Novel method for synthesizing orlistat, intermediate compound and preparation thereof

An orlistat and compound technology, which is applied in the field of synthesis of lipid-lowering drug compounds, can solve the problem that it cannot be fully used for industrialization and the like

Active Publication Date: 2009-01-21
ZEIN BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] The present invention overcomes the deficiencies of the prior art, realizes the total synthesis of orlistat through a new intermediate compound, successfully solves the problem that the above-mentioned several methods cannot b

Method used

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  • Novel method for synthesizing orlistat, intermediate compound and preparation thereof
  • Novel method for synthesizing orlistat, intermediate compound and preparation thereof
  • Novel method for synthesizing orlistat, intermediate compound and preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Preparation of (2S, 3S, 5R)-3-hydroxy-2-hexyl-5-undecyl-valerolactone (1)

[0049] In the dry reaction bottle, add 5-(R)-3-keto-2-hexyl-5-undecyl-valerolactone (refer to Martin Karpf, et al., US5399720 preparation) 141g (0.4mol) and 3.5 L of ethyl acetate was stirred evenly, 52 g of Raney nickel was added, hydrogen gas was introduced at normal pressure, the temperature was controlled at about 30°C, and the reaction was stirred for 24 hours. TLC detection (developing agent: n-hexane: ethyl acetate = 10: 3, silica gel is GF254, observed under iodine smoked color development, the R of raw material f = 0.6). After the reaction is complete, filter and distill at normal pressure until the remaining 250 mL remains. Set aside to crystallize at about -10°C overnight, filter, collect the filter cake, and dry at 60°C for 10 hours under normal pressure to obtain 115 g of white solid. Yield: 81%, m.p.102.2~103.6℃, ​​[α] 20 D +47° (C=1, chloroform). Anal.C 22 h 42 o 3 : C, 74...

Embodiment 2

[0052] Preparation of Compound Ia

[0053] a) Preparation of (2S, 3S, 5R)-2-hexyl-3-benzoyloxy-5-undecyl-valerolactone (10)

[0054] In a dry reaction flask, add compound (1) 48g (0.136mol) and dichloromethane 480mL, under stirring, add 4-dimethylaminopyridine 4.2g, benzoyl chloride 16.8g (0.12mol) and triethylamine 14.2 g (0.14mol), at room temperature, stirring and reacting for 24 hours, TLC detection (developing solvent: n-hexane: ethyl acetate=10:3, silica gel is GF254, observed under iodine smoked color development, the R of the raw material f =0.53), after the reaction is complete, use saturated sodium carbonate solution pH8~9, separate the organic layer, wash the organic layer with water, dry the organic layer with anhydrous sodium sulfate for 3 hours, concentrate the filtrate under normal pressure and evaporate to dryness under reduced pressure, add Methanol 100mL, refrigerated and crystallized overnight, filtered, and the filter cake was dried under normal pressure a...

Embodiment 3

[0058] Preparation of compound Ib

[0059] a) Preparation of (2S, 3S, 5R)-3-benzoyloxy-2-hexyl-5-hydroxyhexadecanoic acid methyl ester (11)

[0060] Add 70 g (0.153 mol) of compound (10) and 350 mL of methanol into the reaction flask, stir evenly, add 0.7 mL of concentrated sulfuric acid, and stir for reaction at room temperature for 24 hours. TLC detection (developing agent: n-hexane: ethyl acetate = 10: 3, silica gel is GF254, observed under iodine smoked color development, the R of raw material f =0.77), after the completion of the reaction, add triethylamine to adjust the pH to about 9, distill under reduced pressure, after the distillation is completed, add 500 mL of n-hexane and 500 mL of water, stir for 10 minutes, separate the organic layer, extract the water layer twice with n-hexane, and combine , washed twice with water, the organic layer was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 68 g of li...

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Abstract

The invention discloses a novel method for synthesizing Orlistat, as well as a novel intermediate compound to which the method relates, i.e. the compound shown in formula (I), wherein the definition of R1 or R2 is detailed in the instruction. The invention also discloses the method for preparing the intermediate compound. The synthesis method disclosed by the invention has cheap and easily available raw material, mild technological condition, simple post treatment, the obtained product with high photic purity, and the whole technology highly is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the synthesis method of lipid-lowering drug compounds, more specifically, the invention relates to a new synthesis method of orlistat, a new intermediate compound and a preparation method thereof. Background technique [0002] In 1987, Weibel et al. (Weibel, E.K.; Hadvary, P.; Kupfer, E.; Lengsfeld, H.J. Antibiot. 1987, 40, 1081. Hochuli, E.; Kupfer, E.; Maurer, R.; Meister, W. .; Mercadal, Y.; Schmidt, K.J.Antibiot.1987, 40, 1086.) The pancreatic lipase inhibitor Lipstatin was isolated and found in Streptomyces toxytricini, compound A is a β lactone compound with two cis double bonds . Weibel et al. also reported some derivatives of Compound A, including the saturated derivative tetrahydrolipstatin (B) of Lipstatin, and found that the β lactone in the structure of Lipstatin compounds is necessary for the inhibition of lipase activity. Inhibiting the activity of pancreatic lipase can inhibit the absorption of fat in food, the...

Claims

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Application Information

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IPC IPC(8): C07D309/12
CPCY02P20/55
Inventor 陈小勇徐天帅王晓琳刘启坪肖玉梅
Owner ZEIN BIOTECHNOLOGY CO LTD
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