Note: Descriptions are shown in the official language in which they were submitted.
~3243~
4js 1 37-21-(5659)
PROCE~S FOR THE PREPARATION OF
ALKYLTHIOALKANOATE SALTS
This application is a division of co-pending Canadian
Application Serial No. 536,595, filed May 7, 1987.
Background to the Invention
This invention relates to the synthesis of alkali metal
salts of methionine and its analogs and, more particularly, to an
improved process for the synthesis of such compounds in high yields
without the necessity of using acrolein or hydrogen cyanide as
precursors.
The hydroxy analog of methionine, i.e., 2-hydroxy-4-
methylthiobutyric acid, is widely used as an animal feed
supplement. According to a conventional process for the
preparation of 2-hydroxy-4-methylthiobutyric acid (HMBA), 2-
hydroxy-4-methylthiobutyronitrile tH~BN) is hydrolyzed with a
mineral acid. As described for example in Blake et al. U.S. patent
2,745,745, HMBN is typically prepared by reacting 3-
methylthiopropionaldehyde with hydrogen cyanide. The 3-
methylthiopropionaldehydyde intermediate is in turn prepared by
condensation of acrolein and methyl mercaptan. Thus, in the
commercial manufacture of HMBA, acrolein and hydrogen cyanide have
been essential starting materials.
The toxicity of hydrogen cyanide is well known. Acrolein is
also toxic, and both materials are flammable as well. Accordingly,
the shipping and handling of these raw materials is costly.
Accordinglyr there has been a long standing need for
commercially feasible processes for the manufacture of 2-hydroxy-4-
methylthiobutyric acid and
4js 2 1324388 37 2l-(5659)
related compounds without the necessity of using
acrolein and hydrogen cyanide as precursor materials.
Plieninger, ~Cleavage of gamma-Butyr~lactone
and alpha-Amino-butyrolactone with Sodium Methylmercap-
tide 0! Selenide. A Synthesis of Methionine.", Chem.Ber_., vol. 83~ pages 265-268 (1950), Chem. Abstracts,
44-9919b describes the reaction of unsubstituted butyro-
lactone and sodium methylmercaptide in a toluene medium.
The refecence also describes the formation of methionine
by reaction of sodium methylmercaptide with alpha-amino-
butyrolactone in toluene. Further described in the
reference is a reaction 0c alpha-amino-butyrolactone
with sodium ~ethyl selenide. Neutralization with acetic
acid converts the alkali metal salt products of these
reactions to the corresponding free acids. Plieninger
further describes the preparation of sodium methylmer-
captide by passing methyl mercaptan into methanol con-
taining metallic sodium, concentrating the resultant
mixture by evaporation of solvent, adding toluene, and
distilling off solvent until the boiling point o~ toluene
is reached. Alternatively, metallic sodium is added to
a solution of methyl mercaptan and li~uid ammonia,
following which toluene is added and ammonia evaporated
to precipitate an amorphous sodium methylmercaptide.
British Patent 651,165 also desc~ibes the
preparation of methionine by the reaction of alpha-amino-
butyrolactone with sodium methyl mercaptide The exam-
ples in this patent describe both a violent reaction
obtained by addition of alpha-amino-butyrolactone (neat)
1324388
4js 3 37-21-(5659)
to dry sodium methylmercaptide (neat), and a suspension
reaction in xylene. Reaction is carried out at a tem-
perature of 150-200C. The sodium salt of methionine
~ obtained from the reaction is acidified with acetic acid
to pH 7. As prior art, the British pater.t also
describes the preparation of methionine by benzoylation
of alpha-aminobutyrolactone, conversion of the N-benzoyl
compound to a gamma-chloro-alpha-benzoylaminobutyric
acid ester by treatment with alcoholic hydrocnloric
acid, and reaction of the ester with sodium methylmer-
captide to produce N-benzoyl methionine. The benzoyl
blocking group is removed by hydrolysis to produce
methionine.
German patent 816,544 (Chem. ~bstracts, vol.
47: 2200e) describes a process for preparing gamma-
alkylthio or -seleno fatty acids or their amino deriva-
tives by reaction o~ the corresponding alkali metal
alkylmercaptide or -selenide with gamma-lactones at
temperatures in the range of 100-200C in the presence
of an inert solvent such as benzene or toluene. The
examples of this patent illustrate reaction of sodium
methylmercaptide with gamma-butyrolactone in a toluene
suspension. Further examples show use of the same
toluene medium for the preparation of methionine from
sodium methylmercaptide and alpha-amino-gamma-butyrolac-
tone.
Chem. Abstracts 51:2853c describes still
another process in which a toluene medium is used for
4iS 4 1~24388 37-21-(5659)
reaction of sodium methylmercaptide with a gamma-butyro-
lactone. In this case the lactone substrate is alpha-
benzoyLamino-gamma-butyrolactone and the benzoyl pro-
tecting group is removed by neutralization with sodium
carbonate to produce D,L-methionine. While the ~ethods
described in Pleininger, British patent 651,165, German
patent 816,544, and CA 51:2835c have been shown to be
effective for the preparation for alkylthiobutyric acid
salts, the yields obtainab~le by reaction in inert sol-
vents such as toluene and xylene have not been commer-
cially attractive.
Aries French patent 2,271,207, describes a
pcocess for the preparation of methionine in which
3-methylthiopropylisonitrile is reacted with a dialkyl
carbonate in the presence of sodium hydride, and the
pcoduct of this reaction is hydrolyzed to methionine.
Reaction ~etween the 3-methylthiopropylisonitrile and
dialkyl carbonate is carried out in dimethylfocmamide,
after which that solvent is removed by evaporation and
the rësidue washed with pentane and dissolved in
methanol, HydroLysis is carried out by addition of
hydrochloric~acit, and methionine is recovered by evapo-
rating~the methanoL and HCl, washing the residue with
isopropyl ether, adding sodium hydroxide to pH 6, and
25 ~crystaIllzing the product from methanol. The 3-methyl-
thiopropylisonitrile starting material is said to be
prepared readily from methylthiopropylamine in accor-
~u ~ dance with the description in Tetrahedron Letters, 1972,
p.~1637.
1324388
4js 5 37-21-(5659~
Jaworski U~S. patent 3,671,212 describes the preparation
of a salt of 2-hydroxy-4-methylthiobutyric acid by hydrolysis of
HMBN. HMBN is preparPd by condensation of methyl mercaptan with 2-
hydroxy-4-chlorobutyronitrile. The reference does not disclose the
method of preparation of the 2-hydroxy-4-chlorobutyronitrile.
Summary of the Invention
It is a feature of certain embodiments of the invention
to provide a novel process for the preparation of alkali metal
salts of methionine, HMBA, and Gther related compounds; to provide
such a process which avoids the need for use of acrolein as a
precursor compound; to provide such a process which avoids the need
for using hydrogen cyanide as a precursor compound; to provide such
a process which provides the product alkali meta~ salt in high
yiéld; and to provide a process which affords economically
acceptable productivity in the manufacture of the aforesaid
products.
In accordance with an embodiment of the present invention
there is provided a process for the preparation of an
alkylthioalkanoate compound corresponding to the formula
R1-S-(CH2)n-CH(R2)-C(O)-OM
where R1 is lower alkyl, M is alkali metal, n is an integer between
2 and 4, inclusive, and R2 is selected from the group consisting of
hydrogen, hydroxy, amino,
-oR3 and
-NH-R4
1324388
4js 6 37-21-(5659)
where R3 is selected from the group consisting of alkyl and aryl r
and R4 is selected from the group consisting of alkyl, aryl, and
acyl the process comprising prepzring a charge mixture by mixing a
source of an alkylmercaptide group and a lactone in an alkaline
medium comprising an aprotic polar organic solvent, the mercaptide
group corresponding to the formula:
R1--S--
where R1 is as defined above, and the lactone corresponding to the
formula R~
where R2 and n are defined as above; and
maintaining the mixture at a temperature of at least 80C for a
time sufficient to form the alkylthioalkanoate compound.
In accordance with another embodiment of the present
inve.ntion there is provided a process for the preparation of a
methylthiobutyrate compound corresponding to the formula:
CH3-s-(cH2)2-cH(R2)-c(o)-oM
where M is alkali metal and R2 is selected from the group
consisting of hydrogen, hydroxyl, amino,
-oR3 and
-NH-R4
where R3 is selected from the group consisting of alkyl and
4js 7 1324~88 37-21-(5659)
aryl, and R4 is selected from the group consisting of alkyl, aryl,
and acyl, the process comprising and preparing a charge mixture by
mixing a source of a methylmercaptide group and a lactone in an
alkaline medium comprising an aprotic polar organic solvent, the
lactone corresponding to the formula: z
\/ \c
where RZ is as defined above; and
maintaining the mixture at a temperature of at least 80C for a
time sufficient to form the methylthiobutyrate compound.
Other features will be in part apparent and in part
pointed out hereinafter.
Description of the Preferred Embodiments
In accordance with the present invention, it has been
discovered that an alkali metal salt of 2-hydroxy-4-
methylthiobutyric acid can be produced, in high yield andeconomically acceptable productivity, by reaction of alpha-
hydroxybutyrolactone and an alkali metal thiomethylate in the
presence of an aprotic polar organic solvent. Although the process
of the invention is especially advantageous for the preparation of
the alkali metal salts of HMBA, it is also effective for the
4js 8 132438837 2l (5659~
synthesis of methionine salts, or the salts o~ unsubsti-
t~ted 4-methylthiobutyric acid~ More generally the
process is effective for the preparation of compounds
corresponding to the formula
R -S-(CH2)n-CH(R )-C(O)-OM
where Rl is a lower alkyl group, preferably containing
from one to about 8 carbon atoms r R2 is hydrogen,
hydroxyl, amino,
-oR3, or
NH-R4
where R3 is alkyl or aryl, R4 is alkyl, aryl, or
acyl, and n is an integer between 2 and 4, inclusive.
Thus, generally, ~he alkali metal mercaptide reactant
corresponds to the formula:
- Rl-S-M
where ~1 is lower alkyl. The lactone reactant used in
the process corresponds the formula
R~
Y(C~
where R ls hydrogen, hydroxyl, or amino and n is an
integer between Z and 4, lnclusive. Instead of the free
amino group, R~ may also be an ether, amide,
4 js 9 1324388 37-21-(5659)
or substituted amine, i.e. a substituent corresponding
to the formula:
-oR3 or
-NH-R4
where R3 is alkyl or aryl and R may be alkyi, aryl,
or acyl. Where R is alkyl it preferably contains
between 1 and abo~t 12 car~on atoms; and where it is
aryl it is preferable unsubstituted phenyl or substi-
tuted phenyl having one to three substituents, each of
the substituents being independently selected from among
alkyl and alkoxy groups having between one and about
fo~r carbon atoms. Typical groups which may constitute
R3 include methyl, ethyl, propyl, octyl, dodecyl,
phenyl, tolyl, and ethoxyphenyl. ~4 may be any of the
groups which may constitute R3, but may also be an
acyl group. Where R4 is acyl, it preferably comprises
a carbonyl group substituted with any of: hydrogen; an
alkyl group containing between 1 and about 12 carbon
atoms; unsubstituted phenyl; or substituted phenyl having
one to three substituents, each substituent of the phenyl
group being independently selected from among alkyl and
alkoxy having between one and about four carbon atoms.
Typical acyl groups which may constitute R4 include
formyl, acetyl, octanoyl, benzoyl, and the like. Gener-
ally, it is not necessary to incorporate a blockinggroup to inhibit side reactions of an amino or hydroxyl
substituent. However, the process of the invention is
ef~ective or conducting the desired synthesis with any
of a variety of substituents of the aforesaid type.
4 js lo 1324388 37-21-(5659)
}t has been found that the yields attainable
through the process of the invention are significantly
superior to those which have been reported for the
synthesis of methionine or related compounds by reaction
of a sodium methyl mercaptide with either an unprotected
alpha-amino-butyrolactone, a protected alpha-amino
butyrolactone, or an unsubstituted butyrolactone.
Although the instant disclosure is not limited to any
particular theory of invention, it is believed that use
of an aprotic polac organic solvent is effective for
limiting side reactions and promoting attack of the
lactone ring by the mercaptide. In the context of this
invention, an aprotic solvent is one which does not
donate protons. In particular, it is believed that the
aprotic solvents used in the process are effective for
solvating the alkali metal cation, but leave the mercap-
tide anion in a substantially non-solvated reactive
condition, thereby promoting the preferred reaction and
producing the 4-methylthiobutyric or other terminal
alkylthioalkanoic acid salt in high yield.
The solvent which is used as the medium for
reaction of the mercaptide and lactone should have a
relatively high dipole moment, preferably 1 or greater,
and also preferably has a dielectric constant of greater
than 10. Advantageously, the reaction medium is consti-
tuted entirely of a solvent, or solvents, of such
character, but the process can also be carried out in
solvent mixtures containing at least 30~ by weight of a
solvent of the preferred type, the remainder being
typically an inert solvent such as, for example, toluene
or xylene. Among the particular aprotic polar solvents
4 j8 11 t~2438837-2l- (5659)
which ~re useful a~ medis for the mercaptide/ lactone
reaction are dimethylformamide, hexamethyl phosphoric
triam~de, dlmethyl sulfoxide, and tetramethylurea~
However, the most preferred solvents are pyridine and
ring substituted alkyl pyridines such as a picoline.
Typically, a ~ubstituted pyridine solvent may ha~e one
to three alkyl substituents, each containing from 1 to
about 5 carbon atoms.
In carrying out the process of the invent;on, -
a solution of the alkali metal mercaptide in the solvent
is preferably prepared initially, and the lactone there-
after added to the solution. Reaction is typically
conducted at a temperature in the range of 80-150C,
most preferably 120-130C, under autogenous pressure.
In order to minimize formation of by-products, it is
important that the reaction be carried out under sub-
stantially anhydrous conditions. The presence of water
or other source of protons tends to promote hydrolytic
cleavage of the lactone between the carbonyl and oxygen
of the ring, yielding a terminal hydroxyl group. h~hen
conducted under the preferred conditions, the reaction
is typically complete within several hours, as con-
veniently determined by periodic sampling of the reac-
tion mixture. Control of the end point is not generally
critical for purposes other than productivity, since
overreaction problems are generally not encountered.
Generally, the lactone and alkali metal mer-
captide are charged to the reaction in substantially
equi~olar proportions. In order to maximize the reac-
tion payload, the reactants are preferably charged to
.
4js 12 13~38837-2l- ~5659)
the polar solvent medium in amounts such that, during
the early stages of the reaction, the alkali metal mer-
captide concentration approaches or moderately ~xceeds
~ the saturation point. At such concentrations, portions
of both the alkali metal mercaptide reactant and the
alkylthioalkanoate product may be at least partially in
the solid phase. To assure even distribution of reac-
tants and promote the progress of the reaction, the
ch~rge mi~ture is prefera~ly agitated vigorously during
the course of the reaction.
After completion of the reaction, the product
may be recovered in any convenient fashion. For
example, the reaction mixture may be diluted with water,
thereby taking up the desired product in the aqueous
lS phase. Impurities, reaction solvent, and unreacted
material may then be extracted from the aqueous phase
with an organic solvent, typically a halogenated solvent
such as chloroform. Concentration of the raffinate
under vacuum yields a residue comprising the~ alkali
metal salt of the substituted or unsubstituted alkyl-
thioalkanoic acid~ Further purification may be
achieved, for example, via recrystallization.
In an alternative process, the product is
taken up in water, impurities are extracted from the
aqueous phase using an organic solvent, and the aqueous
phase acidified with a mineral acid to produce the free
alkylthioalkanoic acid. The free acid is extracted with
a polar organic solvent such as methyl isobutyl ketone,
and the solvent removed by steam distillation to yield
an aqueous residue containing the free acid.
4jS 13 1324388 37-21-(5659)
The alkali metal mercaptide reactant may be
prepared in any of a variety of ways. For example, it
can be prepared by reaction o~ an alkyl mercaptan, such
- as methyl mercaptan, and either metallic sodium or
sodium hydride. Other alkali metals and their hydrides,
such as potassium metal or potassium hydride may also be
used, but sodium is more economical. Preparation from
sodium metal may be carried out in the manner described,
for exa~ple, i~ Plieninger, supra. However, both
metallic alkali metals and alkali metal hydrides are
expensive, dangerous, and difficult to handle. Their
reactions with methylmercaptan are highly exothermic and
uncontrolled, making industrial scale usage normally
undesirable.
In a preferred and particularly advantageous
embodiment of the invention, it has been discovered that
the alkali metal mercaptide may be effectively prepared
by reaction between an alkyl mercaptan and an alkali
metal phenate. This process substantially enhances the
commercial attractiveness of the process because it
avoias the need for using metallic alkali metal or
al~ali metal hydride. Instead, this embodiment of the
invention allows the use alkali metal hydroxides, which
are not only inexpensive but are also routinely used and
transported in high volume commercially, as the ultimate
source of the al~alinity necessary ~oc carrying out the
synthesis of alkylthioalkanoates.
In accordance with this embodiment of the
invention, for~ation of the phenate is carried out in a
~0 crude base reaction system that is prepared by mixing a
4js 14 132~388 37-21-(5659)
substituted or unsubstituted phenol, an alkali metal
hydroxide, and a pyridine or substituted pyridine sol-
vent. Conveniently, generally equimolar proportions of
~ alkali metal hydroxide and phenol are charged to a reac-
tion vessel. The reaction mixture is heated, normally
under atmospheric pressure, to the boiling point of the
azeotrope so that the water of reaction (as well as any
other moisture contained in the charge mixture) is
driven out during or subsequent to the reaction. If
pyridine and unsubstituted phenol are used, therefore,
the react~on mixture is typically distilled at a temper-
ature in the range of 110-120C. Vse of a substituted
pyridine solvent increases the temperature at which the
azeotrope distills off at a given pressure. ~y removal
of water, the mixture is converted to an anhydrous base
reagent containing the alkali metal phenate.
In order to minimize the formation of phenoxy
substituted alkylthioalkanoate in the subsequent mercap-
tide/lactone reaction, it may be advantageous to use a
substituted phenol in the pceparation of the base
reagent. Preferably, the substituted phenol used has a
lower alkyl or lower alkoxy group (containing, for
example, 1 to 10 carbon atoms) in a position ortho to
the phenol hydroxy group. However, other substituents
may be used if they are substantially inert under the
conditions of the various reactions of the process o
the invention; and substitutents may be located in the
meta or para positions as well. Particularly suitable
phenol reactants include 2-methylphenol (o-cresol),
2-ethylphenol, 2-methoxyphenol, 2,4-dimethylphenol,
2,6-di~ethylphenol, and 2,4,6-trimethyl-phenol.
4 js i329~388 37-21- (5659)
An alkali metal mercaptide is produced by
reacting an alkyl mercaptan with the alkali metal
phenate. Preferably, this reaction is effected in a
- system prepared by admixing the alkyl mercaptan with the
anhydrous base reagent. Preferably, at least a slight
excess of mercaptan, from about 1 to about 3 moles per
mole of phenate is supplied to the system in which the
- alkali metal mercaptide is produced. This tends to
exhaust the phenate and prevent its reacting with the
lactone in the subsequent process steps.
The resultant mercaptide is then reacted with
the lactone at 80-lSO~C in the presence of an aprotic
solvent, preferably in the pyridine or substituted pyri-
dine medium in which the phenate and mercaptide are
initially prepared. In a particularly convenient method
for carrying out the process, the lactone and mercaptan
are charged to the reaction vessel, the reaction vessel
is then sealed, and the charge mixture brought to reac-
tion temperature for a time sufficient to complete the
reaction. Preferably, the lactone charge is roughly
stoichiometrically equivalent to the phenate, and the
mercaptan is charged in excess, typically about 1 to
about 3 moles, preferably about 2 moles, per mole of
lactone. To maximize payload, the amoun~s charged are
preferably such that the alkali metal phenate concentra-
tion is approximately at saturation. Reaction is there-
after carried out under autogenous pressure.
After the reaction is complete, as determined,
for example, by periodic sampling, exce5s mercaptan may
be removed by stripping, and the 4~methylthioalkanoate
1324388 37-21-(5659)
product recovered by any convenient method, for example,
the method discussed hereinabove.
The following examples illustrate the inven-
tion:
Example 1
Sodium hydroxide (4 g;,,0.1 mole~, phenol (9.4
g; 0.1 mole) and pyridine.(75 ml) were placed in a 100
ml three'neck r,ound ~ottom flask, and reaction effected
to produce sodium phenate. The reaction product was
heated to boiling under atmospheric pressure, and water
removed by azeotropic distillation. Overheads boiling
out of the flask were passed through a 6 inch Vigreaux
column under nitrogen. During the course of the distil-
lation, the pot temperature ranged from 112 - 118C and
the overheads ranged from a temperature of 97 - 114C.
Approximately 25 ml of water/pyridine overheads was
collected.
.
Thereafter methylmercaptan (5g) was introduced
into the reaction flask by distilling it from a source
condensing it in a dry ice condenser and allowing the
condensate to flow by qravity into the sodium phenate
solution in the flask. Heat was applied to the reeult-
ing mixture. ,After heat had been applied for 5 minutes
and the te~perature of the contents of the flask had
risen to 75C, addition of alpha-hydroxybutyrolactone to
the contents of the flask was commenced. Addition of
alpha-hydroxybutyrolactone (10 g; 0.1 mole) was carried
out over a period of about 10 minutes during which time
4 js 132~88 37~21-t565s)
heating was continued and the temperature of the con-
tents of the flask increased to 90C. After addition of
the alpha-hydroxybutyrolactone was completed, heating
was continued for a period of 2 ho~rs during which the
temperature reached a maximum of 112C. After heat was
removed the reaction mixture was allowed to stand over-
night. The next day the reaction mixturè was diluted
with water (25 ml) and heat reap~lied for a period of
about 45 minutes during which the temperature reach
97C. After cooling, the mixture was dilluted with
chloroform (50 ml) and the aqueous and organic phases
allowed to separate. The aqueous phase was then washed
with two aliquots of chloroform (25 ml each) and
stripped on a rotary evaporator. The residue was stored
in a vacuum oven at approximately 110C.
This syrup was dissolved in water (about 30
ml), acidified with concentrated sulfuric acid (5.3 9),
and extracted with four aliquots of methyl lsobutyl
ketone (25 ml each). Thereafter the MIBK solution was
stripped on a rotary evaporatoc and the residue twice
diluted with water (25 ml each) and stripped to remove
residual MIBK. The resulting product (11.3 g) was
silylated and subjected to GLC analysis. GLC analysis
using an n-dodecane internal standard indicated that the
product was 78.6~ HMBA (59% yield).
Example 2
2,6-dimethylphenol (12.2 9; 0;1 mole), sodium
hydroxide (4 9; 0.1 mole~ and gamma-picoline (approxi-
mately 75 ml) were placed in a 100 ml flask. The
resultant crude base reaction system was heated to its
4js 18 37-21 (5559)
1324388
atmospheric boiling point to remove water. Overheads
were distilled out of the reaction mixture through a 6
inch Vigreaux column, resulting in the collection of
- about 25 ml of distillate. Temperature of the overheads
ranged from 95~ - 145C during the course of the
distillation.
After formation o~ the dimethylphenate and
removal-of water as described above, the anhydro~s base
reagent mixture obtained, comprising sodium
2,6-dimethylphenate and gamma-picoline, was placed in a
Fischer-porter bottle. Methylmercaptan (10 9) and
alpha-hydroxybutyrolactone ~10.2 9) were then added, and
the bottle sealed and placed on a oil bath. The mixture
contained in the bottle was heated under autogenous
pressure for a period of about 7 1/2 hGurs, the tempera-
ture rising to 135C after 1/2 hour, stabilizing at
130C one hour later, and holding at 130 - 131C
throughout the remainder of the reaction. Pressure
within the bottle reached 43 psig at 1 1/2 hours follow-
ing commencement of the reaction, and remained at thatlevel throughout the reaction. When the reaction was
complete, the bottle was unsealed and water ~25 ml) was
added to the reaction mixture to take up the product
acid salt. Contents of the reaction vessel were then
extracted with chloroform (25 ml) for removal of solvent
and phenol from the aqueous phase. ~he resulting
organic extract was in turn extracted with 25 ml of
water for recovery of product, after which the aqueous
phases were combined and washed with two aliquots (25 ml
each) of chloroform. The aqueous phase was then
stripped on a rotary evaporater to afford a gummy solid
4~ 19 37-21-(5659)
1324388
(16.1 9), and the gummy ~olid was dissolved ln water (5
g) to provide a viscou~ ~yrup t21.1 9). This product
was ~ilylated and ~ubjected to GLC analysis. Based on
area ratios observed through GLC analysis, the product
~ 5 was estlmated to contain about 10.5 moles 2-hydroxy-4-
methylthiobutyrate per mole of 2-4-dihydroxvbutyrate
by-product. Use of an internal standard (n-dodecane)
indicated that the product contained 50.55% 2-hydroxy-
4-methylthiobutyrate. Inasmuch as the starting material
(al~ha-hydroxy butyrolac~one) had been determined to be
92~ pure, this corresponded to a yield of 77.2~.
Example 3
Sodium hydroxide (4 9; 0.1 mole) 2,6-dimethyl-
phenol ~12.2 9; 0.1 mole) and gamma-picoline (about 75
ml) were placed in a 100 ml flask under nitrogen pres-
sure, and reaction effected to produce sodi~m
2,6-dimethylphenate. The reaction product was heated to
the atmospheric boiling point for removal of water. A
mixture of water and gam~a-picoline ~as distilled out of
the reaction ~ixture overhead through a 6 inch Vigreaux
columm. Temperature of the overheads ranged from
97-145C during the course of the distillation.
Thereafter, the anhydrous base reagent mixture
containing the sodium 2,6-dimethylphenate was trans-
2S ferred to a ~ischer-Porter bottle. Methylmercaptan (7
g; 0.14 moles~ and alpha-hydroxy butyrolactone ~7.5 9;
0.073 moles) were added to tbe anhydrous base reagent
~ixture in the bottle. ~he bottle was then sealed and
placed in an oil bath and the contents heated under
autogenous pres~ure for a period of 5 1/2 hours to
4js 20 ~32~388 37-21-(5659)
effect conversion of the mercaptan to the sodium mercap-
tide and reaction of the mercaptide with the lactone to
form sodium 2-hydroxy-4-methylthiobutyrate. During the
course of this reaction, the temperature ranged ~rom
105 - 138C and the pressure from 19-37 psig. At the
conclusion of the reaction, the bottle was vented and
water (25 ml) was added. The diluted reaction mixture
was washed with three aliquots of chloroform (25 ml
each) and the combined chloroform solution was washed
with an aliquot of water (25 ml). The aqueous fractions
were combined and stripped on a rotary evaporator to
afford a syrup which was diluted with water to a weight
of 20.0g. GLC analysis of the silylated product
(n-dodecane internal standard) indicated that the sample
contained 40.6% by weight 2-hydroxy-4-methythiobutyrate
(~MBA) monomer and 3.5% 2,4-dihydroxybutyrate. This
represented an HMBA yield of 8.1 g or 80~ based on 92
purity of the starting lactone.
Exampie 4
Sodium hydroxide (49; 0.1 moie), phenol (9.49;
0.1 mole), and pyridine (75 ml) were stirred under
nitrogen and heated to distill pyridine/water through a
6~ Vigreaux column. At the beginning of the distilla-
tion, the temperature in the pot was 112C and the over-
head temperature was 94C. At the conclusion of the
distillation, the pot temperature was 118C and the
overhead temperature was 114C. About 30 to 40 9 of
pyridine/water were distilled off.
After water had been removed from the pot
containing sodium phenate, methylmercaptan (4.89; 0.1
4js 21 37-21-(5659)
1324388
mole) was distilled, condensed in a dry ice condenser
and introduced into the pot, ~ollowing which addition of
butyrolactone to the pot was commenced. About 15
- minutes after the conclusion of the addition of methyl-
mercaptan, all of the butyrolactone (8.6g; 0.1 moles)
had also been added. An hour and forty ,ive minutes
later, with the dry ice condenser still in place in the
vent line from the pot, heat was applied to the charge
mixture and reaction was thereafter continued for
another 2 hr. and 10 minutes, during which time the
temperature rose from 75C with reflux to about 105C.
The heat was then removed and, upon cooling, the reac-
tion mixture became very thick and solids began to pre-
cipitate. By the time the mixture had cooled to room
temperature, the batch was essentially solid.
At this point, water (209) was added and the
resulting mixture heated to 98C and allowed to cool~ A
homogeneous solution was obtained which was then washed
in three aliquots of chloroform (25ml each). The raffi-
nate was stripped on a rotary evaporator and stored in avacuum oven at 100C where it dried to a solid (13.79).
GLC analysis of the silylated product indicated 34.2
area ~ HocH2cH2cH2co2Na~ 63-9 area ~
CH3SCH2CH2CH2CO2Na and 1.7 area ~ unknown
higher boiling materials.
Exampie 5
Sodium hydroxide pellets (49, 0.1 mole),
phenol (9.49; 0.1 mole), and pyridine (75ml) were placed
in a lOOml three neck round bottom flask and heated to
distill pyridine/H2O through a 6~ Vigreaux column.
1 3 2 ~ 3 8 8
About 30 to 40 ml pyridine/H2O distilled over, with a
final overhead temperature of 113C.
On the next day methylmercaptan was distilled,
condensed in a dry ice condenser, and introduced into
the bottom fraction re~aining in the pot from the
pyridine/water distillation. After all of the methyl-
mercaptan (about 59) had been added, and with the dry
,ice co~denser in operatio~ on the vent line from the
pot, heat was applied to the pot and butyrolactone
(8.69) was added while the methylmercaptan was refluxing
at atmospheric pressure. After the lactone had all been
added, heating continued under reflux. About one half
hour after the completion of the addition of lactone,
the reaction mass had reached a temperature of 99C and,
at this point, the heat was turned off.
After the mass had cooled to a te~perature of
about 48C, water (209) was added and heat reapplied.
When the temperature reached about 63C, all the solids
had dissolved. At this point, additional water (5g) was
added to the solution and heating was continued for
another ten ~inutes, raising the temperature to 86C.
The heat was then withdrawn and the solution allowed to
cool ~or about l hour and 45 minutes. The-cooled solu-
tion was washed with three aliquots of chloroform (25ml
each), then reduced on a rotary evaporator. The residue
was dried by storing it in a vacuum oven at 100C. The
dried solid weighed 13.79. Analysis of the silylated
product by GLC showed 44.5 area %
~OCH2C~2C~2CO2Na~ 54.3%
CH3SC~2CH2C~2CO2Na, and 1.0% of an unknown
high boiler.
4js 23 37-21-(5659)
1324388
Example 6
Sodium hydroxide (4g; 0.1 mole), phenol (9.49;
~ 0.1 mole), and pyridine (75ml) were placed in a 100 ml
capacity three neck round bottom flask under N2. Heat
was applied and a fraction (about 30 ml) of pyridine/-
H2O was distilled off through a 6" Vigreaux column
(overhead temperature = 98 - 114C).
Methylmercaptan (59) was distilled, condensed
in a dry ice condenser, and introduced into the result-
ing solution of sodium phenate in pyridine. Introduc-
tion of methylmercaptan was carried out slowly over a
period of about one and one half hours.
With the dry ice condenser in operation on the
vent line from the flask, heat was applied to the mix-
ture in the flask. Within about ten minutes, the mix-
ture reached a temperature of about 75C under reflux.
At this point, addition of butyrolactone to the mixture
was commenced. .A total of 8.6g of butyrolactone was
added over a period of about ten minutes. 3y the time
the addition was completed~ the temperature o~ the mix-
ture had risen to 78C. Heating was continued for
another 2 hours and 15 minutes, during which time the
temperature rose to 114C. Heat was then removed and
the mixture allowed to cool.
On the next day, water (25ml) was added to the
cooled mixture and heat thereupon applied. Within about
35 minutes, the temperature had risen to 96C and the
mixture had become a homogeneous solution. Heat was
.
4js 24 37-21-(5659)
1324388
then removed. After the mixture had cooled, it was
washed three times with 25ml aliquots of chloroform for
extraction of phenol, pyridine and organic impurities.
- The aqueous raffinate was then stripped on a rotary
evaporator, and the residue dried by storage under
vacuum at a temperature of 100 - 110C. The dry solid
product (14.lg) was silylated and analyzed by GLC, and
found to contain 28.8~ HOCH2CH2CH2CO2Na, 67.3
c~3scH2cH2cH2co2Na~ and 3;4% unknown-
Example 7
Sodium hydroxide (49; 0.1 mole) and phenol(9.49; 0.1 mole~ were dissolved in pyridine (75ml).
Heat was applied to the resulting mixture and a water/-
pyridine fraction (25ml) was distilled overhead through
a 6~ Vigreaux column. The temperature of the overheads
ranged from 96 - 113C during the course of the distil-
lation.
Into the resulting dry solution of sodium
phenate in pyridine, methylmercaptan (~.~g) was intro-
Z0 duced by distilling it slowly from another source, con-
densing the vapor in a dry ice condenser, and allowing
the condensate to flow by gravity into the phenate solu-
tion. Introduction of methylmercaptan took place over a
period of about one hour and 40 minutes. After addition
of the methylmercaptan was complete, and with the dry
ice condenser in place on the vent line from the vessel
containing the resulting mixture, heat was applied to
the mixture and addition of butyrolactone was com-
~enced. Over a period of about 5 minutes a total of
4.3g of butyrolactone was added. When this addition had
.
4js 25 37-21-(56S9)
1324388
been completed, the temperature of the mixture was about
7SC. Heating was continued and, when the temperature
reached 77C, .he solids in the mixture had completely
dissolved. Heating was carried out for another hour,
during which time the temperature rose to about 86C.
Later sodium bicarbonate (59) and water (25m})
were added to the reaction mass and heat was applied.
Within about one fialf hour, the temperature rose to
about 96C, at which point the heat was removed. The
aqueous ~lxture was then allowed to cool, after which it
was washed three times with 25ml aliquots of chloro-
form. The aqueo~s raffinate was then stripped on a
rotary evaporator to afford a solid residue (13.lg).
This product was silylated and analyzed by GLC and ~ound
to contain the ~ollowing relative levels (area ~) of
volatile components: 18.2~ HOCH2CH2CH2C02Na,
80.3~ cH3scH2cH2cH2co2Na~ and 0.4~ unknown
peak.
Example 8
Sodium hydroxide (49) and phenol (9.4) were
dissolved in pyridine (75ml) and about 25ml of a
pyridine/water fraction distilled ovec through a
Vigreaux column. The overhead temperature ranged from
94 - 114C during the distillation.
! 25 The solution of sodium phenate in pyridine was
placed in a *Fisher-Porter bottle and c~oled in an ice
bath. Then methylmercaptan (109) and gamma-butyrolactone
(8.69) were introduced into the solution in the bottle.
The bottle was sealed and stirred with a magnetic
. .'
*Trade Mark
.~
4js 26 37-21-(5659)
1324388
stirrer. Heat was then applied and reaction carried out
under autogenous pressure for a period of about 2 hours
and 55 minutes. During this time the temperature rose
- to 89C and the pressure in the bottle reached a maximum
of about 21 psig. Heat was then removed. After the
contents of the bottle had cooled to about room tempera-
ture, it was vented to the atmosphere and water (25ml)
was added to the mixture. The resulting aqueous mixture
was washed with chloroform (three aliquots of 25ml
each), and the aqueous raffinate was then stripped on a
rotary evaporator, yielding a residue weighing about
14.99.
GLC analysis of the silylated product lndi-
cated the ~ollowing area ~ of volatile constituents:
21.6~ ~OCH2C~2CH2CO2Na, 77-4~
CH3SCH2CH2CH2CO2Na, and an unknown high boiler
peak of 0.4~.
Example 9
Sodium hydroxide ~49) and phenol (9.4g) were
dissolved in gamma-picoline ~about 75ml). Heat was
applied to the resulting mixture to effect formation of
sodium phenate and to distill off a fraction comprising
water and picoline (about 25ml). The overhead tempera-
ture ranged from 96 - 144C during the distillation.
The resulting solution of sodium phenate in
picoline was placed in a Fisher-Porter bottle, to which
methylmercaptan (10.39) and butyrolactone (8.69) were
also added. The bottle was then sealed and placed in a
water bath and heat was applied to the contents thereof
, ~, , ;,.
4js 27 37-21-(5659)
1324388
to effect reaction under autogenous pressure. Heating
was continued over a period of about 2 hours and 15
minutes, during which time the temperature rose to about
95C and the pressure reached a maximum of about 22
psig. One half hour after the heat was removed, the
bottle was vented to the atmosphere, and water (25ml)
added to the mixture contained in the bottle.
The resulting a~ueous mixture was.washed three
times with aliquots of chloroform (25ml each), and the
aqueous raffinate thereafter stripped on a rotary
evaporator, yielding 13.99 of solid product. GLC
analysis of the silylated product indicated the follow-
ing composition (area ~) of the volatile components:
0.8~ phenol; 19.1% HOCH2CH2CH2C02Na, 79.1%
CH3SC~2CH2CH2C02Na, and 0.5% of high boilers.
Example 10
Sodium hydroxide (49) and phenol (9 4g) were
dissolved in gam~a-picoline (about 75 ml~. Heat was
applied to effect formation of sodium phenate and to
remove water from the system. Approximately 25ml of a
water/picoline fraction was distilled overhead through a
6~ Vigreaux column. Temperature of the overheads during
the reaction and distillation ranged from 96 - 144C.
The resulting solution of sodium phenate in
picoline was placed in a Fisher-Porter bottle. Also
added to the bottle were methylmercaptan (lOg~ and
butyrolactone (8.69). The bottle was sealed and placed
on an oil bath. Heat was applied via the oil bath.
Reaction ensued under autogenous pressure. During ~he
4js 28 1324388 37 21-t5659)
reaction the temperature rose to 120C, and the pressure
reached a maximum of 36psig. After about 2 hours and 15
minutes, heat was removed. When the reaction mass had
cooled for about one half hour, water (25ml) was added
thereto.
The resultant aqueous mixture was then washed
three times with 25ml aliquots of chloroform. The
aqueous raffinate was stripped on a rotary evaporator,
a~fording a solid residue (15.3g~, a sample of which was
silylated a~d subjected to GLC analysis. The results
showed the following composition of ~olatiie products:
0.3% phenol, 13.5% HOCH2Cff2CH2CO2Na, 84-9~
CH3SCH2CH2CH2C02Na, and 0.97~ of a high boiler
peak.
Example 11
Sodium hydroxide (49) and 2,6-dimethylphenol
(12.29) were dissolved in gamma-picoline (about 75ml~.
Heat was applied to the mixture to remove water from the
mix~ure. About 25ml of a water/picoline mixture were
distilled overhead through a 6" Vigreaux column. The
temperature of the overheads during the reaction and
distillation ranged from 110 - 144C.
$he resulting solution of sodium 2,6-dimethyl-
phenate in picoline was placed in a Fisher Porter
bottle, along with methyLmercaptan (about 10.49) and
butyrolactone (8.59). The bottle was then sealed and
placed in an oil bath. Heat was applied via the 4il
bath and reaction carried out under autogenous pres-
sure. Heating was maintained over a period of about 2
4js 29 37-21-(5659)
1~2~388
and 1/2 hours, during which time the temperature rose to
131C and the pressure reached a maxiumum of about
28psig. About 15 minutes after the heat had been
- removed, the bottle was vented to the atmosphere and
water (25ml) added to the reaction mass.
The resulting aqueous.mixture was washed three
times with 25ml aliquots of chloroform, and the remain-
ing aqueous phase was str;ipped on a .rotary evapor.ator to ..
afford 14.29 of solid product. G~C analysis of.this
product (silylated) indicated the following relative
composition of volatile components: 11.0%
HOCH2CH2CH2C02N '
CH3SCH2CH2CH2C02Na. There was no appreciable
peak which could be attributed to high boilers.
. _
