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Synthesis method and related intermediate of N-(3-alkynylphenyl)-4,6-diaminoquinazoline-based compound

A compound and amino protecting group technology, applied in organic chemistry, bulk chemical production, etc., can solve problems such as unfavorable scale-up production, difficult removal, and high requirements for reducing agents

Inactive Publication Date: 2019-04-30
HUTCHISON MEDIPHARMA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, when reducing the 6-position nitro group, the requirements for the reducing agent used are relatively high, otherwise the phenylethynyl group on the 4-position amine is easily reduced to an alkene, and the alkene impurity is difficult to remove in the subsequent process. affect the quality of the final product
In addition, the above-mentioned process route is relatively cumbersome, which is not conducive to industrial scale-up production

Method used

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  • Synthesis method and related intermediate of N-(3-alkynylphenyl)-4,6-diaminoquinazoline-based compound
  • Synthesis method and related intermediate of N-(3-alkynylphenyl)-4,6-diaminoquinazoline-based compound
  • Synthesis method and related intermediate of N-(3-alkynylphenyl)-4,6-diaminoquinazoline-based compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0243] N 4 Synthesis of -(3-ethynylphenyl)-7-methoxy-quinazoline-4,6-diamine

[0244] 1) Synthesis of N-(4-hydroxyl-7-methoxyquinazolin-6-yl)acetamide

[0245]

[0246] 6-Amino-7-methoxy-4-hydroxyquinazoline (30 g, 0.15 mol), DMF (500 ml), and DIPEA (48 g, 0.375 mol) were sequentially added to a 1000 ml three-neck reaction flask, and replaced with nitrogen. Controlling the internal temperature at 20-25°C, slowly added acetic anhydride (38 g, 0.375 mol) dropwise. After the dropwise addition, keep stirring at 20-25°C overnight, and monitor the reaction by LC-MS. After the reaction was completed, filter with suction, wash the filter cake with DMF, and drain it to obtain an off-white filter cake. The filter cake was dried under reduced pressure at 40-50°C to obtain 35 g of the title compound as an off-white solid with a purity of 98.8% and a yield of 97%. LC-MS: [M+H] + :234

[0247] 1 H NMR (400MHz, DMSO) δ8.26(s, 1H), 8.16(dt, J=8.4, 0.9Hz, 1H), 7.74(dt, J=8.3, 0.9Hz, ...

Embodiment 2

[0261] N 4 Synthesis of -(3-ethynylphenyl)-7-methoxy-quinazoline-4,6-diamine

[0262] 1) Synthesis of 4-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-7-methoxyquinazolin-6-amine

[0263]

[0264] 6-Amino-7-methoxy-4-hydroxyquinazoline (1g, 5.23mmol) was added to DMF (10ml), followed by BOP (3g, 6.78mmol) and DBU (1.06ml, 7.05mmol) , heated to 40-50° C., and reacted for 1 hour, the reaction solution was directly separated by HPLC reverse-phase preparative column to obtain 1.5 g of the target product.

[0265] 1 H NMR (400MHz, DMSO) δ8.26(s, 1H), 8.16(dt, J=8.4, 0.9Hz, 1H), 7.74(dt, J=8.3, 0.9Hz, 1H), 7.61(ddd, J= 8.3,6.9,1.0Hz,1H),7.51(ddd,J=8.3,6.9,1.0Hz,1H),7.35(s,1H),7.34(s,1H),5.99(s,2H),4.02(s ,J=5.9Hz,3H).

[0266] 13 C NMR (100MHz, DMSO) δ162.91, 155.23, 148.58, 147.92, 143.25, 141.74, 129.65, 129.08, 125.69, 120.33, 109.91, 108.81, 105.90, 98.10, 56.71.

[0267] LC-MS: [M+H] + :309

[0268] 2)N 4 Synthesis of -(3-ethynylphenyl)-7-methoxy-quinazoline-4,6-diamine

...

Embodiment 3

[0272] N 4 Synthesis of -(3-ethynylphenyl)-7-methoxy-quinazoline-4,6-diamine

[0273]

[0274] 6-amino-7-methoxy-4-hydroxyquinazoline (0.5g, 2.62mmol) was added to DMF (5ml), and then BOP (1.51g, 3.41mmol) and DBU (0.50ml, 3.33 mmol), heated to 40-50°C, reacted for 2 hours, added 3-alkynylaniline hydrochloride (0.16g, 2.54mmol), reacted for 18 hours, added water 20ml, and precipitated solid. After filtration, the obtained filter cake was added to NaHCO 3 / Na 2 CO 3 In the buffer solution, adjust the pH value to 8-9. After filtering, the filter cake was dried under reduced pressure at 50° C. for two hours to obtain 600 mg of the target product. After testing, its 1 H NMR is consistent with the final product of Example 1.

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Abstract

The present invention relates to a synthesis method and a related intermediate of a N-(3-alkynylphenyl)-4,6-diaminoquinazoline-based compound.

Description

technical field [0001] The invention belongs to the field of pharmaceutical intermediates. More specifically, the present invention relates to a synthesis method and related intermediates of N-(3-alkynylphenyl)-4,6-diaminoquinazoline compounds. Background technique [0002] N-(3-alkynylphenyl)-4,6-diaminoquinazolines are an important class of anticancer drugs. For example, Chinese patent application CN101619043A discloses various epidermal growth factor receptor (EGFR) inhibitors containing N-(3-alkynylphenyl)-4,6-diaminoquinazoline structure. [0003] Patent application CN101619043A also discloses a method for synthesizing various compounds containing N-(3-alkynylphenyl)-4-aminoquinazoline structure, the process route it adopts is based on 2-amino-5-nitrobenzene Nitrile is used as the raw material, and the raw material is first reacted with dimethylformamide dimethyl acetal to generate (E)-N'-(2-cyano-4-nitrophenyl)-N,N-dimethylformamide , and then react with 3-ethynylan...

Claims

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Application Information

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IPC IPC(8): C07D403/12C07D239/94C07D487/04
CPCC07D239/94C07D403/12C07D487/04Y02P20/55
Inventor 张斌
Owner HUTCHISON MEDIPHARMA LTD
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