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Method for synthesizing 1,8-diazaspiro[4.5]decane with protective group
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A diazaspiro and synthetic method technology, applied in the field 1, can solve the problems of difficult purification of intermediates, harsh reaction conditions, and inability to scale production, and achieve the effects of easy industrial operation, fewer reaction steps, and high overall yield
Active Publication Date: 2013-04-10
上海药明康德新药开发有限公司 +2
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It mainly solves the technical problems that the existing 1,8-diazaspiro[4,5]decane compounds have a long synthetic route, low yield, difficult purification of intermediates, harsh reaction conditions, and incapable of large-scale production
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Embodiment 1
[0024]
[0025] 1. Synthesis of N-tert-butoxycarbonyl-4-hydroxyiminopiperidine
[0026]
[0027] A mixture of N-tert-butoxycarbonyl-4-piperidone (250 g, 1.25 mol), hydroxylamine hydrochloride (218 g, 3.125 mol) and potassium carbonate (346 g, 2.5 mol) in ethanol (2 L) was stirred at 50° C. for 0.5 h. TLC monitors the completion of the reaction, the reaction solution is filtered, the filtrate is concentrated under reduced pressure, the residue is dissolved in ethyl acetate, washed with water and brine respectively, dried, and the crude product concentrated under reduced pressure is washed with petroleum ether to obtain a white solid N-tert-butoxycarbonyl- 4-Hydroxyiminopiperidine (193.5 g, 72.3%).
[0028] 1 H NMR (400MHz, CDCl3) d ppm: δ3.512-3.555 (m, 4H), 2.594-2.625 (m, 2H), 2.316-2.346 (m, 2H), 1.468 (s, 9H),
[0029] 2.1 Synthesis of N-tert-butoxycarbonyl-4-nitropiperidine
[0030]
[0031] A mixture of N-tert-butoxycarbonyl-4-hydroxyiminopiperidine (100 g, 0....
Embodiment 2
[0054] Synthetic reference of N-benzyloxycarbonyl-4-nitropiperidine Example 1 Operation steps 1 and 2.
[0055] 1. Synthesis of N-benzyloxycarbonyl-4-propionyl-4-nitropiperidine
[0056]
[0057] N-benzyloxycarbonyl-4-nitropiperidine (10.99 g, 41.6 mmol) and triethylamine (0.42 g, 4.16 mmol) were dissolved in 50 ml of acetonitrile, and acrolein (3.73 g , 133 mmol) and 10 ml of acetonitrile, stirred overnight. TLC (petroleum ether / ethyl acetate=1:1) showed that the starting material disappeared and the reaction was complete. After concentration, the crude product was purified by silica gel column to obtain 9.37 g (73.5%) of N-benzyloxycarbonyl-4-propionyl-4-nitropiperidine as a yellow oil.
[0058] 2. Synthesis of N-benzyloxycarbonyl-1,8-diazaspiro[4,5]decane
[0059]
[0060] Mix N-benzyloxycarbonyl-4-propanalyl-4-nitropiperidine (9.37 g, 30.6 mmol) and 2.0 g of Raney Ni in 50 ml of ethanol, and stir overnight at 20-25 °C under hydrogen pressure of 30 Psi . TLC (pe...
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Abstract
The invention relates to a method for preparing 1,8-diazaspiro[4.5]decane with a protective group, and mainly solves the technical problems that the conventional synthetic route for the 1,8-diazaspiro[4.5]decane is long, the yield is low, an intermediate is difficult to purify, reaction conditions are rigorous, and mass production cannot be performed. The method comprises the following steps of: performing Michael addition reaction on N-PG-4-nitropyridine serving as a raw material and acrylic ester in alcoholic solution or acetonitrile to obtain N-PG-4-propanal-4-nitropyridine; and adding a catalyst into the product in an organic solvent, and performing hydrogenation reduction ring-closing reaction to obtain the 1,8-diazaspiro[4.5]decane with the protective group. The method has the advantages of a few reaction steps, high yield and mild conditions, and is a synthetic method with large-scale preparation value.
Description
Technical field: [0001] The invention relates to a preparation method of 1,8-diazaspiro[4,5]decane with protective groups. Background technique: [0002] 1,8-diazaspiro[4,5]decane derivatives are useful drug intermediates, and WO2007 / 025069A1 reported that compounds containing such core structures have orexin receptor antagonist activity. It is mainly used for the treatment and prevention of the following diseases: eating disorders, obesity, diabetes and other energy metabolism imbalance diseases; sleep disorders, schizophrenia, anxiety and depression, and circadian rhythm disorders. [0003] For the preparation of 1,8-diazaspiro[4,5]decane derivatives, the related compound methods reported in the literature are as follows: [0004] Method 1 is reported by WO2007 / 025069A1, where PG=Bn [0005] As shown in Formula 1: [0006] Formula 1 [0007] [0008] Reagents and yield: (I) sodium cyanide; (II) diallylamine; (III) 2-(2-bromoethyl)-1,3-dioxane, magnesium, tetrahydro...
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