Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C255/00—Carboxylic acid nitriles
  • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
  • C07C255/19—Carboxylic 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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