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Preparation method of trans-N-Boc-1,3-cyclobutanediamine

A technology of n-boc-1 and cyclobutylene diamine, which is applied to the preparation of organic compounds, chemical instruments and methods, and the preparation of carbamic acid derivatives. It can solve the problems of long steps and low yields, and achieve short steps , simple operation, simple and easy purification method

Inactive Publication Date: 2015-08-12
HEBEI UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] In view of the fact that the existing methods for preparing trans-N-Boc-1,3-cyclobutanediamine have long steps and low yields and are difficult to be commercialized, the present invention provides an efficient preparation of trans-N-Boc-1,3 that is easy to commercialize -Cyclobutanediamine method

Method used

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  • Preparation method of trans-N-Boc-1,3-cyclobutanediamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] step one:

[0032] To a solution of 3-methylenecyclobutanecarbonitrile (400 g, 4.3 mol) in ethanol (5 L) and water (5 L) was added potassium hydroxide (2408 g, 43 mol). After refluxing for 2 hours, the pH of the solution was adjusted to 2 with concentrated hydrochloric acid. The precipitated white solid was filtered, washed with water, and dried to obtain Compound 2 (450 g), with a yield of 93.4%. Proton NMR spectrum (400MHz, CDCl 3 )δ: 2.67-3.56 (5H, m), 4.68-4.98 (2H, m), 10.73 (1H, br, s), indicating that the target product was obtained. Its molecular weight is 112.13.

[0033] Step two:

[0034] Triethylamine (590g, 5.9mol), diphenylphosphoryl azide (DPPA) (1273g, 4.7mol) and compound 2 (440g, 3.9mol) were dissolved in tert-butanol (8L) at a reflux temperature of 83°C in sequence , and then reflux for 12 hours. The reaction was quenched with water (2 L), and after the solution was concentrated to 1 / 5 of the original volume, ethyl acetate (7.8 L) was added to t...

Embodiment 2

[0046] step one:

[0047] Same as Step 1 in Example 1.

[0048] Step two:

[0049] Potassium carbonate (814g, 5.9mol), NaN 3 (305.5g, 4.7mol) and compound 2 (440g, 3.9mol) were dissolved in tert-butanol (8L) at a reflux temperature of 83°C, and then refluxed for 12 hours. The reaction was quenched with water (2 L), and after the solvent was concentrated, ethyl acetate (7.8 L) was added to the remaining solution. The organic phase was washed with water, washed with saturated brine, dried, and spin-dried to obtain a white solid, compound 3 (520.6 g), with a yield of 73%. Proton NMR spectrum (400MHz, CDCl 3 )δ:1.36(9H,s),2.56-2.65(2H,m),2.97-3.18(2H,m),4.05-4.23(1H,m),4.05-4.23(1H,m),4.85(1H, br s), 5.08(2H,m).

[0050] Step three:

[0051] Compound 3 (8.0 g, 0.044 mol) was dissolved in dichloromethane (50 mL) and water (50 mL). Then, add RuCl to this reaction solution 3 (0.32g), NaIO 4 (14.1 g, 0.066 mol). After stirring at room temperature for 1 hour, the aqueous pha...

Embodiment 3

[0056] step one:

[0057] Same as Step 1 in Example 1.

[0058] Step two:

[0059] N,N-diisopropylethylamine (762.5g, 5.9mol), TMSN 3 (541.4g, 4.7mol) and compound 2 (440g, 3.9mol) were dissolved in tert-butanol (8L) at a reflux temperature of 83°C, and then refluxed for 12 hours. The reaction was quenched with water (2 L), and after the solvent was concentrated, ethyl acetate (7.8 L) was added to the remaining solution. The organic phase was washed with water, washed with saturated brine, dried, and spin-dried to obtain a white solid, compound 3 (534.8 g), with a yield of 75%. Proton NMR spectrum (400MHz, CDCl 3 )δ:1.36(9H,s),2.56-2.65(2H,m),2.97-3.18(2H,m),4.05-4.23(1H,m),4.05-4.23(1H,m),4.85(1H, br s), 5.08(2H,m).

[0060] Step three:

[0061] Compound 3 (8.0 g, 0.044 mol) was dissolved in DMF (80 mL). Then, add OsO to this reaction solution 4 (0.11 g) and tert-butanol peroxy (26.1 g, 0.176 mol). After stirring at room temperature for 3 hours, ethyl acetate (100 m...

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Abstract

The present invention is a preparation method of trans-N-Boc-1,3-cyclobutanediamine. The method uses easily available 3-methylene-cyclobutyl carbonitrile as a starting material, and conducts 7 steps of reaction including hydrolysis, Curtius rearrangement, oxicracking, reduction, methanesulfonyl chloride protection, substitution and hydrogenation. The invention has the technical characteristics of short reaction step, total yield of up to 49.8% and high purity of the final product (>99%) (the prior art comprises at least 8 steps, and the highest total yield is up to 19%); and N-Boc-1,3-cyclobutanediamine with transconfiguration is selectively synthesized. From the perspective of chemistry, the invention has the characteristics of few steps, simple reaction, high yield, feasible purification method of intermediate and simple operation, and has wide prospect in business application.

Description

technical field [0001] The invention relates to a high-efficiency preparation method of trans-N-Boc-1,3-cyclobutanediamine compounds, which belongs to the preparation technology of pharmaceutical intermediates. Background technique [0002] As an important molecular skeleton, 1,3-cyclobutanediamine is widely used in the design of new drug molecules. Such as 1,3-cyclobutanediamine derivatives CDK1 (Engelhardt, H.; WO2007115999), CDK2, GSK-3 (Ahlijanian, M.K.; WO0210141) and PLK (Stadtmueller, H.; WO2006021544), which have kinase inhibitory effect; The phosphodiesterase inhibitor PDE4 (Kuang, R.; WO 2005116009) and the glycine transportase inhibitor GLyT-1 (Lowe, J.A.; WO 2008065500). In addition, derivatives based on 1,3-cyclobutanediamine have also been designed as insecticides and acaricides. As the basic raw material for the synthesis of 1,3-cyclobutanediamine derivatives, there are few reports on the synthesis methods of trans-N-Boc-1,3-cyclobutanediamine. One of the p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/24C07C269/06
Inventor 刘雅莉袁文蛟刘晓磊
Owner HEBEI UNIV OF TECH
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