This disclosure describes substituted 9,10-dihydro-4H-thieno[3,4-b] [1,5]benzodiazepines which possess analgesic activity.

BRIEF SUMMARY OF THE INVENTION 
This invention relates to new organic compounds and, more particularly, is 
concerned with novel substituted 
9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepines which may be represented 
by the following structural formula: 
##STR1## 
wherein R.sub.1 and R.sub.2 are each individually selected from the group 
consisting of hydrogen, chloro, hydroxy, methoxy, trifluoromethyl, nitro, 
amino and alkyl having up to 4 carbon atoms; R.sub.3 is selected from the 
group consisting of hydrogen, alkyl having up to 6 carbon atoms and 
alkenyl having from 3 to 6 carbon atoms; and R.sub.4 is selected from the 
group consisting of hydrogen, alkyl having up to 6 carbon atoms, 
cycloalkylmethyl having from 4 to 7 carbon atoms, benzyl and 
.beta.-phenethyl. Suitable alkyl groups contemplated by the present 
invention are, for example, methyl, ethyl, isopropyl, sec-butyl, isobutyl, 
n-amyl, isoamyl, tert-pentyl, neopentyl, 1,2-dimethylpropyl, isohexyl, 
2-methylpentyl, and the like. Suitable alkenyl groups may be, for example, 
allyl, methallyl, isopropenyl, 1-butenyl, crotyl, 3-butenyl, etc. 
Appropriate cycloalkylmethyl groups are cyclopropylmethyl, 
cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.

DETAILED DESCRIPTION OF THE INVENTION 
The novel compounds of the present invention are obtainable as crystalline 
materials having characteristic melting points and absorption spectra. 
They are appreciably soluble in many organic solvents such as lower 
alkanols, acetone, ethyl acetate, and the like but are generally insoluble 
in water. These compounds are organic bases and thus are capable of 
forming acid-addition and quaternary ammonium salts with a variety of 
organic anc inorganic salt-forming reagents. Thus, acid-addition salts, 
formed by admixture of the organic free base with up to three equivalents 
of an acid, suitably in a neutral solvent, are formed with such acids as 
sulfuric, phosphoric, hydrochloric, hydrobromic, sulfamic, citric, maleic, 
fumaric, tartaric, acetic, benzoic, gluconic, ascorbic, and related acids. 
In like manner, quaternary ammonium salts may be formed by reaction of the 
free bases with a variety of organic esters of sulfuric, hydrohalic and 
aromatic sulfonic acids. The organic reagents employed for quaternary 
ammonium salt formation are preferably lower alkyl halides. However, other 
organic reagents are suitable for quaternary ammonium salt formation and 
may be selected from among a diverse class of compounds including benzyl 
chloride, phenethyl chloride, naphthyl-methyl bromide, dimethyl sulfate, 
methyl benzenesulfonate, ethyl toluenesulfonate, allyl chloride, methallyl 
bromide and crotyl bromide. The acid-addition and quaternary ammonium 
salts of the novel compounds of the present invention are, in general, 
crystalline solids relatively soluble in water, methanol and ethanol but 
relatively insoluble in non-polar organic solvents such as diethyl ether, 
benzene, toluene, and the like. For purposes of this invention, the free 
bases are equivalent to their non-toxic acid-addition and quaternary 
ammonium salts. 
Certain of the novel compounds of the present invention may be readily 
prepared as set forth in the following reaction scheme: 
##STR2## 
wherein R.sub.5 is alkyl having up to 6 carbon atoms or alkenyl having 
from 3 to 6 carbon atoms and R.sub.1, R.sub.2 and R.sub.4 are as 
hereinabove defined. Alkylation at the 9-position of the 
4,9-dihydro-10H-(thieno)[3,4-b][1,5]benzodiazepin-10-one (II) is 
accomplished by first treating (II) with 50% sodium hydride in mineral oil 
in dimethylformamide as solvent for a few hours at ambient temperatures. 
Then, an alkyl or alkenyl halide of the formula: R.sub.5 -X wherein X is 
chloro, bromo or iodo is added and the reaction mixture is stirred at 
ambient temperatures for a period of time of 8-12 hours to provide the 
9-substituted derivative (III). Reduction of the 9-substituted derivative 
(III) to the final product (IV) is achieved with either lithium aluminum 
hydride or 1 M borane in tetrahydrofuran as solvent at the reflux 
temperature for a period of time of 12-24 hours. 
Other novel compounds of the present invention may be prepared as set forth 
in the following reaction scheme: 
##STR3## 
wherein R.sub.6 is alkyl having up to 5 carbon atoms, cycloalkyl having 
from 3 to 6 carbon atoms, phenyl or benzyl; and R.sub.1, R.sub.2, and 
R.sub.3 are as hereinabove defined. Acylation at the 4-position of the 
4,9-dihydro-10H-thieno[3,4-b][1,5]-benzodiazepin-10-one (V) is 
accomplished by treating (V) with an acyl halide of the formula: R.sub.6 
-CO-X wherein X is chloro or bromo. This acylation is best performed in an 
inert solvent such as benzene, toluene, or dioxane at the reflux 
temperature for a period of time of 2-6 hours and preferably in the 
presence of an acid acceptor such as triethylamine or soda ash. Reduction 
of the 4-acyl-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one (VI) 
then provides the corresponding 
9,10-dihydro-4-substituted-4H-thieno[3,4-b][1,5]-benzodiazepine (VII). A 
variety of chemical reducing agents may be used in this reduction 
including sodium sulfide, sodium borohydride, sodium dithionite and 
lithium aluminum hydride. The reduction may also be carried our with 
active metals such as zinc, tin or iron in acetic acid of mineral acids 
such as hydrochloric acid. Reduction with metal couples such as the 
copper-zinc couple, the tin-mercury couple, aluminum amalgam, soidum 
amalgam or magnesium amalgam; and reduction with formic acid may also be 
used. However, reduction with borane under a nitrogen atmosphere in 
tetrahydrofuran as solvent is the preferred procedure. The borane is added 
as a one molar solution at ice-bath temperature over a period of 10-15 
minutes followed by refluxing for 8-12 hours. When aqueous systems are 
used in the aforementioned chemical reductions, it is at times desirable 
to utilize a water-miscible organic solvent, particularly when the 
starting compound is of limited solubility in the reaction mixture. The 
water-miscible solvent does not alter the course of the reduction but 
merely provides for more efficient reduction, e.g. a shorter reaction time 
by providing more intimate contact of the reagents. A large number of such 
solvents are available for this purpose and include, among others, 
dimethylformamide, dimethoxyoxyethane, methanol, ethanol, dioxane, 
tetrahydrofuran, and the like. 
The compounds of this invention are active analgesic agents when measured 
by the "writhing syndrome" test for analgesic activity as described by 
Siegmund, et al., Proc. Soc. Exp. Biol. and Med., 95, 729 (1957), with 
modifications. This method is based upon the reduction of the number of 
writhes following the intraperitoneal injection of one mg./kg. of body 
weight of phenyl-p-quinone in male Swiss albino mice weighing 18-25 g. The 
syndrome is characterized by intermittent contractions of the abdomen, 
twisting and turning of the trunk and extension of the hind legs, 
beginning 3 to 5 minutes after injection of the phenyl-p-quinone. The test 
compounds are administered orally at the indicated dose to groups of 2 
mice each, 30 minutes before injection of the phenyl-p-quinone. The total 
number of writhes exhibited by each group of mice is recorded for a 3 
minute period commencing 15 minutes after injection of the 
phenyl-p-quinone. A compound is considered active if it reduces the total 
number of writhes in 2 test mice from a control value of approximately 30 
per pair to a value of 18 or less. Table I summarizes the results of this 
test on representative compounds of this invention. 
TABLE I 
______________________________________ 
Dose 
Compound mg./kg. Result 
______________________________________ 
9,10-Dihydro-9-methyl-4H-thieno- 
100 Active 
[3,4-b] [1,5]benzodiazepine 
50 Active 
9,10-Dihydro-4H-thieno[3,4-b]- 
50 Active 
Aspirin 200 Active 
75 Active 
50 Active 
Acetominophen 200 Active 
100 Active 
50 Active 
Controls 30 
______________________________________ 
The compounds of this invention also exhibit analgesia in warm-blooded 
animals when measured by the Brewers' Yeast Pressure Pain Test. To 
determine analgesic activity, a modification of the method of Randall and 
Selitto [Arch. Int. Pharmacodyn, 111, 409, (1957)] is used. This test 
measures the pain threshold of rats whose paws are made sensitive to 
pressure by the injection of 0.1 ml. of a 20% aqueous suspension of 
brewers' yeast into the plantar surface of the left hind paw. Constantly 
increasing force at the rate of 16 g./sec. is applied to the swollen paw 
using an Analgesy Meter, Ugo Basile. The pressure is cut off at 250 g. of 
force when there is no response (sudden struggle or vocalization). Control 
rats, treated with only starch vehicle, respond to a pressure or force of 
about 30 g. Pressure-pain thresholds are always recorded 2 hours after 
brewers' yeast administration. The test compounds are administered orally 
at the same time as the yeast at the indicated dose. Ratios of treated 
(T)/control (C) reaction thresholds are calculated as estimates of 
analgesic efficacy (degree of analgesia obtainable). Test compounds are 
considered active if they produce a 100% elevation of pain threshold (T/C 
1.37). The results of this test on representative compounds of this 
invention appear in Table II. 
TABLE II 
______________________________________ 
Dose 
Compound mg./kg. Result 
______________________________________ 
9,10-Dihydro-9-methyl-4H-thieno- 
60 Active 
[3,4-b] [1,5]benzodiazepine 
9,10-Dihydro-4H-thieno[3,4-b]- 
90 Active 
[1,5]benzodiazepine 
Aspirin 100 Active 
200 Active 
Acetominophen 100 Active 
200 Active 
Controls 1.0 
______________________________________ 
The compounds of this invention exhibit analgesic activity when measured by 
a modification of the method of D. C. Atkinson and A. Cowan, J. Pharm. 
Pharmac., 26, 727 (1974). In this test, male albino Wistar strain rats 
from Royalhart farms, weighing 120-150 g. are deprived of food for about 
20 hours. A 40% suspension of brewers' yeast in physiological saline is 
injected at a concentration of 0.25 ml./rat into the plantar surface of 
the left hind paw of each rat. Three hours later, at which time an 
inflammation of the injected paw has developed, a pre-drug assessment of 
walking gait is made for each rat according to the following scoring 
system: 
0=Normal gait in the presence of a severely inflamed paw. There is 
continuous use of the foot pad. 
0.5=As above with intermittent mild limping. 
1.0=Constant limping, but continuous use of the foot pad. 
1.5=Limping with occasional three-legged gait (paw kept off walking 
surface) or intermittent use of digits in combination with foot pad. 
2.0=Continuousthree-legged gait and/or only the tips of the digits touch 
the walking surface. There is no use of the foot pad. 
More than 95% of the rats exhibit a gait score of 2 before given a test 
compound. Test compounds are administered orally, by gavage, in a suitable 
vehicle at a volume of 0.5 ml./100 g. of body weight. One and/or 2 hours 
later a post-drug assessment of walking gait is made as described above. 
The criterion of an analgesic response for each rat is a 50% reversal of 
the abnormal gait score (post-drug) from the pre-drug score. The results 
of this test on representative compounds of the present invention appear 
in Table III. 
TABLE III 
______________________________________ 
Compound Result 
______________________________________ 
9,10-Dihydro-9-methyl-4H-thieno[3,4-b] 
Active 
[1,5]benzodiazepine 
9,10-Dihydro-4H-thieno[3,4-b][1,5]benzo- 
Active 
diazepine 
9,10-Dihydro-4-methyl-4H-thieno[3,4-b] 
Active 
[1,5]benzodiazepine 
9,10-Dihydro-9-ethyl-4H-thieno[3,4-b] 
Active 
[1,5]benzodiazepine hydrochloride 
9,10-Dihydro-4-ethyl-4H-thieno[3,4-b] 
Active 
[1,5]benzodiazepine 
6,7-Dichloro-9,10-dihydro-9-methyl-4H- 
Active 
thieno[3,4-b][1,5]benzodiazepine 
Aspirin Active 
Acetominophen Active 
______________________________________ 
The compounds of this invention also show antypyretic activity by their 
ability to reduce a hyperthermic response in warm-blooded animals, induced 
by the subcutaneous injection of a suspension of brewers' yeast. This is a 
modification of the method of Teotino, et al., J. Med. Chem., 6, 248 
(1963). A 40% suspension of brewers' yeast in distilled water is 
administered to groups of 5 to 19 rats subcutaneously at 1.0 ml./100 g. of 
body weight. Eighteen hours later, rectal temperatures are recorded and 
test compounds in 2% starch vehicle at the indicated dose or vehicle alone 
is administered. Rectal temperatures are recorded 4 hours later and the 
results are compared with the starch vehicle controls and with reference 
anti-pyretic agents. The results of representative compounds of this 
invention with regard to the amount of temperature reduction they induce 
is recorded in Table IV. 
TABLE IV 
______________________________________ 
Dose Temperature 
Compound mg./kg. Reduction .degree.F. 
______________________________________ 
9,10-Dihydro-9-methyl-4H- 
50 -1.9 
thieno[3,4-b] [1,5]benzo- 
25 -1.8 
diazepine 
9,10-Dihydro-4H-thieno- 
200 -1.7 
[3,4-b] [1,5]benzodiazepine 
9,10-Dihydro-4-methyl-4H- 
200 -0.9 
thieno[3,4-b] [1,5]benzo- 
100 -1.3 
diazepine 
9,10-Dihydro-9-ethyl-4H- 
200 -1.3 
thieno[3,4-b] [1,5]benzo- 
diazepine hydrochloride 
9,10-Dihydro-4-ethyl-4H- 
200 -2.4 
thieno[3,4-b] [1,5]benzo- 
100 -1.8 
diazepine 
6,7-Dichloro-9,10-dihydro- 
100 -2.1 
9-methyl-4H-thieno[3,4-b]- 
[1,5]benzodiazepine 
9,10-Dihydro-6,7,9-tri- 
200 -0.6 
methyl-4H-thieno[3,4-b]- 
[1,5]benzodiazepine 
9,10-Dihydro-4-ethyl-9- 
100 -1.6 
methyl-4H-thieno[3,4-b]- 
[1,5]benzodiazepine 
Aspirin 100 -2.6 
Acetominophen 100 -3.3 
Controls +0.9 
______________________________________ 
The active compounds of this invention can be used in compositions such as 
tablets; the principal active ingredient is mixed with conventional 
tabletting ingredients such as corn starch, lactose, sucrose, sorbitol, 
talc, stearic acid, magnesium stearate, dicalcium phosphate, gums, or 
similar materials such as non-toxic, pharmaceutically acceptable diluents 
or carriers. These tablets or pills can be laminated or otherwise 
compounded to provide a dosage form affording the advantage of prolonged 
or delayed action or predetermined successive action of the enclosed 
medication. For example, the tablet or pill can comprise an inner dosage 
and an outer dosage component, the latter being in the form of an envelope 
over the former. The two components can be separated by an enteric layer 
which serves to resist disintegration in the stomach and permits the inner 
component to pass intact into the duodenum or be delayed in release. A 
variety of materials can be used for such enteric layers or coatings, such 
materials including a number of polymeric acids of mixtures of polymeric 
acids with such materials as shellac, shellac and cetyl alcohol, cellulose 
and the like. A particularly advantageous enteric coating comprises a 
styrene maleic acid copolymer together with known materials contributing 
to the enteric properties of the coating. 
The liquid forms in which the novel compounds of the present invention may 
be incorporated for administration include suitable flavored emulsions 
with edible oils, such as, cottonseed oil, sesame oil, coconut oil, peanut 
oil, and the like, as well as elixirs and similar pharmaceutical vehicles. 
Sterile suspensions or solutions can be prepared for parenteral use. 
Isotonic preparations containing suitable preservatives are also desirable 
for injection use. 
The term dosage form as described herein refers to physically discrete 
units suitable as unitary doses for warm-blooded animal subjects, each 
unit containing a predetermined quantity of active component calculated to 
product the desired therapeutic effect in association with a 
pharmaceutical diluent, carrier or vehicle. 
The specification for the dosage forms of the novel compounds of this 
invention are indicated by characteristics of the active component and the 
particular therapeutic effect desired or the limitations inherent in the 
art of compounding such an active component. 
Examples of suitable oral dosage forms in accord with this invention are 
tablets, capsules, pills, powder packets, granules, wafers, cachets, 
teaspoonfuls, dropperfuls, ampules, vials, segregated multiples of any of 
the foregoing and other forms as herein described. 
The following examples described the preparation of representative 
compounds of this invention. 
EXAMPLE 1 
9,10-Dihydro-9-methyl-4H-thieno[3,4-b][1,5]benzodiazepine 
A mixture of 3.5 g. of 
4,9-dihydro-9-methyl-10H-thieno[3,4][1,5]benzodiazepin-10-one [U.S. Pat. 
No. 3,953,430 (Example 26)] in 60 ml. of dry tetrahydrofuran is stirred 
under nitrogen. While stirring, 45 ml. of 1 M borane in tetrahydrofuran is 
added dropwise. When addition is complete the mixture is heated under 
reflux for 3 hours. The reaction mixture is cooled and 13 ml. of 6 N 
hydrochloric acid is added with stirring. The tetrahydrofuran is distilled 
off at atmospheric pressure. The reaction mixture is cooled in an ice bath 
and swirled with 10 g. of sodium hydroxide pellets. The mixture is 
extracted twice with benzene. The benzene extracts are washed with water, 
dried over sodium sulfate, filtered and concentrated to a viscous brown 
oil. This oil is triturated with 100 ml. of hexane:ether and the solvents 
are removed giving a dark brownish green oil. This oil is purified by 
conventional chromatographic techniques using an alumina column and 40% 
methylene chloride 60% hexane. Concentration of the solvent mixture yields 
a gray-blue crystalline product. The crystals are dissolved in boiling 
hexane, cooled and then collected, washed with hexane and dried to give 
the final desired product, mp. 110.degree.-112.degree. C. 
EXAMPLE 2 
9,10-Dihydro-4H-thieno[3,4-b][1,5]benzodiazepine 
A reaction mixture comprising 3.8 g. of lithium aluminum hydride in 100 ml. 
of dry tetrahydrofuran, 5 g. of 
4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one [U.S. Pat. No. 
3,953,430 (Example 25)] and 125 ml. of dry tetrahydrofuran is heated, with 
stirring under reflux for 18 hours. The reaction mixture is cooled and 4 
ml. of water is carefully added dropwise with stirring and ice bath 
cooling. Following this, 4 ml. of 15% sodium hydroxide and 12 ml. of water 
are added. The mixture is filtered and the precipitate is washed 
thoroughly with tetrahydrofuran and ether. The combined organic phases are 
dried over sodium sulfate filtered and the filtrate is concentrated to 
dryness. The dark brownish-green crystals are triturated in hexane, 
filtered, washed with hexane and dried. The product is heated to boiling 
in 50 ml. of chloroform, filtered and the filtrate is combined with 50 ml. 
of hexane and cooled in a chill room. The crystals are recovered by 
filtration, washed with hexane and dried. Recrystallization from 
chloroform-hexane is repeated. A 200 mg. portion of these crystals is 
recrystallized by dissolving in 10 ml. of chloroform with warming, 
treating with activated charcoal, filtering through diatomaceous earth and 
adding 20 ml. of hexane to the filtrate. These crystals are collected, 
washed with hexane, and dried giving the desired final product, mp. 
167.degree.-169.degree. C. 
EXAMPLE 3 
4,9-Dihydro-4-phenylacetyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one 
A reaction mixture comprising 6.48 g. of 
4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 25 g. of 
phenylacetyl chloride in 100 ml. of benzene is refluxed with stirring for 
3 hours. The mixture is evaporated to an amber oil, combined with 100 ml. 
of ethanol and 6 ml. of 5 N sodium hydroxide and allowed to stand at room 
temperature for one hour. This solution is evaporated to an oily residue 
which is triturated with water and filtered, giving the desired product as 
pale pink crystals, mp. 165.degree.-168.degree. C. 
EXAMPLE 4 
9,10-Dihydro-4-phenethyl-4H-thieno[3,4-b][1,5]benzodiazepine hydrochloride 
A 6.12 g. portion of 
4,9-dihydro-4-phenylacetyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one is 
suspended in 100 ml. of tetrahydrofuran under argon and stirred with 
cooling in an ice bath. To this is added 90 ml. of 1 M diborane in 
tetrahydrofuran over a period of 10 minutes. The mixture is then stirred 
at room temperature until solution is complete, refluxed for 18 hours, 
cooled and 45 ml. of 6 N hydrochloric acid is added. The tetrahydrofuran 
is removed in vacuo and 75 ml. of 5 N sodium hydroxide is added giving the 
desired final product, mp. 195.degree.-197.degree. C. 
EXAMPLE 5 
4-Cyclopropylcarbonyl-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-on 
To a mixture of 10.0 g. of 
4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 100 ml. of 
benzene is added 11 g. of cyclopropanecarbonyl chloride. The mixture is 
refluxed for 3 hours and then filtered. The filtrate is washed four times 
with aqueous sodium bicarbonate, the organic layer is dried over magnesium 
sulfate and then is filtered. The filtrate is evaporated to give the 
desired product as pale pink crystals, mp. 245.degree.-247.degree. C. 
EXAMPLE 6 
4-Cyclopropylcarbonyl-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepine 
hydrochloride 
To 5.69 g. of 
4-cyclopropylcarbonyl-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-o 
ne in 100 ml. of tetrahydrofuran is added 120 ml. of 1 M borane in 
tetrahydrofuran under argon, with stirring in an ice bath. The mixture is 
refluxed for 18 hours, then chilled and 60 ml. of 6 N hydrochloric acid is 
cautiously added. Most of the solvent is evaporated and 100 ml. of 5 N 
sodium hydroxide is added. The mixture is extracted with methylene 
chloride, dried over magnesium sulfate and evaporated giving a gum. Excess 
hydrochloric acid and ethanol are added to the gum and then evaporated 
giving a second gum. Ethanol is added to this second gum producing 
crystals which are recovered giving the desired product as colorless 
crystals, mp. 157.degree.-159.degree. C. (dec.). 
EXAMPLE 7 
9,10-Dihydro-4-methyl-4H-thieno[3,4-b][1,5]benzodiazepine 
A mixture comprising 4 g. of 
4,9-dihydro-4-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one [U.S. Pat. 
No. 3,953,430 (Example 2)] in 75 ml. of tetrahydrofuran is combined with 2 
g. of lithium aluminum hydride in 50 ml. of tetrahydrofuran and refluxed 
under nitrogen with stirring for 10 hours. A 2 ml. portion of water is 
carefully added dropwise with cooling followed by 2 ml. of 15% sodium 
hydroxide and 6 ml. of water. The mixture is filtered and the precipitate 
is washed thoroughly with ether. The filtrate and washings are combined, 
dried over sodium sulfate, filtered and concentrated to a semi-crystalline 
brown oil. The product is triturated with hexane producing a tan 
crystalline solid. This solid is recovered, washed thoroughly with hexane 
and dried. This crystalline material is purified by column chromatography 
(alumina activity II), eluting with methylene chloride:hexane (50:50). 
Evaporation of the solvents yields a solid which is triturated with hexane 
and washed with ether, giving the desired product as pale blue crystals, 
mp. 125.degree.-127.degree. C. 
EXAMPLE 8 
4,9-Dihydro-9-methyl-4-phenylacetyl-10H-thieno[3,4-b][1,5]benzodiazepin-10- 
one 
A slurry of 6.90 g. of 
4,9-dihydro-9-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 4.36 
ml. (5.10 g.) of phenylacetyl chloride in 100 ml. of benzene is refluxed 
with stirring for 5 hours. The reaction mixture is filtered while hot 
through diatomaceous earth. The filtrate is washed twice with aqueous 
sodium bicarbonate and dried over magnesium sulfate causing crystals to 
form. The drying agent and crystals are washed with chloroform and then 
chloroform:methanol (9:1). The washings are evaporated to residual 
crystals which are combined twice with ethanol and filtered giving the 
desired product as tan crystals, mp. 210.degree.-212.degree. C. 
EXAMPLE 9 
9,10-Dihydro-9-methyl-4-phenethyl-4H-thieno[3,4-b][1,5]benzodiazepine 
To a slurry of 6.0 g. of 
4,9-dihydro-9-methyl-4-phenylacetyl-10H-thieno[3,4-b][1,5]benzodiazepin-10 
-one in 100 ml. of dried tetrahydrofuran, cooled in an ice bath, is added 
125 ml. of 1 M borane in tetrahydrofuran, dropwise over 10 minutes. The 
mixture is stirred at room temperature for one hour, refluxed for 6 hours 
and then stirred at room temperature for 16 hours. The reaction is 
decomposed by the addition of 50 ml. of 6 N hydrochloric acid and then 75 
ml. of 5 N sodium hydroxide is added. Most of the solvent is evaporated, 
the residue is extracted with methylene chloride and the extract is 
evaporated to an oil. This oil is dissolved in hot hexane, filtered 
through diatomaceous earth and evaporated to an oil which crystallizes 
giving the desired product as colorless crystals, mp. 
53.degree.-56.degree. C. 
EXAMPLE 10 
4,9-Dihydro-9-ethyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one 
An 11.8 g. portion of 
4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one is reacted with 2.8 
g. of 50% sodium hydride in mineral oil in 175 ml. of dimethylformamide. 
After 2 hours 11.5 g. of ethyl iodide is added and the mixture is stirred 
overnight at room temperature. The reaction mixture is poured into 
ice-water. After 3 hours the brown crystals are collected, washed with 
water and then ether and dried. The solid is heated to boiling in 75 ml. 
of methanol, filtered and the filtrate is treated with charcoal, reheated 
to the boil and filtered through diatomaceous earth. To the filtrate is 
added, portionwise with swirling, 100 ml. of water. The mixture is cooled 
in a chill room and the solid is collected, washed with ether and dried 
giving the desired product, mp. 175.degree.-177.degree. C. 
EXAMPLE 11 
9,10-Dihydro-9-ethyl-4H-thieno[3,4-b][1,5]benzodiazepine hydrochloride 
A mixture of a 4.0 g. portion of 
4,9-dihydro-9-ethyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 100 ml. 
of dried tetrahydrofuran and 5.2 g. of lithium aluminum hydride in 135 ml. 
of tetrahydrofuran is refluxed overnight. The reaction mixture is cooled 
in an ice bath and 5 ml. of water is carefully added dropwise with 
stirring. Then 5 ml. of 15% sodium hydroxide followed by 15 ml. of water 
are added to the stirring mixture. The complex is filtered and washed 
repeatedly with ether. The combined filtrate and washings are dried over 
sodium sulfate, filtered and concentrated to a dark green oil. The oil is 
purified by conventional chromatographic techniques using an alumina 
column and 40% methylene chloride in hexane. Concentration of the solvent 
mixture yields a dark green oil which is combined with hexane and diethyl 
ether and stored in a chill room for 48 hours. The solvents are removed 
and the residue is boiled five times with 50 ml. portions of hexane. The 
hexane extracts are treated with charcoal, filtered through diatomaceous 
earth, and concentrated to a green oil. The oil is dissolved in 50 ml. of 
ether and 7 ml. of 3 N ethanolic hydrochloric acid is added. The crystals 
are collected, washed with ether and recrystallized twice from hot ethanol 
with cooling to give the desired product as the hydrochloride salt, mp. 
201.degree.-203.degree. C. 
EXAMPLE 12 
4-Acetyl-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one 
A reaction mixture comprising 9.9 g. of 
4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 4 g. (3.7 ml.) 
of acetyl chloride in 100 ml. of benzene is refluxed for 3 hours and then 
allowed to stand at room temperature overnight. The precipitate is 
collected, washed with benzene and dried. The solid is crystallized twice 
from hot methanol with cooling giving the desired product, mp. 
228.degree.-230.degree. C. 
EXAMPLE 13 
9,10-Dihydro-4-ethyl-4H-thieno[3,4-b][1,5]benzodiazepine 
A reaction mixture comprising 5 g. of 
4-acetyl-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 225 ml. 
of dried tetrahydrofuran and 6.4 g. of lithium aluminum hydride in 150 ml. 
of dried tetrahydrofuran under nitrogen is stirred with heating to reflux 
overnight. A 6.5 ml. portion of water is added cautiously with stirring 
and cooling followed by 6.5 ml. of 15% sodium hydroxide and 19 ml. of 
water. The complex is filtered and washed thoroughly with ether. The 
combined filtrate and washings is dried over sodium sulfate and 
concentrated to a dark brown viscous oil. The oil is crystallized by 
treatment with 50 ml. of ether:hexane (50:50). The crystalline product is 
dissolved in 15 ml. of 40% methylene chloride in hexane and 
chromatographed on an alumina column eluting with 40% methylene chloride 
in hexane. Fractions 2-8 (50 ml. each) are combined and concentrated 
giving olive green crystals. These crystals are triturated in hexane, 
washed with hexane and dried giving the desired product, mp. 
85.degree.-87.degree. C. 
EXAMPLE 14 
4,9-Dihydro-9-hexyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one 
An 11.8 g. portion of 
4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one is combined with 
2.8 g. of 50% sodium hydride in mineral oil and 175 ml. of 
dimethylformamide and stirred for 2 hours. A 15.7 g. (11 ml.) portion of 
n-hexyl iodide is added and the mixture is stirred overnight. The reaction 
mixture is poured into ice water and the brown oil is separated and 
dissolved in methylene chloride. The dimethylformamide-water mixture is 
extracted twice with methylene chloride. All methylene chloride portions 
are combined, washed with water, dried over sodium sulfate, filtered and 
concentrated to a dark brown oil. This oil is dissolved in 10 ml. of 
methylene chloride and chromatographed on an alumina column. The column is 
eluted with 500 ml. of hexane followed by 30% methylene chloride in hexane 
for fractions 5-13 and methylene chloride:hexane (50:50) for fractions 
14-19. Fraction 6 is concentrated to a dark brown viscous oil (A). 
Fractions 7-19 are combined and concentrated to dryness (B). (A) and (B) 
both crystallize in hexane and are combined, filtered, washed with hexane 
and dried. The product is dissolved with warming in 50 ml. of benzene and 
filtered. To the filtrate is added 100 ml. of hexane and the mixture is 
cooled overnight. The solid is collected, washed with ether and dried, 
giving the desired product, mp. 100.degree.-102.degree. C. 
EXAMPLE 15 
9,10-Dihydro-9-hexyl-4H-thieno[3,4-b][1,5]benzodiazepine hydrochloride 
A solution of 7.8 g. of 
4,9-dihydro-9-hexyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 100 ml. 
of dried tetrahydrofuran is added dropwise, with stirring, under nitrogen, 
to a suspension of 4.2 g. of lithium aluminum hydride in 135 ml. of 
tetrahydrofuran. The reaction mixture is then heated under reflux with 
stirring for 20 hours. The mixture is cooled in an ice bath and stirred 
under nitrogen while 4 ml. of water, 4 ml. of 15% sodium hydroxide and 
then 12 ml. of water are added. The complex is filtered and washed 
thoroughly with ether. The combined filtrate and washings are dried over 
sodium sulfate and filtered. The solvents are removed and the residue is 
triturated with hexane. The blue-green oil is dissolved in 50 ml. of ether 
and treated with 10 ml. of 3 N ethanolic hydrochloric acid followed by an 
additional 150 ml. of ether and stored in a chill room producing a purple 
syrup. The solvent mixture is concentrated to a residue. The residue is 
dissolved with warming in 25 ml. of ethanol, added to the purple syrup and 
warmed to solution. A 25 ml. portion of ether is added, the mixture is 
stored in a chill room and the crystals are recovered, washed with 25 ml. 
of ether and dried (crop #1). A second crop is recovered from the 
rechilled mother liquor in the same manner. Both crops are combined, 
heated to solution in 20 ml. of ethanol, filtered and the filtrate is 
diluted with 100 ml. of ether. Cooling produces crystals which are 
collected, washed with ether and dried giving the desired product, mp. 
147.degree.-149.degree. C. 
EXAMPLE 16 
6,7-Dimethyl-1,3,4,9-tetrahydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one 
A 34 g. portion of 4,5-dimethyl-O-phenylenediamine in one liter of toluene 
is refluxed with stirring. After 70 minutes, 40 g. of 
tetrahydro-4-oxo-3-thiophene carboxylic acid, methyl ester in 500 ml. of 
toluene is added. Refluxing is continued for an additional 4.5 hours and 
then the mixture is allowed to stand overnight. The mixture is cooled and 
the precipitate is collected and dried giving 50.25 g. of 
6,7-dimethyl-1,3,4,9-tetrahydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one 
. 
Employing the same general procedure, the following starting materials 
produce the corresponding mixture of products: 
______________________________________ 
Starting Material Products 
______________________________________ 
4-methoxy-o-phenylenediamine 
7-methoxy-and 6-methoxy-1, 
3,4,9-tetrahydro-10H-thieno- 
[3,4-b] [1,5]benzodiazepin- 
10-one 
4-hydroxy-o-phenylenediamine 
7-hydroxy-and 6-hydroxy-1, 
3,4,9-tetrahydro-10H-thieno- 
[3,4-b] [1,5]benzodiazepin- 
10-one 
4-trifluoromethyl-o-phenylene- 
7-trifluoromethyl- and 6- 
diamine 
trifluoromethyl-1,3,4,9- 
tetrahydro-10H-thieno[3,4- 
b] [1,5]benzodiazepin-10- 
one 
______________________________________ 
EXAMPLE 17 
4,9-Dihydro-6,7-dimethyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one 
To a slurry of 18.8 g. of 
6,7-dimethyl-1,3,4,9-tetrahydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one 
in 150 ml. of pyridine, stirred in an ice bath, is added 10.1 g. of 
N-chlorosuccinimide portionwise over 15 minutes. The mixture is heated on 
a steam bath for 30 minutes, poured into one liter of water and allowed to 
stand overnight. The solid is filtered, washed with water, 1 N 
hydrochloric acid, three times with water and diethyl ether and dried 
giving the desired final product, mp. 233.degree.-238.degree. C. (dec.). 
Employing the same general procedure the following starting materials 
produce the corresponding mixture of products: 
______________________________________ 
Starting Materials Products 
______________________________________ 
7-methoxy and 6-methoxy-1,3,4,9- 
7-methoxy- and 6-methoxy- 
tetrahydro-10H-thieno[3,4-b]-4,9-dihydro-10H-thieno- 
[1,5]benzodiazepin-10-one 
[3,4-b] [1,5]benzodiazepin- 
10-one 
7-hydroxy and 6-hydroxy-1,3,4,9- 
7-hydroxy- and 6-hydroxy- 
tetrahydro-10H-thieno[3,4-b]- 
4,9-dihydro-10H-thieno- 
[1,5]benzodiazepin-10-one 
[3,4-b] [1,5]benzodiazepin- 
10-one 
7-trifluoromethyl and 6-trifluor- 
7-trifluoromethyl- and 6- 
omethyl-1,3,4,9-tetrahydro-10H- -trifluoromethyl-4,9-di- 
thieno[3,4-b] [1,5]benzodiaze- 
hydro-10H-thieno[3,4-b]- 
pin-10-one [1,5]benzodiazepin-10-one 
______________________________________ 
EXAMPLE 18 
9,10-Dihydro-6,7,9-trimethyl-4H-thieno[3,4-b][1,5]benzodiazepine 
To a slurry of 3.88 g. of 
4,9-dihydro-6,7,9-trimethyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 
100 ml. of tetrahydrofuran, cooled in an ice bath and stirred under argon 
is added 60 ml. of 1 M borane in tetrahydrofuran, dropwise over 15 
minutes. The mixture is stirred for one hour at room temperature, refluxed 
for 18 hours, cooled in an ice bath and decomposed by the addition of 30 
ml. of 6 N hydrochloric acid. The mixture is stirred for one hour, 30 ml. 
of 10 N sodium hydroxide is added, stirring is continued for one hour and 
the tetrahydrofuran is evaporated. The remaining aqueous layer is filtered 
giving blue tinted crystals. These crystals are combined with 125 ml. of 
absolute methanol and saturated with gaseous hydrogen chloride. A 25 ml. 
portion of water is added and the mixture is heated on a steam bath until 
solution is complete. The methanol is evaporated in vacuo, 150 ml. of 
water is added and the solution is made basic with 10 N sodium hydroxide. 
The solution is extracted with methylene chloride and the extract is dried 
over magnesium sulfate and evaporated giving the desired product as blue 
crystals, mp. 121.degree.-125.degree. C. 
Employing the same general procedure, the following starting materials 
produce the corresponding mixture of products: 
______________________________________ 
Starting Materials Products 
______________________________________ 
7-methoxy and 6-methoxy-4,9-dihydro- 
9,10-dihydro-7-methoxy- 
10H-thieno[3,4-b] [1,5]benzodiaze- 
and 6-methoxy-4H-thie- 
pin-10-one no[3,4-b] [1,5]benzodi- 
azepine 
7-hydroxy and 6-hydroxy-4,9-dihydro- 
9,10-dihydro-7-hydroxy- 
10H-thieno[3,4-b] [1,5]benzodiaze- 
and 6-hydroxy-4H-thie- 
pin-10-one no[3,4-b] [1,5]benzodi- 
azepine 
7-trifluoromethyl and 6-trifluoro- 
9,10-dihydro-7-trifluoro- 
methyl-4,9-dihydro-10H-thieno[3,4-b]- 
methyl- and 6-trifluoro- 
[1,5]benzodiazepin-10-one 
methyl-4H-thieno[3,4-b]- 
[1,5]benzodiazepine 
______________________________________ 
EXAMPLE 19 
7-Amino-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one 
A 7.8 g. portion of 
4,9-dihydro-7-nitro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in a 
mixture of 200 ml. of pyridine and 50 ml. of methanol with 200 mg. of 10% 
palladium on carbon catalyst was shaken for 2 hours in a Parr 
hydrogenator. The catalyst was filtered and the solvents were removed 
under vacuum on the steam bath. The residue was dissolved in dilute 
hydrochloric acid, filtered, and the filtrate was made alkaline with 
sodium hydroxide. The crystals which form are recovered by filtration and 
air dried given the desired product as a brown powder, m.p. 
212.degree.-215.degree. C. 
EXAMPLE 20 
4,9-Dihydro-9-propyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one 
An 11.8 g. portion of 
4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2.8 g. of 50% 
sodium hydride in mineral oil in 175 ml. of dimethylformamide is stirred 
for 2 hours. A 12.6 g. portion of n-propyl iodide is added and the mixture 
is stirred overnight at room temperature. The reaction mixture is poured 
into ice water. After 3 hours the brown crystals are recovered by 
filtration, washed thoroughly with water, then ether and dried. This solid 
is heated to boiling in 75 ml. of methanol, filtered while hot and the 
filtrate is stored in a chill room. The crystals which form are recovered 
by filtration, washed with ether and dried giving the desired product, mp. 
166.degree.-167.degree. C. 
EXAMPLE 21 
9,10-Dihydro-9-propyl-4H-thieno[3,4-b][1,5]benzodiazepine 
A 5 g. portion of 
4,9-dihydro-9-propyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 100 ml. 
of dried tetrahydrofuran is added dropwise with stirring under nitrogen to 
a suspension of 3.1 g. of lithium aluminum hydride in 100 ml. of 
tetrahydrofuran. The reaction mixture is stirred for 18 hours under 
reflux, then cooled in an ice bath and treated under nitrogen, with 
stirring, with 3 ml. of water, 3 ml. of 15% sodium hydroxide and finally 
with 9 ml. of water. The complex is filtered and washed thoroughly with 
ether. The combined filtrate and washings are dried over sodium sulfate 
and filtered. The filtrate is concentrated to a dark blue oil. A 50 ml. 
portion of hexane:ether (10:1) is added and the mixture is stored in a 
chill room overnight. The solid is filtered, washed with hexane and dried. 
A second crop is obtained from the filtrate and is washed with hexane and 
dried. The two crops are combined, heated to solution in 100 ml. of 
hexane, filtered and cooled giving blue crystals which are collected, 
washed with hexane and dried, mp. 78.degree.-79.degree. C. 
EXAMPLE 22 
9-Allyl-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one 
An 11.8 g. portion of 
4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2.8 g. of 50% 
sodium hydride in mineral oil in 175 ml. of dimethylformamide is stirred 
for 2 hours. A 9 g. (6.4 ml.) portion of allyl bromide is added with 
stirring and the mixture is stirred overnight at room temperature. The 
reaction mixture is poured into ice water. The oily brown solid is 
collected by filtration and dissolved in methylene chloride. The filtrate 
is extracted twice with methylene chloride. The extracts are combined, 
washed with water, dried over sodium sulfate, filtered, and concentrated 
on a steam bath to a dark brown oily solid. The solid is swirled several 
times with fresh portions of hexane and then stored in a mixture of 50 ml. 
of hexane and 150 ml. of ether in a chill room. The crude product is 
collected, dissolved in 10 ml. of methylene chloride and chromatographed 
on an alumina column. After an initial elution with 500 ml. of hexane to 
remove the mineral oil, the column is eluted with 30% methylene chloride 
in hexane, recovering fractions 1-5 (200 ml. each), then 50% methylene 
chloride in hexane, recovering fractions 6-9 (200 ml. each) and finally 
with methylene chloride, recovering fractions 10-15 (200 ml. each). 
Fractions 3-9 are combined and concentrated to a red-orange viscous oil. 
The oil is triturated with ether, giving pale yellow crystals which are 
collected, washed with ether and dried (A). Fractions 10-15 are combined 
and concentrated to dryness giving a red-orange oil (B). Seeds of (A) are 
added to (B) giving pale yellow crystals of the desired product, mp. 
105.degree.-106.degree. C. 
EXAMPLE 21 
9-Allyl-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepine 
A solution of 4.6 g. of 
9-allyl-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 100 ml. 
of dried tetrahydrofuran is added dropwise with stirring, under nitrogen, 
to a suspension of 2.9 g. of lithium aluminum hydride in 100 ml. of dried 
tetrahydrofuran. The reaction mixture is heated under reflux with stirring 
overnight, then cooled in an ice bath and treated, with stirring under 
nitrogen, with 3 ml. of water, 3 ml. of 15% sodium hydroxide and finally 
with 9 ml. of water. The complex is filtered and washed several times with 
ether. The combined filtrate and washings are dried over sodium sulfate, 
filtered and the filtrate is concentrated to a dark blue oil. This oil is 
dissolved in 20 ml. of 30% methylene chloride in hexane and 
chromatographed on an alumina column as described in the previous example. 
Concentration of the solvent mixture yields a dark green oil which is 
heated to boiling in 80 ml. of hexane. The boiling hexane is decanted from 
a dark brown insoluble oil and then cooled giving crystals of the desired 
product, mp. 67.degree.-69.degree. C. 
EXAMPLE 24 
6,7-Dichloro-4,9-dihydro-9-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-on 
A reaction mixture comprising 106 g. of 4,5-dichloro-o-phenylenediamine and 
96 g. of tetrahydro-4-oxo-3-thiophene carboxylic acid, methyl ester in 4 
liters of benzene is refluxed for 5 hours and then cooled overnight. The 
benzene is removed by distillation and replaced by toluene. The mixture is 
refluxed 2 hours, 10 ml. of water and 0.5 ml. of acetic acid are added and 
the mixture is refluxed overnight, cooled to room temperature and 
filtered. The solid is washed with three 100 ml. portions of toluene and 
air dried giving 
6,7-dichloro-1,3,4,9-tetrahydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one 
. 
A 246 g. portion of the compound prepared as described above is suspended 
in 1.4 liters of pyridine (dried over molecular sieves) and chilled to 
less than 10.degree. C. A 127 g. portion of N-chlorosuccinimide 
(recrystallized from benzene) is added in portions, with stirring over 
21/2 hours, while the temperature is maintained at 5.degree. to 10.degree. 
C. The mixture is stirred an additional 20 minutes at 5.degree. to 
10.degree. C., warmed over a one hour period to 25.degree. C., then warmed 
on a steam bath to 80.degree. C. and held at 85.degree.-90.degree. C. for 
40 minutes. The mixture is poured into 5 kg. of ice and allowed to stand 
overnight. The mixture is stirred, filtered, washed with water and dried 
giving 
6,7-dichloro-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one. 
A reaction mixture comprising 13.3 g. of the latter product and 2.4 g. of 
50% sodium hydride in mineral oil in 150 ml. of dry dimethylformamide is 
stirred at room temperature for 2 hours then 9 g. (4 ml.) of methyl iodide 
is added and stirring is continued at room temperature overnight. The 
mixture is poured onto ice and after standing for one hour, the dark brown 
crystalline product is collected, washed with water and dried. This solid 
is boiled three times in separate 250 ml. portions of methanol. The 
combined methanol extracts are heated to boiling, treated with charcoal 
and filtered through diatomaceous earth. The filtrate is concentrated to 
300 ml. and placed in a chill room. The first crop of crystals is 
collected, washed with methanol and dried. These crystals are heated in 
300 ml. of methanol and filtered, removing insoluble material (A). The 
filtrate is concentrated to about 100 ml. and cooled producing brown 
crystals which are collected, washed with ether and dried (B). (A) and (B) 
are combined, dissolved in 300 ml. of boiling acetone, filtered and the 
filtrate is concentrated to 125 ml. and placed in a chill room. The 
crystals which form are collected, washed with acetone and dried, giving 
the desired final product, mp. 265.degree.-267.degree. C. 
EXAMPLE 25 
6,7-Dichloro-9,10-dihydro-9-methyl-4H-thieno[3,4-b][1,5]benzodiazepine 
To a suspension of 4 g. of lithium aluminum hydride in 150 ml. of 
tetrahydrofuran stirred under nitrogen, is added a solution of 10 g. of 
6,7-dichloro-4,9-dihydro-9-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-o 
ne in 350 ml. of tetrahydrofuran. The mixture is stirred under reflux for 
31/2 hours and then allowed to stand overnight. The mixture is cooled in 
an ice bath and treated, under nitrogen with stirring, with 4 ml. of 
water, 4 ml. of 15% sodium hydroxide and 12 ml. of water. The complex is 
filtered and washed with ether. The combined filtrate and washing is dried 
over sodium sulfate, filtered and concentrated to a residue. This residue 
is dissolved in a mixture of 10 ml. of 30% methylene chloride in hexane 
and 10 ml. of methylene chloride and chromatographed on an alumina column 
as described in Example 20. Those fractions which contain the desired 
product as determined by thin layer chromatography are combined and 
concentrated to give a blue-green crystalline solid. The crystalline 
product is heated to the boil in 200 ml. of hexane, and filtered. The 
filtrate is cooled and an standing produces a solid which is collected, 
washed with hexane and dried giving the desired product, mp. 
92.degree.-93.degree. C. 
EXAMPLE 24 
6,7-Dichloro-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepine 
A reaction mixture comprising 6.8 g. of 
6,7-dichloro-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one 
(prepared as described in Example 22) in 125 ml. of dried tetrahydrofuran 
and 2.9 g. of lithium aluminum hydride in 100 ml. of dried tetrahydrofuran 
is refluxed for 7 hours and then allowed to stand overnight. The mixture 
is cooled in an ice bath and treated with stirring with 3 ml. of water, 3 
ml. of 15% sodium hydroxide and 9 ml. of water. The complex is filtered, 
washed with ether and the combined filtrate and washings are dried over 
sodium sulfate, filtered and evaporated under pressure on a steam bath to 
an oily residue. The residue is triturated in hexane. The crystals are 
collected, washed with hexane and dried. This crude product is purified by 
chromatography on an alumina column, dissolving the product in and eluting 
with 10% ethyl acetate in benzene. Fractions of 50 ml. are collected. 
Fractions 2-4 are combined and concentrated to crystals. These crystals 
are dissolved with heating in 30 ml. of benzene, filtered and the filtrate 
placed in a cold room. The resulting crystals are collected washed with 
hexane and dried giving the desired product, mp. 195.degree.-197.degree. 
C. 
EXAMPLE 27 
4,9-Dihydro-4-propionyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one 
A reaction mixture comprising 9.9 g. of 
4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 4.7 g. (4.4 
ml.) of propionyl chloride in 100 ml. of benzene is refluxed for 3 hours 
and allowed to stand overnight. The precipitate is collected, washed with 
benzene and dried. A 3 g. portion of this solid is heated to boiling in 
125 ml. of ethyl acetate, filtered and the filtrate is cooled. The solid 
is collected, washed with hexane and dried giving the desired product, mp. 
222.degree.-224.degree. C. 
EXAMPLE 28 
9,10-Dihydro-4-n-propyl-4H-thieno[3,4-b][1,5]benzodiazepine hydrochloride 
To a suspension of 5.8 g. of lithium aluminum hydride in 150 ml. of dried 
tetrahydrofuran under nitrogen is added, with stirring, a solution of 4.6 
g. of 4,9-dihydro-4-propionyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one 
in 150 ml. of tetrahydrofuran. The mixture is refluxed for 20 hours with 
stirring, then cooled and 6 ml. of water, 6 ml. of 15% sodium hydroxide 
and 18 ml. of water are added dropwise, under nitrogen. The complex is 
filtered and washed with ether. The combined filtrate and washings are 
dried over sodium sulfate, filtered and evaporated to a residue. The 
residue is triturated in ether:hexane (50:50). The first crop is removed 
by filtration. The filtrate is chilled and a second crop is filtered off. 
The filtrate is concentrated to an oil. The oil is treated with 5 ml. of 
3N ethanolic hydrochloric acid and 20 ml. of ether is added. The solid is 
collected, washed with ether and dried. This solid is heated to solution 
in 250 ml. of acetone, filtered and the filtrate is concentrated to 125 
ml. A 125 ml. portion of ether is added, the mixture is cooled for 4 hours 
and the solid is collected, washed with ether and dried giving the desired 
product, mp. 190.degree.-192.degree. C. 
EXAMPLE 29 
4,9-Dihydro-9-methyl-4-propionyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one 
A reaction mixture comprising 7 g. of 
4,9-dihydro-9-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one, 3.1 g. 
(2.9 ml.) of propionyl chloride and 70 ml. of benzene is refluxed for 3 
hours and then allowed to stand for 48 hours. The benzene is distilled 
off. The residue is filtered, washed with ether and dried. The solid is 
heated to boiling in 300 ml. of ethyl acetate, filtered and the filtrate 
is chilled. The crystals are collected, washed with ether and dried giving 
the desired product, mp. 202.degree.-203.degree. C. 
EXAMPLE 30 
9,10-Dihydro-9-methyl-4-propyl-4H-thieno[3,4-b][1,5]benzodiazepine 
A 5 g. portion of 
4,9-dihydro-9-methyl-4-propionyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-on 
e is added to 200 ml. of tetrahydrofuran. To this is added 140 ml. of 1M 
borane, over a 15 minute period in an ice bath under nitrogen. The mixture 
is refluxed for 20 hours, then cooled in an ice bath and 40 ml. of 6N 
hydrochloric acid is added dropwise, with stirring. The tetrahydrofuran is 
distilled off. The reaction mixture is stirred with ice bath cooling and 
31 g. of sodium hydroxide pellets are carefully added portionwise. The 
mixture is extracted twice with 250 ml. of benzene. Water is added to 
solubilize some salts. The mixture is extracted with 250 ml. of ether. The 
ether and benzene extracts are combined, dried over sodium sulfate, 
filtered and concentrated to an oil. This oil is treated with 75 ml. of 
ether:hexane (50:50), cooled and filtered. The filtrate is diluted with 50 
ml. of hexane and cooled for a prolonged period. The solvent mixture is 
decanted from the insoluble material and concentrated to a solid residue. 
The residue is dissolved in 60 ml. of 10% methylene chloride in hexane and 
chromatographed on an alumina column. The column is eluted with 10% 
methylene chloride in hexane, discarding the first 500 ml. of eluant. 
Fractions 2 and 3 are collected (200 ml. each) and the eluate is changed 
to 20% methylene chloride in hexane. Fractions 2-7 (200 ml. each) are 
combined and concentrated giving the desired product as pale yellow 
crystals, mp. 90.degree.-92.degree. C. 
EXAMPLE 31 
4,9-Dihydro-4-hexanoyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one 
A 9 g. portion of 4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one 
and 6.3 g. (6.6 ml.) of hexanoyl chloride in 100 ml. of benzene is 
refluxed for 3 hours. The benzene is distilled off. The residue is 
triturated in ether, washed with ether and dried. This solid is heated to 
boiling in 250 ml. of benzene, filtered and the filtrate is diluted with 
250 ml. of hexane. This mixture is filtered and then cooled. The solid is 
collected, washed with hexane and dried giving the desired product, mp. 
127.degree.-129.degree. C. 
EXAMPLE 32 
4,9-Dihydro-4-hexyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 
9,10-dihydro-4-hexyl-4H-thieno[3,4-b][1,5]benzodiazepine hydrochloride 
To a suspension of 5.4 g. of lithium aluminum hydride in 150 ml. of 
tetrahydrofuran under nitrogen, with stirring, is added 5 g. of 
4,9-dihydro-4-hexanoyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 100 
ml. of tetrahydrofuran. The reaction mixture is stirred under reflux 
overnight. The mixture is cooled and there is added carefully, under 
nitrogen, 5.4 ml. of water, 5.4 ml. of 15% sodium hydroxide and then 16 
ml. of water. The complex is filtered and washed with ether. The combined 
filtrate and washing is dried over sodium sulfate filtered and 
concentrated to an oil. The oil is boiled in 100 ml. of hexane. The hexane 
is decanted and concentrated to an oil. This oil is dissolved with warming 
in 10 ml. of 20% methylene chloride in hexane and chromatographed on an 
alumina column, eluting with the same solvent mixture. The first 75 ml. of 
eluate is discarded. Fractions 1-7 (50 ml.) are collected. The eluate is 
changed to 40% methylene chloride in hexane and fractions 8-15 (50 ml.) 
are collected. The eluate is changed to 60% methylene chloride in hexane 
and fractions 16-18 (50 ml.) and fractions 19-30 (100 ml.) are collected. 
The eluate is changed to methylene chloride and fractions 31-33 (100 ml.) 
are collected. The eluate is changed to 20% methanol in methylene chloride 
and fractions 34-37 (100 ml.) are collected. 
Fractions 1-13 are combined and concentrated giving a green oil. This oil 
is dissolved in 50 ml. of ether, acidified with 5 ml. of 3N ethanolic 
hydrochloric acid and concentrated to dryness. A 5 ml. portion of 3N 
ethanolic hydrochloric acid and excess ether are added producing crystals 
which are collected, washed with ether and dried. These crystals are 
dissolved with warming in 10 ml. of ethanol, diluted with 40 ml. of ether 
and cooled. The crystals are collected, washed with ether and dried giving 
the product 9,10-dihydro-4-hexyl-4H-thieno[3,4-b][1,5]benzodiazepine 
hydrochloride, mp. 143.degree.-145.degree. C. 
Fractions 31-35 are combined and concentrated to a dark green oil. Hexane 
is added and the mixture is chilled overnight. The crystals are collected, 
washed with hexane and dried giving the product 
4,9-dihydro-4-hexyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one, mp. 
112.degree.-113.degree. C. 
EXAMPLE 33 
4,9-Dihydro-9-(2-methylallyl)-10H-thieno[3,4-b][1,5]benzodiazepin-10-one 
An 11.8 g. portion of 
4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 175 ml. of 
dimethylformamide is stirred. A 2.8 g. portion of 50% sodium hydride in 
mineral oil is treated with hexane to remove the mineral oil and then 
added to the reaction mixture. After 2 hours of stirring, 6.7 g. (7.2 ml.) 
of methallyl chloride is added. The mixture is stirred overnight and 
poured into ice-water. The mixture is extracted with four 250 ml. portions 
of methylene chloride. The extracts are combined, washed with water, dried 
over sodium sulfate, filtered and concentrated to dryness. The crude 
product is dissolved in 10 ml. of 40% methylene chloride in hexane and 
chromatographed on an alumina column, eluting with the same solvent. Those 
fractions which contain the desired product as determined by thin layer 
chromatography are combined and concentrated to give the crude product. 
This product is heated to solution in 25 ml. of benzene, filtered and the 
solid which forms is collected, washed with hexane and dried giving the 
desired product, mp. 161.degree.-163.degree. C. 
EXAMPLE 34 
9,10-Dihydro-9-(2-methylallyl)-4H-thieno[3,4-b][1,5]benzodiazepine 
A 4.9 g. portion of 
4,9-dihydro-9-(2-methylallyl)-10H-thieno[3,4-b][1,5]benzodiazepin-10-one 
in 100 ml. of dried tetrahydrofuran is added with stirring and ice bath 
cooling, under nitrogen, to 2.9 g. of lithium aluminum hydride in 100 ml. 
of dried tetrahydrofuran. The mixture is refluxed overnight and then 
decomposed with stirring and cooling under nitrogen by the successive 
addition of 3 ml. of water, 3 ml. of 15% sodium hydroxide and 9 ml. of 
water. The complex is filtered and washed with ether. The combined 
filtrate and washing is dried over sodium sulfate, filtered and evaporated 
to a residue on a steam bath. The residue is recrystallized from hexane 
giving the desired product, mp. 83.degree.-84.degree. C. 
EXAMPLE 35 
4,9-Dihydro-4-hexanoyl-9-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one 
A mixture of 7 g. of 
4,9-dihydro-9-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 4.6 g. 
(4.8 ml.) of hexanoyl chloride in 70 ml. of benzene is heated with 
stirring under reflux for 3 hours. The reaction mixture is stirred with 
cooling in an ice bath for 2 hours, 150 ml. of hexane is added and the 
mixture is placed in a chill room. The solvents are removed in vacuo on a 
steam bath. A 10 ml. portion of ether is added to the residue and the 
mixture is returned to the chill room. The tan crystals are collected by 
filtration, washed with ether and dried. The ether is concentrated giving 
a green oil which is triturated twice with hexane and once with a mixture 
of hexane and ether, giving crystals which are collected, washed with 
ether and dried. The two crops of crystals are combined, dissolved with 
warming in 75 ml. of ether and filtered. The filtrate is concentrated to 
35 ml. and stored in a cold room for 4 hours. The solid is collected, 
washed with ether then hexane and dried, giving the desired product, mp. 
76.degree.-77.degree. C. 
EXAMPLE 36 
9,10-Dihydro-4-n-hexyl-9-methyl-4H-thieno[3,4-b][1,5] benzodiazepine 
To a reaction mixture comprising 3.6 g. of 
4,9-dihydro-4-hexanoyl-9-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one 
in 100 ml. of tetrahydrofuran is added, over a 15 minute period, with 
stirring, in an ice bath, under nitrogen, 90 ml. of 1M-borane. The 
reaction mixture is then refluxed with stirring for 19 hours. The mixture 
is cooled in an ice bath and 30 ml. of 6N hydrochloric acid is added 
dropwise with stirring. The tetrahydrofuran is removed by distillation and 
23 g. of sodium hydroxide pellets are carefully added in the cold with 
stirring. A 15 ml. portion of water is added and the mixture is extracted 
with three 150 ml. portions of benzene. The benzene extracts are combined, 
washed with water, dried over sodium sulfate, filtered and concentrated to 
an oil. This crude product is dissolved in 10 ml. of 20% methylene 
chloride in hexane and chromatographed on an alumina column, eluting with 
the same solvent system. The first 150 ml. of eluent is discarded, then 
100 ml. fractions are collected. Fractions 1-5 are combined and 
concentrated to an oil. The oil is extracted with ether repeatedly. The 
ether extracts are combined, washed with water, dried over sodium sulfate, 
filtered and concentrated to a residue. The residue is dissolved in 10 ml. 
of ether and shaken with 25 ml. of 1N sodium hydroxide. The ether is 
washed with water, dried over sodium sulfate, filtered and concentrated to 
residue. This residue is dissolved in 25 ml. of methylene chloride and 
purified by chromatography on a magnesol column, eluting with methylene 
chloride. The eluant is concentrated giving the desired product as a dark 
amber oil. 
EXAMPLE 37 
4,9-Dihydro-6-nitro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one 
A reaction mixture comprising 91.8 g. of 4-nitro-o-phenylenediamine and 96 
g. of tetrahydro-4-oxo-3-thiophene carboxylic acid, methyl ester in 3.2 
liters of toluene is refluxed for 21/2 hours, 600 ml. of methanol is added 
and refluxing is continued overnight. The methanol is distilled off, 500 
ml. of toluene is added and refluxing is continued for 48 hours. The 
mixture is filtered. The crystals are washed with one liter of benzene, 
boiled with 2 liters of methanol and filtered. The crystals are slurried 
with 2 liters of hot methanol and dried, giving 134.0 g. of 
6-nitro-1,3,4,9-tetrahydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one as 
red crystals. 
A 28.6 g. portion of N-chlorosuccinimide is added over a 30 minute period 
to a slurry of 131.5 g. of the above intermediate in 2 liters of pyridine 
at 3.degree. C. The mixture is stirred and slowly warmed to room 
temperature, then heated on a steam bath for 30 minutes. The solid is 
filtered and washed with pyridine and hexane. The filtrate is allowed to 
stand for a prolonged period. The crystals which form are collected and 
washed with methanol. These crystals are dissolved in 250 ml. of hot 
dimethylformamide, filtered and the filtrate is diluted with 200 ml. of 
absolute ethanol giving the desired product as orange crystals. 
EXAMPLE 38 
9,10-Dihydro-6-nitro-4H-thieno[3,4-b][1,5]benzodiazepine 
An 8 g. portion of 4,9-dihydro-6-nitro-10H-thieno 
[3,4-b][1,5]benzodiazepin-10-one in 155 ml. of tetrahydrofuran is stirred, 
under nitrogen, with cooling in an ice bath. To this is added slowly with 
stirring 155 ml. of 1M borane in tetrahydrofuran over a period of 15 
minutes. The reaction mixture is then stirred at room temperature for one 
hour and then heated under reflux with stirring for 5 hours. The mixture 
is stirred at room temperature for 48 hours. The mixture is stirred and 
cooled in an ice bath while 45 ml. of 6N hydrochloric acid is added 
dropwise. The tetrahydrofuran is distilled off on a steam bath and the 
acidic residue is treated portionwise, with swirling in ice with 35 g. of 
sodium hydroxide pellets. The reaction mixture is extracted with benzene. 
The benzene extracts are concentrated, and the residue is repeatedly 
triturated with ether and filtered. The ether filtrate produces red 
crystals which are collected, washed with ether and dried. This solid is 
heated in 60 ml. of benzene to solution, filtered, and the filtrate is 
concentrated to 30 ml. and cooled. The solid is collected, washed with 
benzene and hexane and dried giving the desired product, mp. 
184.degree.-186.degree. C. 
EXAMPLE 39 
4-Acetyl-4,9-dihydro-9-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one 
A mixture of 7 g. of 
4,9-dihydro-9-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2.7 g. 
of acetyl chloride in 75 ml. of benzene is heated under reflux with 
stirring for 3 hours. The reaction mixture is cooled in an ice bath and 
two crops of brown crystals are collected, washed with benzene, dried and 
combined. Concentration of the benzene provides a third crop which is 
combined with the first two crops, heated to boiling in 250 ml. of ethyl 
acetate and filtered while hot. An equal amount of hexane is added, the 
mixture is cooled and the solid is collected, washed with hexane and 
dried, giving the desired product, mp. 197.degree.-199.degree. C. 
EXAMPLE 40 
9,10-Dihydro-4-ethyl-9-methyl-4H-thieno [3,4-b][1,5]benzodiazepine 
A 150 ml. portion of 1M-borane in tetrahydrofuran is added with stirring 
and cooling to a solution of 5.1 g. of 
4-acetyl-4,9-dihydro-9-methyl-10H-thieno[3,4-b][1,5]-benzodiazepin-10-one 
in 200 ml. of tetrahydrofuran. The reaction mixture is heated under reflux 
for 20 hours, cooled in an ice bath and 52 ml. of 6N hydrochloric acid is 
added dropwise with stirring. The tetrahydrofuran is removed by 
distillation. A 40 g. portion of sodium hydroxide pellets is carefully 
added in the cold with stirring followed by 25 ml. of water. The mixture 
is extracted with three 150 ml. portions of benzene. The benzene extracts 
are combined, washed with water, dried over sodium sulfate, filtered and 
concentrated to dryness. The residue is extracted three times with boiling 
hexane. The combined hexane extracts are cooled and the solid is 
collected, washed with hexane and ether and dried. A second crop is 
recovered from the hexane filtrate and combined with the first crop. The 
solid is dissolved in 25 ml. of methylene chloride, filtered and the 
solvent is evaporated almost to dryness. A 50 ml. portion of hexane is 
added. The solid is collected, washed with hexane and dried, giving the 
desired product as white crystals, mp. 135.degree.-137.degree. C. 
EXAMPLE 41 
4,9-Dihydro-4,9-dimethyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one 
A mixture of 2.8 g. of 
4,9-dihydro-4-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 620 
mg. of 50% sodium hydride in mineral oil in 30 ml. of dry 
dimethylformamide is stirred for 11/4 hours. A 2.1 g. portion of methyl 
iodide is added and the mixture is stirred overnight. The mixture is 
poured onto ice water and the solid is collected and dried. The solid 
changes to a glass which is dissolved in methylene chloride, washed with 
water, filtered and concentrated to dryness. The crude oily solid is 
triturated in hexane and ether. The ether hexane mixture is concentrated 
to a yellow gum, dissolved in 15 ml. of 30% methylene chloride in hexane 
and chromatographed on an alumina column, eluting with the same solvent. 
Four 200 ml. fractions are collected. The solvent is changed to methylene 
chloride:hexane (50:50) for fractions 5-8 (200 ml.). The solvent is 
changed to 100% methylene chloride for fractions 8-11 (200 ml.). The 
solvent is changed to 20% ethyl acetate in benzene for fractions 12-19 
(200 ml.). Fractions 11-19 are combined and concentrated to a yellow oil 
which crystallizes with trituration in hexane, giving the desired product, 
mp. 101.degree.-102.degree. C. 
EXAMPLE 42 
4,9-Dihydro-9-phenethyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one 
To a solution of 17.28 g. of 
4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 100 ml. of 
dimethylformamide is added 4.2 g. of 50% sodium hydride in mineral oil. 
The mixture is stirred for one hour and 16.0 g. of phenethyl bromide and 
20 mg. of potassium iodide are added. The mixture is stirred for 48 hours. 
The solution is evaporated. The residual gum is washed with water and 
hexane, dissolved in methylene chloride, washed with water, dried over 
magnesium sulfate and filtered through magnesol. The crystals which form 
in the filtrate are removed by filtration. This filtrate is evaporated in 
vacuo giving the desired product as dark brown crystals. 
EXAMPLE 43 
9-[4-chloro-3-(trifluoromethyl)benzyl]-4,9-dihydro-10H-thieno[3,4-b][1,5]be 
nzodiazepin-10-one 
To a solution of 8.64 g. of 
4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 100 ml. of 
dimethylformamide is added 2.1 g. of 50% sodium hydride in mineral oil. 
The mixture is stirred for one hour and 10.0 g. of 
4-chloro-3-trifluoromethyl benzyl chloride and 10 mg of potassium iodide 
are added. The mixture is stirred for a prolonged period and the solvent 
is removed in vacuo. The residual gum is dissolved in methylene chloride, 
dried over magnesium sulfate and filtered through magnesol. The filtrate 
is evaporated to give tan crystals which are recrystallized from ethanol 
giving the desired product as off-white crystals, mp. 
181.degree.-183.degree. C. 
EXAMPLE 44 
9-(2-Cyclohexen-1-yl)-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-on 
e 
To a mixture of 11.8 g. of 4,9-dihydro-10H-thieno 
[3,4-b][1,5]benzodiazepin-10-one in 175 ml. of dimethylformamide is added 
2.8 g. of 50% sodium hydride in mineral oil from which the mineral oil has 
been removed. The mixture is stirred for two hours and then 11.9 g. of 
3-bromocyclohexene is added. The reaction mixture is stirred overnight and 
poured into ice water. The brown syrup which separates is collected and 
extracted into methylene chloride. The extracts are washed with water, 
dried over sodium sulfate, filtered and evaporated to an oil. The oil is 
triturated in ether-hexane and cooled for 48 hours. The mixture is 
separated by partition chromatography. Fraction 3 is triturated in hexane, 
filtered and the solid is dried. The solid is triturated in hexane and 
chilled producing crystals. The crystals are collected, washed with hexane 
and dried. These crystals are heated to solution in 12 ml. of ethanol and 
cooled. A 12 ml. portion of hexane is added and the tan crystals are 
collected, washed with hexane and dried giving the desired product, mp. 
147.degree.-149.degree. C. 
EXAMPLE 45 
4-Acetyl-9,10-dihydro-9-ethyl-10H-thieno [3,4-b][1,5]benzodiazepin-10-one 
A mixture of 14 g. of 
4,9-dihydro-9-ethyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 5 g. of 
acetyl chloride in 150 ml. of benzene is heated with stirring under reflux 
for 3 hours and then allowed to stand at room temperature overnight. The 
mixture is concentrated to 75 ml., cooled for 2 hours and 50 ml. of hexane 
is added. The mixture is placed in a chill room. The solid is collected, 
washed with hexane, dried, dissolved in 75 ml. of hot benzene, filtered 
and allowed to stand at room temperature. The solid is collected, washed 
with benzene and then hexane and dried, giving the desired product, mp. 
88.degree.-90.degree. C.