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Preparation method of (3-amino-azetidine-1-yl)-cyclopropyl-ketone

An azetidine and cyclopropyl technology, which is applied in the fields of fine chemical industry and pharmaceutical intermediate synthesis, can solve the problems of being unsuitable for large-scale production, using dangerous reagents, and high process costs, achieving low price and shortening reaction steps. , the effect of improving the reaction efficiency

Pending Publication Date: 2019-07-19
南京合巨药业有限公司
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  • Application Information

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Problems solved by technology

[0011] The technical problem to be solved by the present invention is to overcome the defects of the prior art, provide a preparation method of (3-amino-azetidin-1-yl)-cyclopropyl-methanone, and solve the problem of high cost of the original process. , the route is long, the use of dangerous reagents is not suitable for large-scale production

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  • Preparation method of (3-amino-azetidine-1-yl)-cyclopropyl-ketone
  • Preparation method of (3-amino-azetidine-1-yl)-cyclopropyl-ketone

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preparation example Construction

[0040] A preparation method of (3-amino-azetidin-1-yl)-cyclopropyl-methanone, comprising the following steps:

[0041] (1) Under alkaline conditions, dissolve azetidin-3-one hydrochloride in a solvent, add an acylating reagent to react, and obtain 1-cyclopropanecarbonyl-azetidin-3-one, The reaction process is:

[0042] ;

[0043] Among them, R= or .

[0044] (2) Dissolve 1-cyclopropanecarbonyl-azetidin-3-one in a solvent, add benzylamine, stir to dissolve, add a reducing agent, and react at -5°C~5°C to obtain (3-benzylamine Amino-azetidin-1-yl)-cyclopropyl-methanone, the reaction process is:

[0045] ;

[0046] (3) Dissolve 3-borylamino-azetidin-1-yl)-cyclopropyl-methanone in a solvent, and react with hydrogen in the presence of a catalyst to obtain (3-amino-nitrogen Heterobutan-1-yl)-cyclopropyl-methanone, the reaction process is:

[0047] .

[0048] (3-amino-azetidin-1-yl)-cyclopropyl-methanone obtained by the present invention 1 HNMR picture as shown figu...

Embodiment 1

[0050] (1) Synthesis of 1-cyclopropanecarbonyl-azetidin-3-one:

[0051]

[0052] Add azetidin-3-one hydrochloride (32.30 g, 0.30 mol, 1.0 equiv.) and triethylamine (75.89 g, 0.75 mmol, 2.5 equiv.) into 300 ml of dichloromethane, stir at room temperature After 30 minutes, cyclopropanoyl chloride (34.49 g, 0.33 mol, 1.1 equiv.) was added dropwise, and the mixture was reacted at room temperature for 3 hours. TLC showed that the reaction was complete. Add saturated Na2 CO 3 The solution was 100 ml, the organic phase was separated, the aqueous phase was extracted twice with dichloromethane, and the organic phases were combined. The organic phase was washed twice with 1 N aqueous hydrochloric acid solution, once with saturated brine, and washed with anhydrous Na 2 SO 4 Dry, filter, and concentrate under reduced pressure to obtain 35.90 g of a light yellow solid, with a yield of 86%.

[0053] LC-MS (ESI+): m / z 140.16 (M+H).

[0054] (2) Synthesis of (3-benzylamino-azetidin-1-...

Embodiment 2

[0064] (1) Synthesis of 1-cyclopropanecarbonyl-azetidin-3-one:

[0065]

[0066] At room temperature, cyclopropanecarboxylic acid (2.07 g, 24 mmol, 1.20 equiv.), azetidin-3-one hydrochloride (2.15 g, 20 mmol, 1.0 equiv.), 1-ethyl-(3 -Dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (8.43 g, 44 mmol, 2.2 equiv.) and 4-dimethylaminopyridine (DMAP) (4.89 g, 40 mmol, 2.0 equiv.) Added successively to 40 ml of acetonitrile, stirred overnight at room temperature, TLC showed that the reaction was complete. Add 100 ml of water and extract with ethyl acetate (100 ml*3). The organic phases were combined, and the organic phase was once washed with 1N hydrochloric acid, saturated NaHCO 3 , washed with saturated brine, anhydrous Na 2 SO 4 Dry, filter, and concentrate under reduced pressure to obtain 2.09 g of a light yellow solid, with a yield of 75%.

[0067] LC-MS (ESI+): m / z 140.16 (M+H).

[0068] (2) Synthesis of (3-benzylamino-azetidin-1-yl)-cyclopropyl-methanone:

[00...

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Abstract

The invention discloses a preparation method of (3-amino-azetidine-1-yl)-cyclopropyl-ketone. The preparation method comprises the following steps: dissolving azetidine-3-ketone hydrochloride in a solvent under an alkaline condition, adding an acylation reagent for reaction to obtain 1-cyclopropanecarbonyl-azetidine-3-ketone; dissolving the 1-cyclopropanecarbonyl-azetidine-3-ketone in a solvent, adding benzylamine, stirring and dissolving the benzylamine, and adding a reducing agent for reaction at-5-5 DEG C to obtain (3-benzylamino-azetidine-1-yl)-cyclopropyl-ketone; dissolving 3-boroamino-azetidine-1-yl)-cyclopropyl-ketone in a solvent to react with a reducing agent in the presence of a catalyst to obtain (3-amino-azetidine-1-yl)-cyclopropyl-ketone. The raw materials used in the preparation method provided by the invention are low in price and wide in source, six steps of reaction of an original synthesis method are reduced to three steps of reaction, dangerous reagents are not used,reaction steps are shortened, and reaction efficiency is improved.

Description

technical field [0001] The invention relates to a preparation method of (3-amino-azetidin-1-yl)-cyclopropyl-methanone, which belongs to the technical field of fine chemical and pharmaceutical intermediate synthesis. Background technique [0002] (3-Amino-azetidin-1-yl)-cyclopropyl-methanone (I) is an important intermediate in the synthesis of a class of MAP4K4 inhibitors, especially GNE-495. MAP4K4 is involved in a wide range of physiological processes including cell migration, proliferation, and adhesion. Therefore, research on MAP4K4 inhibitors has important applications in the treatment of systemic inflammation, metabolic disorders, cardiovascular diseases, and cancer. GNE-495 shows excellent MAP4K4 inhibition with good permeability, microsomal stability and cellular potency. Therefore, as a key intermediate, (3-amino-azetidin-1-yl)-cyclopropyl-methanone has a broad market prospect. [0003] Patent WO2013113669A1 reports the synthesis method of (3-amino-azetidin-1-yl)-c...

Claims

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Application Information

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IPC IPC(8): C07D205/04
CPCC07D205/04
Inventor 潘国骏陈书林
Owner 南京合巨药业有限公司
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