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

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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 ...

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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