Preparation method of benzo [e] [1, 3] oxazine-2, 4-diketone

A benzo and oxazine technology, which is applied in the field of preparation of benzo[e][1,3]oxazine-2,4-dione, can solve the problems of high environmental harm and high industrialization cost, and achieve non-toxic effect , Simple operation, low price effect

Active Publication Date: 2022-03-18
苏州天马医药集团天吉生物制药有限公司
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Problems solved by technology

[0009] For this reason, the technical problem to be solved by the present invention is to overcome the problems in the prior art that the environment is very harmful and the cost of industrialization is relatively high.

Method used

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  • Preparation method of benzo [e] [1, 3] oxazine-2, 4-diketone
  • Preparation method of benzo [e] [1, 3] oxazine-2, 4-diketone
  • Preparation method of benzo [e] [1, 3] oxazine-2, 4-diketone

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preparation example Construction

[0037] A first object of the present invention is to provide a preparation method of benzide [e] [1, 3] uase-2,4-diketone, including the following steps, basic conditions, 2-hydroxybenzamide and (Boc) 2 O Under the action of the catalyst, the reaction was reacted in an organic solvent to obtain the benzene [E] [1,3] uxine-2,4-diketone. Carbonylation cycloal reagent diaphrate di-tert-butyl-butyl (BOC) 2 O As a preferred protective reagent, it is used to introduce tert-butoxycarbonyl (BOC) protective agent in synthesis. Under anhydrous conditions, it can be reacted with a thickness of 2-hydroxybenzamide with a weak nucleophilicity.

[0038] In one embodiment of the invention, the chemical reaction flow is:

[0039]

[0040] In one embodiment of the invention, under basic conditions, starting materials and (BOC) at 2-hydroxybenzamide 2 O At the action of the catalyst, the reaction was reacted in an organic solvent to obtain an intermediate tert-butyl ester; an intermediate tert-but...

Embodiment 1

[0057] One kind benzo [e] [1,3] oxazine-2,4-dione Preparation of the following steps:

[0058]

[0059] 500mL four reaction flask was added 2-hydroxybenzamide (13.7g, 0.1mol, 1.0equiv), N, N- dimethylformamide (DMF) (58.5mL), pyridine (5mL at 20-25 ℃, 0.062mol, 0.6equiv), was stirred at this temperature-time (Boc) 2 O (24.0g, 0.11mol, 1.1equiv), was stirred at this temperature for 2h, TLC showed the starting material disappeared, the reaction was stopped, water was added (292 mL), and extracted with ethyl acetate (100mL * 3), the combined extracts washed with water (50 mL ), dried at 40 ℃ the ethyl acetate solution was concentrated to give a residue. The residue, toluene (100 mL), warmed to 90 ℃, stirred for 4h, cool down to 20-25 ℃, suction filtration to give a white crystalline solid (12.5 g), yield 76.7%.

Embodiment 2

[0061] One kind benzo [e] [1,3] oxazine-2,4-dione Preparation of the following steps:

[0062] 2L four reaction flask was added 2-hydroxybenzamide (137g, 1mol, 1.0equiv), N, N- dimethylformamide (DMF) (1370mL), pyridine (50mL, 0.62mol at 20-25 ℃, 0.6equiv), was stirred at this temperature-time (Boc) 2 O (240g, 1.1mol, 1.1equiv), was stirred at this temperature for 2h, then warmed to 80 ℃, stirred for 4h, cool down to 20-25 & deg.] C, was added water (1370mL), the pH adjusted to 1-2 with hydrochloric acid, there white solid precipitated, IH stirred at this temperature, to give a white solid by suction filtration, washed with 1% hydrochloric acid, and dried in a forced air 60 deg.] C 8h, to give a white powder (131 g), yield 80%, HPLC chromatogram as figure 1 , The result indicates that the method of the present invention obtained by preparing benzo [e] [1,3] oxazine-2,4-dione purity is over 99%.

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Abstract

The invention relates to a preparation method of benzo [e] [1, 3] oxazine-2, 4-diketone, and belongs to the technical field of organic compounds. According to the preparation method, under the alkaline condition, 2-hydroxybenzamide and (Boc) 2O react in a solvent under the action of a catalyst, and benzo [e] [1, 3] oxazine-2, 4-diketone is obtained. A carbonylation cyclization reagent di-tert-butyl dicarbonate ester (Boc) 2O is adopted, and the reagent has no strong pungent smell, has no toxic effect on a human body, is low in price and is not limited to transportation and use. (Boc) 2O can be used as a relatively good protective reagent. Under the anhydrous condition, the compound can react with 2-hydroxybenzamide with weak nucleophilicity under the action of a catalyst (N, N-dimethyl pyridine). The preparation method is simple to operate, the purity of the obtained product reaches 98% or above, the yield reaches 80%, and the preparation method is suitable for industrial production.

Description

Technical field [0001] The present invention relates to the field of organic compounds, and more particularly to a preparation method of benzo-2,4-diketone, in particular, of a benzene [E] [1,3]. Background technique [0002] Benzo [E] [1,3] Uase-2,4-diketone is an important intermediate that synthesizes 8- (2-hydroxybenzamide) octoate (SNAC, CAS203787-91-1). SNAC is a new type of amino acid derivative absorbent accelerator. Recent studies have shown that there is no need for dosage form protection, SNAC can promote oral absorption of various protein drug solutions such as heparin and human growth hormone, but does not show significant cytotoxicity, which promotes the absorption mechanism different from common absorption promoters, but The exact mechanism is unclear. (荣, et al, N- [8- (2-hydroxyphenyl) amino] sodium octoate) on the gastrointestinal absorption and mechanism of insulin solution, Journal of Pharmacy, 2003, 38 (12), 953-956). [0003] Benzoxide [E] [1,3] synthesis of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D265/26
CPCC07D265/26
Inventor 黄莉董玉军徐德银李介林沈俊
Owner 苏州天马医药集团天吉生物制药有限公司
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