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A kind of synthetic method of 6-(dibromomethyl)-2-methylquinazolin-4(3h)-one

A technology of methylquinazoline and dibromomethyl is applied in the field of synthesis technology of pharmaceutical intermediates and achieves the effects of good selectivity, high yield and convenient operation

Active Publication Date: 2022-04-22
HONGGUAN BIO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There is no synthetic route of the compound reported in the literature at present

Method used

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  • A kind of synthetic method of 6-(dibromomethyl)-2-methylquinazolin-4(3h)-one
  • A kind of synthetic method of 6-(dibromomethyl)-2-methylquinazolin-4(3h)-one
  • A kind of synthetic method of 6-(dibromomethyl)-2-methylquinazolin-4(3h)-one

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] The first step: the synthesis of tert-butyl (2,6-dimethylquinazolin-4-yl) formate (2)

[0036] Take a 500mL three-necked flask, add 2,6-dimethylquinazolin-4(3H)-one (1) (10g, 57.40mmol), add anhydrous THF (300mL) and lower the temperature to within 10°C under nitrogen protection, then divide Sodium hydride (11.48 g, 287.00 mmol) was added in portions. After the addition, remove the ice bath, slowly rise to room temperature, add Boc 2 O (15.03g, 68.88mmol), then the temperature was raised to 50-60°C and the reaction was stirred for 3 hours, and the reaction was complete as detected by TLC. The system was cooled down to 0-10°C and quenched with water, then extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. Add silica gel to mix the sample, and purify by column chromatography (eluent: petroleum ether: ethyl acetate=20:1) to obtain te...

Embodiment 2

[0042] The first step: the synthesis of tert-butyl (2,6-dimethylquinazolin-4-yl) formate (2)

[0043] Take a 500mL three-necked flask, add 2,6-dimethylquinazolin-4(3H)-one (1) (10g, 57.40mmol), add anhydrous THF (300mL) and lower the temperature to below -10°C under nitrogen protection. Add LDA (2mol / L, 34mL, 68.88mmol) and keep the reaction for about 0.5 hours. After the addition was completed, it was slowly raised to room temperature, and Boc was added 2O (15.03g, 68.88mmol), then the temperature was raised to 50-60°C and the reaction was stirred for 3 hours, and the reaction was complete as detected by TLC. Cool the system down to 0-10°C and add water to quench it, add ethyl acetate to extract, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to remove the solvent, add silica gel to mix the sample, and purify by column chromatography (eluent: Petroleum ether: ethyl acetate = 20:1) to obtain tert-butyl (...

Embodiment 3

[0049] The first step: the synthesis of tert-butyl (2,6-dimethylquinazolin-4-yl) formate (2)

[0050] In a 250mL reaction flask, add DMF (60mL), add 2,6-dimethylquinazolin-4(3H)-one (1) (2.00g, 11.48mmol) under stirring, nitrogen protection, and then add hydrogen in sequence Potassium oxide (3.21g, 57.40mmol), Boc 2 O (3.01g, 13.78mmol), then heated up to 50-60°C and stirred for 2-3h, TLC reaction was complete, then cooled to 0-10°C, filtered to remove inorganic salts, added water and ethyl acetate to extract layers, combined The organic phase was dried and filtered using anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure to remove the solvent, the sample was mixed with silica gel, and purified by column chromatography (eluent: petroleum ether: ethyl acetate = 20:1) to obtain compound 2 (yield 2.52g , yield 80.0%).

[0051] The second step: the synthesis of tert-butyl (6-(dibromomethyl)-2-methylquinazolin-4-yl) formate (3) in the 100mL reaction fl...

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Abstract

The invention relates to a synthesis method of an important pharmaceutical intermediate 6-(dibromomethyl)-2-methylquinazolin-4(3H)-one. The present invention uses 2,6-dimethylquinazoline-4(3H)-ketone (1) as a starting material, and adds a Boc protecting group under alkaline conditions to prepare compound (2), which effectively reduces 2,6 The polarity of dimethylquinazolin-4(3H)-ketone improves the solubility, and at the same time reduces the bromination probability of the 2-methyl group by increasing the steric effect and electronic effect; compound (2) carries out the bromination reaction , highly selectively obtain the 6-methyl dibrominated product (3); finally remove the protecting group by an acidic reagent to obtain highly pure 6-(dibromomethyl)-2-methylquinazoline-4( 3H)‑ketone. The synthesis method of 6-(dibromomethyl)-2-methylquinazolin-4(3H)-one of the present invention has simple process route, convenient operation, good selectivity and high yield.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a synthesis process of a medicine intermediate. Background technique [0002] Raltitrexed, a quinazoline folate analogue, is a novel water-soluble inhibitor of thymidylate synthase, which can cause DNA fragmentation and cell death by inhibiting thymidylate synthase. Compared with 5-fluorouracil, raltitrexed has stronger selectivity, and can replace fluorouracil in the treatment of advanced colorectal cancer, and has become the first-line drug for the treatment of advanced colorectal cancer. [0003] Raltitrexed was developed and created by the British Zeneca Pharmaceutical Company. It was first launched in the UK in 1996. The trade name is Tomudex, and the chemical name is: N-[5-[N-methyl-N-(2-methyl-4-oxo Substitute-3,4-dihydroquinazoline-6-methyl)amino]thiophene-2-formyl]-L-glutamic acid, the structural formula is: [0004] [0005] A key intermediate is invol...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/90
CPCC07D239/90Y02P20/55
Inventor 朱金龙于学彬徐磊杨鑫杰张新丽朱渝峰张旭东
Owner HONGGUAN BIO PHARMA CO LTD
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