MXPA99005368A - Procedure and intermediaries for the manufacturing of piridine-2,3-dicarboxil compounds - Google Patents

Abstract

The present invention relates to: Provides a process for preparing a pyridine-2,3-dicarboxylate derivative through the reaction of a dialkyl alkoxy (or alkylthio) oxaloacetate with an appropriately substituted acrolein compound in the presence of a source of ammonia and a solvent. The present invention also provides intermediary compounds of formula

Description

PROCEDURE AND INTERMEDIARIES FOR THE MANUFACTURING OF PIRIDINE-2.3-DICARBOXYLATE COMPOUNDS BACKGROUND OF THE INVENTION The pyridine-2,3-dicarboxylate derivatives are useful intermediates for the preparation of acids, esters and 2- (2-imidazolin-2-yl) nicotinic salts, as described in U.S. Patent 5,334,576 and in US Pat. U.S. Patent No. 4,798,619. The methods of the literature for preparing pyridine-2,3-dicarboxylates include degradation techniques that require dangerous oxidative methods such as oxidation with nitric acid or peroxide-based oxidation of 2,3-dialkyl or quinolinic precursors. Conventional de novo syntheses of pyridine-2,3-dicarboxylates employing oxaloacetate diesters, or their metal salts such as those described in U.S. Patent No. 5,047,542 and Japanese Patent 01125768A generally provide products with low yield and low purity. The use of halogenated oxaloacetate diesters to prepare pyridine-2,3-d-carboxylate derivatives, while effective, requires the formation of α-halo-β-keto esters such as diethyl chlorooxalacetate, which is known to thermally decompose. , releasing HCI gas and creating potentially dangerous and toxic conditions. Surprisingly, it has now been discovered that pyridine-2,3-dicarboxylate derivatives can be prepared efficiently and inexpensively by using alkoxy (or alkylthio) oxaloacetate diester compounds, as starting materials or as in-situ intermediates.

REF. : 30288"Therefore, it is an object of this invention to provide a safe, efficient, economical and environmentally compatible process for manufacturing pyridine-2,3-d.carboxylate derivatives.It is another objective of this invention to provide a readily available source, It is a feature of the process of the invention that the main by-products consist of alcohols and thiols which can be easily recovered by distillation or extraction.It is another feature of the process of the invention that the recovered alcohols and thiols can be recycled to produce additional starting material, with minimal waste It is an advantage that the compounds of the invention are thermally and chemically stable under a suitable range of conditions and therefore do not require special handling and that do not present any risk particu for the manipulators of the same or for the environment. Other features and objects of the invention will become apparent in the detailed description thereof as set forth below.

COMPENDIUM OF THE INVENTION The present invention provides a process for the manufacture of a compound of formula I (I) wherein R 4 and R 6 are each independently H, C C β alkyl, C-C 6 alkenyl, phenyl or substituted phenyl; R5 is H; halogen; C? -C6 alkyl, optionally substituted with one or more C? -C4 alkoxy groups; C -.- C6 alkenyl; phenyl or substituted phenyl; and R2 and R3 are each independently C? -C6 alkyl. phenyl or phenyl Substituted; which comprises reacting a compound of formula II or an alkali metal salt thereof (II) in which X is O or S; R- is C? -C6 alkyl, phenyl or substituted phenyl; and R2 and R3 are as described for formula I; with at least one molar equivalent of a compound of formula III where R, R5 and R6 are as described for formula I; and a source of ammonia in the presence of a solvent optionally at elevated temperature. The present invention also provides a process for the preparation of a compound of formula I: (i) where R4 and Re are each independently H, C ^ Ce alkyl, d-Cß alkenyl, phenyl or substituted phenyl; R5 is H; halogen; alkyl d-C6. optionally substituted with one or more C C4 alkoxy groups; alkenyl d-C6; phenyl or substituted phenyl; and R2 and R3 are each independently d-Cß alkyl, phenyl or substituted phenyl; which comprises reacting a compound of formula IV (IV) where X is O u S; R- is CrC6 alkyl, phenyl or substituted phenyl; and R2 and R3 are as described for formula I with at least one molar equivalent of a compound of formula III or an alkali metal salt thereof wherein R4, R5 and R6 are as described for formula I in the presence of a solvent optionally at elevated temperature. The present invention also provides intermediate compounds of formula IV (IV) in which X is O u S; Ri is C? -C6 alkyl, phenyl or substituted phenyl; and R2 and R3 are each independently C? -C6 alkyl, phenyl or substituted phenyl. The pyridine-2,3-dicarboxylate compounds of formula I are useful as intermediates in the manufacture of highly potent, environmentally benign imidazoline herbicidal agents of formula V wherein R4 and Re are each independently H, alkyl dCe, C6C6 alkenyl, phenyl or substituted phenyl; and R5 is H; halogen; alkyl d-Cß, optionally substituted with one or more C! -C alkoxy groups; C? -C6 alkenyl; phenyl or substituted phenyl.

DETAILED DESCRIPTION OF THE INVENTION To date, de novo syntheses of the pyridine-2,3-dicarboxylate derivatives have been plagued by products of low yield and low purity or by the use of unstable intermediates of halogenated oxaloacetate. Currently, it has been discovered that the pyridine-2,3-dicarboxylate derivatives of formula I can be prepared effectively and efficiently by the reaction of an amino akoxy (or alkylthio) maleate or fumarate of formula IV with at least one molar equivalent of an α, β-unsaturated ketone of formula III in the presence of a solvent optionally at elevated temperature. The process of the invention is illustrated in reaction step I where X, R f R2, R3, R4, R5, and Re are as described above.

REACTION STAGE The term "substituted phenyl" as used in the specification and claims designates a phenyl ring substituted with one or more substituents which may be the same or different including halogen, NO2, CN, OH, C? -C alkyl, C? C haloalkyl. , C, -C 4 alkoxy, C 1 -C alkylthio, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylamino, di (C 1 -C 4) alkylamino) and / or alkylsulfonyl dC 4. Halogen designates Cl, Br I or F. Haloalkyl designates an alkyl group substituted with one or more halogens which may be the same or different, and haloalkoxy designates an alkoxy group substituted with one or more halogens which may be the same or different.

Suitable solvents that are used in the process of the invention can be any organic solvent that partially or completely solubilizes the reactants and does not participate in the reaction. Examples of organic solvents that may be used include alkanes, chlorohydrocarbons ,. hydrocarbons, aromatic hydrocarbons, ethers, carboxylic acids and esters, carboxylic acid nitriles, carboxamides, and the like, or mixtures thereof. Preferred solvents are alkanols such as methanol, ethanol, propanol, isopropanol, butanol, and the like, preferably ethanol; and aromatic hydrocarbons such as benzene, toluene, xylene, naphthalene, and the like, preferably toluene, or mixtures of alkanols and aromatic hydrocarbons, preferably mixtures of ethanol and toluene. In general, the temperature of the reaction is inversely related to the reaction time, ie, increased temperatures lead to decreased reaction times. However, excessively high reaction temperatures can cause undesirable side reactions and decomposition. In general, the appropriate reaction temperatures may be between 25 0 C - 185 ° C; preferably the reaction temperature is higher than 40 ° C; especially preferred is a range of from 80 ° C to 100 ° C. Therefore according to the process of the present invention, pyridine-2,3-dicarboxylates containing substituents at the 4-position, 5 and 6 can conveniently be prepared by mixing essentially equimolar amounts of an amino alkoxy (or alkylthio) diester of formula IV and an α, β-unsaturated ketone of formula III in the presence of an appropriate solvent at a temperature range of from ambient temperature to the boiling point of the solvent, preferably at reflux temperatures, until the reaction is complete. The product of formula I thus formed can be isolated by conventional chemical processing techniques such as extraction, filtration, distillation, chromatography and the like. Alternatively, the pyridine-2,3-dicarboxylate can be carried out in a process stream without additional purification / isolation steps. The present invention also provides compounds of formula IV H N CO R 2 2 3 (IV) in which X is O or S; R-, alkyl C ^ Ce. phenyl or substituted phenyl; and R2 and R3 are each independently alkyl d-Ce, phenyl or substituted phenyl. The compounds of the invention can exist as cis and trans isomers, IVa and IVb, respectively.

In the specification and claims, the compounds of formula IV that have been illustrated above designate the cis isomer (IVa), the trans isomer (IVb), or mixtures thereof. Preferred compounds of formula IV are those compounds in which X is O and R ^ is methyl, ethyl or phenyl. The compounds of the invention are readily prepared by the reaction of an alkoxy (or alkylthio) oxaloacetate of formula II with a source of ammonia in the presence of a solvent. Advantageously, the compound of formula IV of the invention can be formed in situ and, without further isolation steps, it can react with an α, β-unsaturated ketone of formula III to form the desired product consisting of pyridine-2,3-d Carboxylate of formula I. This additional process of the invention is shown in the reaction step. REACTION STAGE Solvent | Source of I Ammonia i (IV) Sources of ammonia suitable for use in the process of the invention include, but are not limited to, gaseous ammonia or ammonium salts such as ammonium acetate, ammonium bicarbonate, ammonium sulfamate, ammonium formate, and the like. Preferred ammonium salts are ammonium acetate, ammonium sulfamate or ammonium bicarbonate. The solvents and temperatures suitable for use in this process of the invention are the same as those described above for the reaction stage i. The oxaloacetates of formula II can also be used in the process of the invention as alkali metal salts which are shown below where M is an alkali metal such as sodium or potassium.

(He has) In the specification and claims, the compounds of formula II denote the free oxaiacetates and the alkali metal salts of formula Ia thereof. Preferred compounds of formula 11 are those compounds in which X is O and Ri is methyl, ethyl or phenyl. Preferred compounds of formula III are those compounds in which R 4 and R 6 are H and R 5 is H or C 1 -C 4 alkyl optionally substituted with a C 4 -C 4 alkoxy group. The most preferred compounds of formula II are those compounds in which R 4 and R 6 are H and R 5 is H or C 1 -C 4 alkyl optionally substituted with a C 1 -C 4 alkoxy group. The most preferred compounds of formula II are those compounds in which R and R6 are H and R5 is H, methyl, ethyl or methoxymethyl. Therefore, according to a further process of the invention, pyridine-2,3-dicarboxylates containing substituents in the 4, 5 and 6 position can be conveniently prepared by a mixture of essentially equimolar amounts of an alkoxy oxaloacetate (or alkylthio) of formula II or an alkali metal salt thereof, an α, β-unsaturated ketone of formula III, and a source of ammonia in the presence of an appropriate solvent at a temperature range from room temperature to the boiling point of solvent, preferably at reflux temperature until the reaction is essentially complete. The product of formula I thus formed can be isolated by conventional procedures such as extraction, filtration, chromatography or the like. Alternatively, pyridine-2,3-dicarboxylate can be carried out in a process stream, as is, without additional purification / isolation steps. The pyridine-2,3-dicarboxylates of formula I are useful intermediates for the preparation of acids, esters and herbicidal 2- (2-imidazolin-2-yl) nicotinic salts of formula V. For example, the pyridine-2 compound, 3-dicarboxylate of formula I as formed in A * reaction stage io in the reaction stage? it can be reacted with an appropriate amino carboxamide compound of formula VI in the presence of an inert solvent and a strong base to give the imidazolinone compound of formula V as shown in reaction step ni.

REACTION STAGE III 0 °? or sell (II) (III) s (V) Alternatively the diester of formula I produced by the processes of the invention as illustrated in reaction stages I and II can be hydrolyzed to the corresponding diacid, and can be employed in any of the processing routes described in the patent literature for preparing imidazolinones of formula Invention, such as those described in U.S. Patent No. 4,798,619. In order to facilitate a better understanding of the invention, the following examples are presented mainly for the purpose of illustrating some more specific details thereof and the invention should not be considered limited thereto. The terms 13CNMR and 1HNMR designate Carbon 13 and proton nuclear magnetic resonance, respectively. The terms HRGC and HPLC designate high resolution gas chromatography and high performance liquid chromatography, respectively. All parts are parts by weight, unless otherwise specified.

EXAMPLE 1 Preparation of ethyl ethoxyacetate NaOC2H5 CICH2 CO2 C2 H5 C2 H5 OCH2 C2 H5 C2 H5 OH A solution of ethyl chloroacetate (100 g, 99% pure, 0.81 mol) in ethanol is treated with ethanolic sodium ethoxide (282.9 g, 20.6% solution, 0.86 mol NaO C2 H5) in a period of 1 hour at 20 ° C - 30 ° C, it is heated at 40 ° C - 45 ° C for 0.5 hours, cooled to room temperature, treated with diatomaceous earth, stirred for 0.25 hours and filtered. The filter cake is washed with ethanol. The combined filtrates are distilled to obtain the title product, in the form of a colorless liquid, 75.78 g, 98.8% pure (71% yield) p. eb 87 ° C -88 ° C / 59 mm Hg, identified by analysis of 13CNMR and 1HNMR and mass spectrum. EXAMPLE 2 Preparation of diethyl ethoxyoxalacetate (stepwise addition method) A stirred mixture of molten sodium metal (24.15 g, 1.05 mol) in toluene is treated with ethanol (55.2 g, 1.2 mol) over a period of 1 hour at 100 ° C-110 ° C. , it is heated at reflux temperatures for 0.5 h, cooled to 30 ° C, treated with diethyl oxalate (160.6 g, 1.1 mol) in a period of 10 minutes at 30 ° C - 45 ° C, treated with ethyl ethoxyacetate (132 g, 98%, 0.98 mol) over a period of 0.5 hours at 45 ° C - 50 ° C, heated at 55 ° C -60 ° C for 2 hours. , 5 hours and pour in 328 g. of HCl at 14% with cooling. The resulting mixture is separated. The title product is obtained in the organic phase as a 40.9% solution, identified by HRGC analysis with a total yield of 204.2 g (90% yield). EXAMPLE 3 Preparation of diethyl ethoxyoxalacetate (pre-mixed method) A stirred mixture of molten sodium metal (24.15 g, 1.05 mol) in toluene is treated with ethanol (55.2 g, 1.2 mol) over a period of 1 hour at 100 ° C-110 ° C. , it is heated at reflux temperature for 0.5 h, cooled to 45 ° C, treated with diethyl oxalate (160.6 g, 1.1 mol) and ethyl ethoxyacetate (132 g, 98%, 0%). , 98 mol) over a period of 1 hour at 45 ° C - 50 ° C, heated at 55 ° C - 60 ° C for 1.5 hours and poured into 328 g. of HCl at 14% with cooling. The resulting mixture is separated. The title product is obtained in the organic phase as a 32% solution, in organic phase, identified by HRGC analysis with a total yield of 198.2 g (87% yield). EXAMPLE 4 Preparation of diethyl 5-methylpyridine-2,3-dicarboxylate through diethyl ethoxyoxalacetate A solution of diethyl ethoxyoxalacetate (120.1 g, 82.9%, 0.43 mol) in ethanol is treated with a mixture of methacrolein (38.9 g, 97.1%, 0.54 mol) and acid acetic acid (42 g, 0.70 mol) at room temperature, and then tata with anhydrous ammonia (9.2 g, 0.54 mol) over a period of 1 hr. at 25 ° C - 45 ° C, heating at reflux temperatures for 2 hours, cooled to room temperature and concentrated in vacuo to obtain a residue. The residue is treated with toluene, washed with 2NHCl and further concentrated in vacuo. The resulting residue is distilled in vacuo to give the title product as a yellow oil, 74.06 g, 100% pure (73% yield), e.g. eb 150 ° C / 2.5 mm Hg, identified by 13CNMR and 1HNMR.

EXAMPLE 5 Preparation of diethyl 5-methylpyridine-2,3-dicarboxylate through the sodium salt of diethyl ethoxyloxalacetate A stirred mixture of molten sodium metal (24.15 g, 1.05 mol) in toluene is treated with ethanol (55.2 g, 1.2 mol) over a period of 1 hour at 100 ° C-110 ° C. , it is heated at reflux temperatures for 15 minutes, cooled to room temperature, treated with diethyl oxalate (160.6 g, 1.1 mol) at 24 ° C - 45 ° C, then treated with ethyl ethoxyacetate. (132 g, 98%, 0.98 mol) over a period of 0.5 hours at 45 ° C - 50 ° C, is heated at 55 ° C -60 ° C for 2 hours to provide a homogeneous solution. Half of this homogeneous solution is treated with acetic acid (75 g, 1.25 mol) at 25 ° C - 540 ° C, and then treated with methacrolein (38.4 g, 91.4%, 0.50 mol ), is further treated with anhydrous ammonia (11 g, 0.65 mol) over a period of 9.5 hours at 49 ° C - 60 ° C, heated to reflux for 2 hours, cooled to room temperature and treated sequentially with water and HCl (65 g). The resulting mixture is separated to give the title product as a 20.4% solution in the organic phase, 88.6 g (76% yield), identified by HPLC analysis. EXAMPLE 6 Preparation of dimethyl 5-methylpyridine-2,3-dicarboxylate through the sodium salt of diethyl methoxyoxalacetate A mixture of 25% methanolic sodium methoxide (237.6 g, 2.2 mol NaOCH3) and toluene was treated with a mixture of methyl oxalate (129.8 g, 2.2 mol) and methyl methoxyacetate ( 104 g, 1 mol) at 40 ° C - 45 ° C over a period of 1 hour, heated at 45 ° C - 50 ° C for 2 hours, treated sequentially with acetic acid (150 g, 2.5 mol) and methacrolein (93 g, 95%, 1.26 mol) was treated with anhydrous ammonia (18.2 g, 1.07 mol) over a period of 1 hour at 40 ° C-60 ° C, heated to reflux for 2 hours, it was cooled to room temperature and diluted with water. The phases were separated and the aqueous phase was extracted with toluene. The organic phase and the toluene extracts were combined and concentrated in vacuo to give the title product as a 45.8% toluene solution, 91.6 g (44% yield) identified by HPLC analysis. Using essentially the same procedure described above and replacing methyl methoxyacetate with methyl methylthioacetate, the title product was obtained as a 12% solution in toluene, in a yield of 54.9%, identified by HRGC. EXAMPLE 7 Preparation of dimethyl 5-methylpyridine-2,3-dicarboxylate via methylthioacetate and an ammonium salt A mixture of methyl methylthioacetate (25 g, 0.21 mol) and dimethyl oxaloacetate (24.6 g, 0.21 mol) in was added to a suspension of sodium methoxide (12.4 g, 0.23 g). mol) in toluene. The resulting reaction mixture was heated at 80 ° C for 5 hours, cooled to room temperature and poured into dilute aqueous HCl. The mixture was separated and the aqueous phase was extracted with toluene. The organic phases were combined and concentrated in vacuo to give a residue. The residue was dissolved in methanol, treated with ammonium sulfamate (437.5 g, 0.42 mol) and methacrolein (30.7 g, 95% 0.42 mol), heated at reflux temperatures for 20 h. and concentrated in vacuo to give a residue. This residue was divided between toluene and water. The aqueous phase was extracted with toluene. The organic phases were combined and concentrated in vacuo to give the title product in the form of a 4.8% toluene solution, 5.7 g. of product (13% yield) identified by HPLC analysis. EXAMPLE 8 Preparation of diethyl 5-methylpyridine-2,3-dicarboxylate through diethyl ethoxyoxalacetate and an ammonium salt A solution of diethyl ethoxyoxalacetate (4.1 g, 96%, 17 mmol) in ethanol was treated with methacrolein (1.4 g, 95%, 19 mmol) and ammonium sulfamate (2.3 g, 20 mmol), heated at reflux temperatures for 15 hours, cooled to room temperature and concentrated in vacuo to give a residue. The residue was dispersed in a mixture of toluene and water. The resulting mixture was separated. The aqueous phase was further extracted with toluene. The organic phases were combined and concentrated to give the title product in the form of a 7.8% toluene solution, 2.95 g of product (74% yield), identified by HPLC analysis. EXAMPLE 9 Preparation of diethyl 5-ethylpyridine-2,3-dicarboxylate through diethyl ethoxyoxalacetate and an ammonium salt A solution of diethyl ethoxyoxalacetate (2.05 g, 96%, 8.5 mmol) in ethanol was treated with ethacrolein (0.82 g, 9.8 mmol) and ammonium sulfamate (1.16 g, 10.2 g). mmol), heated at reflux temperatures for 15 hours, and concentrated in vacuo to give a residue. The residue was treated with a 1: 1 mixture of toluene and water. The mixture separated. The aqueous phase was extracted with toluene. The organic phases were combined and concentrated to give the title product as a 4.5% toluene solution (78% yield) by HPLC analysis.

EXAMPLE 10 Preparation of ethoxy diethyl amino (a) diethyl amino ethoxyfumarate (b) (a) (b) A solution of diethyl ethoxyoxalacetate (2.1 g, 96%, 8.7 mmol) in ethanol was treated with ammonium sulphamate (1.2 g, 10.5 mmol), heated at reflux temperatures until complete. the reaction by GC analysis (7 hours) and concentrated in vacuo to give a residue. The residue was partitioned between methylene chloride and water. The aqueous phase was extracted with methylene chloride. The organic phases were combined, dried over Na2SO4 and concentrated in vacuo to give the title products as a yellow oil, 1.93 g (92% yield), identified by HNMR 13CNMR analysis, mass spectrum and HRGC as a 1: 1, 5 mixture of a: b.

EXAMPLE 11 Preparation of diethyl 5-methylpyridine-2,3-dicarboxylate via diethyl amino ethoxylate and diethyl amino ethoxyfumarate A mixture of diethyl amino etsximate and diethyl amino ethoxyfumarate (1.93 g, 8.3 mmol) in ethanol was treated with methacrolein (0.7 g, 95%, 9.5 mmol) was heated at reflux temperatures d 15 h. and concentrated in vacuo to give a residue. The residue was divided between toluene and water. The phases were separated and the aqueous phase was extracted with toluene. The organic phases were combined and concentrated to give the title product in the form of a 7.1% toluene solution. EXAMPLE 12 Preparation of dialkyl 5-alkylpyridine-2,3-dicarboxylates via dialkyl alkoxyoxalacetate (ID (III) (I) Using essentially the same procedures described in the examples indicated above, the following 5-alkyl pyridine diester products were obtained and characterized by HPLC analysis. The reaction conditions and the product yields are shown below in Table I. It is noted that in relation to this date the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Claims (1)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A process for the manufacture of a compound of formula I (i) where R and R6 are each independently H, C? -C6 alkyl, C? -C? alkenyl, phenyl or substituted phenyl; R5 is H; halogen; CtC6 alkyl. optionally substituted with one or more C? -C alkoxy groups; C -.- C6 alkenyl; phenyl or substituted phenyl; and R2 and R3 are each independently phenyl or substituted phenyl alkyl; characterized in that it comprises reacting a compound of formula II or an alkali metal salt thereof. (II) in which X is O or S; Ri is d-C6 alkyl, phenyl or substituted phenyl; and R2 and R3 are as described for formula I; with at least one molar equivalent of a compound of formula III (III) wherein R4, R5 and R6 are as described for formula I; and a source of ammonia in the presence of a solvent optionally at elevated temperature. The process according to claim 1, characterized in that which source of ammonia is an ammonium salt. 3. The method according to claim 1, characterized in that the temperature is approximately 25 ° C-185 ° C. 4. A process for the preparation of a compound of formula I: (i) wherein R4 and R6 are each independently H, C? -C6 alkyl, C? -C6 alkenyl, phenyl or substituted phenyl; R5 is H; halogen; C? -C6 alkyl, optionally substituted with one or more C1-C4 alkoxy groups; C? -C6 alkenyl; phenyl or substituted phenyl; and R 2 and R 3 are each independently C 1 -C 6 alkyl, phenyl or substituted phenyl; characterized in that it comprises reacting a compound of formula IV. (IV) in which X is O u S; Ri is alkyl d-Ce, phenyl or substituted phenyl; and R2 and R3 are as described for formula I with at least one molar equivalent of a compound of formula III (III) in which R4, R5 and R6 are as described for the formula in the presence of a solvent optionally at elevated temperature. 5. EL p XBdipáeptD fe apyt with reiviniiicacióri 1 or 4, car. _in-i7prH μxque X is O R1 is methyl, ethyl or phenyl; R4 and R6 are each independently H; and R5 is H, methyl, ethyl or methoxymethyl. 6. El pcoaadirpiai D according to the reivipticaci 1 or 4, catc te? iza or poique the solvent is an aromatic hydrocarbon, an alkanol or a mixture thereof. 7. The proaactip-Lepto according to the reivipiiraci? 6, characterized in that the soluaite is toluene, ethanol or a mixture thereof. 8. A compound of formula IV (IV) characterized because x is or u S; R-, is C? -C6 alkyl, phenyl or substituted phenyl; and R2 and R3 are each independently d-Cß alkyl, phenyl or substituted phenyl. 3. The caipjesto of aajeró c n leivirrlirarri 13, caráota i zarb pagiEi X is O and Ri is methyl, ethyl or phenyl. 10. A process for the manufacture of a compound of formula V: wherein R4 and Re are each independently H, CtC6 alkyl, CtC6 alkenyl, phenyl or substituted phenyl; and R5 is H; halogen; C? -C6 alkyl, optionally substituted with one or more C? -C alkoxy groups; C ^ Ce alkenyl; phenyl or substituted phenyl: because it is necessary to react a cpmpusate of forpula p or the alkali metal salt thereof (II) where X is O u S; Ri is C6 alkyl, phenyl or substituted phenyl; and R2 and R3 are each independently C? -C6 alkyl, phenyl or phenyl substituted with at least one molar equivalent of a compound of formula III (III) wherein R4, R5 and R6 are as described for formula V and a source of ammonia in the presence of a solvent optionally at elevated temperature to give a compound of formula I (I) in which R2, R3, R4, Rs and Re are as previously described; reacting said compound of formula I with an amino amide of formula VI (VI) in the presence of an inert solvent and a strong base to give the carboxylate salt of a desired compound of formula V; and acidifying said carboxylate salt to provide the desired free carboxylic acid compound of formula V.