Note: Descriptions are shown in the official language in which they were submitted.
1~40fi3
THlEN012,3-d]PYRIMIDINE ANTIALLERGIC AGENTS
Field of the Invention
This invention involves a novel series of pyrimitine compounds
having a fused thiophene ring, namely a series of thieno[2,3-dl-
S pyrimldines~ and the structurally related thieno-oxazines, and
thienylamides which are intermediates in the synthesis of the
pyrimidines. It also relates to therapeutic methods ant compositions
employing one of the thieno[2,3-d~pyrimidines, thieno-oxazines, or
thienyloxamates as the active ingredlent.
Description of the Prior Art
The literature most ciosely related to the subiect of this
invention is represented by the follo~ing references.
1. West German patent application 2,104,435 published
August 26, 1971, "New Benzothienopyrimidine Derivatives,
Procedure for Their Preparation and Their Application
in Pharmaceutics."
1~94~fi3
2. Sauter, ee al., Monatsh. 105, 558-562 (1974), "Synthesis
of Basically Substieuted [l]Benzothieno[2,3-d]pyrimidine
Derivatives...."
3. Sauter, et al., Monatsh. 105, 1258-1265 (1974), "Cycli-
zation Reactions to Thiazolo~2,3-a]thieno[2,3-d]pyrimidines."
4. Robba, et al., 8u11. Soc. Chim. Franc, (1974) 2864-2870,
"No. 562.- Thienopyrimidines. rv.- Synthesis and Seudy of
Derivatives of Thiophene Amino Acids and Aminoketones."
5. Wright, et al., J. Med. Chem. 16, 861-2 (1973), "Anti-
asthma Agents. 1. 4-Oxo-4H-tl]benzothieno[2,3-b~pyran-2-
carboxylic Acid and 4-oxo-4H-[l]benzothieno[2~3-d]pyran-2
-carboxylic Acid."
6. Hall, et al., J. Med. Chem. 17, 685-690 (1974), "Quinoline
Derivatives as Antiallergy Agents."
7. Barth, U. S. Patent No. 3,883,653 (May 13, 1975).
Method of Preventing Asthmatic Symptoms.
8. Sellstedt, et al., U. S. Patent No. 3,888,858 (June 10,
1975). 3,4-Dihydro-4-oxo-2-quinazolinecarboxylic Acits,
Salts and Esters as Anti-allergic Agents.
9. Narr, et al., U. S. Patent No. 3,888,851 (June 10, 1975).
2,4-Diamino-Substituted Thieno[3,2-d]pyrimidines and
Salts Thereof.
10. Baetz, U. S. Patent No. 3,888,983 (June 10, 1975).
Derivatives of Thazolino-pyrimidin-6-ones, In Inducing
Analgesia.
11. McClelland, et al., J. Chem. Soc. 78-81 (1948). "Some
1:3-Oxazine Derivatives of Thionaphthen."
~.~
10~40~i3
12. Tinney, et al., J. Med. Chem., 1~, 624-630 (19~4).
"Synthesis and Pharmacological Evaluation of 2,3-
Dihydro-lH-thieno[2,3-e][1,4]diazepines.
References 1, 2, and 3 refer to various thieno[2,3-d]-
pyrimidines, but these substances are distinguished by the nature ofthe substituents in the 2-position and the lack of disclosure of anti-
allergic utility.
Reference 4 refers to 2-aminothiophene-3-carboxylates and
-carboxamides useful for preparing thieno[2,3-d]pyrimidines.
References 5, 6, ~, and 8 involve heterocyclic organic com-
pounds having anti-allergic activity of the type with which the present
invèntion is concerned but these substances involve different hetero-
cyclic ring systems than the thieno[2,3-d]pyrimidines of the present
invention.
References ~, 10, and 11 involve pyrimidine compounds having a
thiophene ring fuset thereto, but they too represent different hetero-
cyclic systems from those with which the present invention is concerned,
and different medical utilities.
Reference 12 refers to hexahydrobenzothieno[2,3-e][1,4]-
diazepin-2-ones which were synthesized for evaluation as anti-anxiety
agents.
Summary of the Invention
This invention provides compounds of Formulas I, IV and V
R3 B ~ C0 2R
For~ula I Formula V
L ~ I CON~2
B NE~C-ACo2R3
Formula IV
-- 3 --
109~Qfi3
These substances are useful in the treatment of diseases of
allergy and particularly asthma, hay fever, and food allergy which are
characterized by episodes of acute attack provoked by inhalation or
ingestion of an allergen. The compounds have the advantage for chronic
prophylactic use of being substantially free of other pharmacologic
activity, and they have low toxicities. Preferred members are orally
active.
The compounds of Formulas IV and V are also useful as inter-
mediates for the manufacture of the compounds of Formula I.
In Formula I, the symbol R2 refers to a carboxylic acid
substituent or a lower alkyl ester or nontoxic pharmacologically inert
metal salt thereof. It also refers to the vinylogous carboxylic acids,
esters, and salts in which R2 is the substituent of CH'CHCo2R3 and
which R3 is hydrogen, lower alkyl having 1-8 carbon atoms, or a non-
toxic pharmacologically inert metal cation. By nontoxic phanmacolo-
gically inert is meant that the cation in the doses required for the
a~m~nistration of one of the salts containing it is without deliterious
effect or interfering pharmacologically action on the host. Suitable
metal cations are preferably the alkali metals sodium and potassium,
but also other nontoxic pharmacologically inert cations such as
calcium, magnesium, aluminum, zinc, and barium. R2 may also be the
methylol gro~p or the formate, or a lower alkyl ester thereof. R2
may also be the carboxaldehyde, 5-tetrazolyl, or ~-(tetrazol-5-yl)-
carbamyl group. To sum up, R2 is a group having one of the following
formulas in which R3 has the meaning given above, and R is lower alkyl
having 1 to 8 carbon atoms.
O O O
-C02R , -CX-CHC02R , -CH20H, -CH20CH, -CH20C~, -CH,
1094Ufi3
, , -CONH ~ N
H H
In formula I, R3 is the same as above, and R5 and R6 may be hydrogen,
lower alkyl having from 1 to 8 carbon atoms, lower alkenyl having from
3 to 6 carbon atoms, lower alkoxy having from 1 to 6 carbon atoms,
hydroxy, nitro, amino, halo including chlorine, bromine, iodine, and
fluorine, phenyl, alkanoyl having from 2 to 6 carbon atoms or they are
bonded to one another to form a cycloalkene ring fused to the thiophene
ring and having a total of from 5 ~o 7 annular ring carbon atoms or
an R-substituted cycloalkene having 5 to 7 annular ring carbon atoms
wherein R has the same meaning as above.
1~ In Formula V, R3 has the same meaning as above and A is
either a covalent bond linking the -Co2R3 group to the ring or it is
the vinyl group, -C~C~-, joining the -Co2R3 group to the ring. The
symbols L and B signify some of the same groups identified for R5
and R6, but their definition is somewhat more limited. L and B may
be hydrogen, lower alkyl having from 1 to 8 carbon atoms, lower alkenyl
having from 3 ~o 6 carbon atoms, phenyl, alkanoyl having from 2 to 6
carbon atoms, or they may be joined to form a cycloalkene ring fused to
the thiophene ring and having from 5 to 7 annular ring carbon -~toms or
R-substituted cycloalkene having from 5 to 7 annular ring carbon atoms
wherein B has the same meaning as above.
In Formula IV, the sym~ols R3, A, L and B ha~e the same
meaning as is indicated for Formula V.
10~40fi3
Accordingly, the in-~ention contemplates a process for
R5 ~ -R3
R6J~ S 1N J--
(I)
wherein:
R2 is -Co2R3, wherein R3 is selected from the group
consisting of hydrogen, lower alkyl having 1 to ~
carbon atoms, and M wherein M is a non-toxic pharma-
cologically inert metal cation, and
RS and R are independently selected from the group consl~ting
of hydrogen, lower alkyl having 1 to 8 carbon atoms,
- iodo, nitro, and amino,
which comprises reacting a 2-aminothiophene-3-carboxamide of Formula II
wherein Z is NH2 or a 2-aminothiophene-3-carboxylic acid of Fromula II
wherein Z is O~ with an acylating agent of Formula III
L C-Z
00
~ ~ 1¦ X-C-~-OR
B S NH2
(II) ~III)
wherein:
X is chloro, bromo, or lower alkoxy l~aving 1 to 8 carbon
atoms, and
R is lower alkyl having 1 to ~ carbon atoms;
-- 6 --
109~0fi3
L and B are independently hydrogen or lower alkyl having 1 to
8 carbon atoms,
to yield, respectively~ a thienyloxamate of Formula rv or a thienyl-
oxazine carboxylate of Formula ~;
B ~ NHC-CO~R 3 ~ C02R
(IV) (V)
S converting the compound of Formula rv to a compound of Formula I by
heating the compound of Formula n in the molten state at a temperature
in the range of 200-265C for from 5 to 15 minutes; converting the
compound of Formula V to a compound of Formula I by treatment thereof
in solution in a protic solvent such as a lower alkanol having 1 to 4
carbon atoms with an amine of the formula R3NH2 or with a soluble
ammonium salt when R3 is H wherein in Formulas rv and V R3, L, and B
are as defined above, and when a compound of Formula I wherein R5 or
R6 is nitro or amino is desired, nitrating a compound of Formula I
wherein R5 or R6 is hydrogen under known conditions for the nitration
of a thiophene compound and thereafter reducing the resulting nitro
compound by catalytic hydrogesation to afford the compound of
Formula I wherein R5 or R6 is amino, and when a compound of Formula I
wherein R5 or R6 is iodo is desired, converting a compound of Formula I
wherein R5 or R5 is hydrogen to the corresponding chloromercuri
derivative and treatment of the latter with iodine and potassium
iodide, and, if desired, converting the resulting compound of
Formula I wherein R2 is the esterified carboxyl group to the corres-
pondlng acid or metal salt by hydrolysis and neutralization.
The invention also iscludes the product of that process and
products of processes derivative from the above process.
- 6a -
: ~;
109~0fi3
Detalled Descri~tion of the Invention
The compounds of Formulas I, IV and V inhlbit the degranula-
tion of sensltized mast cells. Immediate hypersensitivity reactions such
8S a~thma, hay fever, allergic rhinitis, urticaria, and food allergy
are believed to be medisted by reaction of immunoglobulin E, some-
tlmes referred to as reaginic sntibody with an antlgen on the cell
membrane of a mast cell to initiate reactions within the mast cell which
ultimately release mediators such as bradykinin, histamine, serotonin,
or slow reacting substance-A (SRS-A). The mediators effect changes in
end organs such as airways, blood vessels, skin, and mucus ~embranes
resulting in the symptoms of an allergic attack. The present substances
are believed to prevent the release of mediators thereby preventing
~he allergic attack. They are, therefore, usefùl in the prophylactic
treatment of sub~ects posses6ing hypersensitivities of the foregoing
types, and lnhibit acute allergic attacks such as an asthmatic attack.
Preferred compounds are distinguished particularly by the fact that
they are orally active, have very low toxicities, and sre substantially
devoid of other types of pharmacologic action including antihistaminic
action. Thus, they are not primarily of value in the treatment of the
fulminatin~ allergic reactions but are of particular value for use
prophylactically by hypersensitive sub~ects to prevent the mznifes-
tations of allergic reaction on ~xposure to an allergen for the hyper-
sensitive condition.
Activity of test compounds ln the passive cutaneous ana-
phylaxis reacSion (PCA) in the rat has been shown in the prior art to
correlate with ehe utility of active compounds in the treatment of
itnmediate hyperser.sitivity conditions such as asthma. Rat reaginic anti-
serum is prepared substantially according to the method of Mota, Immu-
n~logy 7, 68~-699 (1964) employing male Sprague-Dawley (Carworth Farms) or
10!~40~3
Wlstar (Harlan) rats weig!ling 100-175 g. which are in~ected intra-
muscularly wlth a solution of egg albumin ln saline at a dose of
10 mg. per kg. and intraperltoneally with 2 x 10~ Bordetella pertussis
organlsms. Twelve days after in~ection, the serum i9 collected and
the antibody titer i9 determinet. The sera are pooled which contain
sufficient antibody to cause a 10 mm. spot in the dorsal skin of the
rst in the PCA test after dilution 10 fold. The highest dilution
of antiserum capable of inducing PCA in the rat 48 to 72 hrs. after
ln~ection is non~ally in the range of 50-80. The selected reaginic
anti-sera are stored frozen until use.
For carrying out the test, groups of 5 to 10 male Sprague-
Dawley (Carworth Farms) rats, each rat weighing 100-150 g., are used.
Forty-eight hours prior to the test,the animals are passively sensitized
by intradermal in~ection of 0.1 ml. of diluted antiserum at various
locations on the shaved skin of the back. A dilution of antiserum is
used so that a spot following challenge or 20-25 mm. in diameter
is obtained. A higher dilution of the antiserum is in~ected in
at least one location to allow a more sensitive measure of the
activity of less potent compounds. A latent period of 48 hrs. is
usually allowed before the animals are challenged. According to the
usual screening procedure, 15 min. prior to challenge the tes~ drug is
administered either by intraperitoneal in~ection, intravenous in-
~ection, or orally by gavage. Challenge involves an intravenous in-
~ection of a dose of 25 mg.Jkg. of egg albumin and 25 mg./kg. of
Evans' blue dye in saline. The dye serves simply as a marker.
The response to the antigen challenge in the localities on the skin
which have been previously sensitized results in increased capillary
permeability at the sensitized site and leakage of the blue dye into
Jfi3
the area surrounding the serlsitized site. The PCA response is scored
by measuring the mean spot dlameter on the excised and reversed skin
20-30 min. after challange. In each experiment a group of control
animals receiving no drug ls employed. The percent lnhibltion of the
PCA iq calculated by determinlng the mean dlameters of the spots in
the control ant treated animals and computing the difference between
the squares of the mean dismeters of the control animals and the
treated animals and expressing this difference as a percentage of the
square of the mean diameter of the control animals. Results ~re
expresset as percent lnhibition.
Rats may be in~ected intradermally with O.l ml. of a solution
containing 1 mg./ml. histamlne lO min. prior to sacriflcing. This
permlts a determinatlon of whether the test compound is exerting an
antihistaminic effect on the end organ rather than interferlng with
mediator release from the mast cells in inhibitlng the PCA.
Various doses of test compound in parallel experiments are
employed when a dose response curve is to be constructed for quantita-
tive comparison of potencies among active compounds. The ID~o~ the
do~e at whlch 50% inhibition of the PCA occurs, is determined by
interpolation. In other modifications, various time intervals are
allowed between drug treatment and challenge to ascertain the duration
of drug effect.
A more sophisticated test reflecting the utility of ~he present
substances in the treatment of immunologically induced bronchoconstric-
tion involves an allergic respiratory modei in the rat in which maleHarlan ra~s weighing 225-275 g. each are actively sensitized with egg
albumln and B pertussis vaccine (2 x lO~ organisms per rat) as before
for the prepa~ation of the reaglnic antisera. Thlrteen to fifteen days
109~0fi3
after sensitization, the rats are prepared for intraduodenal admin-
istration of compounds by exposure of the duodenum through a small
abdominal incision, and the ~ugular vein, carotid artery, and trachea
are cannulated. The ~ugular vein cannula is used for the administration
of the egg albumin challange and blood pressure is measured through
the cannulated carotid artery. The tracheal cannula is connected to
a glas~ T-tube one arm of which is open to the atmosphere, and the
other arm of which is connected to a pressure transducer for the
measurement of the insplratory and expiratory pressure. Changes in
inspiratory and expiratory pressure are monitored as a reflection of
changes in airway resistance following challenge with the egg albumin
antigen. The drugs are admini-~tered intraduodenally 15 min. prior to
chall nge with an injection of egg albumin and the changes in airway
resistance relative to the control animals are determined. The
antigenic challenge dose is ad~usted to effect an approximately 36%
decrease in inspiratory and expiratory pre~sure since this was found
to be approximately the maximum which the animals can survive. The
drug effect on this decrease in inspiratory and expiratory pressure
is then determined for various doses of drug. That dose which produces
the half maximal response is determined by interpolation from a dose
response curve (IDl/2 max.).
The data shown in the following table reflects the oral
anti-allergic action some of the substances of the present invention
in the foregoing tests.
-- 10 --
J0~ 3
Oral Anti-Allergic Action In Rats
Allergic Respira-
PCA Response tory Response
Drug 50 ( 1/, max. mg./kg-) LD50*(mg./kg )
5 Procedure 2 15.4 3.8 > 3160
Procedure 27 11.4
Procedure 28 ~ 5.0
Procedure 29 3.1 1.0 1600-5000**
Procedure 36 15.0
10 Procedure 43 6.7
Procedure 44 13.0
Procedure 53 28. Ot
Procedure 55 34. Ot
Procedure 56 28.0
* Acute oral toxicity in the rat
** LD50 is greater than 1600 mg.lkg., but less than 5000 mg.lkg.
t 2 hr. lnterval between drug dosage and challenge.
Cromolyn sodium is inactive on oral administration in the
foregoing tests. This substance is used clinically in the prophylactic
treatment of asthmatic patients by oral inhalation and its activity is
reflected in the foregoing rat PCA test when it is administered by
the intravenous or intraperitoneal in;ection. An ID50 of approximately
1 mg./kg. can be demonstrated in the rat in the PCA test when cromolyn
sodium is administered intravenously simultaneously with the aneigen.
Sim~larly, ~he intrinsic activity of those substances of the present
invention which exhibit a reduced level of activity in the PCA test when
,~
lO!~Qfi3
administered by t;~e oral route~ as com~ared to the activity of the sub-
stances listed ln the foregoing table, may be shown by sdministration
thereof to the test animal by either the intraperitoneal or intravenous
routes.
The activity of the present substances in ir.terfering with
the release of allergic medlator s~bstances may be demonstrated in
vitro by a test involving antagonism of antigen-induced histamine
release from passively sensitized rat peritoneal mase cel s. The method
employed is similar to that described by Kusner, et al., Journal of
Pharmacology and Experimental Therapeutics 184, 41-4G (1973). The test
lnvolves isolation of mast cells from the rat by lavage of the peritoneal
cavity and isolation of the cellular material from the lavage fluid.
The cells are sensitized by shaking in antiserum from rats sensitized
as described above with respect to the passive cutaneous anaphylaxis
test. The sensitized cells are then exposed to the egg albumin antigen
and the release of histamine from the cells is measured by an automated
fluorometric method. The inhibition o histamine release by the
presence of a test compound during challenge of the sensitized cells
i6 a measure of the activity of the test compound. Dose response
curves are prepared employing various concentrations of the test sub-
~tance and the concentration which inhibits histamine release by 50%
(ICso)is determ~ned by interpolation. Cromolyn sodium was found to
exhibit an IC~o of 1 ~ in this test system. The compounds of the
present inventlon prepared by Procedures 2, 3, and 36 were substantially
more potent than cromolyn sodium ir. th~t IC,o values within the rsnge
of 0.3 to 0.8 ~M were exhibited.
`` ~0!~40fi3
Thus, there is provided by the present invention a method
for suppressing the allergic manifestations of immediate hypersensi-
tivity in sensitive warm blooded animals on exposure thereof to the
causative allergen. Mammals sub~ect to lmmediate hypersensitivity
sensltizatlon include man, mouse, rat, hamster, gerbil, dog, cat,
sheep, goat, horse, cow, etc. The process involves administering an
effective dose of one of the compounds of the present invention by
the oral, topical, parenteral, or inhalatlonal routes. The effective
dosage range ln rsts ls from about 1 to 200 mg./kg. of body weight
with the preferred compounds being effective orally in the range of
from about 1 to 15 mg./kg. of body weight. The estimated human dose
for the substance of Procedure 29 i8 ln the range of from 1 to 500 mg.
orally.
Approprlate dosage unit forms for the foregoing application
of the substances of Formulas I, IY, and V such as tablets, solutions
or suspensions for in~ection or inhalation, snd powders for inhalation
may be prepared with conventional pharmaceutical carriers according to
established practices in the pharmaceutical art.
The compounds of the present invention are prepared from
the 2-aminothiophene-3-carbo~amides or 2-aminothlophene 3-carboxylic
acids of Formula II shown ln the following diagram wherein Z is -OH
or -N~. Compounds of Formula II have been previously described by
Gewald, et al., Chem. Berichte 98, 3571 (1965), and ibid., 99, 94 (1966).
Novel compounds of Formula II for use in preparing compounds of this
2~ lnvention may he prepared by obvious ad~ptations of the Gewald, et al.
methods. In Formula II the symbols L and B are lndependently selected
from the group consisting of hydrogen, lower alkyl having 1 to 8 carbon
stoms, lower alkenyl having 3 to 6 carbon atoms, phenyl, alkanoyl having
`` 1c~!~4ofi3
2 to ~ carbon atoms, or together they constltute cycloalkene havlng
S to 7 annular ring carbon atoms or R-subs~ituted cycloalkene having
S to 7 annular rlng carbon a~oms wherein R ls a lower alkyl group having
1 to 8 carbon atoms.
L ~ ONH~
B ~ C-A-COlR'
/~ IV ~
" ~ O
~ + X-C-A-C-OR ~
B 2 III -CO2R'
- II \ VI
~_co~
S The intermediate 2-aminothiophene-3-carboxamides or 2-amino-
thiophene-3-carboxylic acids of Formula II on reaction with an acylating
agent of Pormula III yield the thiophene derivatives of Formula IV or
the oxazine derivatives of Formula V. R9 in Formulas IV, V, and VI is
H, lower alkyl having 1 to 8 carbon atoms, or M wherein M is a non-
toxic pharmacologically acceptable metal cation. The acylating agent
of Formula III ~s an oxalic or 1,4-but-2-enedioic scid derivative.
That i~, A in tha above formulas is either a covalent bond directly
llnking the indicsted gro~ps or it is the vinyl group (-CH=CH-). X
is chloro, bromo, or lower alkoxy ha~ng 1 to 8 carbon atoms and is
- 10~0~3
preferably the ethoxy group whe-l operating on a starting material of
Formula II wherein Z is -OH, and chloro when operating on 8 starting
~aterial of Formula II wherein Z is -NH2-
For preparation of those substances of Formulas V and VI
wherein A is the vinyl group, it is preferred to employ the startingmaterial of Formula II wherein Z is -OH, and employ a lower alkyl
diester or a lower alkyl monoester halide of 1,4-but-2-enedloic acid
as the acylating agent.
For preparation of the intermediates of Formula IV wherein
R' is lower alkyl, the 2-aminothiophene-3-carboxamide of Formula II
wherein Z ls -NH~ is treated in pyridine or other aprotic solvent such
as acetonitrile, benzene, or di-isopropyl ether containing at least
1 molecular proportion of pyridine relative to the acylating reactant
of Formula III which is preferably ethyl oxalyl chloride. The acylating
agent is carefully mixed with the solution of the car~oxamide starting
material at room temperature using gradual addition of the acylating
agent to the intermediate or the reverse with cooling of the reaction
vessel. It i6 undesirable to precool the reactants before commence-
ment of the reaction. After the reaction subsides, a period of
stirring at room tempersture is usually employed as a precaution to
allow completion of the reaction. The intermediate of Formula IV
is then recovered from the reaction mixture by pcuring it into a
protic solvent such as isopropanol and collecting ~he precipitated
intermediate ~y filtration.
The thienyl intermediates of Formula IV are novel compounds
hsving anti-allerglc activity, and sre considered part of the present
invention. The thienyl compounds o Formula IV wherein R' is lower
10~40fi3
alkyl are converted to the thienopyrimidines of the present invention
having Fcrmula VI bg heating in the molten state at a temperature in
the rsnge of about 200-265C., preferably the latter. The progress of
the reaction can be e~timated by the foaming which occurs due to
vaporization of the water for~et in the process as a by-product. In each
specific instance the optimum temperature for carrying out the pyrolysis
can be estimated by visualization of the molten material when heated in
a test tube and determining the temperature at which vigorous evolution
of water vapor occurs.
The oxazines of Formula V are novel compounds ha~ing anti-
allergic activity and are considered part of the present invention.
The oxazines of Formula V wherein R' is lower alkyl are prepared by
reaction of a 2-aminothlophene-3-carboxylic acid of Formula II wherein
Z is -OH with an acylating agent of Formula III under much the same
conditions as those described above for the preparation of the inter-
mediate~ of Formula IV. In this instance it is preferred to employ two
molecular portions of the acylating agent. If a single molecular portion
of acylating agent is employed, a mixture containing the intermediate
2-carbamylthiophene-3-carboxylic acid analogous in structure to the
thiophene csrboxamides of Formula IV may be obtained. The 2-carbamyl-
thiophene-3-carbox~lic acld may be cyclized to the oxazine of Formula V by
treatment with an additional molecular proportion of the acylating agent of
Formula III or other cyclodenydrating agent such as SOCl,. While stepwise
operation in this fashior. i8 possible, there i8 no advantage. It is pre-
ferable to employ two molecular portions of Formula III acylating agent inthe first instance, and to obtain the pure oxazine as the reaction product.
The oxazines of ~ormula V are converted to the thieno-
pyrimidines of Formula VI by reaction with an amine of the formula
~ 16 -
Qfi3
RNH~ wherein R is as defined above or an ammonium salt which is
soluble ln the reaction medium. A protic solvent, ant preferably
a lower alkanol such as ethanol or isopropanol, ls employed as
reaction medium. The reactlon ls carrled out at the reflux tempera-
ture and the product usually crystsllizes from the reaction mixtureon coollng. Suitable ammonium salts are: ammonium benzenesulfonate,
ammonlum fluorlde, ammonium fluorosulfonPee, am~on~um fluosilicate,
ammonium acetate, ammonlum lodlde, ammonium nitrate, ammonlum
hypophosphite, and ammonium valerate. It ls preferred to employ
ammonium acetate optionally in the presence of approximstely one
chemical equivalen~ of acetic acid to form a buffer system and
minimize amide formation from the 2-carboxy ester group.
The compounds of Formula I and VI wherein R' is H or M are
prepared by hytrolysis and neutralizatlon of the corresponding esters
(R' is lower alkyl) as i9 exemplified ln Procedures 3 and 32. The
compounds of Formula IV ln which R3 ls H or M are sometlmes obtained
as by-products ln the preparation of the Formula VI compounds from
the Formula II compounds. They may also be prepared by hydrolysis
and neutrallzation of a Formula IV compound in which R' is lower alkyl.
The compounds of Formula V wherein R' is H may be prepared by selective
hydrolysls of the correspondlng acld halide, and the M salts then formed
by neutrallzation.
The compounds of Formula VI constltute a subgroup of the com-
pounds of Formula I whereln R~ is CO2R3 or CH=CIlCO2R~, and R' and R~
of Formula I correspond ln part respectively to L and B of Formula VI.
They serve as intermedlates for other compounds of Formula I wherein
R and Rs are hydroOxy, alkox~, nitro, amino, or halo~en, or wherein
" ..
R2 ls -CH~OH, -CH~OCH, -CH~QCR, 5-tetrazolyl, ~-(tetrazol-5-yl)carbamyl,
'3
or CH0. Conventior.al aromstic substitution re~ctions known to be
operable on substitutcd thiophenes may be e~.ployed on For~ula ~I
compounds wherein one of L and B is hydrogen to introduce the R5 or
R6 group. For example, a compound of Formula I wherein R or R6 is the
nitro group is prepared by nitration of the corresponding compound
wherein R' or R~s~ respectively, is a hydrogen atom, by treatment of a
solution thereof in trichloroacetic acid and acetic anhydryde with a solu-
tion of nitric acid in trichloroacetic acid. The reaction is carried out
by a careful additlon of the nitrating solution to the reacta~t
solutlon at a temperature of about -15 C. Any temperature from
about 0 to -20 C. may be employed which is convenient. The nitro-
thiophene is recovered from the reaction mixture by quenching with
water and filtering the resulting precipitate. The resulting compound
of Formula I wherein one of R' and R6 is a nitro group may then be
converted to the corresponding amino compound by conventional hydro-
genation processes such as atmospheric pre3sure hydrogenation over a
carbon-supported palladium catalyst employing a solvent medium for
contact of the hydrogen with the catalyst and reactant.
The compounds of Formula I wherein one of R' and R5 is the
amino group may be converted by diazotization and replacement of the
dia20nium group with a halogen atom or a hydroxyl group according
to known reaction conditions. For instance, the amino compound may
be dissolved in aqueous fluoboric acid and treated with sodium nitrite
at ice temperature to yield the corresponding diazonium fluobor~te
salt. The latter on treatment with cuprous chloride, bromide, or
iodide yields the corresponding compound of Formula I wherein R' or R6
is chloro, bromo, or iodo. The diazonium fluoroborate salts may also
be converted to the corresponding fluoro derivatives where one of R'
- lR -
1i3
and R6 i8 the fluoro group by heating at a temperature ~ust above
tha melting point (standard Scheimann reactlon conditions). The
lodo compounds may also be preyared by mercuration of a compound
of Formuia VI where~n L or B is hydrogen by reaction with mercuric
acetate and treatmen; of the mercury derivative with lodine and
potassium iodide.
The compounds of Formula I wherein one of R~ and R6 is
hydroxy are prepared from the intermediate diazonium fluoborate salts
by hydrolysis thereof, preferably with potassium trichloroacetate
~ ln trichloroacetic acid followed by treatment of the reaction product
with water. The hydroxy compounds are converted to alkoxy compounds
under conventional alkylation conditions such as reaction with a
diazoalkane, alkyl iodide, or dialkyl sulfate.
The compounds of Formula I in w~lich R~ is the hydroxymethyl
group or an ester thereof are prepared from the compounds of Formula I
wherein R~ is C02R by reduction with a borohydride derivative such
as lithium borohydride or sodium borohydride. Again, conventional
conditions involving contacting the reactants in a reaction inert
solvent medium are employed. The compounds of Formula I wherein ~2
is the carboxaldehyde group are prepared from the corresponding hydroxy-
methyl compounds by oxidation, for instance, with manganese dioxide or
dimethylsulfoxide in dicyclohexylcarbondiimide under known conditions.
To sum up, the compounds of Formula I are prepared by means
of a process which comprises reacting a compound of Formula II with an
~5 acylating agent of Formula III to provide a compound of For~ula IV or
Formula V. The compound of Formula I~ is then converted into a com-
pound of Formula I by heating in the molten state at a temperature in
the range of 200-265C. for from 5 to 15 min. The compound of Formula V
fi3
is convereed into a compound of Formula I by treatment in solutlon with
an aMine o~ the formula R~NH~ or a soluble ammonium salt employing a
protic solvent such as a lower alkanol having 1 to 4 carbon atoms as
reaction medlum at the reflux temperature. The compound of Formula I
thus produced corresponds to the subgroup deflned by Formula VI above.
If desired, a compound of Formula VI in which one of L or B
is hydrogen, may be converted to the corresponding nitro compound by
nitration under conditions which are known to be operab~e for the
preparation of nitro substituted thiophene compounds by direct nitra-
tion of the corresponding unsubstituted thiophene compound. ~he resultingcompound of Formula I in which R' or R6 is nitro is then converted by
catalytic hydrogenstion of the nitro group to yield a compound of
Formula I in which R' or Rc is amino. The latter may then be diazotized
to form the corresponding diazonium salt, such as the fluoborate salt,
which ln turn may be reacted with a cuprous halite to provide a com-
pound of Formula I wherein R~ or R6 is Cl, Br, or I or the diazonium
salt may ~e hydrolyzed to yield the compound of Formula I wherein one
of R' or R6 is hydroxyl. The diazonium fluoborate salt may also be
heated to its decomposition point to yield the compound of Formula I
wherein one of R' or R6 is fluoro. The hydroxy derivative may be
etherified under conventional conditions for the formation of aromatic
ethers to yield the compound of Formula I wherein R5 or R6 is a lower
alkoxy group having 1 to 6 carbon atoms. Further, a compound of
Formula I in which R' or R6 i9 hydrogen may be converted by known
methods to the mercuric acetate derivative and thence to the corresponding
compound where R~ or R6 is iodo by treatment of the mercuric acetate
derivative with I~ and KI. This is illustrated in the following flow
sheet.
- 20 -
iO~ 0-~3
mercuric
acetate I2,KI
Formula ~ Formula I
L or B i9 hydrogen R' or R is iodine
S nigration
Formula I
R' or R6 is nitro
¦ catalytic hydrogenation
Formula I
R5 or R6 is amino
dlazotization
. ~fluoborste)
C 7,/ ~o
- Formula I heat Formula I
1~ R' or R- is R5 or R6 iq OH
chlorine, ~
bromine or etherify
lodine Formula I
R' or R6 is ~
. fluorine Form lla I
R5 or R5 is -OR
Any of the foregoing compounds of Formula VI in which A is a covalent
bond linki.n~ the CO2R group to the ring may be transformed into a
~5 compound of Formula I in which R~ is 5-tetrazolyl or N-(tetrazol-S-yl)-
carbamoyl according to the following reaction scheme in which R, R5
and R5 have the same meanlng as previously.
.
fi3
~ CO,R ~ ~ ~ N - N
o O O
R~ ~ ~H B~ ~ R~ ~ ~ N
R ls~oNH. RJ~LCN R6J~
Description of Specific Embodiments
The nuclear magnetic resonance spectral characteristics
reported in the following procedures refer to the chemical shifts (~)
expressed as parts per million (ppm) versus tetramethylsilane as
S reference standard except in those instances where D20 is indicated
as solvent where the HDO line at 4.70 ppm was employed. The relative
area reported for the various shifts corresponds to the number of hydrogen
atoms in the involved ~ubstituent, and the nature of the shift as to
multiplicity is reported as broad singlet (bs), singlet (s), multiplet
(m), doublet (d), triplet (t), or quadruplet (q~ with coupling constant
(J value) reported where appropriate. The format iB NMR (solvent):
~(mu~tiplicity, relative srea, J value). Abbreviations for the solvents
are CDCl3 (deuterochloroformj, DMSO-d~ (deuterod~methylsulfoxide),
CF~CO2H (trifluoroacetic acid), and D~O (deuterium oxide). The infrared
1~40fi3
spectrsl data is a listing of ehe wave~engths ln cm. of absorption
~axima which are characteristic of functional ~roups. The infrared
spectra were determined on potassium bromide pel~ets containing 0.5
of the eYperimental substance.
Procedure 1. ETHYL N-C3- (AMINOCARBONYL)-4,5,6,7-TETRA-
HYDROBENZOCb]THIEN-2-YL]OXlu~TE.- A suspension of 72.92 gra~s
(0.41 mole) of 2-amino-4,5,6,7-tetrahydrobenzoCb]thiophene-3-
carboxamide in 2~0 ml. of dry pyridine is stirred at 25 C. during
the addition of 55.25 grams (0.41 mole) of ethyl oxalyl chloride
dissolved in SO ml. of dry acetonitrile in drop-w~se fashion.
Cooling of the reaction vessel by immersion in ice water is employed
and the flask is kept in the ice bath for 30 min. after the addi-
ti~n is complete. The reaction vessel should not be pre-cooled
before commencement of the addition of the ethyl oxalyl chloride.
After the reaction is complete and the ice bath is removet, 150 ml.
of the acetonitrile is added to the reaction mixture to facilitate
stirring, and the mixture is kept overnight with stirring. It is
then poured into isopropanol and the precipitated product is
collected on a filter. The product is air dried, yielding 58.80 g.
(49%) of a yellow solid, m.p. 204.0-205.0 C. A sample of this
material recrystallized from isopropanol exhibited the same melting
point.
NMR (DMSO-d8): 12.88 ~s,l), 7.30 (s,2~, 4.37 (q,2), 2.70
(m,4), 1.75 (m.4), 1.37 (t,3). Infrared (KBr): 1635, 1680, and 1720 cm.
Anal. found: C, 52.68; H, 5.34; N, 9.42.
Procedure 2. ETHYL 3,4,5,6,7,8-HEXAHYDRO-4-OXOBE~ZO-
THIEN0~2,3-d]PYRIMIDINE-2-CARBOXYIATE.- The product of Procedure 1,
8.89 g. (0.030 mole) is melted in a round bottom flask equipped with
- 23 -
10~0fi3
a magnetlc stirring bar and immersed in an oil bath at 261 C.
The molten material is heated with stirring until the evolution
of water as is evidenced by bubbling of the reaction mixture is no
longer evident. About 5-15 min. is sufficient. The molten mass
is then dissolvet in dimethylformamide ant the warm solution is
poured into a volume of methanol larger than the reaction mixture.
The precipitate is collected, and recrystallizet from a mixture
of dimethylformamide and methsnol to yield 4.g2 g. (48~) of the
desired product as fine yellow needles, m.p. 207.0-209.0 C.
NNR (CDCls): 10.35 (bs,1), 4.50 (q,2, J = 7.0 Hz), 2.~0 (m,4),
1.88 (m,4), 1.47 (t,3). Infrared (KBr): 3110, 3030, 2940, 1740, 1670,
1570, 1490, 1465, 1370, 1365, 1300, 1187, and 1035 cm. 1 Ultraviolet
absorption maxima (0.1 N--~Cl) 255, 348 m~; (0.1 N-NaOH) 275, and 311 m~.
A _ . found: C, 55.92; H, 5.53; N, 10.04.
Procedure 3. 3,4,5,6,7,8-HEXAHYDRO-4-0XOBENZOTHIENO~2,3-d]-
PYRIMIDINE-2-CARBO m IC ACID DISODIUM SALT DIHYDRATE CI~H1ON~O~S-2Na-2H20.-
The product of Procedure 2, 12.0 g. (0.043 mole) and 4.0 g. (0.10 mole)
of sodium hydroxide is dissolved in a mixture of 440 ml. of water and
160 ml. of ethsnol and heated on a steam bath until dissolved. Following
dlssolution of the starting material, there i8 a transient precipitation
of the monosodium salt of the product. This material redissolves as
heating is continued until a clear solution finally results. The
solution is stirred at room temperature for 6 hrs. while the desired
disodium salt precipitates. The product is collected on a filter and
sir-dried, yield 10.4 g. (73%). This product failed to melt on heating
in a capillary tube at 355C.
Nl~R ~DMSO-d6): 2 81 (m,4), 1.78 (m,4). Infrared (KBr):
2940, 1630, 1580~ 1550, 1490, 1435, 13~0, 1350, 1320, 1275, 105~, 810,
and i68 ~m. 1.
Anal. found: C, 40.27; H, 3.63; N, 8.40.
- 24 -
10~ i3
Procedure 4. ETHYL S-MF-T~L-6-OCTYL-4-OX0-4R-THIENO-
~2,3-d~[1,3~0XAZTNE-2-CA~BOXYL~TE.- To a suspension of 2-amino-4-
methyl-5-(n-octyl)thiophene-3-carboxylic acid hydrate (~H20),
6.88 g. (0.025 mole), in 25 ml. of dry pyridine which is first
cooled to 0 C. there is added 6.92 g. (0.051 mole) of ethyl
oxalyl chloride in drop-wise fashion. The mixture is stirred at
25 C. for 1 hr. after the addition is complete and then poured
into 1 1. of cold water. The product precipita~es and is
recovered by extraction with octane; yield 6.4 g. (73%), re-
crystallized from low boiling petroleum ether, white crystals,
m.p. 66.0-69.0 C.
NMR (CDClj): 4.48 (q.2, J = 7.1 Hz), 2.81 ~t,2, J = 6.8 Hz),
2.45 (s,3), 1.44 (t,3, J ~ 7.1 Hz), 1.28 (m,12), and 0.88 (m,3).
Infrared (KBr): 2960, 2930, 2860, 1765, 1742, 1588, 1468, 1448, 1368,
1310, 1198, 1150, 1100, 1020, and 770 cm. 1.
Anal. found: C, 61.48; H, 7.21; N, 3.89.
Procedure 4 may be modified by employing 2-~C(ethoxy-
carbonyl)carbonyl]amino]-4-methyl-5-octylthiophene-3-carboxylic acid
as starting material and employing one equivalent of ethyl oxalyl
chloride to effect the cyclization.
Procedure 5. ETHYL 3,4-DIHYDRO-5-METHYL-6-OCTYL-4-
OXOTHIENO[2,3-d~PYRIMIDINE-2-CARBOXYLATE.- A mixture of 5.54 g.
(0.016 mole) of the product of Procedure 4, 1.10 g. ~0.0143 mole)
of ammonium acetate, and 0.385 g. (0.0064 mole) of acetic acid in
50 ml. of absolute ethanol is heated on a steam bath for 40 min.
Upon cooling, the de~ired product crystallizes in the form of
needles which are collected on a filter and dried, yield 4.39 g.
(?9%). After recrystalli~ation from isopropanol, the material was
obtained as off-white needles, m.p. 136.0-137.0C.
10940fi3
NMR ~CDC13): 4.51(q.2, J=7.1 Hz), 2.80~t,2, J~ 6.8 Hz),
2.53(s,3), 1.46(t,3, J=7.1 Hz), 1.30(m,12), 0.89(m,3).
Infrared (~Br): 3180, 3100, 3040, 2925, 2850, 1740, 1680,
1570, 1492, 1470, 1370, 1305, 1193, and 1033 cm. 1
Anal. found: C, 61.53; H, 7.37; N, 8.01.
Procedures 6-12. Additlonal Thienyloxamates. By adaptatlon
of the method of Procedure 1 to the appropriately substituted 2-amino-
thiophene-3-carboxamides, the following correspondingly substituted
ethyl N-C3-(aminocarbonyl)thien-2-yl3Oxamates are prepared. The
physical properties and recrystallization solvents are noted
following the name of each of these substances in Table I.
Table I. Thienyloxamates
Procedure No. Name
6 ETHYL C3-(AMINOCARBONYL)-5-PHENYLTHIEN-2-YL]OXAMATE.
Recrystallized from ethanol-lsopropanol, m.p. 198-
200 C.
Anal. found: C, 56.70; H, 4.56; N, 8.87
7 ETHYL N-[3-(AMINOCARBONYL3-4-METHYL-5-PHENYLTHIEN-2-YL~-
OXAMATE.- Recrystallized from dimethylformamide-
ethanol, m.p. 175-176 C.
8 ETHYL N-[3-(AMINOCARBONYL)-5-HEXYL-4-METHYLTHIEN-2-YL]-
OXAMATE.- Recrystallized from isopropyl acetate-
isopropyl ether, m.p. 147-149 C.
Anal. found: C, 56.31; H, 7.24; N, 8.25.
Hydrolysis of this substance yields N-C3-Aminocarbonyl)-
5-hexyl-4-methylthien-2-y~oxamic acid sodiu~ salt,
C~4H~,N~Q4S-Ns salt, m.p.>350C.
- 26 -
10~0~i3
9 ETHYL ~-C3-(~MINOCARBONYL)-4~ THY.~T~lIEN-2-YL]OXA~TE.-
Recrystallized from dimethylformamide-absolute
ethanol, m.p. 196-198 C.
Anal. found: C, 46.86; H, 4.78; N, 10.76.
ETHYL N-C3-(AMINOCARBONYL)-4-METHYL-5-PENTYLTHI~N-2-
YL]OXAMATE.- Recrystallized from isopropanol, m.p. 153-
154C.
11 ETHYL N-C3-(AMINOCARBON~L)-4^-METHYL-5-t3-METHYL-2-
BUTENYL)THIEN-2-YL]GXAMATE. -Recrystalllzed from iso-
propanol, m.p. 199-200C.
12 ETHYL N-C3-(AMINOCARBONYL)-6-tert-BUTYL-4,5,6,7-TETRA-
-
HYDROBENZO~b]THIEN-2-YL]O ~ATE.- Recrystallized from
- chloroform-ethsnol, m.p. 228.5-231.5 C.
Anal. found: C, 58.28; H, 7.03; N, 7.80.
Procedures 13-19. Additional Thienopyrimidine-2-
Carboxylates by Cvclization of Thienyloxamates.- The products of
the present invention, which are ~isted in Table II, were prepared
by heating the molten thienyloxamates listed in Table I according
to the method of Procedure 2 above. In Table II the figure in
parenthesis following the Procedure No. is the procedure number
for the preparation of the starting material employed.
Table II. Thienopyrimidine-2-Carboxylates
Procedure No. Name
13 (6) ETHYL 3,4-DI~YDRO-4-OXO-6-PHENYLTHIE~0~2,3-d3PYRIMIDI~-
2-CARBOXYLATE.- P~ecrystallized from acetonitrile, yellow
cry~talline solid, m.p. 228.0-232.0~ C.
NMR (CDCl~): 10.80 (bs,1), 7.71 (s,1), 7.45 (m,5), 4.52
(q,2, J - 7.0 Hz), and 1.48 (t,3, J = 7.0 Hz).
10~ 3
Infrared ~XBr): 3440, 3090, 3050, 1720, 1667, 1560, 1468,
1440, 1365, 1178, 1030, 840, 750, and 684 cm. 1.
Anal. found: C, 59.87; H, 4.03; N, 9.32.
14 (7) ETHEL 3.4-DIHYDRO-5-~THYL-4-OXO-6-PHENTYLTHIENOC2,3-d~-
PYRI~IIDINE-2-CARBOXYLATE.- RecrYstallized from dimethyl-
formamide-ethanol, m.p. 225.5-227.5C., yellow crystal-
line solld.
NMR (CDCl~): 10.40 (bs,1), 7.39 (m,5), 4.51 (q,2, J =
7.1 Hz), 2.65 ~s,3), 1.47 (t.3, J - 7.1 Hz).
lQ Infrared ~KBr): 3160, 3090, 302Q, 2980, 2930, 1727, 1665,
1565, 1480, 1368, 1300, 1175, 1030, 1005, 778, 760, 737,
and 695 cm.~1.
Anal. found: C, 61.02; H, 4.38; N, 8.87.
15 (8) ETHYL 3,4-DIHYDRO-6-HEXYL-5-METHYL-4-OXO~HIENO~2,3-d]-
PYRIMIDINE-2-CARBOXYL~TE.- Recrystallized from isopro-
panol, yellow needles, m.p. 134.0-135.0C.
NMR (CDCl9): 10.33 (bs,1), 4.49 (q.2, J = 7.1 Hz),
2.79 ~t,2, J = 7.0 Hz), 2.50 ~s,3~, 1.43 (t,3, J =
7.1 Nz), 1.36 (m,8), 0.88 (m,3).
Infrared (KBr): 3100, 2020, 2840, 1734, 1672, 1565,
1488, 1460, 1365, 1300, 1185, and 1030 cm.
A . found: C, 59.90; H, 6.92; N, 8.61.
16 (9) ETHYL 3~4-DIHYDRO-5--METHYI~-4-OXOTHIENOL2,3-d~PYPlMIDI~E-
2-CARBOXYLATE.- Recrystallized from ethanol, pale
yellow crystals, m.p. 151.5-162.0C.
NMR (DMSO-d~): 12.50 (bs,1), 7.33 (q,1, J = 1.1 Hz),
4.37 (q,2, J = 7.1 Hz), 2.50 (d,3, J - 1.1 Hz) and
1.35 ~t,3, J - 7.1 Hz).
- 2~ -
fi3
Infra~ed (KBr): 31~0, 3080, 1732, 1672, 1570, 1490,
1370, 1300, 1285, 1180, 1155, 1035, and 1010 cm. 1.
Anal. found: C, 50.24; H, 4.22; N, 11.72.
17 (10) ETH~L_3,4-DI~YDP~0-5-METHYL-4-OXO-6-PENTYLTHIENOr2.3-~ -
S PYRIMIDINE-2-CARBOXYLATE.- Recrystallized from isopro-panol, ollve-green crystals, m.p. 152.5-153.5 C.
NMR (CDCl~): 9.80 (bs,1), 4.52 (q,2, J = 7.2 Hz), 2.81
(t,?, J ~ 6.5 Hz), 2.52 (s,3), 1.46 (t,3, J - 7.2 Hz)
1.38 (m,6), and 0.91 (m,3).
Infrared (KBr): 3080, 3020, 2950, 2920, 2842, 1738,
1675, 1568, 1490, 1365, 1300, 1090, and 1030 cm.
Anal. found: C, 58.42; H, 6.65; N, 9.19.
18 (11) ETHYL 3,4-DIHYDRO-5-METHYL-6-(3-METHYL-2-BUTENYL)-4-
OXOTHIENOC2,3-d]PYRIMIDINE-2-CARBOXYLATE.- Chromato-
-
graphed on silica gel and eluted with chloroform.
Evaporatlon of solvent ylelded an oil with fsiled to
crystallize. The nuclear magnetic resonance spectrum
indicated that the product was a mixture of the above
named compound and the -6-(3-methyl-1-butenyl)isomer.
19 (12) ETHYL 7-t-BUTYL-3.4.5.6.7.8-HEXAHYDRO-4-OXOBENZOTHI~NO-
C2,3-d]PYRIMIDINE-2-CARBOXYLATE.- Chromatographed on
~llica gel (hexane) and eluted with ether. Recrystal-
lized from isopropanol, pale yellow powder, m.p. 180.0-
183.0C.
NMR (CDCl9): 10.30 (bs,1), 4.50 (q,2, J - 7.1 Hz),
2.80 (m,4), 2.03 (m,3), 1.45 (t,3, J = 7.1 Hz), and
0.95 (s,9).
Infrared (KBr): 2930, 1730, 1662, 1362, 1300, 1281,
--1
1180, and 1029 cm.
Anal. found: C, 61.30; H, 5.60; N, 8.35.
- 29 -
lO~ fi3
Procetures 20-26. Thienooxazine-2-carboxylic Acids.-
The following thienoo~azines are prepare~ by substitution of the
appropriately substituted 2-aminothiophene-3-carboxylic acids ~n the
method of Procedure 4. The thienooxazines are listed in Table III
with their physical properties and procedural modifications where
such are required.
Table III. Th_enooxazine-2-Carboxylic Acids
Procedure No. Name
ETHYL 5,6,7?8-TETRAHYDRO-4-OXO-4H-BENZ0THIENO[2,3-d]-
~1,3]0XAZINE-2-CARBOXXLATE. Recrystallized from
isopropyl acetate as the hydrate (1/4 H2O), yellow
solid, m.p. 148.5-180.5C.
NMR (DMSO-d6): 4.32 (q,2, J ~ 7.1 Hz), 2.79 (m,4),
1.79 (m,4) and 1.33 (t,3, J - 7.1 Hz).
I~frared (RBr): 2990, 2950, 2880, 1767, 1740, 1640,
1582, I560, 1460, 1372, 1350, 1300, 1185, 1150, 1090,
1020, ant 768 cm 1.
Anal. found: C, 55.23; H, 5.06; N, 4.96.
21 ETHYL 6-ETHYL-5-METXYL-4-OXO-4H-T~IENO[2,3-d][1,3]-
OXAZINE-2-CARBOXYLATE.- 1:1 pyridine-acetonitrile was
used as reaction medium; chromatographed on silica
gel (CHC13): recrystallized from isopropyl ether,
light yellow needles, m.p. g7.5-99.5~C.
NMR (DMSO-d6): 4.36 (q,2, J ~ 7.1 H2), 2.88 (q,2,
J s 7.1 Hz), 2.38 (s,3), 1.32 (~,3, J = 7.1 Hz), and
1.22 (t,3, J s 7.2 Hz).
Infrared (KBr): 2980, 1778, 1760, 1590, 1544, 1470,
1450, 1390, 1320, 1275, 1210, 1170, 1110, 1025, ~54,
924, 915, and 771 cm 1.
Anal. found: C, 54,27; H, 4.94; N, 5.13.
- 30 -
, -
~-J f~;'
10~ 3
22 ETHYL 5-~TIIYL-6-(2-MEl`HYLPROPYL)-4-OXO-4H-THIENO~2,3-d]-
~1,3]0XAZINE-2-G~ BOXYLATE.- Recrystalllze~ hexane,
m.p. 78.5-79.5C.
NMR (DMSO-d6): 4.35 (q,2, J = 7.0 Hz), 2.72 (d,2, J =
6.8 Hz), 2.38 (s,3), 1.87 (m,1), 1.32 (t73, J = 7.0 Hz),
and 0.92 (d,6, J = 6.5 Hz).
Infrared (~Br): 2960, 2935, 2880, 1764, 1740, 1592,
1470, 1374, 1320, 1196, 1160, 1102, and 770 cm. 1.
Anal. found: C, 57.31; H, 5.77; N, 4.84.
23 ETHYL 6-ETHYL-4-OXO-4H-THIENO[2,3-d]C1,3~0XAZI~E-2-
CARBOXYLATE.- 13:1 acetonitrile-pyridine was used as
react~on medium; recrystallized from ethyl acetate-
low boiling petroleum ether, light yellow needles,
m.p. 109.0-111.0C.
NMR (CDCl~): 7.18 (m,1), 4.48 (q,2, J = 7.1 Hz),
2.92 (m,2), 1.43 (t,3, J - 7.1 Hz), and 1.36 (t,3, J =
7.2 Hz).
Infrared ~KBr): 3110, 3000, 1982, 1773, 1752, 1590,
1540, 1375, 1331, 1314, 1215, 1172, 1090, 844, and 769 cm.
Anal. found: C, 51.93; H, 4.26; N, 5.55.
24 ETHYL 6-ACETYL-5-METHYL-4-OXO-4H-TE~IENOC2,3-d]c1,33-
_ OXAZINE-2-cARgoxYLATE~- 3:8 pyrid'ne-aceton~trile was
used ~s reaction medium; chromatographed on silica gel
(CHCl~), recrystallized chloroform-hexane, pale yell~w
platelets, m.p. 102.0-103.0C.
NMR (CDCl3): 4.50 (q,2, J = 7.1 Hz), 2.89 (s,3), 2.62
~s,3), 1.46 ~t,3, J = 7.1 Hz).
Ir.frared (KBr): 2992, 1770, 1752, 1671, 1594, 1510, 1312,
1274, 1238, 1188, 1131, 929, 770, and 574 cm.
Anal. found: C, 51.03; H, 3.92, N, 4.86.
-
lO.'?'~Q1~3
ETHYL 3 ~-DIHY~RO-5 6-DIMETHnL-4-~XOTHIENOr2,3-dlr1.31-
O.YAZINE-2-CARBOXYL~TE.- 2:1 pyrid~ne-acetonit_ile was
used as reactlon medium; recrystallized ethanol, dark
brown crystals, m.p. 129-130C.
NMR (CDCl,): 4.409 (q, 2, J Y 7.2 Hz), 2.44 (s,6),
1.44 (t,3, J - 7.2 Hz).
~nfrared (KBr): 3002, 2980, 1774, 1748, 1590, 1554,
1460, 1372, 1322, 1294~ 1208, 1170~ 1110, 1030, 958,
872, and 775 cm.
Anal. found: C, 51.95; H, 4.49; N, 5.30.
26 ETHYL 6-HEXYL-5-METHYL-4-OXO-4H-THIENO[2,3-d][1,3~-
OXAZINE-2-CAR80XYLATE.- 5:1 acetonltrile-pyridine was
used as reaction medium; recrystallized from low boiling
petroleum ether-ethyl ether, light tan solid, m.p.
56.5-57.0C.
NMR (C~Cl~): 4.63 (q,2, J = 7.0 Hz), 2.92 (t,2, 3 -
6.8 Hz), 2.47 ~s,3), 1.46 (t,3, J = 7.0 Hz), 1.36 (m,8),
and 0.90 (m,3).
Infrared (KBr): 2950, 2920, 2850, 1750, 1580, 1465, 144C,
1370, 1318, 1278, 1205, 1160, 1096, 1016, 920, 906, and
765 cm. 1.
Anal. found: C, 59.44; H, 6.42; N, 4.26; S, 10.01.
Procedures 27-31. Additional Thienopyrimidine-2-carboxylates
From Thieno-oYazine-2-carboxylates.- The method of Procedure 5 is
adapted to the preparation of the compounds listed in Table IV by
sub6titution of the appropriately substituted thieno-oxazine-~-
carboxylate 8S stsrting material. The products produced are identified
in Table IV along with informstion as to purification and identi-
fication. The number in parenthesis next to the ProcedurP ~o
identifies the proce~ura for prepara~ion of the startlng material.
The starting materlals are listed in Table III.
Table IV. Thienopyrimidine-2-Carboxyla es
Procedure No. Name
527 t21) ETHYL 6-ET1~YL-3,4-DIHYDRO-5-METHYL-4-OXOTHIE~0[2,3-d
.
PYRIMIDINE-2-CARBOXYLATE.- Recrystalllzed from absolute
ethanol, white flakes, m.p. 148.5-173.5 C.
NMR tCDCl~): 4.51 (q,2, J-7.1 Hz), 2.85 (q,2, J=7.3 Hz),
2.25 (s,3), 1.46 (t,3, J=7.1 Hz), and 1.30 (t,3, J=7.3 Hz).
Infrared ~K~r): 3180, 3100, 2060, 2930, 1i30, 1680, 1555,
1488, 1460, 1368, 1300, 1186, and 1032 cm. 1.
A . found: C, 54.17; H, 5.50; N, 10.029.
28 (22) ETHYL 3,4-DIHYDR0-5-METHYL-6-(2-METHYLPROPYL)-4-OX0THIEN Q
.
C2,3-d]PYRIMIDINE-2-CARBOXYLATE.- Recrystallized fro~
isopropanol, off-white crystals, m.p. 175-176C.
NMR (DMSO-d6): 12.40 (bs,1), 4.36 (q,2, J~7.1 Hz),
2.68 (d,2, J=6.7 Hz), 2.43 (s,3), 1.88 (m,l), 1.34
(t,3, J=7.1 Hz), and 0.92 (d,6, J=6.5 Hz).
Infrared (KBr): 3090, 2960, 2930, 2870, 1740, 1675,
1570, 1490, 1467, 1383, 1369, 1305, 1194, 1034, and
768 ~
Anal . found:
29 (23) ETHYL 6-ETHYL-3,4-DIHYDR0-4-OXOTHIEN0C2,3-d~PYRI~lIDINE-2-
CARB0XYLATE.- Recrystallized from ethanol, pale yellow
needles, m.p. 163.0-168.0C.
NlIR (CDCl,): 10.30 (bs,1~, 7.26 (t,l, J=1.1 Hz), 4.55
(q,2, J=7.0 H2), 2.92 (m,2~, 1.48 ~t,3, Js7 0 Hz) and
1.38 (t,3, J=7.2 Hz).
- 33 -
O~i3
In~rared (KBr~: 3180, 3120, 3045, 2980, 2945, 2890, 1749,
1694, 1579, 1949, 1376, 1315, 11~4, 10~6, 852, 848, and
770 cm. 1.
An21. found: C, 52.48; H, 4.84; N, 11.21.
30 ~24) ETHYL 6-ACETYL-3,4-DIHYDRO-5-~IET~ m -4-OXOTHIENO~2,3-d}
PYRIMIDINE-2-CARBOXYLATE.- Recrystallized from dimethyl-
formamide-ethanol, off-white needles, m.p. 236.0-242.0C.
NMR (DMSO-d~): 12.30 t~s,1j, 4.38 (q,2, J=7.0 Hz),
2.84 (8, 3), 2.58 (s,3) and 1.35 (t,3, J=7.0 Hz).
Infrared (KBr): 3100, 2980, 1732, 1697, 1655, 1572, 1512,
1430, 1368, 1310, 1233, 1185, and 1027 cm.
Anal. found C, 51.17; H, 4.15; N, 9.90.
31 (25) ETHYL 3,4-DIHYDRO-5,6-DIMETHYL-4-OXOTHIENO~2,3-d]-
PYRIMIDINE-2-CARBOXYLATE.- Recrystallized from aceto-
nitrile, bro~Jn crystalline solid, m.p. 211.5-212.5C.
NMR tCDCl9): 10.60 (bs,1), 4.60 (q,2, J=7.2 Hz),
2.54 (s,3), 2.45 (s,3), and 1.47 (t,3, J=7.2 Hz).
Infrared (KBr): 3170, 3100, 2992, 2920, 1736, 1680,
1562, 1490, 1362, 1298, 1188, 1162, 1035, 1019, and
775 cm.l.
Anal. found: C, 52.14; H, 4.62; N, 10.89.
Procedure 32. 3 4 5 6 7 8-HEXAHYDRO-4-OXOBENZOTHIENO-
.
[2,3-d]PYRIMIDINE-2-CARBOXYLIC AC~D MONOHYDRATE.- The product of
Procedure 3, 5.0 g. i8 dissolved in 150 ml. of warm water znd the
solution clarified by flltration. The filtrate is acidified with
~lacial acetic acid and refrigerated overnight. The precipitate is
collected, washed ~n the filt2r with water and dried, cream colored
fiolid, m.p. 254.5-256.5 C.
- 34 -
10~40~3
NN~ (DMS0-d~): 2.84 (m,4) r 1.79 (m,4).
Infrsred (KBr): 3470, ~100, 3020, 2940, 1695, 1650, 1490,
1440, 1300, 1197, 1145, 1033, 9~0, and 720 cm. 1.
Anal. found: C, 49.39; H,`4.20; N, 10.33.
Procedures 33-45. Additional Thienopyrimidine- -carboxylic
Acid Netal Salts.- The method of Procedure 3 is applied to various other
thienopyrimidine-2-carboxylic esters w~eh the production of various salts.
The substances produced are listed in ~able V along with reference to the
source of the starting material identified by procedure number shown in
parenthesis ad~acent to the Procedure No., and the analytical infor-
mation with respect to these products.
Table V. Salts
Procedure No. Name
33 (5) 3.4-DIHYDRO-5-METHYL-6-OCTYL-4-OXOTHI~NO[2.3-~ PYRIMIDINE-
2-CARBOXYLIC ACID DISODIUN SALT HYDRATE C.~H~N~O~S-~Na-H~O.
Failed to melt at 300C.
N~ (DMSO-d6): 2.79 (t,2 J = 6.9 Hz.), 2.45 (s,3),
1.26 (m,12), and 0.86 (m,3).
Infrared (KBr): 2980, 2945, 2876, 1660, 1630, 1580, 1553,
1493, 1445, 1392, 1360, 1060, and 814 cm.
Anal. found: C) 49.81; H, 5.75; N, 7.05.
34 (13) 3~4-DTHYDRO-4-OXO-6-PHENYLTHIENOC2,3-d~PYRIMIDINE-2-
CARBOXYLIC ACID SODIUM SALT HEMIHYDRATE Cl3H~N2O9S-Na-~H~O.-
.
Crude disodium salt prepared as in Procedure 3 was
di6solved in warm water and carefully acidified with
acetic acid until 8 white precipitate formed; white
powder, m.p. 292.0-294.0~C. (dec.).
10!~40fi~
N~ IIS0-d~: 7.80 (s,~), 7.71 (m,2) and 7.38 (m,3).
Infr~red (KEr): 3430, 3230, 1660, 1465, 1440, 1360, 1290,
1180, 1040, 310, 750, 7C0, and 685 cm. 1.
Anal. found: C, 51.61; H, 3.33; N, 9.08.
35 (14) 3,4-DIHYDRO-5-METHYL-4-OXO-6-PHENYLTHIENO[2,3-dl-
_.
PYRIMIDINE-2-CARBOXYLIC ACID DISODIUN SALT HYDRATE
C,4~ON2O~S.2Na.H~O.- Failed to mele at 350C.
N~MR (CF9COOH): 7.46 (s,5), 2.71 (s,3).
Infrared (KBr): 345G, 2970, 2930, 1620, 1570, 1490, 1440,
1385, 1365? 1295, 1070, 1050, 810, 765, 750. and 700 cm.
Anal. found: C. 48.14; H, 2.83; N, 8.C7.
36 (15) 6-HEXYL-3 4-DIHYDRO-5-~TXXL-4-OXOTHIENO~2,3-d]-
~Y~IMIDINE-2-CARBOXYLIC ACID DISODIUM SALT HYDRATE
CI~HlON2O9s~2Na.l/4H2o.- Isopropanol added to induce preci-
pitation; recrystallized from hot water; pale yellow solid,
falled to melt at 360C.
NMR (CF3COOH): 3.02 (t,2, J=6.5 Hz), 2.63 (s,3), 1.46
(m,8), and 0.94 (m,3).
Infrared (XBr): 2960, 2930, 2860, 1650, 1565, 1480,
1379, 1045, and 785 cm. 1.
Anal. found: C, 49.31; H, 5.30; N, 8.18.
37 (16~ 3,4-DIHYDRO-5-~ETHYL-4-OXOTHIENOC2,3-d]PYRI.MIDINE-2-
-
CARBOXYLIC ACID DISODIU~ SALT DIHYDRATE C~H6N2O3S-2~a-2H~O -
Product recovered by evaporation of solvent and tritura-
tion of residue with hot methanol; off-white powder,
failed to melt at 300C.
NMR (D~O): 6.84 (m,1), 2.49 (m,3).
- 36 -
iO~:?40fi3
In~rared ~KBr~: 2940, 1660. 1630, 1582, 1539, 1S10, 1490,
1439, 1390, 1380, 1350, 12g80, 1076, 1055, 814, 801, 620 cm.
Anal. found: C, 33.40; H, 2.13; N, 9.44.
38 (17) 3,4-DIHYDRO-5-METHYL-4-OXO-6-PENTYLTHIENO~2,3-~ PY~IMIDINE-
2-CARBOXYLIC ACID DISODIUM SALT SESQUIH~DRATE C,3H16N~O3S- Na-
l~H~O. Light yellow solid, failed to melt at 350C.
NMR: 3.00 (t,2, J z 6.5 Hz), 2.62 (9,3), 1.50 (m,6) and
0.96 (m,3).
Infrared (KBr~: 2960, 2924, 2878, 2860, 1654, 1620, 1571,
1482, 1438? 1384, 1370, 1350, 1050, and 805 cm. 1.
Anal. found: C, 44.46; H, 4.85; N, 7.90.
39 (18) 3,4-DIHYDRO-5-METHYL-6-(3-METHYL-2-BUTENYL)-4-OXOTHIENO-
[2,3-d~PYRIMIDINE-2-CARBOXYLIC ACID DISODIUM SALT SESQUI-
HYDRATE CI~H14N203S-2Na-l~H20.- Precipitated from reaction
after evaporation of alcohol by additlon of lsopropanol;
yellow solid, failed to melt at 350C.
NMR (CF~COOH): 6.70 (m,2), 5.55 (m,1), 3.72 (m,3), 2.71
(8,6), 1.85 (m,6), and 1.22 (d,6, J = 6.5 Hz).
Infrared (KBr): 3420, 2965, 2925, 1655, 1625, 1572, 1432,
1384, 1370, 1350, 1050, and 805 c~.
Anal. found: C, 44.37; H, 3.94; N, 7.88.
40 (19) 7-t-BUTYL-3,4,5,6,7,8-~EXAHYDRO-4-OXOBENZOTHIENOC2,3-d]-
PYRIMIDINE-2-CARBOXYLIC ACID DISODI~M SALT DIHYD ATE,
C~5H,6N2O9S-2Na-2H~O.- Dlmethyl3ulfoxide was added to
the reaction mixture for solubilization; product precipi-
tated with isopropanol; failed to melt at 300C.
N~ (CF~COOH):2.98 (m,4), 2.18 (m,2)~ 1.67 (m,l), and
1.02 (s,9). Infrared (KBr): 2960, 1650, 1600, 1572,
10~40fi3
1540, 1479, 1430, 1382, 1317, 1045, and 780 cm. 1.
~nsl. found: C, 46.76; H, 4.92; N, 7.01.
41 (25) 3,4-DI~rY~RO-`5,6-DIMhTHYL-4-OXOTHIENOC2r3-d]PyRI~IIDINE
2-CARBOXYLIC ACID DISODIUlM SALT SESO~UIHYDRATE
C~H~N2O3S-2Na-1~H2O.- Product preclp~tated from aqueous
reaction mixture with isopropanol; gray solid, failed
to melt at 350C.
NMR (CF~COOH): 2.64 (s,6). Infrared (Kbr): 2920, 1650,
1620, 1578, 1550, 1484, 1430, 1~84, 1380, 1350, 1280,
1200, 1050, and 807 cm. 1.
Anal. found: C, 3665; H, 2.90; N, 9.36.
42 (27) 6- ETHYL-3,4-DIHYDRO-5-METHYL-4-OXOTHIENO~2,3-d3PYRIMIDINE-
2-CARBOXYLIC ACID DISODIUM SALT DIHYDRATE CIOH1ON2O3S-2Na-
_
2H20.- Isopropanol was added to the resction mixture to
induce crystallzation of the product; white solid, failed
to melt at 360C.
NMR (D~O): 2.95 (q,2, J=7.2 Hz), 2.49 (9,3), 1.30 (t,3,
J~7.2Hz). Infared (KBr): 2975, 2940, 1650, 1620, 1570,
- 1540, 1484, 1435, 1386, 1355, 1320, 1278, 1050, 808 c~.-1.
Anal. found: C, 37.73; H, 3.41; N, 8.46.
43 ~28) ~4-DIHYDRO-5-METHYL-6-(2-METHYLPROPYL)-4-OXOTHIENO-
r2.3-dlPYRIMIDINE-2-CARBO m IC ACID DISODIUM SALT
SESQUIHYDRATE C12HI4N2O3S.2Na-1t~H2O.- Product preci-
pitated from the reaction mixture on addition of isopro-
2S panol; white solid, failed to melt at 350C.
N~R ~CF9COOH): 2.89 (d,2, J=7.0Hz), 2.63 (s,3), 1.95
(m,2), 1.41 ~m,l), 1.05 (d,6 J=6.5 Hz).
- 3~ ~
~0~4Q~3
Infrared (KBr): 2950, 2922, 2865, 1650, 1620, 1565,
1530, 1465, 1380, 1355, 1200, 1045, and 802 cm. 1.
Anal. found: C, 42.81, H, 4.62; N, 8.35.
- 44 (2~) 6-RTHYL-3,4-DIHY~RO-4-OXOTHIEN0~2,3-d~PYRIMIDINE-2-
-
S ARBOXYLIC ACID DISODIUM SALT DiHYDRATE C9H8N20,S-2Na-2H20.-
Methanol was used as reactlon solvent; white powder,
failed to melt at 360C.
NMR (D~O): 6.89 (s,l), 2.68 (q,2, J=7.2Hz), 1.12 (6,3, J=7.2Hz).
Infrared (KBr): 3440, 2980, 2942, 16S0, 1580, 1540, 1498,
1428, 1350, 1050, 854, 800, and 758 cm. 1.
Anal. found: C, 35,63; H, 3.07; N, 9.12.
45 (30) 6-ACETYL-3,4-DIHYDRO-5-METHYL-4-OXOTHIENOC2,3-d]PYRIMIDINE-
2-CARBOXYLIC ACID DISODIUM SALT SESQUIHXDRATE CloH~N204S-
2Na-l~iH~O.- Yellow solid which fails to melt at 360C.
NMR (CF~COOH): 3.10 (s,3), 2.83 ~s,3).
Infrared (KBr): 3460, 1665, 1633, 1580, 1484, 1438,
1370, 1350, 1305, 1259, 1060, and 812 cm. 1.
Anal. found: C, 37.20; H, 2.65; N, 8.36.
! 46 (58) E-3-(3,4,5,6,7,~-HEXAHYDRO-4-OXOBENZOTHIENOC2,3-d~
PYRIMIDIN-2-YL~-2-PROPENOIC ACID DISODIUM SALT
HYDRATE C1gH1ON2O3S.2Na.3.5H2O.- Product precipitated
by treatment of the reaction mixture with isopropanol;
tan solid, failed to melt at 300C.
NMR (DMSO-d~): 6.98 (s,2), 2.80 (m,4), 1.75 (m,4).
Infared (KBr): 3400, 2930, 2850, 1652, 1565, 1540, 1395,
1290, 11SO, g68, and 806 cm. 1
Anal. found: C, 40.50; H, 4.~0; ~, 7.12.
fi3
47 ~51) 5-AMnLN0-6-ETHYL-3,4-DIHYDRO-4-OgOTHIENO~2,3-d]PYRIMlDrNE-
2-CARBO m IC ACID DISODIUM SALT SESQUI~YDRATE
C9H~N~O~S-2Na-1.5HlO.- Methanol used as reaction
medium; product precipitated with isopropanol; yellow
powder, failed to melt at 250C.
NMR (DMSO-d6): 2.84 (q,2, J~7.2 Hz), 1.25 (t,3,
J~7.2 8z).
Infrared (KBr): 3405, 2975, 1655, 1625, 1590, 1538,
1505, 1410, 1360, 1295, 1050, 809, and 765 cm 1.
Anal. fount: C, 35.34; H, 3.35; N, 13.20.
Procedure 48. ETHYL 3,4-DIHYDR0-5-METHYL-6-NITR0-4-OXOTHIENO-
[2~3-d]PYRrMm INE-2-CARBOXYLATE.- The product of Procedure 16, 1.0 g.
is dissolved in 10 ml. of trifluoroacetic acid and 5 ml. of acetic
anhydride is added to the mixture while it is cooled at -15C. A
lS solution of 1.2 ml. of concentrated nitric acid in 4 ml. of trif1uoro-
acetic acid is then added drop-wise to the solution with stirring at a
temperature of -12 to -15C. After a finely divided yellow precipitate
forms, water, 100 ml., is added to the reaction mixture, and the pre-
cipitate is collected on a filter. This material is the desired product
which is recrystallized from ethanol, m.p. 229-229.5C.
Anal. found: C, 42.23; H, 3.32; N, 14.84.
Procedure 49. ETHYL 6-A~IN0-3,4-DIHYDRO-5-METHYL-4-OXOT~IEN0-
[2,3-d]PYRIMIDINE-2-CARBOXYLATE.- The product of Procedure 48, 2.10 g.
is dissolved in 100 ml. of dry dimethylformamide and hydrogenated at
atmospheric pressure over 1 g. of a 10~ dispersion of palladium carbon.
Approximately 5 min. is required for absorption of the calculated
quantity of hydrogen by the reaction solution. The catalyst is
removed by filtration and the filtrate is poured into 1 1. of
-- ~0 --
~?40fi3
cold water. The product is recovered from the aqueouq solution by
extractlon with chloroform, and the orange solid remaining on evapora-
tion of the solvent ls triturated with isopropanol, and recrystallized
from methanol, yellow needles, m.p. 199.5-215.0C.
NMR (DMSO-d6): 11.40 (bs.l), 6.20 (bs,2), 4.30 (q,2, J=7.0 Hz),
2.25 (s,3), and 1.30 (t,3, J=7.0 Hz). Infrared (KBr): 3422, 3315, 3190,
2996, 1728, 1645, 1622, 1552, 1450, 1365, 1335, 1280, 1180, 1032, 1010,
and 770 cm. 1.
Anal. found: C, 47,38; N. 4.33; N. 16.60.
Procedure 50. ETHYL 6-ETHYL-3,4-DIHYDROs5-~ITRO-4-
OXOTHIENOC2,3-d]PYRIMIDINE-2-CARBOXYLATE.- The product of Procedure 29,
5 g., is converted to the desired product according to tha method
of ~rocedure 48. The product is a pale yellow solid which is
recrystallized from a mixture of chloroform and ethanol, white
crystals, m.p. 200.0-212.0 C.
NMR (DMSO-d6): 13.40 (bs~l), 4.45 (q,2, J=7.0 Hz), 3.02
(q.2, J=7.2 Hz), 1.39 (t,3, J=7.0 Hz), 1.31 (t,3, J=7.2 Hz).
lnfrsred (KBr): 3190, 3115, 3060, 2995, 2g50, 2900, 1755, 1665, 1550,
1525, 1492, 1373, 1315, 1298, 1192, and 795 cm. 1
Anal. found: C, 43.89; H, 3.67; N, 14.08.
Procedure 51. ETHYL 5-AMINO-6-ETHYL-3,4-~IXYDRO-4-OXOTHIENO-
,3-d~PYRIMIDINE-2-CARBO~YLATE.- The product of Procedure 50 is hydro-
genated according to the method of Procedure 49. Approximately 3 hrs.
is required for the calculated quantity of hydrogen to be absorbed. The
catalyst is removed by filtration and the product recovered by concen-
tration of the filtrate to dryness. The residue is recrystallized from
a mixture of methano' and isopropanol to yield a yellow powder~ m.p.
181.5-184.5C.
~ 41 -
40fi3
NMR (CDCL9~: i0.50 (bs,1), 4.60 (q,2, J37.1 Hz), 4.09 (bs,2),
2.74 (q,2, J-7.2 H7), 1.48 (t,3, J=7.1 Hz)~ 1.33 (tJ3, J=7.2 Hz).
Infrsred (KBr): 3390, 3240, ~965, 2920, 1720, 1700, 1612, 1562, 1491,
1470, 1370, 1305, 1180, 795, and 785 cm. 1.
A . found: C, 49.04; H, 4.88; N. 15.56.
Procedure 52. ETHYL 3,4-DIHYDRO-6-~THYL-S-IODO-4-OXOTHIENO-
C2~3-d]PYRIMIDINE-2-CARBOXY'LATE.- The product of Procedure 29, 2.65 g.
(0.0105 mole), and 10.60 g. (0.034 mole) of mercurlc acetate are
dissolved in 35 ml. of glacial acetic acid and heated on a ~team bath
for 1 hr. The mixture is then poured into 400 ml. of saturated
sotium chlorlde solutlon resultlng ln precipitation of the 5-chloro-
mercurl lntermediàte, m.p. 237C. (dec.). This intermedia;e, 4.10 &--
is then added to a solution of 4 g. of iodine and 10 g. of potassium
iodlde in 150 ml. of water. The mixture is kept at room temperature
with stirring for 3 days and then the purplish-black solid is collected
on a filter and wa~hed with ethanoi to yleld 2.70 g. of tan solid,
fslls to melt at 240C. This material ls recrystallized from methanol
to glve a pale yellow, crystalllne product, m.p. 188.0-190.0C.
Anal. found: c, 35.15; H, 3.10; N, 7.36.
Procedure 53. 2-(HYDROXY~THYL)-5-METHYL-6-(2-~ETHYLPROPYL)-
-
THIEN0[2,3-d]PYRIMIDINE-4-(3H)-ONE.- The product of Procedure 28, 2.0 g.
(0.0069 mole) is added in portlons to a solution of 2.0 g. ~0.052 mole)
of sodiu~. borohydryde in 150 ml. of absolute ethsnol. Poaming occurs
during the addition and the solution turns yellow in color. The
2S mlxture is kept at room tempe.rature with stirring for 2 hrs. It
was then poured into lce water with stlrring snd the ~lxture is
acidifled with glacial acetic acid. The acidified solution
ls then extracted with chlorofor~ and the solvent evaporated from the
l. 7
iO~40fi3
extract to yield a y~llow solid. On recrystallization from ethyl
acetate, the product is obtained as a white crystalline solid, m.p.
182-183 C.
NMR (CDCl,): 4.69 (s,2), 2.56 (t,2, J=6.5 Hz), 2.47 (s,3),
1.80 tm,l), O.9S (d,6, J-6.4 Hz). Infrared (KBr): 3320, 3100, 2960,
2875, 1670, 1592, 1381, 131;, 1210, 1090, and 1037 cm. 1.
Anal. found: C, 57.31; H, 6.45; N, 11.08.
Procedure 54. 2-(t~YDROXXMETHYL)-5-METHYL-6-PENTYLTHIENO-
~2,3-d~PYRIMIDINE-4(3H)-ONE.- This substance was prepared by the method
of Procedure 53 employing as stsrting material the product of Procedure 17.
Recrystallized from ethyl acetate, light yellow crystalline solid,
m.p. 158.5-159.5~C.
NMR (CDClg): 4.57 (s,2), 2.78 (t,2, J=7.0 Hz), 2.50 (s,3),
1.46 (m,6), 0.93 (m,3). Infrared (KBr): 3350, 2962, 2930, 2860, 1672,
1606, 1442, 1316, 1215, 1120, 1038, and 782 cm. 1
Anal. found: C, 58.83; H, 6.83; N, 20.46.
Procedure 55. 5,6,7,8-TETRAHYDRO-2-(HYDROXYMETHYI)BENZ0-
THIENO~2,3-d]-4(3H)-PYRIMIDINONE.- The product of Procedure 2, 1.0 g.,
i8 suspended in 50 ml. of absolute ehtanol and 2.0 g. of lithium boro-
hydryde is added portionwise thereto. Evolution of 8 g2S occurs andthe mixture is stirred at room temperature for 1~ hrs.and then refluxed
for 20 min. The mixture is poured into 300 ml. of water, and the aqueous
mixture is then acidifled with glacial acetic acid. The desired product
precipitateC snd is collected on a filter as fine yellow needles, re-
crystallized from a mixture of dimethylformamide and ethanol, m.p.262.5-268O5OC.
NMR (DMSO-d~): 5.36 (bs,1), 4.35 (s,2)9 2.76 (m,4), 1.77 (m,4).
Infrared (KRr): 3120, 2940, 2860, 1670, 15~0, 1450, 1350, 1300, 1200,
- 4~ -
i3
115~, 1080, 1040, 970, aos, and 795 cm. 1
Anal. found: C, 56.02; H, 5.Q9; N, 11.88.
Procedure 56. 6-HEXYL-2-(HYDRO.YYMETHYL~-5-'lFTHYITHTENO-
~2,3-d]PYRIMIDINE-4-(3H)-ONE.- The method of Procedure 53 is spplied
to the product of Procedure 15 for the production of this substance;
recrystallized from ethyl acetate; light tan powder, m.p. 136.0-140.0C.
NMR (DMSO-d~): 11.30 (bs,1), 5.22 (bs,l), 4.33 (s,2), 2.71
(t,2, J~6.6 Hz), 2.38 (s,3)~ 1.31 (m,8), 0.85 (m,3). Infrared (KBr):
3180, 1950, 2920, 2844, 1670, 1595, 1460, 1309, 1208, 1115, 1020, 770 cm. 1
Anal. found: C, 59.76; H, 6.98; N, 9.83.
Procedure 57. (3,4,5,6,7,8-HEXAHYDRO-4-OXOBENZOTHIENOC2,3-dl-
PYRIMIDIN-2-YL)2IETHYL ACETATE.- The product of Procedure 55, O.68 g.,
~0.Q0288 mole) i9 dissolved in 30 ml. of acetonitrile containing 5 ml.
of acetic anhydryde snd 5 ml. of pyridine, and heated for 30 min. at 100C.
The mixture i8 then poured into 150 ml. of cold water yielding the desired
product as a pale yellow solid which is recrystallized from ethyl acetate;
light yellow needles, m.p. 202.0-204.0~C.
NMR (CDCl,): 11.20 (bs,2), 5.08 (s,2), 2.90 (m,4), 2.20 (s,3),
1.86 (m,4). Infrared (KBr): 3125, 3020, 2g50, 2900, 1760, 1673, 1612,
1281, 1260, 1239, 1050 cm. 1
Anal. found: C, 55.93; H, 5.12; N, 10.25.
Procedure 58. ETHYL 3-(3,4,5,6,7,8-HEXAHYDRO-4-oXOBENZO-
THIENO[2,3-d]PYRIMIDIN-2-YL)-~-PP~OPENOAT~.- A solution of sodium
ethoxide in ethanol is prepared from 3.05 g. of sodium and 100 ml.
of ethanol. A mixture of 24.5 g. (0.125 mole) of the product of
Procedure 1 and 21.6 g. (0.125 mole) of diethyl fumarate i~ 300 ml.
of ethanol is then added with the formation of a red solution which
is stirred at the reflux temperature overnight. The mixture is then
0~3
allowed to cool to room temperature and ls poured lnto 1 1. of water
containing 9 g. of acetic acid. The yellow precipitate forms during
stirring for 1.5 hours at room temperature and it is collected by
filtration; wa~hed on the filter with water and dried, yellow solid,
m.p. 285-287 C.
NMR tCF9COOH): 7.78 (d,l, J=16.1 Hz), 7.42 (d,1, J=16.1 Hz),
4.53 (q,2, J=7.2 Hz), 3.05 (m,4), 2.02 (m,4), 1.50 tt,3, J=7.2 Hz).
Infrared (KBr): 3100, 2952, 1727, 1668, 1560, 1471, 1374, 1302, 1255,
1221, 1194, 1168, 990 and 970 cm. 1
Anal. found: C, 59.06; H, 5.25; N, 9.16.
Procedure 59. ETHYL tE)~3-(3,4,5,6,7,8-HEXAHYDRo-4-oXoBE~ZC-
THIENOr2,3-d~rl,310XAZIN-2-YL)-2-PROPENCATE.- To a suspension of 0.985 g.
(0.005 mole) of 2-amino-4,5,6,7-tetrahydrobenzoC~thiophene-3-carboxylic
acid in 10 ml. of acetonitrile containing 1.2 ml. of pyridine which
ls cooled at 0C., there is added with stirring 1.63 g. (0.010 mole)
of ethyl furmaryl chloride. A clear solution forms on completion of
the addition of the ethyl fumaryl chloride and the reaction mixture
is stirred for an addit~onal 1.5 hrs. at ice bath temperature.
Stirrlng is continued overnight at room temperature and the precipi-
tated solid is then collected by filtration and washed with ether,
and finally with aqueous hydrochloric acid, aqueous potassium bicarbonate,
and water. This material is purified by recrystallization from iso
propanol and washed on the filter with isopropyl ether and low boiling
petroleum ether; yellow crystaline solid, m.p. 147.5-148.5 C.
NMR (CDCl~): 7.16 (d,2, J=15.5 hz), 6.89 (d,1, J=15.5 Hz),
4.25 (q,2, J-7.1 Hz), 2.84 (m,4), 1.85 (m,4), 1.31 (t,3, J=7.1 Hz).
Infrared (KBr): 2945, 2930, 2862, 1770, 1715, 1650, 1550, 1464, 1430,
1292, 1255, 1172, 974, and 768 cm. 1.
Anal. found: C, 58.78; H, 4.97; N, 4.59.
- ~5 -
4Q~`'3
Procedure 60. ~-ETHYL-2-(Hk~ROXYMET~L)TITJE~0[2,3-d~-
PY~RIMIDINE-4-(3H)-ONE.- The method of Procedure 53 is applied to the
product of Procedure 29 to yield the deslred product, recrystallized
from 3:1 ethyl acetate:ethanol, m.p. 201.5-202.5C.
NMR ~DMSO-d6): 12.00 (bs,l), 7.12 (s,l), 5.64 (t,l, J = 5.2 Hz),
4.47 td,2, J = 5.2 Hz), 2.90 (q,2, J = 7.1 Hz), 1.30 (t,3, J ~ 7.1 Hz).
Infrared (RBr): 1083, 1140, 1153, 1200, 1279, 1300, 1366, 1428, 1461,
1485, 1535, 1567, 1584, 1640, 1675, 2829, 2844, 2871, 1938, and 2967 cm. 1.
- Anal. found: C, 51.19; H, 4.69; N, 13.25.
Procedure 61. ETHYL 6-HEXYL-4-OXO-4H-THIENO[2,3-d~1,3]-
OXAZINB-2-CARBOXYLATE.- This product is obtained by application of
the method of Procedure 4 to 2-amino-5-(n-hexyl)thiophene-3-carboxylic
acid. The ethyl oxalyl chloride is dissolved in acetonitrile prior
to addition to the amlnothiophene carboxylic acid which is dissolved
ln pyridine. The product is recovered as a light green solid which is
recrystallized from ethanol, m.p. 80-81C.
NMR (CDCl,): 7.30 (s,l), 4.58 ~q,2, J = 7.0 Hz), 2.93 (t,2,
J - 7.1 Hz), 1.48 (t,3, J - 7.0 Hz), 1.40 (m,8), 0.92 (m,3).
lnfrared (~Br): 1285, 1308, 1366, 1388, 1436, 1462, 1478, 1541, 1586,
20~ 1715, 2829, 2861, and 2879 cm 1
Anal. found: C, 58.52; H, 6.16; N, 4.48.
Procedure 62. ETHYL 3,4-DIHnORO-6-HEXYL 4-OXOTHIENO[2~3-d]-
PYRIMIDINE-2-CARBOXYLATE.- The product of Procedure 61 is treated with
ammonium acetate and acetic acid in ethanol as described in Procedure 5
to yleld this product, m.p. 114-115C.
NMR (CDCl,): 11.00 (bs,1), 7.34 (s,l), 4.62 (q,2, J = 7.0 Hz),
2.94 (t,2, J ~ 7.2 Hz), 1.50 (t,3, J = 7.0 Hz), 1.41 (m,8), 0.92 (m,3).
- 46 -
~` Infrared (RBr): 1035, 1104, 1149, 1195, 1221, 1241, 1313, 1373, 1401,
1415, 1481, 1569, 1689, 1741, 2834, 2865, and 2880 cm. 1.
Anal. found: C, 58.49; H, 6.60; N, 9.29.
Procedure 63. ETHYL 6-CHLORO-3,4-DIHYDRO-5-~ETHYL-4-OXO-
THIENO[2,3-d]PYRIMIDINE-2-CARBOXYLATE.- The product of Procedure 49,
0.01 mole, is dissolved in 20 ml. of lOZ aqueous fluoboric acid and
cooled to 0 C. A solution of sodium nitrite, 0.01 mole, in 5 ml. of
water is added in drop-wi~e fashion. The mixture is stirred at 0C.
for 30 min. and then the bulky precipitate of 2-carbethoxy-3,4-
10 dihydro-5-methyl-4-oxothieno[2,3-d]pyrimidin-6-yl diazonium fluoborate
18 collected on a filter and sir dried. The latter, 0.01 mole, is
then added in portion-wlse fashion to 8 solution containing a stoichio-
metric excess of cuprous chloride in concentrated hydrochloric acid
at 0 C. When all of the tiazonium salt had been added, the tempera-
ture was allowed to warm to 20 C. and the mixture was then poured
into ice water and the product filtered yielding the desired 6-chloro
compound.
Procedure 64. ETHYL 6-ETHYL-3,4-DIHYDRO-5-HYDROXY 4-OXOTHIENO-
C2~3~d~pyRIMIDINE-2-cARBoxyLATE~- The diazonium fluoborate salt is
prepared as in Procedure 63 from the amino compound produced in Proce-
dure 51 yielding 0.03 mole of the required diazonium fluoborate. The
latter is added in one portion to a solutlon of 0.03 mole of potassium
trifloroacetate in 13 ml. of trifloroacetic acid at 0C. The mixture
is stirred at 25C. .or one hour and then refluxed overnight. The tri-
floroacetic acid is evaporated in vacuo to give a residue which istrlturated with water and filtered to give the desired product.
- ~7 -
0~3
Procedure fi5. ~lllyL 6-ET~YI.-3,4~ R~-5-.`~THO~Y-4-OXOTHIENO-
C2,3-d]PYRIMIDI~E-2-CARBOXYLAT~.- The product of Procedure 64, 0.01 mole
is dissolved in 100 ml. of ether containing 1 chemical equivalent of
boron trifluoride etherate relative thereto and the solution is cooled
to 0 C. with stirring. A solution of 0.011 mole of diazomethane in
50 ml. of ether is then added portion-wise and the mixture is stirred
st 0 C. until the yellow color disappears. Evaporation of the solvent
yields the decired 5-methoxypyrimldine compound.
Procedure 66. 5 ? 6,7,8-TETRAHYDRO-~-(5-TETRAZOLY~)BENZOTHIENO-
~2~3-d3PYRIMIDINE-4-(3H)-ONE.- The product of Procedure 2, 1.0 g.
(0.0036 mole) is added to 30 ml. of concentrated aqueous ammonia.
Sufficient ethanol is then added to form a clear solution and the
mixtura is clarified by filtration of a small amount of insoluble
material. The solution is kept 4 hours at room temperature while a
pale yellow precipitate forms. The latter is collected by filtra-
tion and air dried to yield 0.80 g. of 3,4,5,6,7,8-hexahydro-4-oxo-
benzothieno[2,3-d]pyrimidine-2-carboxamide, pale yellow solid,
m.p. 278.0-281.0 C. (dec.).
NMR (CDCl,): 12.48 (s,l), 8.30 (s,l), 7.90 (s,l), 2.75 (m,4),
20 1.75 (m,4). Infrared (KBr): 1690 cm.
Anal. fount: C, 53.12; H, 4.45; N, 16.93.
The latter, 0.01 mole, is then added to a mixture of 5 g.
of phosphorous pentachloride in 10 ml. of phosphorous oxachloride.
After the initial exothermlc reaction subsides, the mixture is
heated at 120 C. for 1 hour and then poured into $ce water and
the insoluble material collected on the filter. The collected
material ~s air dried to yield 4-chloro-2-cyano-5,6,7,8-tetrahydro-
4-oxoben~othienoC2,3-d~pyrimidine-4-(3H~-one. The latter is dissolved
-- ~lS --
? ~ ``3
ln 100 ml. of dim~thy1ormamide contalnlng 1.5 g. of sodium azide
and 1.0 g. of an~monium chloride. The mixture is heated for 24 hours
at 105-110 C. The mixture is poured into ice water and the pre-
cipitated 4-azido-2-(5-tetrazolyl)-5,6,7,8-tetrahydrobenzothieno-
C2,3-d]pyrimidine-4-(3H)-one is collected. The latter on hydrolysis
with 2 chemical equivalents of sodium hydroxide dissolved in ethanol
yields the desired product as the sodium salt.
Procedure 67. 5,6,7,8-TET'~AHYDRO-2- N-(TETR~ZOL-5-YL)-
GAR8AMYL BENZOTHIEN~C2,3-d~PYRIMIDINE-4-(3H)-O~.- The product of
Procedure 32 is treated with 20 ml. of thionyl chloride at room
temperature until gas evolution ceases. The excess thionyl chloride
18 then evaporated _ vacuo and the residual acid chloride is
dissolved in 25 ml. of dry dimethylformamide. 5-Aminotetra~ole,
0.01 mole, i8 then added to the mixture which is stirred at room
temperature for 1 hour and then heated on the steam bath for 2 hours.
The mi~ture is then poured into water and filtered to yield the
desired product.
Procedure 68. 3-BUTYL-3,4,5,6,7,8-HEXA'~YDRO-4-OXOBENZO-
THIEN0[2,3-d]PY~IMIDINE-2-CARB0XYLIC ACI'~ SODI'~M SALT 'nE~IHYDRATE
C1sHI~N2O~S-Na~l/2H2o~- A mixture of 2.79 g. (0.01 mole) of the product
of Procedure 20 and 0.73 g. (0.01 mole) of n-butylamine in 50 ml. of
absolute ethanol is heated on a steam bath at reflux temperature for
4 hrs. The mixture is then poured into 500 ml. of cold water and ex~
tracted with chloroform. The extract is dried over magnesium sulfate
and concentrated in vacuo to give 2.83 g. of a brown oil whicn
crystalizes. The crystalline mass is tritrated with 1:1 ether-low
boiiing petroleum e~her and the crystalline material is removed by
filtration. The mother liquor is then concentrated in vacuo to a
_ ~,9 _
0~3
brown oil which i9 chromatographed on silica gel using 1:1 ether-low
boiling petroleum ether for development to yield 1.52 g. of the
desired product as the ethyl ester. The latter is saponified according
to the method of Procedure 3 and the resulting sodium salt is re-
crystallized from i~opropanol-ether to yield O.90 g. (59%) of the
desired product AS an off-white powder, m.p. 265.0-28S.0C. (dec.).
NMR (D~O): 4.04 (m,2), 2.58 (m,4) 1.62 (m,8), 0.92 (m,3).
Infrared (KBr): 2930, 2860, 2680, 2635, 1530, 1450, 1390, 1370, 1190,
1150, 1135, 905, 821, 780 and 744 cm. 1.
Anal. found: C, 53.17; H, 5.31; N, 8.01.
Procedure 69. 6-ETHYL-3,4-DIHYDRO-3-METHYL-4-OXOTHIE~O-
C2,3-dJPYRIMIDINE-2-CARBOXYLIC ACID SODIUM SALT.- The method of Proce-
dure 68 is applied to the oxazine produced by Procedure 23 with sub-
stitution of methylsmine for the butylamine used in Procedure 68 to
y$eld the desired product.
Procedure 70. ETHYL 3,4-DIHYDRO-6-FLUORO-5-METHYL-4-OXOTHIENO-
C2,3-d]PYRIMIDINE-2-CARBOXYLATE.- 2-Carbethoxy-3~4-dihydro-5-methyl-4-
o~othienoC2,3-d~pyrimidin-6-yl diazonium fluoborate, 0.03 mole, is
prepared as described in Procedure 63. The latter is then heated in an
oil bath with adequate ventilation to carry off the boron tr fluoride
liberated by this treatment. A temperature of about 150C. is
sufficient and heating is continued until gas evolution is no longer
evident. The res~due is cool~d, tritrated with water, and filtered
to yield the des~red compound.
Procedure 71. 3,4,5,6,7,8-PEXAHYDRO-4-OXOBENZOTHI~NOr2,3-d~-
PYRIMIDINE-2-CARBOXALDEHYDE.- To a solution of 0.01 mole of the product
of Procedure 55, and 0.3 mo7e of dicyclohexylcarbodiimide in 100 ml~ of
- 50 -
10~ ~01~3
dlmethyl sulfoxide therc is added 0.01 mole of anhydrous orthophosphoric
acid. The mixture is stirred at room temperature for 4 hrs. and 250 ml.
of ethyl acetate is then added ~hereto followed by a solution of 25 g.
of oxalic acid in methanol. Insoluble by product dicyclohexylurea is
removed by filtration. The filtrate is washed with dilute aqueous
sodium bicarbonate solution, the organic layer separated, and dried
over magnesium sulfate. Evaporation of the solvent in vacuo affords
the desired product.
Procedure 72. ETHYL 5,6-DIHYDRO-4-OXO-4H-CYCLOPE~TA[b~-
THIENYL[2,3-d]~1,3]0XAZINE-2-CARLOXYLATE.- Procedure 4 is adapted to
the preparation of this product by using 2-amino-4,5-dihydrocyclopenta-
Cb~thiophene-3-carboxylic acid as starting material.
Procedure 73. ETHYL 3,4,5,6-TETRAHYDRO-4-OXOCYCLOPENTA-
Cb]THIENO[2,3-d~PYRI~IDINE-2-CARBOXYLATE.- The oxazine produced in
Procedure 72 is converted to this product by the method of Procedure 5.
Procedure 74. ETHYL 3,4,5,6-TETRAHYDRO-4-OXO-CYCLOHEPTACb]-
THIENO[2,3-d]C1,3]0XAZINE-2-CAR80XYLATE.- The method of Procedure 4 is
adapted to the preparation of this substance by substitution of 2-amino-
4,5,6,7-tetrahydrocycloheptaCb]thiophene-3-carboxylic acid as the
starting materlal.
Proceture 75. ETHYI 3,4,5,6,7,8-HEXA~DRO-4-OXOCYCLOHEPTA[b~-
THIENO[2,3-d]PYRIMIDINE-2-CARBOXYLATE.- The product of Procedure 74 is
converted to thi substance by the method of Procedure 5.
Procedure 76. (3,4,5,6,7,8-HEXAHYDRO-4-OXOBENZOTHIENOC2,3-d~-
PYRIMIDIN-2-YL)METHYLFORMATE.- The product of Procedure 55, 0.01 mole,
is dissolved in a mixture of 30 ml. of acetic anhydride and 15 ml. of
lOOh' formic acid at 0C. The mixture is then allowed to warm to room
- 51 -
~3
temperature with stirrlng dur ng a period of 1 hr. It is then poured
lnto 200 ml. of ice water and the formate ester is collected.
Procedure 77. N-~3-(AMINOCARBONYL)-4,5,6,7-TETRAHYDROBENZO-
Cb]THIEN-2-YL10XAMIC ACID.- A suspension of 392 g. (2.0 mole) of 2-amino-
4,5,6,7-tetrahytrobenzo ~]thiophene-3-carboxamide and 321.2 g. t2.2 mole)
of diethyl oxylate in 5 1. of absolute ethanol is added to a solution of
sodium ethoxide, ~repared from 50.6 g. (2.2 g. atoms) of sodium, in 2 1.
of absolute ethanol under nitrogen. The mixture is stirred with heating
at the reflux temperature for 6 hrs. and then refrigerated overnight.
It is then diluted with stirring to 15 1. with cool water. A finely
divided precipitate forms which is removed by filtration. The filtrate
is carefullly acidified with 150 g. (2.5 mole) of acetic acid dissolved
in 350 ml. of water. The resulting product which precipitates is
collected on a filter, washed with water and air dried to yield 194.6 g.
(0.7 mole) of the product of Procedure 2. The filtrate is acidified to
pH 2 with concentrated hydrochloric acid and the resulting precipitate is
collected on a filter, washed with water and air dried to gi~e 264.8 g.
(0.99 mole) of the desired product. A portion thereof weighing 25 g.
ls recrystallized from 1.4 1. of dioxane, yield 18.2 g., m.p. 223.5-224.5C.
(dec.).
NMR (DMSO-d6): 7.45 (s,2), 1.79 (B,8). Infrared (KBr): 3520,
3360, 3190, 2950, 2860, 1730, 1640, 1565, 1530, 1460, 1410, 1360, and
1290 cm. 1.
Anal. found: C, 49.04; H, 4.47; N, 10.25.
Procedure 78; Table~s for Oral In~estion.- The following
~ngredients are blended in the dry state in a twin-shell blender and
compressed on a tabiet press using an 11~32 inch die and concave punches.
~O~ i3
Product of Procedure 29 50.0 g.
SucrQse pregranulated for
direct compression210.0 g.
Corn starch 6.0 g.
Microcrystalline cellulose 40.0 g.
Magnesium stearate 1.0 g.
This batch size is for 1,000 tablets and provides a tablet weighing 307 mg.
supplying 50 mg. of active ingredient per tablet. Tablets containing
from 25-200 m8. may be made employing the same ingredients, but ad~usting
the weight and tablet size appropriately.
Procedure 79. Solutlon for Iniection.- The following ingredients
are dissolved in sufficient water for in~ection to make l.0 1. and the
sol~tion is filtered through a membrane filter having a pore size of 0.45 ~m.
Product of Procedure 44 0.2-5.0 g.
Sodium chloride to make
lsotonic qs
Sodium phosphate buffered
to pH 7.5
The filtered solution is filled into clean sterile smpules and flame
sealed- followed by sterilization in an autoclave.
Procedure 80. Powder for Inhalation.- The following ingre-
dients are blended aseptically and filled into hard gelatin capsules,
each containing 50 mg. of the mixture providing 25 ~g. of the active
lngredient.
Product of Procedure 36,
mlcronized 25.0 g.
Lactose powder 25.0 g.
-53 -
fi3
The foregoing ~ suff1cie~ for 1,000 capsules. These capsules are
sultable for dispcnsin~ the powder into the 'nspired air stream using
& breath actuated device. Appropriate adiustments of ~he composition
can be made to give capsules containing 0.5-40 mg. of active ingredient.
Procedure 81. 3,4-~IHYDRO-6-HEXXI-4-OXOTHIENOr2,3-d]PYRIMIDINE-
2-CARBOXYLIC ACID DISODIUM SALT HYDRATE Cl,HI4N209S~2~a-2-l/2H20.-
The method of Procedure 3 is applied to the product of Procedure 62. At
the conclusion of the reaction period the product is precipitated by
adding isopropanol to the reaction mixture. A white gelatinous pre-
cipitate forms and is collected on a filter and dried.
NMR (CF~COOH): 7.52 (s,l), 3.10 (t,2, J = 7.1 Hz), 1.52 (m,8),
0.93 (m,3). Infrared (KBr): 1265, 1346, 1375, 1429, 1471, 1495, 1579,
1605, 1660, 2828, 2861, and 2880 cm. 1.
Anal. found: C, 42.34; H, 4.70; N, 7.42.
Procedure 82. 2~ YDROXY~THYL)-6-HEXYLTHIENOC2,3-d~PYRIMIDINE-
4-(3~)-ONE. - The product of Procedure 62 i~ converted to this substance by
the method of Procedure 53. The product is a tan solid.
NMR (CDClQ): 11.60 (bs,1), 7.14 (8,1), 4.79 (s,2), 2.82 (t,2),
1.40 (m,8), 0.91 (m,3), Infrared (KBr): 1300, 1467, 1590, 1610, 1660,
2822, 2860, and 2878 cm. 1.
The compound of Procedure 28, and the disodium salt of
the corresponding carboxylic acid described in Procedure 43, are pre-
ferred species as inhibitors of the imn~ediate hypersensitivity reaction.
The corresponding dipotassium salt, which is described below in Pro-
cedure 97, is par~icularly preferred for inhibition of the immediate
~40fi3
hypersensitivity reaction in mammal~ where allergic rhinitis is the
maniestation. Due to its potency and water solubility the latter is
suited for use as a nasal solution for application as drops, spray, or
aerosol to the nasal mucosa. A pot~der composition for deposition on
the nasal mucosa following insufflation similar to that of Procedure 80
except for micronizatlon may be employed. For deposition on the
nasal mucosa, a larger particle size of about 100~ is preferred.
Systemlc routes of administration including oral~ rectal, buccal and
parenteral may also be employed. The dipotassium salt (Procedure 97)
exhibits the following ID50 values in the PCA test described on pages 7-9
in rats: oral, 2.7 mg./kg.; intravenous, 0.14 mg./kg.
A publication describing work which is chemically related to
the present disclosure is Arya, V.P., Indian Journal of Chemistry, 10,
1141-1150 (1972) which discloses the substance described abo~e in
Procedure 2.
The following procedures describe additional compounds and
compositions falling within the scope of the invention.
Procedure 83. Ethyl N-C3-(Aminocarbonyl)thien-2-yl]oxamate.-
The method of Procedure 1 is applied to 2-aminothiophene-3-carboxamide
to yield the desired product which is recrystallized from acetonitrile,
m.p. 186.0-187Ø
Anal. Found: C, 44.52; H, 4.16; N, 11.56.
NMR (DMSO-d6): 1.34 (t, 3, 7.0 Hz), 4.48 (q, 2, 7.0 Hz), 7.26 (d, 1, 6.0 Hz),
7.65 (d, 1, 6.0 Hz), 7.80 (bs, 1), 8.19 (bs, 1), and 13.6 (bs, 1).
25 IR- ~KBr): 3415, 3390, 3180, 1730, 1685, 1650, 1590, 1550, and 1280
cm
- 55 -
0~3
This substance exhil~i~s oral ED50 ~ 4.5 m~./kg. of body
weight in the rat PCA test for antiallergic activity described on
pages 7-9 hereof.
Procedure 84. Ethyl 4-Oxo-6-pentyl-4H-thienoC2,3-d][1,3]oxa-
zine-2-carboxylate.- The method of procedure 4 is applied to 2-amino-5-
pentylthiophene-3-carboxylic acid to yield the desired product as a
crystalline solid; recrystallized from di-isopropyl ether, m.p. 69.6-
7o~so~
Anal. Foulld: C, 56.88; H, 5.62; N, 4.66.
10 NMR (CDC13): 0.90 (t, 3, 6.0 Hz), 1.40 (m, 6), 1.47 (t, 3, 7.0 Hz),
2.93 (t, 2, 7.0 Hz), 4.58 (q, 2, 7.0 Hz), and 7.31 (s, 1).
IR (KBr): 3100, 2960, 1770, 1590, 1470, 1430, 1320, 1130, 960, and
770 cm 1.
Procedure 85. Ethyl 4-Oxo-6-propyl-4H-thieno[2,3-d]~1,3]oxa-
lS zine-2-carboxylate.- The method of Procedure 4 is applied to 2-amino-5-
propylthiophene-3-carboxylic acid. The resulting product is recrystallized
from di-isopropyl ether, m.p. 90.5-91.5C.
~nal. Found: C, 53.61; H, 4.88; N, 5.22.
NMR (CDC13): 1.03 (t, 3, 7.0 Hz), 1.50 (t, 3, 7.1 Hz), 1.87 (m, 2,),
20 2.92 (t, 2, 7.0 Hz), 4.60 (~, 2, 7.1 Hz), and 7.34 (s, 1).
IR (KBr): 3120, 1800, 1750, 1375, 1330, 1170, 945, 840, and 765 cm 1.
Procedure 86. Ethyl 6-Isoprop~1-4-oxo-4H-thieno~2,3-d~[1,3~-
oxazine-2-carboxylate.- The method of Procedure 4 is applied to
2-am~no-5-isopropylthiophene-3-carboxylic acid for the production of
the desired product which is recrystallized from di-isopropyl ether,
m.p. 87.5-88.5C.
Anal. Found: C, 53.76; H, 4.79; N, 5.15.
0~3
NMR (CDC13): 1.42 (d, 6, 6.5 ~Iz), 1.48 (t, 3, 6.6 Hz), 3.27 (septet, 1,
6.5 Hz), 4.57 (q, 2, 6.6 ~z), and 7.32 (s, 1). IR (KBrj: 2980, 1780,
1740, 1585, 1475, 1430, 1315, 1205, 1160 and 760 cm 1.
Procedure 87. Ethyl 6-Butyl-4-oxo-4H-thienoC2,3-d~[1,3 }
oxazine-2-carboxylate.- The method of Procedure 4 is applied to
2-amino-5-(n-butyl)thiophene-3-carboxylic acid. The resulting product
is recrystallized from di-isopropyl ether, m.p. 76.0-77.5C.
Anal. Found: C, 55.42; El, 5.24; N, 4.93.
-
NMR (CDC13): 0.96 (t, 3, 6.6 Hz), 1.50 ~t, 3, 7.1 Hz), 1.60 (m, 4),
2.92 (t, 2, 7.2 Hz), 4.57 (q, 2, 7.1 Hz), and 7.33 (s, 1).
IR (KBr): 3100, 2980, 1770, 1590, 1430, 1370, 1320, 1130, 960, and
770 cm 1.
Procedure 88. Butyl 6-Ethyl-3,4-dihydro-4-oxothienoC2,3-d]-
R~rimidine-2-carboxylate.- The product of procedure 29, 5.0 g. (0.019
mole) is dissolved in 20 ml. of butanol and 0.5 g. of p-toluenesulfonic
acid is added thereto. The mixture is refluxed for 3 hrs., filtered
while hot, and the product, which crystallizes on cooling, is collected
and recrystallized from butanol, m.p. 116.0-118.0C.
Anal. Found: C, 56.06; H, 5.73; N, 10~14.
NMR (CDC13): 1.03 (t, 3, 6.3 Hz), 1.42 (t, 3, 7.0 Hz), 1.81 (m, 4),
3.02 (q, 2, 7.0 Hz), 4.61 (t, 2, 6.0 Hz~, 7.50 (s, 1), and 11.6 (bs, 1).
IR (KBr): 3100, 2g70, 1745, 1680, 1660, 1480, 1290, 1185, 840 and
770 cm
Procedure 89. Ethyl 3,4-Dihydro-4-oxothienoC2,3-d]pyrimidine-
2-carboxylate.- The product of Procedure 83 is converted to thls
substance by adaptation of the method of Procedure 2. The product is
purified by cromatography on silica gel using chloroform for elution,
and recrystallized rom isopropanol, m.p. 191.0-192.0C.
O~i3
Anal. Folmd: C, 47.78; H, 3.80; N, 12.19.
NMR (CDCl3): 1.50 (t, 3, ~.0 Hz), 4.66 (~, 2, 7.0 Hz), 7.60 (d, l,
6.0 Hz), 7.76 (d, 1, 6.0 Hz), and 10.8 (bs, 1). IR ~KBr): 3080, 1745,
1680, 1580, 1480, 1460, 1380, 131Q, 1190 and 1040 cm l
Procedure 90. Ethyl 6-Ethyl-3,4-dih~dro-3-methyl-4-oxothieno-
[2,3-d]pyrimidine-2-carboxylate.- The method of Procedure 69 is repeated
except that the saponification step following chromatography is
omitted and two molecular equivalents of acetic acid relative to the
oxazine starting material produced in Procedure 23 is included in the
reaction mixture, The desired product is obtained as a dark oil.
Anal. Found: C, 53.86; H, 5.65; N, 9.58.
NMR (CDC13): 1.36 (t, 3, 7.0 Hz), 1.49 (t, 3, 7.0 Hz), 2.91 (q, 2,
7.0 Hz), 3.72 (s, 3), 4.56 (q, 2, 7.0 Hz), and 7.31 (s, 1?.
IR (KBr): 2970, 1735, 1690, 1560, 1535, 1370, 1290, 1240, 1105 and
15 1020 cm l.
Procedure 91. Ethyl 3,4-Dihydro-6-methyl-4-oxothienoC2,3-d]-
pyrimidine 2-carboxylate.- The method of Procedure 5 is applied to
ethyl 6-methyl-4-oxo-4H-thienoC2,3-d]C],3]oxazine-2-carboxylate
employing ethyl acetate as solvent. The product is recovered as a
20 crystalline solid which may be recrystallized from 95% ethanol, m.p. 204.0-
208.0C
Anal. Found: C, 50.13; H, 4.13; N, ]1.69.
NMR (DMSO-d6): 1.36 (t, 3, 7.0 Hz), 2.55 (s, 3), 4.36 (q, 2, 7.0 Hz),
7.26 (s, 1), and 13.0 (bs, 1). IR (KBr): 3280, 3000, 1750, 1710,
25 1480, 1310, 1285, 1180, 1025, 845, and 760 cm 1.
- 58 -
fla-`~3
Proce(~ure _ Ethyl 3,4-Dihydro-6-(1-methylethyl)-4-oxothicno-
~2,3-d]pyrimidine-2-carboxylate.- The product of Procedure 86 is
converted to the desired product by refluxing with ethanolic ammonium
acetate and acetic acid according to the method of Procedure 5. The
product is recrystallized from ethanol, m.p. 182-183C.
Ana~. Found: C, 54.01; H, 5.19; N, 10.42.
NMR (CDC13): 1.40 (d, 6, 6.5 Hz), 1.51 (t, 3, 7.0 Hz), 3.21 (septet, 1,
6.5 Hz), 4.52 (q, 2, 7.0 Hz), 7.33 (s, 1), and 10.6 (bs, 1).
IR (KBr): 3100, 2960, 1740, 1690, 1570, 1480, 1300, 1185, 1050, and
765 cm 1.
Procedure 93. 3,4-Dihydro-6-(1-methylethyl)-4-oxothieno-
.
C2,3-d~pyrimidine-2-carboxylic Acid Disodium Salt.- The product of
Procedure 92 is hydrolyzed with ethanolic sodium hydroxide according
to the method of Procedure 3. The cooled reaction mixture is
diluted with isopropanol and the product collected on a filter. It
is air dried and ground in a mortor. lt fails to melt when heated
in a capillary tube at 350 C. The elemental analysis corresponded to
the hydrate containing 1.75 moles of water per mole of the disodium
salt.
Anal. Found: C, 38.28; H, 3.74; N, 8.56.
NM~ (D20): 1.15 (d, 6, 6.5 Hz), 2.90 (m, 1), 7.20 (s, 1) and 4.80;
IR (KBr): 2860, 1650, 1570, 1425, 1365, 1340, 1060, 840 and 790 cm
Pro edure 94. Ethyl 6-Butyl-3,4-dihydro-4-oxothienor2,3-d~-
pyrimidine-2-carboxylate.- The product of Procedure 87 is treated
with ethanolic ammonium acetate containing acetic acid according to
the method of Procedure 5. The product is recrystallized from ethanol-
isopropanol, m.p. 144-145C.
- 5~ -
Anal. Found: C, 55.58; H, 6.02; N, 10.00.
NMR (CDC13): 0.98 (t, 3, o.0 l~z), 1.52 (t, 3, 7.0 Hz), 1.53 ~m, 4),
2.90 (t, 2, 7.0 Hz), 4.70 (q, 2, 7.0 Hz), 7.40 ~s, 1), 11.3 (bs, 1).
IR (KBr): 3110, 2960, 1740, 1670, 1490, 1300, 1180, 1030 and 770 cm
Procedure 95. Ethyl 3,4-Dihydro-4-oxo-6-propylthieno-
~2,3-d~pyrimidine-2-carboxylate.- The product of Procedure 85 is
converted to the desired product by treatment with ethanolic ammonium
acetate according to the method of Procedure 5 except that acetic
acid is omitted. The product is recry~tallized from ethanol,
m.p. 169-170C.
Anal. Found: C, 54.49; H, 5.29; N, 10.53.
NMR (CDC13): 1.03 (t, 3, 6.5 Hz), 1.52 (t, 3, 7.0 Hz), 1.88 (m, 2),
2.90 ( t, 2, 6.7 Hz), 4.60 (q, 2, 7.0 Hz), 7.35 (s, 1), and 11.5 (bs, 1).
IR (KBr): 3100, 2960, 1735, 1690, 1570, 1480, 1305, 1185, 1035, and
765 cm 1.
Procedure 96. Ethyl 3,4-Dihydro-4-oxo-6-pentylthien
~d]pyrimidine-2-carboxylate.- The oxazine produced in
Procedure 84 is converted to this product by treatment with ethanolic
ammonium acetate containing acetic acid according to the method of
Procedure 5. The product is recrystallized from a mixture of ethanol
and isopropanol, m.p. 124-125C.
Anal. Found: C, 57.22; H, 6.20; N, 9.52.
NMR (CDC13): G.87 (t, 3, 6.0 l~z), 1.40 (m, 6), 1.47 (t, 3, 7.0 Hz),
2.88 (t, 2, 7.0 Hz), 4.56 (q, 2, 7.0 ~z), 7.32 (s, 1) and 11.7 (bs, 1).
25 IR (KBr): 3100, 2g60, 1760, 1740, 1690, 1490, 1300, ll9Q, 1040 and
770 cm
- 60 -
Procedule 97. 3~4-Dihydro-5-methyl-6-(2-methylpropyl)-4-
oxothienoC2,3-d~pyrimidine-2-carboxylic ~cid nipotassium Salt.-
The product of Procedure 28 is hydrolyzed by treatment of 1.91 g.
thereof with 0.86 g. of potassium hydroxide dissolved in 150 ml. of
isopropanol. The mixture is heated at reflux with stirring for 4 hrs.
It is then allowed to cool and the product collected on a filter.
It is ground in a morter and air dried. It failed to melt when
heated in a capillary tube to 350C. The elemental analysis indicated
that the product was obtained as the hydrate containing 1.75 moles of
water per mole of salt.
Anal. Found: C, 38.66; H, 4.25; N, 7.20.
NMR (D20): 0.88 (d, 6, 6.0 Hz), 1.89 (m, 1), 2.40 (s, 3), 2.61 (d, 2,
6.5 Hz), and 4.80. IR (KBr): 2840, 1650, 1590, 1560, 1535, 1470,
1415, 1340, 1040, and 800 cm 1
1~ Procedure 98. 3,4-Dihydro-3,5-dimethyl-6-octyl-4-oxothieno-
~2,3-d]pyrimidine-2-carboxylic Acid Sodiu~ Salt.- A mixture of 2.34 g.
(0.0064 mole) of the oxazine produced in Procedure 4, 4.47 g. of
40% aqueous methylamine (0.0576 mole), and 5.00 g. (0.0832 mole) of
glacial acetic acid is heated in 40 ml. of absolute ethanol on a
steam bath for 40 min. The mixture is then worked up substantially
as described in Procedure 5 to yield the desired product which melted
at 310.0-315.5C. (dec.). The materiai is obtained as the hydrate
containing 0.25 moles of water per mole of the salt.
Anal. Found: C, 55.36; H, 6.55; ~, 7.70.
25 NMR (DMSO-d6): 0.84 (m,3), 1.30 (m, 12), 2.41 (s, 3~, 2.77 (m,2),
and 3.45 (s, 3). IR (KBr~: 3480, 2940, 2870, 1665, 1650, 1550, 1380,
1330, 1130, 795 and 755 cm 1
Q~
Procedure 99. 6-Hexyl-2-~hydroxymethyl)thieno~2~3-d]-
pyrimidine-4-(3H)one. The product of Procedure 61 is reduced with
sodium borohydride according to the method of Procedure 53. The product
is recrystallized from ethyl acetate, m.p. 141-143C.
Anal. Found: C, 58.84; H, 6.94; N, 10.13.
NMR (CDC13): 0.90 (t, 3, 6.0 Hz), 1.35 (m, 9), 2.81 (t, 2, 7.0 Hz),
4.80 (s, 2), 7.12 (s, 1), and 11.6 (bs, 1). IR (K3r): 3270, 2930,
2860, 1665, 161Q, 1600, 1470, 1300, 840 and 755 cm 1.
Procedure 100. Solution For ~asal Application.- A 1%
solution of the product of Procedure 97 is prepared by dissolving it
in an appropriate quantity of water with an effective amount of pharma-
ceutically acceptable microbial preventative, and sufficient sodium
chloride to provide an isotonic solution. The pH is ad~usted to
pH 9.0 with hydrochloric acid and the product is packaged in bottles
with dropper or spray attachment for nasal application.
