CA1096881A - Preparation of aliphatic and heterocyclic alpha-keto carboxylic acids - Google Patents

Preparation of aliphatic and heterocyclic alpha-keto carboxylic acids

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Publication number
CA1096881A
CA1096881A CA284,976A CA284976A CA1096881A CA 1096881 A CA1096881 A CA 1096881A CA 284976 A CA284976 A CA 284976A CA 1096881 A CA1096881 A CA 1096881A
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Prior art keywords
alpha
carboxylic acid
keto carboxylic
aqueous solution
aqueous
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French (fr)
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Roger R. Gaudette
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WR Grace and Co
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WR Grace and Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/96—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/185—Saturated compounds having only one carboxyl group and containing keto groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
    • C07F1/005—Compounds containing elements of Groups 1 or 11 of the Periodic Table without C-Metal linkages

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

Docket No. 5102 PREPARATION OF ALIPHATIC AND HETEROCYCLIC
ALPHA-KETO CARBOXYLIC ACIDS
Abstract of the Disclosure A crude alkali metal salt of an aliphatic or hetero-cyclic alpha-keto carboxylic acid is prepared by hydrolyzing a 5-alkylidene hydantoin or a hydantoin having the formula

Description

10~68Bl Background of the Invention This invention is in the field of alpha-keto carboxylic acids and the alkali and alkaline earth salts thereof.
Crude alkali metal salts of said acids are prepared by tne reaction represented by the following equation:
Z=C C=O o o ¦ ¦ ~ 3MOH+ H2O~ ~R-C-C-OM + 2NH3 ~ M2C03 H-N N-H
\C/
Il O ~ , in which: (a) Z is CH3-C-CH3, CH3-CH2-ll-CH3, or CH3-CIH Cl=

H H H
(b) R is CH3-C-C~3, CH3-CH2-C-CH3, or CH3-CH- f_; and , CH3 H
(c) ~ is Na or K.
LiOH can be substituted for NaOH or KOH in the reaction represented by the above equation. LiOH is less desirable than NaOH or KOH because of the low solubilities of LiOH and Li2CO3.
Copending application Serial No. 284,975 filed on even date teaches a method for preparing 5-secondary alkylidene hydantoins. Said application is assigned to W. R. Grace & Co.
Alpha-keto carboxylic acids (which are also referred to herein as "alpha-keto acids" and as "keto acids") have many uses including but not limited to those listed below;
1. Keto acids are useful as starting materials for the synthésis of amino acids (Yakabson et al, Biokhimya, 1949, 14, 14-19, Chemical abstracts, 1949, 43, 5084d; Sakurai, J. Biochem. (Tokyo), 1958, 45, 3~9-85, Chemical abstracts - .

1958, 52, 18537h; Japanese patent No. 18,711 (1962), Chemical Abstracts, 1963, 59, 11660p; and Japanese patent ~o. 6884 (1963), Chemical Abstracts, 1963, 59, 11662d).
2. Keto acids are useful as pharmaceuticals against uremia for promoting protein synthesis and for suppressing - urea formation (Walser, German Offenlegungsschrift No. 2,335,215 (1974)).
3. Keto acids are useful as catalysts in the copoly-merization of unsaturated monomers (Dutch patent publication No. 298,715, Chemical Abstracts, 1966, 64, 6842dr and British patent specification No. 1,018,109 (1966)).
4. Keto acids are useful as hair treating agents to protect hair against hydroperoxides (German Auslegeschrift No. 1,158,213 (1963)).
The Kirk-Othmer Encyclopedia (Second Edition, 1966, Vol. ll,!pages 148-149) teaches that unsaturated hydantoins having the formula H

I

Rl-C=f - C=O
\ C /

` - O
in which: (a) Rl is phenyl, p-hydroxyphenyl,.or p-methoxy-phenyl and R2 is hydrogen; or (b) Rl is hydrogen or phenyl and ` R2 is phenyl can be hydrolyzed with dilute alkali.to yield a pla-keco ac.ds.

1~68~1 An apparently undated 25 page bulletin entil:led "HYDANTOIN" which was circulated by Nobel Hoec}lst Chimie, Tour Nobel, 92 Puteaux, (France) teaches the preparation of certain alpha-keto carboxylic acids from hydantoins, ~ illek, Monat~, 1961, 92, 335-342, 343-351, and 352-360, Chemical ~bstracts, 1962, 56, 393e teachcs -the condensation of certain aromatic aldehydes with hydantoin and the alkaline hydrolysis of the products of said condensa-tion to form keto ac.ids.

Summary of the Invention . _ In summary this invention is directed to a process for preparing an alpha-keto carboxylic acid having the formula O O
Il 11 R--C -C -OH
in which R is I H
CH -f-CH , CH3-C-CH2-, or CH -CH -C-CH , said process comprising:
(a) admixing: (i) a hydantoin having the formula æ=c--c=o H-N N-H
\C/
o ln which z is H H
CH3-C-CH3, CH3-C-C=, or Il CH -CH -C-CH , and (ii) a first aqueous solution consisting essentially of ~ater and sodium hydroxide or potassium hydroxide and maintaining the resulting admixture at a tempera-ture effective for forming a second aqueous solution comprising water, and a salt of the alpha-keto carboxylic acid having the formula O O O O
Il 11 11 11 2 n R-C-C-ONa or R-C-C-OK, for a time effective for forming the s.econd aqueous solution, the sodium hydroxide or potassium hydroxide being present in an amount effective for forming the salt of the alpha-keto carboxylic acid;
(b) adjusting the pH of the second aqueous solution to a value effective for forming a third aqueous solu-tion comprising water and the alpha-keto carboxylic acid;

_ 5 _ 1~9~

(c) extraeting the alpha-keto carboxylic acid from the third aqueous solution with an amount of a volatile inert solvent whieh is substantially insoluble in water effective for forming a ~irst non-aqueous solution eonsisting essentially of the volatile inert solvent whieh is substantially insoluble in water and th~ alpha-keto carboxylie aeid; and (d) separating the alpha-keto earboxylic aeid from the first non-aqueous solution by evaporating the volatile inert solvent therefrom, and reeovering the resulting separated alpha-keto earboxylic acid.

Deseription of Preferred Embodiments 1. The first aqueous solution consists essentially of water and'sodium hydroxide. (It is well known that aqueous sodium hydroxide solutions generally eontain sodium carbonate as a minor component).
2. The pH of the seeond aqueous solution is adjusted with hydroehlorie aeid or sulfurie aeid.
3. The temperature of the second aqueous solution is adjusted to about 5-35C (if it is not already at said temperature) before adjusting its pH to a value effeetive for forming an aqueous solution of the alpha-keto carboxylie acid.
4. ~he volatile inert solvent is diethyl ether, diisopropvl ether r ethyl acetate, n-butyl aeetate, or methyl isobutyl ketone.
In another preferred embodiment (Embodiment A) this invention is direeted to a process for preparin~ a first aqueous solution consisting essentially of water and a sodium, potassium, or calcium salt of an alpha-keto carboxylie acid having the formula 6l381 o o Il 11 in which R is CE~3- 1-C113, CH3 f C 2 ' El C113 C113 C112 ¦ 3 r Il said process comprising:
(a) admixing! (i) a hydantoin having the formula ~=f _ c=o Il-N N-~l \C/
Il O
in ,which Z is Il 11 3 ~3, CH3-1-C=, or CH3-CH2-C-cll3, and (ii) a second aqueous solution consisting essentially of sodium hydroxide or potassium hydroxide and maintaining I . the resulting admixture at a temperature effective for forming a third aqueous solution comprising water, - a salt of an alpha-keto carboxylic acid having the formula O O O
Il 11 11 11 ~ . R-C-C-ONa or ~-C-C-OK, 1~9~

for a time effective for forming the third aqueous solu-tion, the sodium hydroxide or potassium hydroxide being present in an amount and concentration effective for forming the third aqueous solution;
(b) adjust.ing the pH of the third aqueous solution to a value effective for forming a fourth aqueous solu-tion comprising water and the alpha-keto Carboxylic acid;
(c) extracting the alpha-keto carboxylic acid from the fourth aqueous solution with an amount of a volatile inert solvent which is substantially insoluble in water effective for forming a non-aqueous solution consisting essentially of the solvent which is substantially insolu-ble in water and the alpha-keto carboxylic acid;
(d) converting the alpha-keto carboxylic acid to its~sodium, potassium, or calcium salt and forming the first aqueous solution by extracting the salt from the non-aqueous solution with an amount of an aqueous system consisting essentially of water and a member selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium carbonate, sodium bicarbonate, and potassium bicarbonate effective for forming the first aqueous solution.
. ~
In especially preferred embodiments of this invention as recited in the above Embodiment A:
1. The second aqueous solution consists essentially of sodium hydroxide and water. (It is well known that aqueous sodium hydroxide solutions generally contain sodium carbonate as a minor component).

.: 30 r ~ .
:' , 1~6~3 2. The pH of the third aqueous solution is adjusted with hydrochloric acid.
3. The temperature of the third aqueous solution is adjusted to about 5-35C (if it is not already at said temperature) before adjusting its pH to a value effective for forming an aqueous solution of the alpha-keto carboxylic acid.
4. The aqueous system consists essentially of an aqueous sodium hydroxide solution.
5. The aqueous system consists essentially of an aqueous potassium hydroxide solution. (It is well known that aqueous potassium hydroxide solutions generally contain potassium carbonate as a minor component~.
6. The aqueous system consists essentially of an aqueous calcium hydroxide solution or slurr~. ~It is well known that aqueous calcium hydroxide slurries generally contain calcium carbonate as a minor component).
7. The volatile inert solvent is diethyl ether, diisopropyl ether, ethyl acetate, n-butyl acetate, or methyl isobutyl ketone.
In another preferred embodiment ("Embodiment B") this invention is directed to a process for preparing a first aqueous solution comprising water and an alkali metal salt of an alpha-keto carboxylic acid, the salt having , ; the formula O O
cH2 -c--c-oM
in which M is an alkali metal ion and Rl is a member selected from the group consisting of .
;~ 30 :
_ g _ ~A

CH 3--, CH3CH2-, C 3 2 2 ' CH - fH--CH3, H2NCH2cH2c 2 -CH2COOH, -CH2SCH3, H
CH 3 - C- CH 2 -, H

H-N N , and ~ CH

~CH 2 the process comprising: (a) forming an admixture by admixing a hydantoin having the formula \\_ //
/c ~\
H-N ~ N-H

O

and a second aqueous solution comprisin~ ~ater and an alkali metal hydroxide; and (b) maintainin~ the admixture at a ' `' "

~;9Q6~381 temperature effective for forming the salt of the alpha-keto carboxylic acid for a time effective for forming the salt, the alkali metal hydroxide being present in an amount and concentration effective for forming the alkali metal salt of the alpha-keto carboxylic acid.
If desired, the first aqueous solution of this embodiment (Embodiment B) can be treated according to the process recited in steps "(b)" through "(d~" of the above Summary by replacing, in step "(b~" of said Summary, the second aqueous solution of said Summary with the first aqueous solution of this embodiment and proceeding as recited in said steps "(b)" through "(d~".
Also, if desired the first aqueous solution of this embodiment (Embodiment B~ can be treated according to the process recited in steps "(b)" through "(d~" of Embodiment A, supra, by replacing, in step "(b)" of said Emhodiment A, the third aqueous solution of said Embodiment A with the first aqueous solution of this embodiment and proceeding as recited in said steps "(b)" through "(d)".
In the process of Embodiment B, sodium hydroxide is a preferred alkali metal hydroxide.
In another preferred embodiment ("Embodiment C") this invention is directed to a process for preparing a first aqueous solution comprising water and an alkali metal salt ; `
of an alpha-keto carboxylic acid, the salt having the formula '~ O O
: . Il 11 ,',: , R2-C--C--OM
;~ ~ in which M is an alkali metal ion and R2 is ~ CH3fHcH2cH2cH3~ CH3C~2CIHCH2CH3' CH3-lc-cH3 ii . 30 CH _I_CH2_, CH3-CH2 Cl CH3-'. ~

lQQ~
the pn~ss comprising: (a) forming an admixture by admixing a hydantoin having the formula Y=f c=o H~N /-H

in which Y is CH CC~ CH CH3~ CH3CH2CCH2C~3' CH3 C CH3, CH3 I C ~ 3 2 3 ~

and a second aqueous solution comprising water and an alkali metal hydroxide; and (b) maintaining the admixture at a temperature effective for forming the salt of the alpha-keto carboxylic acid for a time effective for forming the salt, the alkali metal hydroxide being present in an amount and concentration effective for forming the alkali metal salt of the alpha-keto carboxylic acid.
If desired, the first aqueous solution of this embodiment (Embodiment C) can be treated according to the process recited in steps "(b)" th~ouyh "(d)" of the above Summary by replacing, in step "(b)" of sa~ Summary, the second aqueous solution of said Summary with the first aqueous solution of this embodiment and proceeding as recited in said steps "~b)" through "(d) 1?.
Also, if desired the first aqueous solution of this embodiment (Embodiment C) can be treated according to the process recited in steps "(b)" through "(d)" of Embodiment A, supra, by replacing, in step "(b)" of said Embodiment A, the third aqueous solution of said Embodiment A with the first aqueous solution of this embodiment and proceeding as recited in said steps "(b)" through "(d)".
;
. - 12 ,.. ~ .

In the process o:E Embodiment C, sodium hydroxide is a preferred alkali metal hydroxide.
In another preferred embodiment ("Embodiment D") this invention is directed to a process for preparing a calcium 5 salt of an alpha-keto carboxylic acid, said acid having the formula O O \ O O

Rl CH2 2Ca or R -C-C-O 2Ca in which Rl is a mem~er selected from a first group consisting 1~ of H- , C~13C112-, cll3cll2cll2 Cl13-fll-ll3' -c112~:0011 ~
-Cll SCll3 , ~
,~1 , H-N l~ , H
c~l3-c-cll2- , and Cl~3-cll2-c-cll3 , 25 c~3 .
,.

' .

~Q~68~1 and R2 is CH3CHCH2CH2CH3~ CH3CH2CHCH2CH3~ C~3lH-' CH3CH2CHCH3, or ~ , the process comprising: ~
~a) forming a second aqueous solution containing (or comprising) dissolved carbon dioxide by adjusting the pH
of a first aqueous solution comprising water and an alkali metal ~alt of the alpha-keto carboxylic acid ha~ing the formula O O O O
1 CH2C~C~M, or R2-C-C-M
in which M is an alkali metal iont to about 0.5-4 or 2-3~5 with hydrochloric acid, hydrobromic acid, hydroiodic lS acid, or nitric acid while maintaining the temperature of the first aqueous solution at about 10-40C, or 20-30C
(if the first aqueous solution is not at such temperature it can be brought to such temperature by cooling or heating before adjusting its pH~;
(b~ forming a third aqueous solution having a pH of a ~ 5-4 or 2-3.5 and being substantially free of carbon dioxide by removing carbon dioxide from the second aqueous solution (e.g., by sparging with an inert gas such as nitrogen, helium, argon, or the like, by boiling (prefer-25 ~ ably under reduced pressure), or by stripping with steam);
(c~ forming a fourth aqueous solution comprising water and an alkali metal salt of the alpha-keto carboxylic acid by adjusting the pH of the third aqueous solution to 6.5-8.5 or 7-8 (e~g., by adding an alkali metal hydroxide which is substantially free of alkali metal carbonate to the third aqueous solution), the fourth aqueous solution being sub-stantially free of carbon dioxide moieties;

~Q~

(d) forming a slurry comprising a precipitated calcium salt of the alpha-keto carboxylic acid and a mother liquor by admixing the fourth aqueous solution with an aqueous solution of a calcium salt selected from a second group consisting of calcium chloride, calcium bromide, calcium iodide, and calcium nitrate, the second group member being provided in an amount effective for precipitat-ing the calcium salt ~f the alpha-keto carboxylic acid (e.g., 0.6-0.4 mole of second group member per mole of alkali metal salt of alpha-keto carboxylic acid present in the lot ~f solution being treated); and (e) separating and recovering the precipitated calcium salt of the alpha-keto carboxylic acid.
In the process of this invention as recited in Embodiment D:
l. A further amount of calcium salt of the alpha-keto carboxylic acid can be precipitated from the mother liquor of steps (d~ or (e) by evaporating water therefrom (e.g., by boiling - preferably under reduced pressure or by the use of a rotary evaporator). This can be done before or after the separation step (step (e)). If done after the separation step, an additional crop of product can be sepa~ated and recovered. If only a small amount of alkali metal salt of the alpha-keto carboxylic acid is present in the fourth solution, it may be necessary to evaporate water from the admixture formed by admixing the fourth solution and the second group mem~er (in step (d)) to precipitate the calcium salt of the alpha-keto carboxylic acid. (If desired, such water can be evaporated before adding the second group member.~
2. The precipitated calcium salt o~ the alpha-keto carboxylic acid is separated (in step (e)) at a temperature (e.g., 10-30C or 15-25C) effective ~or such separation.

15a -1~9~

In another preferred embodiment ("Embodiment E") this invention is directed to a process for preparing an alpha-keto carboxylic acid having the formula O O O O
Il 11 11 11 Rl-CH2-C-C-OH or R2-C-C-OH
in which Rl is H- , CH3CH2- , H2NCH2c~2cH2 H , and H-N N , and R2 is CH3cHcH2cH2cH3 CH3CH2C~ HCH2CH3 CH3CH2CHCH3 ~

CH3 ' or C ~} ' the process comprising:
25(a) admixing: (i) a hydantoin having the formula Rl c~=c f=o z=c cl =o Il-N N-H or H-N N-H
\C/ \C~
Il 11 O O

-- 15 1'---~ i8 in which Z is CH3ccH2cH2cH3 , CH3CH2lC 2 3 ' 3 H2llCH3 , CH3fH= , or ~ -and (ii) a fi.rst aqueous solution consisting essentially of water and sodium hydroxide or potassium hydroxide and maintaining the resulting admixture at a tempera-ture effective for forming a second aqueous solutioncomprising water, and a salt of the alpha-keto carboxylic acid having the formula O O O O
~1 11 11 11 Rl-cH2-c-c-oNa~ Rl-CH2-C-C OK~
O o O o , R2-c-C-ONa, or ~2-C-C-OK, for a time effective for forming the second aqueous solution, the sodium hydroxide or potassium hydroxide - being present in an amount and concentration effective for forming the salt of the alpha~keto carboxylic acid;
(b) adjusting the pH of the second aqueous solu-tion to a value effective for forming a third aqueous solution comprising water and the alpha-keto carboxylic - acid;
(c) extracting the alpha-keto carboxylic acid from the third aqueous solution with an amount of a volatile inert solvent which is substantially insoluble in water effective for forming a first non-aqueous solution consisting essentially of the volatile inert solvent which is substantially insoluble in watex and the alpha-keto carboxylic acid;

- 15c -.

1~

lQ~6881 (d) separating the alpha-keto carboxylic acid from the volatile inert solvent by evaporating the volatile inert solvent, and recovering the result~ng separated alpha-keto carboxylic acid.

': ' - ' ' ' . , ' ~ ' - ' - :
.

.

Uetailed D~sc.ripti~n of the lnvention It is an o~ject of this invent.ion to provi~e a n1ct11oc1 for preparing an alpha-keto carboxylic acid having the formula O O
Il 11 1~-C-C-011 in which R is lll Cl,3_f_CI,3 C113-f Cll2 11 C1i3 I
C1.13-cll2-f-c113 Il .

from a h,ydantoin having the formula Z--C I
C
~1 .
o in which Z is Il 11 ., Il l I
C113-C-CH3~ C113 f 11 , C113-c1l2 C C 3;

This can be done by the method recited in the above Summary.
It is another object of this invention to provide a method for preparing an aqueous solution or slurry of a sodium, potassium, or calcium salt of said alpha-keto carboxylic acid la!968Bl from said hydantoin. This can be done by the method recited in Embodiment A, supra. If desired, the sodium, potassium, or calcium salt of said alpha-keto acid can be separated from the aqueous solution thereof by evaporating the water therefrom -preferably using reduced pressure (i.e., a pressure less than 760 mm of mercury absolute1 where evaporating the water.
Other objects o~ this invention include pre-paring salts of alpha-keto carboxylic ac~ds of the type described in Embodiments A, B, C, and D, supra. Such salts can be prepared by the methods recited in said embodiments.
In the process of this invention as recited in the above Summary and the embodiments thereunder, and in certain of the above Preferred Embodiments a volatile inert solvent which is substantially insoluble in water is used to extract the alpha-keto carboxylic acid from an aqueous solution of said acid~
As used herein, the term "volatile inert solvent which is substantially insoluble in water" means an inert solvent boiling between about 30C and 160C at about 760 mm of mercury absolute pressure and whose solubility in water does not exceed about 9 parts per hundred parts of water at about 20QC. The term "inert" as applied to such solvent means that it tsaid solvent~ does not react chemically with water or with the alpha-keto carboxylic acid, The following table lists some solvents which are "volatile inert solvents substantially insoluble in water".

~ - 17 lQ~68Bi Typical Volatile 'Inert S'o'lven'ts'Which Are Substantially 'I'nsoluble'In Water n-amyl alcohol 2-pentanol 3-pentanol 2-methyl-4-butanol 2-methyl-3-butanol the hexyl alcohols n-amyl acetate sec-amyl acetate methyl isobutyl ketone n-butanol diisopropyl ether diethyl ether isopropyl ethyl ether n-butyl acetate di-n-butyl ether ethyl acetate n-propyl acetate n-propyl ether diethyl ketone n-hexanol cyclohexanol ethyl iso-butyl ether ethyl n-hexyl ether ethyl iso-amyl ether methyl iso-butyl ether methyl n-butyl ether methyl n-propyl ether anisole benzene toluene . - 18 -1~6?~Bl ethylbenzene n-propylbenzene ~so-propylbenzene m-xylene o-xylene p-xylene n-pentane iso-pentane n-hexane iso-hexane 2,2-dimethylbutane 3,3-dimethylbutane 3-methylpentane n-heptane isoheptane 2-methylhexane 3-methylhexane 2,2-dimethylpentane 3,3-dimethylpentane 3-ethylpentane 2,2,3-trimethylbutane the octanes the nonanes cyclohexane cycloheptane cyclopentane cyclooctane cyclohexene hexadiene, 1-3 hexadiene, 1-4 : the heptylenes ,. -- 19 Y
1' ~

l~q6~1 the hexylenes petroleum ethers boiling below 150C
at about 760 mm of mercury absolute and mixtures thereof the amyl chlorides the dichloropropanes the hexyl chlorides the butyl chlorides 3-chloro-2,3-dimethylpentane chlorobenzene cyclopentyl chloride chloroform carbontetrachloride l,l-dibromoethane 1,2-dibromoethane dichloroethane 1,2-dichloroethane allyl ether cycloheptene the cyclohexadienes cyclohexyl chloride l-nitrobutane 2-nitrobutane :~ 2-nitro-2-methylpropane the octylenes the butyl chlorides the butyl bromides the ~utyl iodides 2-bormo-2,3-dimethylbutane and other bromo-: 30 butanes bo~ling below about 15QC at about 760 mm o~ mercury absolute X

iO~688~
l-chlorohexane and o-ther chlorohexanes boiliny below about 160C at 760 mm of mercury Wh~r~ s~paratlng an al~ha-keto carboxylic fKOJII .I volatilc inert solvent having a normal boiling point ~bove about 100-110C by evaporating the solvent from the ~cid, I yenerally prefer to use reduced pressure (e.g~, a pressur~ of about 100-200 nun of mcrcury absolute or less) tllereby to reduce or eliminate the possibility of causing thermal decomposition of the acid.

Where convcrting a salt (e.g. ~n alkali metal salt) of an alpha-keto carboxylic acid to the free acid (e.c;. as in the above Sun~ary or En~odiment ~) I generally prefer to do this by adjusting the pll of an aqueous solution of-the salt of th~ al~ha-keto acid to about 0.5-2 or 0.8-1.5 with a strong acid such as hydrochloric acid, sulfuric acid or the like.
The hydantoins recited in ~mbodiment B can be prepared by tll~ following method:

H-C - C=O

llydantoin ¦ l Il-N N-ll \(,/
'li O
can bc admixed with and reacted with an aldehyde havinc3 the formula 1~ -~11() .

in which R1 is a n!ember selected from the grou~ CollsistillcJ of Il--C113C112-, CH3cl~2cH

lOQ&~Bl H2NCH2CH2cH2 -cH2cooH ~
C 2 C 3, H
CH3-C-CH2-, CH3 -CH-- , 0 ,H

H , and ,~ ~
- H-N N, .
~' ' `
:: , in an aqueous reaction medium in the presence of a catalyst (catalytic agent) selected from the group consisting of; (i) .
ammonia; and (ii) a primary amine having a PKb between about 3 and about 5, said catalyst being present in an amount effective for causing the formation of the product hydantoin.
The product hydantoin can be separated (e.g., by crystalliza-tlon followed by filtration, centrifugation, or decantation), dried (if desired), and recovered.
At least a major portion of the product hydantoin will generally preclpitate as it forms. If such precipitation does not occur, the product hydantoin can be caused to precipitate or crystallize by evaporating water from the lQq6~8~

aqueous reaction medium in which it (the product hydantoin) was formed and subsequently cooling the resulting concentrated mixture. Such evaporation is preferably conducted under reduced pressure. A mole ratio of reactant hydantoin to catalyst to aldehyde o~ a~out 1:0.5-10:0.5~4 is generally preferred, residence time is generally 1-8 hours and reaction temperature is about 50-150C. Monoethanolami~e is a preferred catalyst.
Details on the preparation of hydantoins substituted in the 5-position are given in copending application Serial No. 234,975.
The hydantains recited in Embodiment C can be prepared by the following method:

l H-C - C=O

Hydantoin, ¦ l H-N N-H
\C/
11 . .
O
20 can be admixed with and reacted with a ketone having the formula Y=O
;: in which Y is--~ CH3CIICH2cH2cH3, CH3CH2C~CH2CH3, CH3CCH3, . C~3CIHCH= , CH3cH2lclcH3~ or in an aqueous reaction mixture in the presence of a catalyst (catalytic agent) selected from the group consisting of; ~i) ammonia; and (ii) a primary amine having a PKb between about 3 and about 5, said catalyst being present in an amount effective for causing the formation of the product hydantoin.

i~-x-:~
' .`, :~ `h 9~i8~

- The product hydantoin can be separated (e.g., by crystalliza-tion dried (if desired), and recovered.
At least a major portion of the product hydantoin will generally precipitate as it forms. If such precipitation does not occur, the product hydantoin can be caused to precipitate ~ or crystallize by evaporating water from the aqueous reaction medium in which it (the product hydantoin) was~formed and ~subsequently cooling the resulting concentrated mixture.
Such evaporation is preferably conducted under reduced pressure.
A mole ratio of reactant hydantoin to catalyst to ketone of about 1:0.5-10:0.5-4 is generally preferred, residence time is generally 1-8 hours and reaction temperature is about S0-150C. Monoethanolamine is a preferred catalyst.

. , .

i ' ~ .

;~ . , , ;
~ 1~

: ~ .

: , . .

~6881 In the process of this invention, where converting a hydantoin to an alkali metal salt of an alpha-keto carboxylic acid by reacting the hydantoin with an aqueous solution of an alkali metal hydroxide, the: (a) mole ratio of hydantoin to alkali metal hydroxide; (b) concentration of the alkali metal hydroxide; (c) reaction temperature; and (d) contact time (residence time which is often called "reaction time") are not critical. The following are operable parameters:
~he following are operable parameters:
(a) Mole ratio, hydantoin to alkali metal hydroxide, 1:1.25-25 (preferably 1:1.5-6).
(b) Concentration of alkali metal hydroxide (in the reaction system in which the hydantoin is to be converted to al~ali metal salt of the alpha-keto carboxylic acid), 1-26% (preferably 10-20%).
(c) Reaction temperature, 75-150C (preferably 90-110C).
(d) Contact (residence time) 0.5-10 hours (preferably 2-5 hours).
Sulfuric acid, hydrochloric acid, hydrobromic acid, hydro-iodic acid, and nitric acid are preferred acids for loweringpH in the process of this invention (e.g., to convert part or all of an alkali metal salt of an alpha-keto carboxylic acid present in an aqueous solution to free alpha-keto carboxylic acid). However, where calcium ions are present in a system or where calcium ions will be introduced in a later step (i.e., after lowering the pH) I prefer to avoid the use of sulfuric acid because of the low solubility of calcium sulfate.
Where extracting an alpha-keto carboxylic acid from an aqueous solution of such acid with a volatile inert solvent the ratio of such solvent to aqueous solution is not critical.

`` 1~96~

The operable range includes 0.5-1.5 liters or more of such solvent per liter of the aqueous solution, and a preferred amount is 0.75-1 liters of such solvent per liter of the aqueous solution. Preferred volatile inert solvents include diethyl ether, diisopropyl ether, ethyl acetate, n-butyl acetate, and methyl isobutyl ketone.
Where extracting an alpha-keto carboxylic acid (as an alkali metal or calcium salt of the alpha-keto carboxylic acid) from a solution of the free alpha-keto carboxylic acid in a volatile inert solvent with an aqueous system (solution or slurry) containing an alkaline moiety selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, .
~ potassium bicarbonate, calcium hydroxide, and calcium carbonate : .
lS~ an equivalent ratio of keto acid to alkaline moiety of 1:0.8-l.S
is operable and a preferred ratio is 1:0.9-1. One mole of the alpha-keto carboxylic acid is one equivalent thereof. One mole of sodium hydroxide, potassium hydroxide, sodium bicarbonate, or potassium bicarbonate is one equivalent théreof. One mole 20; ;~of~sodium carbonate, potassium, carbonate, calcium carbonate, or calcium hydroxide is two equivalents thereof.
In such extraction, the concentration of the alkaline moiety~ls not critical. Operable concentrations include 0.5-8 equ1valents of the alkaline moiety per liter, and preferred concentrations~are l-S equivalents of said moiety per liter.
As~ is well known to those skilled in the art, a sodium hydroxide solutlon~usually contains some sodium carbonate, a potassium hydroxide solution usually contains some potassium carbonate and a calcium hydroxide solution of slurry usually contains 30~ some calcium carbonate. The solubility of calcium carbonate in water is low (about 0.015 g per 100 g of water at 25C~.

. . ~

1~9~ Bl It is noted that ammonia and an alkali metal carbonate are produced as by-products where a hydantoin of the type recited in the above summary and Preferred embodiments and an alkali metal hydroxide are reacted in an aqueous system to form an alkali metal salt of an alpha-keto carboxylic acid.
Where forming a slurry comprising a calcium salt of an alpha-keto carboxylic acid by reacting an aque~us solution of an alkali metal salt of the alpha-keto carboxylic acid and an aqueous solution of a water soluble inorganic calcium salt (e,g., CaC12, CaBr2, CaI2, or Ca(NO3)2) concentrations of ~3-8 moles of the inorganic calcium salt per liter are oper-able and preferred concentrations thereof are 5_7 moles per liter. Such concentration is not critical. Likewise, the equivalent ratio of alkali metal salt of the alpha-keto carboxyl~ic acid to such inorganic calcium salt is not critical.
,Operable equivalent ratios of alkali metal salt of alpha-keto carboxylic acid to the inorganic calcium salt include 1:0.8-1~5 .
and preferred ratios are 1:0.9-1.
One mole of CaC12, CaBr2, CaI2, or Ca(NO3)2 corresponds to two equivalents of the respective inorganic calcium salt.
, where forming a calcium salt of an aIpha-keto carboxylic acLd by such technique,, the resulting aqueous system (the ; system formed by admixing the aqueous solution of alkali metal salt of'alpha-keto carboxylic acid and the aqueous solution 25~ ~ of~the inorganic calcium salt) is so dilute (contains so much water~ that the calcium sa'lt of the alpha-keto carboxylic acid fails to precipitate from the resulting aqueo~s system, water can be evaporated therefrom (preferably under reduced pressure) until at least a portion of the calcium salt of the alpha-keto carboxylic acid precipitates.

, .

1~6~

Precipitates or crystals, including precipitated calcium salts of alpha-keto carboxylic acids, can be separated by , centrifugation, filtration, or decantation.
A separated precipitated salt of an alpha-keto carboxylic acid can be washed (e.g., with water or preferably with Water satu~ated with such salt), dried (e.g., air dried), and recovered.
As is well known to those skilled in the art, an alkali ' metal or calcium salt of an alpha-keto carboxylic acid can be ; 10 separated and'recovered from an aqueous solution of such salt ` ~ by evaporating water *herefrom (preferably under reduced ` ~ pressure).
The instant invention will be better understood by ' refering to the following specific but nonlimiting examples ~ and prodedures. It is understood'that said invention is not limlted~by these examples and procedures which are offered ' merely~as~illustratlons; it is also understood that modifi-;cations~can;~be~made~without departing from the spirit and scope~of~the~inventlon. ~ ~
20~ The~examples were actually run.
The procedures,,while not w tually run, will illustrate i,~
certain embodiments o my invention. ,'-- ~ :: : :

~: .
' '~:
~ .

l~Q6E~

EXAMPLE l 939 g ~6.1 moles) of 5-iso-butylidenehydantoin was dissolved in 6 gallons of water containing 976 g (24.4 moles) of sodium hydroxide added as a 50% aqueous solution of sodium hydroxide. The resulting solution was boiled for five and one-half hours. Water was added periodically to maintain a substantially constant volume. Ammonia was evolved during the boiling period.
The reacted (boiled) solution was acidified to pH 1 , while cooling to keep the temperature below 30C, with concentrated hydrochloric acid. The resulting acidified solution was extracted with three 3025 ml portions of diethyl ether to remove the keto acid product from the aqueous solu-tion. The three ether extracts were combined and admixed with 6.1~1lters of water. While stirring vlgorously, the pH of the~admixture was adjusted to 7.3 by adding 50% aqueous sodium hydroxide solution thereto. Stirring was then discon-tlnued and the layers were separated.~ The aqueous layer (ca 6.~4 liters)~consisting essentially of the sodium salt of the ao: kéto àcld~plus water and a small amount of ether was concen-trated~in a~rotary~evaporator to a total volume of about 500 ml.
During~the~ev~aporatlon,~3~ crops of crystaline product were co1lected by~filtration. Said crystaline product was washed with~acetone, drled~by exposlng to atmospheric air at about 2~5~ 20C,~and~welghed~ total weight 536.1 g). This material was ident1fled~as pure sodium ~-keto ~iso-caproate. Since the produot~was hydrated, this weight represents a conversion (one pass yleld)~of~ about 54.5g of theory based on the 5-iso-butyllde~nehydantoin charged.

"~
r: ~ ~ 2 9 ~

f~
r,~
r~: '' ' ., . . .. . ' . . ' ,; .

~6~

The general procedure of Example 1, supra, was repeated.
However, in this instance 86~ g (6.2 moles) of 5-iso-propyli-denehydantoln, 6046 g of 50% sodium hydroxide solution (75.6 moles of sodium hydroxide), and 9 liters of water were used to prepare the reaction (hydrolysis) solution. The reaction solu-tion was boiled for about five and one-half hours The result-ing reacted (hydrolyzed) solution was acidified to about pH 1 with concentrated hydrochloric acid. The acidified hydrolyzed solution was then extracted with three 3.1 liter portions of diethyl ether. The ether extracts were combined and mixed with 6.2 liters of water. The pH of the resulting mixture was adjusted to 6.15 while stirring the mixture vigorously. The aqueous phase was separated and concentrated to a thick slurry lS (about 70iO ml) by evaporating in a rotary evaporator. The solid phase was filtered off, washed with acetone, slurried in acetone, filtered, washed with a second portion of acetone, dried in atmospheric air at about 20C, and weighed. The product which weighed 189 g was identified as pure sodium ~-keto iso-valerate. Since the product was hydrated, this represents a ye~ld of about 21 % of theory based on the 5-iso-propylidene-hydantoin charged.

The general procedure of Example 1 was repeated. However, in this instance 557 g (3.6 moles) of 5-sec-butylidenehydantoin, 3520 g of 50~ sodium hydroxide solution (44.0 moles) of sodium hydroxide, and 5280 ml of water were used to prepare the react-ing solution. The pH of the reacted (hydrolyzed) solution was adjusted to 1 with concentrated hydrochloric acid solution.
The resulting acidified mixture was extracted with three 1800 ml , .

1t99~

portions of diethyl ether. The ether extracts were combined and mixed with 3.6 liters of water and the pH was adjusted to 6.25 by adding 50% sodium hydroxide solution thereto while stirring vigorously. The phases were separated and the aqueous phase was concentrated to about 300 ml in a rotary evaporator.
A crop of crystals was separated by filtration and washed and dried according to the general method of Example 2. This crop of crystals, which weighed 130.4 g, was identified as pure sodium D,L- ~-keto ~ -methyl-n-valerate. Since the product was hydrated this corresponded to a conversion of 22% of ; theory based on the 5-sec-butylidenehydantoin charged.

A first solution was prepared by admixing 32 g of an aqueous 50~ sodium hydroxide solution and 124 g of water.
lS A reactibn mixture was prepared by dissolving 15.4 g of 5-iso-butylidenehydantoin in the first solution. A second solution (hydrolyzate) was formed by boiling the reactant solution for two and three-quarter hours in a vented reac-tion zone. During the boiling period water was added as ~required to malntain the volume of the boiling reactant solution~substantially constant.
The hydrolyzate was cooled to about 25 and its pH was adjusted to 3.5 by adding 26 ml of concentrated hydro-chloric acid solution thereto. The resulting acidified hydrolyzate was sparged (at 20C) with nitrogen (0.1 standard cubic feet per hour) for five minutes to remove carbon dioxide, and a third solution was formed by adjusting the pH of the resulting sparged hydrolyzate to 8 with 50% aqueous sodium hydroxide solution.

'~ .
'' The third solution was concentrated to 95 g by evapora-tion at about 45c and 35 mm of mercury, absolute pressure, in a rotary evaporator. The third solution was cooled to 15C to precipitate a solid product which was separated, air dried, weighed, and analyzed. This solid product weighed 9.3 g and was found on analysis to be crude (ca. 78.1%) sodium alpha-keto iso-caproate.

A first solution was prepared by admixing 49 g of an aqueous 50% sodium hydroxide and 75 g of water. A reactant mixture was prepared by dissolving 15.4 g of 5-sec-butylidene-hydantoin in the first solution.
A second solution (hydrolyzate) was prepared by boillng the reactant mixture for two and three-quarter hours in a ~5 vented reactor while adding water as required to maintain the volume of the boiling reactant mixture substantially constant.
The hydrolyzate was cooled to about 25~C and its pH
was adjusted to 3.5 by adding 48 ml of concentrated hydro-chloric acid solution thereto. The resulting acidified hydrolizate was sparged (as in Example 4) for five minutes with nitrogen and a third solution was formed by adjusting the pH of the resulting sparged hydrolyæate to 8 with an aqueous 50%
sodium hydroxide solution. This required about 1 g of the 50%
sodium hydroxide solution.
,!5 The third solution was heated to 65C and a slurry was formed by adding 10 g of an aqueous 436 calcium chloride solution thereto. The slurry was concentrated to 182 g at about 45~C and 35 mm of mercury, absolute pressure, in a , rotary evaporator. The resulting concentrated slurry was ~`

i~:

. .

lQa:~6881 cooled to 25C and the solid component thereof was separated by filtration, recovered, weighed, and analyzed. The recovered solid component weighed 13.1 g and analyzed 70 calcium alpha-keto beta-methyl-n-valerate representing a yield of 61% of theory based on the 5-sec-butylidene-hydantoin charged.
EX~MPLE 6 The sodium salt of 3-indolepyruvicacid was prepared by:
1. Dissolving 11.4 g (0~05 mole~ or 5-(3'-indolyl-methylene)-hydantoin, CH=C~ C=O
N H-N N-H
\C/

O
lS in~llO ml of water containing 12 g of a 50% sodium hydroxide solution to form a reactant mi:~ture; and 2. Boiling the reactant mixture for two hours at about 760 mm of mercury absolute pressure (while adding water from time-to-time as required to maintain the volume substantially constant) to form an aqueous product solution of the sodium salt of 3-indolepyruvic acid.
~n aliquot of the aqueous product solution was acidified to pH 1 to form free3-indolepyruvic acid which was silylated and then submitted to gas chromatography. This established the presence of the sodium salt of3-indolepyruvic acid in the aqueous product solution.
The salts of the alpha-keto carboxylic acids prepared in Examples 1-5, supra, were identified by infrared spectro-scopy by comparing, in each instance, the results of an infrared scan of the synthesized salt with that of an authen-tic sample.

10~6881 The purities of these salts of alpha-keto carboxylic acids prepared in said examples ~ere, in most instances, determined by gas chromatography. In each instance a portion of the keto acid moiety.of the salt was converted to the oxime which was then silylated and submitted to gas chromato-.
graphy.
These methods (infrared spectrophotometry and gas chroma-tography) can be used to identify and determine the purity of each alpha-keto carboxylic acid and each salt of an alpha-. keto carboxylic acid recited in the above Summary and Preferred .
10. Embodiments and to indentify and determine the purity of alpha-. keto carboxylic acids prepared according to the procedures .; presented infra and to identify and determine the purity of each alpha-keto carboxylic acid prepared according to said : : procedur~s.

.
~:~ j~

, . .
. ..
. . . . . . . .
.:
. .
- -. ~ - :
~: . ' ',: . ' . . ... .
.' - : ' ~6~8~

The general method of Example 1 (using 6.1 moles of 5-iso-butylidene-hydantoin as reactant hydantoin) can be repeated through the ether extraction step. Then the method of Example 1 can modified by evaporating the diethyl ether from the diethyl ether solution of the keto acid which was extracted from the acidified hydrolized solution. The r~sulting keto acid can be distilled under reduced pressure to give pure ~-keto iso-caproic acid in a yield of about 80% based on the 5-iso-butylidenehyda'ntoin charged.

The general method of Procedure 1 can be repeated.
However, in this instance the 5-iso-butylidenehydantoin of Pro~edure 1 can be replaced with 5-iso-propylidenehydantoin.
In thisiinstance the product will be ~ -keto iso-valeric acid which will be obtained in a yield of about 70% based on the 5-iso-propylidenehydantoin charged.

The yeneral method of Procedure 1 can be repeated. How-ever, in this instance 5-sec-butylidenehydantoin can be sub-stituted for the 5-iso-butylidenehydantoin of Procedure 1. In this instance, the product will be D,L- ~-keto-~ -methyl-n-valeric acid. Conversion will be 70% of theory based on the 5-sec-butylidenehydantoin charged.

-~ :

~ .

6~

The hydrolysis, acidification, and ether extraction steps of Example 1 can be repeated~ Then,in this instance,the method of said example can be modified by replacing the 5-iso-butylidenehydantoin of Example 1 with 3 moles of a reactanthydantoin having the formula CH3-S-CH2-CH=C-----C=O

\ C /

, ' The ether extract (containing the product alpha-keto carboxylic acid)can be dried over anhydrous sodium sulfate and separated from the sodium sulfate by decantation or filtra-tion. Thé ether can be evaporated from the separated dried 15 ~ ether extract leaving a residue comprising crude product alpha-keto carboxylic acid which can be recovered. The crude alpha-;keto~carboxylic acld which will be obtained in a yield of 20%
(based on t:he reactant hydantoln charged) will have the formula 20~ O

_s-cH2-CH2 C C OH `

The general method of Example l can be repeated and modi-fled by~replacing the S-iso-butylidenehydantoin of said ~ example~with Z.~l moles of a reactant hydantoin having the formula - H-N N-H

O

~ 36 -,, . ~ .

1t~'''6~Bl and by recovering the hydrolyzate solution which can be formed by boiling the solution formed by dissolving the reactant hydantoin in the aqueous sodium hydroxide solution. The resulting hydrolyzate solution will contain a product sodium 5 salt of an alpha-keto carboxylic acid which will be obtained in a yield of 50 % (based on the reactant hydantoin charged).
This salt will have the formula O O
/ \ 11 11 ~ ~C-C-ONa .

10 ~ PROCEDURE 6 The general method of Procedure 1 can be repeated. How-ever, in this instance the method of said procedure can be modified by replacing the 5-iso-butylidenehvdantoin of Procedure 1 with 6.1 moles of a reactant hydantoin having the formula ~1~=0 H-N N-H
\C/

O
The product alpha-keto carboxylic acid which will be obtained in a yield of 40 ~ (based on the reactant hydantoin charged) will have the formula O O
/ \ 11 11 C-C-OH .

A 6.1 mole portion of a reactant hydantoin having the formula .

~ - 37 -~6~

,~ C~i=C C=O
H-N N-H
Il \C/

can be dissolved in 6 gallons of water containing 24.4 moles of sodium hydroxide present as a 50% aqueous solution of sodium hydroxide. The resulting solution can ~e boiled for five and one~half hours to form a hydrolyzate solu-tion. Water can be added periodically to maintain a substantially constant volume. Ammonia will be evol~ed during the boiling period.
The reacted (boiled) solution comprising a sodium salt of an a]pha-keto carboxylic acid, the salt having the formula O O

~ ~ ` ~ CII2-C-C-ONa can be adjusted to 2 with concentrated (ca. 37%) hydrochloric acid solution after cooling to 20-25C and while maintaining the temperature of the hydrolyzate solution at 20-25C.
Carbon dioxide (resulting from by-product sodium carbonate formed during the reaction (hydrolysis) of the reactant hydantoin whereby the product alpha-keto carboxylic acid is formed~ can be removed from the thus acidulated hydrolyzate by sparging for about lO minutes ~ith nitrogen using a nitrogen flow rate of about l.5 standard cubic foot per hour while maintaining the temperature of the solution being sparged at about 30C. If desired, the volume of the solution can be malntained sub-stantially constant by adding make-up water during the sparg-ing period.

~68~J

The pH of the sparged acidulated hydrolyzate solution can be adjusted to about 7.5 with an aqueous S0~ sodium hydroxide solutio~ which is substantially free of sodium carbonate to form an aqueous solution comprising a sodium salt of the alpha-keto carboxylic acid which is substantially free of sodium carbonate. 500 ml of a substantially carbon-ate free aqueous calcium chloride solution (42.5% CaC12 by wei~ht) can be admixed with the sodium carbonate free aqueous solution of the sodium salt of the alpha-keto carboxylic acid to form the calcium salt of said alpha-keto carboxylic acid.
A portion of said calcium salt will precipitate. This pre-cipitate can be separated from the mother liquor from ~hich it precipitated (e.g., by centrifugation or by filtration~, air dried, and recovered.
One?~or more further lots of the calcium salt of said alpha-keto carboxylic acid can be precipitated, separated, air dried, and recovered from the mother liquor by evaporating water therefrom with a rotary evaporator usin~ a temperature of 25-65C and a pressure of 23-l90mm of mercury absolute.
2~ The total wei~ht of the recovered calcium salt of the alpha-keto carboxylic acid will be 271 g representing a yield of 20 % (based on the reactant hydantoin charged).
The formula of the product calcium salt will be.

~ ~ ~ r CH2-C-C-O ¦ Ca .

1~6B131 PROCED~RE 8 Example 4 can be repeated. However, in this instance the method of said example can be modified by recovering the second solution of said example (i.e., the hydrolyzate solution obtained by boiling the solution of 5-iso-butylidenehydantoin and an aqueous sodium hydroxide). The product~(hydrolyzate solution) can be analyzed by evaporating water from a portion thereof (preferably under reduced pressure3 to obtain a solid product for identifi$ation and analysis by infrared spectro-scopy and gas chromatography.

The general method of Procedure 5 can be repeated. How-ever, in this instance the method of said procedure can be modified by converting the alpha-keto carboxylic acid present in the non-aqueous solvent to its potassium salt by extract-ing with an amount of a 10% aqueous potassium carbonate soluw tion effective to forrn an aqueous solution having a pH of 6-8 and comprising water and a potassium salt of the alpha-keto carboxylic acid, said salt having the formula (~}C-C-OK
The yield of said potassium salt will be 45% based on the reactant hydantoin charged.

~ . .
The general method of Procedure 8 can be repeated. How-ever, in this instance the method of said procedure can be modified by adjusting the pH of the second solution (the hydrolyzate3 to 1, extracting the resulting alpha-keto 1096~1 carboxylic acid from the resulting aqueous solution having a pH of 1 with 150 ml of ethyl acetate, and evaporating the ethyl acetate from said keto acid. Yield will be 85~ based on the 5-iso-butylidenehydantoin charged, and the product J keto acid will be alpha-keto iso-caproic acid.

The method of Procedure 10 can be repeated. However, in this instance, the method of said procedure can be modified by convertin~ the alpha-keto carboxylic acid present in the ethyl acetate to its potassium salt by exteacting wlth an amount of a 10% aqueous potassium hydroxide effective to form an aqueous solution having a pH of 6-8 and comprising water and a potassium salt of the alpha-keto carboxylic acid, sald salt being potassium alpha-keto iso-caproate.

The method of Procedure 7 can be repeated. However, in this ïnstance the reactant hydantoin of Procedure 7 can be replaced with 6.1 moles of a reactant hydantoin having the formula H
/_ \ C=IC~=O
~-N N H-N N-H
\C/
Il .
O
The result wilI be substantially the same as in Procedure 7 except that the product calcium salt of the alpha-keto carboxylic acid will have the formula .
~ O O ~ ' ~ ~ 11 11 / - ~ CH2-C-C- Ca 1~6~

The method of Procedure 7 can be repeated. Ilowever, in this instance the reactant hydantoin of Procedure 7 can be replaced with 6.1 moles of a reactant hydantoin having the formula 2NCH2CH2CH2 ~C C C=O
H ¦ ¦ ~

\ C /

The result will be substantially the same as in Procedure 7 except that the product calcium salt will have the formula O o H2NCH2CH2CH2 C C /2 Ca .

t PROCEDURE 14 The method of Procedure 7 can be repeated. However, in this instance the reactant hydantoin of Procedure 7 can be replaced with 6.1 moles of a reactant hydantoin having the formula HOOCCH2CH=C r=O

\ C /
O
The result will be substantially the same as in Procedure 7 except that the product salt will have the formula O-C-CH2CH2-C-C-O Ca .

Reactions occurring in the process of this invention include, but are not limited to those represented by the f o l lowi ng equations:

Rl-CH=C C=O O O

5H-N N-H + 3NaOH ~ H2O = R -CH -C-C-ONa + 2NH + Na CO

O ,, o o o o Il 11 ~1 11 Rl-CH2-C-C-ONa + HCl = Rl-CH2-C-C-OEI + NaCl Il 11 11 11 Rl-CH2-C-C-OH + NaOH = Rl-CH2 C-C-ONa + H O

Na2CO3 + 2HCl = 2NaCl + CO2 + H2O

O O O O
Il 11 11 11 .
2Rl-CH2-C-C-ONa + CaC12 = (Rl-CH2-C-C-0)2Ca + 2NaCl 1~ 0 0 0 0 Il 11 1 11 2Rl-CH2-C-C-OH + Ca(OH)2 = (R1-CH2-C-C-O)2Ca + 2H2O

In the above equations Rl can be as defined in the above preferred embodiments.

C~C C=O

20H-N N-H + 3KOH + H2O = ~ C-C-OK + 2NH3 + K2CO3 .
Cl .
o Among the alpha-keto carboxylic acids and salts thereof which can be prepared according to the method of this invention are:
O O O O
Il 11 11 11 (a) Rl-CH2-C-C-OX; (b) R2-C-C-OII;
O O O O
Il 11 11 11 (c) Rl-CH2-C-C-OMl; and (d) R2--C-C-O

lQQ68Bl in which:
Ml is an alkaline earth ion (e.g., sodium, ~otassium, or lithium) or one--half of a calcium ion.
Rl iS
H- , CH3CH2~

CH3CH2CHCH3, ' CH3CH2CH2CH2 CH -CH-H2NCH2CH2cH2 -CH2COOH , , -CH2SCH3, ~n I
H , or H-N N , and R2 iS

C1~3 CH3CH2CHCH3, CH31CHCH2CH2CH3 , CH3cH2cHcH2cH3 , or C~

- 43a -1~968~1 Said alpha-keto carboxylic acids and said salts can be prepared from hydantoins having the formulas iH
- R -C=C C=O Z =C C=O

R -N N-R2 or H-N N-H
2 \ / \ C /

O O
in which Zl is CH f=
. 10 CH3 CH3iCHCH

CH3CH2 IClCH3 CH31CCH2CH2CH3 , or t CH3CH2C~CH2CH3 . . .
.. . .. .

As used herein, the term "percent (~)" means parts per hundred and "parts" means parts by weight unless otherwise defined where used.
As used herein, the term "mole" has its generally accepted meaning. A mole of a substance is that quantity which contains the same number of molecules of the substance as there are atoms in 12 grams of pure C.

Claims (10)

I CLAIM:
1. A process for preparing an alpha-keto carboxylic acid having the formula in which R is said process comprising:

(a) admixing: (i) a hydantoin having the formula in which Z is and (ii) a first aqueous solution consisting essentially of water and sodium hydroxide or potassium hydroxide and maintaining the resulting admixture at a tempera-ture effective for forming a second aqueous solution comprising water, and a salt of the alpha-keto carboxylic acid, the salt having the formula for a time effective for forming the second aqueous solution, the sodium hydroxide or potassium hydroxide being present in an amount effective for forming the salt of the alpha-keto carboxylic acid;
(b) adjusting the pH of the second aqueous solution to a value effective for forming a third aqueous solu-tion comprising water and the alpha-keto carboxylic acid;
(c) extracting the alpha-keto carboxylic acid from the third aqueous solution with an amount of a volatile inert solvent which is substantially insoluble in water effective for forming a first non-aqueous solution consisting essentially of the volatile inert solvent which is substantially insoluble in water and the alpha-keto carboxylic acid.
2. The process of claim 1 which includes separating the alpha-keto carboxylic acid from the volatile inert solvent by evaporating the volatile inert solvent, and recovering the resulting separated alpha-keto carboxylic acid.
3. The process of claim 1 which includes converting the alpha-keto carboxylic acid to its sodium, potassium, or calcium salt and extracting said salt from the non-aqueous solution with an amount of an aqueous system consisting essentially of water and a member selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, sodium bicarbon-ate, and potassium bicarbonate effective for forming the first aqueous solution.
4. The process of Claim 1 in which the first aqueous solution consists essentially of water and sodium hydroxide.
5. The process of Claim 1 in which the pH of the second aqueous solution is adjusted with hydrochloric acid or sulfuric acid.
6. The process of Claim 1 in which the temperature of the second aqueous solution is adjusted to about 5-35°C, if it is not already at said temperature, before adjusting its pH to a value effective for forming an aqueous solution of the alpha-keto carboxylic acid.
7. The process of Claim 1 in which the volatile inert solvent is diethyl ether, diisopropyl ether, ethyl acetate, n-butyl acetate, or methyl isobutyl ketone.
8. The process of Claim 1 in which the aqueous system consists essentially of an aqueous sodium hydroxide solution.
9. The process of Claim 1 in which the aqueous system consists essentially of an aqueous potassium hydroxide solution.
10; The process of Claim 1 in which the aqueous system consists essentially of an aqueous calcium hydroxide solution or slurry.
CA284,976A 1976-10-07 1977-08-18 Preparation of aliphatic and heterocyclic alpha-keto carboxylic acids Expired CA1096881A (en)

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CA (1) CA1096881A (en)
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DE (1) DE2744305A1 (en)
FR (1) FR2367045A1 (en)
GB (1) GB1550993A (en)
IT (1) IT1088067B (en)
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JPH0623130B2 (en) * 1984-07-10 1994-03-30 三井東圧化学株式会社 Method for producing α-keto acid
JPH0623131B2 (en) * 1984-08-07 1994-03-30 三井東圧化学株式会社 Process for producing alkali metal salt of α-keto acid
IT1206078B (en) * 1987-06-03 1989-04-14 Polifarma Spa PROCEDURE FOR THE PRODUCTION OF 3-INDOLPIRUVIC ACID AND ITS DERIVATIVES THEIR PHARMACEUTICAL USE
DE4216667C2 (en) * 1992-05-20 1994-11-10 Wella Ag Use of alpha-ketodicarboxylic acids against hydrogen peroxide residues in the hair
CN101440012A (en) * 2007-11-23 2009-05-27 赢创德固赛有限责任公司 Method for purifying alpha-oxo-carboxyl acid
CN116891406A (en) * 2023-06-28 2023-10-17 浙江昂利泰制药有限公司 Preparation method of alpha-ketoleucine

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SE7711163L (en) 1978-04-08
DE2744305A1 (en) 1978-04-13
IT1088067B (en) 1985-06-04
FR2367045A1 (en) 1978-05-05
GB1550993A (en) 1979-08-22
CH624919A5 (en) 1981-08-31
NL7710796A (en) 1978-04-11
JPS5346920A (en) 1978-04-27

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