CA1316934C - Process for synthesis of glutamic acid from acrylate, amide and synthesis gas - Google Patents

Abstract

PROCESS FOR SYNTHESIS OF GLUTAMIC ACID
FROM ACRYLATE, AMIDE AND SYNTHESIS GAS
(D#80,522-F) ABSTRACT OF THE DISCLOSURE
A process for the synthesis of glutamic acid intermediate from an acrylate, amide and syngas by reacting them in the presence of a catalyst comprising a cobalt-containing com-poundl a bis-phosphine ligand and a solvent at a pressure of at least 500 psi and a temperature of at least 50°C and thereafter extracting the glutamic acid.

Description

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PROCESS FOR SYNTHESIS OF GLUTAMIC ACID
FROM~ACRYLAI`E, AMIDE~AND~SYNTHESIS GAS
(D#80,522-F) FIELD OF THE INVENTION
This invention relates -to the synthesis o~ glutamic acid from methyl or ethyl acrylates, an amide and syngas.
More particularly this invention uses a cobalt catalyst and a bis-phosphine ligand to synthesize N-acetyl-glutamic acid in one step from methyl or ethyl acrylate and an amide and syn-thesis gas with high yield and linearity using mild pressures and temperatures.

BACKGROUND OF THE INVENTION
Early attempts to synthesize c~ -amino acids or deriva-tives thereof by reacting a Schiff base or a nitrile with carbon monoxide and hydrogen were unsuccessful. [Bullo Chem. Soc. Japan 33 (160) 7~]
U. S~ Patent No. 3,766,266 to Wakamatsu discloses a method of producing an N-acyl- ~ -amino acid which comprises holding an aldehyde, an amide of a carboxylic acid and carbon monoxide at a temperature of 10 to 300C and a pressure of at least 500 atm. in the presence of a carbonylation catalyst until said N-acyl- ~ -amino acid is formed.
In ChemO Comm. 1540 (1971), Wakamatsu, et al. disclose a cobalt catalyzed reactlon which gives various N-acyl amino-acids from an aldehyde, an amide and carbon monoxide. In this :~ ~

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disclosure, while benzaldehyde was used as the starting aldehyde, there was no corresponding j~ -phenyl-substituted amino acid obtained. Instead of the expected amino acid product, a imine was obtained by a simple "amination" react:ion.
An article by Parnaud, et al., in Journal o~ Molecular Catalysis, 6 (1979) 341 350, discusses the synthesis potential and the catalytic mechanism for the reaction wherein N-acyl- ~ -amino acids are produced by reacting an aldehyde, CO
and an amide in the presence of dicobalt octacarbonyl.
In amidocarbonylation, the aldehyde can be generated in situ from allyl alcohol, alkyl halides, oxiranes, alcohols and ole~ins followed by the reaction with an amide and carbon monoxide to produce an N-acyl- ~ -amino acid.
A related Patent, U. S. Patent No. 3,996,288 discloses that when an alcohol or certain of its ester derivatives is held at 50C to 200C and lO to 500 atm. in the presence o~ hydrogen, carbon monoxide, the amide o~ a carboxylic acid and a carbony-lation catalyst, an aldehyde having one more carbon atom than the alcohol or ester is formed in good yield. If the amide has at least one active hydrogen atom on its amide nitrogen, it ~urther reacts with the aldehyde and carbon monoxide to form an N-acyl-amino acid.
; ` Hirai, et al~ discuss a process for combining the tran-sition metal catalyzed isomerization of allyl alcohol to aldehyde .
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and cobalt catalyzed amidocarbonylation to provide a route from allylic alcohols to N-acyl- ~ -amino acids. See Tetrahedron Letters, Vol. 23, No. 24, pp. 2491-2494, 1982.
U. S. Patent No. 4,264,515 by R. Stern et al.discloses a process for obtaining terminal N-acyl- ~ -amino acids by a reaction catalyzed by a cobalt carbonylation catalyst wherein the aldehyde is produced in situ from olefins and CO/H2 mixtures. An unsaturated vegetable oil or C8-C30 monoolefinic compound is re-acted with an amide, carbon monoxide and hydrogen in the presence of a cobalt catalyst. The process is operated in one step and provides for increased selectivity.
A recent review article, published by Ojima in Journal of Organometallic Chemistry, 279 (1985), 203-214, discussed the synthesis of N-acetyl- ~ -amino acids from (a) the isomerization-amidocarbonylation of allylic alcohols, (b) the isomerization-amidocarbonylation of oxiranes and (c) the hydro-formylation-amldocarbonylation of trifluoropropene. The hydro-formylation-amidocarbonylation of trifluoropropene in Ojima's work demonstrated a surprising regioselectivity for products 1 and 2 -, , lL3~3~

3 2 + Co ~ H2 + H2NCoMe Catalyst ~ ~ COMe C~3 N~CoMe The results demonstrated in that work showed the highly regioselective syntheses of N-acetyltrifluorovaline ll) t94~) and N-acetyltrifluoronorvaline (2) (96%) in high yields by using Co2(cO)~-Rh6tco)l6 and Co2(CO)8 as catalysts respectively. The results showed the surprising difference in yield when using Co2(CO)8 as opposed to Co2(CO)8-Rh6(CO)16 catalysts in the spe-cial case of the fluoroolefin substrate.
The use of am.idocarbonylates reactions in substrates containing a functionality such as ester group (that is, methyl or ethyl acrylate) in one step to produce the corresponding mono-ester of the N-acetylglutamate has no~ been previously disclosed.
In a British patent specification No. 828,946 ~1960) titled "Synthetic Process for Producing Glutamic Acid From Acrylonitrile", the reactions involved the hydroformylation of acrylonitrile followed by hydrocyanic acid and ammonia reaction in two steps. In a related patent, V.S. No. 3,766,266, a two-step synthesis from acrylate to aldèhyde is disclosed, fol-lowed by the reaction of acetamide and carbon monoxide to produce :~ :

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the corresponding final product~ glutamic acid. The reaction conditions in the two separate steps are slightly different.
The present invention involves the use of Bis-1,3-(diphenylphosphino) propane in combination with dicobalt octacarbonyl to achieve the conversion of acrylate into glutaric acid derivatives in a single step. K. Murata et al reported earlier the effect of Di(tertiary phosphine) ligand in hydro-formylation of methyl acrylate. (Bull. Chem. Soc. Jpn., 53, 214-218 (1980). The reaction rate was related to the species of bidental phosphine ligand and Co-P ratio. J. Molecular Catalysis 23 (1984), 121-132 and Chem. Commu. (1979) 785, have reported the similar results in CO/H2O reactions. However, ~. Organometallic Chem. 1985, 283, ~o. 1-3, reported that HCo(CO)2 (Bu2PCH2CH2PBu2) was found to be an inactive catalyst for olefin hydroformylation and required an activation period.
; The results of the instant invention using Co2(CO)8 with a bis-phosphine ligand in a one step snythesis are novel in the following respects:
(1) The presence of 1,3-bis~diphenylphosphino propane stabilizes dicobalt octacarbonyl and allows the reaction to pro-ceed predictably at a low temperature in comparison with dicobalt ; octacarbonyl alone.

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(2) The combined Co2(CO)8 and bis phosphine ligand catalyst performs the reaction under milder reaction conditions, for example, as low as 800 psi.
(3~ Rhodium species used in the comparative example affects regioselectivity.
Previous methods known in the art for preparing glutamic acid involve two steps. It would be an advance in the art to devise an inexpensive, one-step method of making glutamic acid in high yields with a great degree of linearity under mild conditions from an acrylate, an amide and syngas.
The instant invention relies on a cobalt catalyst sys-tem for the synthesis of glutamic acid from methyl or ethyl acrylate, acetamide and syngas wherein yields of glutamic acid are as high as 80% and a linearity of ~80% is observed using very mild reaction conditions. After the ester intermediate is obtained, extraction by a acid/base medium such as Na2CO3 or H3PO4 are used to obtain the glutamic acid in good yield.

SUMMARY OF THE INVENTION
-This invention concerns a one-step process for synthesizing gIutamic acid intermediates which comprises con-tacting a mixture of acrylates, amides and syn~as Icarbon monoxide and hydrogen) with a catalyst comprising a cobalt-containing compound and a bis-phosphine ligand in the presence of :."",, ' ~' , .

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~ 8626-197 a solvent at a pressure of 500 to 5,000 psl and a temperature of 50 to 180C.
Accordlng to the present lnvention there is provided a process for the synthesis of a glutamic acld lntermedlate repre-sented by the structures I or II
HOOC \
CHCH2CH2COOR ~I) H or, ~CH3CONH)2CHCH2CH2COOR (II) whereln R is methyl or ethyl comprlslng reactlng an acrylate amlcle and syngas in the presence of a cobalt-catalyst, a bls-phosphlne ligand and a solvent at a pressure of 500 to 5,000 psi and a tem-perature of 50 to 180C for a compound of formula I or 50 to 160C
for a compound of formula II and, where requlred, separating a compound of formula I or II so obtained.
Acrylates are used to produce the N-acetylglutamate lntermediates ln up to 80~ yleld wlth up to 80% llnearlty.
It was found, by reference to Comparative Example VIII, uslng rhodlum, that regloselectlve hydroformylatlon of acrylate at the beta position is the key to glutamlc acid synthesis.
DETAIL~D DESCRIPTION OF THE INVENTION
Ln the narrower and more preferred practice of this invention N-acetylglutamate intermedlates are prepared from a mlxture of acrylates, amides, carbon monoxlde and hydrogen by a proce~s which comprlses contacting said mixture wlth a catalyst . " ~, , .

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6862~-197 system comprlslng a cobalt-containlng compound and a bls-phosphlne llgand in a substantially inert solvent at a temperature of at least 500C and a pressure of at least 500 psi untll substantlal formatlon of the deslred glutamic acld lntermedlate has been achleved.
The glutamlc acid intermedlates are in llquld form at room temperature. These intermediates are predomlnantly linear.
After e~tractlon wlth organlc solvent from a mlneral acld or base such as Na2C03 or H3P04, the product glutamlc acld ls obtalned ln good yleld. The market for glutamlc acld ls one of the largest ln the amino acld group.

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68~26-197 The reaction for producincJ llnear ylutamate lnter-mediates from acrylates can be represented by the following equat~on:
Equakion I:

Catalyst HOOC H-~
CH2=CHCOOR ~ CO/H2 + CH3CONH2 ~ > CHC}12CH2COOR-~ ylu~amic acid (R=CH3 or C2Hs) CH311NH

The reaction for producing an N-acetylglutamate lO lntermediate from ethyl acrylate can be represented by the followlng equation:
~quation II:

// COOEt + CO/H2 + CH3CON~12----~CHC1~2CH2C~t + CHCH2CH2COOEt o (A) (8) In general, two products - N~acetyl-glutamate ~A) and 4,4-bis~acetylamldo)butyrate ~B) were lsolated. Compound ~B) is hydrolyzed and carbonylated lnto compound (A) under hi~her syngas }i,DtJ~
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pressure or temperature. Both compounds led to the desired glutamic acid through the selective hydroformylation of product (C) at the ~ position of acrylate.

~ OC~I CH2cH2cooR (C) C~3CH COOR (D) In Comparative Example VIII, a rhodium catalyst was used and compound (D) was obtained with undesired side products.
Recovery of the glutamic acids from the reaction prod-uct can be carried out by extraction. Two steps of extraction may be used: (1) acetate solvent extractions from the Na2CO3/H20 layer to remove impurity and (2) acetate solvent extraction from the H+/H20 layer to obtain the pure products. In the embodiment of this invention the product was identified by NMR and IR.
The catalyst system suitable for the practice of this invention comprises a cobalt-containing compound and a bis-phosphine ligand in a substantially inert solvent. The bis-phosphine ligand is found to be essential to stabilize the cobalt-containing compound during amidocarbonylation~ The con-trolled experiments represented by comparative Example VIII show the presence of Rh can cause hydroformylation at the alpha :

_ g _ ~31 6934 58626-1~7 posltlon of the methyl acrylate, followed by a s.tde reaction such as Michael addition and lead to a different reaction path.
Regioselective hydroformylatlon of acrylate at the beta positlon ls the key to glutamic acid synthesis. Furthermore, the lnstant catalyst system provldes important advantages over the use o~
cobalt alone:
1) It gives higher ylelds and selectlvltles of the ~-acetylglutamate lntermediate acld products ln one-step under mllder condltlons.
2) It was possible to obtaln as high as 80% linear glutamlc acld product.
In the process of thls inventlon it ls preferable that the cobalt-contalning compound be used wlth a bls-phosphine llgand. Llgands whlch work well ln thls respect lnclude those of the formula ph2P ( CH2 ) XPPh2 wherein x = 1 to 6.
The preferred compounds are 1,6-bis(diphenylphosphino)-hexane, 1,3-bls(dlphenylphosphino)propane and 1,2-bls(diphenylphosphlno)ethane.
It ls worthwhlle to note that rhodlum species seem tohave an adverse effect on production of glutamic acld as shown ln our comparative Example VIII. It was found the rhodlum catalyst ~. ~,, /! J

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performed the hydroformylation at the alpha position of the methyl acrylate, followed by a side reaction such as Michael addition and led to a different reaction path. Therefore, a com-bination of Rh-Co bicatalyst would not be suitable for this process.
The cobalt-containing compound may take many different forms. Yor instance, the cobalt may be added to the reaction mixture in the form of a variety of inorganic or organic cobalt salts, or cobalt carbonyls. The cobalt may, for example, be add-ed as a cobalt halide such as cobalt bromide or cobalt chloride, or it may be added as the salt of an aliphatic or aromatic carboxylic acid such as, for example, cobalt formate, cobalt acetate, cobalt butyrate, cobalt naphthenate, and cobalt stearate. The cobalt carbonyl may be tetracobalt dodecacarbonyl or dicobalt octacarbonyl. The preferred cobalt-containing com pound is dicobalt octacarbonyl.
The physical parameters which are desirable for the ~eedstock of this invention for producing N-acetylamino acid can be described as follows:
The starting acrylate substrates are represented by the structure CH2=CHCOOR .

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The R-group can be methyl or ethyl. Particularly good results are obtained using ethyl acrylate.

Suitable amide-containing coreactants that are useful in the amidocarbonylation reaction have the general structure:

Il Rl CNHR2 where the Rl group may be a combination of aryl, alkyl, arylalkyl and alkylaryl hydrocarbonyl radicals, or hydrogen, including the methyl, ethyl~ butyl, n-octyl, phenyl, benzyl and chlorophenyl groupings. The R2 group must be hydrogen in order to obtain glutaric acid derivatives. Examples of suitable amide coreact-ants include acetamide, benzamide, formamide, and lauramide. The preferred coreactant is acetamide.
The carbon monoxide employed need not satisfy particu~
lar purity requirements al*hough catalyst contaminants should be avoided if the reactlon is intended to continue over an extended period. Particularly in continuous operations, but also in batch experiments, the carbon monoxide and hydrogen gas may also be used in conjunction with up to 1~% by volume of one or more other gases. These other gases may include one or more inert gases such as argon, n~trogen and the like or they may include gases that may, or may not,~undergo reaction under carbon monoxide , .. ,,,., " ~, ... . . .

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~ 8626~:L97 hydrogenation con~itions, such as carbon dioxlde, hydrocarbons, such as methane, ethane, propane and the like, ethers, such as dimethyl ether, methyl ethyl ether and dlethyl ether, alkanols, such as methanol, and the like.
As characterized above, thls process ls operated as a homogeneous liquid phase ml~ture. The reaction ls preferably carried out in an inert solvent. Preferred lnert solvents are those which permlt at least partlal dissolutlon of the cobalt and bls-phosphlne llgand catalyst precursors, the amlde and the olefin. These are generally polar solvents of the ester, ether, ketone, amlde, sulfoxide or aromatic hydrocarbon type, for example, toluene and xylene.
Methyl and ethyl acetate are examples of suitable solvents. Other polar solvents are ethers, such as p-dloxane, methyl tertlary butyl ether, methyl tertlary amyl ether or tetrahydrofuran, tertiary amides, such as dlmethyl formamide, dlmethyl sulfoxlde and ethylene carbonate.
The preferred solvent ls ethyl acetate.
In all these synthesls in order to achleve a high degree of selectivity the amount of carbon monoxlde, acrylate and amide present in the reaction mlxture should be sufficlent to at least satlsfy the stolchlometry of the deslred formation of glutamic acld lntermediates as shown ln ~quation I above. Excess carbon . ~' :,,~1 '' - , ~L3~9~
68~26-197 monoxide over the stoichiometric amount may be present and is ~esirable.
The quantity of cobalt-contalning compound and bls-phosphlne llgand to be used ln the catalyst o~ the lnventlon may vary. The process ls conducted ln the presence of a catalytlcally effec-tive ~uantlty of ~he actlve cobalt-contalning compound whlch glYes the desired proclllct in reasonable yleld. The reaction pro-ceeds when employing as llttle as about 0.1 we~ght percent of the cobalt-contalning compound based on the total weight of the re-action mlxture. The upper concentration is dictated by a varlety of Eactors includlng catalyst cost, partlal pressures of carbon ~onoxide and hydrogen, operating temperature, etc. A cobalt-containing compound concentrat:Lon oE from about 0.1 to about 10 percent, along with a bls-phosphlne ligand concentration of from about Q.l to 1.0 molar ratio based on phosphlne to cobalt is generally deslrable ln the practice of thls lnvention.
Partlcularly superior results are obtained when the above-noted components of the catalyst system are combined as follows on a molar basls: Cobalt-containing compound, to bis-phosphine llgand 10:1 to 1:1 ln molar ratlo.
The operating conditions may vary over a wide range.
The reaction temperature may vary from 25C to 300C or 100C to 180C. The preferred temperature ls from 120C to 150C. The pressure may ' .

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range from 500 psi to 3000 psi or more. It appears that higher selectivities are obtained when operating at moderate pressures, in the range from 800 to 2000 psi~
The amidocarbonylation reaction of this invention is best conducted in a carbon monoxide-rich atmosphere, although some hydrogen gas should also be present in order to achieve max-imum cobalt catalyst activity. The hydrogen to carbon monoxide molar ratio in the reactor may be varied, for example~ within the range from 20:1 to 1:20, but preferably it should be rich in car-bon monoxide and the H2:CO ratio should be in the range 5:1 to 1:5.
The desired products of the synthesis using acrylate olefins are glutamic acid intermediates, such as, for example N-acetylglutamate. Also formed are significant amounts of methyl 4,4-bis(acetamido)butyrate by-products. Each of these products, including by-products can be recovered from the reaction mixture by conventional means such as extraction.
The novel process of the invention can be conducted in a batch, semi~continuous or continuous manner. The catalyst can be initially introduced into the reaction zone batchwise, or it may be continuously or intermittently introduced into such a zone during the course of the synthesis reaction. Operating con ditions can be adjusted to optimize the formation of the desired glutamic acid product, and said material may be recovered by ' " ., ,: : , , ' : ', ' '` ' ' ~,' ~, '' ' ' ~
, methods known to the art, such as extraction. A fraction rich in the catalyst components may then be recycled to the reaction zone, if desired, and additional producis generated.
The products have been identified in this work by one or more of the following analytical procedures: viz, gas liquid phase chromatography (glc), gas chromatography/infrared spectroscopy (GC/IR), nuclear magnetic resonance ~nrnr) and ele-mental analysis, or a combination of these techniques. Analysis have for the most part, been by molar weight; all temperatures are in degrees centigrade and all pressures in pounds per square inch (psi).
The yield (mole %) of N-acetylglutamate derivative in this synthesis using an acrylate is estimated basis Equation I
using the formula:

Moles of N-acetYlqlutamate acids obtained ~ Moles of acrylate char ~ x 100%
:

To illustrate the process of the invention, the follow-ing examples are given. Examples I-IX demonstrate the method of using acrylates in the process of this invention. It is to be understood, however, that the examples are given in the way of illustration and are not to be regarded as limiting the invention in any way.

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A 300 ml stainless-steel stirred autoclave was charged dicobalt octacarbonyl ~1.02gr 3.0 mmoles), bis-1,3-(diphenylphosphino)propane (0.312g, 0.76 mmoles), methyl acrylate (17.2g, 200 mmoles), acetamide (11.8g, 200 mmoles) and ethyl acetate (20g). The reactor was purged of air with the mixture of CO/H2 (1:1 ratio) and heated to 130C. At ~he temper-ature range of 123-140C, the pressure was increased to 800 psi and held for four hours. During the process, the increment of syngas was added and totally 490 psi of syngas consumptlon was recorded. The reactor was cooled to room temperature, excess gas vented and the liquid products (52.ly) was recovered.
The H-nmr analysis showed two major products at 1.25 to 1.0 molar ratio of Compounds I and II:

~1 I HOC O CH CONH

(I) (II) EXAMPLE II
A glass-lined rocking autoclave was charged with dicobalt octacarbonyl (0.34g, 1 mmole), bis-1,3-(diphenylphos ' 6 9 3 L~L

phino)propane (0.416g, 1 mmole), methyl acrylate ~8.6g, 100 mmoles), acetamide 15.9g 100 mmoles) and ethyl aeetate ilOg)-The reactor was purged with syngas, pressured at 800 psi (CO/H2=1:1) and heated to 130C. A-t this temperature, the pres-sure was inereased to 2000 psi and held for 4 hours. The recovered liquid product solution (27.7g~ was analyzed by H-nmr and showed ca. 70% yield to product X and :[I at 3.5 to 1.0 ratioO

EXAMPLE III
The identical experimental procedures of Example I were employed. The reactor was eharged with dieobalt octaearbonyl (0.34g, 1 mmole), 1,3-bis~diphenylphosphino)propane (0.206g, 0.5 mmole), ethyl aerylate (10.0g, 100 mmoles), acetamide ~5.9g, 100 mmoles~ and toluene (20g~.
The reaction conditions were ca. 130C, 800 psi ~CO/H2=1:1), and 4 hours. The reeovery produet solution eon-tained two layers: 20.9g for the top layer and 15.4g for the bottom layer. The bottom layer solution eontained produet III
and IV at 3.7 to 2.0 molar ratio.

HOOC \ CH3CONH

CHCH2CH~COOC2H5 CHCH2CH2CC2H5 CH CN CH CONH
; 3 IIH 3 O
(III) (IV) i, . . .

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EX~MPLE IV
Procedures identical to -those oE Example I were employed. The reactor was charged with dicobalt octacarbonyl (0.34g, 1 mmole), bis-1,3-(diphenylphosphino)propane (0.206g, 0.5 mmole~, methyl acrylate (8.6g, 100 mmolPs3, acetamide (5.9g, 100 mmoles) and ethyl acetate (25.0g). The reaction conditions were 800 psi (CO/H2-1:1), ca. 130C and 4 hours.
The product solution (40.6g) showed the molar ratio of I:II at 2.4:1Ø

EX~MPLE V
The experimental procedures of Example I were repeated.
The reactor was charged with dicobalt octacarbonyl tO.34g, 1 mmole), bis-~1,3-diphenylphosphino)propane (0.206g 0.5 mmole), methyl acrylate (8.6g, 1~0 mmoles), acetamide ~5.9g, 100 mmoles) and toluene 125g). The reaction conditions were 114-139C, 800 psi and 4 hours. The product solution contained two layers.
The top layer solution 26.6g and the bottom layer solution 13.0g.
The H-nmr analysis oE the bottom layer showed the presence of product I:II at 2.7:1.0 molar ratio.

EXAMPLE VI (Comparative) The experimental procedures of Example I were repeated.
~ The reactor was charged with dicobalt octacarbonyl .:`

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(0.17g, 0.5 mmoles), bis-1,3-(diphenylphosphino)propane (0.103g Q.25 mm), methyl acrylate (8.6g, 100 mmoles~, acetamide (5.9g, 100 mmoles) and toluene ~25g~. The reaction conditions were 116-124C, 800 psi and 4.5 hours. The procluct solution contained the recovery starting material only.
The ratio of catalyst to substrate and the reaction temperature are important ~actors for amido acid synthesis.

EXAMPLE VII - (Comparative) Procedures identical to those of Example VI were used, except no acetamide was used. The reactor was charged with Co2(CO)8 (0.17g, 0.5 mmole), bis-1,3-(diphenylphosphino)propane (0.103g, 0.25 mmole), methyl acrylate (8.6g, 100 mmoles) and toluene (25.0g). The reaction conditions were ca. 120C, 800 psi and 3.0 hours. The analysis o* the product solution showed 93%
conversion of methyl acrylate and 91% selectivity to methyl ester of 3-formyl propionic acid (V).

OHCCH2CH2COOCH3 (V) The above two comparative examples indicated two-step reactions involved in process (a) hydroformylation of acrylate to ~3~3~

3-formyl propionate and process Ib) amidocarbonylation of (V) to amidoacid, required different conditions EXAMPLE VIII ~
Experimental procedures similar to Example VI were employed, except HRh(CO~(PPh3)3 was used instead of dicobalt octacarbonyl. Under the similar reaction conditions there was no amido acid product observed. It was found that Rh catalyst performed the hydroformylation at the alpha position of the methyl acrylate, followed by a side reaction such as a Michael addition led to a different reaction path.

EXAMPLE IX
A glass-lined reactor was charged with dicobalt octacarbonyl (5.1g, 15 n~oles), acetamide (53g, 898 mmoles), ethyl acrylate (75g, 750 mmoles), and p-dioxane (150g~. The re-actor was purged of air and pressured with CO/H2 (1:1 ratio) to 500 psi. The system was heated to 130C-153C, then pressured with CO/H2 to 2000 psi. During two hours reaction time, 2000 psi of pressure was maintained by ~requently adding increments of CO/H2 gas. After cooling to room temperature, a homogeneous, light-brown solution (314.3g) was recovered. An aliquot of the product mixture was added with 10% Na2CO3 and then solid K2CO3 to aliquot the PH=10. The solution was extracted twice by methyl ~3 1~5~

acetate to remove the by-products. The aqueous solution was then adjusted with 85~ phosphoric acid until PH2 and again extracted with ether and methyl acetate to afford 126g of compound (I).
The structure (I) was confirmed by H-NMR and IR.

HOOC\

/CHCH2CH2COC2~I5 CH3llNH

The cobalt contamination in the product was 118 ppm after one extraction and was 7.0 ppm after the second extraction.

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Claims (18)

1. A process for the synthesis of a glutamic acid inter-mediate represented by the structures I or II

(I) or, (CH3CONH)2CHCH2CH2COOR (II) wherein R is methyl or ethyl comprising reacting an acrylate amide and syngas in the presence of a cobalt-catalyst, a bis-phosphine ligand and a solvent at a pressure of 500 to 5,000 psi and a tem-perature of 50 to 180°C for a compound of formula I or 50 to 160°Cfor a compound of formula II and, where required, separating a compound of formula I or II so obtained.

2. A process according to claim 1 wherein a compound of formula I ls obtained and separated.

3. A process according to claim 1 wherein a compound of formula II is obtained and separated.

4. A process of claim l, 2 or 3 wherein the acrylate is selected from the group consisting of methyl acrylate and ethyl acrylate.

5. A process of claim 1, 2 or 3 wherein the amide is acet-amide.

6. A process of clalm 1, 2 or 3 wherein the cobalt-containing compound is selected from the group consisting of cobalt carbonyls, cobalt halides and cobalt carboxylates.

7. A process of clalm 5 wherein the cobalt-containing compound is selected from the group consisting of dicobalt octacarbonyl, cobalt(II) acetate, cobalt(II) chloride and cobalt(II) bromide.

8. A process of claim 7 wherein the cobalt-containing compound is dicobalt octacarbonyl.

9. A process of claim 1, 2 or 3 wherein the bis-phosphine ligand is selected from the group consisting of 1,3-bis(diphenyl-phosphino)propane, 1,6-bis(diphenylphosphino)-hexane and 1,2-bis(diphenylphosphino)ethane.

10. A process of claim 9 wherein the bis-phosphine ligand is of the formula Ph2P(CH2)xPPh2, where X = 1-6.

11. A process of claim 9 wherein the bis-phosphine ligand is 1,3-bis(diphenylphosphino)propane.

12. A process of claim 1, 2 or 3 wherein the solvent is an acetate, ether or aromatic compound.

13. A process of claim 1, 2 or 3 wherein the solvent is selected from the group consisting of methyl acetate, ethyl acetate, toluene, xylene and p-dioxane.

14. A process of claim 1, 2 or 3 wherein the pressure range is 800 to 3,000 psi.

15. A process of claim 1, 2, or 3 wherein the temperature range is 100 to 160°C.

16. A process of claim 1, 2 or 3 wherein the temperature range is 120 to 150°C.

17. A process of claim 1, 2 or 3 wherein after the N-acetylglutamate intermediate is obtained, a mineral acid is used to extract the glutamic acid.

18. A process according to any one of claims 1, 7, 8, 10 or 11 wherein R is methyl and the compound of formula II is obtained and separated.