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Method for preparing vitaletine

A solvent and compound technology, applied in the field of vildagliptin preparation, can solve the problems of increasing product cost, unfavorable environmental protection, and relatively expensive price, and achieve the effects of low cost, less by-products, and improved reaction efficiency and conversion rate

Active Publication Date: 2018-10-16
上海三牧化工技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Though this method yield and product quality improve to some extent, sodium metabisulfite used has strong SO smell, is unfavorable for environmental protection, and 2-picoline-N-borane price is more expensive, improves product cost

Method used

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  • Method for preparing vitaletine
  • Method for preparing vitaletine
  • Method for preparing vitaletine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Synthesis of Compound II

[0037] Glyoxylic acid monohydrate 27.6g (0.30mol, 1.5eq), 3-amino-1-adamantanol 33.5g (0.20mol, 1.0eq), diisopropylethylamine 38.8g (0.30mol, 1.5eq ) and 250g of tetrahydrofuran were put into the reaction flask, 51.1g (0.50mol, 2.5eq) of acetic anhydride was added dropwise, heated to reflux and stirred for 2 hours, the remaining raw materials were controlled in HPLC to be less than 1%, 50g of water was added, stirred for 30 minutes, and separated, The aqueous layer was extracted once with 50 g of dichloromethane, and the organic layer was concentrated under reduced pressure to obtain 42.8 g of off-white solid Compound II with a yield of 96.1% and a purity of 96.6%. 1H-NMR (400MHz, DMSO-d6): 4.34 (s, 1H), 2.08 (m, 2H), 1.46-1.24 (m, 12H), 7.73 (s, 1H), 13.24 (s, 1H); m / z(ESI + )224.0(MH) + .

Embodiment 2

[0039] Synthesis of Compound II

[0040] Glyoxylic acid monohydrate 22.1g (0.24mol, 1.2eq), 3-amino-1-adamantanol 33.5g (0.20mol, 1.0eq), triethylamine 20.2g (0.20mol, 1.0eq) and 250g di Chloromethane was put into the reaction flask, 40.9g (0.40mol, 2.0eq) of acetic anhydride was added dropwise, stirred at room temperature for 10 hours, and the remaining raw materials were controlled by HPLC to less than 3%, 50g of water was added, stirred for 30 minutes, separated, and the water layer was used 50g of dichloromethane was extracted once, and the organic layer was concentrated under reduced pressure to obtain 41.8g of off-white solid compound II, with a yield of 93.7% and a purity of 94.2%; m / z (ESI + )224.0(MH) + .

Embodiment 3

[0042] Synthesis of compound III

[0043]Under nitrogen protection, compound II 42.8g (0.19mol, 1.0eq), (S)-pyrrolidine-2-carbonitrile 18.3g (0.19mol, 1.0eq), boric acid tris(2,2, Put 11.7g (38mmol, 0.2eq) of 2-trifluoroethyl) ester and 350g toluene into the reaction flask connected with the water separator, heat and reflux for 12 hours, separate 3.4g of water, crystallize at room temperature, filter, filter 50.5g of white solid compound III was obtained, with a yield of 88.2% and a purity of 98.6%. 1 H-NMR(400MHz, CDCl3):1.45-1.64(m,14H),2.09(m,1H),2.25-2.38(m,4H),3.40-3.54(m,1H),3.57-3.67(m,1H ),4.70-4.75(t,1H),7.79(s,1H).m / z(ESI + )302.2 (MH) + .

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Abstract

The invention discloses a method for preparing vitaletine, and belongs to the field of synthesizing of medicine intermediates. The method comprises the following steps of using 3-amino-1-amantadol andmonohydrated acetaldehyde acid as raw materials, and performing imidization reaction, so as to obtain (3-hdyroxyl amantadine)acetic acid; under the catalyzing function of tris(2,2,2-trifluoroethyl)borate, acylating and condensing with (S)-pyrrolidine-2-formonitrile, so as to obtain (2S)-1-[[(3-hydroxyl tricyclic[3.3.1.1[3,7]]decane-1-yl)imino]acetyl]pyrrolidine-2-formonitrile; reducing by palladium carbon / ammonium formate, so as to obtain the vitaletine. The method has the advantages that one-pot process is adopted, the operation is simple, fewer impurities are contained, the product is easyto purify, the purifying step is not needed, the cost is reduced, and the method is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a method for preparing vildagliptin. Background technique [0002] Vildagliptin chemical name (-)-(2S)-1-[[(3-hydroxytricyclo[3.3.1.1[3,7]]decane-1-yl)amino]acetyl]pyrrolidine-2 -formonitrile (structure shown in formula (I)), vildagliptin is a dipeptidylase type IV (DDPIV) inhibitor developed by Novartis, Switzerland, which can be used to treat type 2 diabetes, either alone or Combined use with other antidiabetic drugs can significantly reduce the level of glycosylated hemoglobin, has good tolerance and no significant adverse reactions, and is a new diabetes drug with good application prospects. In September 2007, it was approved as a low-dose drug by the European Union, and it has also been approved in Brazil and Mexico. [0003] [0004] There are many synthetic methods of vildagliptin reported in the literature, mainly including the following methods: [0005] T...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16
CPCC07D207/16
Inventor 高峰谢楠
Owner 上海三牧化工技术有限公司
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