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Branched polyhydroxy pyrrole derivatives and preparation method and application

A technology for compounding polyhydroxypyrrolidine and its derivatives, which is applied in the field of branched polyhydroxypyrrolidine derivatives and their preparation and application, and can solve the problem of limited polyhydroxypyrrolidine synthesis methods, low yield, and inability to synthesize other substituents, etc. question

Inactive Publication Date: 2009-09-09
INST OF CHEM CHINESE ACAD OF SCI
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, the synthetic methods of polysubstituted polyhydroxypyrrolidines are very limited.
et al proposed a method for synthesizing such compounds in 2001 (Eur.J.Org.Chem.2001, 2547-2558), but this method is limited to the synthesis of methyl-substituted polyhydroxypyrrolidine, and cannot synthesize other substituents The analogue of B.G.Davis et al. proposed a kind of glycosyl ring imine and Grignard reagent addition reaction to prepare the method for 2,5-substituted polyhydroxypyrrolidine in 2002, but productive rate is lower (B.G. Davis, et al, Org. Lett., 2002, 4, 103-106.)

Method used

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  • Branched polyhydroxy pyrrole derivatives and preparation method and application
  • Branched polyhydroxy pyrrole derivatives and preparation method and application
  • Branched polyhydroxy pyrrole derivatives and preparation method and application

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Experimental program
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Effect test

Embodiment 1

[0081] Embodiment 1: synthetic (3R, 4S, 5R)-2-trityloxymethyl-3,4-O-isopropylidene-5-benzyl-1-pyrroline-N-oxide (nitrone (2))

[0082] (2S, 3S, 4R, 5S)-N-hydroxyl-2-benzyl-3,4-O-isopropylidene-5-trityloxymethylpyrrolidine (1) (2.20 g 4.22 mmol ) was dissolved in 20 ml of dichloromethane, cooled to 0°C, manganese dioxide (3.7 g, 42.2 mmol) was added, and stirred overnight. TLC showed that the reaction of the raw material was complete, and the solid residue was removed by filtration, the solvent was evaporated under reduced pressure, and 2.1 g of the product was obtained by column chromatography, with a yield of 95%.

[0083] Spectral data:

[0084] 1 H NMR (CDCl 3 )δ (ppm): 1.33 (s, 6H, CH 3 ), 3.12 (dd, J=14.1, 4.2Hz, 1H, PhCH 2 ), 3.17 (dd, J=14.4, 6.3Hz, 1H, PhCH 2 ), 4.03 (dt, J=15.0, 1.5Hz, 1H, TrOCH 2 ), 4.18 (d, J=15.0Hz, 1H, TrOCH 2 ), 4.31 (t, J=1.5Hz, 1H, H-5), 4.52 (d, J=6.3Hz, 1H, H-4), 4.63 (dd, J=6.0, 0.6Hz, 1H, H-3 ), 7.10-7.45 (m, 20H, ArH).

[0085] FT...

Embodiment 2

[0086] Example 2: Synthesis of (2S, 3R, 4S, 5S)-N-hydroxyl-2-methyl-2-trityloxymethyl-3,4-O-isopropylidene-5-benzylpyrrolidine (Hydroxylamine (3))

[0087] Dissolve nitrone (2) (1.34 g, 2.58 mmol) in anhydrous tetrahydrofuran, add methylmagnesium iodide solution (1.0M, 6.5 ml) dropwise, react at -78°C to room temperature, and use Conventional method processing. 1.2 g of product were obtained. Yield: 84%.

[0088] Spectral data:

[0089] 1 H NMR (CDCl 3 )δ(ppm): 1.17(s, 3H), 1.19(s, 3H), 1.74(s, 3H), 2.80(dd, J=14.1, 8.7Hz, 1H), 3.06-3.11(m, 1H,) , 3.27(dd, J=14.1, 3.6Hz, 1H), 3.46(t, J=10.2Hz, 2H), 4.25(d, J=6.3Hz, 1H), 4.27(d, J=7.5Hz, 1H) , 6.69(s, 1H), 7.23-7.40(m, 15H), 7.55-7.60(m, 5H).

[0090] FT-Ms Calcd.for C 35 h 38 NO 4 [M+H] + :536.2801, found: 536.2797.

Embodiment 3

[0091] Embodiment 3: synthesis (2S, 3R, 4S, 5S)-2-methyl-2-trityloxymethyl-3,4-O-isopropylidene-5-benzylpyrrolidine (secondary amine ( 4))

[0092] Hydroxylamine (3) (0.42 g, 0.78 mmol) was dissolved in dichloromethane, dropped into an aqueous solution of acetic acid suspended with 0.51 g (7.8 mmol) of zinc powder, a catalytic amount of copper acetate was added, and stirred at room temperature until TLC It shows that the reaction of raw materials is complete. Conventional post-treatment to obtain 300 mg of the product. Yield: 73.7%.

[0093] Spectral data:

[0094] 1 H NMR (CDCl 3 )δ (ppm): 1.22 (s, 3H), 1.33 (s, 3H), 1.54 (s, 3H), 2.03 (brs, 1H), 2.70 (dd, J=13.8, 7.2Hz, 1H), 2.89 ( dd, J=13.5, 5.7Hz, 1H), 3.07(s, 2H), 3.46(dd, J=12.0, 5.4Hz, 1H), 4.33(dd, J=6.9Hz, 4.8Hz, 1H), 4.45( d, J=6.9Hz, 1H), 7.22-7.45(m, 20H).

[0095] FT-Ms Calcd.for C 35 h 38 NO 3 [M+H] + :520.2852, found: 520.2858.

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Abstract

The invention discloses a branched polyhydroxypyrrolidine derivative, a preparation method and application thereof. The branched polyhydroxypyrrolidine derivative provided by the present invention has a structural formula such as formula I, R1 is hydroxymethyl, etc., R2 and R3 are hydrogen, etc., R4 is C1-C20-alkyl, etc., R5 is hydrogen, etc., R6 is hydrogen etc., R7 is hydroxyl etc. Polyhydroxyl pyrrolidine is the most important component of naturally occurring imino sugars. The present invention provides a general method for synthesizing branched polyhydroxypyrrolidine compounds. The method is to add glycosylnitrone and nucleophilic reagent The obtained hydroxylamine is oxidized to obtain a substituted nitrone, and then added to obtain a multi-substituted hydroxylamine. Repeatedly, a highly branched polyhydroxy azapyrrolidine compound can be obtained. The method of the invention has the advantages of mild reaction conditions, high yield, high stereoselectivity, etc., and is a practical synthetic method for preparing this type of novel 2,5-multi-substituted polyhydroxypyrrolidine compounds.

Description

technical field [0001] The invention relates to a branched polyhydroxypyrrolidine derivative, a preparation method and application thereof. Background technique [0002] Branched polyhydroxypyrrolidine derivatives refer to polyhydroxypyrrolidine compounds containing multiple substituents at the 2,5-position of the pyrrole ring. Polyhydroxypyrrolidine compounds are similar in structure to furanose and contain multiple hydroxyl groups, except that the oxygen atom on the sugar ring is replaced by a nitrogen atom. It is the most important type of imino sugar compound. Iminosugar compounds are well known inhibitors of glycosidases and glycosyltransferases, for example, 1,4-dideoxy-1,4-imino-D-arabinose and 1,4-dideoxy-1,4- Imino-D-ribose is a naturally occurring imino sugar with good glycosidase inhibitory properties. Among them, imino sugars such as Basen and Miglitol have become drugs for treating diabetes. In view of the remarkable biological activity and potential medicina...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H5/06C07D207/46C07D207/12C07D207/16
CPCY02P20/582
Inventor 俞初一傅颖黄木华高红云
Owner INST OF CHEM CHINESE ACAD OF SCI