Preparation method of medical intermediate, namely N-Boc-trans-4-methyl-L-proline methyl ester

A technology of proline methyl ester and n-boc-, which is applied in the field of biomedicine, can solve the problems of poor stereoselectivity, and achieve the effects of shortening the reaction cycle, being environmentally friendly, and high total yield

Inactive Publication Date: 2019-10-25
SHENZHEN ELDERLY MEDICAL RES INST +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0016] In order to solve the above problems, a kind of preparation method of N-Boc-trans-4-methyl-L-proline methyl ester provided by the invention, the preparation method of the present invention overcomes prior art in preparing N-Boc- Trans-4-methyl-L-proline 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 medical intermediate, namely N-Boc-trans-4-methyl-L-proline methyl ester
  • Preparation method of medical intermediate, namely N-Boc-trans-4-methyl-L-proline methyl ester
  • Preparation method of medical intermediate, namely N-Boc-trans-4-methyl-L-proline methyl ester

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Experimental program
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Embodiment 1

[0068] Embodiment 1: the synthesis of compound 15

[0069]

[0070] Firstly, compound 15 was prepared according to the literature (Tetrahedron Letters, 2017, 58, 3966-3969).

[0071] 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.

[0072] 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

[0073] Embodiment 2: the synthesis of compound 17

[0074] 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.

[0075] 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

[0076] Embodiment 3: the synthesis of compound 18

[0077] Compound 17 (20g, 53mmol) was dissolved in methanol / tetrahydrofuran / water mixed solvent (1:1:1, 150mL), and lithium hydroxide monohydrate solid (11g, 265mmol) 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 (150mL), combined organic phases were washed with water (100mL), washed with saturated brine (150mL), 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.

[0078] Dissolve the above intermediate acid (R)-4,5-bis(tert-butyldimethylsilyloxy)pentanoic acid in anhydrous THF (200mL), add triethylamine (22.1mL, 159mmol ) and trimethylacetyl chloride (6.5mL, 53mmol), re...

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Abstract

The invention discloses a preparation method of N-Boc-trans-4-methyl-L-proline methyl ester. The preparation method comprises the following steps that a compound D-glutamate is subjected to diazotization reaction, esterification reaction and hydrolysis to obtain a compound 16; the compound 16 reacts with TBSCl to obtain a compound 17; the compound 17 is hydrolyzed and then react with (R)-4-benzyl-2-oxazolidinone to obtain a compound 18; the compound 18 is subjected to substitution reaction to obtain a compound 19; the compound 19 is reduced to obtain a compound 20, and then the compound 20 reacts with DPPA and DBU to prepare a compound 21; the compound 21 is subjected to deprotection to obtain a compound 22; the compound 22 is subjected to dehydroxylation and then is dissolved in methyl alcohol, reaction is conducted under the conditions of potassium hydroxide and iodine to obtain a compound 23 ; the compound 23 is subjected to deprotection and then reacts with paratoluensulfonyl chloride to obtain a compound 24; and the compound 24 reacts for ring forming under the catalytic condition, and an alkaline substance is added to react with Boc anhydride to obtain a compound 4. Accordingto the preparation method, the defect that in the prior art, when N-Boc-4-methyl proline methyl ester is prepared, stereoselectivity is poor is overcome, an initiator low in cost and easy to obtain is used, and the preparation yield is increased.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to a preparation method of N-Boc-trans-4-methyl-L-proline methyl ester. Background technique [0002] Studies on the biological activity of peptides have found that some peptides have important effects on 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, it has become an important direction of biopharmaceutical research to modify the structure of biologically active polypeptides to enhance the stability of polypeptides to enzymes, improve bioavailability and biological activity. [0003] At present, the structural modification of polypeptides can be achieved by cyclizing active peptides, unnatural amino acid substitutions, and synthetic peptide analogs—peptoids or pseudopeptides. The structure of amin...

Claims

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Application Information

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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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