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Antihypertensive drug cilazapril intermediate and preparation method thereof

A cilazapril and anti-hypertensive technology, which is applied in the direction of organic chemistry methods, chemical instruments and methods, separation of optical compounds, etc., can solve the problems of inapplicability to industrial production, complicated column passing process, and excessive discharge of three wastes, etc., to avoid The effects of splitting through the column, simplifying the synthesis process, and reducing the three wastes

Active Publication Date: 2009-10-21
ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The above-mentioned route method has a complicated column passing process, is not suitable for industrial production, and discharges a lot of three wastes, polluting the environment

Method used

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  • Antihypertensive drug cilazapril intermediate and preparation method thereof
  • Antihypertensive drug cilazapril intermediate and preparation method thereof
  • Antihypertensive drug cilazapril intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] The preparation of the compound N-phthaloylamino-L-glutamic anhydride of structural formula 4, concrete reaction formula is as follows:

[0019]

[0020] 20 g of L-glutamic acid and 31.9 g of N-ethoxycarbonylphthalic imide were sequentially added to 360 ml of an aqueous solution containing 28.8 g of sodium carbonate. Stir at room temperature, then extract with ethyl acetate. After the water layer was cooled, the water phase was adjusted to pH=2 with hydrochloric acid, then extracted with ethyl acetate, washed with saturated sodium chloride solution, dried, filtered, and concentrated under reduced pressure to obtain an oily product, which was recrystallized from water to obtain a white solid product N - Phthalylamino-L-glutamic acid 19.0g Melting point: 153-154°C

[0021] 18.5 g of N-phthaloylamino-L-glutamic acid was dissolved in 53.1 g of acetic anhydride, and heated to 110° C. for 5 minutes. Concentrate and add ether. After filtration, 16.5 g of white solid prod...

Embodiment 2

[0023] The compound of structural formula 1 (2S)-5-[(S)-3-(tetrahydro-3-tert-butoxycarbonyl)pyridazinyl-1-yl]-2-(1,3-dioxo-2H- Preparation of isoindol-2-yl)-5-oxopentanoic acid

[0024] Example 2

[0025] Add 9.2g of the compound of structural formula 2 to 40ml of tetrahydrofuran, stir to form a suspension solution, slowly drop into 140ml of 5% sodium bicarbonate solution to alkalinize and remove L-type tartaric acid, then drop into 30ml of tetrahydrofuran solution of 7.1g of the compound of structural formula 4, at room temperature After stirring for half an hour, after the reaction was complete, the aqueous layer was extracted with 30ml of ethyl acetate. The extracted aqueous layer was cooled to 0-5°C, and the pH value was adjusted to 3 with concentrated hydrochloric acid. A white solid was precipitated, and 10.8g of compound 1 was obtained after filtration. MS: (M+Na) + =468 +

Embodiment 3

[0027] Dissolve 33.5g of sodium bicarbonate in 350ml of water, drop into 150ml of tetrahydrofuran solution of 44.8g of compound of structural formula 2, then add 50ml of tetrahydrofuran solution of 34.5g of compound of structural formula 4, stir at room temperature for one hour, extract water with 60ml of ethyl acetate layer, the extracted water layer was cooled to 0-5°C, and the pH value was adjusted to 3.5 with concentrated hydrochloric acid, a large amount of white solid was precipitated, and 55.5 g of compound 1 was obtained after filtration. MS: (M+Na) + =468 +

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Abstract

An antihypertensive drug cilazapril intermediate is the compound of the structural formula 1, which is obtained by the steps of alkalising the compound of structural formula 2 to remove L-tartaric acid and obtaining the compound of structural formula 3, subjecting the compound of structural formula 3 and the compound of structural formula 4 to a reaction to obtain a single SS-configuration compound 1 of structural formula 1. The compound of structural formula 1 in the invention is cyclized to obtain the compound of structural formula 8. The compound of structural formula 8 is processed by reduction through borane, protective group removal and suprafacial chain condensation, and is processed by tertiary butyl protective group removal under the action of hydrochloric acid gas so as to obtainthe antihypertensive drug cilazapril 13. The invention uses front split, obtains a single SS-configuration new compound of structural formula 1, avoids column-passing spit in subsequent procedures, s implifies synthesis technology, decreases cost, and reduces three wastes. Thus, the invention is more suitable for commercial production.

Description

technical field [0001] The invention relates to the preparation of an antihypertensive drug cilazapril intermediate and a preparation method. Background technique [0002] Cilazapril is a specific long-acting angiotensin-converting enzyme inhibitor that can inhibit the renin-angiotensin-aldosterone system (RAAS), thereby inhibiting the conversion of angiotensin I (Ang I) into a potent vasoconstrictor. Efficacy of Angiotensin II (Ang II). Reduce peripheral vascular resistance and blood pressure. For the treatment of various degrees of essential hypertension and renal hypertension. It can also be used in combination with digitalis or diuretics to treat chronic heart failure. [0003] The method for preparing Cilazapril has following several at present: [0004] In the patent US6201118 or US6512111, the preparation method of the compound of the racemic structure formula 6 is prepared from the compound of the structure formula 5 and the compound of the structure formula 4, a...

Claims

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Application Information

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IPC IPC(8): C07D403/06C07B57/00
CPCY02P20/55
Inventor 唐超钟静芬时惠麟
Owner ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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