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Method for synthesizing chiral pharmaceutical intermediate 3-amino tetrahydropyrane and salt thereof

A technology of aminotetrahydropyran and synthesis method, which is applied in the field of synthesis of chiral pharmaceutical intermediate 3-aminotetrahydropyran (and its salts), can solve the difficulty of splitting racemates, the high cost, and the development of , The production has no problems such as literature reports, and achieves the effects of low cost, short synthesis route and reduced production cost.

Inactive Publication Date: 2011-04-27
苏州汉德创宏生化科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the problem that often exists in the actual synthesis is that the racemate is often synthesized instead of a single chiral structure. For example, it is difficult to split the racemate and the cost is high.
[0004] The development and production of chiral (racemic) 3-aminotetrahydropyran and its hydrochloride have not been reported in the literature

Method used

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  • Method for synthesizing chiral pharmaceutical intermediate 3-amino tetrahydropyrane and salt thereof
  • Method for synthesizing chiral pharmaceutical intermediate 3-amino tetrahydropyrane and salt thereof
  • Method for synthesizing chiral pharmaceutical intermediate 3-amino tetrahydropyrane and salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Synthesis of 1,5-(2-dibenzylamino)glutarate bisbenzyl ester (2a) (Method A)

[0043] Add 1200 milliliters of water, 1.6mol sodium hydroxide (65 grams), 2.2mol potassium carbonate (306 grams), 1.2mol glutamic acid (180 grams), 4.8mol benzyl bromide (2457 g), after dropping, reflux and stir for 30 minutes, cool to 10-30°C, add 1200 ml of ethyl acetate for extraction, wash the organic phase with 600 ml of brine, dry over anhydrous sodium sulfate, filter off the desiccant, and concentrate to obtain 300 1 g of crude product was directly used in the next reaction. 1 H NMR (400MHz, CDCl3) δ7.55-7.21 (m, 20H), 5.30 (d, J=12.2Hz, 1H), 5.25-5.13 (m, 1H), 5.07-4.96 (m, 2H), 3.92 ( d, J=13.7Hz, 2H), 3.54(d, J=13.7Hz, 2H), 3.44(q, J=7.3Hz, 1H), 2.54(dt, J=16.6, 7.1Hz, 1H), 2.44- 2.32(m, 1H), 2.18-2.05(m, 2H).MS(ESI)M / Z508[M+H] +

[0044] Synthesis of 1,5-(2-dibenzylamino)pentanediol (3)

[0045] Add 300 ml of tetrahydrofuran into a three-necked flask with a stirrer, and add 0.1...

Embodiment 2

[0053] Synthesis of dimethyl 1,5-(2-tert-butoxycarbonylamino)pentanoate (2b) (Method B)

[0054] Add 7 liters of methanol into a three-necked flask with a stirrer, cool to 0°C, slowly drop in 12.1 mol trimethylchlorosilane (1320 g), stir for 30 minutes, then add 4.8 mol glutamic acid (700 g ), react at room temperature until the reaction is complete. After cooling to 0°C, 25.6mol triethylamine (2600g) and 5.76mol di-tert-butyl dicarbonate (1257g) were slowly added dropwise in sequence, and stirred at 10-30°C until the reaction was complete after dropping. Concentrate, pour the residue into 5 liters of water, extract twice with 9 liters of ethyl acetate, combine the organic phases, wash with 4 liters of brine, dry over anhydrous sodium sulfate, filter off the desiccant, and concentrate the filtrate to obtain 1300 grams of light yellow oil is the product. 1 H NMR (400MHz, CDCl 3 )δ5.09(s, 1H), 4.33(s, 1H), 3.75(s, 3H), 3.68(s, 3H), 2.52-2.31(m, 2H), 2.19(td, J=13.5, 7.4Hz , ...

Embodiment 3

[0064] Synthesis of 3-Dibenzylaminotetrahydropyran (4)

[0065] N 2Under protection, add 2.38mol 1,5-(2-dibenzylamino)pentanediol (780 grams), 5 liters of dichloromethane and 9.99mol triphenylphosphine (873 gram), then add 9.99mol diisopropyl azodicarboxylate (DIAD, 673 grams) to the reaction mixture, and stir until the reaction is complete. Concentration gave 720 g of a white crude product, that is, 3-dibenzylaminotetrahydropyran. MS(ESI)M / Z 282[M+H] + .

[0066] All the other steps are the same as in Example 1.

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Abstract

The invention relates to a new method for synthesizing chiral pharmaceutical intermediate 3-amino tetrahydropyrane and salt thereof, in particular to a method for synthesizing racemic pharmaceutical intermediate 3-amino tetrahydropyrane and salt thereof. The method is characterized by comprising a step C of: cooling glycol 3 and triphenyl phosphorus to the temperature of below 0 DEG C in an ice bath under the protection of nitrogen; slowly dropwise adding diisopropyl azodicarboxylate or diethyl azodicarboxylate into a mixture of the glycol 3 and the triphenyl phosphorus; reacting at the temperature of between 10 and 30 DEG C after dripping until the reaction is performed completely; and concentrating and drying to obtain a white solid 4 rough product, wherein the molar ratio of the glycol to the triphenyl phosphorus to the diisopropyl azodicarboxylate or the diethyl azodicarboxylate is 1:(1-3):(1-3); the used raw materials are cheap and readily available; a synthesis route is short; all reaction intermediates and a final product are not required to be subjected to column chromatographic purification; and a large amount of R or S-type 3-amino tetrahydropyrane with high optical activity and racemate thereof can be conveniently prepared from natural L or D-type glutamic acid or racemate thereof serving as a raw material. The method has the advantages of low cost and higher efficiency; and an obtained product has high chemical purity and optical purity.

Description

technical field [0001] The invention relates to 3-aminotetrahydropyran, in particular to a novel synthesis method of a chiral pharmaceutical intermediate 3-aminotetrahydropyran (and its salt. Background technique [0002] 3-Aminotetrahydropyran is a colorless oily liquid with the molecular formula C 5 h 11 NO, the molecular weight is 101.15. Its hydrochloride is a crystalline white powder with the molecular formula C 5 h 12 ClNO, the molecular weight is 137.61. It is generally prepared as hydrochloride and used as an important pharmaceutical intermediate, mainly used in the synthesis of new drug AMPA receptor enhancers. This type of drug (US Patent US20100120764) is mainly used for the treatment of nervous system diseases such as Parkinson's disease, schizophrenia, sleep shock, mood disorder and memory loss. [0003] A large number of experimental data have found that chirality is split into chiral compounds, which have many specific properties. For example, after spli...

Claims

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Application Information

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IPC IPC(8): C07D309/14
CPCY02P20/55
Inventor 茅仲平葛永辉马东旭曹建华蒋国强谭进王伟陈玉宏王永强朱鑫
Owner 苏州汉德创宏生化科技有限公司
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