Process for the preparation of cyanoacetic acid esters

Abstract

The present invention relates to a method for producing a cyanoacetate, which method involves contacting a salt of an alkyl formyl acetate, an alkenyl formyl acetate, an alkynyl formyl acetate, or an aryl formyl acetate with a hydroxyamine under appropriate conditions and for a time sufficient to produce the cyanoacetate.

Description

[0001] background Technical Field

[0002] The present invention relates to a method for producing a cyanoacetate, which method involves contacting a salt of an alkyl formyl acetate, an alkenyl formyl acetate, an alkynyl formyl acetate, or an aryl formyl acetate with a hydroxyamine under appropriate conditions and for a time sufficient to produce the cyanoacetate. Background Art

[0003] Cyanoacrylate adhesives are known for their ability to bond quickly and to adhere to a wide variety of substrates. They are marketed as "super glue" type adhesives. They are used as general purpose adhesives because they are one component adhesives, are very economical (as only a small amount will suffice), and generally do not require any equipment to achieve curing.

[0004] Traditionally, cyanoacrylate monomers have been produced by a Knoevenagel condensation reaction between a formaldehyde precursor (such as paraformaldehyde) and an alkyl cyanoacetate in the presence of a basic catalyst. During the reaction, the cyanoacrylate monomer is formed and polymerized in situ to form a prepolymer. The prepolymer is then thermally cracked or depolymerized to produce the cyanoacrylate monomer. Although various improvements and variations have been introduced, the process has remained essentially unchanged over time. See e.g. US 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 to form cyanoacrylates.

[0005] Vijayalakshmi et al., J.Ad.Sci.Technol. , 4,9,733 (1990) describes several processes for the synthesis of cyanoacetic acid esters and the corresponding cyanoacrylates which are prepared from chloroacetic acid and its esters by subsequent reaction with sodium cyanide.

[0006] Guseva et al., Russian Chem.Bull. , 42, 3, 478 (1993) describes functionalized cyanoacetates, many of which are used in the subsequent synthesis of the corresponding cyanoacrylates. See also Guseva et al., RussianChem.Bull. ,43,4,595(1994) and Golobolv and Gruber, Russian Chem. Rev. , 66, 11, 953 (1997)]. Cyanoacetic acid esters having silanized functional groups have been described. See e.g.Senchenya et al., Russian Chem.Bull. ,42,5,909(1993) and European Patent Document No. EP 0 459 617.

[0007] The preparation of monofunctional cyanoacetates, difunctional cyanoacetates, trifunctional cyanoacetates, and tetrafunctional cyanoacetates (although as curing agents for epoxy resins for adhesive applications) has been described. Renner et al., "Cure of Epoxy Resins with Esters of Cyanoacrylic Acid", J.Polym.Sci., Polym.Chem.Ed. ,23,2341(1985) and U.S. Patent Nos. 4,202,920 and 4,512,357.

[0008] It would be desirable to find alternative synthetic methods for preparing cyanoacetic acid esters, particularly if such methods used readily available and inexpensive starting materials. It would be even more desirable if such methods produced the subject cyanoacetic acid esters in high yields and were easily isolated. Summary of the invention

[0009] At a high level, the process of the present invention provides for the preparation of cyanoacetic acid esters. In one aspect, the process uses two steps. The first step is to contact an alkyl, alkenyl, alkynyl or aryl acetate with an alkyl, alkenyl, alkynyl or aryl formate in the presence of a base for a time sufficient to form a salt of an alkyl, alkenyl, alkynyl or aryl formyl acetate. The second step is to contact the salt of the alkyl, alkenyl, alkynyl or aryl formyl acetate so formed with a hydroxylamine under appropriate conditions for a time sufficient to produce the cyanoacetic acid ester.

[0010] Optionally, after one or each of these steps, a separation step may be performed. After the first step, the salt of the alkyl, alkenyl, alkynyl or aryl formyl acetate thus formed may be separated from the reactants and / or any by-products. After the second step, the cyanoacetate thus formed may be separated from the reactants and / or any by-products.

[0011] More specifically, and in particularly desirable embodiments, the first step is to react ethyl formate with an alkyl acetate (such as ethyl acetate) in the presence of a base (such as sodium or potassium hydride or sodium or potassium alkoxide) under appropriate conditions for a time sufficient to produce ethyl 3-oxopropionate enolate. The enolate may optionally be isolated prior to use in forming ethyl cyanoacetate. Whether or not isolated, the ethyl 3-oxopropionate enolate may be reacted with ammonium hydroxide hydrochloride to produce ethyl cyanoacetate.

[0012] In another aspect, the process of the invention can be carried out in a single step. Here, an alkyl, alkenyl, alkynyl or aryl acetate is contacted with an alkyl, alkenyl, alkynyl or aryl formate under alkaline conditions for a time sufficient to form a salt of an alkyl, alkenyl, alkynyl or aryl formyl acetate, and thereafter hydroxylamine is mixed therewith under appropriate conditions for a time sufficient to produce a cyanoacetate.

[0013] Alternatively, in another aspect, the process of the present invention may be carried out in one step, wherein a salt of an alkyl formyl acetate, an alkenyl formyl acetate, an alkynyl formyl acetate or an aryl formyl acetate is contacted with a hydroxyamine acid under appropriate conditions and for a time sufficient to produce a cyanoacetate, and optionally, the cyanoacetate so formed is separated therefrom. DETAILED DESCRIPTION

[0014] As described above, in one aspect, the present invention provides a method for preparing a cyanoacetic acid ester, the steps of the method comprising:

[0015] (a) contacting an alkyl, alkenyl, alkynyl or aryl acetate with an alkyl, alkenyl, alkynyl or aryl formate in the presence of a base for a period of time sufficient to form a salt of an alkyl, alkenyl, alkynyl or aryl formyl acetate;

[0016] (b) optionally isolating therefrom the salt of the alkyl, alkenyl, alkynyl or aryl formyl acetate thus formed;

[0017] (c) contacting an alkyl formyl acetate, an alkenyl formyl acetate, an alkynyl formyl acetate or an aryl formyl acetate with a hydroxyamine under appropriate conditions and for a period of time sufficient to produce a cyanoacetate;

[0018] (d) optionally isolating therefrom the cyanoacetic acid ester thus formed.

[0019] The alkyl acetate, alkenyl acetate, alkynyl acetate or aryl acetate may be selected from any one or more of the following: the following alkyl acetates: methyl acetate, ethyl acetate, propyl acetate, butyl acetate, pentyl acetate, hexyl acetate, heptyl acetate or octyl acetate, to name a few; the following alkenyl acetates: such as allyl acetate; the following alkynyl acetates: such as ethynyl acetate; or the following aryl acetates: phenyl acetate, benzyl acetate or phenylethyl acetate, to name a few.

[0020] The alkyl acetate, alkenyl acetate, alkynyl acetate or aryl acetate should be used in an amount of about 0.5 to about 5 (eg, about 1 to about 3.5) molar equivalents.

[0021] The alkyl formate, alkenyl formate, alkynyl formate or aryl formate is selected from: methyl formate, ethyl formate, propyl formate, butyl formate, pentyl formate, hexyl formate, heptyl formate or octyl formate, to name a few; from the following alkenyl formates: for example allyl formate; from the following alkynyl formates: for example acetylene formate; or from the following aryl formates: phenyl formate, benzyl formate or phenylethyl formate, to name a few.

[0022] The alkyl formate, alkenyl formate, alkynyl formate, or aryl formate should be used in an amount of about 0.5 to about 2.0 molar equivalents.

[0023] The base used in step (a) above should be a Group I metal cation (such as sodium or potassium) associated with an anion (such as a hydride or an alkoxide (such as a methoxy or ethoxy)).

[0024] The base should be used in an equimolar amount to an excess amount relative to either or both of the alkyl, alkenyl, alkynyl or aryl acetate and the alkyl, alkenyl, alkynyl or aryl formate, respectively.

[0025] Suitable conditions may include the use of an organic polar solvent, such as an organic polar aprotic solvent. A desirable choice of such solvent is an ether, such as a dialkyl ether (eg, diethyl ether) or a cyclic ether (eg, tetrahydrofuran).

[0026] The reaction time and reaction temperature can vary from as little as about 1 hour (or even less) at elevated temperature conditions (e.g., above about 60° C. (e.g., about 100° C.) to about overnight (e.g., about 18 to about 24 hours) at lower temperatures (e.g., about room temperature) without providing an additional heat source.

[0027] The alkyl, alkenyl, alkynyl or aryl formyl acetate formed in step (a) above (and optionally separated in step (b) above) may be selected from: methyl formyl acetate, ethyl formyl acetate, propyl formyl acetate, butyl formyl acetate, pentyl formyl acetate, hexyl formyl acetate, heptyl formyl acetate, octyl formyl acetate, allyl formyl acetate, propargyl formyl acetate, phenyl formyl acetate, phenylethyl formyl acetate or benzyl formyl acetate, to name a few.

[0028] In order to form a cyanoacetate from any of these alkyl formyl acetates, alkenyl formyl acetates, alkynyl formyl acetates or aryl formyl acetates, hydroxyamine should be used.

[0029] The hydroxylamine acid may be selected from hydroxylamine hydrochloride, hydroxylamine sulfur dioxide, hydroxylamine sulfate, and combinations thereof.

[0030] The amount of hydroxylamine may be less than about equimolar or greater than about equimolar relative to the alkyl formyl acetate, alkenyl formyl acetate, alkynyl formyl acetate, or aryl formyl acetate. As little as about 0.25 to less than one-half molar equivalent of hydroxylamine may be used, and as much as about 1.5 molar equivalents of hydroxylamine may be used.

[0031] The reaction should be carried out under acidic conditions. For this purpose, an inorganic acid (such as hydrochloric acid) or an organic acid (such as acetic acid) should be used. The amount of acid should be sufficient to reduce the pH to less than 7, such as less than about 4, desirably less than about 3, more desirably less than about 2.

[0032] Suitable conditions may include the use of an organic polar solvent, such as an organic polar protic solvent. Desirable choices for such solvents are alcohols (such as methanol and ethanol).

[0033] Reaction times and reaction temperatures can vary from as little as about 1 hour (or even less) at elevated temperature conditions (eg, about 90°C) to about overnight (eg, about 18 to about 24 hours) at that temperature.

[0034] The cyanoacetate formed in this manner may be cyanoacetic acid C 1-20 Alkyl esters, cyanoacetic acid C 6-20 Aryl ester, cyanoacetic acid C 7-20 Alkyl ester or cyanoacetic acid C 7-20 Any of the arylalkyl esters, any of which may be replaced by one or more hydroxyl groups or C 1-20 For example, the cyanoacetic acid ester formed can be cyanoacetic acid C 1-20 Alkyl ester, wherein the C 1-20The alkyl group may be straight 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 substituted or interrupted by halogen or halogen-containing groups (e.g., trimethylsilylalkyl, such as methyl, ethyl or propyl), or substituted or interrupted by halogen or halogen-containing groups.

[0035] Thus, the cyanoacetate may be methyl cyanoacetate, ethyl cyanoacetate, propyl cyanoacetate (e.g. n-propyl cyanoacetate or isopropyl cyanoacetate), propargyl cyanoacetate, butyl cyanoacetate (e.g. n-butyl cyanoacetate or isobutyl cyanoacetate), pentyl cyanoacetate (e.g. n-pentyl cyanoacetate or isopentyl cyanoacetate), hexyl cyanoacetate, octyl cyanoacetate (e.g. n-octyl cyanoacetate or 2-ethylhexyl cyanoacetate), nonyl cyanoacetate, oxynonyl cyanoacetate, decyl cyanoacetate, dodecyl cyanoacetate , allyl cyanoacetate, acetylene cyanoacetate, butylene cyanoacetate, cyclohexyl cyanoacetate, tetrahydrofurfuryl cyanoacetate, chloroethyl cyanoacetate, 2,2,2-trifluoroethyl cyanoacetate, hexafluoroisopropyl cyanoacetate, alkyl cyanoacetate alkoxyethers (such as methoxymethyl cyanoacetate, methoxyethyl cyanoacetate, methoxybutyl cyanoacetate, ethoxyethyl cyanoacetate, propoxyethyl cyanoacetate, butoxymethyl cyanoacetate or butoxyethyl cyanoacetate) and dimethylsiloxane esters of 2-cyanoacetic acid. However, this list is not exhaustive.

[0036] Cyanoacetate can also be cyanoacetic acid C 6-20 Aryl esters (eg phenyl cyanoacetate).

[0037] Alternatively, the cyanoacetate may be a cyanoacetic acid C selected from phenylethyl cyanoacetate, benzyl cyanoacetate or toluoyl cyanoacetate. 7-20 Arylalkyl esters.

[0038] The separation step(s) should produce a product that is substantially free of reactants and by-products.

[0039] In another aspect, a method for preparing cyanoacetic acid esters is provided, comprising a step. The steps of the method comprise:

[0040] The salt of an alkyl formyl acetate, alkenyl formyl acetate, alkynyl formyl acetate or aryl formyl acetate is contacted with a hydroxyamine acid under appropriate conditions and for a time sufficient to produce a cyanoacetate. Optionally, the cyanoacetate so formed can be isolated therefrom.

[0041] In yet another aspect, a method for preparing cyanoacetic acid esters is provided comprising a step. The steps of the method comprise:

[0042] Alkyl acetate, alkenyl acetate, alkynyl acetate or aryl acetate is contacted with alkyl formate, alkenyl formate, alkynyl formate or aryl formate in the presence of a base for a time sufficient to form a salt of alkyl formyl acetate, alkenyl formyl acetate, alkynyl formyl acetate or aryl formyl acetate, and thereafter hydroxylamine is mixed therewith under appropriate conditions for a time sufficient to produce a cyanoacetate. Optionally, the cyanoacetate so formed can be separated therefrom.

[0043] Here, as described above, the alkyl formyl acetate, alkenyl formyl acetate, alkynyl formyl acetate or aryl formyl acetate is selected from methyl formyl acetate, ethyl formyl acetate, propyl formyl acetate, butyl formyl acetate, pentyl formyl acetate, hexyl formyl acetate, heptyl formyl acetate, octyl formyl acetate, allyl formyl acetate, propargyl formyl acetate, phenyl formyl acetate, phenylethyl formyl acetate or benzyl formyl acetate.

[0044] As mentioned above, cyanoacetate is cyanoacetic acid C 1-20 Alkyl esters, cyanoacetic acid C 6-20 Aryl ester, cyanoacetic acid C 7-20 Alkyl ester or cyanoacetic acid C 7-20 Arylalkyl esters, any of which may be replaced by one or more hydroxyl groups or C 1-20 Alkyl ether group substituted. 1-20 The alkyl group 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 substituted or interrupted by halogen or halogen-containing groups.

[0045] Thus, the cyanoacetic acid ester may be selected from the group consisting of: 1-20 Alkyl esters: methyl cyanoacetate, ethyl cyanoacetate, propyl cyanoacetate, butyl cyanoacetate, pentyl cyanoacetate, octyl cyanoacetate, alkyl cyanoacetate alkoxy ether, allyl cyanoacetate, and combinations thereof. Alternatively, the cyanoacetate may be C cyanoacetate 6-20 Aryl ester (such as phenyl cyanoacetate). Cyanoacetate can also be a cyanoacetic acid C selected from phenylethyl cyanoacetate, benzyl cyanoacetate or toluoyl cyanoacetate. 7-20 Arylalkyl esters.

[0046] Process step (b) [or step (b) and step (d)] should be substantially free of reactants and / or by-products.

[0047] Although reaction times are given generally above, times can be monitored by reference to the formation of the desired product using NMR spectroscopy, as indicated in the Examples. Reaction times can be adjusted depending on the identity of the specific reactants, the scale of the reaction and whether heat is added to the reaction conditions.

[0048] The following examples are intended to illustrate the present invention but are in no way intended to limit the present invention.

[0049] Example

[0050] Embodiment 1:

[0051] Two-step reaction

[0052] A. Synthesis of Sodium Enolate from Ethyl Formylacetate (EFA) and Ethyl Acetate (EA)

[0053]

[0054] In being equipped with reflux exchanger and N2 balloon inert atmosphere through oven-dried 1L three-necked flask, add alkali (for example, sodium hydride, sodium methoxide or sodium ethoxide or its potassium counterpart).The organic solvent that comprises ethyl acetate is added with or without other solvent (for example, diethyl ether or THF), then at room temperature in the time period of 10 minutes, drip ethyl formate (or methyl formate).The suspension diethyl ether (being 50mL for 35mmol alkali) of gained is diluted, after this, is filtered and washed and vacuum-dried with diethyl ether (50mL) again, to obtain the enolate of off-white solid form. 1 H-NMR (60MHz, D2O): δ8.63 (br, 1H), 4.08 (q, J = 7.2Hz, 2H), 1.23 (t, J = 7.2Hz, 3H).

[0055] Table 1

[0056] Optimization of reaction conditions for the formation of sodium enolate salt

[0057]

[0058] In Table 1, the preliminary reactions are recorded as using sodium hydride as the base (entries 1-5). Although the reaction was successful when THF was used as the solvent (entry 1), the yield was poor. When diethyl ether was used as the solvent, the yield increased and the salt was isolated (entry 2). When excess sodium hydride was used as the base under concentrated reaction conditions (2.9 M), the yield of the salt increased (entry 5).

[0059] Sodium ethoxide was also used as a base instead of sodium hydride. Although the initial results with ethanol or acetonitrile as solvent were not satisfactory (entries 6 and 7), the salt was isolated in moderate yield with diethyl ether as solvent (56%, entry 10). When ethyl acetate was used, the reaction produced similar yields (55%, entry 11).

[0060] B. Synthesis of ECnA from Sodium Enolate

[0061]

[0062] In an oven-dried 500 mL round-bottom flask equipped with a reflux condenser and a N2 balloon, sodium enolate (10.0 g) was added, followed by solvent and NH2OH salt. The reaction mixture was heated to reflux for 10 minutes, and then Bronsted acid was added dropwise until the desired pH was reached. The reaction mixture was further refluxed, and then cooled to room temperature. The solid was filtered, washed with ethanol, and the combined filtrate was evaporated in a rotary evaporator to obtain a crude product. 50.0 mL of distilled water was added to the crude product, and then extracted with chloroform (3×50 mL). The chloroform extract was washed with distilled water (2×50 mL), and then with brine (2×50 mL), after which the extract was dried and evaporated with Na2SO4 to obtain a crude product, which was then purified by vacuum distillation (kettle temperature=60°C, crosshead temperature=35°C, 0.45 mbar). 1 H NMR (60MHz, CDCl3): δ4.18 (q, J=6.6Hz, 2H), 3.42 (s, 2H), 1.24 (t, J=6.6Hz, 3H).

[0063] Table 2

[0064] Optimization of reaction conditions for ECnA formation

[0065]

[0066] When a mixture of enolate and hydroxylamine hydrochloride (excess) was heated to reflux under acidic conditions in anhydrous ethanol, ethyl cyanoacetate was isolated in 69% yield after extraction with chloroform and water (entry 4). When equimolar amounts of hydroxylamine hydrochloride were used, the yield increased to 81% (entry 5). The yield of ethyl cyanoacetate also increased when excess solvent was used (see entries 5 and 6).

Claims

1. A method for preparing cyanoacetic acid esters, the steps of the method comprising: (a) contacting an alkyl, alkenyl, alkynyl or aryl acetate with an alkyl, alkenyl, alkynyl or aryl formate in the presence of a base for a period of time sufficient to form a salt of an alkyl, alkenyl, alkynyl or aryl formyl acetate; (b) optionally isolating therefrom the salt of the alkyl, alkenyl, alkynyl or aryl formyl acetate so formed; (c) contacting the salt of the alkyl, alkenyl, alkynyl or aryl formyl acetate so formed with 0.25 to 1.5 molar equivalents of a hydroxylamine acid for a period of time sufficient to produce the cyanoacetate under appropriate conditions, wherein the conditions include a pH below 7 and the use of an alcohol as a solvent, wherein the hydroxylamine acid is selected from hydroxylamine hydrochloride or hydroxylamine sulfur trioxide; (d) optionally isolating therefrom the cyanoacetic acid ester thus formed.

2. The method of claim 1, wherein the conditions of step (a) are contained in an organic polar solvent or an organic polar protic solvent.

3. The method of claim 1, wherein the conditions of step (a) comprise room temperature.

4. The method of claim 1, wherein the alkyl acetate, alkenyl acetate, alkynyl acetate or aryl acetate is selected from methyl acetate, ethyl acetate, propyl acetate, butyl acetate, pentyl acetate, hexyl acetate, heptyl acetate, octyl acetate, allyl acetate, propargyl acetate, phenyl acetate, phenylethyl acetate or benzyl acetate.

5. The method of claim 1, wherein the alkyl formate, alkenyl formate, alkynyl formate or aryl formate is selected from methyl formate, ethyl formate, propyl formate, butyl formate, pentyl formate, hexyl formate, heptyl formate, octyl formate, allyl formate, propargyl formate, phenyl formate, phenylethyl formate or benzyl formate.

6. The method of claim 1, wherein the alkaline conditions are formed by sodium hydride, potassium hydride, sodium alkoxide, potassium alkoxide, and combinations thereof.

7. The method of claim 1, wherein the salt of the alkyl formyl acetate, alkenyl formyl acetate, alkynyl formyl acetate or aryl formyl acetate is selected from the sodium or potassium salt of the enol structure of methyl formyl acetate, ethyl formyl acetate, propyl formyl acetate, butyl formyl acetate, pentyl formyl acetate, hexyl formyl acetate, heptyl formyl acetate, octyl formyl acetate, allyl formyl acetate, propargyl formyl acetate, phenyl formyl acetate, phenylethyl formyl acetate or benzyl formyl acetate.

8. The method of claim 1, wherein the cyanoacetate is cyanoacetic acid C 1-20 Alkyl esters, cyanoacetic acid C 6-20 Aryl ester, cyanoacetic acid C 7-20 Alkyl ester or cyanoacetic acid C 7-20 Arylalkyl esters, any of which may be replaced by one or more hydroxyl groups or C 1-20 Alkyl ether group substitution.

9. The method of claim 1, wherein the cyanoacetate is cyanoacetic acid C 1-20 Alkyl ester, wherein the C 1-20 The alkyl group 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 substituted or interrupted by halogen or halogen-containing groups.

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

11. The method of claim 1, wherein the cyanoacetate is cyanoacetic acid C 6-20 Aryl esters.

12. The method of claim 1, wherein the cyanoacetate is phenyl cyanoacetate.

13. The method of claim 1, wherein the cyanoacetate is a cyanoacetic acid C selected from phenylethyl cyanoacetate, benzyl cyanoacetate or toluoyl cyanoacetate. 7-20 Arylalkyl esters.

14. The process of claim 1, wherein step (b) is substantially free of starting materials and / or by-products.

15. The process of claim 1, wherein step (d) is substantially free of starting materials and / or by-products.

16. A method for preparing a cyanoacetic acid ester, the steps of the method comprising: (i) contacting a salt of an alkyl formyl acetate, alkenyl formyl acetate, alkynyl formyl acetate or aryl formyl acetate with 0.25 to 1.5 molar equivalents of a hydroxylamine acid for a period of time sufficient to produce a cyanoacetate under appropriate conditions, wherein the conditions include a pH below 7 and the use of an alcohol as a solvent, wherein the hydroxylamine acid is selected from hydroxylamine hydrochloride or hydroxylamine sulfur trioxide; (ii) optionally isolating therefrom the cyanoacetic acid ester thus formed.

17. A method for preparing a cyanoacetic acid ester, the steps of the method comprising: (i) contacting an alkyl, alkenyl, alkynyl or aryl acetate with an alkyl, alkenyl, alkynyl or aryl formate in the presence of a base for a time sufficient to form a salt of an alkyl, alkenyl, alkynyl or aryl formyl acetate, followed by mixing 0.25 to 1.5 molar equivalents of a hydroxylamine acid therewith under appropriate conditions for a time sufficient to produce a cyanoacetate, wherein the conditions include a pH below 7 and the use of an alcohol as a solvent, wherein the hydroxylamine acid is selected from hydroxylamine hydrochloride or hydroxylamine sulfur trioxide; (ii) optionally isolating therefrom the cyanoacetic acid ester thus formed.

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