CN101575319B - Process for preparing lapatinib synthetic intermediate - Google Patents

Abstract

The invention relates to a process for preparing a lapatinib synthetic intermediate, which is characterized by comprising the following process steps: mixing 5-iodo-2-aminobenzonitrile and DMF-DMA; heating and refluxing the mixture at a temperature of between 90 and 100 DEG C for 1 to 2 hours, and performing reduced pressure distillation at a pressure of 0.1 MPa and at a temperature of between 70 and 80 DEG C for 10 to 30 minutes to remove excessive DMF-DMA; adding glacial acetic acid and 3-chloro-4-(3-fluorophenyl-methoxy) aniline; heating and refluxing the mixture at a temperature of between90 and 100 DEG C for 1 hour, cooling the mixture to the room temperature, and pouring the mixture to ice water; performing vacuum filtration, and washing a filter cake with the ice water and then wit h methanol; and performing vacuum drying on the filter cake to obtain a faint yellow solid N-(3-chloro-4-(3-fluorophenylmethoxy)phenyl)-6-iodoquinazoline-4-amine. The route avoids the use of thionyl chloride or phosphorus oxychloride and reduces pollutions to the environment; besides, the process has high yield and simple operation and is suitable for industrial production.

Description

The preparation technology of synthetic intermediate of lapatinib

1. Technical field

The invention belongs to the field of chemical industry and pharmacy, and in particular relates to a preparation process of a synthetic intermediate of lapatinib.

2. Background technology

Lapatinib

The chemical name is N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-(5-((2-(methylsulfonyl)ethylamino)methyl)furan-2- Base) quinazolin-4-amine bis(4-methylbenzenesulfonate) monohydrate, a new type of tyrosine kinase inhibitor developed by GlaxoSmithKline, for the treatment of HER-2 overexpression For patients with advanced or metastatic breast cancer, it was approved for marketing by the US FDA in March 2007. N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodoquinazolin-4-amine (1) is a key intermediate for the synthesis of lapatinib, and its CAS accession number is 231278-20-9. The preparation process currently used is: 5-iodo-2-aminobenzoic acid is used as the starting material, and 4-hydroxy-6-iodoquinazoline is obtained by cyclization of formamidine acetate, and thionyl chloride or phosphorus oxychloride Chlorination gives 4-chloro-6-iodoquinazoline, which is then condensed with 3-chloro-4-(3-fluorobenzyloxy)aniline to give 1 (accompanying drawing 1, route 1). Among them, the synthesis of 4-chloro-6-iodoquinazoline uses 4-hydroxyl 6-iodoquinazoline as a raw material, which reacts with excess thionyl chloride or phosphorus oxychloride, and the post-treatment is difficult and causes great environmental pollution.

3. Contents of the invention

Technical problem: This patent provides a new method for the synthesis of key intermediate N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodoquinazolin-4-amine from lapatinib Preparation Process.

Technical scheme: a preparation process for lapatinib synthetic intermediates, the process steps are: mixing 5-iodo-2-aminobenzonitrile and DMF-DMA (N,N-dimethylformamide dimethyl acetal) , the feeding ratio of 5-iodo-2-aminobenzonitrile and DMF-DMA is 1:1-5, reflux at 90-100°C for 1-2h, 0.1MPa/70-80°C for 10-30min under reduced pressure to remove excess DMF-DMA, add glacial acetic acid, 3-chloro-4-(3-fluorobenzyloxy)aniline, based on the mass of 5-iodo-2-aminobenzonitrile, the feeding amount of the glacial acetic acid is 1-40ml/ g, the molar ratio of 3-chloro-4-(3-fluorobenzyloxy)aniline and 5-iodo-2-aminobenzonitrile is 1:0.6-3, heated to reflux at 90-100°C for 1h, cooled to room temperature, Pour into ice water, filter with suction, wash the filter cake with ice water, then with methanol, and dry in vacuo to obtain light yellow solid N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6 - Iodoquinazolin-4-amine.

The molar ratio of 5-iodo-2-aminobenzonitrile and DMF-DMA is preferably 1:2-3.

Based on the mass of 5-iodo-2-aminobenzonitrile, the dosage of glacial acetic acid is 5-20ml/g.

The molar ratio of 3-chloro-4-(3-fluorobenzyloxy)aniline and 5-iodo-2-aminobenzonitrile is 1:1-1.5.

Beneficial effects: the synthesis route avoids the use of thionyl chloride or phosphorus oxychloride, thereby reducing environmental pollution; the yield is high, the operation is simple, and it is suitable for industrial production.

4. Description of drawings

Fig. 1 Process route diagram for the preparation of N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodoquinazolin-4-amine. Wherein Route 1 is the prior art synthetic route, and Route 2 is the synthetic route of the present application.

5. Specific implementation

The following examples can enable those skilled in the art to fully understand the present invention, but do not limit the present invention in any way.

Example 1 Preparation of N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodoquinazolin-4-amine (1)

Add 5-iodo-2-aminobenzonitrile (18.4g, 75mmol), DMF-DMA (N,N-dimethylformamide dimethyl acetal, 40ml) into a 100ml eggplant-shaped bottle, heat to reflux at 90-100°C After 1h, excess DMF-DMA was distilled off under reduced pressure, glacial acetic acid (100ml), 3-chloro-4-(3-fluorobenzyloxy)aniline (15g, 59.5mmol) were added and heated to reflux for 1h, cooled to room temperature, poured Pour into ice water (500ml), filter with suction, wash the filter cake with ice water (about 500ml), wash with methanol (1L), and vacuum dry to obtain 124.8g of light yellow solid, yield 82.4%.

¹ H NMR (DMSO-d6, 300Hz): 5.26(s, 2H); 7.18(m, 1H); 7.34-7.26(m, 3H); 7.47(m, 1H); 7.56(d, J=8.7Hz, 1H); 7.75(d, J=8.8Hz, 1H); 8.03(s, 1H); 8.11(d, J=8.6Hz, 1H); 8.61(s, 1H); 8.95(s, 1H); 9.84( s, 1H); ¹³ C NMR (DMSO-d6, 300MHz): 162.2 (d, J=970Hz), 156.3, 154.7, 149.7, 148.7, 141.2, 139.6 (d, J=30Hz), 133.0, 131.3, 130.5 ( d, J=33Hz), 129.7, 123.9, 123.2(d, J=10.8Hz), 122.1, 121.1, 116.8, 114.6(d, J=82.8Hz), 114.3, 114.0(d, J=87.3Hz), 91.3 , 69.4; LC-MS: 506 [M+H] ⁺ .

Example 2 Preparation of N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodoquinazolin-4-amine (1)

Mix 5-iodo-2-aminobenzonitrile and DMF-DMA, the molar ratio of 5-iodo-2-aminobenzonitrile and DMF-DMA is 1:1-5, heat and reflux at 90-100°C for 1h, 0.1MPa /70-80°C under reduced pressure distillation for 30 minutes to remove excess DMF-DMA, add glacial acetic acid, 3-chloro-4-(3-fluorobenzyloxy)aniline, based on the mass of 5-iodo-2-aminobenzonitrile, The feeding amount of the glacial acetic acid is 1-40ml/g, and the molar ratio of 3-chloro-4-(3-fluorobenzyloxy)aniline and 5-iodo-2-aminobenzonitrile is 1: 1-3, Heat to reflux at 90-100°C for 1h, cool to room temperature, pour into ice water, filter with suction, wash the filter cake with ice water, then methanol, and dry in vacuo to obtain light yellow solid N-(3-chloro-4-(3 -fluorobenzyloxy)phenyl)-6-iodoquinazolin-4-amine.

The molar ratio of 5-iodo-2-aminobenzonitrile and DMF-DMA is preferably 1:2-3.

Based on the mass of 5-iodo-2-aminobenzonitrile, the dosage of glacial acetic acid is preferably 5-20ml/g.

The molar ratio of 3-chloro-4-(3-fluorobenzyloxy)aniline to 5-iodo-2-aminobenzonitrile is preferably 1:1-1.5.

Claims (1)

1. a preparation technique for lapatinib synthetic intermediate, is characterized in that processing step is: 5-iodo-2-aminobenzonitrile and DMF-DMA are mixed, 5-iodo-2-aminobenzonitrile and DMF- The feeding molar ratio of DMA is 1:2-3, heating and reflux at 90-100°C for 1-2h, 0.1MPa/70-80°C for 10-30min under reduced pressure distillation to remove excess DMF-DMA, add glacial acetic acid, 3-chloro- 4-(3-fluorobenzyloxy) aniline, in terms of 5-iodo-2-aminobenzonitrile mass, the charging capacity of the glacial acetic acid is 5-20mL/g, 3-chloro-4-(3-fluoro The molar ratio of benzyloxy)aniline and 5-iodo-2-aminobenzonitrile is 1:1-1.5, heated and refluxed at 90-100°C for 1h, cooled to room temperature, poured into ice water, filtered with suction, and the filter cake is washed with ice Washed with water, then with methanol, and dried in vacuo to give N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodoquinazolin-4-amine as a pale yellow solid.

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