阅读说明：本技术 制备氰基乙酸酯方法 (Process for preparing cyanoacetic acid esters ) 是由 C·达菲 J·奥沙利文 C·戈夫 U·法里德 J·拉莫斯 M·塔伊特伦金 I·科沃卡德内 于 2020-04-17 设计创作，主要内容包括：本发明涉及使用天冬酰胺作为氰基乙酰胺的前体制备氰基乙酸酯的方法,氰基乙酰胺是形成氰基乙酸酯的原料。(The present invention relates to a process for preparing cyanoacetic esters using asparagine as a precursor to cyanoacetamide, which is a starting material for forming cyanoacetic esters.)

1. A process for the preparation of cyanoacetate esters comprising the steps of:

(a) contacting asparagine with a halogenating agent in an acidic environment to form cyanoacetamide;

(b) optionally, isolating the cyanoacetamide thus formed therefrom;

(c) contacting the cyanoacetamide so formed with an alcohol in the presence of a mineral acid to form a cyanoacetate ester;

(d) optionally, isolating the cyanoacetate so formed therefrom.

2. The process of claim 1, wherein step (a) is carried out under suitable conditions and for a time sufficient to produce cyanoacetamide.

3. The process of claim 1, wherein step (c) is carried out under suitable conditions and for a time sufficient to produce a cyanoacetate.

4. The process of claim 1, wherein step (b) produces cyanoacetamide substantially free of halogenating agent and acid and by-products.

5. The process of claim 1, wherein step (d) produces a cyanoacetate ester that is substantially free of cyanoacetamide, alcohol, and mineral acid and by-products.

6. The method of claim 1, wherein the cyanoacetate ester is cyanoacetic acid C_1-20Alkyl esters, cyanoacetic acid C_6-20Aryl esters, cyanoacetic acid C_7-20Alkylaryl esters or cyanoacetic acids C_7-20Aralkyl esters, any of which may be substituted by one or more hydroxy groups or C_1-20Alkyl ether groups.

7. The method of claim 1, wherein the cyanoacetate ester is cyanoacetic acid C_1-20Alkyl esters, wherein C_1-20Alkyl groups may be straight-chain or branched, contain one or more points of unsaturation and may be substituted and/or interrupted by one or more heteroatoms or heteroatom-containing groups, or by halogen-containing groups.

8. The method of claim 1, wherein the cyanoacetate ester is cyanoacetic acid C selected from_1-20Alkyl ester: methyl cyanoacetate, ethyl cyanoacetate, propyl cyanoacetate, butyl cyanoacetate, pentyl cyanoacetate, octyl cyanoacetate, alkoxy ether alkyl cyanoacetate, allyl cyanoacetate, and combinations thereof.

9. The method of claim 1, wherein the cyanoacetate ester is cyanoacetic acid C selected from phenyl cyanoacetate_6-20An aryl ester.

10. The process of claim 1 wherein said cyanoacetate is selected from the group consisting of phenethyl cyanoacetate, cyanoacetic acidCyanoacetic acid C of benzyl ester or toluyl cyanoacetate_7-20An aralkyl ester.

11. The method of claim 1, wherein the halogenating agent is selected from the group consisting of trihaloisocyanuric acid, an N-halosuccinimide, a hypochlorite salt, and an N-halo-p-toluenesulfonamide salt.

12. The process of claim 1 wherein the halogenating agent is selected from tribromoisocyanuric acid or trichloroisocyanuric acid.

13. The method of claim 1, wherein the halogenating agent is selected from N-chlorosuccinimide or N-bromosuccinimide.

14. The method of claim 1, wherein the halogenating agent is selected from sodium hypochlorite or calcium hypochlorite.

15. The method of claim 1 wherein the halogenating agent is selected from the group consisting of sodium salt of N-chloro-p-toluenesulfonamide.

16. The method of claim 1, wherein the acidic environment of step (a) is due to the addition of a citrate buffer.

17. The method of claim 1, wherein the acidic environment of step (a) is due to the addition of a citrate phosphate buffer.

18. The method of claim 1, wherein the alcohol is an alkyl alcohol, an aryl alcohol, an alkaryl alcohol, or an aralkyl alcohol.

19. The process of claim 1 wherein the alcohol is selected from the group consisting of methanol, ethanol, propanol, propiolic alcohol, butanol, pentanol, hexanol, octanol, nonanol, oxanonanol, decanol, dodecanol, alanol, cyclohexanol, tetrahydrofurfuryl alcohol, chloroethanol, 2,2, 2-trifluoroethanol, hexafluoroisopropanol, alkoxy ether alkanols, dialkylsiloxanols or trialkylsilyl alkanols.

20. The method of claim 1, wherein the alcohol is an aromatic alcohol.

21. The method of claim 1, wherein the alcohol is selected from phenol, benzyl alcohol, or derivatives thereof.

22. The process of claim 1, wherein the inorganic acid used in step (c) is selected from the group consisting of sulfuric acid, sulfurous acid, sulfonic acid, phosphoric acid, phosphorous acid, phosphonic acid, hydrochloric acid, and hydrobromic acid.

23. The process of claim 22, wherein the mineral acid is used in step (c) in an amount of about 0.5 to about 1.5 equivalents relative to about 1 equivalent of cyanoacetamide.

24. The process of claim 22, wherein the mineral acid is used in step (c) in an amount of about 0.6 to about 1.2 equivalents relative to about 1 equivalent of cyanoacetamide.

25. The process of claim 1, wherein the alcohol in step (c) is used in excess relative to either or both of the cyanoacetamide and the mineral acid.

26. The method of claim 1, wherein the cyanoacetate is formed in an amount of about 70% or more.

27. The method of claim 1, wherein the cyanoacetate is formed in an amount of about 90% or more.

28. The method of claim 1, wherein step (b) is substantially free of asparagine, halogenating agent, and by-products.

29. The process of claim 1, wherein step (d) is substantially free of cyanoacetamide, mineral acid, and/or alcohol and by-products.

Technical Field

The present invention relates to a process for preparing cyanoacetic esters using asparagine as a precursor of cyanoacetamide, which is a starting material for forming cyanoacetic esters.

Background

Cyanoacrylate adhesives are known for their ability to quickly bond and adhere to a variety of substrates. They are sold as "supersize" type adhesives. They are useful as general purpose adhesives because they are one-part adhesives, are very economical because only small amounts are needed, and generally do not require any equipment to effect cure.

Traditionally, cyanoacrylate monomers are prepared by Knoevenagel condensation reactions between formaldehyde precursors (e.g., paraformaldehyde) and alkyl cyanoacetates with basic catalysts. During the reaction, cyanoacrylate monomers are formed and polymerized in situ to form a prepolymer. The prepolymer is then thermally cracked or depolymerized to produce cyanoacrylate monomers. While various modifications and variations have been introduced, this approach remains substantially unchanged over time. See, for example, U.S. patent nos. 6,245,933, 5,624,699, 4,364,876, 2,721,858, 2,763,677, and 2,756,251. Thus, one use of cyanoacetate esters can be seen in the formation of cyanoacrylates.

Vijayalakshmi et al, j.ad.sci.technol.,4,9,733(1990) describe some methods of synthesizing cyanoacetates and corresponding cyanoacrylates, including preparation from chloroacetic acid and their esters by subsequent reaction with sodium cyanide.

Guseva et al, Russian chem.Bull.,42,3,478(1993) describe functionalized cyanoacetates, many of which are used in the subsequent synthesis of the corresponding cyanoacrylates. [ see also Guseva et al, Russian chem. Bull.,43,4,595(1994), and Goloblov and Gruber, Russian chem.Rev.,66,11,953 (1997). Cyanoacetates with siliconized functional groups have been described. See, e.g., Senchenya et al, Russian chem. ball., 42,5,909(1993), and european patent document No. EP 0459617.

It would be desirable to find an alternative synthetic method for the preparation of cyanoacetates, particularly if such method uses readily available and inexpensive starting materials. It would be further desirable if such a process produced the target cyanoacetate in high yield, was easy to isolate, and used starting materials that were at least considered safe.

Disclosure of Invention

At a high level, the process of the invention provides for the preparation of cyanoacetic esters by the steps comprising:

(a) contacting asparagine with a halogenating agent in an acidic environment to form cyanoacetamide;

(b) optionally, isolating the cyanoacetamide thus formed therefrom;

(c) contacting the cyanoacetamide so formed with an alcohol in the presence of a mineral acid to form a cyanoacetate ester;

(d) optionally, isolating the cyanoacetate so formed therefrom. The optional first separation step (b)) should produce cyanoacetamide substantially free of halogenating agent and acid and by-products. The optional second separation step (d)) should produce a cyanoacetate ester that is substantially free of cyanoacetamide, alcohol, and mineral acid and by-products. Steps (a) and (c) should be carried out under appropriate conditions for a time sufficient to produce cyanoacetamide and cyanoacetate, respectively.

Detailed description of the preferred embodiments

As described above, the present invention provides a process for preparing a cyanoacetate ester, comprising the steps of:

(a) contacting asparagine with a halogenating agent in an acidic environment to form cyanoacetamide;

(b) optionally, isolating the cyanoacetamide thus formed therefrom;

(c) contacting the cyanoacetamide so formed with an alcohol in the presence of a mineral acid to form a cyanoacetate ester;

(d) optionally, isolating the cyanoacetate so formed therefrom. The optional first separation step (b)) should produce cyanoacetamide substantially free of halogenating agent and acid and by-products. The optional second separation step (d)) should produce a cyanoacetate ester that is substantially free of cyanoacetamide, alcohol, and mineral acid and by-products. Steps (a) and (c) should be carried out under appropriate conditions for a time sufficient to produce cyanoacetamide and cyanoacetate, respectively.

The cyanoacetic acid ester formed by the process of the invention may be cyanoacetic acid C_1-20Alkyl esters, cyanoacetic acid C_6-20Aryl esters, cyanoacetic acid C_7-20Alkylaryl esters or cyanoacetic acids C_7-20Aralkyl esters, any of which may be substituted by one or more hydroxy groups or C_1-20Alkyl ether groups.

More specifically, the cyanoacetate may be cyanoacetic acid C_1-20Alkyl esters, wherein C_1-20Alkyl groups may be straight-chain or branched, contain one or more points of unsaturation and may be substituted and/or interrupted by one or more heteroatoms or heteroatom-containing groups (such as trimethylsilylalkyl groups, such as methyl, ethyl or propyl), or by halogen-containing groups. For example, the cyanoacetate ester may be the following ester of cyanoacetic acid: methyl ester, ethyl ester, propyl ester (such as n-propyl ester or isopropyl ester), propargyl ester, butyl ester (such as n-butyl ester or isobutyl ester), pentyl ester (such as n-pentyl ester or isopentyl ester), hexyl ester, octyl ester (such as n-octyl ester or 2-ethylhexyl ester), nonyl ester, oxononyl ester (oxononyl ester), decyl ester, dodecyl ester, allyl ester, acetylene ester, butenyl ester, cyclohexyl ester, tetrahydrofurfuryl ester, chloroethyl ester, 2,2, 2-trifluoroethyl ester, hexafluoroisopropyl ester, alkoxyether alkyl cyanoacetate (such as methoxymethyl ester, methoxyethyl ester, methoxybutyl ester, ethoxyethyl ester, propoxyethyl ester, butoxymethyl ester or butoxyethyl ester), and dimethylsiloxy ester of 2-cyanoacetic acid. But such statements are by no means exhaustive.

The cyanoacetate may also be cyanoacetic acid C_6-20An aryl ester, a carboxylic acid ester,such as phenyl cyanoacetate.

Alternatively, the cyanoacetate may be cyanoacetic acid C_7-20Aralkyl esters, for example phenylethyl cyanoacetate, benzyl cyanoacetate or toluyl cyanoacetate.

In carrying out the process, the cyanoacetamide is formed from asparagine in step (a) and then becomes the starting material or precursor for the cyanoacetate.

Asparagine should be used in an amount of about 1 equivalent. The term "equivalent" is intended to cover molar equivalents, whenever used herein.

The halogenating agent used in the process of the present invention may be selected from the group consisting of trihaloisocyanuric acid, N-halosuccinimide, hypochlorite and N-halo-p-toluenesulfonamide salt.

When the halogenating agent is a trihaloisocyanuric acid, the halogenating agent may be selected from tribromoisocyanuric acid or trichloroisocyanuric acid ("TCCA").

When the halogenating agent is an N-halosuccinimide, the halogenating agent may be selected from N-chlorosuccinimide or N-bromosuccinimide.

When the halogenating agent is hypochlorite, the halogenating agent may be selected from sodium hypochlorite or calcium hypochlorite.

When the halogenating agent is an N-halo-p-toluenesulfonamide salt, the halogenating agent may be N-chloro-p-toluenesulfonamide sodium salt.

The halogenating agent should be used in an amount of about 0.5 to about 5 equivalents, for example about 1 to about 2.5 equivalents, based on 1 equivalent of asparagine.

The halogenating agent and asparagine react in an acidic environment. An acidic environment may be created by adding an acidic buffer solution. I.e. an acidic buffer solution having a pH of less than 7 and typically made from a salt of a weak acid and a weak acid (which may be the same or different from the weak acid used). Thus, citric acid and citric acid sodium salt will be acidic buffer solutions. Ideally, disodium hydrogen phosphate may be used in combination with citric acid.

The cyanoacetamide thus formed may be isolated or used in situ. The yield of cyanoacetamide should be greater than about 70%, e.g., close to quantitative.

When the cyanoacetate is formed from cyanoacetamide, the cyanoacetamide should be used in an amount of about 1 equivalent, from which the other reactants can be determined.

An alcohol is used to perform the esterification of step (c). The selected alcohol may be an alkanol, an aromatic alcohol, an alkaryl alcohol or an aralkyl alcohol. The identity of the alcohol selected will depend on the desired cyanoacetate to be prepared. Thus, if it is sought to prepare the corresponding respective alkyl cyanoacetates, the alcohol may be selected from methanol, ethanol, propanol (e.g. isopropanol), propiolic alcohol (propargols), butanol (e.g. isobutanol), pentanol (e.g. isoamyl alcohol), hexanol, octanol, nonanol, oxanonanol, decanol, dodecanol, alanol, cyclohexanol, tetrahydrofurfuryl alcohol, chloroethanol, 2,2, 2-trifluoroethanol, hexafluoroisopropanol, alkoxy ether alkanols (e.g. methoxymethanol, methoxyethanol, methoxybutanol, ethoxyethanol, propoxyethanol, butoxymethanol or butoxyethanol), dialkylsiloxanols (e.g. dimethylsilanol or diethylsiloxanol), trialkylsilyl alkanols (e.g. trimethylsilylcarbinol, trimethylsilylethanol or trimethylsilylpropanol). Alternatively, if the alcohol of choice is an aromatic alcohol, such as phenol, benzyl alcohol, or derivatives thereof, the corresponding aryl cyanoacetate will be formed.

The alcohol should be used in an amount of about 2.5 to about 25 equivalents, for example about 5 to about 10 equivalents, desirably about 5 to about 7.5 equivalents, as compared to 1 equivalent of cyanoacetamide.

The inorganic acid used in the process of the present invention may be selected from sulfuric acid, sulfurous acid, sulfonic acid, phosphoric acid, phosphorous acid, phosphonic acid, hydrochloric acid or hydrobromic acid.

The inorganic acid should be used in an amount of about 0.5 to about 1.5 equivalents relative to about 1 equivalent of cyanoacetamide, for example about 0.6 to about 1.2 equivalents relative to about 1 equivalent of cyanoacetamide, desirably about 0.6, about 0.9 or about 1.2 equivalents relative to about 1 equivalent of cyanoacetamide.

The alcohol should be used in excess relative to one or both of the cyanoacetamide and the mineral acid.

In the process of the present invention, cyanoacetate esters are formed in a yield of about 70% or greater, for example about 90% or greater.

Although the reaction times are given generally above, the times can be monitored by reference to the desired product using NMR spectroscopy, as described in the examples. The reaction time can be adjusted depending on the characteristics of the specific reactants, the scale of the reaction and whether the reaction conditions are heated or not.

For the optional steps of (b) and/or (d), the cyanoacetate may be isolated using suitable separation and/or isolation techniques.

The following examples are intended to illustrate, but in no way limit, the present invention.

Examples

We use j.leThe reaction conditions reported in Green chem, 13,807-09(2011) refer to glutamic acid oxidative decarboxylation, using N-bromosuccinimide as the halogenating agent and a phosphate-saline buffer at pH of about 5 to form cyanoacetamide, according to the following synthetic scheme:

cyanoacetamide was formed in about 80% yield without isolation of the product.

Example 1

To a stirred solution of L-asparagine (3.0 g, 20 mmol, 1.0 eq) in phosphate buffer (made of citric acid and disodium hydrogen phosphate) (90mL) at pH 5 was slowly added a solution of NBS (10.7 g, 60 mmol, 3.0 eq) in DMF (20 mL). The reaction mixture was stirred at room temperature overnight and quenched with sodium thiosulfate until colorless. Pure NMR results indicated that the desired product had formed with a peak at 3.38ppm and an estimated conversion of about 80%.

Example 2

We used the reaction conditions reported in Z. -L.Wu et al, Tetrahedron: Asymmetry,14,2133-42(2003) for the esterification of amides of cyanoacetamides, the synthetic scheme is as follows:

applying the synthesis conditions of Z.L.Wu to obtain the cyanoethyl acetate. The yields varied as shown in the table below. The sulfuric acid equivalent weight varied with the reaction time of the last example. Table 1 below shows each of the six entries, with 1 equivalent of cyanoacetamide (30 g) and 5.75 equivalents of ethanol (94.5 g).

TABLE 1

From entries 3-5, it can be seen that only those having about 70% or higher are within the scope of the method of the present invention. Thus, to obtain the desired yield, a range of mineral acids from about 0.6 to about 1.2 is considered significant.

Confirmation of ethyl cyanoacetate formation was obtained by NMR spectroscopic analysis.