
Multi-step reaction with 6 steps 1: potassium carbonate; tetrabutylammonium iodide / acetone / 120 h / Heating 2: acetic acid; nitric acid / 24 h / 20 °C 3: hydrogen / PtO2*H2O / methanol / 20 °C / 2585.74 Torr 4: 84 percent / 12 h / 165 - 170 °C 5: phosphoryl choride; N,N-diethylaniline / 0.67 h / 70 - 90 °C 6: pyridine / propan-2-ol View Scheme
Multi-step reaction with 6 steps 1: potassium carbonate; tetrabutylammonium iodide / acetone 2: acetic acid; nitric acid / 24 h / 20 °C 3: hydrogen / PtO2*H2O / methanol / 20 °C / 2585.74 Torr 4: 84 percent / 12 h / 165 - 170 °C 5: phosphoryl choride; N,N-diethylaniline / 0.67 h / 70 - 90 °C 6: pyridine / propan-2-ol View Scheme
Multi-step reaction with 7 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 7.1: hydrogenchloride / water; dichloromethane; methanol / 3 h / 25 °C View Scheme

3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (183322-16-9) → erlotinib hydrochloride (183319-69-9)

Conditions	Yield
Multi-step reaction with 5 steps 1: acetic acid; nitric acid / 24 h / 20 °C 2: hydrogen / PtO2*H2O / methanol / 20 °C / 2585.74 Torr 3: 84 percent / 12 h / 165 - 170 °C 4: phosphoryl choride; N,N-diethylaniline / 0.67 h / 70 - 90 °C 5: pyridine / propan-2-ol View Scheme
Multi-step reaction with 6 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 6.1: hydrogenchloride / water; dichloromethane; methanol / 3 h / 25 °C View Scheme

ethyl 2-amino-4,5-bis(2-methoxyethoxy)-benzoate (179688-27-8) → erlotinib hydrochloride (183319-69-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: 84 percent / 12 h / 165 - 170 °C 2: phosphoryl choride; N,N-diethylaniline / 0.67 h / 70 - 90 °C 3: pyridine / propan-2-ol View Scheme

2-nitro-4,5-bis(2-methoxyethoxy)benzoic acid ethyl ester (179688-26-7) → erlotinib hydrochloride (183319-69-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: hydrogen / PtO2*H2O / methanol / 20 °C / 2585.74 Torr 2: 84 percent / 12 h / 165 - 170 °C 3: phosphoryl choride; N,N-diethylaniline / 0.67 h / 70 - 90 °C 4: pyridine / propan-2-ol View Scheme
Multi-step reaction with 4 steps 1.1: tin(II) chloride dihdyrate / methanol / 25 - 35 °C 1.2: 0 - 30 °C 2.1: 25 - 145 °C 3.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / Reflux 4.1: isopropyl alcohol / 4 h / 25 - 45 °C / Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1.1: palladium 10% on activated carbon / ethanol / 10 h / 20 °C 1.2: 20 °C 2.1: ammonium formate; triethylamine / 6 h / 160 °C 3.1: oxalyl dichloride / N,N-dimethyl-formamide; dichloromethane / 3 h / 50 °C 4.1: methanol / 3 h / 20 - 30 °C 4.2: 3 h / 50 °C 5.1: hydrogenchloride / water; dichloromethane; methanol / 3 h / 25 °C View Scheme

2-methyl-4-(3-aminophenyl)-3-butyn-2-ol (69088-96-6) → erlotinib hydrochloride (183319-69-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: NaOH / toluene / 1 h / Heating 2: 98 percent / propan-2-ol / 18 h / Heating View Scheme
Multi-step reaction with 2 steps 1: sodium hydroxide / toluene / 4 h / 105 - 110 °C / Inert atmosphere 2: toluene; acetonitrile / 25 °C / Inert atmosphere; Reflux View Scheme
Multi-step reaction with 2 steps 1.1: acetonitrile / 5 h / 25 °C / Inert atmosphere; Reflux 2.1: sodium hydroxide / butan-1-ol; water / pH 10 - 12 / Inert atmosphere 2.2: 24 h / 115 - 120 °C 2.3: 20 - 25 °C View Scheme
Multi-step reaction with 2 steps 1: acetonitrile / 5 h / Inert atmosphere; Reflux 2: sodium hydroxide; water / butan-1-ol / pH 10 - 12 / Inert atmosphere View Scheme

3-acetylenephenylamine (54060-30-9) + 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1) → N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-N-(2-methoxyethyl)quinazolin-4-amine + erlotinib hydrochloride (183319-69-9)

Conditions	Yield
In isopropyl alcohol for 1.5 - 2h; Product distribution / selectivity; Heating / reflux;

2-amino-4,5-bis-(2-methoxyethoxy)-benzonitrile (950596-58-4) + 3-acetylenephenylamine (54060-30-9) + orthoformic acid triethyl ester (122-51-0) → erlotinib hydrochloride (183319-69-9)

Conditions	Yield
Stage #1: 2-amino-4,5-bis-(2-methoxyethoxy)-benzonitrile; 3-acetylenephenylamine; orthoformic acid triethyl ester; acetic acid In isopropyl alcohol for 4h; Reflux; Stage #2: With hydrogenchloride In isopropyl alcohol at 20℃; pH=3.0 - 4.0; Product distribution / selectivity;

erlotinib trifluoroacetate (1246445-24-8) → erlotinib hydrochloride (183319-69-9)

Conditions	Yield
With hydrogenchloride In isopropyl alcohol at 25 - 30℃; Product distribution / selectivity;

4-(methylthio)-6,7-bis(2-methoxyethoxy)quinazoline (958669-57-3) + 3-acetylenephenylamine (54060-30-9) + hydrochloric salt of m-aminophenylacetylene → erlotinib hydrochloride (183319-69-9)

Conditions	Yield
In isopropyl alcohol for 15h; Reflux;
In isopropyl alcohol for 15h; Reflux;

4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1) → erlotinib hydrochloride (183319-69-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: pyridine / isopropyl alcohol / 1 h / 80 °C 1.2: 1 h / 20 °C 2.1: trichlorophosphate / N,N-dimethyl-formamide / 0.5 h / 80 °C 2.2: 0.5 h / 0 - 40 °C 3.1: lithium diisopropyl amide / n-heptane; tetrahydrofuran; ethylbenzene / 0.5 h / 0 °C / Inert atmosphere 3.2: 15 h / 20 °C 3.3: 3 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: pyridine / isopropyl alcohol / 1 h / 80 °C 1.2: 1 h / 20 °C 2.1: trichlorophosphate / N,N-dimethyl-formamide / 0.5 h / 80 °C 2.2: 0.5 h / 0 - 40 °C 3.1: sec.-butyllithium / cyclohexane; tetrahydrofuran / 0.5 h / 0 °C / Inert atmosphere 3.2: 15 h / 20 °C 3.3: 1 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: pyridine / isopropyl alcohol / 1 h / 80 °C 1.2: 20 °C 2.1: trichlorophosphate / N,N-dimethyl-formamide / 0.5 h / 80 °C 2.2: 0 - 40 °C 3.1: sec.-butyllithium / cyclohexane; tetrahydrofuran / 0 °C / Inert atmosphere 3.2: 20 °C 3.3: 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: pyridine / isopropyl alcohol / 1 h / 80 °C 1.2: 20 °C 2.1: trichlorophosphate / N,N-dimethyl-formamide / 0.5 h / 80 °C 2.2: 0 - 40 °C 3.1: lithium diisopropyl amide / n-heptane; tetrahydrofuran; ethylbenzene / 0 °C / Inert atmosphere 3.2: 15 h / 20 °C 3.3: 20 °C View Scheme
With hydrogenchloride In water; N,N-dimethyl-formamide

3-acetylenephenylamine (54060-30-9) + 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1) → 6,7-bis(2-methoxyethoxy)-3,4-dihydroquinazolin-4-one (179688-29-0) + erlotinib hydrochloride (183319-69-9)

Conditions	Yield
Stage #1: 3-acetylenephenylamine; 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline With pyridine In isopropyl alcohol at 80℃; for 1h; Stage #2: With hydrogenchloride In 1,4-dioxane; diethyl ether; chloroform at 20℃; for 1h; Product distribution / selectivity;
Stage #1: 3-acetylenephenylamine; 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline With pyridine In isopropyl alcohol at 80℃; for 1h; Stage #2: With hydrogenchloride In 1,4-dioxane; diethyl ether; chloroform at 20℃;

methanesulfonic acid (75-75-2) + erlotinib hydrochloride (183319-69-9) → N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, methanesulfonic acid salt

Conditions	Yield
Stage #1: erlotinib hydrochloride With sodium hydroxide In water; ethyl acetate at 60 - 70℃; pH=10 - 11; Stage #2: methanesulfonic acid In ethyl acetate Heating / reflux;	100%
Stage #1: erlotinib hydrochloride With sodium hydroxide In water; ethyl acetate pH=8 - 9; Stage #2: In isopropyl alcohol Stage #3: methanesulfonic acid at 62 - 70℃; for 34h;	93%
Stage #1: erlotinib hydrochloride With sodium hydrogencarbonate In dichloromethane; water Stage #2: In isopropyl alcohol Stage #3: methanesulfonic acid	69%
Stage #1: erlotinib hydrochloride With 50percent NaOH In water; ethyl acetate at 50℃; for 0.25h; Stage #2: methanesulfonic acid at 50℃; for 4h; Further stages.;	111.76 g

sodium docusate (577-11-7) + erlotinib hydrochloride (183319-69-9) → erlotinib 1,4-bis(2-ethylhexoxy)-1 ,4-dioxobutane-2-sulfonate

Conditions	Yield
In dichloromethane; water at 20℃;	98%

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;

water (7732-18-5) + erlotinib hydrochloride (183319-69-9) → erlotinib hydrochloride monohydrate

Conditions	Yield
In dimethyl sulfoxide at 45℃; Temperature;	92.5%

maleic acid (110-16-7) + erlotinib hydrochloride (183319-69-9) → [6,7-bis(2-methoxyethoxy)-4-chinazolinyl](3-ethynylphenyl)amine maleate

Conditions	Yield
Stage #1: erlotinib hydrochloride With ammonium hydroxide In water; ethyl acetate at 50℃; for 0.5h; Stage #2: maleic acid In ethanol; ethyl acetate at 20℃; for 24h;	89%

erlotinib hydrochloride (183319-69-9) → C22H25N3O5

Conditions	Yield
With sulfuric acid at 50℃; Reagent/catalyst; Temperature; Cooling with ice;	84%

Adipic acid (124-04-9) + erlotinib hydrochloride (183319-69-9) → [6,7-bis(2-methoxyethoxy)-4-chinazolinyl](3-ethynylphenyl)amine adipinate (1429636-54-3)

Conditions	Yield
Stage #1: erlotinib hydrochloride With ammonium hydroxide In water; ethyl acetate at 50℃; for 0.5h; Stage #2: Adipic acid In ethanol; ethyl acetate for 24h; Cooling with ice;	72%

ethylenediamine platinum(II) nitrate (50475-22-4) + erlotinib hydrochloride (183319-69-9) → C24H31ClN5O4Pt

Conditions	Yield
Stage #1: erlotinib hydrochloride With triethylamine In N,N-dimethyl-formamide at 20℃; for 2h; Stage #2: ethylenediamine platinum(II) nitrate In N,N-dimethyl-formamide at 65℃; for 17h;	29%

cis-Pt(ethylenediamine)nitrate-chloride (468724-95-0) + erlotinib hydrochloride (183319-69-9) → C24H31ClN5O4Pt

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 65℃; for 17h;	22%

Upstream product

• 183318-53-8 2-Piperidinone,3-amino-6-(fluoromethyl)-,(3S-cis)-(9CI) 
• 18331-71-0 5-butylisatin 
• 18331-68-5 (2E)-N-(4-BUTYLPHENYL)-2-(HYDROXYIMINO)ACETAMIDE 
• 18331-34-5 5-Benzylidene-3-ethyl rhodanine 
• 183313-30-6 N1-Benzyl-4-chloro-N2-methyl-N2-[2-oxo-2-(3,4,5-trimethoxyphenyl)acetyl]-N1-[3-(4-pyridyl)-1-[2-(4-pyridyl)ethyl]propyl]-L-phenylalaninamide dimethanesulfonate 
• 18331-31-2 (2R,4aS,13aS)-4-hydroxy-2-methyldecahydro-5H,9H,12H-indeno[7a,1-h]indolizin-12-one 
• 183-31-3 3H-Spiro[1,3-benzothiazole-2,1'-cyclopentane] 
• 183311-60-6 5-bromo-2-(2,2,5,5-tetramethyl- 1,2,5-azadisilolidin-1-yl)pyridine 
• 183311-31-1 Carbamic acid, (4-amino-5-pyrimidinyl)-, 1,1-dimethylethyl ester (9CI) 
• 18331-13-0 8α-Hydroxyserratinane-5,13-dione 
• 183311-28-6 Carbamic acid,N-(3-amino-4-pyridinyl)-, 1,1-dimethylethyl ester 
• 18330-94-4 3,6-Diaminobenzophenone 
• 18330-76-2 2-AMinobenzothiazole-6-carboxylic Acid Hydrochloride 
• 183307-04-2 N-(3-ethylphenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide 

Downstream Products

• 183320-00-5 [6,7-Bis(2-chloroethoxy)-quinazolin-4-yl]-(3-ethynylphenyl)amine Hydrochloride 
• 183320-04-9 6-O-DesMethoxyethyl-6-O-chloroethyl Erlotinib Hydrochloride 
• 183320-12-9 Didesmethyl Erlotinib Hydrochloride Salt 
• 183320-15-2 Desmethyl Erlotinib Acetate 
• 183320-29-8 CP 373413 
• 183320-51-6 OSI-420 
• 18332-12-2 3,5-diphenyl-2-thioxo-1,3-thiazolidin-4-one 
• 183321-69-9 Erlotinib Hydrochloride 
• 183321-74-6 Erlotinib 
• 183321-82-6 Erlotinib iMpurity 
• 183321-83-7 Erlotinib iMpurity B 
• 183321-84-8 4-[(3-Ethynylphenyl)amino]-6,7-bis(2-hydroxyethoxy)quinazoline 
• 183321-85-9 4-QuinazolinaMine, 7-(2-chloroethoxy)-N-(3-ethynylphenyl)-6-(2-Methoxyethoxy)- 
• 183321-86-0 OSI-420 

Recommend Products

• 958669-57-3  4-(methylthio)-6,7-bis(2-methoxyethoxy)quinazoline 
• 207226-02-6  hydrochloric salt of m-aminophenylacetylene 
• 108-42-9  3-chloro-aniline 
• 591-19-5  m-Bromoaniline 
• 585-79-5  m-nitrobromobenzene 
• 33432-52-9  2-methyl-4-(3-nitrophenyl)-3-butyn-2-ol 
• 299912-59-7  3-butyn-2-ol, 4-[3-[[6,7-bis(2-methoxyethoxy)-4-quinazolinyl]amine]phenyl]-2-methyl, hydrochloride 
• 468724-95-0  cis-Pt(ethylenediamine)nitrate-chloride 
• 50475-22-4  ethylenediamine platinum(II) nitrate 
• 179688-26-7  2-nitro-4,5-bis(2-methoxyethoxy)benzoic acid ethyl ester 
• 179688-27-8  ethyl 2-amino-4,5-bis(2-methoxyethoxy)-benzoate 
• 183322-16-9  3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester 
• 3943-89-3  Ethyl protocatechuate 
• 80407-64-3  3,4-bis(2-methoxyethoxy)benzaldehyde 

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