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Preparation method for afatinib

A technology of afatinib and a synthetic method, applied in the field of synthesis of heterocyclic compounds, can solve problems such as inability to obtain products, affect stereoselectivity, and unsatisfactory reaction yield, so as to reduce refining processes, improve purity, and reduce production cost effect

Active Publication Date: 2016-02-17
TIANJIN PHARMACN MEDICAL TECH
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

However, the literature also pointed out that under normal conditions without substituents, the reaction product should be mainly in the trans structure, indicating that whether it is a charge-absorbing or a supply-donating group, it will affect the stereoselectivity of the reaction, resulting in the inability to obtain the desired product. The product
And also pointed out in this document, when adopting methyl alcohol, acetonitrile to carry out the HWE reaction of acetaldehyde and diformonitrile phosphate as solvent, it is easier to react than in common tetrahydrofuran solvent, and when reacting in methanol, the trans structure in the product More (about 65:35), but in this reaction, a strong charge-absorbing group was adopted in the phosphoric acid ester, and there was triethyl phosphonoacetate used in the preparation of trans-4-dimethylamino croton markedly different
And through experiments, we found that the reaction yield of trans-4-dimethylamino croton hydrochloride is not ideal when purely using methanol as a solvent and adopting HWE reaction

Method used

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  • Preparation method for afatinib
  • Preparation method for afatinib
  • Preparation method for afatinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1～4

[0024] Embodiment 1~4, the synthesis of trans-4-dimethylamino croton hydrochloride

[0025]

[0026] Operating process:

[0027] 1) Dissolving triethyl phosphonoacetate (II) in solvent 1, the weight to volume ratio of triethyl phosphonoacetate to solvent 1 is 1:A;

[0028] 2) NaOH is added to solvent 2 and stirred evenly, the weight ratio of NaOH to triethyl phosphonoacetate (II) is B, and the weight-to-volume ratio of NaOH to solvent 2 is 1:C, the NaOH dispersed in solvent 2 Slowly add the triethyl phosphonoacetate (II) dissolved in solvent 1 obtained in step 1), and stir for 1 h after the addition is complete to obtain the reaction solution (3), and the reaction temperature is controlled at T1°C;

[0029] 3) Dissolve N,N-dimethylaminoacetaldehyde bisulfite (I) in water and slowly add it dropwise to the reaction solution (3). Descending to obtain the reaction solution (4), the molar ratio of the N,N-dimethylaminoglyoxal bisulfite (I) to triethyl phosphonoacetate (II) is ...

Embodiment 5-1

[0035] Synthesis of Embodiment 5-1 Afatinib (VI)

[0036] The trans-4-dimethylaminocroton hydrochloride (III) prepared by the method of Example 1 was used as raw material, the content was 98.5%, and the feeding amount was 165.6g. The reaction process was as follows:

[0037] Dissolve trans-4-dimethylaminocroton hydrochloride (III) in 1200mL of anhydrous tetrahydrofuran, cool to 0±5°C, add 315mL of oxalyl chloride dropwise, and react at 25±5°C for 4 hours after dropping , and cool the solution to 0±5°C for later use.

[0038] Add 311g of compound (V) (content 99.0%) into 2400mL of anhydrous tetrahydrofuran, cool down to 0±5°C, add the above solution dropwise, and react at 0±5°C until the reaction is detected by TLC. Add 1% sodium hydroxide aqueous solution dropwise to the reaction solution until the pH is 8-9, add 30L of purified water, a large amount of solids are precipitated, filter, wash the solids until the filtered water is neutral, drain and dry to obtain afatinib (VI ...

Embodiment 5-2

[0039] Yield of Afatinib=(Afatinib (VI) quality*content / 485.9) / (Compound (V) quality*0.99 / 374.8) Synthesis of Example 5-2 Afatinib (VI)

[0040] Using the same raw material ratio and process as in Example 5-1, the difference is that ammonia water is used instead of sodium hydroxide aqueous solution to neutralize the reaction solution, the pH is adjusted to 6-7, and 380 g of afatinib (VI) is obtained after washing and drying. The content is 98.5%, and the molar yield based on compound (V) is 93.8%.

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Abstract

The invention provides a preparation method for afatinib. The preparation method comprises the following steps: subjecting trans-4-dimethylaminocrotonic acid hydrochloride (III) to chlorination so as to obtain trans-4-dimethylaminocrotonyl chloride hydrochloride (IV); and reacting the compound (IV) with N4-(3-chloro-4-fluoro-phenyl)-7-((S)-tetrahydrofuran-3-yl-oxy)quinazoline-4,6-diamine (V) so as to prepare afatinib (VI). Reaction equations are described in the specification.

Description

Technical field: [0001] The present invention relates to a method for synthesizing a heterocyclic compound containing two heterocyclic rings connected by a bond containing a heteroatom as a bond chain. Background technique: [0002] Afatinib (Afatinib), chemical name (E)-4-dimethylamino-but-2-enoic acid-(4-(3-chloro-4-fluoro-phenylamino)-7-((S )-tetrahydrofuran-3-yloxy)-quinazolin-6-yl)-amide (CAS: 850140-72-6), its structural formula is as follows: [0003] [0004] Afatinib is a multi-target small molecule oral drug developed by Boehringer Ingelheim, Germany, which belongs to the irreversible inhibitor of epidermal growth factor receptor (EGFR) and human epidermal receptor (HER2) tyrosine kinase. As the first drug for the treatment of lung cancer after the failure of epidermal growth factor receptor inhibitor therapy, it is mainly aimed at the treatment of advanced breast cancer and non-small cell lung cancer in clinical practice. Chinese patent document CN103755688A ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12C07C229/30C07C227/10
Inventor 田东奎何磊
Owner TIANJIN PHARMACN MEDICAL TECH
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