Novel preparation of trityl group candesartan cilexetil intermediate

A technology of trityl candesartan and a new method is applied in the new field of preparation of trityl candesartan cilexetil intermediates, and can solve the problem that methyl benzoate is not easily available, complicated to operate, and a large amount of candesartan medoxomil. Preparation difficulties, etc.

Active Publication Date: 2008-12-17
APELOA PHARM CO LTD +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The first two methods all are to synthesize the intermediate 3-nitro-2-tert-butoxyaminobenzoic acid methyl ester earlier, and then hydrolyze. There are two active hydrogens in the structure of the hydrolyzed product, and this route is introduced earlier and has higher Active tetrazolyl, so in the whole synthetic route, the auxiliary steps of corresponding protective group and deprotection group have to be added, which complicates the operation, thus making the large-scale preparation of candesartan cilexetil difficult
Although the latter method avoids the N-protection and deprotection reactions of selective protection and tetrazolyl that exist in the first two methods, and simplifies the synthetic route, the intermediate 3-nitro-2-tert-butoxy Methyl aminobenzoate is not readily available and still needs to be prepared

Method used

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  • Novel preparation of trityl group candesartan cilexetil intermediate
  • Novel preparation of trityl group candesartan cilexetil intermediate

Examples

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Comparison scheme
Effect test

Embodiment 1

[0010] Example 1 Preparation of 2-methyl formate-6-nitro-benzoic acid

[0011] Add 200g of 3-nitrophthalic acid and 1L of methanol into the reaction flask. 104 mL of thionyl chloride was added dropwise in an ice-water bath, and the drop was completed in 2 hours; the temperature was raised to reflux, and the reaction was carried out for 24 hours. The reaction mixture was concentrated to dryness, washed with petroleum ether, and filtered to obtain 210.5 g of 2-methyl formate-6-nitro-benzoic acid as a white solid, with a yield of 99%.

Embodiment 2

[0012] Example 2 Preparation of 2-amino-3-nitro-benzoic acid methyl ester

[0013] Add 100g of 2-methylformate-6-nitro-benzoic acid, 800mL of chloroform, and 133.3mL of 98% sulfuric acid into the reaction flask in sequence. At room temperature, 56 g of sodium azide was added in batches, and the addition was completed in about 100 minutes; the temperature was raised to 50° C., and the reaction was carried out for 22 hours. The reaction mixture was cooled to room temperature, decanted off the solvent, washed with chloroform, added 400 mL of water, and filtered to obtain 78.4 g of a yellow solid with a yield of 90%.

Embodiment 3

[0014] Example 3 One of the preparation methods of 2-ethoxy-4-formic acid methyl ester-3-hydrogen-benzimidazole

[0015] 5g 2-amino-3-nitro-benzoic acid methyl ester, 50mL concentrated hydrochloric acid, 25g SnCl 2 2H 2 O was added to the reaction flask in turn, and reacted at room temperature for 5 hours. The pH of the reaction mixture was adjusted to 8 with saturated sodium carbonate solution, extracted with ethyl acetate, the organic phases were combined, and the solvent was distilled off to obtain 4 g of light yellow solid of methyl 2,3-diamino-benzoate.

[0016] The 2,3-diamino-benzoic acid methyl ester obtained above, 5.6 mL of glacial acetic acid, and 6 g of tetraethyl orthoformate were sequentially added into the reaction flask, and reacted at room temperature for 3 hours. Concentrate the reaction mixture to dryness, add 50mL H 2 O, cooled to 5°C, and filtered to obtain 4.25 g of white solid 2-ethoxy-4-formic acid methyl ester-3-hydrogen-benzimidazole, with a yield ...

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Abstract

The invention discloses a novel technology for synthesizing an intermediate of trityl candesartan; the synthesis steps thereof comprise: (1) a preparation method of 2-menthyl formate-6-nitryl-benzoic acid; (2) a preparation method of 2-amido-3-nitryl-methyl benzoate; (3) a preparation method of 2, 3-diaminobenzene menthyl formate; (4) a preparation method of 2-oxethyl-4-menthyl formate-3-H-benzimidazole; and (5) the preparation method of the intermediate of trityl candesartan.

Description

technical field [0001] The present invention relates to a preparation method of an important intermediate of candesartan cilexetil, an antihypertensive drug with significant curative effect, and more specifically relates to a preparation method of a candesartan cilexetil intermediate protected by a trityl group. Background technique [0002] [0003] Candesartan cilexetil is a commercially available non-peptide angiotensin II (Ang II-1) receptor antagonist drug, chemical name: (±)-2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid 1-[[(cyclohexyloxy)carboxylic acid]oxy]ethyl ester. [0004] The current common synthetic methods mainly include the following: [0005] One is that 2,3-diaminobenzoic acid methyl ester is the final product candesartan cilexetil (Kubo.K, Kohara.Y etc., J.Med.Chem. , 1993, 36:2343-2349). One route is to use 3-nitrobenzoic acid as a raw material to obtain the intermediate 3-nitro-2-tert-butoxyaminobenzo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/10C07D257/04C07D235/26
Inventor 王飞
Owner APELOA PHARM CO LTD
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