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Compound and application thereof in preparing erlotinib

A compound and cyclization technology, used in the preparation of erlotinib, pharmaceutical intermediates, and the preparation of N--6,7-bis--4-quinazolineamine Field

Active Publication Date: 2012-09-12
HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] The purpose of the present invention overcomes the low yield of preparing erlotinib hydrochloride in the prior art, the materials used pollute the environment, the reaction condition requirements are high and the operation is not easy enough, Technical defects that cannot be industrialized, provide a high yield, no pollution, mild reaction, easy operation, and a preparation method for erlotinib that is suitable for industrialization

Method used

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  • Compound and application thereof in preparing erlotinib
  • Compound and application thereof in preparing erlotinib
  • Compound and application thereof in preparing erlotinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1 : Synthesis of 2-amino-4,5-bis-(2-methoxyethoxy)benzonitrile (compound 3)

[0051] 1. Synthesis of 3,4-bis-(2-methoxyethoxy)benzonitrile

[0052] 5L of N,N-dimethylformamide was added to a 10L reactor, and 3,4-dihydroxybenzonitrile (320g, 2.37mol), 2-chloroethyl methyl ether (670g, 7.09mol), Potassium carbonate 1Kg, potassium iodide 90g, heated to 100°C for reaction. After the reaction was complete as detected by TLC, it was cooled, poured into 10L of ice water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain brown oily 3,4-bis-(2-methoxy Ethoxy)benzonitrile (600 g).

[0053] 2. Synthesis of 2-nitro-4,5-bis-(2-methoxyethoxy)benzonitrile

[0054] 1.5 L of concentrated nitric acid was added to a 3 L reaction flask, and 3,4-bis-(2-methoxyethoxy)benzonitrile (600 g, 2.39 mol) was added dropwise with stirring at room temperature. After dropping, the reaction was he...

Embodiment 2

[0058] Example 2: Synthesis of (E)-N'-(3-(3-hydroxyl-3-methyl-1-butyne)phenyl)-N,N-dimethylformamidine (compound 1)

[0059] 4-(3-Aminophenyl)-2-methyl-3-butyn-2-ol (5g, 28.6mmol) was suspended in 20mL N,N-dimethylformamide, and 5mL N , N-dimethylformamide diisopropyl acetal and 0.2mL glacial acetic acid, N 2 Under protection, heat to reflux at about 140°C until the reaction is completed. After cooling, the reaction solution was concentrated under reduced pressure to obtain compound 1 (5 g), with a purity of 97% and a yield of 76.1%.

Embodiment 3

[0062] Embodiment 3: the synthesis of compound 1

[0063] 4-(3-Aminophenyl)-2-methyl-3-butyn-2-ol (5g, 28.6mmol) was suspended in 20mL butanone, and 15mL N,N-dimethylformaldehyde was added successively under stirring at room temperature Amide dimethyl acetal and 0.2 mL glacial acetic acid, N 2 Under protection, heat to reflux at about 50°C until the reaction is completed. After cooling, the reaction solution was concentrated under reduced pressure to obtain Compound 1 (5.8 g), with a purity of 95% and a yield of 88.3%.

[0064]

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Abstract

The invention discloses two new compounds which are chemically named as (E)-N'-(3-(3-hydroxy-3-methly-1-butyne) phenyl)-N,N-dimethyl formamidine (compound 1) and 4-(3-(6,7-bi-(2-methoxy ethyoxyl)-4-quinazoline amine) phenyl)-2-methyl-3-butyne-2-alcohol (compound 2). The invention also discloses a preparation method for the two compounds. According to the preparation method, 4-(3-amino phenyl)-2-methyl-3-butyne-2-alcohol reacts with a formylation reagent, thereby obtaining the compound 1, and 2-amino-4,5-bi-(2-methoxy ethyoxyl) cyanophenyl is cyclized with the compound 1 under the condition of acid catalysis, thereby obtaining the compound 2. The invention also discloses applications of the two compounds in preparing erlotinib and salts thereof and specific preparation methods. The compounds and the preparation method disclosed by the invention have the advantages that the raw materials are easily obtained, fewer reagents are used in the whole process, the reaction condition is mild, the operation is simple and the compounds are suitable for industrial production.

Description

[0001] technical field [0002] The present invention relates to the field of synthesis of pharmaceutical compounds, in particular, pharmaceutical intermediates, and their use in the preparation of N-(3-ethynylphenyl)-6,7-bis-(2-methoxyethoxy)-4 - Use in quinazolinamine (erlotinib) and a process for the preparation of erlotinib. Background technique [0003] [N-(3-ethynylphenyl)-6,7-bis-(2-methoxyethoxy)-4-quinazolinamine hydrochloride (erlotinib hydrochloride, Erlotinib Hydrochloride, trade name : Tarceva, Tarceva) is a selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, which was launched in 2004 and is currently clinically used for the treatment of non-small cell lung cancer. [0004] [0005] There are many preparation methods of erlotinib hydrochloride, but there are three representative ones: [0006] Method 1 Rodney Caughren Schnur of Pfizer Inc. N. Y. of the United States has patented in the United States Alkynyl and azido-substitut...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C257/12C07D239/94
Inventor 胡祖耀孔祥文蔡永丰
Owner HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST