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Method for preparing D-(+)-biotin intermediate

A technology of biotin and intermediates, applied in chemical instruments and methods, chemical/physical processes, physical/chemical process catalysts, etc., can solve the problem of poor stability and reproducibility of carbonyl reduction coupling reaction, harsh synthesis conditions, mercapto marine products Low toxicity and other problems, to achieve the effect of relatively low toxicity and easy purchase

Active Publication Date: 2012-06-27
安徽泰格生物技术股份有限公司
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Problems solved by technology

[0007] Although this method is simple and convenient, there are also many problems, such as some raw materials (such as sodium isocyanate) are difficult to obtain, and the intermediate (4aR)-1,3-dibenzyl-4-(1-adipic acid monomethyl ester The synthesis conditions of acylthiomethyl)-imidazole-2,5-dione are harsh, and the reaction needs continuous stirring for 7 days; the yield of mercaptohydantoin is low, and it is difficult to realize industrial production; the stability and reproducibility of the carbonyl reductive coupling reaction are poor, etc. Wait

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  • Method for preparing D-(+)-biotin intermediate
  • Method for preparing D-(+)-biotin intermediate
  • Method for preparing D-(+)-biotin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1 Tetrahydro-(4R)-carboxy-(2s)-phenylthiazole

[0040] Dissolve 50g (0.32mol) of L-cysteine ​​hydrochloride in 500mL of water, add 42g (0.31mol) of sodium acetate trihydrate, and stir for 0.5h. Then add w(C 2 h 5 OH)=250 mL of 95% ethanol, 35 mL of benzaldehyde, and stirred at 20° C. for 3 h. Cool in an ice bath to below 5°C and stir for 2h. After the reaction was completed, it was filtered, and the filter cake was washed twice with ethanol to obtain 70 g of white solid compound II (90% yield).

[0041] 1 HNMR (DMS0), δ: 7.40 (m, 5H), 6.8 (bm, 1H), 5.8 (s, 1H), 4.4-4.0 (dd, 1H), 3.5-3.0 (m, 2H).

[0042] Elemental Analysis C 10 h 11 NO 2 S (209.27) measured value (theoretical value), %: w (C) = 56.87 (57.40), (H) = 5.28 (5.30), w (N) = 6.81 (6.69), w (S) = 15.89 (15.32 ).

Embodiment 2

[0043] Example 2 (7aR)-3-phenyl-1H, 3H-imidazo[1,5-C]thiazole-(6,7aH)-5,7-dione

[0044] Dissolve 30g of compound II and 22g of sodium cyanate obtained in Example 1 in 300mL of glacial acetic acid, heat and reflux in a water bath at 90°C for 12 hours, until the heat of reaction turns into a yellow transparent liquid, spin and concentrate to obtain an oily yellow liquid, which is dissolved in 1000mL In water, a yellow-white precipitate is produced. After filtration, the filter cake was washed with 500 mL of tetrahydrofuran, then saturated brine, dried over anhydrous magnesium sulfate, concentrated by rotation to remove the solvent, and crystallized by adding n-hexane to obtain 27 g of compound III as a yellow solid (yield 80%).

[0045] IR (KBr tablet), v / cm -1 : 1725, 1394; 1 HNMR (CDCl 3 ), δ: 3.20-3.37 (m, 2H), 4.58-4.63 (t, J=7.4Hz, 1H), 7.26-7.46 (m, 5H), 8.67 (br, 1H).

Embodiment 3

[0046] Example 3 (7aR)-3-phenyl-6-benzyl-1H, 3H-imidazo[1,5-C]thiazole-(6H,7aH)5,7-dione

[0047] Dissolve 10.0g of compound III (0.043mol) in 30mL of N,N-dimethylformamide, add 6g of potassium carbonate and 5.5mL of benzyl bromide under stirring, and heat to reflux at 50°C in a water bath for 5h. After the reaction was completed, the insoluble matter was removed by filtration, concentrated by rotation to obtain a viscous liquid, which was dissolved in 45 mL of methanol, stirred at room temperature for 20 min, crystallized at 0° C., and filtered to obtain 12 g of white crystal compound IV (yield 85.7%).

[0048] 1 HNMR (CDCl 3 ), δ: 7.30~7.45 (m, 1OH), 6.41 (s, 1H), 4.67 (s, 2H), 4.52 (t, 1H), 3.30 (dd, 1H), 3.15 (dd, 1H).

[0049] Elemental Analysis C 18 h 16 N 2 o 2 S (324.4) measured value (theoretical value), %: w (C) = 66.41 (66.58), w (H) = 4.91 (4.93), w (N) = 8.71 (8.63), w (S) = 9.95 ( 9.86).

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Abstract

The invention provides a method for preparing a D-(+)-biotin intermediate. The method comprises the steps of: taking L-cysteine monohydrochloride as a starting material; using benzaldehyde and sodium cyanate as a ring closure reagent to synthesize (7aR)-3-phenyl-6-benzyl-1H, 3H-imidazo[1, 5-C]thiazole-(6H, 7aH)-5, 7-dione through the cyclization; then utilizing benzyl bromide to perform benzyl protection on N atoms; then taking zinc as a reducing agent to perform ring-opening synthesis on N, N-dibenzyl-L-sulfhydryl hydantoin; introducing a side chain through an esterification reaction with monomethyl adipate acyl chloride; and taking titanium as the reducing agent to perform reductive ring closure to generate the intermediate. According to the method, the cheap and readily available sodium cyanate is used as the ring closure reagent to replace sodium isocyanate which is toxic and difficult to purchase in an original method, reaction conditions are optimized and reaction order is adjusted, so the disadvantages of harsh reaction conditions and low yield in the original method of ring opening first and then benzyl protection are overcome by the method of performing benzyl protection on the N atoms of an imidazole part first and then performing ring opening; and the total yield reaches 34.0-38.0 percent.

Description

technical field [0001] The present invention relates to a compound synthesis method, in particular to a biotin intermediate: (6aR)-1,3-dibenzyl-4-(4-methoxycarbonylbutyl)-dihydro-thieno Process for the preparation of [3,4-d]imidazol-2-one. It belongs to the field of mechanochemical synthesis. Background technique [0002] (6aR)-1,3-Dibenzyl-4-(4-methoxycarbonylbutyl)-dihydro-thieno[3,4-d]imidazol-2-one has the following structural formula: [0003] [0004] The compound is a key intermediate for the synthesis of biotin by a stereospecific method. Under the induction of a chiral carbon, it is hydrogenated in cis, and then debenzylated and hydrolyzed to obtain D-biotin. [0005] Stereospecific synthesis of biotin using L-cysteine ​​or L-cystine and other substances with optical activity as the starting material is a relatively stable synthesis method, which is different from the traditional Hoffmann-La Roche production technology. Compared with this method, it has many a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D495/04B01J23/80
Inventor 孙林刘平
Owner 安徽泰格生物技术股份有限公司
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