A kind of synthetic method of 8-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}octane-3-one

A trimethylsilyl-based and synthetic method technology, which is applied in the direction of preparation of carbamic acid derivatives, compounds of group 4/14 elements of the periodic table, silicon organic compounds, etc., can solve the problem of relatively harsh production conditions, high production costs, Problems such as complex process, to achieve the effect of favorable quality control and improvement, mild process conditions, and reasonable technical solutions

Active Publication Date: 2022-02-18
SUZHOU FUSHILAI PHARMA CO LTD
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  • Application Information

AI Technical Summary

Problems solved by technology

Although people have developed a racemization method for S-lipoic acid, the conversion of S-lipoic acid into cyclic lipoic acid is relatively harsh on actual production conditions, corrosive to equipment, and the yield is low, resulting in expensive production costs; The second is to use 6,8-dihydroxyoctanoic acid methyl ester or 6-hydroxy-8-chlorooctanoic acid methyl ester as the starting material to make mesylate, and then stereoselectively form R-lipoic acid. The process of this method is more complicated , especially not easy to obtain pure product; the third is to hydrolyze racemic 6,8-dichlorooctanoic acid ethyl ester into (±) dichlorooctanoic acid, and then use a resolving agent to split, rethio and cyclization, the method is basically Can save costs, but because about 50% of S-(-)-6,8-dichlorooctanoic acid is still unused, the cost is higher
[0007] The preparation methods of R-lipoic acid in the prior art, including the three methods mentioned above, all have high cost, low yield and large raw material consumption, which cannot meet the requirements of industrialized scale-up production, and because of high waste discharge Disadvantages of not meeting the requirements of green production

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  • A kind of synthetic method of 8-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}octane-3-one
  • A kind of synthetic method of 8-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}octane-3-one
  • A kind of synthetic method of 8-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}octane-3-one

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] A) Synthesis of Intermediate-1:

[0036] Diphenylmethylamine (5.0g, 27.3mmol) was dissolved in dichloromethane (80mL), triethylamine (6.0g, 59.3mmol) was added, cooled to 0°C, di-tert-butyl dicarbonate (6.0g, 27.5mmol) was added ), raised to 20°C and stirred for 12h, quenched with dropwise addition of water, added ethyl acetate (50mL), stirred for 5min, separated into layers, collected the organic phase, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, added N,N-di Methylformamide (50mL), cooled to 0°C, added 60% NaH (1.7g, 42.5mol), stirred at 0°C for 30min, added 1,5-dibromopentane (8.2g, 35.7mmol), reacted at 20°C 12h, add dropwise a mixture of ethyl acetate and saturated brine (50mL, 1:1) to quench, separate the layers, collect the organic phase, wash with brine, dry over anhydrous sodium sulfate, concentrate to dryness under reduced pressure, ethyl acetate-petroleum Recrystallization from a mixed solvent of ether gave Intermedia...

Embodiment 2

[0045] A) Synthesis of Intermediate-1:

[0046] Diphenylmethylamine (12.0g, 65.5mmol) was dissolved in dichloromethane (150mL), triethylamine (13.0g, 0.13mol) was added, cooled to 0°C, di-tert-butyl dicarbonate (15.0g, 68.7mmol) was added ), raised to 20°C and stirred for 12h, quenched with dropwise addition of water, added ethyl acetate (80mL), stirred for 5min, separated into layers, collected the organic phase, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, added N,N-di Methylformamide (100mL), cooled to 0°C, added 60% NaH (4.5g, 0.11mol), stirred at 10°C for 45min, added 1,5-dibromopentane (21.0g, 91.3mmol), reacted at 35°C 6h, dropwise add ethyl acetate and saturated brine mixture (100mL, 1:1) to quench, separate the layers, collect the organic phase, wash with brine, dry over anhydrous sodium sulfate, concentrate to dryness under reduced pressure, ethyl acetate-petroleum Recrystallization from a mixed solvent of ether gave Intermedi...

Embodiment 3

[0052] A) Synthesis of Intermediate-1:

[0053] Diphenylmethylamine (16.6g, 90.6mmol) was dissolved in dichloromethane (200mL), triethylamine (18.0g, 0.18mol) was added, cooled to 0°C, di-tert-butyl dicarbonate (20.0g, 91.6mmol) was added ), raised to 20°C and stirred for 12h, quenched with dropwise addition of water, added ethyl acetate (100mL), stirred for 5min, separated into layers, collected the organic phase, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, added N,N-di Methylacetamide (200mL), cooled to 0°C, added 60% NaH (7.0g, 0.18mol), stirred at 15°C for 1h, added 1,5-dibromopentane (29.0g, 0.13mol), reacted at 30°C 9h, add dropwise a mixture of ethyl acetate and saturated brine (500mL, 1:1) to quench, separate layers, collect the organic phase, wash with brine, dry over anhydrous sodium sulfate, concentrate to dryness under reduced pressure, ethyl acetate-petroleum Recrystallization from an ether mixed solvent gave Intermediate-...

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Abstract

A method for synthesizing 8-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}octane-3-one belongs to the technical field of pharmaceutical chemical synthesis. Steps: first protect benzhydrylamine with N-Boc, and then react with sodium hydride to obtain its sodium salt intermediate, which is subjected to a substitution reaction with 1,5-dibromopentane to obtain intermediate-1; intermediate ‑1 yields the zinc bromide intermediate, which is subsequently reacted with methyl 3‑{[2‑(trimethylsilyl)ethoxy]methoxy}propionate to yield intermediate ‑2, which is decomposed by catalytic hydrogenation Protection reaction, obtain lipoic acid intermediate 8-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}octane-3-one. The technical process conditions are mild, the raw materials are easy to obtain, and the purity of each intermediate is high, which is beneficial to the quality control and improvement of the production of raw materials, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a synthesis method of 8-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}octane-3-one. Background technique [0002] α-lipoic acid is a vitamin-like compound that can eliminate free radicals that accelerate aging and cause disease. It is both water-soluble and fat-soluble. Universal antioxidant drug. α-lipoic acid has a certain effect on the treatment of many diseases such as liver disease, diabetes, HIV virus, tumor, nervous system degeneration, radiation injury, arsenic, mercury, cadmium and other heavy metal poisoning, for example, it can assist in the treatment of type II diabetes and improve Pancreatic islets function in glucose metabolism, protect nerve cells, prevent cataracts, prevent muscle damage and so on. [0003] As shown in the following chemical structural formula, in the molecular structure of α-lipoic acid, there is a chiral carb...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F7/08C07F3/06C07C269/04C07C271/14
CPCC07F7/081C07F7/083C07F3/06C07C269/04C07C2603/18C07C271/14
Inventor 吴磊石晓青赵雪锋曾陵
Owner SUZHOU FUSHILAI PHARMA CO LTD
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