阅读说明：本技术 制备氰基乙酸酯的方法 (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：本发明涉及使用氰基乙酰胺作为前体制备氰基乙酸酯的方法。(The present invention relates to a process for preparing cyanoacetic acid esters using cyanoacetamide as a precursor.)

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

(a) contacting cyanoacetamide with an alcohol in the presence of a mineral acid under suitable conditions for a time sufficient to produce a cyanoacetate ester;

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

2. 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.

3. The method of claim 1, wherein the cyanoacetate ester is cyanoacetic acid C_1-20Alkyl esters, wherein C_1-20Alkyl groups may 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.

4. 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.

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

6. The method of claim 1, wherein the cyanoacetate ester is a cyanoacetic acid C selected from phenethylcyanoacetate, benzyl cyanoacetate, or toluoyl cyanoacetate_7-20An aralkyl ester.

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

8. 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.

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

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

11. The method of claim 1, wherein the inorganic acid is sulfuric acid, sulfurous acid, sulfonic acid, phosphoric acid, phosphorous acid, phosphonic acid, hydrochloric acid, or hydrobromic acid.

12. The process of claim 1 wherein the inorganic acid is used in an amount of about 0.5 to about 1.5 equivalents relative to about 1 equivalent of cyanoacetamide.

13. The process of claim 1 wherein the inorganic acid is used in an amount of about 0.6 to about 1.2 equivalents relative to about 1 equivalent of cyanoacetamide.

14. The process of claim 1 wherein the alcohol is used in excess of either or both of the cyanoacetamide and the mineral acid.

15. The method of claim 1, wherein cyanoacetate is formed in an amount of about 70% or greater.

16. The method of claim 1, wherein cyanoacetate is formed in an amount of about 90% or greater.

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

Technical Field

The present invention relates to a method for preparing cyanoacetic acid esters using cyanoacetamide as a precursor.

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 used as general-purpose adhesives because they are one-component adhesives, are very economical because only small amounts are needed, and generally do not require any equipment to effect curing.

Traditionally, cyanoacrylate monomers are prepared by Knoevenagel condensation reactions between formaldehyde precursors (such as paraformaldehyde) and alkyl cyanoacetates with basic catalysts. In 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. This approach remains substantially consistent over time, although various modifications and variations have been introduced. 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, it can be seen that one use of cyanoacetates is for 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 its esters by subsequent reaction with sodium cyanide.

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

The preparation of mono-, di-, tri-and tetra-functional cyanoacetates has been described, although it is useful as a curing agent for epoxy resins for adhesive applications. Renner et al, "Cure of Epoxy Resins with Esters of Cyanoacrylic Acid", J.Polym.Sci, Polym.chem.Ed.,23,2341(1985) and U.S. Pat. Nos. 4,202,920 and 4,512,357.

Despite the state of the art, it would be desirable to find alternative synthetic methods for the preparation of cyanoacetates, particularly if such methods use 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 present invention provides for the preparation of cyanoacetic esters by the steps comprising:

(a) contacting cyanoacetamide with an alcohol in the presence of a mineral acid under suitable conditions for a time sufficient to produce a cyanoacetate ester;

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

The separation step should produce a cyanoacetate ester that is substantially free of cyanoacetamide, alcohol, mineral acid, and by-products.

Detailed Description

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

(a) contacting cyanoacetamide with an alcohol in the presence of a mineral acid under suitable conditions for a time sufficient to produce a cyanoacetate ester;

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

The separation step should produce a cyanoacetate ester that is substantially free of cyanoacetamide, alcohol, mineral acid, and by-products.

The cyanoacetic acid ester formed by the process of the invention may be cyanoacetic acid C_1-20An alkyl ester,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, oxynonyl ester, decyl ester, dodecyl ester, allyl ester, acetylene ester, butenyl ester, cyclohexyl ester, tetrahydrofurfuryl ester, chloroethyl ester, 2,2, 2-trifluoroethyl ester, hexafluoroisopropyl ester, alkoxy ether 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 this list is by no means exhaustive.

Ideally, the cyanoacetate ester so formed should be 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.

The cyanoacetate may also be cyanoacetic acid C_6-20Aryl esters, such as phenyl cyanoacetate.

Alternatively, the cyanoacetate may be cyanoacetic acid C_7-20Aralkyl esters such as phenylethyl cyanoacetate, benzyl cyanoacetate and toluyl cyanoacetate, to name a few.

In carrying out the process, cyanoacetamide is a starting material or precursor for a cyanoacetate ester.

The cyanoacetamide may be cyanoacetamide itself or a derivative thereof. Cyanoacetamide derivatives include mono-or di-substituted cyanoacetamides, wherein the substituents may be alkyl, alkenyl, alkynyl or aryl. For example, alkyl substituted cyanoacetamides include methyl, ethyl, propyl or butyl substituted cyanoacetamides; aryl substituted cyanoacetamides include phenyl cyanoacetamide or benzyl cyanoacetamide. The substituted cyanoacetamides may also have halogen or hydroxy substitution thereon. Commercially available examples of such cyanoacetamide derivatives include, for example, N-diethyl-2-cyanoacetamide.

The cyanoacetamide should be used in an amount of about 1 equivalent, and other reactants may be used according to the amount. Whenever used herein, the term "equivalent" is intended to cover molar equivalents.

Performing the esterification of step (a) using an alcohol. 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 the desired product.

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.

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, 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 starting material.

The alcohol should be used in excess of either 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 broadly given above, the times can be monitored by reference to the formation of the desired product using NMR spectroscopy, as described in the examples. The reaction time can be adjusted depending on the identity (identity) of the particular reactants, the scale of the reaction and whether the reaction conditions are heated.

For the optional step of (b), suitable separation and/or isolation techniques may be used to obtain the cyanoacetate.

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

Examples

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.