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Large scale synthesis of 1,2,4- and 1,3,4- oxadiazole carboxylates

a technology of oxadiazole and carboxylate, which is applied in the field of large-scale synthesis of 1,2,4- and 1,3,4-oxadiazole carboxylate, can solve the problems of inability to generate a wide variety of 1,2,4-oxadiazoles, requires the use of expensive starting materials, and is not suitable for large-scale synthesis, so as to achieve safe, cost-effective, and efficient effects

Inactive Publication Date: 2005-07-14
KOLB HARTMUTH C +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009] This invention provides for efficient, scalable, safe, and cost effective methods for the preparation of 1,2,4- and 1,3,4-oxadiazoles.

Problems solved by technology

A limitation of this method is the availability of the starting amidoxime, which is usually prepared by treating a substituted oximyl chloride the highly toxic and caustic ammonia gas.
This method also requires the use of expensive starting materials and cannot be used to generate a wide variety of 1,2,4-oxadiazoles.
In addition, this procedure is not readily amenable to large scale synthesis.
First, the procedure is extremely inefficient, affording yields of 6 to 30 percent.
Second, it is not amenable to scale up.
Finally, this method uses acidic dehydrating agents, which will destroy any acid labile groups.
Next, the preparation of the diacylhydrazide requires the use of triethylamine, a very odiferous and relatively expensive base.
The method also requires numerous expensive and time consuming chromatographic separations in order to obtain the pure desired product.
Finally, many 1,3,4-oxadiazoles are acid labile and readily decompose when attempting to remove the BOC group with HCl.
Another key limitation of the prior art methods for producing the 1,2,4- and 1,3,4-oxadiazoles is that the tertiary-butoxy carbonyl (BOC) nitrogen-protecting group is left intact at the end of the synthesis.
The use of toxic HCl gas is also undesirable.

Method used

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  • Large scale synthesis of 1,2,4- and 1,3,4- oxadiazole carboxylates
  • Large scale synthesis of 1,2,4- and 1,3,4- oxadiazole carboxylates
  • Large scale synthesis of 1,2,4- and 1,3,4- oxadiazole carboxylates

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of Anhydrides

1. 3-[(tert-Butoxy)carbonylamino]propanoyl 3-[(tert-butoxy)carbonylamino]propanoate (1a)

[0075]

[0076] A solution of N,N-dicyclohexylcarbodiimide (DCC) (109 g, 0.529 mol) in dry methylene chloride (200 ml) is added dropwise to a 0° C. solution of BOC protected β-alanine (200 g, 1.058 mol) in dry methylene chloride (800 ml.) After the addition is complete, the reaction mixture is stirred for 2 hours. The resulting N,N-dicyclohexylurea (DCU) is removed via filtration, and the filtrate is concentrated in vacuo to yield the crude anhydride 1a, which is used directly in the next step without further purification.

example 2

Synthesis of Amidoximes

1. Ethyl 2-amino-2-(hydroxyimino)acetate (2a)

[0077]

[0078] Water (600 ml) is added dropwise over a period of two hours to a vigorously stirred, room temperature mixture of ethyl cyanoformate (99 g, 1 mol), hydroxylamine hydrochloride (105 g, 1.5 mol ) and sodium carbonate (82 g, 0.77 mol ) in ethanol (1 L.) The resulting solution is stirred until the starting material has been consumed. When the reaction is complete, most of the solvent is removed in vacuo and the resulting residue is extracted with methylene chloride (3×200 ml.) The combined organic extracts are washed with brine (250 ml), dried (Na2SO4), filtered and concentrated to afford 120.1 g (91%) of compound 2a as a white solid. Further purification can be achieved by crystallization from chloroform and hexanes. 1H NMR (CDCl3): δ 9.15(br s, OH), 5.12(br s, 2H), 4.32(q, 2H), 1.42(t, J=7.1 Hz, 3H). 13C NMR (CDCl3): δ 161.4, 144.4, 62.8, 14.3.

2. Ethyl 3-amino-3-(hydroxyimino)propanoate (2b)

[0079]

[0080...

example 3

Synthesis of 1,2,4-Oxadiazoles

1. Ethyl 5-{2-[(tert-butoxy)carbonylamino]ethyl}-1,2,4-oxadiazole-3-carboxylate (3a)

[0081]

[0082] Amidoxime 2a (46.6 g, 0.353 mol) in dry pyridine (100 ml) is added dropwise to a room temperature solution of crude anhydride 1a in dry pyridine (300 ml.) The reaction mixture is then refluxed for 6 hours. During this time, the reaction is monitored by TLC on silica gel using ether / hexanes (2:1) as the eluent. Upon consumption of the starting material, the reaction mixture is cooled to room temperature and then water (200 ml) is added. The solvent is evaporated in vacuo, and the resulting residue is dissolved in methylene chloride (300 ml) and washed sequentially with water (200 ml), saturated sodium bicarbonate (3×100 ml) and brine (100 ml). The organic phase is dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product. The crude product is then filtered through a pad of silica gel using hexanes / ether (2:1) as the eluent t...

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Abstract

Disclosed are efficient and scalable processes for preparing 1,2,4- and 1,3,4-oxadiazole carboxylates from readily available starting materials.

Description

BACKGROUND OF THE INVENTION [0001] 1. Field of the Invention [0002] This invention relates to an efficient and scalable process for preparing 1,2,4- and 1,3,4-oxadiazole carboxylates from readily available starting materials. [0003] 2. Description of the Related Art [0004] Oxadiazoles are widely used as ester and amide bioisosteres. They are also useful as antiviral agents, neuroprotectants, and anti-inflammatory agents. An object of the present invention is to develop an efficient, scalable, and cost effective procedure for preparing multigram quantities of 1,2,4- and 1,3,4-oxadiazole carboxylates from readily available starting materials. [0005] 1,2,4-Oxadiazoles can be prepared by condensing an amidoxime with an acid chloride or an acid anhydride. A limitation of this method is the availability of the starting amidoxime, which is usually prepared by treating a substituted oximyl chloride the highly toxic and caustic ammonia gas. This method also requires the use of expensive star...

Claims

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Application Information

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IPC IPC(8): C07D271/06C07D271/10
CPCC07D271/10C07D271/06
Inventor KOLB, HARTMUTH C.KANAMARLAPUDI, RAMANAIAH C.RICHARDSON, PAUL F.
Owner KOLB HARTMUTH C