A kind of preparation method of γ-lactam bridged dipeptide compound

A technology for lactam bridges and compounds, which is applied in the field of preparation of γ-lactam bridged dipeptide compounds, can solve the problems of low yield in the cyclization step and decrease in the total yield of the route, and achieve high product yield and benefit Environmental protection and simple synthetic route

Active Publication Date: 2021-05-14
ACCELA CHEMBIO CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In this route, cyclization is required, and the yield of the cyclization step is low, so that the total yield of the whole route is reduced

Method used

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  • A kind of preparation method of γ-lactam bridged dipeptide compound
  • A kind of preparation method of γ-lactam bridged dipeptide compound
  • A kind of preparation method of γ-lactam bridged dipeptide compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] In this example, the preparation process of 2-{4-[(tert-butoxy)carbonylamino]-2-oxopyrrolidinyl}acetic acid is as follows:

[0057]

[0058] The preparation method comprises the following steps:

[0059] Synthesis of tert-butyl 2-[4-(methoxycarbonyl)-2-oxopyrrolidinyl]acetate (3'):

[0060] Add 100ml of methanol, compound 1' (25g, 0.16mol, 1.0eq) and compound 2' (25g, 0.19mol, 1.2eq) into a 250ml three-necked flask, and reflux for 16h under nitrogen protection. The reaction is basically complete by TLC, spin-dried, Low-boiling impurities were distilled off under reduced pressure, and the residue was distilled to obtain compound 3' (38 g, yield 93%). MS-EI = 257.1. 1 H NMR (300MHz, CDCl 3 ): δ4.09-3.83 (m, 2H), 3.75-3.66 (m, 5H), 3.36-3.25 (m, 1H), 2.84-2.64 (m, 2H), 1.47 (s, 9H).

[0061] Synthesis of 1-{[(tert-butyl)oxycarbonyl]methyl}-5-oxopyrrolidine-3-carboxylic acid (4'):

[0062] Add 200ml of tetrahydrofuran and compound 3' (38g, 0.15mol, 1eq) into a 500ml...

Embodiment 2

[0068] In this example, the preparation process of (S)-2-methyl-2-{4-[(tert-butoxy)carbonylamino]-2-oxopyrrolidinyl}acetic acid is as follows:

[0069]

[0070] The preparation method comprises the following steps:

[0071] Synthesis of tert-butyl (S)-2-methyl-2-[4-(methoxycarbonyl)-2-oxopyrrolidinyl]acetate (8):

[0072] Add 100ml of methanol, compound 1' (22.7g, 0.14mol, 1.0eq) and compound 7 (24g, 0.168mol, 1.2eq) into a 250ml three-necked flask, and reflux for 16h under nitrogen protection. The reaction is basically complete by TLC, spin-dried, Low-boiling impurities were distilled under reduced pressure, and the residue was distilled to obtain compound 8 (28 g, yield 75%). MS-EI = 271.1. 1 H NMR (300MHz, CDCl3): δ4.82-4.72(m, 1H), 3.81-3.61(m, 5H), 3.36-3.19(m, 1H), 2.84-2.63(m, 2H), 1.46(s, 9H), 1.42-1.37 (m, 3H).

[0073] Synthesis of (S)-1-{1-[(tert-butyl)oxycarbonyl]ethyl}-5-oxopyrrolidine-3-carboxylic acid (9):

[0074] Add 200ml of tetrahydrofuran and compou...

Embodiment 3

[0080] In this example, the preparation process of (S)-2-(2-methylpropyl)-2-{4-[(tert-butoxy)carbonylamino]-2-oxopyrrolidinyl}acetic acid is as follows :

[0081]

[0082] The preparation method comprises the following steps:

[0083] Synthesis of tert-butyl (S)-2-(2-methylpropyl)-2-[4-(methoxycarbonyl)-2-oxopyrrolidinyl]acetate (13):

[0084] Add 100ml of methanol, compound 1' (16.8g, 0.11mol, 1.0eq), compound 12 (31.32g, 1.5eq, 0.165mol) into a 250ml three-necked flask, and reflux for 16h under nitrogen protection. The reaction is basically complete by TLC, and spin-dried , Low-boiling impurities were distilled off under reduced pressure, and the residue was distilled to obtain compound 13 (28.8 g, yield 82%). MS-EI=313. 1H NMR (300MHz, CDCl3): δ4.69(t, 1H), 3.83-3.67(m, 4H), 3.51(t, 1H), 3.24-3.12(m, 1H), 2.78-2.57(m, 2H) , 1.70-1.56 (m, 2H), 1.41 (s, 10H), 0.93-0.88 (m, 6H).

[0085] Synthesis of (S)-1-{1-[(tert-butyl)oxycarbonyl]-3-methylpropyl}-5-oxopyrrolidine-3...

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Abstract

The present invention provides a preparation method of γ-lactam bridged dipeptide compounds. The method is to react a dibasic acid ester shown in formula I with tert-butoxycarbonylethylamine shown in formula II to obtain 2 shown in formula III. ‑[4‑(alkoxycarbonyl)‑2‑oxopyrrolidinyl acetate; said 2‑[4‑(alkoxycarbonyl)‑2‑oxopyrrolidinyl acetate is Hydrolysis in the presence of 2-(4-carboxy-2-oxopyrrolidinyl) acetate shown in formula IV; Butanol reacts in the presence of diphenylphosphoryl azide to obtain the pyrrolidinyl acetate of Boc protection shown in formula V; then hydrolysis obtains 2-{4-[(tert-butoxy)carbonylamino] shown in formula VI ‑2‑Oxopyrrolidinyl}acetic acid. The preparation method of the invention does not use sulfide, is beneficial to environmental protection, has simple synthesis route and high yield.

Description

technical field [0001] The invention belongs to the technical field of compound synthesis, and relates to a preparation method of γ-lactam bridged dipeptide compounds. Background technique [0002] γ-lactam bridged dipeptide compounds have important uses in the polypeptide pharmaceutical industry, and are important pharmaceutical intermediates for the synthesis of auxin (hGH) and polypeptides. However, the current synthetic methods have problems such as long route, low yield, strong taste, difficult purification and environmental protection. [0003] Nicholas J.Ede.Tetrahedron Letters, 1990, vol.31, No.42, p.6071-6074 reported a preparation method of γ-lactam bridged dipeptide compounds, and its synthetic route is as follows: [0004] [0005] Need to use sulfide sodium methyl mercaptide in this route, it has very obvious smell, and the product containing sulfur that is prepared by sodium methyl mercaptide also has very obvious smell, although final product has removed s...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/023C07K1/06C07K1/02
CPCC07K5/0202
Inventor 林安健郭涛孙栋栋吴勇陈立煌
Owner ACCELA CHEMBIO CO LTD
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