Precursor of Lisinopril compound and synthetic method

A synthesis method and compound technology are applied to the precursors of lisinopril compounds and the field of synthesis thereof, and can solve problems such as unfavorable factors in industrial production

Inactive Publication Date: 2004-10-27
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Summarizing the synthesis process of the above documents, all involve the control of chirality, and the use of highly toxic drugs such as sodium cyanoborohydride, which brings unfavorable factors to industrial production

Method used

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  • Precursor of Lisinopril compound and synthetic method
  • Precursor of Lisinopril compound and synthetic method
  • Precursor of Lisinopril compound and synthetic method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Embodiment 1: diazotization

[0049] 0.01mol of lysine trifluoroacetate and 0.035mol of potassium bromide were dissolved in 2.5N sulfuric acid (0.052mol), cooled to -5°C in an ice-salt bath, and the mixture was added dropwise with 0.01-0.02mol of nitrous acid under stirring Sodium aqueous solution, after the dropwise addition, the temperature rises naturally, stirs at room temperature for about 5 hours (overnight), stops stirring, and stands still, the yellow oil and water are separated, the upper layer of water is poured off, and after post-treatment, ethyl acetate The extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated to obtain a colorless oily liquid with a yield of 86%.

[0050] The spectrogram data is as follows:

[0051] H-NMR: CDCL3, δ7.2 (NH, S, 1H); δ3.4 (NCH 2 , t, 2H); δ4.3(BrCH, m, 1H) δ1.6-2.2(CH 2 CH 2 CH 2 , m, 6H)

[0052] MS: M 306

[0053] Optical rotation: CHCl 3 , c=1, α=-18.5°

Embodiment 2

[0054] Embodiment 2: condensation reaction

[0055] Dissolve 0.1 mol of bromic acid generated in the first step in CH 2 Cl 2 0.11 mol of thionyl chloride was added dropwise in an ice-water bath. After the dropwise addition, it was changed to a reflux device and refluxed for 4 hours.

[0056] Dissolve 0.2 mol of proline in an appropriate amount of chloroform, add dropwise the chloroform solution of 0.1 mol of the above-mentioned acid chloride under stirring, stir overnight for reaction, post-treatment, and recrystallize to obtain the compound Yield 95%.

[0057] H-NMR: CDCl 3 δ7.16 (CONH, S, 1H); δ4.85 (BrCH, m, 1H); δ4.30 (CHCOOH, m, 1H); δ3.80-3.58 (5'-CH 2 , m, 2H); δ3.42-3.25 (NHCH 2 , m, 2H); δ2.40-1.95 (3'-CH 2 , 4'-CH 2 , 3-CH 2 , m, 6H); δ1.70-1.30 (4-CH 2 ,5-CH 2 , m, 4H).

[0058] MS: ESI, M403

Embodiment 3

[0059] Embodiment 3: ring closing reaction

[0060] compound Dissolve in DMF, add 0.1mol sodium bicarbonate under stirring, react until TLC detects that there is no raw material, post-treatment, dissolve in ethyl acetate, wash with water, wash with brine, dry with anhydrous sodium sulfate, concentrate, and recrystallize to obtain the ring-closed product Compound, yield 86%.

[0061] H-NMR: CDCl 3 δ7.00-6.80 (NH, S, 1H); δ4.80 (3-CH, t, 1H); δ4.25 (6-CH, t, 1H); δ3.60 (9-CH 2 , m, 2H); δ3.4(NHCH 2 , m, 2H); δ2.40-1.60 (1'-CH 2 , 2'-CH 2 , 3’-CH 2 ,7-CH 2 ,8-CH 2 , m, 10H).

[0062]

[0063] ESI: M+1 323

[0064] Optical rotation value: CHCl3, c=1.0035, α=-110.89°

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Abstract

A precursor of lisinopril is prepared from activated alpha bromoacid and proline or its derivative through condensation to generate bipeptide, closing cycle in molecular under the action of strong alkali, opening lactone cycle by alkali in solvent to obtain the compound containing free hydroxy and carboxy, protecting or activating said two radicals, and condensating with high-benzene ethyl lactamate. Its advantages are high output rate and no pollution.

Description

technical field [0001] The invention relates to a precursor of lisinopril (LISINOPRIL) compounds and a synthesis method thereof. Background technique [0002] Lisinopril is an antihypertensive drug, which belongs to angiotensin converting enzyme inhibitor (Angiotensin converting enzyme inhibition), and has three S-configuration chiralities in the molecular structure of the drug. Its mode of action is to convert the angiotensin 1 precursor of decapeptide into a vasoconstrictor --- angiotensin 2, thus becoming a clinically effective drug for the treatment of hypertension, and also a hot topic synthesized by chemists from all over the world. , and its synthesis process has been studied, and the main process routes are as follows: [0003] 1: Genji Iwasaki; Rieko Kimura etc., chem.pharm.bull, 1989.280-283. [0004] [0005] 2: Thomas J. Blacklock, Richard F. Human, etc., J. Org. Chem. 1988, 836-842 [0006] [0007] 3: M.T.Wu, A.W.Douglas, D.L.Ondeyka, etc., J.Pharm.Sci...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/02C07D233/64C07D498/04
Inventor 马大为邓平
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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