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Method for synthesizing penem-like pharmaceutical intermediate 4AA

A synthesis method and 4AA technology, which are applied in chemical instruments and methods, compounds of Group 4/14 elements of the periodic table, and production of bulk chemicals, etc., can solve the problems of large dosage, difficult control, heavy metal pollution, etc. High, mild reaction conditions, less effect

Inactive Publication Date: 2008-09-17
SHOUGUANG FUKANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] From the above mechanism, it can be seen that the reaction is a decarboxylation oxidation process, because Pb(AcO) 4 It has the dual functions of catalysis and oxidation, and the lead compound that becomes a low-valence state after oxidation cannot be restored to use. Therefore, in this method, Pb 3 o 4 A large amount is used, and heavy metal pollution is serious; what actually works in the reaction is Pb(OAc) 4 , while Pb(OAc) 4 It is easy to decompose when exposed to water, so the reaction needs to be operated under anhydrous conditions, which is not easy to control; the oxidation deprotection reaction uses CAN as an oxidant, which also has the disadvantages of large dosage and heavy metal pollution, which is not conducive to environmental protection

Method used

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  • Method for synthesizing penem-like pharmaceutical intermediate 4AA
  • Method for synthesizing penem-like pharmaceutical intermediate 4AA
  • Method for synthesizing penem-like pharmaceutical intermediate 4AA

Examples

Experimental program
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Effect test

Embodiment 1

[0026] Example 1: (3R, 4R)-3-[(1'R)-tert-butyldimethylsiloxyethyl]-4-acetoxy-1-p-methoxyphenyl-2-aza Synthesis of cyclobutanone (formula II)

[0027] Add 250 mL of glacial acetic acid and a small amount of acetic anhydride into a three-necked flask, and put in (3S, 4S)-3-[(1'R)-tert-butyldimethylsiloxyethyl]-4-carboxy-1-p-methoxy phenyl-2-azetidinone (formula I) 10g and KHSO 5 80g, stir and heat up to about 40°C, and add 0.5g of porphyrin manganese catalyst in batches within 30min. Then keep warm at 45-50°C for 8 hours, filter after the reaction is completed, wash the filter cake with water and alcohol in turn, dry, recover the catalyst and apply it mechanically, the filtrate is distilled under reduced pressure to recover the solvent, the solid is dissolved in dichloromethane, and water, saturated NaHCO 3 , washed with saturated brine, the oil layer was dried, and the solvent was evaporated to dryness, and the product was obtained after recrystallization, which was detected ...

Embodiment 2

[0028] Example 2: (3R, 4R)-3-[(1'R)-tert-butyldimethylsiloxyethyl]-4-acetoxy-1-p-methoxyphenyl-2-aza Synthesis of cyclobutanone (formula II)

[0029] Add 250 mL of glacial acetic acid and a small amount of acetic anhydride into a three-necked flask, and put in (3S, 4S)-3-[(1'R)-tert-butyldimethylsiloxyethyl]-4-carboxy-1-p-methoxy Base phenyl-2-azetidinone (formula I) 10g, stir and heat up to about 40°C, pass into O 2 , Add 0.5 g of porphyrin manganese catalyst in batches within 1 h. Then keep warm at 45-50°C for 8 hours, filter after the reaction is completed, wash the filter cake with water and alcohol in turn, dry, recover the catalyst and apply it mechanically, the filtrate is distilled under reduced pressure to recover the solvent, the solid is dissolved in dichloromethane, and water, saturated NaHCO 3 , washed with saturated brine, the oil layer was dried, and the solvent was evaporated to dryness, and the product was obtained by recrystallization, which was detected as...

Embodiment 3

[0030] Example 3: Synthesis of (3R, 4R)-3-[(1'R)-tert-butyldimethylsiloxyethyl]-4-acetoxy-2-azetidinone (4AA)

[0031] (3R, 4R)-3-[(1'R)-tert-butyldimethylsiloxyethyl]-4-acetoxy-1-p-methoxyphenyl-2-azetidinone (Formula II) 13g, dissolved in 250mL of methanol, cooled to 0 ° C, passed into O 3 React for 3h, after the reaction is completed, add Na 2 S2 o 3 And thiourea, stirred at room temperature for 30min. The reaction solution was concentrated to 1 / 3. The concentrated solution was cooled to -10-0°C, white crystals were precipitated, filtered, dried, and recrystallized in n-hexane to obtain white crystals, which were detected as 4AA with a yield of 90%. (mp: 107-108°C, [α] D 23 : 49.08 (c1.0, CHCl 3 ); Literature: mp: 106-108°C, [α] D 23 : 48.75 (c1.05, CHCl 3 ))

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Abstract

The invention provides a preparation method of intermediate 4AA of the penem medicine, which belongs to the technology field of medicine. The method uses compound shown as formula I as the raw material in the presence of manganese-porphyrin complex compound as the catalyst, decarboxylation oxidizing with oxidizer, and oxidizing with O3 for removing the protective group to obtain 4AA.

Description

technical field [0001] The invention relates to a synthesis method of an intermediate in the technical field of medicine, in particular to a synthesis method for preparing penem drug intermediate 4AA. Background technique [0002] 4AA, namely (3R,4R)-3-[(1'R)-tert-butyldimethylsiloxyethyl]-4-acetoxy-2-azetidinone, is a synthetic penem drug key intermediates. Penem drugs are a group of new-type β-lactam antibiotics. There are imipenem, meropenem and faropenem that have been marketed in China, and there are many varieties that are undergoing clinical trials. Therefore, it is of great significance to study the synthesis of penem drug intermediates. There are 3 chiral centers and a lactam ring in the 4AA structure, which is the focus and difficulty of 4AA synthesis. [0003] One of the currently used synthetic routes is the synthesis of 4AA through two-step reactions reported in the document J.Am.Chem.Soc, 1987, 109 (4): 1129-1135: [0004] [0005] The reaction proceeds ...

Claims

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Application Information

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IPC IPC(8): C07F7/18
CPCY02P20/55
Inventor 杨磊宋伟国董良军袁晋亭杨春程甲宗青
Owner SHOUGUANG FUKANG PHARMA
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