WO1992012962A1 - Process for the production of cyanoacetic acid - Google Patents

Process for the production of cyanoacetic acid Download PDF

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Publication number
WO1992012962A1
WO1992012962A1 PCT/US1992/000588 US9200588W WO9212962A1 WO 1992012962 A1 WO1992012962 A1 WO 1992012962A1 US 9200588 W US9200588 W US 9200588W WO 9212962 A1 WO9212962 A1 WO 9212962A1
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Prior art keywords
caa
cada
cah
oxidation
acid
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PCT/US1992/000588
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French (fr)
Inventor
A. Ray Bulls
Jere D. Fellmann
Roy A. Periana
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Catalytcca Inc.
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Priority to JP4505430A priority Critical patent/JPH06507154A/en
Publication of WO1992012962A1 publication Critical patent/WO1992012962A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00Carboxylic acid nitriles
    • C07C255/01Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/19Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and carboxyl groups, other than cyano groups, bound to the same saturated acyclic carbon skeleton

Definitions

  • Especially preferred partially oxidized propionitrile compounds include cyanoacetaldehyde (CA), its hydrate (CAH) or acetal (CADA). Suitable oxidants include oxygen, ozone, hydrogen peroxide, peracids, nitrites, and the like.
  • the partially oxidized propionitrile compound is preferably produced from acrylonitrile.
  • An optional step is the esterification of the cyanoacetic acid.
  • the current technology for the preparation of CAA involves the reaction of chloroacetic acid (or its ester) with NaCN. Although this technology has been practiced commercially for some time, it suffers from high cost due to the chloroacetic acid and the environmental concerns surrounding the use of NaCN.
  • CAA is of interest since it has application as a raw material for the pharmaceutical and specialty chemical industry. It can also be used for the preparation of mafonic acid and its esters, which acids and esters are also used in the synthesis of pharmaceuticals.
  • CAA or its esters can be made from ACN.
  • Smidt teaches (Angew. Chem., 71. Jahr. 1959, Nr. 19, p 626) that ACN can be oxidized by PdCI 2 to 2-ketopropionitrile.
  • Lioyd suggests (US 3,410,807) that oxidation of ACN in an alcoholic media produces CADA but fails to exemplify it further.
  • CADA is the acetal of cyanoacetaldehyde (CA), not 2-ketopropionitrile.
  • Hosokawa et. al. (Bull. Chem. Soc. Jpn., 63, 166-169, 1990 and Ace. Chem.
  • ACN can be oxidized to the corresponding cyclic acetal in a 1 ,3-propandiol/DME media using a PdCI 2 (CH 3 CN) 2 with CuCl 2 or BiCI 3 -LiCI as a co-catalyst.
  • Ube also shows in two independent and non-related disclosures that ACN can be oxidized to the acetal of cyanoacetic acid (CADA) using alkylnitrite esters (US 4,504,422) and CADA can be oxidized to CAE using hydroxylamine as a stoichiometric oxidant (US 4,438,041).
  • CADA cyanoacetic acid
  • US 4,438,041 alkylnitrite esters
  • Hydroxylamine is not a conventional oxidant. Hydroxylamine is typically used in combination with aldehydes in their conversion to the corresponding nitrite. Ube, consequently, was apparently attempting to prepare malononrtrile from C
  • Especially preferred partially oxidized propionitrile compounds include
  • cyanoacetaldehyde CA
  • CAH cyanoacetaldehyde
  • CADA acetal
  • Suitable oxidants include oxygen, ozone, hydrogen peroxide, peracids, nitrites, and the like.
  • the partially oxidized propionitrile compound is preferably produced from acrylonftriie.
  • An optional step is the esterification of the product cyanoacetic acid. This overall reaction scheme is outlined as follows:
  • oxidation of partially oxidized propionitrile compounds with oxygen, ozone, peracids (RCOOOH, where R is H or C n H n+2 ), alkyl nitrites (RONO, where R is C n H n+2 ) and hydrogen peroxide or mixtures thereof requires the stoichiometric use of the oxidant.
  • An especially preferred oxidant is an equimolar combination of carboxylic acids (RCOOH), particularly formic acid (HCOOH) and hydrogen peroxide. This combination forms peracids (RCOOOH), including performic acid (HCOOOH) when formic acid is the carboxylic acid is the acid, in situ.
  • CAA is also easliy converted to the ester by acid catalyzed hydrolysis using alcohols.
  • Suitable acids include strong mineral acids such as H 2 SO 4 , glacial acetic acid, HCI, etc. Sulfuric acid is easpecially preferred because of its cost and ready acailability but others are suitable. Strong acidic ion exchange resins (Dowex, Amberlyst, etc.) are also suitable.
  • the reaction may be carried out in an appropriate solvent such as toluene, benzene, and similar materials. Toluene is a desirable solvent since it is tolerant of the strong acid catalyst and (when
  • ethylcyanoacetate is the product of ethanol and CAA) may be separated from the reaction mixture by distillation of an azeotrope of
  • oxidation catalysts such as Wacker-type catalysts (PdCI 2 /CuCI 2 ), FeCI 3 PdCI 2 , Na 2 PdCl 4 , HPA's (especially H5PMo10V25O40), platinum group metals and their salts (palladium, platinum, rhodium, ruthenium, iridium, ond osmium and the halides, sulfates, nitrates, phosphates, and acetates thereof) or other soluble oxidation catalysts in a suitable polar reaction media (H 2 O; short chain alcohols, (CH 3 OH to C 12 H 25 OH) such as methanol, ethanol, propanol, isopropanol, etc.; ethers, aldehydes, etc.) will result in oxidation catalysts in a suitable polar reaction media (H 2 O; short chain alcohols, (CH 3 OH to C 12 H 25 OH) such as methanol, ethanol, propan
  • the oxidants used in this step may the same as those used in the step of oxidizing the partially oxodixzed propionitrile to CAA, e.g., oxygen, ozone, peracids (RCOOOH, where R is H or C n H n+2 ), alkyl nitrites
  • the Pd and co-catalyst were added to a 300 cc autoclave.
  • the total volume of reactants, diluents, feedstocks, and catalysts was about 150 cc.
  • the pressure varied between atmospheric and 100 psi.
  • the materials were added to the reactor, the reactor was heated to the reaction temperature, stirring at 1000-2000 rpm was commenced, and samples were periodically taken.
  • the feedstocks, catalysts, and solvents were added to a glass reactor having magnetic stirring.
  • the total volume was about 30 cc.
  • thermometer A stream of O 3 (0.08 to 2%) in oxygen or air was generated with a Polymetrics ozone generator and passed through the solution (at 200-2000 cc/min) with stirring at a temperature between 0# and 25#C. The progress of the reaction was monitored via high pressure liquid chromatography.
  • a solution of CAH in H 2 O or acetic acid (typically from 1 to 10% CAH by weight) was added to a 100 cc stainless steel reactor equipped with an internal stirrer, a sample port, and an external heating jacket.
  • Acid e.g., H s4
  • the appropriate catalyst was then added to the solution to a concentration between 10 and 100mM.
  • Oxygen or air was charged to the reactor to a pressure of 5 to 100 psig.
  • the solution was heated to a temperature of 50-120# C with stirring. Samples of the reaction solution were collected periodically and the progress of the reaction was determined by high pressure liquid chromatography.
  • the ethyl ester of CAA was added to an aqueous solution with H 2 SO 4 and heated to 55# C for 16 hr.
  • CAA was dissolved with the acid in absolute ethanol and refluxed for eight hours.
  • the following examples illustrate the oxidation of ACN to CA derivatives, CADA, CAH and RACN.
  • Examples 4-5 Oxidation of ACN to CADA using Na 2 PdCl 4 /CuCl 2 in EtOH/water media. This example shows the use of this catalyst in EtOH/water media.
  • Example 6 Oxidation of ACN to CAH using Na 2 PdCl 4 /CuCl 2 in
  • Examples 7-8 Oxidation of ACN using Na 2 PdCI 4 /HPA In alcoholic media.
  • Example 10 Oxidation of ACN to CAA using PdCI 2 /CuCl 2 in water.
  • This example shows the one-step oxidation of ACN to CAA.
  • Example 16 Hydrolysis of methyl-CADA using liquid acids.
  • Example 17 Hydrolysis of ethoxyacrylonitrile (EACN).
  • Example 18 Oxidation of CAH using ozone.
  • Examples 20 and 21 oxidation of CA and derivatives using hydrogen peroxide alone or In combination with carboxylic acids.
  • Example 23 Oxidation of CAH with oxygen using various free radical initiation catalysts.
  • Example 24 Oxidation of CAH with oxygen using a non-free radical catalysts (Na 2 PdCl 4 /HPA).
  • Example 25 Oxidation of CAH with oxygen using a non-free radical cataivsts ( Na 2 PdCl 4 /CuCl 2 ).
  • Example 26 Hydrolysis of ethyl ester of CAA.
  • Example 27 Esterification of CAA with ethanol.
  • the reactant (CACA, CAH, or CADA) was dissolved in an appropriate solvent (H 2 O or glacial acetic acid) and loaded into a 250 cc 3-neck Morton flask equipped with a magnetic stir bar and thermometer.
  • An appropriate solvent H 2 O or glacial acetic acid
  • the progress of the reaction was monitored by high pressure liquid chromatography.
  • the aqueous carboxylic acid (formic, CAA, or acetic acid), was loaded in a 500 cc 3-neck Morton flask equipped with an overhead mechanical stirrer and a reflux condensor. Additional acid (i.e. H 2 SO 4 ) can be added to the solvent to increase the acidity.
  • Additional acid i.e. H 2 SO 4
  • Equimolar amounts of substrate i.e. CADA or EtOACN [EACN]
  • 50% H 2 O 2 were fed into the stirred solution over a period of 1 to 6 hours at 40#C to 60#C.
  • the solution was stirred an additional 1-2 hours at temperature.
  • the product mixture was determined by high pressure liquid chromatography and GC analysis.
  • the feed material (CAH, CACA, or CADA), H 2 O, and H 2 SO 4 were added to a 100 cc 3-neck Morton flask equipped with a mechanical stir bar. Approximately 1 equivalent of hydrogen peroxide was charged into the solution with stirring. The temperature of the solution was kept between 25°C and 60°C. The solution was stirred an additional 1-2 hours at temperature. The product mixture was determined by high pressure liquid chromatography and GC analysis.
  • CAH ca. 10 mol% which can likely be recovered and recycled.
  • a small amount of CAA-ester ca. ⁇ 1%) and CO 2 was also detected.
  • a minor byproduct may be formic acid.
  • formic acid was the major constituent in the solvent, it was impossible to accurately quantify any small increase.
  • CAA-ester (ca. 3%) which may represent additionai yield of CAA.
  • H 2 O 2 utilization was found to be 86%.
  • H 2 O 2 utilization was obtained by comparing the mole ratio of CAA (produced)/H 2 O 2 (initial) against the CAA yield. Approximately 70 to 80 % of the H 2 O 2 was utilized for the production of CAA. There was still evidence of active peroxide after 5.5 hours, suggesting that the reaction had not come to completion.
  • the CAA yield was also found to be H 2 O 2 concentration dependent.
  • the yield of CAA peaked at a H 2 O 2 solution concentration of about 1.6 wt %.
  • the utilization dropped and the CO 2 production increased.
  • the reaction rate decreased giving lower CAA yields after the same reaction time.
  • the actual H 2 O 2 concentration in the reaction media was only about 1 to 2 wt %.
  • the carboxylic acid used to generate the peracid in-situ can also be varied. We have demonstrated the use of not only formic but acetic and CAA acids in combination with hydrogen peroxide. The table below shows examples of these results using various CA derivatives.
  • Oxygen or air was charged to the reactor to a pressure of 5 to 100 psig. The solution was heated to a temperature of 50 to 120#C with stirring. Samples of the reaction solution were collected periodically and the progress of the reaction was determined by high pressure liquid chromatography.
  • This example investigated the use of free radical initiation catalysts in aqueous and acetic acid solvents.
  • the table details the results of some of the experiments from the free radical initiated oxidation of CAH to CAA using oxygen.
  • the metal catalyzed oxidation of aldehydes is carried out commercially in a carboxylic acid solvent utilizing the free aldehyde and not the hydrate. Since water is a more convenient solvent for our process we attempted to find a water based oxidation catalyst for this conversion. Using either a manganese or cobalt catalyst, in water, has thus far led to complete oxidation of the CAH. However, using a heteropolyacid (HPA) as the catalyst provided the improved results shown in Table 1. This suggests that the HPA is acting as a free radical initiator but is much milder than either manganese or cobalt.
  • HPA heteropolyacid

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

This is a process for preparing cyanoacetic acid (CAA) or its esters by further oxidizing a partially oxidized propionitrile compound of the following formula: N}C-CHx-CHy-AB, where A is -H, -OH, or -OR; and B is -OH, -OR, or = O; x=1 or 2, y=0 or 1 (depending upon the selection of A and B); but where B is =O, A is -H, and x=0; and where y=1, x=0, B is -OH or -OR. Especially preferred partially oxidized propionitrile compounds include cyanoacetaldehyde (CA), its hydrate (CAH) or acetal (CADA). Suitable oxidants include oxygen, ozone, hydrogen peroxide, peracids, nitrites, and the like. The partially oxidized propionitrile compound is preferably produced from acrylonitrile. An optional step is the esterification of the cyanoacetic acid.

Description

PROCESS FOR THE PRODUCTION OF CYANOACETIC ACID
Field of the Invention
This is a process for preparing cyanoacetic acid (CAA) or its esters by further oxidizing a partially oxidized propionitrile compound of the following formula:
N) C-CHx-CHy-AB where A is -H, -OH, or -OR; and B is -OH, -OR, or =O; x=1 or 2, y=0 or 1 (depending upon the selection of A and B); but where B is =0, A is - H, and x=0; and where y=1, x=0, B is -OH or -OR. Especially preferred partially oxidized propionitrile compounds include cyanoacetaldehyde (CA), its hydrate (CAH) or acetal (CADA). Suitable oxidants include oxygen, ozone, hydrogen peroxide, peracids, nitrites, and the like. The partially oxidized propionitrile compound is preferably produced from acrylonitrile. An optional step is the esterification of the cyanoacetic acid.
Background of the Invention
The current technology for the preparation of CAA involves the reaction of chloroacetic acid (or its ester) with NaCN. Although this technology has been practiced commercially for some time, it suffers from high cost due to the chloroacetic acid and the environmental concerns surrounding the use of NaCN.
CAA is of interest since it has application as a raw material for the pharmaceutical and specialty chemical industry. It can also be used for the preparation of mafonic acid and its esters, which acids and esters are also used in the synthesis of pharmaceuticals.
The art does not teach that CAA or its esters can be made from ACN. Smidt teaches (Angew. Chem., 71. Jahr. 1959, Nr. 19, p 626) that ACN can be oxidized by PdCI2 to 2-ketopropionitrile. In contrast, Lioyd suggests (US 3,410,807) that oxidation of ACN in an alcoholic media produces CADA but fails to exemplify it further. CADA is the acetal of cyanoacetaldehyde (CA), not 2-ketopropionitrile. In agreement with Lioyd, Hosokawa et. al. (Bull. Chem. Soc. Jpn., 63, 166-169, 1990 and Ace. Chem. Res., 23(2),49-54, 1990) shows that ACN can be oxidized to the corresponding cyclic acetal in a 1 ,3-propandiol/DME media using a PdCI2(CH3CN)2 with CuCl2 or BiCI3-LiCI as a co-catalyst. Ube also shows in two independent and non-related disclosures that ACN can be oxidized to the acetal of cyanoacetic acid (CADA) using alkylnitrite esters (US 4,504,422) and CADA can be oxidized to CAE using hydroxylamine as a stoichiometric oxidant (US 4,438,041). Hydroxylamine is not a conventional oxidant. Hydroxylamine is typically used in combination with aldehydes in their conversion to the corresponding nitrite. Ube, consequently, was apparently attempting to prepare malononrtrile from CADA.
It is important to point that several potential intermediates in our process have been prepared by indirect means. Ube teaches (J 57-0,203,052) that CADA can be hydrolyzed to CA using an acid catalyst. There are several references (US 4,277,418, DE 3,641,604, DE 3,222,519, DE
3,211,679, JP 83-26,855, JP 58-26,855) which teach either the conversion of CADA to the corresponding alkoxyacrylonitrile (ROCH=CHCN) or vice versa. Additionally, CA is commonly obtained from ACN as the acetal (CADA). Typically a PdCI2/CuCI2 catalyst in an alcoholic media has been used.
CH2=CHCN + 1/2 O2 + 2 ROH - - -> (RO)2CHCH2CN (ACN) (CADA)
The only reported oxidation of a cyanoacetaldehyde we have found has come from Ube. There, it was reported that CADA can be oxidized to CAA-ester (CAE) by reaction with hydroxylamine:
(RO)2CHCH2CN + HONH2 - - -> ROCOCH2CN
The oxidation of aldehydes or acetals by oxygen and of acetlas by ozone and peracids has been described but never with a deactivated acetal such as CADA.
None of the prior art shows the oxidation of the listed partially oxidized propionitrlile compounds to directly produce CAA. The prior art similarly does not show the combination of theat step with either the esterification of the CAA to its ester or the production of the listed partially oxidized propionitrlile compounds from ACN.
Summary of the Invention
This is a process for preparing cyanoacetic acid (CAA) or its esters by further oxidizing a partially oxidized propionitrile compound of the following formula:
N) C-CHx-CHy-AB where A is -H, -OH, or -OR; and B is -OH, -OR, or =O; x=1 or 2, y=0 or 1 (depending upon the selection of A and B); but where B is =O, A is -
H, and x=0; and where y=1, x=0, and B is -OR or -OH. Especially preferred partially oxidized propionitrile compounds include
cyanoacetaldehyde (CA), its hydrate (CAH) or acetal (CADA). Suitable oxidants include oxygen, ozone, hydrogen peroxide, peracids, nitrites, and the like. The partially oxidized propionitrile compound is preferably produced from acrylonftriie. An optional step is the esterification of the product cyanoacetic acid. This overall reaction scheme is outlined as follows:
[O] [O] esterify
ACN - - - - - - - - > CAH - - - - - - - > CAA - - - - - - - - - -> ECA
CA CADA RACN CADA/CAH.
Description of the Invention
This is a process for preparing cyanoacetic acid [CAA] (or it esters) by further oxidizing a partially oxidized propionitrile compound of the following formula:
N) C-CHx-CHy-AB where A is -H, -OH, or -OR; and B is -OH, -OR, or =O; x=1 or 2, y=0 or 1 (depending upon the selection of A and B); but where B is =O, A is - H, and x=0; and where y=1, x=0, and B is not =O, with selected oxidants. Especially preferred partially oxidized propionitrile compounds include cyanoacetaldehyde (CA), its hydrate (CAH) or acetal (CADA). Additionally, the inventive process includes the optional steps of:
a.) producing the partially oxidized propionitrile by oxidizing acetonitrile (ACN), and
b.) esterifiying the product CAA to produce alkylcyanoacetates. Oxidation of Partially oxidized propionitrile compounds
The oxidation of partially oxidized propionitrile compounds with oxygen, ozone, peracids (RCOOOH, where R is H or CnHn+2), alkyl nitrites (RONO, where R is CnHn+2) and hydrogen peroxide or mixtures thereof requires the stoichiometric use of the oxidant. An especially preferred oxidant is an equimolar combination of carboxylic acids (RCOOH), particularly formic acid (HCOOH) and hydrogen peroxide. This combination forms peracids (RCOOOH), including performic acid (HCOOOH) when formic acid is the carboxylic acid is the acid, in situ.
In the case of ozone, we have some evidence that it has been used catalytically in combination with oxygen but not with CA. This invention deals only with the use of stoichiometric ozone as an oxidant. The use of oxygen is quite novel since oxygen is a considerably less potent oxidant than a peroxide or peracid is.
The oxidative conversion of either CAH or CADA to CAA or ECA is generally described in the following equations:
N) C-CH2-CH-(OH)2 + [O] - - -> N) C-CH2-C-OOH N) C-CH=CH-(OH) + [O] - - -> N) C-CH2-C-OOH N) C-CH2-CH-(OR)2 + [0] - - -> N) C-CH2-C-OOR N) C-CH=CH-(OR) + [O] - - -> N) C-CH2-C-OOR
Conversion of CAA to the corresponding ester
CAA is also easliy converted to the ester by acid catalyzed hydrolysis using alcohols.
N) C-CH2-COOH + ROH - - -> N) C-CH2-C-OOR + H2O where R is CnH2n +1. Suitable acids include strong mineral acids such as H2SO4, glacial acetic acid, HCI, etc. Sulfuric acid is easpecially preferred because of its cost and ready acailability but others are suitable. Strong acidic ion exchange resins (Dowex, Amberlyst, etc.) are also suitable. The reaction may be carried out in an appropriate solvent such as toluene, benzene, and similar materials. Toluene is a desirable solvent since it is tolerant of the strong acid catalyst and (when
ethylcyanoacetate is the product of ethanol and CAA) may be separated from the reaction mixture by distillation of an azeotrope of
H2O/ethanol/toluene.
Formation of partially oxidized propionitrile bv oxidation of acetonitrile Acetonitrilθ is a fairly inexpensive feedstock. Using any of a variety of oxidation catalysts such as Wacker-type catalysts (PdCI2/CuCI2), FeCI3 PdCI2, Na2PdCl4, HPA's (especially H5PMo10V25O40), platinum group metals and their salts (palladium, platinum, rhodium, ruthenium, iridium, ond osmium and the halides, sulfates, nitrates, phosphates, and acetates thereof) or other soluble oxidation catalysts in a suitable polar reaction media (H2O; short chain alcohols, (CH3OH to C12H25OH) such as methanol, ethanol, propanol, isopropanol, etc.; ethers, aldehydes, etc.) will result in oxidation of the ACN to the partially oxidized propionitrile compound described above: N) C-CHx-CHy-AB. The catalyst need be present in a catalytic amount which often is between 1 ppm and 10% by weight of the catalyst in the solution.
The oxidants used in this step may the same as those used in the step of oxidizing the partially oxodixzed propionitrile to CAA, e.g., oxygen, ozone, peracids (RCOOOH, where R is H or CnHn+2), alkyl nitrites
(RONO, where R is CnHn+2) and hydrogen peroxide or mixtures thereof. The invention has been disclosed by direct description. Below may be found a number of examples showing various aspects of the invention. The examples are only examples of the invention and are not to be used to limit the scope of the invention in any way.
EXAMPLES
Procedures
In examples 1-8, the Pd and co-catalyst were added to a 300 cc autoclave. The total volume of reactants, diluents, feedstocks, and catalysts was about 150 cc. The pressure varied between atmospheric and 100 psi. The materials were added to the reactor, the reactor was heated to the reaction temperature, stirring at 1000-2000 rpm was commenced, and samples were periodically taken.
In example 9, the feedstocks, catalysts, and solvents were added to a glass reactor having magnetic stirring. The total volume was about 30 cc.
In examples 11-17, the various feeds (ethyl-CADA, methyl-CADA, or ethoxyacrylonitrile), acid, and H2O were added to round bottom flasks. The flasks were heated under reduced pressure to remove the alcohol as formed. The yield and purity of the aqueous solutions was
determined by high pressure liquid chromatography.
In examples 18 and 19, the reactants (CACA or CAH) were dissolved in an appropriate solvent (H2O or glacial acetic acid) and loaded into a 250 cc 3-neck Morton flask equipped with a magnetic stir bar and
thermometer. A stream of O3 (0.08 to 2%) in oxygen or air was generated with a Polymetrics ozone generator and passed through the solution (at 200-2000 cc/min) with stirring at a temperature between 0# and 25#C. The progress of the reaction was monitored via high pressure liquid chromatography.
In examples 20-22, water or aqueous carboxylic acid was loaded into a 500 cc 3-neck Morton flask equipped with an overhead mechanical stirrer and a reflux condenser. Addition acid was used to increase the acidity. Equimoiar amounts of substrate (CADA or EACN) and 50% H2O2 were fed into the stirred solution over a period of 1 to 6 hours at 40#-6Q#C. The solution was stirred an additional 1-2 hours at temperature. The product mixture was analyzed using high pressure liquid chromatography and GC analysis.
In examples 23-25, a solution of CAH in H2O or acetic acid (typically from 1 to 10% CAH by weight) was added to a 100 cc stainless steel reactor equipped with an internal stirrer, a sample port, and an external heating jacket. Acid (e.g., Hs4) was added to the solution as needed to help stabilize the CAH. The appropriate catalyst was then added to the solution to a concentration between 10 and 100mM. Oxygen or air was charged to the reactor to a pressure of 5 to 100 psig. The solution was heated to a temperature of 50-120# C with stirring. Samples of the reaction solution were collected periodically and the progress of the reaction was determined by high pressure liquid chromatography.
In example 26, the ethyl ester of CAA was added to an aqueous solution with H2SO4 and heated to 55# C for 16 hr.
In example 27, CAA was dissolved with the acid in absolute ethanol and refluxed for eight hours. The following examples illustrate the oxidation of ACN to CA derivatives, CADA, CAH and RACN.
Examples 1-3: Oxidation of ACN using Na2PdCl4/CuCl2 in alcoholic media.-
These examples show the use of this catalyst with a variety of alcohols to make CADA and CAH.
Figure imgf000011_0001
Examples 4-5: Oxidation of ACN to CADA using Na2PdCl4/CuCl2 in EtOH/water media. This example shows the use of this catalyst in EtOH/water media.
Figure imgf000011_0002
Example 6: Oxidation of ACN to CAH using Na2PdCl4/CuCl2 in
Figure imgf000011_0003
Examples 7-8: Oxidation of ACN using Na2PdCI4/HPA In alcoholic media.
These examples show the use of this catalyst with a variety of alcohols to make CADA and CAH.
Figure imgf000012_0001
Example 9: Oxidation of ACN to CADA using PdCI2 and EtONO in EtOH.
Figure imgf000012_0002
Example 10: Oxidation of ACN to CAA using PdCI2/CuCl2 in water.
This example shows the one-step oxidation of ACN to CAA.
Figure imgf000012_0003
Examples 11-15: Hydrolysis of ethyl-CADA using various acids.
These examples show the hydrolysis of CADA and alkoxyacrylonitrile to CAH.
Figure imgf000013_0001
(All reactions were conducted at 70# C for 75 minutes under 200 mm Hg. The reduced pressure was used to remove the EtOH as it formed in order to drive the equilibrium to favor CAH formation.)
Example 16: Hydrolysis of methyl-CADA using liquid acids.
Figure imgf000013_0002
Example 17: Hydrolysis of ethoxyacrylonitrile (EACN).
Figure imgf000013_0003
The following examples illustrate the oxidation of CAH or CADA to CAA or CAE using non-oxygen based oxidants (i.e. ozone, peracids, hydrogen peroxide)
Example 18: Oxidation of CAH using ozone.
Figure imgf000014_0002
Example 19: Oxidation of CACA (where CACA = ethylene glycol CADA) using ozone.
Figure imgf000014_0001
Examples 20 and 21: oxidation of CA and derivatives using hydrogen peroxide alone or In combination with carboxylic acids.
Figure imgf000015_0001
Exampie 22- Oxidation of CA and derivatives using hydrogen peroxide in combination with carboxylic acids
Figure imgf000016_0001
The following examples illustrate the oxidation of CAH to CAA using oxygen as the oxidant.
Example 23: Oxidation of CAH with oxygen using various free radical initiation catalysts.
Figure imgf000017_0001
Example 24: Oxidation of CAH with oxygen using a non-free radical catalysts (Na2PdCl4/HPA).
Figure imgf000018_0001
Example 25: Oxidation of CAH with oxygen using a non-free radical cataivsts ( Na2PdCl4/CuCl2).
Figure imgf000018_0002
The following examples illustrate the hydrolysis of CAE and the
esterification of CAA.
Example 26: Hydrolysis of ethyl ester of CAA.
Figure imgf000018_0003
Example 27: Esterification of CAA with ethanol.
Figure imgf000019_0001
Procedures
The following procedures were used in the following examples to oxidize various partially oxidized propionitriles using hydrogen peroxide, ozone, and peracids.
Reactions of O3 with CA equivalents:
The reactant (CACA, CAH, or CADA) was dissolved in an appropriate solvent (H2O or glacial acetic acid) and loaded into a 250 cc 3-neck Morton flask equipped with a magnetic stir bar and thermometer. A stream of O3 (0.08 to 2%) in oxygen (or air) was generated with a Polymetrics ozone generator and passed through the solution (at 200- 2000 cc/min) with stirring at a temperature between 0 and 25#C. The progress of the reaction was monitored by high pressure liquid chromatography.
Reaction of hydrogen peroxide/carboxylic acid with CA equivalents:
The aqueous carboxylic acid (formic, CAA, or acetic acid), was loaded in a 500 cc 3-neck Morton flask equipped with an overhead mechanical stirrer and a reflux condensor. Additional acid (i.e. H2SO4) can be added to the solvent to increase the acidity. Equimolar amounts of substrate (i.e. CADA or EtOACN [EACN]) and 50% H2O2 were fed into the stirred solution over a period of 1 to 6 hours at 40#C to 60#C. The solution was stirred an additional 1-2 hours at temperature. The product mixture was determined by high pressure liquid chromatography and GC analysis.
Reaction of hydrogen peroxide with CA equivalents in H2O:
The feed material (CAH, CACA, or CADA), H2O, and H2SO4 were added to a 100 cc 3-neck Morton flask equipped with a mechanical stir bar. Approximately 1 equivalent of hydrogen peroxide was charged into the solution with stirring. The temperature of the solution was kept between 25°C and 60°C. The solution was stirred an additional 1-2 hours at temperature. The product mixture was determined by high pressure liquid chromatography and GC analysis.
EΞxample 28 Ozone Oxidation of CAH
Ozone reacts with CAH at room temperature to give CAA. The Table below shows results at pH = 1 and low ozone (0.08%) concentration.
Figure imgf000020_0001
We examined the influence of pH and ozone concentration on the CAA yield obtained from the oxidation of CAH by ozone. This was done by setting the desired pH by titration with Na2CO3 or NaHCO3. The ozone concentrations were variable: 2%, 0.4% and 0.08%. The results from these experiments are shown in the following Table.
Figure imgf000021_0001
The five general trends observed are:
╌ The rate of oxidation dramatically increased as a function of both ozone concentration and pH. The fastest rates were observed with the highest ozone concentrations and highest pH.
╌ The selectivity to CAA slightly increased as the ozone concentration decreased.
╌ The selectivity to CAA increased as the pH increased.
╌ Generally, the selectivity to CAA decreased as the conversion increased.
Example 29 Ozone Oxidation of CADA
The open literature shows the oxidation of alkyl and aromatic acetals to the corresponding esters. Although no literature was found describing the oxidation of deactivated acetals such as CADA, it seemed reasonable that the oxidation of CADA was possible only through the use of potent oxidants. It is known that the selectivity to the corresponding ester is somewhat poor with noncyclic acetals (such as those derived from ethanol), whereas the selectivity improves with cyclic acetals (such as those derived from ethyiene glycol). We prepared ethylene glycol-CADA [or the cyclic acetal of cyanoacetaldehyde (CACA), characterized it by NMR and obtained a response factor for high pressure liquid chromatography] for use in ozone oxidation experiments.
Ozonolysis of CACA with a 2 % O3/O2 mixture produced the
corresponding ester. The reaction rate was found to increase
significantly when 2% versus 0.08 % ozone was used. The data show that this is a highly selective reaction below 70% conversion. Above a 70 % conversion level, unidentified products were preferentially formed.
The use of stoichiometric ozone likely would only be considered only if an inexpensive ozone generator were to be available. However, we believe that the hydroxyethyl ester of CAA is difficult to make by any other route.
Example 30 Peracid Oxidation of CADA and CAH
The high yield and fast reaction rate obtained from the oxidation of the acetal with ozone suggested that a more fruitful approach to CAA could potentially be achieved through the oxidation of CADA with peracids. The reaction of peracids with acetals yields the corresponding esters.
The reaction of ethyl-CADA with 30% peracetic acid in acetic acid showed, after 13 hr at ambient temperature, a 12 % selectivity to CAA-ester at 60% conversion. Surprisingly, a large amount (48 % selectivity) of CAA was found in the reaction mixture. Since CADA hydrolyses readily under these conditions this suggested that the small amount of H2O2 and H2O present in peracetie acid must have been responsible for the production of CAA from the intermediacy of CAH. Therefore a new approach was attempted for the conversion of CADA (via CAH) directly into CAA using a mixture of water and a peracid.
To test this concept, an aqueous mixture containing CAH was reacted with an excess amount of 30% peracetie acid. This gave a rapid reaction and high selectivity to CAA (after 1 hr at ambient temperature CAH conversion - 90% with a mol % selectivity to CAA = 77%) was obtained. The increased reaction rate of CAH over CADA (in the absence of added water) suggested that CAH was an intermediate in the oxidation of CADA to CAA.
Example 31 Hydrogen peroxide Oxidation of CADA and CAH
The oxidation of an acetal to a carboxylic acid with hydrogen peroxide or a peracid has little precedence in the literature. Generally, acetals are oxidized with a peracid to the corresponding carboxylic acid ester.
Our data suggest that CADA is first hydrolyzed to CAH which is in turned oxidized by the peracid. The use of the peracid is desired since our control experiments showed that when CAH was oxidized with H2O2 alone, the yields were somewhat lower than with a peracid (mol % seiectivityH2O2 = 50% versus mol % selectivityPeracatic acid = 80%).
An economical way of generating performic acid, in the presence of large amounts of water, is by combining H2O2 and formic acid. Formic acid is commercially available in 96% and 88% aqueous mixtures. Additionally, since it forms an azeotrope with water it can be conveniently distilled to a 77% concentration. We examined both 96% and 77% formic acid in combination with near stoichiometric quantities of H2O2 and found similar results.
We examined the oxidation of CADA in H2O2/formic acid media for the effectiveness of CAA synthesis. Ethyl-CADA reacts cleanly with about one equivalent of H2O2 (1.04 mol H2O2/mol CADA) in 96% formic acid. A small amount of acid catalyst (such as H2SO4 or HCI) can be added to speed the reaction rate at 40#C. Alternatively, simply heating the solution in the absence of added acid to about 60#C results in similar reaction rates (rate was about 1×10-7 mol cc-1 sec-1).
For the H2O2 oxidation of ethyl-CADA at 100 % conversion, the selectivity to CAA was approximately 88 mol % by high pressure liquid
chromatography. The only major byproduct identified was CAH (ca. 10 mol%) which can likely be recovered and recycled. A small amount of CAA-ester (ca. < 1%) and CO2 was also detected. A minor byproduct may be formic acid. However, since formic acid was the major constituent in the solvent, it was impossible to accurately quantify any small increase.
In one experiment, we obtained a crude CAA product (78 % isolated yield) by removal of the solvent and washing with methylene chloride. The melting point was measured at 66-68#C, in accordance with the literature for CAA. The product was analyzed by 1H and 13C NMR and FTIR and compared with standard CAA. We found that the CAA prepared by this procedure was > 99+ % pure by 1H NMR.
Recrystallization of the crude product from ether/heptane afforded 60% of CAA as pure white crystals (mp 66.5-67.5#C). This demonstrated the feasibility of product separation and purification for this step. Similar results have been achieved with methyl-CADA in 77% formic acid. The principle difference appears to be that the rate of hydrolysis of methyl-CADA is approximately 4.5 times slower than the ethyl derivative. In order to achieve a comparable rate, we increased the acid catalyst concentration from ca. 0.2 M to 0.8 M. At 100% conversion of methyl- CADA (reaction time = 200 min) the CAA yield was 84 mol %. The principle byproduct was CAH (which can potentially be recycled).
Another byproduct was CAA-ester (ca. 3%) which may represent additionai yield of CAA. The H2O2 utilization was found to be 86%.
We found that the yield of CAA was a function of the amount of H2O2 present in 77% formic acid. The excess H2O2 needed (1.38 mol
H2O2/mol CADA) to achieve 98 mol % CAA yield was indicative of a less than stoichiometric utilization of the H2O2 in the water-formic acid-performic acid system. Although the highest yields were achievable with the excess H2O2, quite acceptable yields were obtained with
stoichiometric amounts of H2O2 (ca. 82%).
A measure of H2O2 utilization was obtained by comparing the mole ratio of CAA (produced)/H2O2 (initial) against the CAA yield. Approximately 70 to 80 % of the H2O2 was utilized for the production of CAA. There was still evidence of active peroxide after 5.5 hours, suggesting that the reaction had not come to completion.
The CAA yield was also found to be H2O2 concentration dependent. The yield of CAA peaked at a H2O2 solution concentration of about 1.6 wt %. At higher H2O2 concentrations, the utilization dropped and the CO2 production increased. At a low H2O2 concentration the reaction rate decreased giving lower CAA yields after the same reaction time. We have found acceptable results when charging 50 % H2O2 to the reactor. However, after dilution with the reaction solvent the actual H2O2 concentration in the reaction media was only about 1 to 2 wt %.
Therefore low initial H2O2 concentrations can be employed provided the solution concentration is not less than 1 wt% H2O2.
Example 32 Use of other Carboxylic Acids
The carboxylic acid used to generate the peracid in-situ can also be varied. We have demonstrated the use of not only formic but acetic and CAA acids in combination with hydrogen peroxide. The table below shows examples of these results using various CA derivatives.
Figure imgf000026_0001
Procedures
The following procedure was used in example 33 set out below in which CAH is oxidized to CAA using O2.
To a 100 cc stainless steel reactor equipped with an internal stirrer, a sampling port, and an external heating jacket was added a solution of CAH in H2O or acetic acid (typically from 1 to 10% CAH by weight). Acid (e.g. H2SO4) can be added to the solution to help stabilize the CAH. The appropriate catalyst was then added to the solution (catalyst
concentrations are typically between 10 and 100 mM). Oxygen (or air) was charged to the reactor to a pressure of 5 to 100 psig. The solution was heated to a temperature of 50 to 120#C with stirring. Samples of the reaction solution were collected periodically and the progress of the reaction was determined by high pressure liquid chromatography.
Example 33
This example investigated the use of free radical initiation catalysts in aqueous and acetic acid solvents. The table details the results of some of the experiments from the free radical initiated oxidation of CAH to CAA using oxygen.
Figure imgf000027_0001
Clearly, these results showed that CAH can be oxidized under these conditions to CAA. In general, the selectivity declined as conversion increased. The best results showed a selectivity of 66% at 10% conversion, the selectivity dropped to 45% at 28% conversion.
Generally, the metal catalyzed oxidation of aldehydes is carried out commercially in a carboxylic acid solvent utilizing the free aldehyde and not the hydrate. Since water is a more convenient solvent for our process we attempted to find a water based oxidation catalyst for this conversion. Using either a manganese or cobalt catalyst, in water, has thus far led to complete oxidation of the CAH. However, using a heteropolyacid (HPA) as the catalyst provided the improved results shown in Table 1. This suggests that the HPA is acting as a free radical initiator but is much milder than either manganese or cobalt.
Due to the low selectivity obtained from oxidation of CAH in this manner, a non-free radical catalyst was sought. We have found that the electrophilic oxidation of CAH (in water at 75#C) to CAA could be accomplished with the use of a stoichiometric amount of palladium (+2). With this oxidant greater selectivities of CAA were obtained even in water and under acidic conditions, similar to the HPA experiment. This verified that a non-radical oxidation of CAH to CAA is preferred over a free radical oxidation.
Figure imgf000028_0001
Figure imgf000029_0002
Even though stoichiometric use of palladium is economically impractical, this experiment shows that much higher yields are obtainable with an electrophilic oxidant as compared to a free radical initiator. The data appears to show that the radical pathway leads to higher losses than the electrophilic mechanism. Therefore several non-radical approaches were investigated.
A Pd/HPA catalyst gave results somewhat better than HPA alone but far less than for stoichiometric palladium.
Figure imgf000029_0001
Assuming first order kinetics for all three cases (stoichiometric Pd, HPA and Pd/HPA) we found that the rates of oxidation of CAH using HPA and Pd/HPA catalysts are quite similar. However, the stoichiometric palladium oxidation rate is notably slower (the relative rates for stoichiometric palladium, HPA and Pd/HPA are 1:1.5:1.7). Therefore the product distribution is largely being controlled by the HPA free radical oxidation of CAH, with very little contribution from palladium. In order to develop a highly selective catalyst for this step was necessary to minimize the free radical pathway and favor the electrophilic pathway. ln order to minimize the fosses due to free radical oxidation a less oxidizing co-catalyst was sought to replace the HPA. We selected CuCI2 as that cocatalyst. CuCI2 was less oxidizing than HPA and that the relative rate of free radical consumption of CAH was approximately 15 times slower than HPA.
These data indicated that a PdCI2/CuCI2 catalyst would perform considerably better than the corresponding PdCI2/HPA catalyst. This was found to be the case.
Although the Pd/HPA catalyst displayed 1.5 times the reaction rate, the mol % yield of CAA was considerably higher with the Pd/Cu catalyst. At 100% conversion, we anticipate that the CAA yield could reach 45%. This is reasonable since the selectivity was a constant 45% throughout the experiment. The reaction rate was about 10-9 mol cc-1 sec-1).
It should be dear that one having ordinary skill in this art would envision equivalents to the processes found in the claims that follow and that these equivalents would be within the scope and spirit of the claimed invention.

Claims

WE CLAIM AS OUR INVENTION:
1. A process for producing cyanoacetic acid by further oxidizing a partially oxidized propionitrile compound of the following formula:
N) C-CHx-CHy-AB where A is -H, -OH, or -OR; and B is -OH, -OR, or =O; x= 1 or 2, y=0 or 1 (depending upon the selection of A and B); but where B is =O, A is -H, and x=0; and where y=1, x=0, and B is not =O.
2. The process of claim 1 where the partially oxidized propionitrile compounds are selected from cyanoacetaldehyde, its hydrate, or acetal.
3. The process of daim 1 where the oxodation takes place with with oxygen, ozone, peracids (RCOOOH, where R is H or CnHn+2), alkyl nitrites (RONO, where R is CnHn+2) and hydrogen peroxide or mixtures thereof.
4. The process of claim 1 including the step of oxidizing
acetonitrile to produce the partially oxidized propionitrile
compounds.
5. The process of claim 1 including the step of esterifying the product cyanoacetic acid.
PCT/US1992/000588 1991-01-24 1992-01-24 Process for the production of cyanoacetic acid WO1992012962A1 (en)

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EP0583694A1 (en) * 1992-08-20 1994-02-23 BASF Aktiengesellschaft Process for the preparation of cyanoacetic acid alkylesters
WO2001016092A1 (en) * 1999-08-30 2001-03-08 Lonza Ag Method for producing cyanoacetic acid esters
US6700010B1 (en) 1999-08-30 2004-03-02 Lonza Ag Method for producing cyanoacetic acid esters

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WO2008004115A1 (en) * 2006-06-30 2008-01-10 Zach System S.P.A. Process for preparing gabapentin

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See also references of EP0568621A4 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0583694A1 (en) * 1992-08-20 1994-02-23 BASF Aktiengesellschaft Process for the preparation of cyanoacetic acid alkylesters
US5347032A (en) * 1992-08-20 1994-09-13 Basf Aktiengesellschaft Preparation of alkyl cyanoacetates
WO2001016092A1 (en) * 1999-08-30 2001-03-08 Lonza Ag Method for producing cyanoacetic acid esters
US6700010B1 (en) 1999-08-30 2004-03-02 Lonza Ag Method for producing cyanoacetic acid esters

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