Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~- ~08~
The chemistry of oxazolines has been reviewed
extensively in three major review articles: (1) Wiley
et al., Chemical Reviews, Volume 44, 447(1949); (2)
Seeliger et al., Angew. Chem. International Addition,
Volume 5, No. 10, 875 (1966); and (3) Frump, Chemical
Reviews, 1971, Volume 71, 5483. Such review articles
indicate ~hat a wide variety of ring-opening reactions
of oxazolines are known but surprisingly few reactions
of hydrogen sulfide with oxazolines have ever been
considered.
Tomalia et al., in U.S. Patent 3,670,046
~aught that certain bisoxazolines react with bismercaptans
or hydrogen sulfide to produce polymers. Tomalia et al.
also taught in U.S. Patents 3,~30,996, 3,723,451 and
3,746,691 that hydrogen sulfide reacts with certain
2-alkenyl-2-oxazolines to produce the corresponding
bis(2-oxazolinylethyl)sulfides. However, neither of
these references mentions the preparation of N-(2-mercapto-
ethyl)alkanamides.
It has now been discovered that N-t2-mercaptoethyl)
alkanamides can be prepared in excellent yield by the present
invention, which is a process for preparing an N-(2-mercapto-
ethyl)alkanamide comprising reacting under anhydrous con-
ditions (a) a 2-H-2-oxazoline or a 2-alkyl-2-oxazoline
having the formula
1 1
R2 - C - N
¦ ~C - R
R3 - C 0
~ ~4
-17,732A-F -1-
" ' ' :
1~8~9S6
wherein R is hydrogen or an alkyl group of from 1 to 18
carbon atoms and each of Rl to R4 are hydrogen, lower
alkyl, hydroxy-substituted lower alkyl or phenyl, with
(b) hydrogen sulfide.
Such products form a known class of useful
compounds having many members, all of which can be
hydrolyzed with aqueous ~HCl to form a 2-mercaptoethylamine
hydrochloride which has utility, when neutralized, as an
epoxy curing agent, as an acid scavenger and as a pharma-
ceutical intermediate.
The reactants in the instant process are known
classes of reactants. The 2-H-a-oxazolineS and 2-alkyl-2-
-oxazolines correspond to the formula
Il :
R2 - C - N
¦ C - R
R3 - C - 0
~.. .
in which R is hydrogen or an alkyl group of from 1 to 18
carbon atoms, and preferably R is methyl or ethyl. Each
of Rl to R4 is hydrogen, lower alkyl (from 1 to 6 carbon
atoms), hydroxy-substituted lower alkyl or phenyl. Pref-
erably, Rl and R2 are hydrogen, methyl, ethyl or hydroxy-
methyl and R3 and R4 are each hydrogen. Most preferably,
Rl to R4 are each hydrogen.
Examples of suitable such 2-alkyl~2-oxazoline
reactants include those of -formula I having the values
of R and Rl to R4 set forth in Table I.
17,732A-F -2-
.. .
- ~ . . : . . ' : ,' .: : ,
. ' : :, . :, . : .
r `~ lV~ 5~;
TABLE I
R Rl R2 R3 R~
H H H H H
CH3 H H H
2H5 H H H H
C7H15 H ~ H H
CllH23 H H H H
C17H35 H H H H
CH3 C6H5 H H H
C5HllC6H5 H H C6H5
C2H5 CH3 H H
CH3 CX3 CH3 H
C8H17CH2H CH2H H H
C2H5 C~Hg ~ H C6H5
CH3 H H CH3 CH3
C2H5 H H H C2H5
The 2-oxazolines used herein are normally
prepared by reacting an alkanoic acid with an ethanolamine
to form the corresponding acid/amine salt or amide, which
in turn is heated in the presence of an aluminum oxide
catalyst to form the corresponding 2-alkyl-2-oxazoline
product.
The reaction may be conducted neat or in an
organic solvent that is inert in the instant process.
Suitable such solvents include the lower alkanols and
particularly methanol and combinations of such lower
alkanols with conventional hydrocarbon solvents (e.g.
benzene, toluene, etc.). It is preferred to conduct the
instant process neat or in methanol. It is also preferred
to conduct the reaction under substantially anhydrous
conditions. The 2-oxazolines are susceptible to hydrolysis
17,732~-F -3-
S6
by water and essentially anhydrous conditions are
therefore required to optimize product yield.
The stoichiometry of the reaction requires
1 mole of hydrogen sulfide per mole of 2-alkyl-2-
-oxazoline reactant. More or less than the stoichio-
metric amount of either reactant can be used. However,
it is preferred to use an excess of hydrogen sulfide to
effect $he completion of the reaction and to maximize
the product yield at the expense of by-products, such
as bis(alkanamidoethyl) sulfide.
The order of addition or method of blending
the reactants is not critical. From a procedural standpoint,
however, it is advantageous to add the hydrogen sulfide
incrementally to a reaction vessel precharged with the -~
oxazoline reactant, mainly for effectively controlling
the reaction temperature.
Substantially any reaction temperature of from
about 20 to about 200C can be used but we normally prefer
to conduct the reaction at a temperature of from about
50 to about 150C. At these temperatures, the reaction
may be conducted under autogenous or superatmospheric
pressures in conventional pressure equipment. The instant
reaction is e~othermic and normally will not require
additional heat after ~he reaction is star~ed. Normally,
it is advantageous to conduct the reaction in equipment
where the temperature can be controlled by cooling.
It has been observed that the reaction rate
and product yields are lower when a reaction temperature
in lower ranges are used (e.g. from about 20 to about 70).
17,732A~F _4_
.. ~ . ~.
95!6i
In these instances the product yields can be increased
by warming the reaction mixture to the preferred tem-
perature range (e.g. 100-150C). This post-heating
step appears to cause at least one of the by-products
(e.g. a hydroxyethyl thiocarboxamide) to thermally revert
to the starting materials and/or rearrange to the desired
product.
Example 1 - Preparation o~ N-(2-mercaptoethyl)acetamide
A l-liter Parr pressure reactor was charged with
192.2 g of anhydrous methanol and hydrogen sulfide (73.0 g;
2.14 moles; 7 percent excess) and the stirred solution
heated to 100C. 2-Methyl-2-oxazoline (169.3 g; 1.99 moles)
was then pumped into the sealed bomb through a check valve
at a rate of approximately 2.5 g/minute. The temperature
of the stirred solution rose to 111C during addition and
the pressure within the bomb dropped from 320 to 65 psig
(22.6-4.59 kg./cm.2). The drop in pressure indicates
conversion of H2S to the desired alkanamide. To insure
complete conversion, the reactor was heated at this tem-
perature for an additional 4 hours. During this post heating
period the bomb pressure remained constant indicating the
reaction was essentially complete. The reaction mixture
was cooled and volatiles removed therefrom under reduced
pressure. Analysis of the remaining pot material by
standard iodide/iodate titration (mercaptan functional
group analysis) indicated 201.9 g of the desired amide,
and 85.1 percent yield based on the oxazoline charged.
Distillation under reduced pressure produced a 92.6 percent
recovery of a water-white, viscous liquid boiling at 125C/
0.9 mm Hg. Bis(acetamidoethyl)sulfide was produced as a
17.732A-F -5-
~L~)8~6
by~product in amounts which essentially accounted for
the remainder of the reactants.
N-(2-mercaptoethyl)propionamide was produced
in similarly good yields under essentially the same
process conditions.
Bxam~e~ Preparation of N-(2-mercaptoethyl)propionamide
2-Ethyl-2-oxazoline (496.4 g; 5.01 moles) was
charged to a l-liter stainless steel Parr reactor, equipped
with a stirrer, heating means, and a dip tube designed to
introduce H2S below the surface of the liquid oxazoline.
The oxazoline was warmed to 70C and hydrogen sulfide
(189.5 g, 5.56 moles) was added to the reaction vessel
through the dip tube at a rate of 3.7 g per minute. The
temperature was maintained at 70-75C during the addition
of H2S and for an additional 4.3 hours after the addition
was complete. The reaction mixture was subsequently heated
at 150C for 5 hours. Aiter this post-heating step, the
reaction mixture was cooled to 85C, excess H2S vented to
a caustic scrubber, and nitrogen bubbled through the
remaining liquid reaction mixture to remove residual ~2S.
Analysis of the clear, brown liquid product (653.7 g) thus
obtained indicated that the desired product~ N-(2-mercapto-
ethyl)propionamide, was produced in 86.8 percent of theo-
retical yield, based on the oxazoline charged. The desired
product was recovered from the crude product by use of a
falling film still and was thus obtained as a water white
liquid containing a minor amount (less than 5 percent) of
2-ethyl-2-thiazoline. The presence of this thiazoline is
not a disadvantage since it also hydrolyzes under the
conditions set forth below to form the mercaptoethylamine
hydrochloride.
17,732A-F -6-
'~ . . .
-, .
,.:
s~
Example 3 - Preparation of Mercaptoethylamine Hydrochloride
An aliquot o-f the N-(2-mercaptoethyl)acetamide
from Example 1 above (119.2 g; 1.00 mole) and 19.5 percent
aqueous HCl (205.6 g; 1.10 mole) were combined in a re-
action vessel equipped with a magnetic stirrer and reflux
condensor. The reaction mixture was heated to reflux
(approximately 107C) for 4 hours, under a nitroge~ blanket.
Volatiles were then removed from the reaction mixture under
vacuum leaving a viscous, slightly yellow pot liquid which
crystallized to a whIte solid upon cooling. The crystalline
material (114.0 g) was identified by its nuclear magnetic
resonance and infrared spectra as mercaptoethylamine
hydrochloride. This salt is an item of commerce having
several utilities, especially its use as a pharmaceutical
intermediate. This salt can also be neutralized with a
base (e.g., NaOH) and used as an epoxy curing agent in epoxy
resins. Both the mercapto group and amino group are reactive
with the epoxy moiety. See "Handbook of Epoxy Resins" by
Lee and Neville, McGraw-Hill Book Company (1967). ~urther,
the neutralized salt can be used as an acid scavenger to
inhibit acid corrosion. Other mercaptoethylamines can be
similarly used.
17,732A-F _7_
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