Note: Descriptions are shown in the official language in which they were submitted.
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=
CH3 H
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
- .
6883
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 /
11
` - 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.
-- 3 --
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
H CH3
881
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
CH3
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
-- 6
6l381
o o
Il 11
R-C -C--011
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,
C113
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 ~ .
:'
- 8 -
,
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 -,
CH3
H
H-N N , and
~ CH
~CH 2
CH3
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
'
`'
10 -
"
~;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-
CH3 H
-- 11 --
'. ~
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,
11
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
11 11 11 11
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'
2NCII2C 2 2
-c112~:0011 ~
-Cll SCll3 ,
~
,~1 ,
H-N l~ ,
H
c~l3-c-cll2- , and Cl~3-cll2-c-cll3
, 25 c~3
.
,.
- 13 -
'
.
~Q~68~1
and R2 is
CH3CHCH2CH2CH3~ CH3CH2CHCH2CH3~ C~3lH-'
CH3
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;
- 14 -
~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
- 15 -
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- ,
CH3
CH3CH2- ,
CH3C 2 2
H2NCH2c~2cH2
-CH2COOH
-CH2SCH3
H , and
H-N N ,
and R2 is
CH3cHcH2cH2cH3
CH3CH2C~ HCH2CH3
CH3CH2CHCH3 ~
31
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 ~ -
CH3
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
11 11 11 11
, 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
C113
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
- 16 -
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
- 20 -
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
- 21 -
lOQ&~Bl
H2NCH2CH2cH2
-cH2cooH ~
C 2 C 3,
H
CH3-C-CH2-,
C 3
CH3 -CH-- ,
CH3 1
CH3--CH2--1 CH3
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
- 22 -
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
CH3
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.
- 23 -
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.
- 25 -
`` 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~.
- 26 -
. . ~
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.
27 -
,
.
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~
EXAMPLE 2
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.
EXAMPLE 3
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
- 30 -
, .
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.
EXAMPLE 4
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.
- 31 -
'~ .
''
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.
EXAMPLE 5
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~:
- 32 -
. .
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.
- 33 -
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~
PROCEDURE 1
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.
PROCEDURE 2
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.
PROCEDURE 3
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.
-~ :
~ .
- 35 -
6~
PROCEDURE 4
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 /
11
, '
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 `
PROCEDURE 5
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/
11
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 .
PROCEDURE 7
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.
- 38
~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
H 2
.
- 39 -
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.
PROCEDURE 9
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
11
(~}C-C-OK
The yield of said potassium salt will be 45% based on the
reactant hydantoin charged.
PROCEDURE 10
~ . .
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
- 40 -
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.
PROCEDURE 11
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.
PROCEDURE 12
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
30 -N N
- 41 -
1~6~
PROCEDURE 13
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
11 11 1
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 00
11 11 11
O-C-CH2CH2-C-C-O Ca .
- 42 -
1096881
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
11 11
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
0 0 0 0
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
11 11
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
- 43 -
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~
CH3CH2CH2
CH3CH2CHCH3,
' CH3CH2CH2CH2
CH -CH-
CH3
H2NCH2CH2cH2
-CH2COOH ,
, -CH2SCH3,
CH3CHCH2-
~n I
H , or
H-N N , and
R2 iS
CH31CH
CH3CHCH2-
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
1 1
R -N N-R2 or H-N N-H
2 \ / \ C /
O O
in which Zl is
CH f=
. 10 CH3
CH3iCHCH
CH3
CH3CH2 IClCH3
CH31CCH2CH2CH3 , or
t CH3CH2C~CH2CH3
. . .
.. . .. .
81
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.
