Preparation method of medicinal intermediate N-Boc-cis-4-methyl-L-proline methyl ester

A proline methyl ester, n-boc- technology, applied in the field of biomedicine, can solve problems such as poor stereoselectivity, and achieve the effects of shortening the reaction period, simple and convenient separation and purification, and high yield

Inactive Publication Date: 2019-08-20
SHENZHEN ELDERLY MEDICAL RES INST +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0020] In order to solve the above problems, the preparation method of a kind of pharmaceutical intermediate N-Boc-cis-4-methyl-L-proline methyl ester provided by the present invention, the preparation method of the present invention overcomes prior art in the preparation of N -Boc-4-methylproline methyl ester has the disadvantage of poor stereoselectivity, using cheap and easy-to-obtain starting materials to improve the yield of preparation

Method used

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  • Preparation method of medicinal intermediate N-Boc-cis-4-methyl-L-proline methyl ester
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  • Preparation method of medicinal intermediate N-Boc-cis-4-methyl-L-proline methyl ester

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Embodiment 1

[0072] Embodiment 1: the synthesis of compound 15

[0073]

[0074] Firstly, compound 15 was prepared according to the literature (Tetrahedron Letters, 2017, 58, 3966-3969).

[0075] Compound D-glutamic acid (60g, 407.8mmol) was dissolved in concentrated hydrochloric acid (120mL) and water (60mL), cooled to -10°C, an aqueous solution (120mL) of sodium nitrite (42g, 608.7mmol) was added, slowly After rising to room temperature and reacting for 18 hours, it was concentrated under reduced pressure, the solid residue was extracted with ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure to obtain an intermediate.

[0076] Dissolve the above intermediate in methanol (300 mL), add concentrated hydrochloric acid (0.3 mL), heat to reflux for 12 h, add solid sodium bicarbonate to quench the reaction, concentrate under reduced pressure to obtain the crude product, and use petroleum ether: ethyl acetate = 1 : 1 is the eluent flash column chromatography t...

Embodiment 2

[0077] Embodiment 2: the synthesis of compound 17

[0078] Compound 15 (40g, 227mmol) was dissolved in anhydrous THF (500mL), cooled to 0 degrees, borane dimethyl sulfide complex (10M, 23mL) was added, and sodium borohydride solid (0.5g) was added after 1h , reacted for another 1 h, quenched the reaction with methanol, and concentrated under reduced pressure to obtain the intermediate (R)-methyl 4,5-dihydroxypentanoate.

[0079] The above intermediate (R)-methyl 4,5-dihydroxypentanoate was dissolved in DMF (100mL), imidazole (46g, 681mmol) and tert-butyldimethylsilyl chloride (68g, 454mmol) were added, and the Reaction overnight, add water (600mL) to quench the reaction, extract three times with dichloromethane (300mL), combine the organic phase with 1M KHSO 4 Solution (200mL), washed with water (200mL), washed with saturated brine (200mL), separated, the organic phase was dried by adding anhydrous sodium sulfate, concentrated under reduced pressure, and eluted with petroleum...

Embodiment 3

[0080] Embodiment 3: the synthesis of compound 18

[0081] Compound 17 (40g, 106mmol) was dissolved in methanol / tetrahydrofuran / water mixed solvent (1:1:1, 300mL), and lithium hydroxide monohydrate solid (22g, 530mmol) was added under cooling in an ice-water bath. After 30min, it was raised to room temperature and stirred for reaction 3h, cooled in an ice-water bath, added dilute hydrochloric acid to acidify the solution to PH = 2, extracted three times with ethyl acetate (200mL), combined organic phases were washed with water (200mL), washed with saturated brine (200mL), separated, and the organic phase was added without Dry over sodium sulfate and concentrate under reduced pressure to obtain the intermediate acid (R)-4,5-bis(tert-butyldimethylsilyloxy)pentanoic acid.

[0082] Dissolve the above intermediate acid (R)-4,5-bis(tert-butyldimethylsilyloxy)pentanoic acid in anhydrous THF (500mL), add triethylamine (44.2mL, 318mmol ) and trimethylacetyl chloride (13mL, 106mmol), r...

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Abstract

The invention discloses a preparation method of a medicinal intermediate N-Boc-cis-4-methyl-L-proline methyl ester. The preparation method comprises the following steps: a compound D-glutamic acid isdiazotized, esterified and hydrolyzed to obtain a compound 16; the compound 16 is reacted with TBSCl to obtain a compound 17; the compound 17 is hydrolyzed, and then reacted with (S)-4-benzyl-2-oxazolidone to obtain a compound 18; the compound 18 undergoes a substitution reaction to obtain a compound 19; the compound 19 is reduced to form a compound 20, and the compound 20 is reacted with DPPA andDBU to obtain a compound 21; the compound 21 is deprotected to obtain a compound 22; the compound 22 is dehydroxylated, then is dissolved in methanol, and the obtained solution is reacted in the presence of potassium hydroxide and iodine to obtain a compound 23; the compound 23 is deprotected, and then reacts with paratoluensulfonyl chloride to obtain a compound 24; and the compound 24 undergoesa cyclization reaction under a catalytic condition, an alkaline substance is added, and the obtained mixture reacts with Boc anhydride to obtain a compound 3. The preparation method of the invention overcomes the defect of poor stereoselectivity in the preparation of the N-Boc-cis-4-methyl-L-proline methyl ester in the prior art, uses the cheap and easily-available starting material, and increasesthe yield of the preparation.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to a method for preparing a pharmaceutical intermediate N-Boc-cis-4-methyl-L-proline methyl ester. Background technique [0002] In the study of biologically active peptides, many synthetic or isolated peptides are of great significance to the occurrence, development or treatment of diseases. However, because polypeptides are easily hydrolyzed by proteases in the body, their bioavailability is low and their action time is short, so their applications are limited. Therefore, structural modification of biologically active peptides to enhance the stability of enzymes, improve bioavailability and biological activity has become an important direction in the research of alternative medicinal chemistry. [0003] At present, the structural modification of polypeptides can be achieved by cyclizing active peptides, unnatural amino acid substitutions, and synthetic peptide analogues or pseudopeptid...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16
CPCC07B2200/07C07D207/16
Inventor 龙伯华吴正治李利民
Owner SHENZHEN ELDERLY MEDICAL RES INST
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