Thiophene ethanolamines substituted on the nitrogen atom with an alkyl or aralkyl radical and optionally substituted on the thiophene portion, are disclosed. The thiophene ethanolamines possess antihypertensive and .beta.-receptor blocking activities. Methods for their preparation and use are given.

BACKGROUND OF THE INVENTION 
(a) Field of the Invention 
This invention relates to thiophene ethanolamines, to processes for their 
preparation and to intermediates therefor. 
More specifically, the compounds of this invention are thiophene 
ethanolamines characterized further in that they are substituted on the 
nitrogen atom with an alkyl or an aralkyl radical and are optionally 
substituted on the thiophene portion. 
(B) Description of the Prior Art 
The prior art relating to thiophene ethanolamines is rather niggardly. An 
early report by C. F. Heubner, et al., J. Org. Chem., 18, 21 (1953), 
described the preparation of the thiophene ethanolamine, 
.alpha.-(aminomethyl)thiophene-2-methanol, which was found to have pressor 
activity. In 1968, E. D. Bergmann and Z. Goldschmidt, J. Med. Chem., 11, 
1121 (1968), described some corresponding N-alkyl derivatives of the 
latter thiophene ethanolamine, noting that these derivatives possessed no 
significant pharmacologic activity. A still more recent report, C. Carrol, 
et al., J. Med. Chem., 16, 882 (1973), described a related series of 
N-substituted thiophene ethanolamines, the substitution being alkyl, 
phenyl or such that the nitrogen atom forms part of a pyrrolidine, 
piperidine or morpholine ring. A variety of pharmacologic properties were 
reported for the series including the property that they antagonized the 
hypotensive response to isoproterenol. 
Unexpectedly, we have found that the compounds of the present invention, 
and particularly the N-(aralkyl)-thiophene ethanolamines are potent 
antihypertensive and .beta.-receptor blocking agents. These properties 
together with their relatively low toxicity and the direct manner in which 
these compounds are prepared render them useful and practical for the 
treatment of hypertensive conditions and lessening undersirable 
.beta.-adrenergic stimulation of the myocardium. 
SUMMARY OF THE INVENTION 
The thiophene ethanolamines of this invention are represented generally by 
the formula ArCHOR.sup.1 CHR.sup.2 NR.sup.3 R.sup.4 in which Ar is the 
radical 
##STR1## 
wherein X.sup.1, X.sup.2 and X.sup.3 are selected from the group 
consisting of hydrogen, halo, lower alkyl, lower alkoxy and phenyl; 
R.sup.1 is hydrogen or lower alkyl, R.sup.2 is hydrogen or lower alkyl; 
R.sup.3 is hydrogen or lower alkyl; and R.sup.4 is lower alkyl, 
2-indol-3-ylethyl or a phenethyl radical of the formula, 
##STR2## 
wherein R.sup.5 is hydrogen or lower alkyl, R.sup.6 is hydrogen or hydroxy 
and R.sup.7, R.sup.8 and R.sup.9 are the same or different selected from 
the group consisting of hydrogen, lower alkyl, lower alkoxy, hydroxy and 
halo, or R.sup.6 and R.sup.7 are joined to form a methylenedioxy radical 
and R.sup.8 is hydrogen; or R.sup.3 and R.sup.4 together with the nitrogen 
to which they are joined form a 4-phenyl-, 4-(4-methoxyphenyl)- or 
4-(o-tolyl)-piperazin-1-yl group with the proviso that when Ar is the 
radical 
##STR3## 
wherein X.sup.1, X.sup.2 and X.sup.3 are selected from the group 
consisting of hydrogen or halo, R.sup.4 is other than lower alkyl as 
defined herein; and by the formula ArCH(CHR.sup.2 OH)NR.sup.3 R.sup.4 in 
which Ar, R.sup.2, R.sup.3 and R.sup.4 are as defined herein. 
The preferred ethanolamines of this invention are represented by the 
formula 
ArCHOR.sup.1 CHR.sup.2 NR.sup.3 R.sup.4 
in which Ar is selected from the group consisting of 2-thienyl, 5-(lower 
alkyl)-2-thienyl, 5-phenyl-2-thienyl and 4,5-dichloro-2-thienyl; R.sup.1 
is hydrogen or lower alkyl; R.sup.2 is hydrogen or lower alkyl; R.sup.3 is 
hydrogen or lower alkyl; and R.sup.4 is 2-indol-3-ylethyl, a substituted 
phenethyl of the formula 
##STR4## 
wherein R.sup.5 is hydrogen or lower alkyl, R.sup.6 is hydrogen or hydroxy 
and R.sup.7, R.sup.8 and R.sup.9 are the same or different selected from 
the group consisting of hydrogen, lower alkyl, lower alkoxy, hydroxy and 
halo or R.sup.7 and R.sup.8 are joined to form a methylenedioxy radical 
and R.sup.9 is hydrogen; or R.sup.3 and R.sup.4 together with the nitrogen 
to which they are joined form a 4-(4-methoxyphenyl)- or 
4-(o-tolyl)-piperazin-1-yl group; and by the formula ArCH(CHR.sup.2 
OH)NR.sup.3 R.sup.4 in which Ar, R.sup.2, R.sup.3, and R.sup.4 are as 
defined herein. 
DETAILED DESCRIPTION OF THE INVENTION 
The term "lower alkyl" as used herein contemplates straight chain alkyl 
radicals containing from one to six carbon atoms and branched chain alkyl 
radicals containing from three to four carbon atoms and includes methyl, 
ethyl, propyl, isopropyl, butyl, isobutyl, 2-methylpentyl, hexyl and the 
like. 
The term "lower alkoxy" as used herein contemplates both straight and 
branched chain alkoxy radicals containing from one to four carbon atoms 
and includes methoxy, ethoxy, isopropoxy, t-butoxy and the like. 
The term "halo" as used herein contemplates halogens and includes chlorine, 
bromine and iodine. 
The term "alkanoyl" as used herein contemplates the radical COCH.sub.2 
R.sup.2 in which R.sup.2 is hydrogen or lower alkyl as defined herein. 
The compounds of this invention form salts with pharmaceutically acceptable 
acids. Such acid addition salts are included within the scope of this 
invention. 
The acid addition salts are prepared by reacting the corresponding base 
form of the thiophene ethanolamine with at least one equivalent, or 
preferably with an excess of the appropriate acid in an organic solvent, 
for example, ether or an ethanol-ether mixture. These salts, when 
administered to mammals, possess the same pharmacologic activities as the 
corresponding bases. For many purposes it is preferable to administer the 
salts rather than the base compounds. Among the acid addition salts 
suitable for this purpose are salts such as the sulfate, phosphate, 
lactate, oxalate, maleate, citrate, hydrobromide and hydrochloride. Both 
the base compounds and the salts have the distinct advantage of possessing 
a relatively low order of toxicity. 
The stereochemical isomers of the compounds of this invention, made 
possible by the occurrence of asymmetric centers contained therein, are 
also included within the scope of this invention. 
The antihypertensive effect of the compounds of this invention and their 
acid addition salts is demonstrated in standard tests, for example, in 
tests conducted in the spontaneously hypertensive rat such as described by 
I. Vavra, et al., Can. J. Physiol. Pharmacol., 51 727 (1973). For 
instance, the following compounds have been found to be active in this 
test at 50 mg/kg or less when they are given by gavage as a single dose. 
.alpha.-{[3,4-dimethoxyphenethyl)amino]methyl}-2-thiophenemethanol oxalate 
(Example 15), 
.alpha.-{[3,4-dimethoxyphenethyl)amino]methyl}-5-methyl-2-thiophenemethanol 
oxalate (Example 16), and 
.alpha.-{[(3,4-dimethoxyphenethyl)amino]methyl}-5-phenyl-2-thiophenemethano 
l hydrochloride (Example 19). 
Thus an embodiment of this invention includes the method of lowering blood 
pressure in a hypertensive host such as a mammal by administering a 
therapeutically effective amount of the compounds of this invention to the 
host. 
The .beta.-receptor blocking activity of the compounds and their acid 
addition salts is demonstrated also in standard tests such as those 
described by E. Westermann and K. Stock in "International Symposium on 
Drugs Affecting Lipid Metabolism, 3rd, Milan, 1968", W. J. Holmes, et al., 
Ed., Plenum Press, New York, 1969, pp 45 - 61. 
When the compounds of this invention and their acid addition salts are 
employed as antihypertensive or .beta.-receptor blocking agents in 
warm-blooded mammals, e.g. rats and mice, they are used alone or in 
combination with pharmacologically acceptable carriers. The proportion of 
the compound is determined by its solubility and chemical nature, chosen 
route of administration and standard biological practice. For example, 
they are administered orally in solid form containing such excipients as 
starch, milk sugar, certain types of clay and so forth. They may also be 
administered orally in the form of solutions or they may be injected 
parenterally. For parenteral administration they are used in the form of a 
sterile solution containing other solutes, for example, enough saline or 
glucose to make the solution isotonic. 
The dosage of the present therapeutic agents will vary with the form of 
administration and the particular compound chosen. Furthermore, it will 
vary with the particular host under treatment. Generally, treatment is 
initiated with small dosages substantially less than the optimum dose of 
the compound. Thereafter, the dosage is increased by small increments 
until the optimum effect under the circumstance is reached. In general, 
the compounds of this invention are most desirably administered at a 
concentration level that will generally afford effective results without 
causing any harmful or deleterious side effects and preferably at a level 
that is in a range of from about 0.1 mg to about 100 mg per kilo per day, 
although as aforementioned variations will occur. However, a dosage level 
that is in the range of from about 5.0 mg to about 50 mg per kilo per day 
is most desirably employed in order to achieve effective results. 
PROCESS 
One method for preparing the compounds of this invention is illustrated as 
follows: 
AR--H.fwdarw.ArCOCH.sub.2 R.sup.2 .fwdarw.ArCOCHR.sup.2 Y.fwdarw. 
ArCHOHCHR.sup.2 Y.fwdarw.ArCHOR.sup.1 CHR.sup.2 NR.sup.3 R.sup.4 
in which R.sup.1 is hydrogen, Y is bromo, chloro or iodo and Ar, R.sup.2, 
R.sup.3 and R.sup.4 are as defined herein. 
The requisite starting materials of formula Ar--H are either known or are 
prepared readily by known methods. Examples of the known thiophene 
starting materials include the commercially available 2-chlorothiophene 
and 2-bromothiophene. 2,3-Dibromothiophene is described by S. O. Lawesson, 
Arkiv. Kemi, 11, 378 (1957), 3,4-dibromothiophene is described by S. 
Gronowitz, Acta Chem. Scand., 13, 1045 (1959), 2,3-dichlorothiophene, 
3,4-dichlorothiophene are described by Corral, et al., cited above, 
2-methoxythiophene is described by J. Sice, J. Amer. Chem. Soc., 75, 3697 
(1953), 3,4-dimethoxy thiophene is described by E. W. Fager, J. Amer. 
Chem. Soc., 67, 2217 (1945), 2-methylthiophene is described by F. S. 
Fawcett, J. Amer. Chem. Soc., 68, 1420 (1946) and 2-phenylthiophene is 
described by A. I. Kosak, et al., J. Amer. Chem. Soc., 76, 4450 (1954) . 
General methods for making any of the halo, alkyl, alkoxy, and aryl 
thiophenes of formula Ar--H are described in general textbooks; for 
example, Rodd's Chemistry of Carbon Compounds, 2nd ed., S. Coffey, Ed., 
Vol. IV-A, Elsevier Scientific Publishing Co., Amsterdam, 1973 pp 220 - 
255 and "Heterocyclic Compounds", R. C. Elderfield, Ed., Vol. 1, John 
Wiley & Sons, Inc., New York and London, 1950, pp 208 - 276. 
With reference to the process the thiophene starting materials of formula 
Ar--H are subjected to acylation to give the corresponding 2-acylthiophene 
derivatives of formula ArCOCH.sub.2 R.sup.2 in which Ar and R.sup.2 are as 
defined above. Although a variety of methods are reported for 
accomplishing this acylation, see for example the aforementioned 
textbooks, a preferred method for obtaining the 2-acylthiophene 
derivatives of formula ArCOCH.sub.2 R.sup.2 in which R.sup.2 is hydrogen 
or lower alkyl involves treating the appropriate thiophene of formula 
Ar--H with an appropriate alkanoyl chloride or bromide, for example, 
acetyl chloride or propionyl bromide, in an inert organic solvent, 
preferably benzene or toluene, at temperatures ranging from -20.degree. to 
80.degree. C, preferably 0.degree. to 30.degree. C for two to 72 hours, 
preferably six to 72 hours. 
Alternatively, the 2-acylthiophenes are prepared from the appropriate 
thiophene of formula Ar--H according to a modification of the method of W. 
Steinkopf and W. Kohler, Justus Liebigs' Ann. Chem., 532, 250 (1937). The 
latter method involves treating the thiophene with an organic lithium 
reagent, preferably n-butyl lithium in an inert solvent, preferably 
tetrahydrofuran, ether, hexane and the like, to generate the corresponding 
2-thienyl lithium derivative. The latter derivative is reacted with carbon 
dioxide to give the corresponding 2-thiophene carboxylic acid which on 
treatment with the appropriate lower alkyl lithium gives the desired 
2-acylthiophene. 
A number of the 2-acylthiophenes utilized in the process of this invention 
are known; for example, 2-acetylthiophene described by J. R. Johnson and 
G. E. May, Org. Synth., 18, 1 (1938); 2-propionylthiophene, described by 
H. A. Bruson and T. W. Riener, J. Amer. Chem. Soc. 70, 214 (1948) and 
2-acetyl-3,4-dichlorothiophene described by E. Profft and G. Solf, J. 
Prakt. Chem., 24, 38 (1964). See also the general textbooks noted above. 
In the next step the 2-acylthiophene is converted by halogenation to the 
corresponding haloketone of formula ArCOCHR.sup.2 Y in which R.sup.2 is 
hydrogen or lower alkyl and Y is bromo, chloro or iodo. This conversion is 
accomplished readily by halogenating agents known to be effective for 
introducing a halogen atom .alpha. to a ketone. In a preferred embodiment 
of this conversion the halogenation is effected with substantially an 
equimolar amount of elemental bromine, pyridumium bromide or cupric 
bromide in an inert organic solvent, preferably chloroform or acetic acid, 
to obtain the corresponding bromoketone, ArCOCHR.sup.2 Br. Similar 
conversions to the corresponding chloroketone or iodoketone are 
accomplished with elemental chlorine or iodine, respectively. In these 
cases the halogenation proceeds readily. Convenient times and temperatures 
include 10 to 60 minutes and 0.degree. to 30.degree. C. 
Several of the haloketones of formula ArCOCHR.sup.2 Y have been described 
previously; for example 2-(bromoacetyl)thiophene, described by Heubner, et 
al., cited above, 2-(chloroacetyl)thiophene, described by W. S. Emerson 
and T. M. Patrick, J. Org. Chem., 13, 724 (1948) and 
2-(chloroacetyl)-3,4-dichlorothiophene, described by Profft and Solf, 
cited above. 
In the next step the .alpha.-haloketone of formula ArCOCHR.sup.2 Y in which 
Ar, R.sup.2 and Y are as defined herein is reduced with a complex metal 
hydride to give the corresponding halohydrin of formula ArCHOHCHR.sup.2 Y. 
Examples of suitable complex metal hydrides for this reduction are sodium 
borohydride, lithium aluminium hydride and diborane. Sodium borohydride is 
preferred. The reduction is carried out in a non-reactive solvent medium. 
When sodium borohydride is used, preferred solvents include methanol or 
tetrahydrofuran. When lithium aluminum and diborane are used as the 
reducing agent, preferred solvents include the non-hydroxylic solvents, 
for example, diethyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane 
and the like. Generally the reaction is best performed at temperatures 
ranging from 0.degree. to 40.degree. C for periods varying from 30 minutes 
to 24 hours. While equivalent quantities of reactants may be used, it is 
preferable to use the reducing agent in moderate excess. 
The halohydrin so obtained is used thereafter for N-alkylation of the 
appropriate primary or secondary amine of formula NHR.sup.3 R.sup.4 to 
obtain the corresponding thiophene ethanolamine of formula ArCHOR.sup.1 
CHR.sup.2 NR.sup.3 R.sup.4 in which R.sup.1 is hydrogen and R.sup.2, 
R.sup.3 and R.sup.4 are as defined herein. One method for effecting this 
N-alkylation includes bringing the reactants together in the presence of a 
base; suitable bases for this purpose are alkali metal carbonates and 
alkali metal bicarbonates. The ratio of reactants will depend on the 
starting material that is employed and the product that is desired. When 
the starting material is a primary amine, a secondary amine product is 
obtained by using slightly more than one equivalent of alkylating agent 
and base, whereas a tertiary amine product is obtained by using somewhat 
more than two equivalents of alkylating agent and base. When the starting 
material is a secondary amine, a tertiary amine product is obtained by 
using slightly more than one equivalent of alkylating agent and base. 
Depending upon the particular alkylating agent and base chosen, a variety 
of solvents and reaction conditions may be used. Some examples of suitable 
solvents are aromatic hydrocarbons, ethers, lower alkanols, lower 
aliphatic ketones, and other non-reactive solvents, such as dimethyl 
sulfoxide, N,N-dimethylformamide, and and acetonitrile. The temperature 
and duration of the reaction are not critical and may be varied over a 
wide range, depending upon the particular alkylating agent and solvent 
that are used. Generally it is most convenient and efficacious to carry 
out the reaction at the reflux temperature of the reaction mixture for a 
period of one hour to several days. 
The requisite primary and secondary amines of formula NHR.sup.3 R.sup.4 are 
either known or are prepared by known methods; for example, see "Methoden 
der Organic Chemie", (Houben-Weyl), E. Muller, Ed., Vol. II/I, Georg 
Thieme Verlag, Stuttgart, 1957, pp 9 - 1033. 
Using similar N-alkylation conditions any of the aforementioned secondary 
amines (i.e., compounds of formula ArCHOR.sup.1 CHR.sup.2 NR.sup.3 R.sup.4 
in which R.sup.3 is hydrogen) are converted to corresponding tertiary 
amines. Preferred conditions include treating the secondary amine with 
about five to ten molar equivalents of the appropriate lower alkyl halide 
or aralkyl halide in an inert organic solvent, for instance, ethanol, 
tetrahydrofuran or benzene, from one to 24 hours or more at a temperature 
ranging from about 20.degree.-80.degree. C. 
In a preferred embodiment of the process the N-alkylation is effected by 
heating the bromohydrin with 1.0 to 1.5 molar equivalents of the primary 
or secondary amine either together in a pressurized container at 
80.degree. - 120.degree. C or at 40.degree. to 120.degree. C in the 
presence of an inert organic solvent. Generally the reactants are heated 
together for 3 to 24 hours. Preferred solvents for this latter conditions 
include benzene, toluene, dioxane and tetrahydrofuran. 
It should be noted that in the aforementioned N-alkylation reactions, a 
by-product is sometimes encountered. This by-product is isomeric to the 
expected thiophene ethanol and has the general formula ArCH(CHR.sup.2 
OH)NR.sup.3 R.sup.4 in which Ar, R.sup.2, R.sup.3 and R.sup.4 are as 
defined herein. These isomers also possess useful antihypertensive 
properties as demonstrated in the above tests. Accordingly, these isomers 
and their corresponding acid addition salts with pharmaceutically 
acceptable acids can be formulated and used for this purpose in the manner 
described above for the thiophene ethanolamines. 
In the case where the thiophene ethanolamines of this invention are the 
compounds of formula ArCHOR.sup.1 CHR.sup.2 NR.sup.3 R.sup.4 in which 
R.sup.1 and R.sup.2 are hydrogen, R.sup.3 and R.sup.4 are as defined 
herein and Ar is the radical 
##STR5## 
wherein X.sup.1, X.sup.2 and X.sup.3 are selected from the group of 
hydrogen and lower alkoxy with the proviso that at least one of X.sup.1, 
X.sup.2 or X.sup.3 is lower alkoxy, the following alternative procedure 
has been found to be convenient: 
##STR6## 
in which X.sup.1, X.sup.2 and X.sup.3 are as defined in the last instance 
and R.sup.3 and R.sup.4 is as defined herein. 
With reference to this latter process the substituted thiophene of formula 
l is reacted with a organolithium reagent in an inert solvent. Suitable 
organolithium reagents include n-butyl lithium, n-propyl lithium, phenyl 
lithium and the like. Suitable inert solvents include ether, 
tetrahydrofuran, hexane and the like. In this manner the corresponding 
thienyl lithium derivative is generated. The lithium derivative is then 
reacted with a dialkyl oxalate, preferably dimethyl oxalate, to give the 
corresponding ester of formula 2 in which R.sup.10 is lower alkyl, 
preferably methyl. This ester is then hydrolyzed with a strong base, for 
example, sodium or potassium hydroxide, in the presence of sufficient 
water to effect hydrolysis. The hydrolysis is performed using a suitable 
solvent, for example, methanol or ethanol. The reaction mixture is 
maintained at a temperature of from 25.degree. C to the reflux temperature 
of the mixture until hydrolysis occurs, usually from 10 minutes to 6 hours 
is sufficient. The reaction mixture is then rendered acidic with an acid, 
for example, acetic acid, hydrochloric acid, sulfuric acid and the like, 
and the free acid (compound 3) isolated. 
At this point the latter free acid is subjected to amidation. The amidation 
is accomplished readily by first treating the acid with a lower alkyl 
chloroformate, preferably ethyl chloroformate, in the presence of 
triethylamine, to afford the corresponding mixed anhydride. Reaction of 
the mixed anhydride with the appropriate amine of formula HNR.sup.3 
R.sup.4 gives the corresponding amide of formula 4. 
Thereafter, treatment of the latter amide with a suitable complex metal 
hydride yields the corresponding desired thiophene ethanolamine of formula 
5. Examples of suitable complex metal hydrides are lithium aluminum 
hydride, aluminum hydride-aluminum chloride, diborane and sodium 
borohydride-aluminum chloride; lithium aluminum hydride being preferred. 
In a special modification of the latter step the amide of formula 4 in 
which R.sup.3 is hydrogen is first treated with triethyloxonium 
fluoroborate in an inert organic solvent, for example, chloroform or 
methylene dichloride, to give the intermediate iminoether fluoroborate. 
Subsequent reduction of the latter intermediate with an alkali metal 
borohydride, preferably sodium borohydride, give the corresponding desired 
thiophene ethanolamine of formula 5 in which R.sup.3 is hydrogen. 
Finally, in the case where it is desired to obtain the thiophene 
ethanolamines of formula ArCHOR.sup.1 CHR.sup.2 NR.sup.3 R.sup.4 in which 
R.sup.1 is lower alkyl (i.e., R.sup.1 forms part of a lower alkoxy group), 
the preferred mode of preparation involves a modification of the above 
process in which the halohydrin of formula ArCHOHCHR.sup.2 Y in which Ar, 
R.sup.2 and Y are as defined herein is treated with the appropriate lower 
alkanol in the presence of an acid catalyst, for example, 
p-toluenesulfonic acid, sulfuric acid or boron trifluoride etherate, to 
give the corresponding lower alkoxy derivative of formula ArCHOR.sup.1 
CHR.sup.2 Y in which Ar, R.sup.2 and Y are as defined herein and R.sup.1 
is lower alkyl. Conversion of the latter compound of the corresponding 
amine in the same manner described herein- before gives the thiophene 
ethanolamines of this invention of formula ArCHOR.sup.1 CHR.sup.2 NR.sup.3 
R.sup.4 in which Ar, R.sup.2, R.sup.3 and R.sup.4 are as defined herein 
and R.sup.1 is lower alkyl.

The following examples illustrate further this invention. 
EXAMPLE 1 
Acylation - Method A 
By following the procedure described by J. R. Johnson and G. E. May, Org. 
Synth., 18, 1 (1938), for the preparation of 2-acetylthiophene, the 
following 2-acylthiophenes are obtained: 
2-acetyl-5-bromothiophene, mp 94.degree. - 94.degree. C, from 
2-bromothiophene and acetyl chloride; 
2-acetyl-5-chlorothiophene, mp 46.degree. C, from 2-chlorothiophene and 
acetyl chloride; 
2-acetyl-3,4-dibromothiophene, mp 80.degree. - 81.degree. C, from 
3,4-dibromothiophene and acetyl chloride; 
2-acetyl-4,5-dibromothiophene, mp 84.degree. - 85.degree. C, from 
2,3-dibromothiophene and acetyl chloride; 
2-acetyl-3,4-dichlorothiophene, mp 51.degree. - 52.degree. C, from 
3,4-dichlorothiophene and acetyl chloride; 
2-acetyl-4,5-dichlorothiophene, mp 66.degree. - 67.degree. C, from 
2,3-dichlorothiophene and acetyl chloride; 
2-acetyl-3,4-dimethoxythiophene, mp 102.degree. C, from 
3,4-dimethoxybenzene and acetyl chloride; 
5-chloro-2-propionylthiophene, mp 50.degree. - 51.degree. C, from 
2-chlorothiophene and propionyl chloride; 
2-acetyl-5-methylthiophene, nmr (CDCl.sub.3) .delta. 2.50 (s, 3H), 2.55 (s, 
3H), 6.83 (m, 1H), 7.57 (d, 1H), from 2-methylthiophene and acetyl 
chloride; and 
2-acetyl-5-phenylthiophene, mp 115.degree. C, from 2-phenylthiophene and 
acetyl chloride. 
EXAMPLE 2 
Acylation - Method B 
Another method for preparing 2-acylthiophene is exemplified by the 
following preparation of 2-acetyl-5-phenylthiophene: 
A solution of 2-phenylthiophene (16.0 g, 0.1 mole) in 100 ml anhydrous 
tetrahydrofuran (THF) is treated dropwise with a solution of n-butyl 
lithium (0.11 mole) in hexane (2 M solution). Thereafter the mixture is 
stirred for 1 hr. The resulting black solution is poured onto 50 g of 
solid CO.sub.2 covered with ether. When all the CO.sub.2 is evaporated, 
the mixture is treated with 200 ml of water, acidified with 10% HCl and 
extracted with ether. The extract is washed with 5% NaOH. The latter 
washings are cooled and rendered acidic with 20% HCl. The resulting 
precipitate is collected and recrystallized from 100 ml CCl.sub.4 to give 
5-phenyl 2-thiophenecarboxylic acid, mp 180.degree. C, 
.gamma..sub.max.sup.CHCl 3 1665 cm.sup.-1, as yellow green crystals. 
The latter compound (16.7 g, 0.08 mole) in 300 ml of anhydrous ether is 
cooled to -50.degree. C and treated dropwise with methyl lithium (0.16 
mole) in ether (1M solution). The mixture is allowed to warm to 0.degree. 
C over a period of 2 hr. Thereafter the mixture is poured onto cold 5% HCl 
and extracted with ether. The extract is washed with 5% NaHCO.sub.3, water 
and brine, dried (MgSO.sub.4) and concentrated to give a yellow solid 
which is purified by chromatography on silica gel to give pure 
2-acetyl-5-phenylthiophene, mp 115.degree. C, .gamma..sub.max.sup.CHCl 3 
1650 cm, identical to the product of the same name described in Example 1. 
Other 2-acylthiophenes are obtained by this procedure by utilizing the 
appropriate thiophene of formula Ar-H; for example, the use of 
2,3-dichlorothiophene gives 2-acetyl-4,5-dichlorothiophene. 
EXAMPLE 3 
HALOGENATION 
The haloketones are obtained by procedures which are exemplified as 
follows: 
Method A 
A solution of 2-acetyl-5-phenylthiophene (11.7 g, 0.058 mole), described in 
Examples 1 and 2, in 100 ml of glacial acetic acid is treated dropwise 
with bromine (9.3 g, 0.058 mole). The mixture is stirred for 1/2 hr, 
poured into cold water and extracted with chloroform. The extract is 
washed with water, 5% NaHCO.sub.3 and brine, dried (K.sub.2 CO.sub.3) and 
concentrated to give a yellow solid. The solid is subjected to 
chromatography on silica gel to give bromomethyl 5-phenyl-2-thienyl ketone 
(ArCOCHR.sup.2 Y; Ar is 5-phenyl-2-thienyl, R.sup.2 = H and Y = Br); mp 
114.degree. C. 
Method B 
A solution of 5-methyl-2-thienyl methyl ketone (24.8 g, 0.177 mole), 
described in Example 1, in 170 ml chloroform is treated with pyridinium 
bromide perbromide (56.7 g, 0.177 mole). The mixture is stirred for 21/2 
hr. The resulting deep red solution is poured into ice water. The mixture 
is extracted with ether. The extract is washed with water and brine, dried 
(MgSO.sub.4), and concentrated to give a brown liquid. The oil is purified 
by chromatography on silica gel to give bromomethyl-5-methyl-2-thienyl 
ketone (ArCOCHR.sup.2 Y; Ar is 5-methyl-2-thienyl, R.sup.2 = H and Y = 
Br); .gamma..sub.max.sup.film 1650 cm.sup.-1, nmr (CDCl.sub.3) .delta. 
2.58 (s, 3H), 4.3 (s, 2H), 6.86 (m, 1H), 7.67 (m, 2H). 
Method C (method of L. C. King and G. K. Ostrum, J. Org. Chem., 29, 3459 
(1964): 
A stirred suspension of cupric bromide (20.7 g) in 50 ml ethyl acetate is 
heated to reflux. 2-Acetylthiophene (7.0 g) dissolved in 50 ml chloroform 
is added rapidly from a dropping funnel. The reaction mixture is heated 
further with vigorous stirring until the black cupric bromide had all been 
converted to the white cuprous bromide (about 2 hr.). The reaction mixture 
is cooled, filtered and concentrated. The resulting oil is subjected to 
chromatography on silica gel. Evaporation of the eluant (benzene-hexane, 
8:2) gives bromomethyl 2-thienyl ketone (ArCOCHR.sup.2 Y; Ar is 2-thienyl, 
R.sup.2 = H and Y = Br); bp 100.degree. C/0.2mm, .gamma..sub.max.sup.CHCl 
3 1660, 1410 cm.sup.-1. 
The following table lists other haloketones prepared by either method A, B 
or C, as indicated, together with the requisite starting materials 
described in Example 1. 
__________________________________________________________________________ 
STARTING MATERIAL METHOD 
HALOKETONE 
__________________________________________________________________________ 
2-acetyl-5-bromothiophene 
A bromomethyl 5-bromo-2- 
thienyl ketone, mp 90 - 91.degree. C 
2-acetyl-5-chlorothiophene 
B bromomethyl 5-chloro-2- 
thienyl ketone, mp 72 - 73.degree. C 
2-acetyl-3,4-dibromothiophene 
C bromomethyl 3,4-dibromo- 
2-thienyl ketone, 
mp 80 - 82.degree. C 
2-acetyl-4,5-dibromothiophene 
A bromomethyl 4,5-dibromo-2- 
thienyl ketone, mp 67.5 - 
70.degree. C 
2-acetyl-3,4-dichlorothiophene 
C bromomethyl 3,4-dichloro- 
2-thienyl ketone, mp 46 - 
47.degree. C 
2-acetyl-4,5-dichlorothio- 
B bromomethyl 4,5-dichloro- 
phene 2-thienyl ketone, 
.gamma..sub.max.sup.CHCl.sbsp.3 1665, 1520, 1405 
cm.sup.-1 
2-acetyl-3,4-dimethoxythio- 
B and C 
bromomethyl 3,4-dimethoxy- 
phene 2-thienyl ketone, 
.gamma..sub.max.sup.CHCl.sbsp.3 3120, 1650 
cm.sup.-1 
bromomethyl 5-bromo- 
3,4-dimethoxy-2-thienyl 
ketone, mp 94.degree. C, isolated 
as a by-product (separated 
by chromatography) when 
method C is used. 
5-chloro-2-propionyl- 
B 1-bromoethyl 5-chloro-2- 
thiophene thienyl ketone, 
.gamma..sub.max.sup.CHCl.sbsp.3 1660, 1410 
cm.sup.-1 
__________________________________________________________________________ 
EXAMPLE 4 
Reduction 
A solution of the haloketone, bromomethyl 2-thienyl ketone (6.0 g), 
described in Example 3, in 40 ml of methanol is cooled to 0.degree. C. 
Sodium borohydride (1.11 g) in 10 ml of methanol is added rapidly to the 
solution. After 15 minutes the reaction mixture is diluted with ice-water 
and extracted with ether. The extract is washed with water and brine, 
dried (MgSO.sub.4) and concentrated to give 
.alpha.-(bromomethyl)-2-thiophenemethanol; .gamma..sub.max.sup.CHCl 3 
3550, 3400, 1060, 1035 cm.sup.-1 (ArCHOHCHR.sup.2 Y; Ar = 2-thienyl, 
R.sup.2 = H and Y = Br). 
By following the procedure of Example 4 and using the appropriate 
haloketone as starting material the other corresponding halohydrins of 
formula ArCHOHCHR.sup.2 Y are obtained. Examples of such halohydrins are 
listed in the following table together with the requisite starting 
material described in Example 3. 
__________________________________________________________________________ 
EXAMPLE 
STARTING MATERIAL 
HALOHYDRIN 
__________________________________________________________________________ 
5 bromomethyl 5-bromo-2- 
.alpha.-(bromomethyl)-5-bromo-2- 
thienyl ketone thiophenemethanol, 
.gamma..sub.max.sup.CHCl.sbsp.3 3540, 3400 cm 
6 bromomethyl 5-chloro-2- 
.alpha.-(bromomethyl)-5-chloro-2- 
thienyl ketone thiophenemethanol, 
.gamma..sub.max.sup.CHCl.sbsp.3 3570, 3350, 1062, 
1000 cm.sup.-1 
7 bromomethyl 3,4-dibromo- 
.alpha.-(bromomethyl)-3,4-dibromo- 
2-thienyl ketone 
2-thiophenemethanol, 
.gamma..sub.max.sup.CHCl.sbsp.3 3560, 3350 cm 
8 bromomethyl 4,5-dibromo- 
.alpha.-(bromomethyl)-4,5- 
2-thienyl ketone 
dibromo-2-thiophenemethanol, 
.gamma..sub.max.sup.CHCl.sbsp.3 3570, 3300 
cm.sup.-1 
9 bromomethyl 3,4-dichloro- 
.alpha.-(bromomethyl)-3,4-dichloro- 
2-thienyl ketone 
2-thiophenemethanol, 
.gamma..sub.max.sup.CHCl.sbsp.3 3575, 3350, 3120, 
1345, 1075 cm.sup.-1 
10 bromomethyl 4,5-dichloro- 
.alpha.-(bromomethyl)-4,5-dichloro- 
2-thienyl ketone 
2-thiophenemethanol, 
.gamma..sub.max.sup.CHCl.sbsp.3 3570, 3350, 1540, 
1040 cm.sup.-1 
11 bromomethyl 3,4-dimethoxy- 
.alpha.-(bromomethyl)-3,4-dimethoxy- 
2-thienyl ketone 
2-thiophenemethanol, 
.gamma..sub.max.sup.CHCl.sbsp.3 3560, 3400, 3130 
cm.sup.-1 
12 1-bromoethyl 5-chloro- 
.alpha.-(1-bromoethyl)-5-chloro-2- 
2-thienyl ketone 
thiophenemethanol 
13 bromomethyl 5-methyl 
.alpha.-(bromomethyl)-5-methyl-2- 
2-thienyl ketone 
thiophenemethanol, nmr (CDCl.sub.3) 
.delta. 2.47 (m, 4H), 3.6 (m, 2H), 
5.0 (m, 1H), 6.8 (m, 2H) 
14 bromomethyl 5-phenyl- 
.alpha.-(bromomethyl)-5-phenyl-2 
2-thienyl ketone 
thiophenemethanol, nmr (CDCl.sub.3) 
.delta. 2.75 (1H), 3.65 (m, 2H), 
5.1 (m, 1H), 6.9 - 7.65 (m, 7H) 
__________________________________________________________________________ 
EXAMPLE 15 
.alpha.-{[(3,4-Dimethoxyphenethyl)amino]methyl}-2-thiophenemethanol 
(ArCHOR.sup.1 CHR.sup.2 NR.sup.3 R.sup.4 ; Ar = 2-thienyl, R.sup.1, 
R.sup.2 and R.sup.3 = H and R.sup.4 = 3,4-dimethoxyphenethyl) 
A solution of the halohydrin, .alpha.-(bromomethyl)-2-thiophenemethanol 
(11.4 g, 0.055 mole), described in Example 4, and the primary amine, 
3,4-dimethoxyphenethylamine (15 g, 0.083 mole), in 200 ml toluene is 
heated at reflux for 12 hr. The mixture is cooled to 25.degree. C, shaken 
with 10% NaOH an the layers separated. The aqueous layer is extracted with 
chloroform and the combined organic phases washed with water and brine, 
dried (K.sub.2 CO.sub.3) and concentrated. The resulting dark brown oil is 
purified by chromatography on silica gel to give the title compound as an 
oil; nmr (CDCl.sub.3) 2.9 (m, 6H), 3.45 (2H), 3.85 (s, 6H), 5.05 (m, 1H), 
6.7 - 7.3 (m, 6H). 
The oxalic acid addition salt (oxalate) of the title compounds has mp 
154.degree. - 155.degree. C. 
EXAMPLE 16 
.alpha.-{[(3,4-Dimethoxyphenethyl)amino]methyl}-5-methyl-2-thiophenemethano 
l (ArCHOR.sup.1 CHR.sup.2 NR.sup.3 R.sup.4 ; Ar = 5-methyl-2-thienyl, 
R.sup.1, R.sup.2 and R.sup.3 = H and R.sup.4 = 3,4-dimethoxyphenethyl) 
A solution of the halohydrin, 
.alpha.-(bromomethyl)-5-methyl-2-thienylmethanol (5.0 g, 0.0226 mole), 
described in Example 13, and the primary amine, 
3,4-dimethoxyphenethylamine (6.2 g, 0.0339 mole), in 30 ml of dioxane is 
heated at reflux for 3 hr. The mixture is cooled to room temperature, 
diluted with 200 ml of chloroform and shaken with 10% NaOH. The organic 
phase is separated and washed with water and brine, dried (K.sub.2 
CO.sub.3) and concentrated to give a light brown oil. The concentrate is 
subjected to chromatography on silica gel using methanol-chloroform (1:9) 
as the eluant. Concentration of the first fractions affords 
.beta.-(3,4-dimethoxyphenethylamino)-5-methyl-2-thienylethanol; nmr 
(CDCl.sub.3) .delta. 2.27 (s, 2H), 2.47 (s, 3H), 2.8 (m, 3H), 3.7 (m, 2H), 
3.87 (s, 6H) and 6.75 (m, 5H), an isomer of the title compound; the oxalic 
acid addition salt of this isomer having mp 108.degree. - 110.degree. C. 
Concentration of the following second fractions affords the title 
compound; nmr (CDCl.sub.3) .delta. 2.45 (s, 3H), 3.0 (m, 6H), 3.85 (s, 
6H), 4.45 (2H), 5.1 (t, J = 6, 2H), 6.8 (m, 5H); the oxalic acid addition 
salt thereof having mp 160.degree. C. 
By following the procedures of Examples 15 and 16 and using the appropriate 
halohydrin and the appropriate primary or secondary amine, other thiophene 
ethanolamines of this invention are obtained. Examples of such thiophene 
ethanolamines are listed in the following table together with the 
requisite starting materials. The halohydrin starting materials are noted 
by the example in which they are prepared. 
__________________________________________________________________________ 
EXAMPLE IN 
WHICH HALOHYDRIN 
AMINE OF THIOPHENE ETHANOLAMINE 
EXAMPLE 
IS PREED FORMULA, NHR.sup.3 R.sup.4 
OF FORMULA ArCHOHCHR.sup.2 NR.sup.3 
__________________________________________________________________________ 
R.sup.4 
17 4 1-(o-tolyl)- 
.alpha.-(2-thienyl)-4-(o-tolyl)-1- 
piperazine piperazineethanol; mp 81 - 86.degree. C; 
nm- 
(CDCl.sub.3) .delta. 2.3 (s, 3H), 2.9 
(m, 10H), 4.0 (broad s, 1H), 
5.1 (t, J = 7, 1H), 7.2 (m, 7H); 
the hydrochloric acid addition 
salt (hydrochloride) has mp 221.degree. C 
18 13 3,4-(methylene- 
5-methyl-.alpha.-{[3,4-(methylenedioxy)- 
dioxy)phenethyl- 
phenethyl]aminono}methyl-2- 
amine thiophenemethanol, mp 93 - 94.degree. C; 
nmr (CDCl.sub.3) .delta. 2.42 (s, 3H), 
2.8 
(m, 6H), 3.1 (s, 2H), 4.9 (t, 
J = 6, 1H), 5.9 (s, 2H), 6.7 
(m, 5H); the hydrochloric acid 
addition salt has mp 183 - 185.degree. C, 
nmr (DMSO-d.sub.6) .delta. 2.49 (s, 3H) 
19 14 3,4-dimethoxy- 
.alpha.-{[(3,4-dimethoxyphenethyl)- 
phenethylamine 
amino]methyl}-5-phenyl-2-thio- 
phenemethanol; nmr (CDCl.sub.3) .delta. 
2.9 (m, 6H), 3.16 (s, 2H), 3.82 
(s, 6H), 5.0 (m, 1H), 6.75 - 
7.7 (m, 10H); corresponding 
hydrochloric acid addition salt 
has mp 185.degree. C (dec) 
20 11 isopropylamine 
3,4-dimethoxy-.alpha.-(isopropyl- 
aminomethyl)-2-thiophenemethanol; 
mp 74 - 75.degree. C; the hydrochloric 
acid addition salt has mp 102 - 
103.degree. C; the corresponding isomer, 
3,4-dimethoxy-.beta.-(isopropylamino)- 
2-thiopheneethanol has 
bp 110.degree. C/0.5 mm 
21 10 3,4-dimethoxy- 
4,5-dichloro-.alpha.-{[(3,4-dimethoxy- 
phenethylamine 
phenethyl)amino]methyl}-2-thio- 
phenemethanol; .gamma..sub.max.sup.CHCl.sbs 
p.3 3600, 1595 
1515, 1465 cm.sup.-1 ; the hydrochloric 
acid addition salt has mp 160 - 
161.degree. C 
22 10 2-(indol-3-yl)- 
4,5-dichloro-.alpha.-{[(2-indol-3- 
ethylamine- 
ylethyl)amino]methyl}-2-thio- 
(tryptamine) 
phenemethanol; mp 43 - 45.degree. C; 
the hydrochloric acid addition 
salt has mp 204 - 205.degree. C 
23 10 3,4,5-trimethoxy- 
4,5-dichloro-.alpha.-{[(3,4,5-tri- 
phenethylamine 
methoxyphenethyl)amino]methyl}- 
2-thiophenemethanol; nmr (CDCl.sub.3) 
.delta. 2.75 (m, 6H), 2.90 (s, 2H), 
3.80 (s, 9H), 4.75 (m, 1H), 
6.33 (s, 2H), 6.66 (s, 1H); the 
hydrochloric acid addition salt 
has mp 167 - 168.degree. C 
24 10 .alpha.-[1-(methyl- 
4,5-dichloro-.alpha. [N-methyl-N- 
amino)ethyl]- 
(.beta.-hydroxy-.alpha.-methylphenethyl)- 
benzyl alcohol 
amino]methyl}-2-thiophene- 
(d,l-ephedrine) 
methanol; nmr (CDCl.sub.3) .delta. 1.08 
(d, 3H), 6.60 (s, 1H), 7.30 
(s, 5H); the hydrochloric acid 
addition salt has mp 63 - 65.degree. C 
25 10 p-hydroxy- 4,5-dichloro-{[p-hydroxyphen- 
phenethylamine 
ethyl)amino]methyl}-2-thiophene- 
(tyramine) methanol; nmr (CDCl.sub.3) .delta. 2.75 
(m, 6H), 4.70 (s, 3H), 4.73 
(t, 1H); the hydrochloric acid 
addition salt has mp 180 - 181.degree. C 
26 10 p-chloro- 4,5-dichloro-.alpha.-{[(p-chlorophen- 
phenethylamine 
ethyl)amino]methyl}-2-thio- 
phenemethanol; mp 107 - 110.degree. C; 
- the hydrochloric acid addition 
salt has mp 175 - 176.degree. C 
27 10 p-methyl- 4,5-dichloro-.alpha.-{[(p-methyl- 
phenethylamine 
phenethyl)amino]methyl}-2- 
thiophenemethanol; mp 92 - 
94.degree. C; the hydrochloric acid 
addition salt has mp 231.degree. C (dec) 
28 10 p-methoxy- 4,5-dichloro-.alpha.-{[(p-methoxy- 
phenethylamine 
phenethyl)amino]methyl}-2- 
thiophenemethanol; mp 95 - 100.degree. 
C; 
the hydrochloric acid addition 
salt has mp 202.degree. C 
29 10 1-(p-methoxy- 
.alpha.-(4,5-dichloro-2-thienyl)-4- 
phenyl)piperazine 
(p-methoxyphenyl)-1-piper- 
azineethanol; mp 126 - 128.degree. C; 
the dihydrochloric acid 
addition salt has mp 213 - 
215.degree. C (dec) 
30 10 3,4-(methyl- 
4,5-dichloro-.alpha.-{[(3,4-methyl- 
enedioxy)- enedioxy)phenethyl]amino}methyl- 
phenethylamine 
2-thiophenemethanol; mp 99 - 
103.degree. C; the hydrochloric acid 
addition salt has mp 215.degree. C (dec) 
31 12 isopropyl- 5-chloro-.alpha.-[1-(isopropylamino)- 
amine ethyl]-2-thiophenemethanol; 
.gamma..sub.max.sup.CHCl.sbsp.3 3300, 
1460, 1145, 1130, 
1060, 995 cm.sup.-1 ; the hydrochloric 
acid addition salt has mp 200.degree. C 
(dec); two corresponding 
isomers, erythro- and threo-5- 
chloro-.beta.-(isopropylamino)-.alpha.- 
methyl-2-thiopheneethanol have 
.gamma..sub.CHCl.sbsb.3.sup.max 3410, 
1450, 1120, 1060, 
990 cm.sup.-1 and .gamma..sub.CHCl.sbsb.3.s 
up.max 3400, 1450, 
1065, 990 cm.sup.-1, respectively. 
__________________________________________________________________________ 
EXAMPLE 32 
N-(3,4-Dimethoxyphenethyl)-.beta.-methoxy-2-thiopheneethylamine 
(ArCHOR.sup.2 CHR.sup.2 NR.sup.3 R.sup.4 ; Ar = 2-thienyl, R.sup.1 = 
CH.sub.3, R.sup.2 and R.sup.3 = H and R.sup.4 = 3,4-dimethoxyphenethyl) 
A solution of the halohydrin, .alpha.-(bromomethyl)-2-thiophenemethanol 
(10.0 g, 0.048 mole), described in Example 4, and p-toluenesulfonic acid 
(1.0 g) in 100 ml of the lower alkanol methanol, is heated at reflux for 5 
hr. The mixture is concentrated and the concentrate extracted with ether. 
The ether extract is washed with water and brine, dried (MgSO.sub.4) and 
concentrated to yield a brown liquid which is purified by chromatography 
on silica gel to give .alpha.-(bromomethyl)-2-thiophenemethanol methyl 
ether; nmr (CDCl.sub.3) .delta. 3.36 (s, 3H), 3.58 (m, 2H), 4.68 (t, J = 
6.5, 1H), 7.02 (m, 1H), 7.05 (m, 1H), 7.31 (m, 1H). 
A solution of the latter compound (15.0 g, 0.068 mole) and the amine, 
3,4-dimethoxyphenethylamine (18.5 g, 0.102 mole) in 200 ml toluene is 
heated at reflux for 21 hr. The mixture is cooled to room temperature, 
shaken with 200 ml 5% NaOH and extracted with chloroform. The combined 
organic extracts are washed with water and brine, dried (K.sub.2 CO.sub.3) 
and concentrated to give a brown liquid. The liquid is purified by 
chromatography to yield the title compound; 
.gamma..sub.max.sup.CHCl.sbsp.3 3290, 2980, 2910, 2820, 1510, 1260 
cm.sup.-1. 
The oxalic acid addition salt of the title compound has mp 210.degree. C. 
By following the procedure of Example 32 and using the halohydrins, for 
example, those described in Examples 4 - 14, together with the appropriate 
lower alkanol and amine, the corresponding lower alkyl ethers of the 
thiophene ethanolamine of this invention are obtained, for example, the 
corresponding lower alkyl ethers of the thiophene ethanolamines of 
Examples 15 - 31. 
EXAMPLE 33 
.alpha.-{[N-(3,4-dimethoxyphenethyl)-N-methylamino]methyl}-5-methyl-2-thiop 
henemethanol (ArCHOR.sup.1 CHR.sup.2 NR.sup.3 R.sup.4 ; Ar = 
5-methyl-2-thienyl, R.sup.1 and R.sup.2 = H, R.sup.3 = CH.sub.3 and 
R.sup.4 = 3,4-dimethoxyphenethyl) 
A solution of 
.alpha.-{[(3,4-dimethoxyphenethyl)amino]methyl}-5-methyl-2-thiophenemethan 
ol (2.29 g, 0.007 mole), described in Example 16, and the lower alkyl 
halide, iodomethane (9.94 g, 0.07 mole), in 70 ml benzene is stirred at 
25.degree. C for 3 days. The mixture is concentrated under reduced 
pressure. The residual oil is taken up in methanol and made alkaline with 
10% NaOH. The mixture is extracted with chloroform. The extract is washed 
with water, dried (K.sub.2 CO.sub.3) and concentrated to give a yellow 
oil, which is purified by chromatography to give the title compound; nmr 
(CDCl.sub.3) .delta. 2.41 (s, 3H), 2.46 (s, 3H), 2.6 - 2.8 (m, 6H), 3.68 
(s, 1H), 3.83 (s, 3H), 3.88 (s, 3H), 4.88 (t, 1H), 6.6 - 6.9 (m, 5H). 
The oxalic acid addition salt has mp 149.degree. C. 
By following the procedure of Example 33 and using the appropriate 
secondary amine, namely a thiophene ethanolamine in which R.sup.3 is 
hydrogen, for example, those described in Example 15 to 23, together with 
the appropriate lower alkyl halide, the corresponding thiophene 
ethanolamines in which R.sup.3 is lower alkyl are obtained. 
EXAMPLE 34 
.alpha.-(Isopropylaminomethyl)-5-methoxy-2-thiophenemethanol (ArCHOR.sup.1 
CHR.sup.2 NR.sup.3 R.sup.4 ; Ar = 5-methoxy-2-thienyl, R.sup.1, R.sup.2 
and R.sup.3 = H and R.sup.4 = isopropyl) 
2-Methoxythiophene (15.4 g) is dissolved in 100 ml anhydrous THF and butyl 
lithium (0.135 moles) in hexane is added dropwise. The solution is stirred 
at room temperature 15 hr and then heated at reflux for 1 hr. After 
cooling, the clear solution is tranferred to a dropping funnel by means of 
a siphon. The solution of thienyl lithium is added dropwise to a solution 
of diethyl oxalate (19.7 g) in 150 ml THF at -78.degree. C. After stirring 
2 hr at -78.degree. C, the mixture is brought to -10.degree. C and treated 
with saturated NH.sub.4 Cl solution. The aqueous fraction is separated and 
extracted several times with ether. The combined ether extracts are washed 
with water and brine, dried (MgSO.sub.4) and concentrated. Chromatography 
on silica gel (eluant = benzene) gives 5-methoxy-2-thiopheneglyoxylic acid 
ethyl ester (2; X.sup.1 = CH.sub.3 O, X.sup.2 and X.sup.3 = H and R.sup.10 
= C.sub.2 H.sub.5); mp 136.degree. - 137.degree. C after 
recrystallization from benzene-hexane. 
The latter ester (25 g) is stirred in 500 ml of 5% aqueous KOH in methanol 
(250 ml H.sub.2 O, 250 ml CH.sub.3 OH, 25 g KOH) at room temperature for 
about 2 hr. The mixture is diluted with water and extracted several times 
with ether to remove all neutral material. The aqueous fraction is cooled 
with crushed ice, acidified with 10% HCl and extracted with ether. The 
ether extract is washed with water and brine, dried (MgSO.sub.4) and 
concentrated to give 5-methoxy-2-thiopheneglyoxylic acid (3; X.sup.1 = 
CH.sub.3 O, X.sup.2 and X.sup.3 = H and R.sup.10 = H); 
.gamma..sub.max.sup.CHCl.sbsp.3 3000, 1630, 1625, 1530 cm.sup.-1. 
The latter acid (14.0 g) and triethylamine (1.1 g) are dissolved in 100 ml 
anhydrous THF and cooled to 0.degree. C under a nitrogen atmosphere. 
Methyl chloroformate (8.5 g) in 5 ml THF is added dropwise and the 
solution is stirred for 2 hr at 0.degree. C. After this time, 
isopropylamine (30 ml) is added dropwise and the solution is again stirred 
for 2 hr at 0.degree. C. The reaction mixture is then poured onto water, 
separated and the aqueous fraction is extracted several times with ether. 
The ether fractions are washed with water and brine, dried (MgSO.sub.4) 
and concentrated. The crude product is subjected to chromatography on 
silica gel (750 g, benzeneethyl acetate, 95:5). Evaporation of the eluate 
and recrystallization of the residue from hexane-benzene gives 
N-isopropyl-5-methoxy-2-thiopheneglyoxylamide; mp 72.degree. - 73.degree. 
C. 
To freshly distilled boron trifluoride etherate (61.0 mmoles) dissolved in 
30 ml anhydrous ether, distilled epichlorohydrin (4.19 g, 46.0 mmoles) is 
added at such a rate to cause the solution to reflux. After addition, the 
solution is heated at reflux for 1.5 hr with vigorous stirring. The 
reaction mixture is cooled and most of the ether is removed with a pipette 
and the solid residue is dried with a stream of dry nitrogen. Anhydrous 
methylene chloride (50 ml) and the 
N-isopropyl-5-methoxy-2-thiopheneglyoxylamide (8.0 g, 39.0 mmole), 
described above, is added and the solution is stirred at room temperature 
for 56 hr. The methylene chloride is evaporated and replaced with 50 ml 
anhydrous methanol. The solution is cooled to 0.degree. C. and sodium 
borohydride (4.0 g) is added portionwise over a period of 4 hr. The 
mixture is brought to room temperature, stirred for 24 hr then quenched 
with ice-water. The aqueous solution is extracted several times with 
ether. The combined ether extract are washed with water and brine, dried 
(MgSO.sub.4) and concentrated. The product is purified by chromatography 
on silica gel (400 g, chloroformmethanol, 8:2). Evaporation of the eluate 
and recrystallization of the residue from hexane gives the title compound; 
mp 81.degree. C, .gamma..sub.max.sup.CHCl.sbsp.3 3300, 3100, 1650, 1505, 
1220 cm.sup.-1. 
The oxalic acid addition salt of the title compound has mp 100.degree. - 
101.degree. C.