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Preparation method of (4S, 5R)- half-ester

A chiral catalyst and structural formula technology, applied in organic chemistry methods, chemical instruments and methods, asymmetric synthesis, etc., can solve the problems of expensive chiral auxiliary agents, insufficient raw material sources, harsh reaction temperature, etc. High stereoselectivity and easy synthesis

Inactive Publication Date: 2008-10-15
FUDAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the above splitting methods all have defects such as high price, insufficient source of raw materials, poor splitting efficiency and inconvenient recycling.
[0006] Gerecke et al. (Helv ChimActa, 1970, 53, 991) reported that using cholesterol as a chiral auxiliary agent reacted with cyclic acid anhydride (II) to form diastereomer cyclic acid half esters, which were separated by recrystallization (4S, 5R )-half-ester (I); European Patent 92194 prepares (4S, 5R)-half-ester (I) by optically active substituting chiral secondary alcohol and tert-butanol as chiral auxiliary agent; but the chiral auxiliary agent used in these methods exists Defects such as expensive, difficult to prepare and inconvenient to recycle
[0007] European Patent 84892, Chen Fen'er, etc. (Advanced Synthesis & Catalysis, 2005, 347, 549) respectively reported the preparation of stereoselective hydrolysis of internal elimination diesters using pig liver esterase and polymerized pig liver esterase as catalysts (4S, 5R)-half ester (I); Chinese patents 1473832 and 101157655 respectively describe the use of chiral amine (1S, 2S)-1-(4-nitrophenyl)-2-N, N-dimethylamino -3-trityloxy-1-propanol and 9-propargylquinine are the method for asymmetric alcoholysis of cyclic anhydride (II) to prepare (4S, 5R)-half ester (I) as catalyst, but these The methods all have defects such as small production scale, complex operation, harsh reaction temperature, etc.

Method used

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Examples

Experimental program
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Embodiment 1

[0024] Example 1 cis-1,3-dibenzylimidazolin-2-one-2H-furo[3,4-d]imidazole-2,4,6-trione (33.6g, 0.10mol), catalyst A(R 3 =-CH=CH 2 , R 4 =-OR 5 , R 5 =CH 3 , Z=S) (65.34 g, 0.11 mol) and methyl tert-butyl ether (4 L) were placed in a dry reaction flask, anhydrous methanol (40.4 mL, 1 mol) was added dropwise at 25° C., and stirring was continued for 24 hours. After the reaction was completed, 2M hydrochloric acid (400 mL) was added to the residue, stirred for 10 min, left to stand, and the organic layer was separated and dried over anhydrous sodium sulfate. Filtration, filtrate decompression recovery solvent obtains white crystalline powder I (R 1 -H, Ar = -Ph, R 2 =-CH 3 , 36g, 98%), mp149~150℃, [α] D 22 =+2.74° (c 0.20, CHCl 3 )IR(KBr): v=2979, 2384, 2281, 1742, 1463, 1229, 1169, 767cm -1 .

[0025] 1 HNMR (CDCl 3 ): δ=3.54(s, 1H, OCH 3 ), 4.00~4.04 (m, 2H, C 6a -H,C 3a -H), 4.16~4.80 (dddd, 4H, 2×CH 2 C 6 h 5 ), 7.19~7.53 (m, 10H, 2×ArH) ppm.EI-MS: (m / z, ...

Embodiment 2

[0027] Example 2 cis-1,3-dibenzylimidazolin-2-one-2H-furo[3,4-d]imidazole-2,4,6-trione (33.6g, 0.10mol), catalyst A(R 3 =-CH=CH 2 , R 4 =-OR 5 , R 5 =CH 3, Z=S) (5.94g, 0.01mol), 1,4-dioxane (8L) were placed in a dry reaction flask, and propynyl alcohol (58.2mL, 1mol) was added dropwise at 25°C and continued to stir for 24 Hour. After the reaction was completed, 2M hydrochloric acid (40 mL) was added to the residue, stirred for 10 min, left to stand, and the organic layer was separated and dried over anhydrous sodium sulfate. Filtration, the filtrate reclaims solvent under reduced pressure, obtains white crystalline powder I (R 1 -H, Ar = -Ph, R 2 =propargyl, 37.2g, 95%), mp132.7~135.8℃, [α] D 25 =+14.3° (c 1.0, CHCl 3 ).

Embodiment 3

[0028] Example 3 cis-1,3-dibenzylimidazolin-2-one-2H-furo[3,4-d]imidazole-2,4,6-trione (33.6g, 0.10mol), catalyst A(R 3 =-CH=CH 2 , R 4 =-OR 5 , R 5 =CH 3 , Z=S) (65.34g, 0.11mol), 1,4-dioxane (4L) were placed in a dry reaction flask, and anhydrous methanol (40.4mL, 1.0mol) was added dropwise at 25°C and stirred continuously 24 hours. After the reaction was completed, 2M hydrochloric acid (400 mL) was added to the residue, stirred for 10 min, left to stand, and the organic layer was separated and dried over anhydrous sodium sulfate. Filtration, the filtrate reclaims solvent under reduced pressure, obtains white crystalline powder I (R 1 -H, Ar = -Ph, R 2 =-CH 3 , 35.2g, 96%), mp148~150℃, [α] D 22 =+2.70° (c 0.20, CHCl 3 ).

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Abstract

The invention belongs to the organic chemistry technical field, in particular to a preparation method for (4S, 5R)-half ester. The invention is characterized in that preparing (4S, 5R)-half ester under the presence of 9-epiquinine urea catalyst by enantioselective ring opening cyclic polyanhyride and alcohol. The preparation method enables (4S, 5R)-half ester to obtain high yields and high stereo selectivity under room temperature conditions, and the reactive raw material is cheap and available, the catalyst can be recovered quantitatively and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic chemistry, and in particular relates to a preparation method of (4S, 5R)-half ester. Background technique [0002] The structural formula of compound (4S, 5R)-half ester is shown in (I) formula: [0003] [0004] where R 1 for hydrogen, C 1 ~C 6 Alkyl, phenyl, alkyl substituted phenyl or alkoxy substituted phenyl, Ar is phenyl, alkyl substituted phenyl, alkoxy substituted phenyl, nitro substituted phenyl, halophenyl, thienyl , furyl or naphthyl; R 2 for C 1 ~C 6 Alkyl, C 3 ~C 6 Cycloalkyl, C 2 ~C 6 Alkenyl, aralkyl or aralkenyl. [0005] (4S,5R)-half ester (I) is an important intermediate in the synthesis of (+)-biotin ((+)-Biotin, vitamin H). At present, the preparation of this compound mainly includes chiral resolution method, chiral auxiliary method and asymmetric catalysis method. (Helv Chim Acta, 1970,53,991) report by Gerecke et al. (Helv Chim Acta, 1970,53,991) report the ea...

Claims

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Application Information

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IPC IPC(8): C07D491/048B01J31/02C07B53/00
Inventor 陈芬儿熊非
Owner FUDAN UNIV
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