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

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

Uses

1. Used in Oncology:
Erlotinib hydrochloride is used as an EGFR inhibitor for the treatment of advanced or metastatic non-small cell lung cancer (NSCLC) after the failure of first-line therapy. It is also used as a first-line therapy in combination with gemcitabine for the treatment of metastatic pancreatic cancer and in treating malignant gliomas.
2. Used in Anticancer Applications:
Erlotinib hydrochloride is used as an HER1/EGFR inhibitor with an IC50 of 2 nM, showing more than 1000-fold increased sensitivity for EGFR compared to human c-Src or v-Abl. It is particularly effective against EGFR positive tumors and is beneficial for patients who have never smoked.
3. Used in Drug Development:
Erlotinib hydrochloride is used as a key intermediate in the development of new drugs targeting the epidermal growth factor receptor (EGFR) tyrosine kinase. Its structural similarity to gefitinib allows for improved pharmacokinetic properties, making it a valuable compound in the development of novel anticancer drugs.
4. Used in Pharmaceutical Research:
Erlotinib hydrochloride is used as a research tool for studying the role of EGFR in various cancers and for understanding the mechanisms of action of EGFR inhibitors. It is also used in the development of drug delivery systems to improve the bioavailability and therapeutic outcomes of EGFR-targeted therapies.

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.

Originator

Pfizer (US)

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

• 54060-30-9 3-acetylenephenylamine 
• 183322-18-1 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline 
• 183321-74-6 erlotinib 
• 958669-57-3 4-(methylthio)-6,7-bis(2-methoxyethoxy)quinazoline 
• 207226-02-6 hydrochloric salt of m-aminophenylacetylene 
• 179688-29-0 6,7-bis(2-methoxyethoxy)-3,4-dihydroquinazolin-4-one 
• 958669-56-2 6,7-bis(2-methoxyethoxy)quinazoline-4(3H)-thione 
• 1006377-63-4 C₁₃H₁₉NO₅ 
• 80407-68-7 3,4-bis(2-methoxyethoxy)-benzonitrile 
• 236750-65-5 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile 
• 80407-64-3 3,4-bis(2-methoxyethoxy)benzaldehyde 
• 139-85-5 3,4-dihydroxybenzaldehyde 
• 3943-89-3 Ethyl protocatechuate 
• 183322-16-9 3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester 

Downstream Products

• 248594-19-6 N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, methanesulfonic acid salt 
• 183321-74-6 erlotinib 
• 1429636-54-3 [6,7-bis(2-methoxyethoxy)-4-chinazolinyl](3-ethynylphenyl)amine adipinate 

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Relevant articles and documents

Convergent approach for commercial synthesis of gefitinib and erlotinib

An efficient, economical and large-scale convergent synthesis of epidermal growth factor receptor- tyrosine kinase inhibitors gefitinib (1, Iressa) and erlotinib (2, Tarceva) approved by U.S. FDA for the treatment of non-small-cell lung cancer is described. The formation of 4-anilinoquinazolines are achieved in a simple one-pot reaction of suitable forniamidine intermediates and substituted anilines involving Dimroth rearrangement, thereby avoiding the need to make quinazolin-4(3H)-one intermediates, which require a large experimental inputs. Using this process, we have produced drug candidates 1 with overall yield of 66% from 4-methoxy-5-[3-(4-morpholinyl) propoxy]-2-nitrobenzonitrile (3) and 2 with 63% from 4-bis(2-methoxyethoxy)-2-nitrobenzonitrile (6) on a multigram scale.

Improved synthesis of gefitinib and erlotinib hydrochloride- anticancer agents

A highly efficient and commercially viable process for the synthesis of 6,7-dihydroxy-4-anilinoquinazoline derivatives gefitinib (1) and erlotinib hydrochloride (2), used for the treatment of non-small cell lung cancer (NSCLC) and pancreatic cancer, is reported. This new process has improved yields and avoids the unstable 4-chloroquinazoline intermediate. The intermediates and final products were characterized by 1H and 13C nuclear magnetic resonance (NMR), mass spectra (MS), and elemental analysis, and purities of final products were determined by high performance liquid chromatogram (HPLC) and potentiometric titration methods. Copyright Taylor & Francis Group, LLC.

Solubility of two polymorphs of erlotinib hydrochloride in isopropanol and acetone from (273.15 to 303.15) K

In this work the solubility of two polymorphic forms A and B of erlotinib hydrochloride in isopropanol (IPA) and acetone were determined by means of high-performance liquid chromatography (HPLC) in the temperature range from (273.15 to 303.15) K. The experimental data were correlated with the modified Apelblat equation. In particular, the effect of the surfactant Tween 80 on the solubility of both polymorphs was studied as well. The results show that the solubility of both polymorphs generally increases with the temperature, and polymorph A has a higher solubility than polymorph B which indicates that polymorph A is the metastable form. The modified Apelblat equation shows a good agreement with the experimental data with a percent error less than 3 %. Furthermore, the solubility of both polymorphs increases in a linear fashion with increasing the content of Tween 80 in organic solvents, wherein Tween 80 presents a same solubilization capacity to both polymorphs and a higher solubilization capacity in acetone than in IPA.

Preparation method of erbtinib

The invention discloses a preparation method of erbtinib. The method comprises the following steps: carrying out a cyclization reaction on a compound represented by formula 1 to obtain a compound represented by formula 2, carrying out a chlorination reaction on the compound of the formula 2 to obtain a compound represented by formula 3, and carrying out a substitution salification reaction on thecompound of the formula 3 to obtain the compound erbtinib represented by formula 4. The preparation method of erbtinib can greatly shorten the production cycle when used for preparing erbtinib hydrochloride, can effectively avoid the defects of long production cycle, serious environmental pollution, unstable intermediate, difficult product purification, complex operation and the like, and has theadvantages of short reaction steps, simple operation, easy reaction, high product purity, high yield and low cost. The addition amount of reactants is properly controlled, the environmental requirements are clear, and a clear and new production direction is provided for process production.

Preparation method of erlotinib hydrochloride

The invention relates to a preparation method for erlotinib hydrochloride. The preparation method comprises the following steps: reacting 2-amino-4,5-dimethoxybenzoic acid with formamide to generate acompound 5, carrying out a bromination reaction on the compound 5, and subjecting a bromination product and 3-acetenyl aniline to a reaction and amination to generate a compound 3; and reacting the compound 3 with 48% hydrobromic acid under the action of a catalyst to obtain a compound 2, and reacting the compound 2 with iodoethylmethyl ether under the action of an alkali and the catalyst to generate erlotinib hydrochloride. The method has the advantages of mild conditions, low impurity content, safety, no pollution and environmental protection, and is suitable for industrial production.

The preparation method of the [...] hydrochloride

The invention provides a preparation method for an erlotinib hydrochloride crystal form. The preparation method is as follows: mixing erlotinib free alkaline with an organic solvent, and dropwise adding concentrated hydrochloric acid under a low-temperature condition to obtain high-purity erlotinib hydrochloride crystal form. The preparation method disclosed by the invention has characteristics of being easy in obtaining of materials, controllable in quality (concentrated hydrochloric acid), good in repeatability, simple to operate, high in yield, low in cost, and high in obtained sample purity, is more suitable for industrial production, and has very high economic benefits.

Preparation method for high-purity erlotinib hydrochloride

The invention belongs to the field of pharmaceutical synthesis, and provides a method for preparing high-purity erlotinib hydrochloride. The method comprises the following steps: 6,7-di(2-methoxyethoxy)quinazoline-4-one is used as a raw material, chlorination is performed to obtain 4-chloro-6,7-di(2-methoxyethoxy)quinazoline (compound I), refining is performed on the compound I, the refined compound I is reacted with 3-aminophenylacetylene, and therefore the high-purity erlotinib hydrochloride is obtained, wherein the purity obtained by HPLC is 99.85% or more, and the content of an impurity 1and an impurity 2 is less than 0.06%. The method provided by the invention is suitable for industrial large-scale production.

A method for preparing environmental protection of erlotinib hydrochloride

The invention discloses an environment-friendly method for preparing high-yield erlotinib hydrochloride. The method comprises the following steps: directly performing cyclic condensation by taking 2-amino-4,5-di(2-methoxy ethyoxyl) ethyl benzoate hydrochloride as a key intermediate, reacting with aminophenylacetylene to generate erlotinib hydrochloride after performing chlorination, and refining to obtain the high-purity erlotinib hydrochloride. The process route provided by the invention is mild in reaction condition and high in yield; the first-class reagent and other reagents harmful to the environment and the operators are not used, the byproduct is few, the aftertreatment is simple and the commercial process can be easily processed.

Method for preparing compound

The invention provides a method for preparing a compound as shown in a formula I which is described in the specification. The method comprises a step of contacting a compound as shown in a formula III which is described in the specification or a derivative thereof with a compound as shown in a formula II which is described in the specification so as to obtain the compound as shown in the formula I. In the formulas, R1 and R2 are hydrogen, alkoxy groups or heteroaromatic rings, preferably alkoxy groups; and R is hydrogen, an alkyl group, a phenyl group, a substituted phenyl group or a naphthyl group. The compound as shown in the formula I is a tinib drug intermediate 6,7-disubstituted quinazolinone. According to the method provided in embodiments in the invention, aldoketones are used as cyclization raw materials in replacement of carboxylic acids for preparation of tinib drug intermediate, and since the aldoketones are not corrosive, the method has low requirements on reaction equipment and is more favorable for industrial production.

Synthesis method of erlotinib hydrochloride

The invention discloses a synthesis method of erlotinib hydrochloride. The synthesis method comprises the following steps: (1) at a first working section: preparing 3-methoxyl-4-hydroxybenzonitrile from vanillin and hydroxylammonium chloride; (2) at a second working section: synthesizing 3,4-dihydroxybenzonitrile; (3) at a third working section: synthesizing 3,4-di(2-methoxyethoxy)phenylacetonitrile; (4) at a fourth section: synthesizing 4,5-di(2-methoxyethoxy)-2-nitrophenylacetonitrile; (5) at a fifth working section: synthesizing 4,5-di(2-methoxyethoxy)-2-aminophenylacetonitrile hydrochloride; and (6) at a sixth working section: synthesizing the erlotinib hydrochloride. The synthesis method of the erlotinib hydrochloride, disclosed by the invention, has the advantages of reasonable design, easiness of obtaining raw materials, relatively low production cost, simplicity and easiness of operation and is suitable for industrial production.