U.S. patent application number 09/731570 was filed with the patent office on 2001-12-13 for 1,3,6,-trihydro-6-aza-3-oxapentalen-2-one derivatives for the treatment of neoplasia.
Invention is credited to Pamukcu, Rifat, Sperl, Gerhard.
Application Number | 20010051651 09/731570 |
Document ID | / |
Family ID | 26870575 |
Filed Date | 2001-12-13 |
United States Patent
Application |
20010051651 |
Kind Code |
A1 |
Sperl, Gerhard ; et
al. |
December 13, 2001 |
1,3,6,-trihydro-6-aza-3-oxapentalen-2-one derivatives for the
treatment of neoplasia
Abstract
1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One Derivatives for
inhibiting neoplastic conditions.
Inventors: |
Sperl, Gerhard; (Horsham,
PA) ; Pamukcu, Rifat; (Spring House, PA) |
Correspondence
Address: |
Robert W. Stevenson
Cell Pathways, Inc.
702 Electronic Drive
Horsham
PA
19044
US
|
Family ID: |
26870575 |
Appl. No.: |
09/731570 |
Filed: |
December 6, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09731570 |
Dec 6, 2000 |
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09258989 |
Feb 26, 1999 |
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6160003 |
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09258989 |
Feb 26, 1999 |
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09174815 |
Oct 19, 1998 |
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5939417 |
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Current U.S.
Class: |
514/412 ;
548/453 |
Current CPC
Class: |
A61K 31/407 20130101;
C07D 491/04 20130101 |
Class at
Publication: |
514/412 ;
548/453 |
International
Class: |
A61K 031/395; C07D
491/048 |
Claims
We claim:
1. A compound of the formula: 5wherein R.sub.1 and R.sub.2 are
independently selected from the group consisting of hydrogen, lower
alkyl, and benzyl; R.sub.3 is selected from the group consisting of
substituted or unsubstituted phenyl, benzyl, pyridinyl, pyrrolyl,
pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl,
piperidinyl, tetrazolyl, morpaolinyl, triazinyl, furfuryl, and
thiophenyl, and lower alkyl, wherein said substitutents are one to
three independently selected from the group consisting of halogen,
lower alkyl, lower alkoxy, amino, lower alkylamino, di-lower
alkylamino, hydroxy, nitro, nitrile, carboxyl, aminosulfonyl, lower
alkyl mercapto, and lower alkylsulfonyl; R.sub.4 is selected from
the group consisting of substituted or unsubstituted phenyl,
benzyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrazolyl,
pyrazolidinyl, imidazolyl, imidazolidinyl, piperidinyl, tetrazolyl,
morpholinyl, triazinyl, furfuryl, thiophenyl, and lower alkyl;
wherein said substitutents are one to three independently selected
from the group consisting of halogen, lower alkyl, lower alkoxy,
amino, lower alkylamino, di-lower alkylamino, hydroxy, nitro,
nitrile, carboxyl, aminosulfonyl, lower alkyl mercapto, and lower
alkylsulfonyl; R.sub.5 is selected from the group consisting of
hydrogen, lower alkyl, halogen, hydroxy, amino, lower alkyl amino,
and dilower alkylamino; Y is selected from the group consisting of
CH.sub.2, C.dbd.O, CH--OH m is an integer from 0-3 X is selected
from the group consisting of CH.sub.2, C.dbd.O, CH--OH, and
SO.sub.2; and n is an integer from 0-2.
2. The compound of claim 1 wherein R.sub.1 and R.sub.2 are
independently selected from the group consisting of hydrogen, lower
alkyl.
3. The compound of claim 2 wherein R.sub.1 and R.sub.2 are both
hydrogen.
4. The compound of claim 2 wherein R.sub.3 is selected from the
group consisting of substituted or unsubstituted phenyl, pyridinyl,
pyrrolyl, pyrazolyl, imidazolyl, triazinyl, furfuryl, and
thiophenyl, and lower alkyl, wherein said substitutents are one to
three independently selected from the group consisting of lower
alkyl, lower alkoxy, amino, lower alkylamino, di-lower alkylamino,
carboxyl, aminosulfonyl, and lower alkylsulfonyl.
5. The compound of claim 3 wherein R.sub.3 is selected from the
group consisting of substituted or unsubstituted phenyl, pyridinyl,
pyrazinyl, pyrimidinyl, and triazinyl wherein said substitutents
are one to three independently selected from the group consisting
of lower alkyl, lower alkoxy, di-lower alkylamino, aminosulfonyl,
and lower alkylsulfonyl
6. The compound of claim 4 wherein R.sub.4 is selected from the
group consisting of substituted or unsubstituted phenyl, pyridinyl,
pyrrolyl, imidazolidinyl, morpholinyl, triazinyl, thiophenyl, and
lower alkyl; wherein said substitutents are one to three
independently selected from the group consisting of lower alkoxy,
amino, di-lower alkylamino, hydroxy, nitrile, carboxyl,
aminosulfonyl, and lower alkylsulfonyl.
7. The compound of claim 5 wherein R.sub.4 is selected from the
group consisting of substituted or unsubstituted phenyl, pyridinyl,
morpholinyl, triazinyl, thiophenyl, and lower alkyl; wherein said
substitutents are one to three independently selected from the
group consisting of lower alkoxy, di-lower alkylamino,
aminosulfonyl, and lower alkylsulfonyl.
8. The compound of claim 6 wherein R.sub.5 is selected from the
group consisting of hydrogen, lower alkyl, hydroxy, and dilower
alkylamino.
9. The compound of claim 7 wherein R.sub.5 is selected from the
group consisting of hydrogen and lower alkyl.
10. The compound of claim 8 wherein Y is selected from the group
consisting of C.dbd.O and CH--OH and m is an integer from 0-2.
11. The compound of claim 9 wherein Y is C.dbd.O, and m is 0 or
1
12. The compound of claim 10 wherein X is selected from the group
consisting of CH.sub.2, C.dbd.O, and SO.sub.2; and n is 0 or 1.
13. A method of treating a patient having neoplasia comprising
administering a pharmacologically effective amount of a compound of
Formula I to the patient with a neoplasia sensitive to such a
compound: 6wherein R.sub.1 and R.sub.2 are independently selected
from the group consisting of hydrogen, lower alkyl, and benzyl;
R.sub.3 is selected from the group consisting of substituted or
unsubstituted phenyl, benzyl, pyridinyl, pyrrolyl, pyrrolidinyl,
pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, piperidinyl,
tetrazolyl, morpaolinyl, triazinyl, furfuryl, and thiophenyl, and
lower alkyl, wherein said substitutents are one to three
independently selected from the group consisting of halogen, lower
alkyl, lower alkoxy, amino, lower alkyl amino, di-lower alkylamino,
hydroxy, nitro, nitrile, carboxyl, aminosulfonyl, lower alkyl
mercapto, and lower alkylsulfonyl; R.sub.4 is selected from the
group consisting of substituted or unsubstituted phenyl, benzyl,
pyridinyl, pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl,
imidazolyl, imidazolidinyl, piperidinyl, tetrazolyl, morpholinyl,
triazinyl, furfuryl, thiophenyl, and lower alkyl; wherein said
substitutents are one to three independently selected from the
group consisting of halogen, lower alkyl, lower alkoxy, amino,
lower alkylamino, di-lower alkylamino, hydroxy, nitro, nitrile,
carboxyl, aminosulfonyl, lower alkyl mercapto, and lower
alkylsulfonyl; R.sub.5 is selected from the group consisting of
hydrogen, lower alkyl, halogen, hydroxy, amino, lower alkyl amino,
and dilower alkylamino; Y is selected from the group consisting of
CH.sub.2, C.dbd.O, CH--OH m is an integer from 0-3 X is selected
from the group consisting of CH.sub.2, C.dbd.O, CH--OH, and
SO.sub.2; and n is an integer from 0-2.
14. The method of claim 13 wherein R.sub.1 and R.sub.2 are
independently selected from the group consisting of hydrogen, lower
alkyl.
15. The method of claim 14 wherein R.sub.1 and R.sub.2 are both
hydrogen.
16. The method of claim 14 wherein R.sub.3 is selected from the
group consisting of substituted or unsubstituted phenyl, pyridinyl,
pyrrolyl, pyrazolyl, imidazolyl, triazinyl, furfuryl, and
thiophenyl, and lower alkyl, wherein said substitutents are one to
three independently selected from the group consisting of lower
alkyl, lower alkoxy, amino, lower alkylamino, di-lower alkylamino,
carboxyl, aminosulfonyl, and lower alkylsulfonyl.
17. The method of claim 15 wherein R.sub.3 is selected from the
group consisting of substituted or unsubstituted phenyl, pyridinyl,
pyrazinyl, pyrimidinyl, and triazinyl wherein said substitutents
are one to three independently selected from the group consisting
of lower alkyl, lower alkoxy, di-lower alkylamino, aminosulfonyl,
and lower alkylsulfonyl.
18. The method of claim 16 wherein R.sub.4 is selected from the
group consisting of substituted or unsubstituted phenyl, pyridinyl,
pyrrolyl, imidazolidinyl, morpholinyl, triazinyl, thiophenyl, and
lower alkyl; wherein said substitutents are one to three
independently selected from the group consisting of lower alkoxy,
amino, di-lower alkylamino, hydroxy, nitrile, carboxyl,
aminosulfonyl, and lower alkylsulfonyl.
19. The method of claim 17 wherein R.sub.4 is selected from the
group consisting of substituted or unsubstituted phenyl,
morpholinyl, triazinyl, thiophenyl, and lower alkyl; wherein said
substitutents are one to three independently selected from the
group consisting of lower alkoxy, di-lower alkylamino,
aminosulfonyl, and lower alkylsulfonyl.
20. The method of claim 18 wherein R.sub.5 is selected from the
group consisting of hydrogen, lower alkyl, hydroxy, and dilower
alkylamino.
21. The method of claim 19 wherein R.sub.5 is selected from the
group consisting of hydrogen and lower alkyl.
22. The method of claim 20 wherein Y is selected from the group
consisting of C.dbd.O and CH--OH and m is an integer from 0-2.
23. The method of claim 21 wherein Y is C.dbd.O, and m is 0 or
1
24. The method of claim 22 wherein X is selected from the group
consisting of CH.sub.2, C.dbd.O, and SO.sub.2; and n is 0 or 1.
Description
[0001] This application is a continuation of U.S. application Ser.
No. 09/258,989 filed Feb. 26, 1999, which is a divisional of U.S.
application Ser. No. 09/174,815 filed Oct. 19, 1998, both of which
are incorporated herein by reference.
TECHNICAL FIELD
[0002] This invention relates to compounds and methods for inducing
or promoting apoptosis and for arresting uncontrolled neoplastic
cell proliferation, methods that are specifically useful in the
arresting and treatment of neoplasias, including precancerous and
cancerous lesions.
BACKGROUND OF THE INVENTION
[0003] Pharmaceuticals that are effective against early stage
neoplasias comprise an emerging and expanding area of research and
potential commercial development. Such pharmaceuticals can delay or
arrest development of precancerous lesions into cancers. Each year
in the United States alone, untold numbers of people develop
precancerous lesions, which exhibit a strong statistically
significant tendency to develop into malignant tumors, or cancer.
Such lesions include lesions of the breast (that can develop into
breast cancer), lesions of the skin (that can develop into
malignant melanoma or basal cell carcinoma), colonic adenomatous
polyps (that can develop into colon cancer), cervical dysplasia
(cervical cancer) and other such neoplasms.
[0004] Such compounds and methods are particularly beneficial to
sub-populations of patients who repeatedly develop precancerous
lesions, and therefore have a statistically higher probability of
getting cancer. Many cancer types (e.g., breast, colon, prostate
etc.) have such patient sub-populations.
[0005] The search for drugs useful for treating and preventing
neoplasias in their earliest stages is intensive because
chemotherapy and surgery on cancer itself is often not effective,
and current cancer chemotherapy has severe side effects. Such
cancer-preventative compounds are also envisaged for recovered
cancer patients who retain a risk of cancer reoccurrence, and even
for cancer patients who would benefit from compounds that
selectively induce apoptosis in neoplastic, but substantially not
in normal cells.
[0006] Because it is believed that chronic administration of
cancer-preventative pharmaceuticals is necessary to inhibit or
arrest the development of neoplasia, standard cancer
chemotherapeutic drugs are not considered appropriate drugs for
cancer chemoprevention because whatever cancer preventative (as
opposed to cancer-fighting) capabilities those drugs may possess do
not outweigh their severe side effects. Most standard
chemotherapeutics are now believed to kill cancer cells by inducing
apoptosis (also sometimes referred to as "programmed cell death").
Apoptosis naturally occurs in many tissues in the body. Apoptosis
plays a critical role in tissue homeostasis, that is, it ensures
that the number of new cells produced are correspondingly offset by
an equal number of cells that die. Apoptosis is especially
pronounced in self-renewing tissues such as bone marrow, immune
cells, gut, and skin. For example, the cells in the intestinal
lining divide so rapidly that the body must eliminate cells after
only three days to protect and prevent the overgrowth of the
intestinal lining.
[0007] Standard chemotherapeutics promote apoptosis not only in
cancer cells, but also in normal human tissues, and therefore have
a particularly severe effect on tissues where apoptosis is
especially pronounced (e.g. hair, gut and skin). The results of
those effects include hair loss, weight loss, vomiting and bone
marrow immune suppression. Thus, standard chemotherapeutics are
inappropriate for cancer prevention, particularly if chronic
administration is indicated.
[0008] Several non-steroidal anti-inflammatory drugs ("NSAIDs"),
originally developed to treat arthritis, have shown effectiveness
in inhibiting and eliminating colonic polyps. Polyps virtually
disappear when the patients take the drug, particularly when the
NSAID sulindac is administered. However, the continued prophylactic
use of currently available NSAIDs, even in high colon cancer-risk
patients, is still marked by severe side reactions that include
gastrointestinal irritations, perforations, ulcerations and kidney
toxicity believed to be produced by inhibition of prostaglandin
synthetase activity ("PGE-2"). Such inhibition is a requirement for
the NSAIDs anti-inflammatory action since elevated levels of PGE-2
are associated with inflammation. PGE-2 plays a protective function
in the gastrointestinal tract, which is the reason such gastric
side effects arise with chronic NSAID therapy, which is rarely
indicated for arthritis sufferers, acute therapy being the norm for
them. However, chronic administration of sulindac is important for
high cancer-risk patients to eliminate and prevent future polyps
which cause gastric side effects in many such patients. Once NSAID
treatment is terminated due to such complications, the neoplasms
return, particularly in high risk patients.
[0009] Compounds such as those disclosed in U.S. Pat. No. 5,643,959
have exhibited advantages in the treatment of neoplastic lesions
since such compounds have been shown to induce apoptosis in
neoplastic cells but not in normal cells in humans (see Piazza et
al. Gastroenterology Vol. 112, A629, 1997). Thus, the severe side
effects due to induction of apoptosis in normal cells by
conventional chemotherapeutics are avoided by these novel
therapeutics (see, Piazza et al. Cancer Research Vol. 57, pp.
2452-2459, 1997). In addition, such compounds do not exhibit the
gastric side effects associated with NSAIDs since such compounds do
not substantially inhibit PGE-2. More potent compounds with such
neoplasia specificity but without substantial PGE-2 activity are
desirable.
SUMMARY OF THE INVENTION
[0010] This invention represents potent compounds that inhibit the
growth of neoplastic cells, for treating patients with neoplastic
lesions. This invention also involves methods for inducing such
specific inhibition of neoplastic cells by exposing such cells to a
pharmacologically effective amount of those compounds described
below to a patient in need of such treatment. Such compositions are
effective in modulating the growth of neoplasms.
DETAILED DESCRIPTION OF THE INVENTION
[0011] As discussed above, the present invention includes compounds
of Formula I below (as well as their pharmaceutically acceptable
salts) for treating a patient with neoplastic, particularly
precancerous, and cancerous lesions: 1
[0012] wherein R.sub.1 and R.sub.2 are independently selected from
the group consisting of hydrogen, lower alkyl, and benzyl;
[0013] R.sub.3 is selected from the group consisting of substituted
or unsubstituted phenyl, benzyl, pyridinyl, pyrrolyl, pyrrolidinyl,
pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, piperidinyl,
pyrazinyl, piperazinyl, pyrimidinyl, tetrazolyl, morpholinyl,
triazinyl, furfuryl, and thiophenyl, and lower alkyl, wherein said
substitutents are one to three independently selected from the
group consisting of halogen, lower alkyl, lower alkoxy, amino,
lower alkylamino, di-lower alkylamino, hydroxy, nitro, nitrile,
carboxyl, aminosulfonyl, lower alkyl mercapto, and lower
alkylsulfonyl;
[0014] R.sub.4 is selected from the group consisting of substituted
or unsubstituted phenyl, benzyl, pyridinyl, pyrrolyl, pyrrolidinyl,
pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, piperidinyl,
pyrazinyl, piperazinyl, pyrimidinyl, tetrazolyl, morpholinyl,
triazinyl, furfuryl, thiophenyl, and lower alkyl; wherein said
substitutents are one to three independently selected from the
group consisting of halogen, lower alkyl, lower alkoxy, amino,
lower alkylamino, di-lower alkylamino, hydroxy, nitro, nitrile,
carboxyl, aminosulfonyl, lower alkyl mercapto, and lower
alkylsulfonyl;
[0015] R.sub.5 is selected from the group consisting of hydrogen,
lower alkyl, halogen, hydroxy, amino, lower alkyl amino, and
dilower alkylamino;
[0016] Y is selected from the group consisting of CH.sub.2,
C.dbd.O, CH--OH
[0017] m is an integer from 0-3
[0018] X is selected from the group consisting of CH.sub.2,
C.dbd.O, CH--OH, and SO.sub.2; and
[0019] n is an integer from 0-2.
[0020] Preferred compounds of this invention include those
where
[0021] R.sub.1 and R.sub.2 are independently selected from the
group consisting of hydrogen and lower alkyl;
[0022] R.sub.3 is selected from the group consisting of substituted
or unsubstituted phenyl, pyridinyl, pyrrolyl, pyrazolyl,
imidazolyl, pyrazinyl, pyrimidinyl, triazinyl, furfuryl,
thiophenyl, and lower alkyl, wherein said substituents are one to
three independently selected from the group consisting of lower
alkyl, lower alkoxy, amino, lower alkylamino, and dilower
alkylamino, carboxyl, aminosulfonyl and alkylsulfonyl.
[0023] R.sub.4 is selected from the group consisting of substituted
or unsubstituted phenyl, pyridinyl, pyrroyl, imidazolidinyl,
pyrazinyl, piperazinyl, pyrimidinyl, morpholinyl, triazinyl,
thiophenyl, and lower alkyl, wherein said substituents are one to
three independently selected from the group consisting of lower
alkoxy, amino, di-lower-alkylamino, hydroxy, nitrile, carboxyl,
aminosulfonyl and alkylsulfonyl;
[0024] R.sub.5 is selected from the group consisting of hydrogen,
lower alkyl, hydroxy and diloweralkylamino;
[0025] Y is selected from the group consisting of CH--OH and
C.dbd.O;
[0026] m is an integer from 0-2;
[0027] X is selected from the group consisting of CH.sub.2, C.dbd.O
and SO.sub.2; and
[0028] n is either 0 or 1
[0029] More preferred compounds of this invention include those
wherein
[0030] R.sub.1 and R.sub.2 are both lower alkyl;
[0031] R.sub.3 is selected from the group consisting of phenyl,
pyridinyl, pyrazinyl, pyrimidinyl, and triazinyl, wherein said
substituents are one to three independently selected from the group
consisting of lower alkyl, lower alkoxy, di-lower-alkylamino,
aminosulfonyl and alkyl sulfonyl;
[0032] R.sub.4 is selected from the group consisting of substituted
or unsubstituted phenyl, pyridinyl, pyrazinyl, pyrimidinyl,
morpholinyl, triazinyl, thiophenyl, and lower alkyl, wherein said
substituents are one to three independently selected from the group
consisting of lower alkoxy, di-lower-alkylamino, aminosulfonyl and
alkylsulfonyl.
[0033] R.sub.5 is selected from the group consisting of hydrogen
and lower alkyl;
[0034] Y is C.dbd.O;
[0035] M is 0 or 1;
[0036] X is CH.sub.2; and
[0037] n=0
[0038] The present invention is also a method of treating
individuals with neoplastic lesions by administering a
pharmacologically effective amount of an enterically coated
pharmaceutical composition that includes compounds of this
invention.
[0039] Preferably, such compounds are administered without
therapeutic amounts of an NSAID.
[0040] Also, the present invention is a method of inhibiting the
growth of neoplastic cells by exposing the cells to an effective
amount of compounds of Formula I As used herein, the term
"precancerous lesion" includes syndromes represented by abnormal
neoplastic, including dysplastic, changes of tissue. Examples
include dysplasic growths in colonic, breast, bladder or lung
tissues, or conditions such as dysplastic nevus syndrome, a
precursor to malignant melanoma of the skin. Examples also include,
in addition to dysplastic nevus syndromes, polyposis syndromes,
colonic polyps, precancerous lesions of the cervix (i.e., cervical
dysplasia), esophagus, prostatic dysplasia, bronchial dysplasia,
breast, bladder and/or skin and related conditions (e.g., actinic
keratosis), whether the lesions are clinically identifiable or
not.
[0041] As used herein, the term "cancerous" refers to lesions that
are malignant. Examples include malignant melanomas, breast cancer,
prostate cancer and colon cancer.
[0042] As used herein, the term "neoplasm" refers to both
precancerous and cancerous lesions and hyperplasia.
[0043] As used herein, the term "halo" or "halogen" refers to
chloro, bromo, fluoro and iodo groups, and the term "alkyl" refers
to straight, branched or cyclic alkyl groups and to substituted
aryl alkyl groups. The term "lower alkyl" refers to C.sub.1 to
C.sub.8 alkyl groups.
[0044] The term "lower alkoxy" refers to alkoxy groups having from
1 to 8 carbons, including straight, branched or cyclic
arrangements.
[0045] The term "lower alkylmercapto" refers to a sulfide group
that is substituted with a lower alkyl group; and the term "lower
alkyl sulfonyl" refers to a sulfone group that is substituted with
a lower alkyl group.
[0046] The term "pharmaceutically acceptable salt" refers to
non-toxic acid addition salts and alkaline earth metal salts of the
compounds of Formula I. The salts can be prepared in situ during
the final isolation and purification of such compounds, or
separately by reacting the free base or acid functions with a
suitable organic acid or base, for example. Representative acid
addition salts include the hydrochloride, hydrobromide, sulfate,
bisulfate, acetate, valerate, oleate, palmetate, stearate, laurate,
borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate,
maleate, fumarate, succinate, tartrate, glucoheptonate,
lactobionate, lauryl sulfate salts and the like. Representative
alkali and alkaline earth metal salts include the sodium, calcium,
potassium and magnesium salts.
[0047] It will be appreciated that certain compounds of Formula I
can possess an asymmetric carbon atom and are thus capable of
existing as enantiomers. Unless otherwise specified, this invention
includes such enantiomers, including any racemates. The separate
enantiomers may be synthesized from chiral starting materials, or
the racemates can be resolved by conventional procedures that are
well known in the art of chemistry such as chiral chromatography,
fractional cyrstallization of diastereomeric salts and the
like.
[0048] Compounds of this invention may be formulated into
pharmaceutical compositions together with pharmaceutically
acceptable carriers for oral administration in solid or liquid
form, or for intraveneous, rectal or topical administration,
although carriers for oral administration are most preferred.
[0049] Pharmaceutically acceptable carriers for oral administration
include capsules, tablets, pills, powders, troches and granules. In
such solid dosage forms, the carrier can comprise at least one
inert diluent such as sucrose, lactose or starch. Such carriers can
also comprise, as is normal practice, additional substances other
than diluents, e.g., lubricating agents such as magnesium stearate.
In the case of capsules, tablets, troches and pills, the carriers
may also comprise buffering agents. Carriers such as tablets, pills
and granules can be prepared with enteric coatings on the surfaces
of the tablets, pills or granules. Alternatively, the enterically
coated compound can be pressed into a tablet, pill, or granule, and
the tablet, pill or granules for administration to the patient.
Preferred enteric coatings include those that dissolve or
disintegrate at colonic pH such as shellac or Eudraget S.
[0050] Pharmaceutically acceptable carriers include liquid dosage
forms for oral administration, e.g., pharmaceutically acceptable
emulsions, solutions, suspensions, syrups and elixirs containing
inert diluents commonly used in the art, such as water. Besides
such inert diluents, compositions can also include adjuvants such
as wetting agents, emulsifying and suspending agents, and
sweetening, flavoring and perfuming agents.
[0051] Pharmaceutically acceptable carriers for topical
administration include DMSO, alcohol or propylene glycol and the
like that can be employed with patches or other liquid-retaining
material to hold the medicament in place on the skin so that the
medicament will not dry out.
[0052] Pharmaceutically acceptable carriers for rectal
administration are preferably suppositories that may contain, in
addition to the compounds of this invention excipients such as
cocoa butter or a suppository wax, or gel.
[0053] The pharmaceutically acceptable carrier and compounds of
this invention are formulated into unit dosage forms for
administration to a patient. The dosage levels of active ingredient
(i.e., compounds of this invention) in the unit dosage may be
varied so as to obtain an amount of active ingredient effective to
achieve lesion-eliminating activity in accordance with the desired
method of administration (i.e., oral or rectal). The selected
dosage level therefore depends upon the nature of the active
compound administered, the route of administration, the desired
duration of treatment, and other factors. If desired, the unit
dosage may be such that the daily requirement of the active
compound is in one dose, or divided among multiple doses for
administration, e.g., two to four times per day.
[0054] The pharmaceutical compositions of this invention are
preferably packaged in a container (e.g., a box or bottle, or both)
with suitable printed material (e.g., a package insert) containing
indications, directions for use, etc. The general scheme for
producing compounds useful in this invention is illustrated and
explained below. 2
[0055] Scheme I describes the general procedure which leads to
compounds of Formula I. An appropriate chloromethyl lower
alkylketone (R.sub.5--C(O)--CH.sub.2--Cl) is added to a mixture of
an appropriate di-loweralkylacetone dicarboxylate, preferably the
diethylester (EtO.sub.2C--CH.sub.2--C(O)--C(R.sub.1,
R.sub.2)--CO.sub.2Et) and a lower alkylamine (R.sub.4--NH.sub.2),
preferably in an aqueous medium. The reaction temperature is
preferably maintained just below 60.degree. C., and after a few
hours, the mixture is treated with ice-hydrochloric acid (reaction
1). The thus obtained ring-closed pyrrole (a) is acylated with an
acyl halide under Friedel-Crafts reaction conditions to give the
pyrrole-ester (c) (reaction 3). The 5-acyl product (c) is subjected
to a hydrolysis with moderately concentrated alkali (e.g., NaOH) to
yield the free di-acid (d) (reaction 4), which is partly
reesterified with an acidic solution of ethanol to give the
5-acyl-3-carboxy-pyrrole-ester derivative (e) (reaction 5).
Decarboxylation of the carboxy group in 3-position is accomplished
by heating (e) in a suitable organic solvent (reaction 6) to yield
the alkyl 5-acyl-pyrrole-ester-derivative (f), which is hydrolysed
(e.g., with NaOH) to give the free acid (i) (reaction 10). The
pyrrole acid derivative (i) is subjected to N-bromosuccunimide to
yield the lactone (j) (reaction 11).
[0056] In an alternative way to achieve the lactone (j), the acyl
rest in 5-position is added at a later stage. Starting with the
pyrrole derivative (a), hydrolysis in the usual manner (e.g., with
NaOH; see, reaction 2) gives the dicarboxylic acid (b). Partial
reesterification with an acidic solution of ethanol yields the
3-carboxy-pyrrole-ester derivative (g) (reaction 7), which is
decarboxylated in the 3-position by heating it in a suitable
solvent (e.g., quinoline) (reaction 9). The resulting pyrrole-ester
(h) is subjected to a Friedel Crafts reaction with an acylhalide to
yield the 5-acyl-pyrrole-ester derivative (f), which is converted
to the lactone (j), as described above (see reactions 10 and 11). 3
4
[0057] Scheme II is employed when R.sub.4 is hydrogen. A
substituted oxime and a substituted ethylacetonedicarboxylate are
allowed to react according to a Knorr pyrrole synthesis in glacial
acetic acid and zinc dust to yield the ring closed pyrrole (k)
(reaction 12). Hydrolysis of the diester (k) with a moderately
concentrated alkali (e.g., NaOH) gives the free dicarboxylic acid
(1) (reaction 13), which is re-esterified with an acidic ethanol
solution (reaction 14) to yield the ethyl 5-acyl-3-carboxy pyrrole
ester derivative (m). Decarboxylation of the carboxy group in
3-position is accomplished by heating the ester (m) in an organic
solvent (e.g., quinoline) (reaction 15) to give the pyrrole-ester
(n), which is hydrolysed in the usual manner (e.g., with NaOH) to
yield the free acid (o) (reaction 16). After protecting the
secondary amine by reaction with t-butyloxycarbonyl-anhydride
(reaction 17), the lactone (q) is formed by reaction with
N-bromosuccinimide (reaction 18). The BOC-group is removed with
trifluoroacetic acid, followed by a mild basic workup (e.g.,
NaHCO.sub.3) to yield the lactone (r) (reaction 19).
[0058] Scheme III is employed if R.sub.4 is a group which is
sensitive towards Friedel Crafts conditions, (i.e., Reactions 9 or
3 in Scheme I). The lactone (r) in a basic solution is allowed to
react with an alkylhalide(R.sub.4--(X).sub.n-Hal), acylhalide or
sulfonylhalide to give the N-substituted lactone (s) (reaction 20),
which can be reduced with sodium borohydride to the lactone (t)
with a secondary alcohol in position 5 (reaction 21).
[0059] Scheme IV is employed if a nitrile, i.e.,
1-methyl-pyrrole-2-aceton- itrile, is available as a starting
material for reaction 22, which is a Friedel Crafts acylation with
R.sub.3--C(O)--Cl and AlCl.sub.3 as reagents. The nitrile (u) is
hydrolysed with base (reaction 23) to give the acid (v). The
lactone (s) is formed by reaction with N-bromosuccinimide (reaction
24).
[0060] To summarize, the reagents and conditions for Scheme I-III
are as follows (numbers refer to reactions):
[0061] 1. aqueous solution, <60.degree. C.; H.sup.+
[0062] 2. A) NaOH (25-50%)
[0063] B) HCl
[0064] 3. Friedel-Crafts reaction with R.sub.3--C(O)--Cl
[0065] 4. A) NaOH (25-50%)
[0066] B) HCl
[0067] 5. EtOH, H.sup.+
[0068] 6. .DELTA., quinoline, --CO.sub.2.Arrow-up bold.
[0069] 7. EtOH, H.sup.+ (Other lower alkylalcohols can be employed
instead of ethanol.)
[0070] 8. .DELTA., quinoline, --CO.sub.2.Arrow-up bold.
[0071] 9. Friedel-Crafts reaction with R.sub.3--C(O)--Cl
[0072] 10. A) NaOH (25-50%)
[0073] B) HCl
[0074] 11. N-bromosuccinimide
[0075] 12. Knorr pyrrole synthesis conditions: Zn/CH.sub.3COOH
[0076] 13. A) NaOH (25-50%)
[0077] B) HCl
[0078] 14. EtOH, H.sup.+ (Other lower alkylalcohols can be employed
instead of ethanol)
[0079] 15. .DELTA., quinoline, --CO.sub.2.Arrow-up bold.
[0080] 16. A) NaOH (25-50%);
[0081] B) HCl
[0082] 17. (BOC).sub.2O
[0083] 18. N-bromosuccinimide
[0084] 19. A) CF.sub.3COOH/CH.sub.2Cl.sub.2
[0085] B) base
[0086] 20. R.sub.4--(X).sub.n-Hal
[0087] 21. NaBH.sub.4
[0088] 22. Friedel-Crafts reaction with R.sub.3--C(O)--Cl
[0089] 23. 1N NaOH reflux
[0090] 24. N-Bromosuccinimide
[0091] The following examples are intended to illustrate, but not
to limit, the scope of the present invention.
EXAMPLE 1
6-Methyl-5-(p-Toluoyl)-1 3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0092] (A) 5-(p-Toluoyl)-1-methylpyrrole-2-acetonitrile
[0093] To a cooled suspension of 26.6 g. (0.2 mole) aluminum
chloride in 80 ml. dichloroethane is added dropwise 30.8 g. (0.2
mole) p-toluoyl chloride. The resulting solution is added dropwise
to a solution of 1-methylpyrrole-2-acetonitrile in 80 ml.
dichloroethane cooled externally with an ice bath. After the
addition, the resulting solution is stirred at room temperature for
twenty minutes and then refluxed for three minutes. The solution is
poured into ice acidified with dilute hydrochloric acid. The
organic and aqueous fractions are separated. The aqueous fraction
is extracted once with chloroform. The organic fractions are
combined and washed successively with
N,N-dimethyl-1,3-propanediamine- , dilute hydrochloric acid,
saturated sodium bicarbonate solution and saturated sodium chloride
solution. The organic fraction is dried over anhydrous magnesium
sulfate. The solvent is then evaporated off. Upon trituration of
the residue with methanol, a solid crystallizes,
5-(p-toluoyl)-1-methylpyrrole-2-acetonitrile, which is removed by
filtration and purified by recrystallization from benzene.
Additional product is isolated from the mother liquors which are
combined, concentrated in vacuo, and the resulting oily residue
column chromatographed on neutral alumina using hexane, benzene and
ether as successive solvents. The product is isolated by
concentrating in vacuo the first few major compound-bearing
fractions (10% ether in benzene). The solids are combined and
recrystallized from methanol and then from benzene-hexane, m.p.
102-105.degree. C.
[0094] (B) 5-(p-Toluoyl)-1-methylpyrrole-2-acetic acid
[0095] A solution of 3.67 g. (0.015 mole) of
5-(p-toluoyl)-1-methylpyrrole- -2-acetonitrile, 24 ml. of 1N sodium
hydroxide, and 50 ml. of 95% ethanol is stirred and refluxed for
twenty-four hours. The resulting solution is poured into ice
acidified with dilute hydrochloride acid. A white solid
precipitates which is extracted into ether. The ether phase is
washed with a saturated solution of sodium chloride and dried over
anhydrous magnesium sulfate. The solvent is evaporated and a white
solid, 5-(p-toluoyl)-1-methylpyrrole-2-acetic acid, is obtained
which is recrystallized twice from isopropanol, m.p.
155-157.degree. C.
[0096] (C)
6-Methyl-5-(p-toluoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one
[0097] N-bromosuccinimide (0.94 g, 5.2 mmol) is added stepwise at
0C to a stirred solution of 5-(p-toluoyl)-1-methylpyrrole-2-acetic
acid (0.70 g, 2.39 mmol) in DMA/water (6 ml, 0.1 ml). After 30
minutes at 0.degree. C., stirring is continued overnight at room
temperature. The solution is added dropwise to stirred ice water
(150 ml). A white precipitate is filtered off, is washed with water
(2.times.10 ml), and is dried in vacuo. Recrystallization from
methylene chloride-n-hexane gives a white solid,
6-methyl-5-(p-toluoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one,
with m.p. 148-151.degree. C. (R.sub.1=H, R.sub.2=H,
R.sub.3=4-methylphenyl, R.sub.4=CH.sub.3, R.sub.5=H, Y=CO, m=1,
n=0). Formula: C.sub.15H.sub.13NO.sub.3; Molecular Mass: 255.27
g/mol; .sup.1H-NMR [ppm] (CDCl.sub.3): 2.43 (s,3,Ph--CH.sub.3);
3.85 (s,2,--CH.sub.2-C.dbd.O); 3.97 (s,3,N--CH.sub.3); 6.71
(s,1,.dbd.CH--); 7.25-7.72 (AB, 4,ar.); IR [cm.sup.-1] (KBr): 1740
C.dbd.O; 1630 C.dbd.C.
EXAMPLE 2
6-Methyl-5-(p-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0098] (A) Ethyl 5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetate
[0099] To a solution of (22.0 g. (0.131 mole) of ethyl
N-methylpyrrole-2-acetate and 24.5 g. (0.14 mole) of
p-chlorobenzoyl chloride in 120 ml. of carbon disulfide is added
35.0 g. (0.262 mole) of anhydrous aluminum chloride over a period
of 20 minutes with intermittant cooling to keep the temperature at
25.degree. C. The mixture is stirred for an additional 20 minutes.
The carbon disulfide solvent is then decanted and discarded. The
red gummy residue is washed with hexane and dilute hydrochloric
acid and ice is added to the mixture. The mixture is extracted with
ether. The ether solution is shaken with an aqueous solution of
dimethylaminopropylamine and washed with dilute hydrochloric acid
followed by brine. The solution is dried over magnesium sulfate and
treated with charcoal. After removal of the charcoal, the solvent
is evaporated in vacuo leaving a partially crystalline red oil as a
residue. This material is extracted with three 500 ml. portions of
boiling pentane. The combined pentane extracts are evaporated in
vacuo, and the residue is crystallized from 60 ml. of cold
methanol. The resulting solid is collected and washed with cold
methanol; there is obtained about 6.3 g of a white crystalline
solid, ethyl 5-(p-chlorobenzoyl)-1-methylpyrrole-2- -acetate, m.p.
74-76.degree. C. Recrystallization from methyl cyclohexane raises
the melting point to 78-80.degree. C.
[0100] (B) 5-(p-Chlorobenzoyl)-1-methylpyrrole-2-acetic acid
[0101] A suspension of 3.06 g. (0.01 mole) of
ethyl-5-(p-chlorobenzoyl)-1-- methylpyrrole-2-acetate in 25 ml. of
0.5 N sodium hydroxide is refluxed for 30 minutes. About two-thirds
of this solution is cooled, washed with ether, and then acidified
with dilute hydrochloric acid. The resulting solid precipitate is
collected by filtration, dried and recrystallized from
ethanol-water to give the product,
5-(p-chlorobenzoyl)-1-metylpyrrol- e-2-acetic acid; m.p.
189-191.degree. C. Upon recrystallization from ethanol-water, the
melting point is 188-190.degree. C. Analysis: Calcd. for
C.sub.14H.sub.12ClNO.sub.3 : C, 60.54;H, 4.36; N, 5.05%. Found: C,
60.54;H, 4.37; N, 5.14%.
[0102] (C)
6-Methyl-5-(p-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-
-2-one 5-(p-Chlorobenzoyl)-1-methylpyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
6-methyl-5-(p-chlorobenzoyl-
)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R.sub.1=H, R.sub.2=H,
R.sub.3=p-chlorophenyl, R.sub.4=CH.sub.3, R.sub.5=H, Y=CO, m=1,
n=0).
EXAMPLE 3
6-Methyl-5-(3'4'-Dibromobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0103] (A) Ethyl 5-(3'4'-dibromobenzoyl)-1-methyl-pyrrole-2-acetate
and 5-benzoyl-1-methyl-pyrrole-2-acetic acid
[0104] By following the procedure of Example 2, part A, except that
an equivalent quantity of 3'4'dibromobenzoyl chloride is employed
in place of the p-chlorobenzoylchloride used in Example 2, ethyl
5-(3'4'-dibromobenzoyl)-1-methyl-pyrrole-2-acetate is produced; and
5-(3'4'-dibromobenzoyl)-1-methyl-pyrrole-2-acetic acid is produced
when the procedure of Example 2, part B is employed.
[0105] (B)
6-Methyl-5-(3'4'-dibromobenzoyl)-1,3,6-trihydro-6-aza-3-oxapent-
alen-2-one 5-(3',4')-Dibromobenzoyl-1-methyl-pyrrole-2-acetic acid
is subjected to the procedure of Example 1, part C to produce
6-methyl-5-(3'4'-dibromobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one
(R.sub.1=H, R.sub.2=H, R.sub.3=3'4'-dibromobenzoyl,
R.sub.4=CH.sub.3, R.sub.5=H, Y=CO, m=1, n=0).
EXAMPLE 4
6-Methyl-5-Benzoyl-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0106] (A) 5-Benzoyl-1-methylpyrrole-2-acetonitrile
[0107] To a chilled suspension of 9.7 g. (0.07 mole) of alumonum
chloride in 45 ml. methylene chloride is added 9 ml. (0.07 mole)
benzoyl chloride. The resulting solution is added dropwise to a
solution of 1-methylpyrrole-2-acetonitrile in 30 ml. methylene
chloride while cooling externally with an ammonium chloride ice
bath (temperature below 5.degree. C.). After the addition is
complete, the reaction mixture is stirred at 0.degree. C. for
fifteen minutes and then poured into ice acidified with 3N
hydrochloric acid. The acidic fraction is extracted three times
with methylene chloride. The organic fractions are combined and
washed consecutively with N,N-dimethyl-1,3-propanediamine and 3N
hydrochloric acid. The organic solution is dried over anhydrous
magnesium sulfate. The solvent is then evaporated off to yield an
oily residue which is column chromatographed on neutral alumina
using hexane, benzene and ethylacetate as successive solvents. The
first few fractions having ultraviolet absorption in the 240-260
m.mu. range contain the desired product. These fractions are
combined, the solvent evaporated off, and the oily residue, when
triturated with methanol, yields the crystalline product,
5-benzoyl-1-methylpyrrole-2-acetonitrile, m.p. 106-108.degree.
C.
[0108] (B) 5-Benzoyl-1-methylpyrrole-2-acetic acid:
[0109] A suspension of 2.42 g. (0.11 mole) of
5-benzoyl-1-methylpyrrole-2-- acetonitrile, 0.9 g. (0.22 mole)
sodium hydroxide, 6 ml. water, and 0.5 ml. ethanol, is stirred and
refluxed for one hour. The resulting solution is cooled and
extracted in water and chloroform. The aqueous fraction is made
acidic with 3N hydrochloric acid. A white solid,
5-benzoyl-1-methylpyrrole-2-acetic acid, precipitates which is
filtered and washed with a hexane-ether solution, m.p.
144-145.degree. C. Analysis: Calcd. for C.sub.14H.sub.13 NO.sub.3:
C, 69.12;H, 5.39; N, 5.76%. Found: C, 69.23;H, 5.47; N, 5.78%.
[0110] (C)
6-Methyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one
[0111] 5-Benzoyl-1-methylpyrrole-2-acetic acid is subjected to the
procedure of Example 1, part C to produce
6-methyl-5-benzoyl-1,3,6-trihyd- ro-6-aza-3-oxapentalen-2-one
(R.sub.1=H, R.sub.2=H, R.sub.3=phenyl, R.sub.4=CH.sub.3, R.sub.5=H,
Y=CO, m=1, n=0).
EXAMPLE 5
6-Methyl-5-(m-Chlorobenzoyl)-13
6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0112] (A) 5-(m-Chlorobenzoyl)-1-methylpyrrole-2-acetonitrile
[0113] To a cooled suspension of 16.6 g. (0.12 mole) aluminum
chloride in 60 ml. 1,2-dichloroethane is added dropwise 23 g. (0.12
mole) m-chlorobenzoylchloride. The resulting suspension is added
dropwise to a cooled solution of 15 g. (0.12 mole)
1-methylpyrrole-2-acetonitrile in 60 ml. 1,2-dichloroethane. The
reaction mixture is stirred for about twenty minutes at room
temperature and then heated and refluxed for three minutes. The
reaction is terminated by pouring the mixture into ice acidified
with 3N hyrochloric acid. The resulting two fractions are
separated. The aqueous fraction is washed with chloroform. The
organic fractions are combined and washed consecutively with
N,N-dimethyl-1,3-propanediamine, 3N hydrochloric acid and saturated
sodium chloride solution. The organic fraction is then dried over
anhydrous magnesium sulfate. The solvent is evaporated, and the
resulting residue is triturated with cold methanol to yield a
precipitate of the desired product which is filtered off and set
aside. The methanol filtrate is concentrated in vacuo, and the
remaining oily residue is chromatographed on a column packed with
neutral alumina using hexane, benzene and ether as the successive
solvents. The desired product is isolated by evaporation of the
first few compound-bearing (ether) fractions. The solids are
combined and recrystallized from methanol to yield
5-(m-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile, m.p.
122-127.degree. C. Analysis: Calcd. for C.sub.14H.sub.11ClN.sub.2O:
N, 10.83%. Found: N, 10.52
[0114] (B) 5-(m-Chlorobenzoyl)-1-methylpyrrole-2-acetic acid
[0115] A mixture of 2.8 g. (0.01 mole) of
5-(m-chlorobenzoyl)-1-methylpyrr- ole-2-acetonitrile, 22 ml. of 1N
sodium hydroxide solution and 5 ml. ethanol is stirred at reflux
for 15 hours. Some of the ethanol is evaporated. The remaining
solution is poured into ice acidified with dilute hydrochloric
acid. A white solid, 5-(m-chlorobenzoyl)-1-methylpyrr- ole-2-acetic
acid, precipitates which is recrystallized twice from methanol:
water, m.p. 165.degree. C. Analysis: Calcd. for C.sub.14H.sub.12
ClNO.sub.3: C, 60.54;H, 4.36; N, 5.05%. Found: C, 60.61;H, 4.40; N,
4.87%.
[0116] (C)
6-Methyl-5-(m-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-
-2-one
[0117] 5-(m-Chlorobenzoyl)-1-methylpyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
6-Methyl-5-(m-chlorobenzoyl-
)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R.sub.1=H, R.sub.2=H,
R.sub.3=m-chlorophenyl, R.sub.4=CH.sub.3, R.sub.5=H, Y=CO, m=1,
n=0).
EXAMPLE 6
6-Methyl-5-(p-Bromobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0118] (A) 5-(p-bromobenzoyl)-1-methylpyrrole-2-acetonitrile
[0119] The procedure of Example 5 is repeated except that an
equivalent quantity of p-bromobenzoyl chloride is used in place of
the m-chlorobenzoyl chloride used therein to yield,
5-(p-bromobenzoyl)-1-meth- ylpyrrole-2-acetonitrile, m.p.
139-141.degree. C.
[0120] (B) 5-(p-Bromobenzoyl)-1-methylpyrrole-2-acetic acid
[0121] By following the procedure of Example 5B, using an
equivalent quantity of the nitrile from part A in place of the
5-(m-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile used therein
5-(p-bromobenzoyl)-1-methylpyrrole-2-acetic acid, m.p. 188.degree.
C. is obtained.
[0122] (C)
6-Methyl-5-(p-bromobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen--
2-one
[0123] 5-(p-Bromobenzoyl)-1-methylpyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
6-methyl-5-(p-bromobenzoyl)-
-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R.sub.1=H, R.sub.2=H,
R.sub.3=p-bromophenyl, R.sub.4=CH.sub.3, R.sub.5=H, Y=CO, m=1,
n=0).
EXAMPLE 7
6-Methyl-5-(p-Fluorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0124] (A) 5-(p-Fluorobenzoyl)-1-methylpyrrole-2-acetonitrile
[0125] The procedure of Example 5A is repeated except that an
equivalent quantity of p-fluorobenzoyl chloride is used in place of
the m-chlorobenzoyl chloride used therein to yield
5-(p-fluorobenzoyl)-1-meth- ylpyrrole-2-acetonitrile, m.p. 134-1
36.degree. C.
[0126] (B) 5-(p-Fluorobenzoyl)-1-methylpyrrole-2-acetic acid
[0127] By following the procedure of Example 5B, using an
equivalent quantity of the nitrile from part A in place of the
5-(m-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile used therein,
5-(p-fluorobenzoyl)-1-methylpyrrole-2-acetic acid, m.p.
164-165.degree. C. is obtained.
[0128] (C)
6-Methyl-5-(p-fluorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-
-2-one
[0129] 5-(p-Fluorobenzoyl)-1-methylpyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
6-methyl-5-(p-fluorobenzoyl-
)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R.sub.1=H, R.sub.2=H,
R.sub.3=p-fluorophenyl, R.sub.4=CH.sub.3, R.sub.5=H, Y=CO, m=1,
n=0).
EXAMPLE 8
6-Methyl-5-(o-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0130] (A) 5-(o-Chlorobenzoyl)-1-methylpyrrole-2-acetonitrile
[0131] To a cooled suspension of 14 g. (0.105 mole) aluminum
chloride in 45 ml. dichloroethane is added dropwise, 18.5 g. (0.105
mole) o-chlorobenzoyl chloride. The resulting solution is added
dropwise to a cooled (0.degree. C.) solution of
1-methylpyrrole-2-acetonitrile in 45 ml. dichloroethane keeping the
temperature at approximately 10.degree. C. The mixture is stirred
at room temperature for about twenty minutes, and then refluxed for
three minutes. It is poured into ice acidified with 3N hydrochloric
acid, and the resulting two layers are separated. The aqueous
fraction is extracted twice with chloroform. The organic fractions
are combined and washed twice with N,N-dimethyl-1,3-propanediam-
ine, once with 3N hydrochloric acid and once with saturated sodium
chloride solution. The organic fraction is dried over anhydrous
magnesium sulfate. The solvent is evaporated, and the resulting oil
is chromatographed on a column packed with neutral alumina using
benzene and ether as successive solvents. The first
compound-bearing fractions contain the desired product. The solvent
is evaporated and the resulting oil crystallizes upon treatment
with methanol. The solid product,
5-(o-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile, is purified by
recrystallization from benzene:cyclohexane solution, m.p.
80-85.degree. C.
[0132] (B) 5-(o-Chlorobenzoyl)-1-methylpyrrole-2-acetic acid
[0133] A solution of 2.4 g. (0.009 mole) of
5-(o-chlorobenzoyl)-1-methylpy- rrole-2-acetonitrile, 18 ml. of 1N
sodium hydroxide and 18 ml. 95% ethanol is stirred and refluxed for
seven hours. The ethanol is evaporated off, and the remaining solid
residue is dissolved in water and washed with chloroform. The
aqueous layer is made acidic with 3N hydrochloric acid. An oil
precipitates which crystallizes when scratched. The solid is
filtered and washed with water and hexane. The solid is purified by
recrystallization from methanol:water and again from ether:hexane,
m.p. 140-141.degree. C. Analysis: Calcd. for C.sub.14H.sub.12
ClNO.sub.31: C, 60.54;H, 4.36; N, 5.05%. Found: C, 60.55;H, 4.43;
N, 4.91%.
[0134] (C)
6-Methyl-5-(o-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-
-2-one
[0135] 5-(o-Chlorobenzoyl)-1-methylpyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
6-Methyl-5-(o-chlorobenzoyl-
)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R.sub.1=H, R.sub.2=H,
R.sub.3=o-chlorophenyl, R.sub.4=CH.sub.3, R.sub.5=H, Y=CO, m=1,
n=0).
EXAMPLE 9
6-Methyl-5-(2',4'-Dichlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-On-
e
[0136] (A)
5-(2',4'-Dichlorobenzoyl)-1-methylpyrrole-2-acetonitrile
[0137] To a suspension of 16.6 g. (0.125 mole) of aluminum chloride
in 60 ml. 1,2-dichloroethane is added 26.2 g. (0.125 mole) of
2,4-dichlorobenzoyl chloride. The resulting solution is added
slowly to a solution of 15 g. (0.125 mole) of
1-methylpyrrole-2-acetonitrile in 60 ml. 1,2-dichloroethane while
cooling externally with an ice bath. After the addition is
complete, the mixture is stirred for 40 minutes at room temperature
followed by heating at reflux for 3 minutes. It is then poured into
ice acidified with dilute hydrochloric acid. The organic phase is
separated and washed successively with N,N-dimethyl-1,3-propaned-
iamine, 3N hydrochloric acid, and saturated sodium chloride
solution. It is then dried over magnesium sulfate and the solvent
evaporated. The resulting red oily residue is chromatographed on a
column packed with neutral alumina and eluted with benzene and
ether. The first compound-bearing fractions upon evaporation yield
a white solid,
5-(2',4'-dichlorobenzoyl)-1-methylpyrrole-2-acetonitrile, which is
purified by recrystallization from methanol, m.p. 129-130.degree.
C. Analysis: Calcd. for C.sub.14H.sub.10Cl.sub.2N.sub.2O: N, 9.56%.
Found: N, 9.51%.
[0138] (B) 5-(2',4'-Dichlorobenzoyl)-1-methylpyrrole-2-acetic
acid
[0139] A solution of 4.3 g. (0.015 mole) of
5-(2',4'-dichlorobenzoyl)-1-me- thylpyrrole-2-acetonitrile in 30
ml. 1N sodium hydroxide and 30 ml. 95% ethanol is refluxed
overnight. The solution is concentrated and poured into dilute
hydrochloric acid. A white solid, 5-(2',4'-dichlorobenzoyl)-1-
-methylpyrrole-2-acetic acid precipitates which is recrystallized
from isopropanol and methanol, m.p. 165-166.degree. C. Analysis:
Calcd. for C.sub.14H.sub.11Cl.sub.2NO.sub.3: C, 53.86;H, 3.55; N,
4.68%. Found: C, 53.97;H, 3.66; N, 4.69%.
[0140] (C)
6-Methyl-5-(2',4'-dichlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxape-
ntalen-2-one 5-(2',4'-Dichlorobenzoyl)-1-methylpyrrole-2-acetic
acid is subjected to the procedure of Example 1, part C to produce
6-methyl-5-(2',4'-dichlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-o-
ne (R.sub.1=H, R.sub.2=H, R.sub.3=2',4'-dichlorophenyl,
R.sub.4=CH.sub.3, R.sub.5=H, Y=CO, m=1, n=0).
EXAMPLE 10
6-Methyl-5-(o-Toluoyl)-13 6-Trihydro-6-Aza-3-Oxapentalen-2-One
6-Methyl-5-(m-Toluoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
6-Methyl-5-(p-Ethylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
6-Methyl-5-(3,4-Dimethylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0141] (A) By repeating the procedure of Example 8A, except that an
equivalent quantity of o-toluoyl chloride, m-toluoyl chloride,
p-ethylbenzoyl chloride and 3,4-dimethylbenzoyl chloride is used in
lieu of the 2,4-dichlorobenzoyl chloride used therein, there are
obtained as respective products the corresponding 5-(o-toluoyl),
5-(m-toluoyl), 5-(p-ethylbenzoyl) and 5-(3',4'-dimethylbenzoyl)
derivatives of 1-methylpyrrole-2-acetonitrile.
[0142] (B) The procedure of Example 8B is repeated, using an
equivalent quantity of each of the foregoing nitrites in place of
the 5-(2',4'-dichlorobenzoyl)-1-methylpyrrole-2-acetonitrile used
therein, to yield the products identified above, which are the
corresponding 5-(o-toluoyl), 5-(m-toluoyl), 5-(p-ethylbenzoyl) and
5-(3',4'-dimethylbenzoyl) derivatives of 1-methylpyrrole-2-acetic
acid.
[0143] (C) The 5-(o-toluoyl), 5-(m-toluoyl), 5-(p-ethylbenzoyl) and
5-(3',4'-dimethylbenzoyl) derivatives of 1-methylpyrrole-2-acetic
acid from part B are each separately subjected to the procedure of
Example 1, part C to produce
6-methyl-5-(o-toluoyl)-1,3,6-trihydro-6-aza-3-oxapental- en-2-one,
6-methyl-5-(m-toluoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one,
6-methyl-5-(p-ethylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one,
and
6-methyl-5-(3,4-dimethylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one-
, respectively.
EXAMPLE 11
6-Methyl -5-(p-Anisoyl)-1,3
6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0144] (A) Methyl 5-(p-anisoyl)-1-methylpyrrole-2-acetate
[0145] A solution of 17.0 g. (0.1 mole) of p-anisoyl chloride and
13.3 g. (0.1 mole) of aluminum chloride in 200 ml. of methylene
chloride is added over 5 minutes to a solution of methyl
1-methylpyrrole-2-acetate in 100 ml. of methylene chloride at ice
bath temperature. The mixture is stirred for 25 minutes and poured
into ice acidified with dilute hydrochloric acid. The organic layer
is separated and the aqueous layer is washed with methylene
chloride. The combined organic solutions are washed successively
with dimethylaminopropylamine solution, dilute hydrochloric acid
and brine and then dried over anhydrous magnesium sulfate. The
solvent is evaporated in vacuo to give a dark oily residue which is
crystallized from 40 ml. of cold methanol. The solid is collected
by filtration, washed with cold methanol and recrystallized from
methanol to give white crystalline methyl
5-(p-anisoyl)-1-methylpyrrole-2-acetate, m.p. 104-1 05C.
[0146] (B) 5-(p-Anisoyl)-1-methylpyrrole-2-acetic acid
[0147] A solution of 3.00 g. (0.0105 mole) of methyl
5-(p-anisoyl)-1-methylpyrrole-2-acetate in 12 ml. (0.012 mole) of
IN sodium hydroxide solution and 5 ml. of 95% ethanol is refluxed
for 30 minutes. The solution is diluted with water, and the ethanol
is evaporated in vacuo. The solution is filtered, and the filtrate
acidified with dilute hydrochloric acid. The precipitated solid is
collected by filtration, dried and recrystallized from
methanol-water to give white 5-(p-anisoyl)-1-methylpyrrole-2-acetic
acid, m.p. 170-171.degree. C. Analysis: Calcd. for
C.sub.15H.sub.15NO.sub.4: C, 65.92;H, 5.53; N, 5.13%. Found: C,
66.01;H, 5.62; N, 5.12%
[0148] (C)
6-Methyl-5-(p-anisoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one
[0149] 5-(p-Anisoyl)-1-methylpyrrole-2-acetic acid is subjected to
the procedure of Example 1, part C to produce
6-methyl-5-(p-anisoyl)-1,3,6-tr- ihydro-6-aza-3-oxapentalen-2-one
(R.sub.1=H, R.sub.2=H, R.sub.3=4'-methoxyphenyl, R.sub.4=CH.sub.3,
R.sub.5=H, Y=CO, m=1, n=0).
EXAMPLE 12
6-Methyl-5-(m-Anisoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
6-Methyl-5-(p-Ethoxybenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0150] By repeating the procedures of Examples 11A and 11B
successively, except that an equivalent quantity each of m-anisoyl
chloride and p-ethoxybenzoyl chloride is initially employed in
place of p-anisoyl chloride, there are obtained as ester products,
the corresponding 5-(m-anisoyl) and 5-(p-ethoxybenzoyl) derivatives
of methyl 1-methylpyrrole-2-acetate, and as acid products, the
above-captioned corresponding 5-(m-anisoyl) and 5-(p-ethoxybenzoyl)
derivatives of 1-methylpyrrole-2-acetic acid, respectively. The
acids are converted to the corresponding lactones following the
procedure of Example 1, part C (R.sub.1=H, R.sub.2=H,
R.sub.3=3'-methoxyphenyl or 4'-ethoxyphenyl, R.sub.4=CH.sub.3,
R.sub.5H, Y=CO, m=1, n=0).
EXAMPLE 13
6-Methyl-5-(3'-Chloro-4'-Toluoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0151] (A) 5-(3.degree.
Chloro-p-toluoyl)-1-methylpyrrole-2-acetonitrile
[0152] 21.4 grams (0.114 mole) of 3-chloro-4-methylbenzoylchloride
is added to a suspension of 15.2 g. (0.114 mole) aluminum chloride
in 50 ml. 1,2-dichloroethane. The resulting solution is added
dropwise to a chilled solution of 13.7 g. (0.114 mole) of
1-methylpyrrole-2-acetonitrile in 50 ml. 1,2-dichloroethane. After
the addition is complete, the mixture is stirred for ten minutes at
room temperature, and then heated to reflux for three minutes. It
is poured into ice acidified with dilute HCl. The organic phase is
separated and washed consecutively with
N,N-dimethyl-1,3-propanediamine, 3N hydrochloric acid and saturated
sodium chloride solution. It is then dried over anhydrous magnesium
sulfate, and the solvent evaporated off. A white solid,
5-(3'-chloro-p-toluoyl)-1-methylpyrrole-2-acetonitrile,
precipitates from the resulting oily residue upon trituration with
methanol which is purified by recrystallization from methanol, m.p.
116-118.degree. C. Analysis: Calcd. for C.sub.15H.sub.13ClN.sub.2O:
N, 10.26%. Found: N, 10.38%.
[0153] (B) 5-(3'-Chloro-p-toluoyl)-1-methylpyrrole-2-acetic
acid
[0154] A solution of 3.5 g. (0.0013 mole) of
5-(3'-chloro-p-toluoyl)-1-met- hylpyrrole-2-acetonitrile in 18 ml.
95% ethanol and 26 ml. 1N sodium hydroxide is heated at reflux
overnight. The reaction mixture is then cooled and poured into
dilute hydrochloric acid. The resulting white precipitate,
5-(3'-chloro-p-toluoyl)-1-methylpyrrole-2-acetic acid, is filtered
off and purified by recrystallization once from isopropanol, m.p.
176-178.degree. C.
[0155] (C)
6-Methyl-5-(3'-chloro-4'-toluoyl)-1,3,6-trihydro-6-aza-3-oxapen-
talen-2-one
[0156] 5-(3'-Chloro-p-toluoyl)-1-methylpyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
6-methyl-5-(3'-chloro-4'-
-toluoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R.sub.1=H,
R.sub.2=H, R.sub.3=3'-chloro-4'-methylphenyl, R.sub.4=CH.sub.3,
R.sub.5=H, Y=CO, m=1, n=0).
EXAMPLE 14
6-Methyl-5-(3',4'-Dimethoxybenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-O-
ne
[0157] (A) Methyl
5-(3',4'-dimethoxybenzoyl)-1-methylpyrrole-2-acetate
[0158] By repeating the Friedel-Crafts procedures of Example 11
with an equivalent amount of an appropriately substituted benzoyl
chloride, methyl
5-(3',4'-dimethoxybenzoyl)-1-methylpyrrole-2-acetate is
obtained.
[0159] (B) The transformation of the acetic acid ester of part (A)
to its acetic acid is performed according to example 11 part B to
yield 5-(3',4'-dimethoxybenzoyl)-1-methylpyrrole-2-acetic acid
[0160] (D)
6-Methyl-5-(3',4'-dimethoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxap-
entalen-2-one
[0161] The acid from part B above is subjected to the procedure of
Example 1, part C to produce
6-methyl-5-(3',4'-dimethoxybenzoyl)-1,3,6-trihydro-6-
-aza-3-oxapentalen-2-one (R.sub.1=H, R.sub.2=H,
R.sub.3=3',4'-dimethoxyphe- nyl, R.sub.4=CH.sub.3, R.sub.5=H, Y=CO,
m=1, n=0).
EXAMPLE 15
6-Methyl-5-(3',5'-Dinitrobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0162] (A) Methyl
5-(3',5'-dinitrobenzoyl)-1-methylpyrrole-2-acetate
[0163] By repeating the Friedel-Crafts procedures of Example 11
with an equivalent amount of an appropriately substituted benzoyl
chloride, methyl
5-(3',5'-dinitrobenzoyl)-1-methylpyrrole-2-acetate.
[0164] (B) 5-(3',5'-dinitrobenzoyl)-1-methylpyrrole-2-acetic
acid
[0165] The transformation of the acetic acid ester of part (A) to
its acetic acid is performed according to the hydrolysis procedure
of Example 11B is repeated with an equivalent amount of the pyrrole
acetate obtained in part (A) to yield
5-(3',5'-dinitrobenzoyl)-1-methylpyrrole-2-acetic acid.
[0166] (C)
6-Methyl-5-(3',5'-dinitrobenzoyl)-1,3,6-trihydro-6-aza-3-oxapen-
talen-2-one
[0167] 5-(3',5'-dinitrobenzoyl)-1-methylpyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
6-methyl-5-(3',5'-dinitr-
obenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R.sub.1=H,
R.sub.2=H, R.sub.3=3',5'-dinitrophenyl, R.sub.4=CH.sub.3, R.sub.5H,
Y=CO, m=1, n=0).
EXAMPLE 16
6-Methyl-5-(3'-Bromo-4'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen--
2-One
[0168] (A) Methyl
5-(3'-bromo-4'-chlorobenzoyl)-1-methylpyrrole-2-acetate By
repeating the Friedel-Crafts procedures of Example 11 with an
equivalent amount of an appropriately substituted benzoyl chloride,
methyl 5-(3'-bromo-4'-chlorobenzoyl)-1-methylpyrrole-2-acetate is
obtained.
[0169] (B) 5-(3'-bromo-4'-chlorobenzoyl)-1-methylpyrrole-2-acetic
acid
[0170] The transformation of the acetic acid ester of part (A) to
its acetic acid is performed according to the hydrolysis procedure
of Example 11B is repeated with an equivalent amount of the pyrrole
acetate obtained in part (A) to yield
5-(3'-bromo-4'-chlorobenzoyl)-1-methylpyrrole-2-acet- ic acid.
[0171] (C)
6-Methyl-5-(3'-Bromo-4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-o-
xapentalen-2-one
[0172] 5-(3'-bromo-4'-chlorobenzoyl)-1-methylpyrrole-2-acetic acid
is subjected to the procedure of Example 1, part C to produce
6-methyl-5-(3'-Bromo-4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-
-2-one (R.sub.1=H, R.sub.2=H, R.sub.3=3'-bromo-4'-chlorophenyl,
R.sub.4=CH.sub.3, R.sub.5=H, Y=CO, m=1, n=0).
EXAMPLE 17
6-Methyl-5-(2',3',5'-Tribromobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-
-One
[0173] (A) Methyl 5-(2',3
',5'-tribromobenzoyl)-1-methylpyrrole-2-acetate
[0174] By repeating the Friedel-Crafts procedures of Example 11
with an equivalent amount of an appropriately substituted benzoyl
chloride, methyl
5-(2',3',5'-tribromobenzoyl)-1-methylpyrrole-2-acetate is
obtained.
[0175] (B) 5-(2',3',5'-tribromobenzoyl)-1-methylpyrrole-2-acetic
acid
[0176] The transformation of the acetic acid ester of part (A) to
its acetic acid is performed according to the hydrolysis procedure
of Example 11B is repeated with an equivalent amount of the pyrrole
acetate obtained in part (A) to yield
5-(2',3',5'-tribromobenzoyl)-1-methylpyrrole-2-aceti- c acid.
[0177] (C)
6-Methyl-5-(2',3',5'-tribromobenzoyl)-1,3,6-trihydro-6-aza-3-ox-
apentalen-2-one
[0178] 5-(2',3',5'-tribromobenzoyl)-1-methylpyrrole-2-acetic acid
is subjected to the procedure of Example 1, part C to produce
6-methyl-5-(2',3',5'-tribromobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen--
2-one (R.sub.1=H, R.sub.2=H, R.sub.3=2',3',5'-tribromophenyl,
R.sub.4=CH.sub.3, R.sub.5=H, Y=CO, m=1, n=0).
EXAMPLE 18
6-Methyl-5-(3',4',5'-Trimethoxybenzoyl)-1,3,6-Trihydro
-6-Aza-3-Oxapentalen-2-One
[0179] (A) Methyl
5-(3',4',5'-trimethoxybenzoyl)-1-methylpyrrole-2-acetate
[0180] By repeating the Friedel-Crafts procedures of Example 11
with an equivalent amount of an appropriately substituted benzoyl
chloride, methyl
5-(3',4',5'-trimethoxybenzoyl)-1-methylpyrrole-2-acetate is
obtained.
[0181] (B) 5-(3',4',5'-trimethoxybenzoyl)-1-methylpyrrole-2-acetic
acid
[0182] The transformation of the acetic acid ester of part (A) to
its acetic acid is performed according to the hydrolysis procedure
of Example 11B is repeated with an equivalent amount of the pyrrole
acetate obtained in part (A) to yield
5-(3',4',5'-trimethoxybenzoyl)-1-methylpyrrole-2-ace- tic acid.
[0183] (C)
6-Methyl-5-(3',4',5'-trimethoxybenzoyl)-1,3,6-trihydro-6-aza-3--
oxapentalen-2-one
[0184] 5-(3',4',5'-trimethoxybenzoyl)-1-methylpyrrole-2-acetic acid
is subjected to the procedure of Example 1, part C to produce
6-methyl-5-(3',4',5'-trimethoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentale-
n-2-one (R.sub.1=H, R.sub.2=H, R.sub.3=3',4',5'-trimethoxyphenyl,
R.sub.4=CH.sub.3, R.sub.5=H, Y=CO, m=1, n=0).
EXAMPLE 19
6-Methyl-5-(p-Acetaminobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
(A) 5-(p-Nitrobenzoyl)-1-methylpyrrole-2-acetonitrile
[0185] A solution of 46.4 g. (0.25 mole) of p-nitrobenzoyl chloride
in 100 ml. 1,2-dichloroethane is added portionwise to a suspension
of 32.2 g. (0.25 mole) aluminum cloride in 100 ml.
1,2-dichloroethane. This mixture is added dropwise to a chilled
solution of 30.0 g. (0.25 mole) 1-methylpyrrole-2-acetonitrile in
100 ml. 1,2-dichloroethane. After the addition is complete, the
mixture is stirred for twenty minutes at room temperature and then
refluxed for four minutes. It is poured into ice acidified with 2N
hydrochloric acid. The organic phase is separated and washed
successively with N,N-dimethyl-1,3-propanediamine, 3N hydrochloric
acid and saturated sodium chloride solution. It is then dried over
magnesium sulfate and the solvent evaporated in vacuo. The
resulting semi-solid residue is triturated with cold methanol from
which the product,
5-(p-nitrobenzoyl)-1-methylpyrrole-2-acetonitrile, crystallizes. It
is removed by filtration and purified by recrystallization from
acetone, m.p. 167-169.degree. C.
[0186] (B) 5-(p-Aminobenzoyl)-1-methylpyrrole-2-acetonitrile
[0187] A solution of 7 g. (0.026 mole) of
5-(p-nitrobenzoyl)-1-methylpyrro- le-2-acetonitrile in 450 ml. of
ethyl acetate containing 1 g. palladium-on-carbon catalyst is
hydrogenated in a Parr shaker under 44 p.s.i. of hydrogen until the
theoretical amount of hydrogen is consumed. The catalyst is
filtered off, and the solvent evaporated in vacuo. A yellow solid,
5-(p-aminobenzoyl)-1-methylpyrrole-2-acetonitrile remains, m.p.
137-142.degree. C.
[0188] (C) 5-(p-Acetaminobenzoyl)-1-methylpyrrole-2-acetic acid
[0189] A suspension of 6.0 g. (0.025 mole) of
5-(p-aminobenzoyl)-1-methylp- yrrole-2-acetonitrile, 25 ml. 95%
ethanol and 25 ml. /N sodium hydroxide is refluxed overnight. The
ethanol is then evaporated in vacuo, and the remaining suspension
is poured into ice acidified with dilute hydrochloric acid to pH 5.
The resulting solid is partitioned between sodium bicarbonate
solution and chloroform. The insoluble substances are filtered from
the two-phase mixture. The sodium bicarbonate layer is separated
and acidified slowly with dilute hydrochloric acid. Solids
precipitate at various pHs which are separated by filtration. The
desired product, 5-(p-aminobenzoyl)-1-methylpyrrole-2-acetic acid,
precipitates at pH 3, m.p. 173-175.degree. C. Acylation with acetic
anhydride in pyridine yields the title compound.
[0190] (D)
6-Methyl-5-(p-Acetaminobenzoyl)-1,3,6-trihydro-6-aza-3-oxapenta-
len-2-one
[0191] 5-(p-Acetaminobenzoyl)-1-methylpyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
6-methyl-5-(p-aminobenzo-
yl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R.sub.1=H, R.sub.2=H,
R.sub.3=p-acetaminophenyl, R.sub.4=CH.sub.3, R.sub.5=H, Y=CO, m=1,
n=0).
EXAMPLE 20
6-Methyl-5-(p-Nitrobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0192] (A) Ethyl 5-(1p-Nitrobenzyl)-1-methylpyrrole-2-acetate
[0193] A solution of 5.5 g. (0.03 mole) of p-nitrobenzoyl chloride
in 60 ml. methylene chloride is added to a suspension of 3.9 g.
(0.03 mole) aluminum chloride in 20 ml. methylene chloride. The
resulting suspension is added dropwise to a chilled (-15.degree.
C.) solution of ethyl 1-methylpyrrole-2-acetate in 50 ml. methylene
chloride. The solution is stirred for 15 minutes at -10.degree. C.
and at room temperature for 15 minutes. The reaction mixture is
poured into ice-dilute hydrochloric acid. The organic phase is
separated and washed successively with
N,N-dimethyl-1,3-propanediamine, 3N hydrochloric acid and a
saturated solution of sodium chloride, dried over anhydrous
magnesium sulfate, and the solvent evaporated in vacuo. A solid,
ethyl 5-(p-nitrobenzoyl)-1-meth- ylpyrrole-2-acetate, crystallizes
from the remaining oily residue which is isolated by
recrystallization from methanol, m.p. 103-106.degree. C.
[0194] (B) 5-(p-Nitrobenzoyl)-1-methylpyrrole-2-acetic acid
[0195] A solution of 3.2 g. (0.01 mole) of ethyl
5-(p-nitrobenzoyl)-1-meth- ylpyrrole-2-acetate and 25 ml. ethanol
is brought to reflux. To this is added dropwise 10 ml. of 1N sodium
hydroxide solution. After the addition is complete, the ethanol is
evaporated and the residue is acidified with dilute hydrochloric
acid. The resulting solid, 5-(p-nitrobenzoyl)-1-methy-
lpyrrole-2-acetic acid, is separated by filtration and purified by
recrystallization from ethanol, m.p. 192-195.degree. C.
[0196] (C)
6-Methyl-5-(p-nitrobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen--
2-one
[0197] 5-(p-Nitrobenzoyl)-1-methylpyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
6-methyl-5-(p-nitrobenzoyl)-
-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R.sub.1=H, R.sub.2=H,
R.sub.3=p-nitrophenyl, R.sub.4=CH.sub.3, R.sub.5=H, Y=CO, m=1,
n=0).
EXAMPLE 21
6-Methyl-5-(p-Cyanobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0198] (A) Ethyl 5-(p-cyanobenzoyl)-1-methylpyrrole-2-acetate
[0199] A solution of 5.0 g. (0.03 mole) of p-cyanobenzoyl chloride
in 60 ml. of methylene chloride is added to a suspension of 40 g.
of aluminum chloride in 30 ml. methylene chloride. The resulting
mixture is added dropwise to a chilled solution of 5.0 g. (0.03
mole) of ethyl 1-methylpyrrole-2-acetate in 15 ml. of methylene
chloride. The resulting mixture is stirred at room temperature for
20 minutes, and then poured into ice acidified with dilute
hydrochloric acid. The organic phase is separated, washed
successively with N,N-dimethylaminopropylamine, 3N hydrochloric
acid and brine, and dried over anhydrous magnesium sulfate. The
solvent is evaporated in vacuo. The resulting solid, which
separates from the oily residue on standing, is recrystallized from
methanol to give pure ethyl
5-(p-cyanobenzoyl)-1-methylpyrrole-2-acetate, m.p. 117-120.degree.
C.
[0200] (B) 5-(p-Cyanobenzoyl)-1-methylpyrrole-2-acetic acid
[0201] A solution of 0.5 g. (0.0017 mole) of ethyl
5-(p-cyanobenzoyl)-1-me- thylpyrrole-2-acetate in 3 ml. ethanol is
brought to reflux and 1.7 ml. of IN sodium hydroxide solution is
added dropwise. The mixture is refluxed for 3 minutes, and the
ethanol is then evaporated in vacuo. The residue is diluted with
water and acidified with dilute hydrochloric acid. A white solid
precipitates, 5-(p-cyanobenzoyl)-1-methylpyrrole-2-acetic acid,
which is collected by filtration and dried, m.p. 196-198.degree.
C.
[0202] (C)
6-Methyl-5-(p-cyanobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen--
2-one
[0203] 5-(p-Cyanobenzoyl)-1-methylpyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
6-methyl-5-(p-cyanobenzoyl)-
-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R.sub.1=H, R.sub.2=H,
R.sub.3=p-cyanophenyl, R.sub.4=CH.sub.3, R.sub.5=H, Y=CO, m=1,
n=0).
EXAMPLE 22
Rac-1,6-Dimethyl-5-(p-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2--
One
[0204] (A) Ethyl
5-(p-chlorobenzoyl)-.alpha.-methyl-1-methylpyrrole-2-acet- ate
[0205] A solution of 6.68 g. (0.0219 mole) of ethyl
5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetate in 50 ml. of ether is
added to a solution of 0.94 g. (0.024 mole) of sodamide in about
150 ml. of liquid ammonia at -33.degree. C. The mixture is allowed
to reflux for 15 minutes and 3.10 g. (0.0219 mole) of methyl iodide
is added. The mixture is stirred for one hour; then the ammonia is
allowed to boil off. Ether and enough ammonium chloride to
neutralize any anion are added. The mixture is poured into dilute
hydrochloric acid and the ether solution is separated and washed
with sodium bisulfite solution, sodium bicarbonate solution and
brine. It is dried over anhydrous magnesium sulfate and evaporated
to give an oily residue whch crystallizes upon standing. The solid
is recrystallized successively from cyclohexane and methanol to
give a white crystalline solid, ethyl
5-(p-chlorobenzoyl)-.alpha.-methyl-- 1-methylpyrrole-2-acetate,
m.p. 67-68.degree. C.
[0206] (B)
5-(p-Chlorobenzyl)-.alpha.-methyl-1-methylpyrrole-2-acetic acid
[0207] A solution of 4.05 g. (0.0126 mole) of ethyl
5-(p-chlorobenzoyl-.alpha.-methyl-1-methylpyrrole-2-acetate, 15 ml.
of 1N sodium hydroxide solution and 2 ml. of ethanol is refluxed
for 30 minutes. The solution is cooled, diluted with water and
filtered. The filtrate is acidified with dilute hydrochloric acid.
The precipitated solid is collected and recrystallized from
methanol-water to give a white crystalline solid,
5-(p-chlorobenzoyl)-.alpha.-methyl-1-methylpyrrole-2-a- cetic acid,
m.p. 135-136.degree. C. Analysis: Calcd. for
Cl.sub.5H.sub.14ClNO.sub.3: C, 61.76; H, 4.83; N, 4.82% Found: C,
61.68:H, 4.86; N, 4.89%
[0208] (C)
5-(p-Chlorobenzoyl)-.alpha.-methyl-1-methylpyrrole-2-acetonitri- le
To a suspension of sodium hydride (12.2 g. of 50% w/w NaH in
mineral oil) in 1,2-dimethoxyethane is added
5-(p-chlorobenzoyl)-1-methylpyrrole-- 2-acetonitrile (62.6 g., 0.24
mole) in 1,2-dimethoxyethane over a period of 1/2 hr. at room
temperature. After the addition is complete, the mixture is stirred
for 1 hour and then 35 g. (0.25 mole) of methyl iodide is added.
The reaction mixture is stirred for an additional 3 hours,
concentrated under reduced pressure, diluted with water and
extracted with chloroform. After drying, the chloroform is removed
leaving a brown solid residue which is triturated with cold
methanol to give yellow crystals of
5-(p-chlorobenzoyl)-.alpha.-methyl-1-methylpyrrole-2-acetonit-
rile, m.p. 145-148.degree. C. Two recrystallizations from methanol
raises the m.p. to 151.5-152.5.degree. C.
[0209] (D)
5-(p-Chlorobenzoyl)-.alpha.-methyl-1-methylpyrrole-2-acetic
acid
[0210] 27.1 g. (0.1 mole) sample of
5-(p-chlorobenzoyl)-.alpha.-methyl-1-m- ethylpyrrole-2-acetonitrile
is hydrolyzed by refluxing for 16 hours with 8 g. (0.2 mole) of
sodium hydroxide in 350 ml. of aqueous ethanol. Upon concentration
in vacuo, the sodium salt separates which is filtered off and
dissolved in water. After acidification with dilute HCl, the
corresponding acid,
5-(p-chlorobenzoyl)-.alpha.-methyl-1-methylpyrrole-2-- acetic acid,
precipitates. The original basic filtrates are also acidified,
extracted with chloroform and concentrated. The residual solid is
combined with the previous solid and recrystallized from
methanol-water to give the pure product,
5-(p-chlorobenzoyl)-.alpha.-meth- yl-1-methylpyrrole-2-acetic acid,
m.p. 139-141.degree. C.
[0211] (E)
Rac-1,6-dimethyl-5-(p-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxa-
pentalen-2-one
[0212] 5-(p-Chlorobenzoyl)-.alpha.-methyl-1-methylpyrrole-2-acetic
acid is subjected to the procedure of Example 1, part C to yield
rac-1,6-dimethyl-5-(p-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-
-one (R.sub.1=CH.sub.3, R.sub.2=H, R.sub.3=p-chlorophenyl,
R.sub.4=CH.sub.3, R.sub.5=H, Y=CO, m=l, n=0).
EXAMPLE 23
[0213] Rac-1-Ethyl-6-Methyl-5-(p-Chlorobenzoyl)-1,3,6-Trihydro
-6-Aza-3-Oxapentalen-2-One
[0214] (A)
5-(p-Chlorobenzoyl)-.alpha.-ethyl-1-methylpyrrole-2-acetic acid
[0215] A solution of 6.5 g (0.021 mole) of ethyl
5-(p-chlorobenzoyl)-1-met- hylpyrrole-2-acetate in 60 ml. of ether
is added to a suspension of 1.25 g. (0.032 mole) of sodamide in 150
ml. of refluxing liquid ammonia. After 10 minutes, 4.98 g. (0.032
mole) of ethyl iodide is added. The mixture is stirred for 1.5
hours, and an additional 1.0 g. (0.0064 mole) of ethyl iodide is
added. Stirring is continued for 30 minutes and ammonium chloride
is then added to neutralize any anion. The mixture is allowed to
warm to room temperature and the ammonia allowed to escape. Ether
is added, and the mixture poured into dilute hydrochloric acid. The
ether layer is separated, and the aqueous layer is washed with
ether. The combined ether solutions are washed successively with
sodium bisulfite solution and brine and then dried over anhydrous
magnesium sulfate. The solvent is evaporated in vacuo to give about
7.4 g. of a yellow oily residue containing ethyl
5-(p-chlorobenzoyl)-.alpha.-ethyl-1-methylpyrrol- e-2-acetate,
which is used as such in the following transformation to acid
procedure. A 6.9 g. sample of the oily residue is dissolved in 30
ml. of ethanol and 11.4 ml. of 1N sodium hydroxide is added. The
mixture is refluxed for 1 hour. The solvent is then evaporated in
vacuo, and the residue partitioned between ether and water. The
aqueous layer is separated and acidified with dilute hydrochloric
acid. The precipitated oil, which is separated, crystallizes on
scratching to give a solid,
5-(p-chlorobenzoyl)-.alpha.-ethyl-1-methylpyrrole-2-acetic acid,
which is collected and dried, m.p. 108-112.degree. C. After
successive recrystallizations from ether-methylcyclohexane,
benzene-hexane, methylcyclohexane and ether-hexane, the m.p. is
110-114.degree. C. Analysis: Calcd. for C.sub.16H.sub.16ClNO.sub.3:
C, 62.84;H, 5.27; N, 4.58% Found: C, 63.01;H, 5.36; N, 4.61%
[0216] (B)
Rac-1-ethyl-6-methyl-5-(p-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-
-oxapentalen-2-one
[0217] 5-(p-Chlorobenzoyl)-.alpha.-ethyl-1-methylpyrrole-2-acetic
acid is subjected to the procedure of Example 1, part C to produce
rac-1-ethyl-6-methyl-5-(p-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapental-
en-2-one (R.sub.1=ethyl, R.sub.2=H, R.sub.3=p-chlorophenyl,
R.sub.4=CH.sub.3, R.sub.5=H, Y=CO, m=1, n=0).
EXAMPLE 24
[0218]
Rac-1-(n-Butyl)-6-Methyl-5-Benzoyl-1,3,6-Trihydro-6-Aza-3-Oxapental-
en-2-One
[0219] (A) 5-Benzoyl-.alpha.-(N-butyl)-1-methylpyrrole-2-acetic
acid
[0220] The alkylation and ester-to-acid transformation procedures
of Example 23 are repeated except that an equivalent amount of an
appropriate 5-Aryl-1-methylpyrrole-2-acetic acid alkyl ester and an
equivalent amount of an appropriate alkyl halide alkylating agent
are employed to yield
5-benzoyl-.alpha.-(n-butyl)-1-methylpyrrole-2-acetic acid.
[0221] (B)
Rac-1-(n-butyl)-6-methyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxape-
ntalen-2-one
[0222] 5-Benzoyl-.alpha.-(n-butyl)-1-methylpyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
rac-1-(n-butyl)-6-methyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-o-
ne (R.sub.1=n-butyl, R.sub.2=H, R.sub.3=phenyl, R.sub.4=CH.sub.3,
R.sub.5=H, Y=CO, m=1, n=0).
EXAMPLE 25
[0223] Rac-1,6-Dimethyl-5-(4'-Methoxybenzoyl)-1,3,6-Trihydro
-6-Aza-3-Oxapentalen-2-One
[0224] (A)
5-(p-Methoxybenzoyl)-.alpha.-methyl-1-methylpyrrole-2-acetic
acid
[0225] The alkylation and ester-to-acid transformation procedures
of Example 23 are repeated except that an equivalent amount of an
appropriate 5-Aryl-1-methylpyrrole-2-acetic acid alkyl ester and an
equivalent amount of an appropriate alkyl halide alkylating agent
are employed to yield
5-(p-methoxybenzoyl)-.alpha.-methyl-1-methylpyrrole-2-a- cetic
acid.
[0226] (B)
Rac-1,6-dimethyl-5-(4'-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-o-
xapentalen-2-one
[0227] 5-(p-Methoxybenzoyl)-(x-methyl-1-methylpyrrole-2-acetic acid
is subjected to the procedure of Example 1, part C to produce
rac-1,6-dimethyl-5-(4'-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-
-2-one (R.sub.1=CH.sub.3, R.sub.2=H, R.sub.3=4'-methoxyphenyl,
R.sub.4=CH.sub.3, R.sub.5=H, Y=CO, m=1, n=0).
EXAMPLE 26
Rac-1-(n-Propyl)-6-Methyl-5-Benzoyl-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-O-
ne
[0228] (A) 5-Benzoyl-.alpha.-(n-propyl)-1-methylpyrrole-2-acetic
acid
[0229] The alkylation and ester-to-acid transformation procedures
of Example 23 are repeated except that an equivalent amount of an
appropriate 5-Aryl-1-methylpyrrole-2-acetic acid alkyl ester and an
equivalent amount of an appropriate alkyl halide alkylating agent
are employed to yield
5-benzoyl-.alpha.-(n-propyl)-1-methylpyrrole-2-acetic acid.
[0230] (B)
Rac-1-(n-propyl)-6-methyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxap-
entalen-2-one
[0231] 5-Benzoyl-.alpha.-(n-propyl)-1-methylpyrrole-2-acetic acid
is subjected to the procedure of Example 1, part C to produce
rac-1-(n-propyl)-6-methyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2--
one (R.sub.1=n-propyl, R.sub.2=H, R.sub.3=phenyl, R.sub.4=CH.sub.3,
R.sub.5H, Y=CO, m=1, n=0).
EXAMPLE 27
Rac-1,6-Dimethyl-5-(4'-Cyanobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2--
One
[0232] (A)
5-(p-Cyanobenzoyl)-.alpha.-methyl-1-methylpyrrole-2-acetic acid
[0233] The alkylation and ester-to-acid transformation procedures
of Example 23 are repeated except that an equivalent amount of an
appropriate 5-Aryl-1-methylpyrrole-2-acetic acid alkyl ester and an
equivalent amount of an appropriate alkyl halide alkylating agent
are employed to yield
5-(p-cyanobenzoyl)-.alpha.-methyl-1-methylpyrrole-2-ace- tic
acid.
[0234] (B)
Rac-1,6-dimethyl-5-(4'-cyanobenzoyl)-1,3,6-trihydro-6-aza-3-oxa-
pentalen-2-one
[0235] 5-(p-Cyanobenzoyl)-.alpha.-methyl-1-methylpyrrole-2-acetic
acid is subjected to the procedure of Example 1, part C to produce
(R.sub.1=CH.sub.3, R.sub.2=H, R.sub.3=4'-cyanophenyl,
R.sub.4=CH.sub.3, R.sub.5=H, Y=CO, m=1, n=0).
EXAMPLE 28
Rac-1,6-Dimethyl-5-(3'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-
-One
[0236] (A)
5-(m-Chlorobenzoyl)-.alpha.-methyl-1-methylpyrrole-2-acetic
acid
[0237] The alkylation and nitrile-to-acid transformation procedures
of Examples 22C and 22D, respectively, are repeated except that an
equivalent amount of an appropriate
5-Aryl-1-methylpyrrole-2-acetonitrile and an equivalent amount of
an appropriate alkyl halide alkylating agent are employed to yield
5-(m-chlorobenzoyl)-.alpha.-methyl-1-methylpyrrole-- 2-acetic
acid.
[0238] (B)
Rac-1,6-dimethyl-5-(3'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-ox-
apentalen-2-one
[0239] 5-(m-Chlorobenzoyl)-.alpha.-methyl-1-methylpyrrole-2-acetic
acid is subjected to the procedure of Example 1, part C to produce
rac-1,6-dimethyl-5-(3'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen--
2-one (R.sub.1=CH.sub.3, R.sub.2H, R.sub.3=3'-chlorophenyl,
R.sub.4=CH.sub.3, R.sub.5=H, Y=CO, m=1, n=0).
EXAMPLE 29
Rac-1-Ethyl-6-Methyl-5-(4'-Fluorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapental-
en-2-One
[0240] (A)
5-(p-Fluorobenzoyl)-.alpha.-ethyl-1-methylpyrrole-2-acetic acid
[0241] The alkylation and nitrile-to-acid transformation procedures
of Examples 22C and 22D, respectively, are repeated except that an
equivalent amount of an appropriate
5-Aryl-1-methylpyrrole-2-acetonitrile and an equivalent amount of
an appropriate alkyl halide alkylating agent are employed to yield
5-(p-fluorobenzoyl)-.alpha.-ethyl-1-methylpyrrole-2- -acetic
acid.
[0242] (B)
rac-1-ethyl-6-methyl-5-(4'-fluorobenzoyl)-1,3,6-trihydro-6-aza--
3-oxapentalen-2-one
[0243] 5-(p-Fluorobenzoyl)-.alpha.-ethyl-1-methylpyrrole-2-acetic
acid is subjected to the procedure of Example 1, part C to produce
rac-1-ethyl-6-methyl-5-(4'-fluorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapenta-
len-2-one (R.sub.1=ethyl, R.sub.2=H, R.sub.3=4-fluorophenyl,
R.sub.4=CH.sub.3, R.sub.5=H, Y=CO, m=1, n=0).
EXAMPLE 30
Rac-1
6-Dimethyl-5-(4'-Methylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-
-One
[0244] (A)
5-(p-Methylbenzoyl)-.alpha.-ethyl-1-methylpyrrole-2-acetic acid
[0245] The alkylation and nitrile-to-acid transformation procedures
of Examples 22C and 22D, respectively, are repeated except that an
equivalent amount of an appropriate
5-Aryl-1-methylpyrrole-2-acetonitrile and an equivalent amount of
an appropriate alkyl halide alkylating agent are employed to yield
5-(p-methylbenzoyl)-.alpha.-ethyl-1-methylpyrrole-2- -acetic
acid.
[0246] (B)
rac-1,6-dimethyl-5-(4'-methylbenzoyl)-1,3,6-trihydro-6-aza-3-ox-
apentalen-2-one
[0247] 5-(p-Methylbenzoyl)-.alpha.-ethyl-1-methylpyrrole-2-acetic
acid is subjected to the procedure of Example 1, part C to produce
rac-1,6-dimethyl-5-(4'-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen--
2-one (R.sub.1=CH.sub.3, R.sub.2=H, R.sub.3=4'-Methylphenyl,
R.sub.4=CH.sub.3, R.sub.5=H, Y=CO, m=1, n=0).
EXAMPLE 31
Rac-1,6-Dimethyl-5-(2',4'-Dichlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapenta-
len-2-One
[0248] (A)
5-(2',4'-Dichlorobenzoyl)-.alpha.-methyl-1-methylpyrrole-2-acet- ic
acid
[0249] The alkylation and nitrile-to-acid transformation procedures
of Examples 22C and 22D, respectively, are repeated except that an
equivalent amount of an appropriate
5-Aryl-1-methylpyrrole-2-acetonitrile and an equivalent amount of
an appropriate alkyl halide alkylating agent are employed to yield
5-(2',4'-dichlorobenzoyl)-.alpha.-methyl-1-methylpy- rrole-2-acetic
acid.
[0250] (B)
rac-1,6-dimethyl-5-(2',4'-dichlorobenzoyl)-1,3,6-trihydro-6-aza-
-3-oxapentalen-2-one
[0251]
5-(2',4'-Dichlorobenzoyl)-.alpha.-methyl-1-methylpyrrole-2-acetic
acid is subjected to the procedure of Example 1, part C to produce
rac-1,6-dimethyl-5-(2',4'-dichlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapent-
alen-2-one (R.sub.1=CH.sub.3, R.sub.2=H,
R.sub.3=2',4'-dichlorophenyl, R.sub.4=CH.sub.3, R.sub.5=H, Y=CO,
m=1, n=0).
EXAMPLE 32
Rac-1-Ethyl-6-Methyl-5-(3'-Chloro-4'-Methylbenzoyl)-1,3,6-Trihydro-6-Aza-3-
-Oxapentalen-2-One
[0252] (A)
5-(3'-Chloro-4'-methylbenzoyl)-.alpha.-ethyl-1-methylpyrrole-2--
acetic acid.
[0253] The alkylation and nitrile-to-acid transformation procedures
of Examples 22C and 22D, respectively, are repeated except that an
equivalent amount of an appropriate
5-Aryl-1-methylpyrrole-2-acetonitrile and an equivalent amount of
an appropriate alkyl halide alkylating agent are employed to yield
5-(3'-chloro-4'-methylbenzoyl)-.alpha.-ethyl-1-meth-
ylpyrrole-2-acetic acid.
[0254] (B)
rac-1-ethyl-6-methyl-5-(3'-chloro-4'-methylbenzoyl)-1,3,6-trihy-
dro-6-aza-3-oxapentalen-2-one
[0255]
5-(3'-Chloro-4'-methylbenzoyl)-.alpha.-ethyl-1-methylpyrrole-2-acet-
ic acid is subjected to the procedure of Example 1, part C to
produce
rac-1-ethyl-6-methyl-5-(3'-chloro-4'-methylbenzoyl)-1,3,6-trihydro-6-aza--
3-oxapentalen-2-one (R.sub.1=CH.sub.3, R.sub.2=H,
R.sub.3=3'-Chloro-4'-Met- hylphenyl, R.sub.4=CH.sub.3, R.sub.5=H,
Y=CO, m=1, n=0).
EXAMPLE 33
5-(4'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0256] (A) 5-(p-Chlorobenzoyl)-pyrrole-2-acetonitrile
[0257] To a chilled suspension of 26.80 g. (0.2 mole) of aluminum
chloride in 110 ml. of methylene chloride is added dropwise 35 g.
(0.2 mole) of p-chlorobenzoyl chloride. The mixture is added
dropwise to a solution of 21.22 g. (0.2 mole) of
pyrrole-2-acetonitrile in 125 ml. methylene chloride which is
cooled externally with an ammonium chloride ice bath. After
addition is complete, the reaction mixture is stirred for ten
minutes at 0.degree. C. and then poured into ice acidified with
dilute hydrochloric acid. A solid precipitate,
5-(p-chlorobenzoyl)-pyrrole-2-ace- tonitrile, which is filtered
off, washed with hot methanol and dried, m.p. 203-205.degree.
C.
[0258] (B) 5-(p-Chlorobenzoyl)-pyrrole-2-acetic acid
[0259] A solution of 3.6 g. (0.015 mole) of
5-(p-chlorobenzoyl)-pyrrole-2-- acetonitrile, 30 ml. 1N sodium
hydroxide solution, and 30 ml. 95% ethanol is refluxed and stirred
for 6 hours. The ethanol is evaporated off in vacuo. The resulting
solid is dissolved in water and the solution filtered from
insolubles. The filtrate is acidified with dilute hydrochloric
acid. A white solid precipitates, 5-(p-chlorobenzoyl)-pyrrol-
e-2-acetic acid, which is purified by recrystallization from
acetone water (1:1), m.p. 210.degree. C.
[0260] (C) BOC 5-(p-chlorobenzoyl)-pyrrole-2-acetic acid
[0261] The pyrrole nitrogen is protected with the t-butyl carbamate
group employing (BOC).sub.20 as a reagent according to D. S.
Tarbell Proc. Natl. Acad. Sci (USA), 69, 730 (1972).
[0262] (D) BOC
5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalene-2--
one
[0263] BOC 5-(p-chlorobenzoyl)-pyrrole-2-acetic acid is subjected
to the procedure of Example 1, part C to produce BOC
5-(4'-chlorobenzoyl)-1,3,6-- trihydro-6-aza-3-oxapentalen-2-one
[0264] (C)
5-(4'-Chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalene-2-one
[0265] The BOC group is removed from the BOC-lactone employing
trifluoroacetic acid as a reagent according to Y. Masui, Bull.
Chem. Soc. Japan 53, 464 (1980)(R.sub.1=H, R.sub.2=H,
R.sub.3=4'-chlorophenyl, R.sub.4=H, R.sub.5=H, Y=CO, m=1, n=0).
EXAMPLE 34
5-Benzoyl-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0266] (A) 5-Benzoyl-pyrrole-2-acetonitrile
[0267] The procedure of Example 33A is repeated, except that an
equivalent amount of an appropriate benzoyl chloride is used in
place of the p-chlorobenzoyl chloride used therein
5-benzoyl-pyrrole-2-acetonitrile is obtained.
[0268] (B) 5-Benzoyl-pyrrole-2-acetic acid
[0269] The procedure of Example 33B is repeated using an equivalent
amount of 5-benzoyl-pyrrole-2-acetonitrile obtained in part A of
this Example in place of 5-(p-chlorobenzoyl)-pyrrole-2-acetonitrile
to yield 5-benzoyl-pyrrole-2-acetic acid.
[0270] (C) BOC 5-benzoyl-pyrrole-2-acetic acid
[0271] The procedure of Example 33C is repeated using
5-benzoyl-pyrrole-2-acetic acid to produce BOC
5-benzoyl-pyrrole-2-acetic acid.
[0272] (D) BOC
5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one
[0273] BOC 5-benzoyl-pyrrole-2-acetic acid is subjected to the
procedure of Example 1, part C to produce BOC
5-benzoyl-1,3,6-trihydro-6-aza-3-oxap- entalen-2-one.
[0274] (E) 5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one
[0275] The procedure of Example 33E is repeated using BOC
5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one to produce
5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R.sub.1=H,
R.sub.2=H, R.sub.3=phenyl, R.sub.4=H, R.sub.5=H, Y=CO, m=1,
n=0).
EXAMPLE 35
5-(p-Fluorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0276] (A) 5-(p-Fluorobenzoyl)-pyrrole -2-acetonitrile
[0277] The procedure of Example 33A is repeated, except that an
equivalent amount of an appropriate benzoyl chloride is used in
place of the p-chlorobenzoyl chloride used therein to give
5-(p-fluorobenzoyl)-pyrrole -2-acetonitrile.
[0278] (B) 5-(p-Fluorobenzoyl)-pyrrole-2-acetic acid
[0279] The procedure of Example 33B is repeated using an equivalent
amount of 5-(p-fluorobenzoyl)-pyrrole-2-acetonitrile obtained in
part A of this Example in place of
5-(p-chlorobenzoyl)-pyrrole-2-acetonitrile to yield
5-(p-fluorobenzoyl)-pyrrole-2-acetic acid.
[0280] (C) BOC 5-(p-fluorobenzoyl)-pyrrole-2-acetic acid
[0281] The procedure of Example 33C is repeated using
5-(p-fluorobenzoyl)-pyrrole-2-acetic acid to give BOC
5-(p-fluorobenzoyl)-pyrrole-2-acetic acid.
[0282] (D) BOC
5-(p-fluorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-on- e
[0283] BOC 5-(p-fluorobenzoyl)-pyrrole-2-acetic acid is subjected
to the procedure of Example 1, part C to produce BOC
5-(p-fluorobenzoyl)-1,3,6-t- rihydro-6-aza-3-oxapentalen-2-one.
[0284] (E)
5-(p-Fluorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one
[0285] The procedure of Example 33E is repeated using BOC
5-(p-fluorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one to
give 5-(p-fluorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one
(R.sub.1=H, R.sub.2H, R.sub.3=4'-fluorophenyl, R.sub.4=H,
R.sub.5=H, Y=CO, m=1, n 0).
EXAMPLE 36
5-(p-Methylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0286] (A) 5-(p-methylbenzoyl)-pyrrole-2-acetonitrile
[0287] The procedure of Example 33A is repeated, except that an
equivalent amount of an appropriate benzoyl chloride is used in
place of the p-chlorobenzoyl chloride used therein
5-(p-methylbenzoyl)-pyrrole-2-aceto- nitrile is obtained.
[0288] (B) 5-(p-Methylbenzoyl)-pyrrole-2-acetic acid
[0289] The procedure of Example 33B is repeated using an equivalent
amount of each pyrrole-acetonitrile obtained in part A of this
Example in place of 5-(p-chlorobenzoyl)-pyrrole-2-acetonitrile to
yield 5-(p-methylbenzoyl)-pyrrole-2-acetic acid.
[0290] (C) BOC 5-(p-methylbenzoyl)-pyrrole-2-acetic acid.
[0291] The procedure of Example 33C is repeated using
5-(p-methylbenzoyl)-pyrrole-2-acetic acid to give BOC
5-(p-methylbenzoyl)-pyrrole-2-acetic acid
[0292] (D) BOC
5-(p-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-on- e
[0293] BOC 5-(p-methylbenzoyl)-pyrrole-2-acetic acid is subjected
to the procedure of Example 1, part C to produce BOC
5-(p-methylbenzoyl)-1,3,6-t- rihydro-6-aza-3-oxapentalen-2-one.
[0294] (E)
5-(p-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one
[0295] The procedure of Example 33E is repeated using produce BOC
5-(p-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one to
yield 5-(p-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one
(R.sub.1=H, R.sub.2=H, R.sub.3=4'-methylphenyl, R.sub.4=H,
R.sub.5=H, Y=CO, m=1, n=0).
EXAMPLE 37
5-(p-Methoxybenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
(A) 5-(p-methoxybenzoyl)-pyrrole-2-acetonitrile
[0296] The procedure of Example 33A is repeated, except that an
equivalent amount of an appropriate benzoyl chloride is used in
place of the p-chlorobenzoyl chloride used therein
5-(p-methoxybenzoyl)-pyrrole-2-acet- onitrile is obtained.
[0297] (B) 5-(p-methoxybenzoyl)-pyrrole-2-acetic acid
[0298] The procedure of Example 33B is repeated using an equivalent
amount of 5-(p-methoxybenzoyl)-pyrrole-2-acetonitrile obtained in
part A of this Example in place of
5-(p-chlorobenzoyl)-pyrrole-2-acetonitrile to yield
5-(p-methoxybenzoyl)-pyrrole-2-acetic acid.
[0299] (C) BOC 5-(p-methoybenzoyl)-pyrrole-2-acetic acid
[0300] The procedure of Example 33C is repeated using
5-(p-methoxybenzoyl)-pyrrole-2-acetic acid to give BOC
5-(p-methoybenzoyl)-pyrrole-2-acetic acid.
[0301] (D) BOC
5-(p-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-o- ne
[0302] BOC 5-(p-methoxybenzoyl)-pyrrole-2-acetic acid is subjected
to the procedure of Example 1, part C to produce BOC
5-(p-methoxybenzoyl)-1,3,6--
trihydro-6-aza-3-oxapentalen-2-one.
[0303] (E)
5-(p-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one
[0304] The procedure of Example 33E is repeated using BOC
5-(p-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one to
produce
5-(p-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one
(R.sub.1=H, R.sub.2=H, R.sub.3=4'-methoxyphenyl, R.sub.4=H,
R.sub.5=H, Y=CO, m=1, n=0).
EXAMPLE 38
5-(3'-Chloro-4'-Methoxybenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0305] (A)
5-(3'-chloro-4'-methoxybenzoyl)-pyrrole-2-acetonitrile
[0306] The procedure of Example 33A is repeated, except that an
equivalent amount of an appropriate benzoyl chloride is used in
place of the p-chlorobenzoyl chloride used therein to give
5-(3'-chloro-4'-methoxybenz- oyl)-pyrrole-2-acetonitrile.
[0307] (B) 5-(3'-Chloro-4'-methylbenzoyl)-pyrrole-2-acetic acid
[0308] The procedure of Example 33B is repeated using an equivalent
amount of 5-(3'-chloro-4'-methoxybenzoyl)-pyrrole-2-acetonitrile
obtained in part A of this Example in place of
5-(p-chlorobenzoyl)-pyrrole-2-acetonit- rile to yield
5-(3'-chloro-4'-methylbenzoyl)-pyrrole-2-acetic acid.
[0309] (C) BOC 5-(3'-chloro-4'-methylbenzoyl)-pyrrole-2-acetic
acid
[0310] The procedure of Example 33C is repeated using
5-(3'-chloro-4'-methylbenzoyl)-pyrrole-2-acetic acid to yield BOC
5-(3'-chloro-4'-methylbenzoyl)-pyrrole-2-acetic acid.
[0311] (D) BOC
5-(3'-chloro-4'-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxap-
entalen-2-one
[0312] BOC 5-(3'-chloro-4'-methylbenzoyl)-pyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce BOC
5-(3'-chloro-4'-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one.
[0313] (E)
5-(3'-chloro-4'-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapenta-
len-2-one
[0314] The procedure of Example 33E is repeated using BOC
5-(3'-chloro-4'-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one
to yield
5-(3'-chloro-4'-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapental-
en-2-one (R.sub.1=H, R.sub.2=H, R.sub.3=3'-chloro-4'-methylphenyl,
R.sub.4=H, R.sub.5=H, Y=CO, m=1, n=0).
EXAMPLE 39
5-(2',4'-Dichlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0315] (A) 5-(2',4'-dichlorobenzoyl)-pyrrole-2-acetonitrile
[0316] The procedure of Example 33A is repeated, except that an
equivalent amount of an appropriate benzoyl chloride is used in
place of the p-chlorobenzoyl chloride to give
5-(2',4'-dichlorobenzoyl)-pyrrole-2-acet- onitrile.
[0317] (B) 5-(2',4'-dichlorobenzoyl)-pyrrole-2-acetic acid
[0318] The procedure of Example 33B is repeated using an equivalent
amount of 5-(2',4'-dichlorobenzoyl)-pyrrole-2-acetonitrile obtained
in part A of this Example in place of
5-(p-chlorobenzoyl)-pyrrole-2-acetonitrile to yield
5-(2',4'-dichlorobenzoyl)-pyrrole-2-acetic acid.
[0319] (C) BOC 5-(2',4'-dichlorobenzoyl)-pyrrole-2-acetic acid
[0320] The procedure of Example 33C is repeated using
5-(2',4'-dichlorobenzoyl)-pyrrole-2-acetic acid to produce BOC
5-(2',4'-dichlorobenzoyl)-pyrrole-2-acetic acid.
[0321] (D) BOC 5-(2',4
'-dichlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapental- en-2-one
[0322] BOC 5-(2',4'-dichlorobenzoyl)-pyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce BOC
5-(2',4'-dichlorobenzoy-
l)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one.
[0323] (E) 5-(2
',4'-dichlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-
-one
[0324] The procedure of Example 33E is repeated using BOC
5-(2',4'-dichlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one
to yield
5-(2',4'-dichlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one
(R.sub.1=H, R.sub.2=H, R.sub.3=2',4'-dichlorophenyl, R.sub.4=H,
R.sub.5=H, Y=CO, m=1, n=0).
EXAMPLE 40
6-Ethyl-5-(4'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0325] (A) 5-(p-chlorobenzoyl)-1-ethylpyrrole-2-acetonitrile
[0326] A mixture of 24.4 g. (0.1 mole)
5-(p-chlorobenzyl)-pyrrole-2-aceton- itrile, 41.7 g. (0.3 mole) of
potassium carbonate and 16.1 g. (0.105 mole) of ethyl iodide in 300
ml. of methylethylketone is refluxed overnight. The reaction
mixture is then poured into water and extracted with chloroform.
The organic solutions are combined, dried over anhydrous magnesium
sulfate, and the solvent evaporated in vacuo. The residue is
crystallized from 2-propanol to give about 13 g. of crude solid.
The solid is sublimed overnight at 140.degree. C. and 0.025 mm. Hg.
The sublimate is successively recrystallized from 2-propanol,
benzene and hexane to give
5-(p-chlorobenzoyl)-1-ethylpyrrole-2-acetonitrile as a white solid,
m.p. 145-147.degree. C. Analysis: Calcd. for
C.sub.15H.sub.13ClN.sub.2O: N, 10.2%. Found: N, 10.54%.
[0327] (B) 5-(p-chlorobenzoyl)-1-ethylpyrrole-2-acetic acid
[0328] A suspension of 3.52 g. (0.013 mole) of
5-(p-chlorobenzoyl)-1-ethyl- pyrrole-2-acetonitrile in 26 ml. 1N
sodium hydroxide and 50 ml. of ethanol is refluxed for six hours.
The mixture is then diluted with water and cooled. A solid
precipitates which is filtered off and set aside. The ethanol is
evaporated from the filtrate in vacuo. The collected precipitate is
added to the concentrated filtrate, and the mixture is extracted
with chloroform. The aqueous phase is separated, acidified with
dilute hydrochloric acid, and the resulting precipitate (A) is
collected by filtration and dried. The chloroform phase is
evaporated and the residue refluxed with 12 ml. of 1N sodium
hydroxide and 24 ml. of ethanol for 6 hours. The ethanol is
evaporated in vacuo, and the remaining solution is diluted with
water and washed with chloroform. The aqueous solution is acidified
with dilute hydrochloric acid and the precipitated solid (B) is
collected and dried. The two samples of acidic material (A and B)
are combined and recrystallized from aqueous isopropanol to give
5-(p-chlorobenzoyl)-1-ethylpyrrole-2-acetic acid as a white solid,
m.p. 149-153.degree. C. Analysis: Calcd. for
C.sub.15H.sub.14ClNO.sub.3: C, 61.75;H, 4.83; N, 4.80%. Found: C,
61.78;H, 4.94; N, 4.96%.
[0329] (C)
6-ethyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-
-2-one
[0330] 5-(p-Chlorobenzoyl)-1-ethylpyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to yield
6-ethyl-5-(4'-chlorobenzoyl)--
1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R.sub.1=H, R.sub.2=H,
R.sub.3=4'-chlorophenyl, R.sub.4=ethyl, R.sub.5H, Y=CO, m=1,
n=0).
EXAMPLE 41
6-(n-Propyl)-5-(4'-Methylphenyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0331] (A)
5-(p-methylbenzoyl)-1-(n-propyl)pyrrole-2-acetonitrile
[0332] The N-alkylation procedure of Example 40A is followed with
an equivalent amount of N-unsubstituted
5-(p-methylbenzoyl)-pyrrole-2-aceton- itrile and an equivalent
amount of n-propyl iodide as the N-alkylating agent, to yield
5-(p-methylbenzoyl)-1-(n-propyl)pyrrole-2-acetonitrile.
[0333] (B) 5-(p-methylbenzoyl)-1-(n-propyl)pyrrole-2-acetic
acid
[0334] The nitrile-to-acid transformation procedure of Example 40B
is repeated, except that an equivalent amount of the acetonitrile
obtained in part A of this Example is used as the starting
acetonitrile to yield
5-(p-methylbenzoyl)-1-(n-propyl)pyrrole-2-acetic acid.
[0335] (C)
6-(n-propyl)-5-(4'-methylphenyl)-1,3,6-trihydro-6-aza-3-oxapent-
alen-2-one
[0336] 5-(p-methylbenzoyl)-1-(n-propyl)pyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
6-(n-propyl)-5-(4'-methy-
lphenyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R.sub.1=H,
R.sub.2=H, R.sub.3=4'-methylphenyl, R.sub.4=n-propyl, R.sub.5H,
Y=CO, m=1, n=0)
EXAMPLE 42
6-Ethyl-S
-(4'-Methoxyphenyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0337] (A) 5-(p-methoxybenzoyl)-1-ethylpyrrole-2-acetonitrile
[0338] The N-alkylation procedure of Example 40A is followed with
an equivalent amount of N-unsubstituted
5-(p-methoxybenzoyl)-pyrrole-2-aceto- nitrile and an equivalent
amount of ethyl iodide as the N-alkylating agent, to yield
5-(p-methoxybenzoyl)-1-ethylpyrrole -2-acetonitrile.
[0339] (B) 5-(p-methoxybenzoyl)-1-ethylpyrrole-2-acetic acid
[0340] The nitrile-to-acid transformation procedure of Example 40B
is repeated, except that an equivalent amount of the acetonitrile
obtained in part A of this Example is used as the starting
acetonitrile to yield 5-(p-methoxybenzoyl)-1-ethylpyrrole-2-acetic
acid.
[0341] (C)
6-ethyl-5-(4'-methoxyphenyl)-1,3,6-trihydro-6-aza-3-oxapentalen-
-2-one
[0342] 5-(p-methoxybenzoyl)-1-ethylpyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
6-ethyl-5-(4'-methoxyphenyl-
)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R.sub.1=H, R.sub.2H,
R.sub.3=4'-methoxyphenyl, R.sub.4=ethyl, R.sub.5=H, Y=CO, m=1,
n=0).
EXAMPLE 43
6-(n-Butyl)-5-(2',4'-Dichlorobenzoyl)-1,6-Trihydro-6-Aza-3-Oxapentalen-2-O-
ne
[0343] (A)
5-(2',4'-dichlorobenzoyl)-1-(n-butyl)pyrrole-2-acetonitrile
[0344] The N-alkylation procedure of Example 40A is followed with
an equivalent amount of N-unsubstituted
5-(2',4'-dichlorobenzoyl)-pyrrole-2-- acetonitrile and an
equivalent amount of n-butyl iodide as the N-alkylating agent, to
yield 5-benzoyl-1-ethylpyrrole-2-acetonitrile
5-(2',4'-dichlorobenzoyl)-1-(n-butyl)pyrrole-2-acetonitrile.
[0345] (B) 5-(2',4'-dichlorobenzoyl)-1-(n-butyl)pyrrole-2-acetic
acid
[0346] The nitrile-to-acid transformation procedure of Example 40B
is repeated, except that an equivalent amount of the acetonitrile
obtained in part A of this Example is used as the starting
acetonitrile to yield
5-(2',4'-dichlorobenzoyl)-1-(n-butyl)pyrrole-2-acetic acid.
[0347] (C)
6-(n-butyl)-5-(2',4'-dichlorobenzoyl)-1,3,6-trihydro-6-aza-3-ox-
apentalen-2-one
[0348] 5-(2',4'-dichlorobenzoyl)-1-(n-butyl)pyrrole-2-acetic acid
is subjected to the procedure of Example 1, part C to produce
6-(n-butyl)-5-(2',4'-dichlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen--
2-one (R.sub.1=H, R.sub.2=H, R.sub.3=2',4'-dichlorophenyl,
R.sub.4=n-butyl, R.sub.5=H, Y=CO, m=1, n=O).
EXAMPLE 44
6-Ethyl-5-Benzoyl-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
(A) 5-benzoyl-1-ethylpyrrole -2-acetonitrile
[0349] The N-alkylation procedure of Example 40A is followed with
an equivalent amount of N-unsubstituted
5-benzoyl-pyrrole-2-acetonitrile and an equivalent amount of ethyl
iodide as the N-alkylating agent, to yield 5-benzoyl-1-ethylpyrrole
-2-acetonitrile.
[0350] (B) 5-benzoyl-1-ethylpyrrole-2-acetic acid
[0351] The nitrile-to-acid transformation procedure of Example 40B
is repeated, except that an equivalent amount of the acetonitrile
obtained in part A of this Example is used as the starting
acetonitrile to yield 5-benzoyl-1-ethylpyrrole-2-acetic acid.
[0352] (C)
6-ethyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one
[0353] 5-benzoyl-1-ethylpyrrole-2-acetic acid is subjected to the
procedure of Example 1, part C to produce
6-ethyl-5-benzoyl-1,3,6-trihydr- o-6-aza-3-oxapentalen-2-one
(R.sub.1=H, R.sub.2=H, R.sub.3=phenyl, R.sub.4=ethyl, R.sub.5=H,
Y=CO, m=1, n=0).
EXAMPLE 45
Rac-1-Methyl-6-Ethyl-5-(p-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentale-
n-2-One
[0354] (A)
5-(p-chlorobenzoyl)-.alpha.-methyl-1-ethylpyrrole-2-acetic acid
[0355] The alkylation and transformation procedures of Examples 22C
and 22D, respectively, are repeated, except that an equivalent
amount of the alkylpyrrole-acetonitrile obtained in Example 40 is
used in place of the starting acetonitrile used in Example 22C, and
an equivalent amount of methyl iodide is used as the alkylating
agent, to yield
5-(p-chlorobenzoyl)-.alpha.-methyl-1-ethylpyrrole-2-acetic
acid.
[0356] (B)
rac-1-methyl-6-ethyl-5-(p-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-
-oxapentalen-2-one
[0357] 5-(p-chlorobenzoyl)-.alpha.-methyl-1-ethylpyrrole-2-acetic
acid is subjected to the procedure of Example 1, part C to produce
rac-1-methyl-6-ethyl-5-(p-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapental-
en-2-one (R.sub.1=methyl, R.sub.2=H, R.sub.3=p-chlorophenyl,
R.sub.4=ethyl, R.sub.5=H, Y=CO, m=1, n=0).
EXAMPLE 46
Rac-1-Methyl-6-Ethyl-5-Benzoyl-1,3,6-Trihydro-6-Aza-3-Oxapentalene-2-One
[0358] (A) 5-benzoyl-.alpha.-methyl-1-ethylpyrrole-2-acetic
acid
[0359] The alkylation and transformation procedures of Examples 22C
and 22D, respectively, are repeated, except that an equivalent
amount of alkylpyrrole-acetonitrile obtained in Example 44 is used
in place of the starting acetonitrile used in Example 22C, and an
equivalent amount of methyl iodide is used as the alkylating agent,
to yield 5-benzoyl-.alpha.-methyl-1-ethylpyrrole-2-acetic acid.
[0360] (B)
rac-1-methyl-6-ethyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapental-
ene-2-one
[0361] 5-benzoyl-.alpha.-methyl-1-ethylpyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
rac-1-methyl-6-ethyl-5-b-
enzoyl-1,3,6-trihydro-6-aza-3-oxapentalene-2-one (R.sub.1=methyl,
R.sub.2=H, R.sub.3=phenyl, R.sub.4=ethyl, R.sub.5=H, Y=CO, m=1,
n=0).
EXAMPLE 47
Rac-1-Ethyl-6-(n-Propyl)-5-(p-Methylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapen-
talen-2-One
[0362] (A)
5-(p-methylbenzoyl)-.alpha.-ethyl-1-(n-propyl)pyrrole-2-acetic
acid
[0363] The alkylation and transformation procedures of Examples 22C
and 22D, respectively, are repeated, except that an equivalent
amount of alkylpyrrole-acetonitrile obtained in Example 41 is used
in place of the starting acetonitrile used in Example 22C, and an
equivalent amount of ethyl iodide is used as the alkylating agent,
to yield
5-(p-methylbenzoyl)-.alpha.-ethyl-1-(n-propyl)pyrrole-2-acetic
acid.
[0364] (B)
rac-1-ethyl-6-(n-propyl)-5-(p-methylbenzoyl)-1,3,6-trihydro-6-a-
za-3-oxapentalen-2-one
[0365]
5-(p-methylbenzoyl)-.alpha.-ethyl-1-(n-propyl)pyrrole-2-acetic acid
is subjected to the procedure of Example 1, part C to produce
rac-1-ethyl-6-(n-propyl)-5-(p-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxape-
ntalen-2-one (R.sub.1=ethyl, R.sub.2=H, R.sub.3=4'-methylphenyl,
R.sub.4=n-propyl, R.sub.5=H, Y=CO, m=1, n=0).
EXAMPLE 48
Rac-1-Methyl-6-(n-Butyl)-5-(2',4'-Dichlorobenzoyl)-1,3,6-Trihydro-6-Aza-3--
Oxapentalen-2-One
[0366] (A)
5-(2',4'-Dichlorobenzoyl)-1-methyl-1-(n-butylpyrrole)-2-acetic
acid
[0367] The alkylation and transformation procedures of Examples 22C
and 22D, respectively, are repeated, except that an equivalent
amount of alkylpyrrole-acetonitrile obtained in Example 43 is used
in place of the starting acetonitrile used in Example 22C, and an
equivalent amount of methyl iodide is used as the alkylating agent,
to yield
5-(2',4'-dichlorobenzoyl)-.alpha.-methyl-1-(n-butylpyrrole)-2-acetic
acid
[0368] (B)
rac-1-methyl-6-(n-butyl)-5-(2',4'-dichlorobenzoyl)-1,3,6-trihyd-
ro-6-aza-3-oxapentalen-2-one
[0369]
5-(2',4'-dichlorobenzoyl)-.alpha.-methyl-1-(n-butylpyrrole)-2-aceti-
c acid is subjected to the procedure of Example 1, part C to
produce
rac-1-methyl-6-(n-butyl)-5-(2',4'-dichlorobenzoyl)-1,3,6-trihydro-6-aza-3-
-oxapentalen-2-one (R.sub.1=methyl, R.sub.2=H,
R.sub.3=2',4'-dichloropheny- l, R.sub.4=n-butyl, R.sub.5=H, Y=CO,
m=1, n=0).
EXAMPLE 49
6-Benzyl-5-(4'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0370] (A) 1-benzyl-5-(p-chlorobenzoyl)-pyrrole-2-acetonitrile
[0371] A solution of 8.43 ml. (0.0663 mole) of p-chlorobenzoyl
chloride and 8.8 g. (0.0663 mole) of aluminum chloride in 100 ml.
of 1,2-dichloroethane is added to a solution of 13.0 g. (0.0663
mole) of 1-benzylpyrrole-2-acetonitrile in 50 ml. of
1,2-dichloroethane at 5.degree. C. over a 5 minute period. The
mixture is stirred for 15 minutes, and then heated quickly to
reflux for 3 minutes. The reaction mixture is poured into
ice-hydrochloric acid and then filtered. The aqueous layer is
separated and washed with chloroform. The combined organic
solutions are washed successively with N,N-dimethylaminopropylami-
ne solution, dilute hydrochloric acid, and brine and then dried
over anhydrous magnesium sulfate. The solvent is evaporated and the
oily residue dissolved in benzene-methylcyclohexane and seeded with
crystals of 1-benzyl-4-(p-chlorobenzoyl)-pyrrole-2-acetonitrile.
After crystallization of the latter substance is complete, the
mother liquor is filtered and evaporated and the residue
crystallized from methanol. The crystals thus obtained are
recrystallized from methanol to give
1-benzyl-5-(p-chlorobenzoyl)-pyrrole-2-acetonitrile as a yellow
solid, m.p. 104-106.degree. C.
[0372] (B) 1-benzyl-5-(p-chlorobenzoyl)-pyrrole-2-acetic acid
[0373] A suspension of 3.0 g. (0.009 mole) of
1-benzyl-5-(p-chlorobenzoyl)- -pyrrole-2-acetonitrile in 20 ml. of
ethanol and 18 ml. (0.018 mole) of 1N sodium hydroxide is refluxed
for 6 hours. The mixture is diluted with water, and the ethanol
evaporated in vacuo. The solution is washed with chloroform and
ether and acidified with 3N hydrochloric acid. The precipitated
solid is collected and dried in vacuo to give
1-benzyl-5-(p-chlorobenzoyl)-pyrrole-2-acetic acid as white
crystals, M.P. 162-163.degree. C. Analysis: Calcd. for
C.sub.20H.sub.15ClNO.sub.3 C, 67.70;H, 4.65; N, 3.96%. Found: C,
67.79;H, 4.65; N, 3.97%.
[0374] (C)
6-benzyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentale-
n-2-one
[0375] 1-benzyl-5-(p-chlorobenzoyl)-pyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
6-benzyl-5-(4'-chlorobenzoy-
l)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R.sub.1=H, R.sub.2=H,
R.sub.3=4'-chlorophenyl, R.sub.4=phenyl, R.sub.5=H, Y=CO,
X=CH.sub.2, m=1, n=1).
EXAMPLE 50
5-Benzoyl-6-Benzyl-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0376] (A) 1-benzyl-5-benzoyl-pyrrole-2-acetonitrile
[0377] The procedure of Example 49 is followed with an equivalent
amount of benzoyl chloride in place of the p-chlorobenzoyl chloride
used therein to yield
1-benzyl-5-benzoyl-pyrrole-2-acetonitrile.
[0378] (B) 1-benzyl-5-benzoyl-pyrrole-2-acetic acid
[0379] The nitrile-to-acid transformation procedure of Example 49B
is followed using an equivalent amount of the acetonitrile obtained
in part A of this Example to yield
1-benzyl-5-benzoyl-pyrrole-2-acetic acid.
[0380] (C)
5-benzoyl-6-benzyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one
[0381] 1-benzyl-5-benzoyl-pyrrole-2-acetic acid is subjected to the
procedure of Example 1, part C to produce
5-benzoyl-6-benzyl-1,3,6-trihyd- ro-6-aza-3-oxapentalen-2-one
(R.sub.1=H, R.sub.2=H, R.sub.3=phenyl, R.sub.4=phenyl, R.sub.5=H,
Y=CO, X=CH.sub.2, m=1, n=1).
EXAMPLE 51
6-Benzyl-5-(4'-Bromobenzoyl-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0382] (A) 1-benzyl-5-(p-bromobenzoyl)-pyrrole-2-acetonitrile
[0383] The procedure of Example 49 is followed with an equivalent
amount of p-bromo benzoyl chloride in place of the p-chlorobenzoyl
chloride used therein to yield
1-benzyl-5-(p-bromobenzoyl)-pyrrole-2-acetonitrile.
[0384] (B) 1-benzyl-5-(p-bromobenzoyl)-pyrrole-2-acetic acid
[0385] The nitrile-to-acid transformation procedure of Example 49B
is followed using an equivalent amount of the acetonitrile obtained
in part A of this Example to yield
1-benzyl-5-(p-bromobenzoyl)-pyrrole-2-acetic acid.
[0386] (C)
6-benzyl-5-(4'-bromobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-
-2-one
[0387] 1-benzyl-5-(p-bromobenzoyl)-pyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
6-benzyl-5-(4'-bromobenzoyl-
)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R.sub.1=H, R.sub.2=H,
R.sub.3=4'-bromophenyl, R.sub.4=phenyl, R.sub.5=H, Y=CO,
X=CH.sub.2, m=1, n=1).
EXAMPLE 52
6-Benzyl-5-(4'-Ethoxybenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0388] (A) 1-benzyl-5-(p-ethoxybenzoyl)-pyrrole-2-acetonitrile
[0389] The procedure of Example 49 is followed with an equivalent
amount of p-ethoxy benzoyl chloride in place of the p-chlorobenzoyl
chloride used therein to yield
1-benzyl-5-(p-ethoxybenzoyl)-pyrrole-2-acetonitrile- .
[0390] (B) 1-benzyl-5-(p-ethoxybenzoyl)-pyrrole-2-acetic acid
[0391] The nitrile-to-acid transformation procedure of Example 49B
is followed using an equivalent amount of the acetonitrile obtained
in part A of this Example to yield
1-benzyl-5-(p-ethoxybenzoyl)-pyrrole-2-acetic acid.
[0392] (C)
6-benzyl-5-(4'-ethoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentale-
n-2-one
[0393] 1-benzyl-5-(p-ethoxybenzoyl)-pyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
6-benzyl-5-(4'-ethoxybenzoy-
l)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R.sub.1=H, R.sub.2=H,
R.sub.3=4'-ethoxyphenyl, R.sub.4=phenyl, R.sub.5=H, Y=CO,
X=CH.sub.2, m=1, n=1).
EXAMPLE 53
6-Benzyl-5-(2',4-Dichlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0394] (A)
-benzyl-5-(2',4'-dichlorobenzoyl)-pyrrole-2-acetonitrile
[0395] The procedure of Example 49 is followed with an equivalent
amount of 2',4'-dichlorobenzoyl chloride in place of the
p-chlorobenzoyl chloride used therein to yield
1-benzyl-5-(2',4'-dichlorobenzoyl)-pyrrole- -2-acetonitrile.
[0396] (B) 1-benzyl-5-(2',4'-dichlorobenzoyl)-pyrrole-2-acetic
acid
[0397] The nitrile-to-acid transformation procedure of Example 49B
is followed using an equivalent amount of the acetonitrile obtained
in part A of this Example to yield
1-benzyl-5-(2',4'-dichlorobenzoyl)-pyrrole-2-a- cetic acid.
[0398] (C)
6-benzyl-5-(2',4'-dichlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxape-
ntalen-2-one
[0399] 1-benzyl-5-(2',4'-dichlorobenzoyl)-pyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
6-benzyl-5-(2',4'-dichlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-o-
ne (R.sub.1=H, R.sub.2=H, R.sub.3=2',4'-dichlorophenyl,
R.sub.4=phenyl, R.sub.5=H, Y=CO, X=CH.sub.2, m=1, n=1).
EXAMPLE 54
6-Benzyl-5-(3',4'-Dimethylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-On-
e
[0400] (A)
1-benzyl-5-(3',4'-dimethylbenzoyl)-pyrrole-2-acetonitrile
[0401] The procedure of Example 49 is followed with an equivalent
amount of 3',4'-dimethylbenzoyl chloride in place of the
p-chlorobenzoyl chloride used therein to yield
1-benzyl-5-(3',4'-dimethylbenzoyl)-pyrrole- -2-acetonitrile.
[0402] (B) 1-benzyl-5-(3',4'-dimethylbenzoyl)-pyrrole-2-acetic
acid
[0403] The nitrile-to-acid transformation procedure of Example 49B
is followed using an equivalent amount of the acetonitrile obtained
in part A of this Example to yield
1-benzyl-5-(3',4'-dimethylbenzoyl)-pyrrole-2-a- cetic acid.
[0404] (C)
6-benzyl-5-(3',4'-dimethylbenzoyl)-1,3,6-trihydro-6-aza-3-oxape-
ntalen-2-one
[0405] 1-benzyl-5-(3',4'-dimethylbenzoyl)-pyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
6-benzyl-5-(3',4'-dimethylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-o-
ne (R.sub.1=H, R.sub.2=H, R.sub.3=3',4'-dimethylphenyl,
R.sub.4=phenyl, R.sub.5=H, Y=CO, X=CH.sub.2, m=1, n=1).
EXAMPLE 55
Rac-1-Methyl-6-Benzyl-5-(4'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapenta-
len-2-One
[0406] (A)
1-benzyl-5-(p-chlorobenzoyl)-.alpha.-methyl-pyrrole-2-acetic
acid
[0407] The alkylation and transformation procedures of Examples 22C
and 22D, respectively, are repeated, except that an equivalent
amount of 1-benzyl-5-(4'-chlorobenzoyl)-pyrrole-2-acetonitrile and
an equivalent amount of methyl halide as the alkylating agent are
used to yield
1-benzyl-5-(p-chlorobenzoyl)-.alpha.-methyl-pyrrole-2-acetic
acid.
[0408] (B) rac-1-methyl-6-benzyl-5-(4'-chlorobenzoyl)-1,
3,6-trihydro-6-aza-3-oxapentalen-2-one
[0409] 1-Benzyl-5-(p-chlorobenzoyl)-.alpha.-methyl-pyrrole-2-acetic
acid is subjected to the procedure of Example 1, part C to produce
rac-1-methyl-6-benzyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapent-
alen-2-one (R.sub.1=methyl, R.sub.2=H, R.sub.3=4'-chlorophenyl,
R.sub.4=phenyl, R.sub.5=H, Y=CO, X=CH.sub.2, m=1, n=1).
EXAMPLE 56
Rac-1-(n-Propyl)-6-Benzyl-5-Benzoyl-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-O-
ne
[0410] (A) 1-benzyl-5-benzoyl-.alpha.-(n-propyl)-pyrrole-2-acetic
acid
[0411] The alkylation and transformation procedures of Examples 22C
and 22D, respectively, are repeated, except that an equivalent
amount of 1-benzyl-5-benzoyl-pyrrole-2-acetonitrile and an
equivalent amount of n-propyl halide as the alkylating agent are
used to yield
1-benzyl-5-benzoyl-.alpha.-(n-propyl)-pyrrole-2-acetic acid.
[0412] (B)
rac-1-(n-propyl)-6-benzyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxap-
entalen-2-one
[0413] 1-Benzyl-5-benzoyl-.alpha.-(n-propyl)-pyrrole-2-acetic acid
is subjected to the procedure of Example 1, part C to produce
rac-1-(n-propyl)-6-benzyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2--
one (R.sub.1=n-propyl, R.sub.2=H, R.sub.3=phenyl, R.sub.4=phenyl,
R.sub.5=H, Y=CO, X=CH.sub.2, m=1, n=1).
EXAMPLE 57
Rac-1-Ethyl-6-Benzyl-5-(4'-Bromobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentale-
n-2-One
[0414] (A)
1-Benzyl-5-(p-bromobenzoyl)-.alpha.-ethyl-pyrrole-2-acetic acid
[0415] The alkylation and transformation procedures of Examples 22C
and 22D, respectively, are repeated, except that an equivalent
amount of 1-benzyl-5-(4'-bromobenzoyl)-pyrrole-2-acetonitrile and
an equivalent amount of ethyl halide as the alkylating agent are
used to yield
1-benzyl-5-(p-bromobenzoyl)-.alpha.-ethyl-pyrrole-2-acetic
acid.
[0416] (B)
rac-1-ethyl-6-benzyl-5-(4'-bromobenzoyl)-1,3,6-trihydro-6-aza-3-
-oxapentalen-2-one
[0417] 1-Benzyl-5-(p-bromobenzoyl)-.alpha.-ethyl-pyrrole-2-acetic
acid is subjected to the procedure of Example 1, part C to produce
rac-1-ethyl-6-benzyl-5-(4'-bromobenzoyl)-1,3,6-trihydro-6-aza-3-oxapental-
en-2-one (R.sub.1=ethyl, R.sub.2=H, R.sub.3=4'-bromophenyl,
R.sub.4=phenyl, R.sub.5=H, Y=CO, X =CH.sub.2, m=1, n=1).
EXAMPLE 58
Rac-1-Methyl-6-Benzyl-5-(4'-Ethoxybenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapenta-
len-2-One
[0418] (A)
1-Benzyl-5-(p-ethoxybenzoyl)-.alpha.-methyl-pyrrole-2-acetic
acid
[0419] The alkylation and transformation procedures of Examples 22C
and 22D, respectively, are repeated, except that an equivalent
amount of 1-benzyl-5-(4'-ethoxybenzoyl)-pyrrole-2-acetonitrile and
an equivalent amount of methyl halide as the alkylating agent are
used to yield
1-benzyl-5-(p-ethoxybenzoyl)-.alpha.-methyl-pyrrole-2-acetic
acid.
[0420] (B)
rac-1-methyl-6-benzyl-5-(4'-ethoxybenzoyl)-1,3,6-trihydro-6-aza-
-3-oxapentalen-2-one
[0421] 1-benzyl-5-(p-ethoxybenzoyl)-.alpha.-methyl-pyrrole-2-acetic
acid is subjected to the procedure of Example 1, part C to produce
rac-1-methyl-6-benzyl-5-(4'-ethoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapent-
alen-2-one (R.sub.1=methyl, R.sub.2=H, R.sub.3=4'-ethoxyphenyl,
R.sub.4 phenyl, R.sub.5=H, Y=CO, X=CH.sub.2, m=1, n 1).
EXAMPLE 59
Rac-1-Ethyl-6-Benzyl-5-(2',4'-Dichlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxap-
entalen-2-One
[0422] (A)
1-Benzyl-5-(2',4'-dichlorobenzoyl)-.alpha.-ethyl-pyrrole-2-acet- ic
acid
[0423] The alkylation and transformation procedures of Examples 22C
and 22D, respectively, are repeated, except that an equivalent
amount of 1-benzyl-5-(2',4'-dichlorobenzoyl)-pyrrole-2-acetonitrile
and an equivalent amount of ethyl halide as the alkylating agent
are used to yield
1-benzyl-5-(2',4'-dichlorobenzoyl)-.alpha.-ethyl-pyrrole-2-acetic
acid.
[0424] (B)
rac-1-ethyl-6-benzyl-5-(2',4'-dichlorobenzoyl)-1,3,6-trihydro-6-
-aza-3-oxapentalen-2-one
[0425]
1-Benzyl-5-(2',4'-dichlorobenzoyl)-.alpha.-ethyl-pyrrole-2-acetic
acid is subjected to the procedure of Example 1, part C to produce
rac-1-ethyl-6-benzyl-5-(2',4'-dichlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxa-
pentalen-2-one (R.sub.1=ethyl, R.sub.2=H,
R.sub.3=2',4'-dichlorophenyl, R.sub.4=phenyl, R.sub.5=H, Y=CO,
X=CH.sub.2, m=1, n=1).
EXAMPLE 60
Rac-1-Methyl-6-Benzyl-5-(3',4'-Dimethylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxa-
pentalen-2-One
[0426] (A)
1-Benzyl-5-(3',4'-dimethylbenzoyl)-.alpha.-methyl-pyrrole-2-ace-
tic acid The alkylation and transformation procedures of Examples
22C and 22D, respectively, are repeated, except that an equivalent
amount of 1-benzyl-5-(3',4'-dimethylbenzoyl)-pyrrole-2-acetonitrile
and an equivalent amount of methyl halide as the alkylating agent
are used to yield
1-benzyl-5-(3',4'-dimethylbenzoyl)-.alpha.-methyl-pyrrole-2-acetic
acid.
[0427] (B)
rac-1-Methyl-6-benzyl-5-(3',4'-dimethylbenzoyl)-1,3,6-trihydro--
6-aza-3-oxapentalen-2-one
[0428]
1-Benzyl-5-(3',4'-dimethylbenzoyl)-.alpha.-methyl-pyrrole-2-acetic
acid is subjected to the procedure of Example 1, part C to produce
rac-1-methyl-6-benzyl-5-(3',4'-dimethylbenzoyl)-1,3,6-trihydro-6-aza-3-ox-
apentalen-2-one
[0429] R.sub.1=methyl, R.sub.2=H, R.sub.3=3'4'-dimethylphenyl,
R.sub.4=phenyl, R.sub.5=H, Y=CO, X=CH.sub.2, M=1, n=1
EXAMPLE 61
6-Methyl-5-(4'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0430] (A) 5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile
[0431] An acylating solution is prepared by the slow addition of
278 g. (1.58 moles) of p-chlorobenzoyl chloride to 210 g. (1.58
moles) of aluminum chloride in 750 ml. of ethylene chloride. The
resulting solution is added to a solution of 190 g. (1.58 moles) of
N-methylpyrrole-2-aceton- itrile in 750 ml. of ethylene chloride.
The temperature is maintained at 20-22.degree. C. during the
addition; and the solution is further stirred at room temperature
for one hour. The solution is then heated rapidly to 74-76.degree.
C. at which point there is a vigorous evolution of hydrogen
chloride gas. This temperature is maintained about 5 minutes, and
the solution is cooled rapidly and poured into ice water. The
product is extracted with methylene chloride and washed with water.
The organic solution is then shaken with an excess of an aqueous
solution of N,N-dimethylaminopropylamine followed by dilute
hydrochloric acid to remove any excess p-chlorobenzoyl chloride.
After a final wash with brine, the solution is dried over anhydrous
magnesium sulfate. Distillation of the solvent leaves a residue
which crystallizes. Recrystallization from methyl alcohol yields
the product, 5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile,
m.p. 120-124.degree. C. After two additional recrystallizations
from methanol, the m.p. is 127-131.degree. C.
[0432] (B) 5-(p-Chlorobenzoyl)-1-methylpyrrole-2-acetic acid
[0433] A mixture of 129 g. (0.52 mole) of
5-(p-chlorobenzoyl)-1-methylpyrr- ole-2-acetonitrile and 88 g. (1.1
moles) of 50% sodium hydroxide solution in 800 ml. of ethanol and
500 ml. of water is stirred and refluxed for about 18 hours with
slow evolution of ammonia. The solution is then cooled to about
50.degree. C. and acidified by adding 110 ml. of concentrated
hydrochloric acid. The mixture is cooled, and the precipitated
product, 5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetic acid, is
filtered and recrystallized from methanol, m.p. 193-195.degree. C.
(dec.). A second crop is obtained upon concentration of the mother
liquor for a total yield of about 67% of theoretical. Analysis:
Calcd. for C.sub.14H.sub.11ClNO.sub.3: N, 5.05%. Found: N,
5.06%.
[0434] (C)
6-Methyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentale-
n-2-one
[0435] 5-(p-Chlorobenzoyl)-1-methylpyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
6-methyl-5-(4'-chlorobenzoy-
l)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R.sub.1=H, R.sub.2=H,
R.sub.3=4'-chlorophenyl, R.sub.4=methyl, R.sub.5=H, Y=CO,
m=1,n=0).
EXAMPLE 62
4-Methyl-5-Benzoyl-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0436] (A) 1-Phenyl-1,2,3-butanetrione-2-oxime
[0437] The procedure described by Ceresole in Ber., 17, 815 (1884),
wherein 1-aryl-1,3-butanediones are reacted with nitrous acid to
yield the corresponding 1-aryl-1,2,3-butanetrione-2-oximes, is
followed to prepare 1-phenyl-1,2,3-butanetrione-2-oxime, m.p.
130-131.degree. C.
[0438] (B) Ethyl
5-benzoyl-3-ethoxycarbonyl-4-methylpyrrole-2-acetate
[0439] A solution of 71 g. (0.37 mole) of
1-phenyl-1,2,3-butanetrione-2-ox- ime in 350 ml. glacial acetic
acid and 50 ml. of water is added to 75.5 g. diethyl
acetonedicarboxylate in 350 ml. of glacial acetic acid at
70.degree. C. Concurrently, a mixture of 73 g. (1.12 mole) of zinc
dust and 91.5 g. (1.12 mole) of anhydrous sodium acetate is added
in portions at such a rate that the temperature is maintained near
100.degree. C. After the additions are complete (about 45 minutes),
the mixture is refluxed for one hour and poured into iced water.
The resulting crude semisolid is collected by filtration and
recrystallized twice from methanol to give ethyl
5-benzoyl-3-ethoxycarbonyl-4-methylpyrrole-2-aceta- te, m.p.
152-154.degree. C. Analysis: Calcd. for C.sub.19H.sub.21NO.sub.5:
C, 66.46;H, 6.16; N, 4.08%. Found: C, 66.50;H, 6.20; N, 4.17%.
[0440] (C) 5-Benzoyl-3-carboxy-4-methylpyrrole-2-acetic acid
[0441] A mixture of 3.4 g. of ethyl
5-benzoyl-3-ethoxy-carbonyl-4-methylpy- rrole-2-acetate, 10 g. of
50% sodium hydroxide solution and 10 ml. of water is refluxed for 2
hours. The reaction mixture is then diluted with water and
acidified with dilute hydrochloric acid. The precipitated solid is
collected by filtration, air-dried, and recrystallized from
acetone-water to yield the product,
5-benzoyl-3-carboxy-4-methylpyrrole-2- -acetic acid, as white
crystals, m.p. 250-253.degree. C.
[0442] (C) Ethyl 5-benzoyl-3-carboxy-4-methylpyrrole-2-acetate
[0443] A solution of 8.0 g. (0.028 mole) of
5-benzoyl-3-carboxy-4-methylpy- rrole-2-acetic acid in 80 ml. of
0.5% ethanolic hydrogen chloride is refluxed for 90 minutes. The
solution is charcoaled, filtered, and the filtrate evaporated in
vacuo to yield a crystalline residue which is recrystallized from
acetone to give ethyl 5-benzoyl-3-carboxy-4-methylpyr-
role-2-acetate, m.p. 183-185.degree. C.
[0444] (E) 5-Benzoyl-4-methylpyrrole-2-acetic acid
[0445] A solution of 4.13 g. (0.0131 mole) of ethyl
5-benzoyl-3-carboxy-4-methyl-pyrrole-2-acetate in 80 ml. of
quinoline in the presence of a trace amount of copper chromite is
heated at 180-183.degree. C. for 5 hours. The mixture is poured
into dilute hydrochloric acid and extracted three times with ether.
The ether extracts are combined and washed successively with dilute
hydrochloric acid, sodium bicarbonate solution and brine and then
dried over anhydrous magnesium sulfate. The solvent is evaporated
in vacuo to give about 4 g. of semisolid ethyl
5-benzoyl-4-methylpyrrole-2-acetate which is used in the following
hydrolysis procedure without further purification. The entire
semisolid is dissolved in 20 ml. of ethanol and 20 ml. of 1N sodium
hydroxide solution is added. The mixture is heated under reflux for
30 minutes. The solvent is then evaporated in vacuo, and the
residue dissolved in water and washed with ether. The aqueous
solution is acidified with dilute hydrochloric acid and the
resulting crystalline solid (1.6 g., 50% yield) is collected by
filtration and air-dried. The product,
5-benzoyl-4-methylpyrrole-2-acetic acid is recrystallized three
times from acetone-water with charcoaling, m.p. 167-168.degree.
C.
[0446] (F) BOC-5-benzoyl-4-methylpyrrole-2-acetic acid
[0447] The procedure of Example 1, part C is repeated using
5-benzoyl-4-methylpyrrole-2-acetic acid to give
BOC-5-benzoyl-4-methylpyr- role-2-acetic acid.
[0448] (G) BOC
4-methyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one
[0449] The procedure of Example 33C is repeated using
BOC-5-benzoyl-4-methylpyrrole-2-acetic acid to give BOC
4-methyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one.
[0450] (H)
4-Methyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one
[0451] The procedure of Example 33E is repeated using BOC
4-methyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one to give
4-methyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one
(R.sub.1=H, R.sub.2=H, R.sub.3=phenyl, R.sub.4=H, R.sub.5=methyl,
Y=CO, m=1, n=0).
EXAMPLE 63
4-Methyl-5-(4'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0452] (A) 1-(p-Chlorophenyl)-1,2,3-butanetrione-2-oxime
[0453] The procedure described by Ceresole in Ber., 17, 815 (1884),
wherein 1-aryl-1,3-butanedion is reacted with nitrous acid to yield
the corresponding 1-aryl-1,2,3-butanetrione-2-oxime, is followed to
prepare 1-(p-chlorophenyl)-1,2,3-butanetrione-2-oxime.
[0454] (B)
Ethyl-5-(p-chlorobenzyl)-3-ethoxycarbonyl-4-methyl-pyrrole-2-ac-
etate
[0455] By repeating the procedure of Example 62, part B with an
equivalent amount of 1-(p-chlorophenyl)-1,2,3-butanetrione-2-oxime,
ethyl-5-(p-chlorobenzyl)-3-ethoxycarbonyl-4-methylpyrrole-2-acetate
is obtained.
[0456] (C) 5-(p-Chlorobenzoyl)-3-carboxy-4-methylpyrrole-2-acetic
acid
[0457] The hydrolysis procedure of Example 62, part C is repeated,
except that an equivalent amount of the ester obtained in part B of
this Example is used to yield
5-(p-chlorobenzoyl)-3-carboxy-4-methylpyrrole-2-acetic acid.
[0458] (D) Ethyl
5-(p-chlorobenzoyl)-3-carboxy-4-methylpyrrole-2-acetate
[0459] The partial reesterification procedure in Example 62D above
is repeated using an equivalent amount of the acid obtained in part
C of this Example to yield ethyl
5-(p-chlorobenzoyl)-3-carboxy-4-methylpyrrole- -2-acetate.
[0460] (E) 5-(p-Chlorobenzoyl)-3-carboxy-4-methylpyrrole-2-acetic
acid
[0461] The procedure of Example 62, part E is repeated using an
equivalent amount of the ester obtained in part D of this Example
to yield 5-(p-chlorobenzoyl)-4-methylpyrrole-2-acetic acid.
[0462] (F) BOC 5-(p-chlorobenzoyl)-4-methylpyrrole-2-acetic
acid
[0463] The procedure of Example 33C is repeated using
5-(p-chlorobenzoyl)-4-methylpyrrole-2-acetic acid to give BOC
5-(p-chlorobenzoyl)-4-methylpyrrole-2-acetic acid.
[0464] (G) BOC 4-methyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3
oxapentalen-2-one
[0465] BOC 5-(p-chlorobenzoyl)-4-methylpyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce BOC
4-methyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one.
[0466] (H) 4-methyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3
oxapentalen-2-one
[0467] The procedure of Example 33E is repeated using BOC
4-methyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one
to produce
4-methyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen--
2-one (R.sub.1=H, R.sub.2=H, R.sub.3=4'-chlorophenyl, R.sub.4=H,
R.sub.5=methyl, Y=CO, m=1, n=0).
EXAMPLE 64
4-Methyl-5-(4'-Methylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0468] (A) 1-(p-Methylphenyl)-1,2,3-butanetrione-2-oxime
[0469] The procedure described by Ceresole in Ber., 17, 815 (1884),
wherein 1-aryl-1,3-butanediones are reacted with nitrous acid to
yield the corresponding 1-aryl-1,2,3-butanetrione-2-oximes, is
followed to prepare
1-(p-methylphenyl)-1,2,3-butanetrione-2-oxime.
[0470] (B) Ethyl
5-(p-methylbenzoyl)-3-ethoxycarbonyl-4-methylpyrrole-2-ac-
etate
[0471] By repeating the procedure of Example 62, part B with an
equivalent amount of 1-(p-methylphenyl)-1,2,3-butanetrione-2-oxime,
ethyl
5-(p-methylbenzoyl)-3-ethoxycarbonyl-4-methylpyrrole-2-acetate is
obtained.
[0472] (C)
Ethyl-5-(p-methylbenzoyl)-3-carboxy-4-methylpyrrole-2-acetic
acid
[0473] The hydrolysis procedure of Example 62, part C is repeated,
except that an equivalent amount of the ester obtained in part B of
this Example is used to yield ethyl
5-(p-methylbenzoyl)-3-carboxy-4-methylpyrrole-2-ac- etic acid.
[0474] (D) Ethyl 5-(p
-methylbenzoyl)-3-carboxy-4-methylpyrrole-2-acetate
[0475] The partial reesterification procedure in Example 62 D above
is repeated using an equivalent amount of the acid obtained in part
C of this Example to yield ethyl
5-(p-methylbenzoyl)-3-carboxy-4-methylpyrrole- -2-acetate.
[0476] (E) 5-(p-methylbenzoyl)-4-methylpyrrole-2-acetic acid
[0477] The procedure of Example 62, part E is repeated using an
equivalent amount of the ester obtained in part D of this Example
to yield 5-(p-methylbenzoyl)-4-methylpyrrole-2-acetic acid.
[0478] (F) BOC 5-(p-methylbenzoyl)-4-methylpyrrole-2-acetic
acid
[0479] The procedure of Example 33C is repeated using
5-(p-methylbenzoyl)-4-methylpyrrole-2-acetic acid to produce BOC
5-(p-methylbenzoyl)-4-methylpyrrole-2-acetic acid.
[0480] (G) BOC
4-Methyl-5-(4'-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapen-
talen-2-one
[0481] BOC 5-(p-methylbenzoyl)-4-methylpyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce BOC
4-methyl-5-(4'-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one.
[0482] (G) 4-Methyl-5-(4
'-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapental- en-2-one
[0483] The procedure of Example 33E is repeated using BOC
4-methyl-5-(4'-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one
to give
4-methyl-5-(4'-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-o-
ne (R.sub.1=H, R.sub.2=H, R.sub.3=4'-methylphenyl, R.sub.4=H,
R.sub.5=methyl, Y=CO, m=1, n=0).
EXAMPLE 65
4-Methyl-5-(4'-Methoxybenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0484] (A) 1-(p-Methoxyphenyl)-1,2,3-butanetrione-2-oxime
[0485] The procedure described by Ceresole in Ber., 17, 815 (1884),
wherein 1-aryl-1,3-butanediones are reacted with nitrous acid to
yield the corresponding 1-aryl-1,2,3-butanetrione-2-oximes, is
followed to prepare
1-(p-methoxyphenyl)-1,2,3-butanetrione-2-oxime.
[0486] (B) Ethyl
5-(p-methoxybenzoyl)-3-ethoxycarbonyl-4-methylpyrrole-2-a-
cetate
[0487] By repeating the procedure of Example 62, part B with an
equivalent amount of
1-(p-methoxyphenyl)-1,2,3-butanetrione-2-oxime, ethyl
5-(p-methoxybenzoyl)-3-ethoxycarbonyl-4-methylpyrrole-2-acetate is
obtained.
[0488] (C) Ethyl
5-(p-methoybenzoyl)-3-carboxy-4-methylpyrrole-2-acetate
[0489] The hydrolysis procedure of Example 62, part C is repeated,
except that an equivalent amount of the ester obtained in part B of
this Example is used to yield ethyl
5-(p-methoxybenzoyl)-3-carboxy-4-methylpyrrole-2-a- cetate.
[0490] (D) Ethyl
5-(p-methoxybenzoyl)-3-carboxy-4-methylpyrrole-2-acetate.
[0491] The partial reesterification procedure in Example 62 D above
is repeated using an equivalent amount of the acid obtained in part
C of this Example to yield ethyl
5-(p-methoxybenzoyl)-3-carboxy-4-methylpyrrol- e-2-acetate.
[0492] (E) 5-(p-methoxybenzoyl)-4-methylpyrrole-2-acetic acid
[0493] The procedure of Example 62, part E is repeated using an
equivalent amount of the ester obtained in part D of this Example
to yield 5-(p-methoxybenzoyl)-4-methylpyrrole-2-acetic acid.
[0494] (F) BOC 5-(p-methoxybenzoyl)-4-methylpyrrole-2-acetic
acid
[0495] The procedure of Example 33C is repeated using
5-(p-methoxybenzoyl)-4-methylpyrrole-2-acetic acid to produce BOC
5-(p-methoxybenzoyl)-4-methylpyrrole-2-acetic acid.
[0496] (G) BOC
4-methyl-5-(4'-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxape-
ntalen-2-one
[0497] BOC 5-(p-methoxybenzoyl)-4-methylpyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce BOC
4-methyl-5-(4'-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one
[0498] (H)
4-Methyl-5-(4'-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapental-
en-2-one
[0499] The procedure of Example 33E is repeated using BOC
4-methyl-5-(4'-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one
to give
4-methyl-5-(4'-methoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-
-2-one (R.sub.1=H, R.sub.2H, R.sub.3=4'-methoxyphenyl, R.sub.4=H,
R.sub.5=methyl, Y=CO, m=1, n=0).
EXAMPLE 66
6-Benzyl-5-(4'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0500] (A) 2-Dimethylaminomethyl-1-benzylpyrrole
[0501] A solution of 8.2 g. (0.1 mole) dimethylamine hydrochloride
in 8 ml. formalin is added dropwise to 17.12 g. (0.1 mole) of
1-benzylpyrrole. The mixture is stirred at room temperature until
solution occurs (about 4 hours). The solution is poured into 10%
sodium hydroxide solution and then extracted into ether three
times. The combined organic fractions are washed with a saturated
solution of sodium chloride, dried over magnesium sulfate and the
solvent evaporated in vacuo. The product,
2-dimethylaminomethyl-1-benzylpyrrole, is distilled at reduced
pressure, b.p. 73.degree. C., 0.025 mm. Hg.
[0502] (B) 2-Dimethylaminomethyl-1-benzylpyrrole methiodide
[0503] A solution of 100 g. (0.47 mole) of
2-dimethylaminomethyl-1-benzylp- yrrole in 200 ml. of absolute
ethanol is cooled to 5.degree. C. To this is added dropwise 29.4
ml. (0.47 mole) of methyl iodide. A white solid precipitates. The
suspension is stirred until the precipitate is so thick that
additional stirring becomes impossible. The solid,
2-dimethylaminomethyl-1-benzylpyrrole methiodide, is filtered off
and dried in vacuum.
[0504] (C) 1-Benzylpyrrole-2-acetonitrile
[0505] A suspension of 88.9 g. (0.25 mole) of
2-dimethylaminomethyl-1-benz- ylpyrrole methiodide is added to a
suspension of 12.8 g. (0.26 mole) of sodium cyanide in 40 ml.
dimethylsulfoxide. The mixture is heated under reflux for 3 hours,
and stirring at room temperature is continued overnight. The
reaction mixture is poured into water and extracted three times
with ether. The combined ether extracts are washed with brine and
dried over anhydrous magnesium sulfate. The ether solvent is
evaporated in vacuo to give an oily residue which crystallizes upon
standing. Recrystallization from methylcyclohexane yields the
product, 1-benzylpyrrole-2-acetonitrile, m.p. 62-63.degree. C.
[0506] (D) 1-Benzyl-5-(p-chlorobenzoyl)-pyrrole-2-acetonitrile
[0507] A solution of 8.43 ml. (0.067 mole) of p-chlorobenzoyl
chloride and 8.8 g. (0.067 mole) of aluminum chloride in 100 ml. of
1,2-dichloroethane is added to a solution of 13.0 g. (0.067 mole)
of 1-benzylpyrrole-2aceton- itrile in 50 ml. of 1,2-dichloroethane
at 5.degree. C. over a 5 minute period. The reaction mixture is
stirred for 15 minutes and then heated quickly to reflux for 3
minutes. The mixture is poured into ice-hydrochloric acid and then
filtered. The aqueous layer is separated and washed with
chloroform. The combined organic fractions are washed successively
with N,N-dimetylaminopropylamine solution, dilute hydrochloric acid
and brine and then dried over anhydrous magnesium sulfate. The
solvent is evaporated to yield an oily residue from which the
desired compound is isolated by column chromatography on neutral
alumina with a 50-50 mixture of benzene ether as the eluting
solvent. Evaporation of the elute affords
1-benzyl-5-(p-chlorobenzoyl)-pyrrole-2-a- cetonitrile as a yellow
solid which is recrystallized from methanol, m.p. 106-108.degree.
C.
[0508] (E) 1-Benzyl-5-(p-chlorobenzoyl)-pyrrole-2-acetic acid
[0509] The nitrile-to-acid transformation procedure of Example 49B
is followed using an equivalent amount of the acetonitrile obtained
in Part D of this example to yield
1-benzyl-5-(p-chlorobenzoyl)-pyrrole-2-acetic acid.
[0510] (F)
6-Benzyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentale-
n-2-one
[0511] 1-Benzyl-5-(p-chlorobenzoyl)-pyrrole-2-acetic acid is
subjected to the procedure of Example 1, Part C to produce
6-benzyl-5-(4'-chlorobenzoy-
l)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R.sub.1=H, R.sub.2=H,
R.sub.3=4'-chlorophenyl, R.sub.4=phenyl, R.sub.5=H, Y=CO,
X=CH.sub.2, m=1, n=1).
EXAMPLE 67
6-Methyl-5-(4'-Isopropylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0512] (A)
5-(p-Isopropylbenzoyl)-1-methylpyrrole-2-acetonitrile
[0513] To a suspension of 17.5 g. (0.131 mole) aluminum chloride in
60 ml. 1,2-dichloroethane is added 24 g (0.131 mole)
p-isopropylbenzoyl chloride. The resulting mixture is added slowly
and dropwise to a chilled solution (0.degree. C.) of 15.7 g. (0.131
mole) 1-methylpyrrole-2-acetoni- trile in 100 ml. of
1,2-dichloroethane. After the addition is complete, the mixture is
stirred at room temperature for twenty minutes and heated at reflux
for three minutes. The reaction mixture is then cooled and poured
into ice-dilute hydrochloric acid. The organic phase is separated
and washed successively with N,N-dimethyl-1,3-propanediamine,
dilute hydrochloric acid and a saturated solution of sodium
chloride; dried over magnesium sulfate; and the solvent evaporated.
The product, 5-(p-isopropylbenzyl)-1-methylpyrrole-2-acetonitrile,
is isolated from the residual oil by column chromatography. The
column is packed with acid washed alumina and eluted with benzene,
ether and etylacetate. The product is found in the first
compound-bearing fraction which absorbs ultraviolet light at
approximately 250 m.mu.. It is purified by recrystallization twice
in ether: pentane. m.p. 59-64.degree. C. Anal. Calcd. for
C.sub.17H.sub.18 N.sub.2O: N, 10.53%. Found: N, 10.71%.
[0514] (B) 5-(p-isopropylbenzoyl)-1-methylpyrrole-2-acetic acid
[0515] A solution of 6.5 g. (0.024 mole) of
5-(p-isopropylbenzoyl)-1-methy- lpyrrole-2-acetonitrile, 52 ml. 1N
sodium hydroxide and 50 ml. 95% ethanol are heated at reflux
overnight. The ethanol is then evaporated, and the remaining yellow
solution is poured into ice-dilute hydrochloric acid. A precipitate
forms which is separated by filtration and recrystallized in ether:
hexane. The solid is then partitioned between sodium bicarbonate
solution and ether. The sodium bicarbonate phase is separated and
acidified with dilute hydrochloric acid. The white precipitate,
5-(p-isopropylbenzoyl)-1methylpyrrole-2-acetic acid, is filtered
and dried in vacuo, m.p. 98-101.degree. C. Anal. Calcd. for
C.sub.17H.sub.19 NO.sub.3: N, 4.91%. Found: N, 5.14%.
[0516] (C)
6-Methyl-5-(4'-isopropylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapent-
alen-2-one
[0517] 5-(p-Isopropylbenzoyl)-1-methylpyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
6-methyl-5-(4'-isopropyl-
benzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R.sub.1=H,
R.sub.2=H, R.sub.3=4'-isopropylphenyl, R.sub.4=methyl, R.sub.5=H,
Y=CO, m=1, n=0).
EXAMPLE 68
6-Methyl-5-(2'-Toluoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0518] (A) 1-methyl-5-(o-toluoyl)-pyrrole.-2-acetonitrile
[0519] To a solution of 24 g. (0.20 mole) of
1-methylpyrrole-2-acetonitril- e and 30.92 g. (0.20 mole) o-toluoyl
chloride in 200 ml. methylene chloride (cooled externally to
-20.degree. C.) is added dropwise 23.4 ml. (0.20 mole) of stannic
chloride. After the addition is complete, the yellow mixture is
permitted to come to room temperature. The mixture is then poured
into ice-dilute hydrochloric acid. The two phases are separated.
The organic phase is washed consecutively with
N,N-dimethyl-1,3-propanediamine, 3N hydrochloric acid, and
saturated sodium chloride solution; dried over magnesium sulfate;
and the product, 1-methyl-5-(o-toluoyl)-pyrrole-2-acetonitrile, is
separated from the residual oil by chromatography. The column is
packed with acid washed alumina in hexane. The eluant is benzene.
The product is found in the first compound bearing fraction as
determined by ultraviolet absorption at 260 m.mu.. The benzene is
evaporated and the resultant solid is purified by recrystallization
twice from methanol, m.p. 90-92.5.degree. C.
[0520] (B) 1-methyl-5-(o-toluoyl)-pyrrole-2-acetic acid
[0521] A solution of 10.6 g. (0.0445 mole) of
1-methyl-5-(o-toluoyl)-pyrro- le-2-acetonitrile, 89 ml. 1N sodium
hydroxide and 10 ml. 95% ethanol is heated at reflux for 18 hours,
cooled and poured into dilute hydrochloric acid, and extracted with
chloroform. The chloroform phase is separated and extracted with
sodium bicarbonate solution. The product,
1-methyl-5-(o-toluoyl)-pyrrole-2-acetic acid, is precipitated from
the aqueous phase upon treatment with 3N hydrochloric acid,
separated by filtration, and purified by recrystallization in
isopropanol using charcoal while the solution is still warm, and
subsequent recrystallization with methanol, m.p. 133-135.degree. C.
Anal. Calcd. for C.sub.15H.sub.15NO.sub.3: C, 70.02;H, 5.88; N,
5.44%. Found: C, 70.07;H, 5.97; N, 5.54%.
[0522] (C)
6-Methyl-5-(2'-toluoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-on-
e
[0523] 1-Methyl-5-(o-toluoyl)-pyrrole-2-acetic acid is subjected to
the procedure of Example 1, part C to produce
6-methyl-5-(2'-toluoyl)-1,3,6-t- rihydro-6-aza-3-oxapentalen-2-one
(R.sub.1=H, R.sub.2=H, R.sub.3=2'-methylphenyl, R.sub.4=methyl,
R.sub.5=H, Y=CO, m=1, n=0).
EXAMPLE 69
6-Methyl-5-(2'-Thienoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0524] (A) 1-Methyl-5-(2'-thienoyl)-pyrrole-2-acetonitrile
[0525] A solution of 20.0 g. (0.15 mole) of aluminum chloride and
22.0 g. (0.15 mole) of thiophene-2-carboxylic acid chloride in 200
ml. 1,2-dichloroethane is added to a solution of 18.0 g. (0.15
mole) of 1-methyl-pyrrole-2-acetonitrile in 100 ml. of
1,2-dichloroethane at 5.degree. C. over a period of 5 minutes. The
mixture is stirred for 20 min. and then quickly heated to reflux
for 3 minutes. It is poured into ice-hydrochloric acid. The organic
layer is separated and the aqueous solution washed with
1,2-dichloroethane. The combined organic solutions are washed
consecutively with water, N,N-dimethylaminopropylamine, dilute
hydrochloric acid and brine. The solution is then dried over
magnesium sulfate and the solvent evaporated in vacuo. The residue
crystallizes to give a yellow solid which shows two spots on thin
layer chromatography (1:1 ethyl acetate, cyclohexane on silica
gel). The solid is dissolved in benzene and seeded with crystals of
1-methyl-5-(2'-thienoyl)-pyrrole-2-ac- etonitrile obtained by
exhaustive crystallization from benzene. After crystallization, the
supernatant liquid is decanted from the precipitated
1-methyl-5-(2'-thienoyl)-2-acetonitrile and evaporated. The
thus-obtained solid is recrystallized from methanol and seeded with
crystals of 1-methyl-5-(2'-thienoyl)-pyrrole-2-acetonitrile which
were obtained by exhaustive crystallization of a another run from
methanol. The mother liquor from the crystallization of the latter
compound is evaporated and recycled through the same
crystallization processes. After four cycles, there is obtained
1-methyl-5-(2'-thienoyl)-pyrrole-2-acetonitrile, m.p.
132-133.degree. C.
[0526] (B) 1-Methyl-5-(2'-thienoyl)-pyrrole-2-acetic acid
[0527] A suspension of 7.35 g. (0.032 mole) of
1-methyl-5-(2'-thienoyl)-py- rrole-2-acetonitrile in 30 ml. of 95%
ethanol and 64 ml. (0.064 mole) of IN sodium hydroxide solution is
refluxed for 5 hours. The mixture is cooled, and the ethanol
evaporated in vacuo. Water is added, and the solution is washed
successively with methylene chloride and ether and clarified with
charcoal. The solution is acidified with dilute hydrochloric acid
and the precipitated solid, 1-methyl-5-(2'-thienoyl)-py-
rrole-2-acetic acid, is collected and dried in vacuo, m.p.
140-142.degree. C. It is recrystallized from methanol-water to give
the product as a white solid, m.p. 141-142.degree. C. Anal. Calcd,
for C.sub.12H.sub.11NO.sub.3S: C, 57.83;H, 4.45;H 5.62%. Found: C,
57.81;H, 4.44; N 5.68%.
[0528] (C)
6-Methyl-5-(2'-thienoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-o-
ne
[0529] 1-Methyl-5-(2'-thienoyl)-pyrrole-2-acetic acid is subjected
to the procedure of Example 1, part C to produce
6-methyl-5-(2'-thienoyl)-1,3,6-- trihydro-6-aza-3-oxapentalen-2-one
(R.sub.1=H, R.sub.2=H, R.sub.3=2'-thiophenyl, R.sub.4=methyl,
R.sub.5=H, Y=CO, m=1, n=0).
EXAMPLE 70
6-Methyl-5-(5'-Methyl-2
'-Thienoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-O- ne
[0530] (A)
1-Methyl-5-(5'-methyl-2'-thienoyl)-pyrrole-2-acetonitrile
[0531] To a suspension of 25.54 g. (0.019 mole) anhydrous aluminum
chloride in 70 ml. of 1,2-dichloroethane is added 30.7 g. (0.019
mole) 5-methyl-2-thienoyl chloride. The resulting solution is added
dropwise to a chilled (0C.) solution of 24 g. (0.02 mole)
1-methylpyrrole-2-acetonitr- ile. After the addition, the solution
is stirred at room temperature for approximately 40 minutes, and
then heated at reflux for 3 minutes and poured onto ice acidified
with dilute hydrochloric acid. The two phases are separated. The
organic phase is washed successively with
N,N-dimethyl-1,3-propanediamine, 3N hydrochloric acid and saturated
sodium chloride solution. It is then dried over magnesium sulfate
and the solvent evaporated. The resulting solid,
1-methyl-5-(5'-methyl-2'-thienoy- l)-pyrrole-2-acetonitrile, is
separated by filtration and purified by washing in cold methanol
and benzene, m.p. 118-121.degree. C.
[0532] (B) 1-Methyl-5-(5'-methyl-2'-thienoyl)-pyrrole-2-acetic
acid
[0533] A solution of 10.5 g. (0.043 mole) of
1-methyl-5-(5'-methyl-2'-thie- noyl)-pyrrole-2-acetonitrile, 86 ml.
IN sodium hydroxide and 50 ml. 95% ethanol is refluxed for 15 hours
and then cooled and poured into 3N hydrochloric acid. The white
precipitate, 1-methyl-5-(5'-methyl-2'-thieno- yl)-pyrrole-2-acetic
acid, is collected by filtration, air dried, and recrystallized
twice in acetonitrile, m.p. 152-154.degree. C. Anal. Calcd. for
C.sub.13H.sub.13NO.sub.3S: C, 59.37; H, 4.98; N, 5.33. Found: C,
59.15;H, 4.99; N, 5.64.
[0534] (C)
6-Methyl-5-(5'-methyl-2'-thienoyl)-1,3,6-trihydro-6-aza-3-oxape-
ntalen-2-one
[0535] 1-Methyl-5-(5'-methyl-2'-thienoyl)-pyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
6-methyl-5-(5'methyl-2'-thienoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-on-
e (R.sub.1=H, R.sub.2=H, R.sub.3=5'-methyl-2'-thiophenyl,
R.sub.4=methyl, R.sub.5=H, Y=CO, m=1, n=0).
EXAMPLE 71
6-Methyl-5-(p-Trifluoromethylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-
-One
[0536] (A)
1-methyl-5-(p-trifluoromethylbenzoyl)-pyrrole-2-acetonitrile
[0537] A solution of 14.4 g. (0.12 mole) of
1-methylpyrrole-2-acetonitrile and 25 g. (0.12 mole) of
p-trifluoromethylbenzoyl chloride in 120 ml. methylene chloride is
chilled to -25.degree. C. (external bath). Then 14 ml. (0.12 mole)
stannic chloride is added dropwise over a half hour. The resultant
suspension is permitted to come to room temperature and poured into
ice-dilute hydrochloric acid. The aqueous phase is separated and
washed successively with N,N-dimethyl-1,3-propane-diamine, 3N
hydrochloric acid and a saturated solution of sodium chloride. The
solvent is evaporated, and the product is isolated from the
residual oil by column chromatography using acid-washed alumina.
The solvents hexane, benzene, and ether are used as eluents. The
first compound-bearing fraction not giving a positive Enrlich's
test (in benzene) is collected. The solvent is evaporated and the
resultant solid,
1-methyl-5-(p-trifluoromethylbenzoyl)-pyrrole-2-acetonitrile, in
purified by recrystallization from isopropanol, m.p.
95-97.5.degree. C.
[0538] (B) 1-Methyl-5-(p-trifluoromethylbenzoyl)-pyrrole-2-acetic
acid
[0539] A solution of 2.2 g. (0.0075 mole) of
1-methyl-5-(p-trifluoromethyl- benzoyl)-pyrrole-2-acetonitrile, 15
ml. 95% ethanol and 15 ml. 1N sodium hydroxide is refluxed for 18
hours. The ethanol is evaporated. The resultant yellow solid is
dissolved with water and poured into dilute hydrochloric acid. The
resultant white precipitate
1-methyl-5-(p-trifluoromethylbenzoyl)-pyrrole-2-acetic acid, is
collected by filtration and purified by recrystallization from
isopropanol, m.p. 152-154.degree. C. Anal. Calcd. for
C.sub.15H.sub.12F.sub.3NO.sub.3: C, 57.88;H, 3.89; N, 4.50%. Found:
C, 57.92;H, 4.12; N, 4.38%.
[0540] (C)
6-Methyl-5-(p-trifluoromethylbenzoyl)-1,3,6-trihydro-6-aza-3-ox-
apentalen-2-one
[0541] 1-Methyl-5-(p-trifluoromethylbenzoyl)-pyrrole-2-acetic acid
is subjected to the procedure of Example 1, part C to produce
6-methyl-5-(p-trifluoromethylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen--
2-one (R.sub.1=H, R.sub.2=H, R.sub.3=4'-trifluoromethylphenyl,
R.sub.4=methyl, R.sub.5=H, Y=CO, m=1, n=0).
EXAMPLE 72
4,6-Dimethyl-5-(p-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0542] (A) Ethyl 1,4-dimethyl-3-ethoxycarbonylpyrrole-2-acetate
[0543] To a solution of 500 ml. of 25% aqueous methylamine is added
93 g. (0.46 mole) of diethylacetone-dicarboxylate. To the mixture
is added 72 g. (0.782 mole) of chloroacetone over a 10-minute
period. The temperature is kept below 60.degree. C. by external
cooling. After 2 hours, the mixture is poured into ice-hydrochloric
acid. The solid is collected by filtration, washed with water and
air dried. It is recrystallized from hexane to give ethyl
1,4-dimethyl-3-ethoxycarbonylpyrrole-2-acetate as a white solid,
m.p. 71-72.degree. C. Anal. Calcd. for C.sub.13H.sub.19NO.sub.4: C,
61.64;H, 7.56; N, 5.53%. Found: C, 61.64;H, 7.64; N, 5.71%.
[0544] (B) Ethyl 5-(p-chlorobenzoyl)-1,4
dimethyl-3-ethoxycarbonylpyrrole-- 2-acetate
[0545] A solution of 17.5 g. (0.1 mole) p-chlorobenzoyl chloride
and 13.3 g. (0.1 mole) aluminum chloride in 150 ml. of
dichloroethane is added rapidly to a solution of 25.3 g. (0.1 mole)
of ethyl 1,4-dimethyl-3ethoxycarbonylpyrrole-2-acetate in 100 ml.
of refluxing 1,2-dichloroethane. The solution is refluxed for 3.5
hours and poured into ice-hydrochloric acid. The organic layer is
separated, and the aqueous layer washed with 1,2-dichloroethane.
The combined organics are washed successively with water,
N,N-dimethylaminopropylamine, dilute HCl and brine. The solution is
then dried over anhydrous magnesium sulfate and the solvent
evaporated in vacuo. The residue product is crystallized from
cyclohexane and recrystallized from methanol to give ethyl
5-(p-chlorobenzoyl)-1,4 dimethyl-3-ethoxycarbonylpyrrole-2-acetate
as a white solid, m.p. 91-93.degree. C.
[0546] (C)
5-(p-Chlorobenzoyl)-3-carboxy-1,4-dimethylpyrrole-2-acetic acid
[0547] A suspension of 17.3 g. (0.0435 mole) of ethyl
5-(p-chlorobenzoyl)-1,4 dimethyl-3-ethoxypyrrole-2-acetate in 170
g. of 25% sodium hydroxide is heated under reflux for 3 hours. The
suspension is poured into ice, and the resulting yellow solution is
added to ice-hydrochloric acid with stirring. The precipitated
solid is collected by filtration, air dried and recrystallized from
acetone containing 10% water to give
5-(p-chlorobenzoyl)-3-carboxy-1,4-dimethylpyrrole-2-acetic acid as
a white solid, m.p. 253-254.degree. C.
[0548] (D) Ethyl
5-(p-chlorobenzoyl)-3-carboxy-1,4-dimethylpyrrole-2-aceta- te
[0549] A suspension of 2.0 g. of
5-(p-chlorobenzoyl)-3-carboxy-1,4-dimethy- lpyrrole-2-acetic acid
in 20 ml. of 0.5% ethanolic hydrogen chloride is heated under
reflux. The solid gradually dissolves. After 40 minutes, a white
crystalline solid precipitates. The solution is cooled, and the
solid product, ethyl
5-(p-chlorobenzyl)-3-carboxy-1,4-dimethylpyrrole-2-a- cetate, is
filtered and dried, m.p. 197-198.degree. C.
[0550] (E) Ethyl
5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate
[0551] A 9.0 g. (0.0255 mole) sample of ethyl
5-(p-chlorobenzoyl)-3-carbox- y-1,4-dimethylpyrrole-2-acetate is
heated under nitrogen at 210 to 230.degree. C. for 2 hours. Gas
evolves. The residue is molecularly distilled in a sublimator at
195.degree. C., 0.05 mm/Hg. The sublimate is recrystallized from
cyclohexane to give ethyl 5-(p-chlorobenzoyl)-1,4-dim-
ethylpyrrole-2-acetate as a white solid, m.p. 107-109.degree.
C.
[0552] (F) 5-(p-Chlorobenzoyl)-1,4-dimethylpyrrole-2-acetic
acid
[0553] A suspension of 4.0 g. (0.0125 mole) of ethyl
5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate in 26 ml. of 0.5
N sodium hydroxide (0.013 mole) is heated under reflux for 30
minutes. The resulting solutions is acidified with dilute
hydrochloric acid, and the precipitated solid is collected by
filtration, air dried and recrystallized from 2-propanol to give
5-(p-chlorobenzoyl)-1,4-dimethylpy- rrole-2-acetic acid as a white
crystalline solid, m.p. 178-179.degree. C. Anal. Calcd. for
C.sub.15H.sub.14 ClNO.sub.3: C, 61.76;H, 4.83; N, 4.82%. Found: C,
61.68; H, 4.96; N, 4.89%.
[0554] (G)
4,6-Dimethyl-5-(p-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapent-
alen-2-one
[0555] 5-(p-Chlorobenzoyl)-1,4-dimethylpyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
4,6-dimethyl-5-(p-chloro-
benzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R.sub.1=H,
R.sub.2=H, R.sub.3=4'-chlorophenyl, R.sub.4=methyl, R.sub.5=methyl,
Y=CO, m=1, n=0).
EXAMPLE 73
4,6-Dimethyl-5-(p-Toluoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0556] (A) Ethyl
1,4-dimethyl-3-ethoxycarbonyl-5(p-toluoyl)-pyrrole-2-acet- ate
[0557] A solution of 30.8 g. p-toluoyl chloride and 26.6 g. (0.2
mole) of aluminum chloride in 250 ml. of 1,2-dichloroethane is
added to a refluxing solution of 50.6 g. (0.2 mole) of ethyl
3-ethoxycarbonyl-1,4-di- methylpyrrole-2-acetate in 250 ml. of
1,2-dichloroethane over 30 minutes. The mixture is heated under
reflux for 90 minutes, and poured into ice-diluted hydrochloric
acid. The organic solution is separated, washed with brine, and
dried over magnesium sulfate. The solvent is evaporated in vacuo,
and the residue is recrystallized from methanol to give ethyl
1,4-dimethyl-3-ethoxycarbonyl-5-(p-toluoyl)-pyrrole-2-acetate as a
white solid, m.p. 108-111.degree. C.
[0558] (B) 3-Carboxy-1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetic
acid
[0559] A suspension of 54 g. (0.145 mole) of ethyl
1,4-dimethyl-3-ethoxyca- rbonyl-5-(p-toluoyl)-pyrrole-2-acetate in
500 g. of 25% sodium hydroxide is heated at just below reflux for 3
hours. The yellow suspension is then poured into ice-hydrochloric
acid, and the precipitated solid is collected, air dried and
recrystallized from acetone-water to give
3-carboxy-1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetic acid as a
white solid, m.p. 229-230.degree. C. Anal. Calcd. for
C.sub.17H.sub.17NO.sub.5: C, 64.75;H, 5.43; N, 4.44%. Found: C,
64.86;H, 5.53; N, 4.47%.
[0560] (C) Ethyl
3-carboxy-1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetate
[0561] A solution of 37 g. (0.118 mole) of
3-carboxy-1,4-dimethyl-5-(p-tol- uoyl)-pyrrole-2-acetic acid in 370
ml. of ethanol containing 1.8 g. of dry hydrogen chloride is heated
under reflux for 45 minutes. The solution is cooled, and the solid
which precipitated, ethyl 3-carboxy-1,4-dimethyl-5--
(o-toluoyl)-pyrrole-2-acetate, is collected, m.p. 200-202.degree.
C.
[0562] (D) Ethyl 1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetate
[0563] A solution of 33.0 g. (0.096 mole) of ethyl
3-carboxy-1,4-dimethyl-- 5-(p-toluoyl)-pyrrole-2-acetate in 200 ml.
of quinoline with 0.1 g. copper chromite added is heated under
nitrogen for 6 hours at 200.degree. C., then for 30 minutes at
220.degree. C. The quinoline is distilled off in vacuo. The residue
is dissolved in ether and washed successively with dilute
hydrochloric acid, dilute sodium hydroxide, and brine; dried over
magnesium sulfate; and the solvent evaporated in vacuo to give a
brown oily residue which crystallizes. It is recrystallized from
methanol, sublimed at 150.degree. C. (0.025 mm/Hg) and
recrystallized from hexane to give ethyl
1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetate as a white solid, m.p.
90-93.degree. C.
[0564] (E) 1,4-Dimethyl-5-(p-toluoyl)-pyrrole-2-acetic acid
[0565] A suspension of 8.5 g. (0.0284 mole) of ethyl
1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetate in 29 ml. of IN sodium
hydroxide solution is heated under reflux for 20 minutes. The
yellow solution is diluted with water and added to dilute
hydrochloric acid. The precipitated solid is collected, dried in
vacuo, and recrystallized from 2-propanol to give
1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetic acid as a white solid,
m.p. 160-161.degree. C. Anal. Calcd. for C.sub.16H.sub.17NO.sub.3:
C, 70.83;H, 6.32; N, 5.16%. Found: C, 70.90;H, 6.39; N, 5.25%.
[0566] (F)
4,6-Dimethyl-5-(p-toluoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-
-one
[0567] 1,4-Dimethyl-5-(p-toluoyl)-pyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
4,6-dimethyl-5-(p-toluoyl)--
1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R.sub.1=H, R.sub.2=H,
R.sub.3=4'-methylphenyl, R.sub.4=methyl, R.sub.5=methyl, Y=CO, m=1,
n=0).
EXAMPLE 74
4,6-Dimethyl-5-Benzoyl-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0568] (A) 5-Benzoyl-1,4-dimethylpyrrole-2-acetic acid
[0569] By following the procedure outlined in Example 72B-F, except
that an equivalent quantity of benzoyl chloride is employed as the
starting acylating agent in place of the p-chlorobenzoyl chloride
used in Example 72B, there is obtained
5-benzoyl-1,4-dimethylpyrrole-2-acetic acid.
[0570] (B)
4,6-Dimethyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one
[0571] 5-Benzoyl-1,4-dimethylpyrrole-2-acetic acid is subjected to
the procedure of Example 1, part C to produce
4,6-dimethyl-5-benzoyl-1,3,6-tr- ihydro-6-aza-3-oxapentalen-2-one
(R.sub.1=H, R.sub.2=H, R.sub.3=phenyl, R.sub.4=methyl,
R.sub.5=methyl, Y=CO, m=1, n=0).
EXAMPLE 75
4,6-Dimethyl-5-(2',3',5'-Tribromobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapental-
en-2-One
[0572] (A)
5-(2',3',5'-Tribromobenzoyl)-1,4-dimethylpyrrole-2-acetic acid
[0573] By following the procedure outlined in Example 72B-F, except
that an equivalent quantity of 2,3,5-tribromobenzoyl chloride is
employed as the starting acylating agent in place of the
p-chlorobenzoyl chloride used in Example 72B, there is obtained
5-(2',3',5'-tribromobenzoyl)-1,4-d- imethylpyrrole-2-acetic
acid.
[0574] (B)
4,6-Dimethyl-5-(2',3',5'-Tribromobenzoyl)-1,3,6-Trihydro-6-Aza--
3-Oxapentalen-2-One
[0575] 5-(2',3',5'-Tribromobenzoyl)-1,4-dimethylpyrrole-2-acetic
acid is subjected to the procedure of Example 1, part C to produce
4,6-dimethyl-5-(2',3',5'-tribromobenzoyl)-1,3,6-trihydro-6-aza-3-oxapenta-
len-2-one (R.sub.1=H, R.sub.2=H, R.sub.3=2',3',5'-tribromophenyl,
R.sub.4=methyl, R.sub.5=methyl, Y=CO, m=1, n=0).
EXAMPLE 76
4-Ethyl-6-Methyl-5-(4'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-
-One
[0576] (A) 1-Chloro-2-butanone
[0577] Chlorination of methylethylketone is carried out according
to Bruylant and Houssiau [Bull. Soc. Chem. Belg., 6, 492 (1952)].
The mixture obtained is fractionally distilled at atmospheric
pressure through a Vigreaux column. The fraction boiling at
135-144.degree. C. is shown by vapor phase chromatography to
contain approximately 75% 1-chloro-2-butanone and 25%
3-chloro-2-butanone. This fraction may be used in the next step
without further separation.
[0578] (B) Ethyl
3-ethoxycarbonyl-4-ethyl-1-methylpyrrole-2-acetate
[0579] A 900 ml. solution of 25% aqueous methylamine is cooled in
an ice bath and 101 g. (0.5 mole) of diethyl acetone decarboxylate
is added. To the mixture is added 110 g. of the 1-chloro-2-butanone
obtained in part A. Intermittant cooling is applied to keep the
temperature below 60.degree. C. The mixture is stirred for one hour
and poured into ice-hydrochloric acid. The crystalline product is
collected by filtration and recrystallized from methanol to yield
ethyl 3-ethoxycarbonyl-4-ethyl-- 1-methylpyrrole-2-acetate as in a
white solid, m.p. 65-67.degree. C.
[0580] (C) Ethyl
(5-p-chlorobenzoyl)-3-ethoxycarbonyl-4-ethyl-1-methylpyrr-
ole-2-acetate
[0581] A solution of 13.8 g. (0.0788 mole) of p-chlorobenzoyl
chloride and 10.5 g. (0.0788 mole) of aluminum chloride in 120 ml.
of 1,2-dichloroethane is added to a refluxing solution of 21.8 g.
(0.0788 mole) of ethyl
3-ethoxycarbonyl-4-ethyl-1-methylpyrrole-2-acetate. The mixture is
heated under reflux for 10 hours and stirred at room temperature
for an additional 10 hours. It is then poured into ice-hydrochloric
acid. The organic layer is separated, and the aqueous layer washed
with 1,2-dichloroethane. The combined organics are washed
successively with water, N,N-dimethylaminopropylamine, dilute HCl
and brine. The solution is then dried over anhydrous magnesium
sulfate and the solvent evaporated in vacuo. The residual red oily
residue crystallizes on standing. It is recrystallized twice from
methanol to give ethyl
(5-chlorobenzoyl)-3-ethoxycarbonyl-4-ethyl-1-methyl-pyrrole-2--
acetate as a white solid, m.p. 72-74.degree. C.
[0582] (D)
3-carboxy-5-(p-chlorobenzoyl)-4-ethyl-1-methylpyrrole-2-acetic
acid
[0583] A suspension of 18.2 g. (0.044 mole) of ethyl
5-(p-chlorobenzoyl)-3-ethoxycarbonyl-4-ethyl-1-methylpyrrole-2-acetate
in 170 ml. of 25% aqueous sodium hydroxide solution is heated under
reflux for 3 hours. It is cooled, diluted with water and acidified
with dilute hydrochloric acid. The precipitated solid is collected
by filtration and air dried. It is recrystallized from
acetone-water to give
3-carboxy-5-(p-chlorobenzoyl)-4-ethyl-1-methylpyrrole-2-acetate
acid, m.p. 211-212.5.degree. C.
[0584] (E) Ethyl
3-carboxy-5-(p-chlorobenzoyl)-4-ethyl-1-methylpyrrole-2-a-
cetate
[0585] A solution of 13.8 g. (0.0375 mole) of
3-carboxy-5-(p-chlorobenzoyl- )-4-ethyl-1-methylpyrrole-2-acetic
acid in 140 ml. of 0.5% ethanolic hydrogen chloride is heated under
reflux for 45 minutes. After cooling, the precipitated solid is
collected. A second crop is obtained by partial evaporation of the
solvent, recrystallized from ethanol and combined with the first
crop to give ethyl 3-carboxy-5-(.gamma.-chlorobenzoyl)-4-ethyl--
1-methylpyrrole-2-acetate, m.p. 184-186.degree. C.
[0586] (F) Ethyl
5-(p-chlorobenzoyl)-4-ethyl-1-methylpyrrole-2-acetate
[0587] A 13.7 g. (0.035 mole) sample of ethyl
3-carboxy-5-(p-chlorobenzoyl- )-4-ethyl-1-methypyrrole-2-acetate is
heated at 200.degree. C. to 210C. under nitrogen for 90 minutes.
The resulting oil is molecularly distilled at 185.degree. C. and
0.1 mm pressure to yield a solid which is recrystallized from
cyclohexane and then methanol to give ethyl
5-(p-chlorobenzoyl)-4-ethyl-1-methylpyrrole-2-acetate as a white
solid, m.p. 73-75.degree. C.
[0588] (G) 5-(p-Chlorobenzoyl)-4-ethyl-1-methylpyrrole-2-acetic
acid
[0589] A suspension of 4.5 g. (0.0136 mole) of ethyl
5-(p-chlorobenzoyl)-4-ethyl-1-methylpyrrole-2-acetate in 28 ml. 0.5
N sodium hydroxide and 1 ml. of ethanol is heated under reflux for
30 minutes. The mixture is then poured into ice-dilute hydrochloric
acid. The precipitated solid is filtered, air dried and
recrystallized from 2-propanol to give
5-(p-chlorobenzoyl)-4-ethyl-1-methylpyrrole-2-acetic acid as a
white solid, m.p. 129-131.degree. C. Anal. Calcd. for
C.sub.16H.sub.16ClNO.sub.3: C, 62.85;H, 5.29; N, 4.5%. Found: C,
62.58;H, 5.40; N, 4.83%.
[0590] (H)
4-Ethyl-6-methyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-ox-
apentalen-2-one
[0591] 5-(p-Chlorobenzoyl)-4-ethyl-1-methylpyrrole-2-acetic acid is
subjected to the procedure of Example 1, Part C to produce
4-ethyl-6-methyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen--
2-one (R.sub.1=H, R.sub.2=H, R.sub.3=4'-chlorophenyl,
R.sub.4=ethyl, R.sub.5=methyl, Y=CO, m=1, n=0).
EXAMPLE 77
Rac-1,4,6-Trimethyl-5-(p-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-
-2-One
[0592] (A) Ethyl
5-(p-chlorobenzoyl)-1,4,.alpha.-trimethylpyrrole-2-acetat- e
[0593] 6.4 grams (0.02 mole) of ethyl
5-(p-chlorobenzoyl)-1,4-dimethylpyrr- ole-2-acetate is dissolved in
100 ml. of dimethyl sulfoxide (DMSO) and added to a slurry of 0.48
g. (0.02 mole) of sodium hydride in approximately 30 ml. of DMSO.
The mixture is stirred for 30 minutes before 2.84 g. (0.02 mole) of
methyl iodide is added. Stirring is continued for 15 minutes. The
reaction mixture is then poured into water, and the precipitate
filtered off and recrystallized from 2-propanol to yield ethyl
5-(p-chlorobenzoyl)-1,4,.alpha.-trimethylpyrrole-2-acetate, m.p.
88-90.degree. C.
[0594] (B)
5-(p-Chlorobenzoyl)-1,4,.alpha.-trimethylpyrrole-2-acetic acid
[0595] An ethanol solution of 2.9 g. (0.0087 mole) of ethyl
5-(p-chlorobenzoyl)1,4,.alpha.-trimethylpyrrole-2-acetate is added
to 17.5 ml. 0.5 N sodium hydroxide solution, and the mixture is
heated under reflux for one hour. The ethanol is evaporated in
vacuo, and the solution poured into dilute hydrochloric acid. The
precipitated solid is collected by filtration and recrystallized
from ether-cyclohexane to give
5-(p-chlorobenzoyl)-1,4,.alpha.-trimethylpyrrole-2-acetic acid as a
white solid, m.p. 153-154.degree. C. Anal. Calcd. for
C.sub.16H.sub.16ClNO.sub.- 3: C, 62.85;H, 5.29; N, 4.58%. Found: C,
62.74;H, 5.22; N, 4.47%.
[0596] (C)
Rac-1,4,6-trimethyl-5-(p-chlorobenzoyl)-1,3,6-trihydro-6-aza-3--
oxapentalen-2-one
[0597] 5-(p-Chlorobenzoyl)-1,4-trimethyl-pyrrole-2-acetic acid is
subjected to the procedure of Example 1, Part C to produce
rac-1,4,6-trimethyl-5-(p-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentale-
n-2-one (R.sub.1=methyl, R.sub.2H, R.sub.3=4'-chlorophenyl,
R.sub.4=methyl, R.sub.5=methyl, Y=CO, m=1, n=0).
EXAMPLE 78
Rac-1,4,6-Trimethyl-5-(4'-Toluoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-On-
e
[0598] (A) Ethyl
1,4,.alpha.-trimethyl-5-(p-toluoyl)-pyrrole-2-acetate
[0599] The methylation procedure of Example 77A is repeated, except
that an equivalent quantity of the ester obtained from Examples 73D
is methylated instead of the ethyl
5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2- -acetate used in Example
77A, to yield ethyl 1,4,.alpha.-trimethyl-5-(p-to-
luoyl)-pyrrole-2-acetate.
[0600] (B) 1,4,.alpha.-trimethyl-5-(p-toluoyl)-pyrrole-2-acetic
acid
[0601] The hydrolysis procedure of Example 77B is followed in
transforming the .alpha.-methyl ester obtained in part A of this
Example to yield
1,4,.alpha.-trimethyl-5-(p-toluoyl)-pyrrole-2-acetic acid.
[0602] (C)
Rac-1,4,6-trimethyl-5-(4'-toluoyl)-1,3,6-trihydro-6-aza-3-oxape-
ntalen-2-one
[0603] The acid from Example 78B is subjected to the procedure of
Example 1, part C to produce
rac-1,4,6-trimethyl-5-(4'-toluoyl)-1,3,6-trihydro-6--
aza-3-oxapentalen-2-one (R.sub.1=methyl, R.sub.2=H,
R.sub.3=4'-methylphenyl, R.sub.4=methyl, R.sub.5=methyl, Y=CO, m=1,
n=0).
EXAMPLE 79
Rac-1,4,6-Trimethyl-5-Benzoyl-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0604] (A) Ethyl
1,4,.alpha.-trimethyl-5-benzoyl-pyrrole-2-acetate
[0605] The methylation procedure of Example 77A is repeated, except
that an equivalent quantity of the ester obtained from Example 74A
is methylated instead of the ethyl
5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2- -acetate used in Example
77A, to yield ethyl 1,4,.alpha.-trimethyl-5-benzo-
yl-pyrrole-2-acetate.
[0606] (B) 1,4,.alpha.-trimethyl-5-benzoyl-pyrrole-acetic acid
[0607] The hydrolysis procedure of Example 77B is followed in
transforming the .alpha.-methyl ester obtained in part A of this
Example to yield 1,4,.alpha.-trimethyl-5-benzoyl-pyrrole-2-acetic
acid.
[0608] (C)
Rac-1,4,6-trimethyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentale-
n-2-one
[0609] The acid from Example 79B is subjected to the procedure of
Example 1, part C to produce
rac-1,4,6-trimethyl-5-benzoyl-1,3,6-trihydro-6-aza-3-
-oxapentalen-2-one (R.sub.1=methyl, R.sub.2=H, R.sub.3=phenyl,
R.sub.4=methyl, R.sub.5=methyl, Y=CO, m=1, n=0).
EXAMPLE 80
4-Ethyl-1,6-Dimethyl-5-Benzoyl-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0610] (A) Ethyl
4-ethyl-1,.alpha.-dimethyl-5-benzoyl-pyrrole-2-acetate
[0611] The methylation procedure of Example 78A is repeated, except
that an equivalent quantity of the ester obtained from Examples
73D, 74A and 76F is methylated instead of the ethyl
5-(p-chlorobenzoyl)-1,4-dimethylpy- rrole-2-acetate used in Example
77A, to yield ethyl 4-ethyl-1,
.alpha.-dimethyl-5-benzoyl-pyrrole-2-acetate
[0612] (B) 4-Ethyl-1,.alpha.-dimethyl-5-benzoyl-pyrrole-2-acetic
acid
[0613] The hydrolysis procedure of Example 77B is followed in
transforming the .alpha.-methyl ester obtained in part A of this
Example to yield
4-ethyl-1,.alpha.-dimethyl-5-benzoyl-pyrrole-2-acetic acid.
[0614] (C)
Rac-4-ethyl-1,6-dimethyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxape-
ntalen-2-one
[0615] The acid from Example 80B is subjected to the procedure of
Example 1, part C to produce
rac-4-ethyl-1,6-dimethyl-5-benzoyl-1,3,6-trihydro-6--
aza-3-oxapentalen-2-one. (R.sub.1=methyl, R.sub.2H, R.sub.3=phenyl,
R.sub.4=methyl, R.sub.5=ethyl, Y=CO, m=1, n=0).
EXAMPLE 81
1,6-Dimethyl-5-(4
'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxa-Pentalen-2-O- ne
Synthesized with (-) Acid
[0616] (A)
(-)-5-(p-Chlorobenzoyl)-1,.alpha.-dimethylpyrrole-2-acetic acid
[0617] A solution of 16.5 g. (0.057 mole) of racemic
5-(p-chlorobenzoyl)-.alpha.-methyl-1-methylpyrrole-2-acetic acid
and 6.8 g. (0.057 mole) of (+)-.alpha.-methylbenzylamine in 95%
ethanol deposits crystals on standing. The solid is collected and
recrystallized twice from 2-propanol to give 4.4 g. of salt, m.p.
181-182.degree. C., the mother liquors being set aside for use as
shown in Example 82. The salt is partitioned between ether and 3N
hydrochloric acid. The ether layer is washed with dilute
hydrochloric acid and brine and dried over magnesium sulfate. The
solvent is evaporated in vacuo. The solid residue is dissolved in
hot ether and methylcyclohexane is added. The ether is allowed to
evaporate and the precipitated solid, (-)-5-(p-chlorobenzoyl)--
1,.alpha.-dimethylpyrrole-2-acetic acid, is collected by
filtration: (13% yield), m.p. 106-107.degree. C.
[0618] (B)
1,6-Dimethyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxa-pe-
ntalen-2-one synthesized with (-) acid
[0619] The acid from Example 81A is subjected to the procedure of
Example 1, part C to produce 1,6-dimethyl-5-(4
'-chlorobenzoyl)-1,3,6-trihydro-6-- aza-3-oxa-pentalen-2-one
(R.sub.1=methyl, R.sub.2=H, R.sub.3=4'-chlorophenyl,
R.sub.4=methyl, R.sub.5H, Y=CO, m=1, n=0).
EXAMPLE 82
1,6-Dimethyl-5-(4'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
Synthesized with (+) Acid
[0620] (A)
(+)-5-(p-Chlorobenzoyl)-1,.alpha.-dimethylpyrrole-2-acetic acid
[0621] The mother liquors set aside in Example 81 are evaporated to
dryness. The residue is acidified with 3N hydrochloric acid and the
precipitated acid is extracted into ether. The ether solution is
then extracted with saturated sodium bicarbonate solution. The
latter is acidified with dilute HCl, and the precipitated solid is
extracted into ether. The ether solution is washed with brine,
dried over anhydrous magnesium sulfate and evaporated to dryness to
yield 5-(p-chlorobenzoyl)-.alpha.-methyl-1-methylpyrrole-2-acetic
acid [presumably rich in the (+) enanthiomorph] as a yellow solid.
A 14.8 g. sample is dissolved in ethanol. To the solution is added
6.15 g. (.051 mole) of (-)-.alpha.-methylbenzylamine. A crystalline
salt precipitates on standing which is collected and recrystallized
three times from 2-propanol to give about 6.6 g. of white crystals,
m.p. 175-177.degree. C. The salt is partitioned between ether and
3N HCl solution. The ether layer is washed with dilute HCl and
brine and dried over magnesium sulfate. The solvent is partially
evaporated in vacuo, and methylcyclohexane is added. The ether is
allowed to evaporate at room temperature, and the precipitate is
collected. It is recrystallized once more in the same manner to
yield (21% yield) of (+)-5-(p-chlorobenzoyl)-1-
,.alpha.-dimethylpyrrole-2-acetic acid as a white solid, m.p.
105.5-106.5.degree. C.
[0622] (B)
1,6-Dimethyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxa-pe-
ntalen-2-one synthesized with (+) acid
[0623] The acid from Example 82A is subjected to the procedure of
Example 1, part C to produce
1,6-dimethyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-a-
za-3-oxa-pentalen-2-one (R.sub.1=methyl, R.sub.2H,
R.sub.3=4'-chlorophenyl- , R.sub.4=methyl, R.sub.5H, Y CO, m=1,
n=0).
EXAMPLE 83
4,6-Dimethyl-5-(4'-Fluorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0624] (A) 3-Carboxy-1,4-dimethylpyrrole-2-acetic acid
[0625] A mixture of 176 g. (0.7 mole) of ethyl
1,4-dimethyl-3-ethoxycarbon- ylpyrrole-2-acetate and 1760 ml. of
25% sodium hydroxide solution is heated under reflux for 3 hours
and then cooled and acidified with dilute hydrochloric acid. The
precipitated solid is filtered and air dried. There is obtained
3-carboxy-1,4-dimethylpyrrole-2-acetic acid as a gray solid, m.p.
220-222.degree. C.
[0626] (B) Ethyl 3-carboxy-1,4-dimethylpyrrole-2-acetate
[0627] A solution of 130 g. (0.66 mole) of
3-carboxy-1,4-dimethylpyrrole-2- -acetic acid in 1300 ml. of 0.5%
ethanolic hydrogen chloride is heated under reflux for 45 minutes,
and then filtered while hot. A white solid, ethyl
3-carboxy-1,4-dimethylpyrrole-2-acetate, precipitates from the
filtrate on cooling, m.p. 182-185.degree. C.
[0628] (C) Ethyl 1,4-dimethylpyrrole-2-acetate
[0629] A 70.0 g. sample (0.31 mole) of ethyl
3-carboxy-1,4-dimethylpyrrole- -2-acetate is heated under nitrogen
at 190-210.degree. C. until gas evolution ceases. The resulting
yellow liquid is distilled at 82-90.degree. C. at 0.25 mm. to give
about 41 g. (73% yield) of a clear colorless liquid, ethyl
1,4-dimethylpyrrole-2-acetate.
[0630] (D) Ethyl
1,4-dimethyl-5-(p-fluorobenzoyl)-pyrrole-2-acetate
[0631] A solution of 3.95 g. (0.025 mole) of p-fluorobenzoyl
chloride and 3.32 g. (0.025 mole) of aluminum chloride in 20 ml. of
1,2-dichloroethane is added dropwise to a solution of 4.52 g.
(0.025 mole) of ethyl 1,4-dimethylpyrrole-2-acetate in 20 ml. of
1,2-dichloroethane at room temperature. The reaction mixture is
stirred for 2 hours, and then cooled and poured into ice-dilute
HCl. The organic phase is separated and washed successively with
N,N-dimethyl-1,3-propanediamine, dilute hydrochloric acid and a
saturated solution of sodium chloride; dried over anhydrous
magnesium sulfate; and the solvent evaporated. The residue is
triturated with hot hexane and crystals form upon cooling. There is
obtained about 1.9 g. (25% yield) of ethyl
1,4-dimethyl-5-(p-fluorobenzoyl)-pyrrole-2-ac- etate as a white
solid, m.p. 84-86.degree. C. Upon recrystallization from methanol,
the m.p. is 87-89.degree. C.
[0632] (E) 1,4-Dimethyl-5-(p-fluorobenzoyl)-pyrrole-2-acetic
acid
[0633] A suspension of 3.03 g. (0.01 mole) of ethyl
1,4-dimethyl-5-(p-fluorobenzoyl)-pyrrole-2-acetate in 11 ml. of 1N
sodium hyroxide solution is heated under reflux for 30 minutes. The
solution is filtered while hot and acidified with dilute
hydrochloric acid. The precipitate is collected, air dried and
recrystallized from 2-propanol to give about 2.5 g. (91% yield) of
1,4-dimethyl-5-(p-fluorobenzoyl)-pyrrole- -2-acetic acid as a white
solid, m.p. 176-178.degree. C.
[0634] (F)
4,6-Dimethyl-5-(4'-fluorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapen-
talen-2-one
[0635] 1,4-Dimethyl-5-(p-fluorobenzoyl)-pyrolle-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
4,6-dimethyl-5-(4'-fluor-
obenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R.sub.1=H,
R.sub.2=H, R.sub.3=4'-fluorophenyl, R.sub.4=methyl, R.sub.5=methyl,
Y=CO, m=1, n=0).
EXAMPLE 84
4,6-Dimethyl-5-(4'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalene-2-On-
e
[0636] (A) Ethyl
5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate
[0637] The Friedel-Crafts acylation procedure of Example 83D is
followed except that an equivalent quantity of
p-chlorobenzoyl-chloride is substituted for the p-fluorobenzoyl
chloride used therein to yield ethyl
5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate, m.p.
107-109.degree. C.
[0638] (B) 1,4-Dimethyl-5-(p-chlorobenzoyl)pyrrole-2-acetic
acid
[0639] The ester of part A of this Example is hydrolyzed in
accordance with the procedure of Example 83E to yield
1,4-dimethyl-5-(p-chlorobenzoy- l)pyrrole-2-acetic acid.
[0640] (C)
4,6-Dimethyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapen-
talene
[0641] 1,4-Dimethyl-5-(p-chlorobenzoyl)pyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
4,6-dimethyl-5-(4'-chlor-
obenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalene (R.sub.1=H,
R.sub.2=H, R.sub.3=4'-Chlorophenyl, R.sub.4=Methyl, R.sub.5=Methyl,
Y=CO, m=1,n=0).
EXAMPLE 85
4,6-Dimethyl-5-(4'-Nitrobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0642] (A) Ethyl
5-(p-nitrobenzoy)-1,4-dimethylpyrrole-2-acetate
[0643] The Friedel-Crafts acylation procedure of Example 83D is
followed except that an equivalent quantity of .rho.-nitrobenzoyl
chloride is substituted for the p-fluorobenzoyl chloride used
therein to yield ethyl
5-(p-nitrobenzoyl)-1,4-dimethylpyrrole-2-acetate.
[0644] (B) 1,4-Dimethyl-5-(p-nitrobenzoyl)pyrrole-2-acetic acid
[0645] The ester of part A of this Example is hydrolyzed in
accordance with the procedure of Example 83E to yield
1,4-dimethyl-5-(p-nitrobenzoyl- )pyrrole-2-acetic acid.
[0646] (C)
4,6-Dimethyl-5-(4'-nitrobenzoyl)-1,3,6-trihydro-6-aza-3-oxapent-
alen-2-one
[0647] 1,4-Dimethyl-5-(p-nitrobenzoyl)pyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
4,6-dimethyl-5-(4'-nitro-
benzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R.sub.1=H,
R.sub.2=H, R.sub.3=4'-nitrophenyl, R.sub.4=methyl, R.sub.5=methyl,
Y=CO, m=1, n=0).
EXAMPLE 86
4,6-Dimethyl-5-Benzoyl-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0648] (A) Ethyl 5-benzoyl-1,4-dimethylpyrrole-2-acetate
[0649] The Friedel-Crafts acylation procedure of Example 83D is
followed except that an equivalent quantity of benzoylchloride is
substituted for the p-fluorobenzoyl chloride used therein to yield
ethyl 5-benzoyl-1,4-dimethylpyrrole-2-acetate, m.p. 78-80.degree.
C.
[0650] (B) 1,4-Dimethyl-5-benzoyl-pyrrole-2-acetic acid
[0651] The ester of part A of this Example is hydrolyzed in
accordance with the procedure of Example 83E to yield
1,4-dimethyl-5-benzoyl-pyrrole- -2-acetic acid.
[0652] (C)
4,6-Dimethyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one
[0653] 1,4-Dimethyl-5-benzoyl-pyrrole-2-acetic acid is subjected to
the procedure of Example 1, part C to produce
4,6-dimethyl-5-benzoyl-1,3,6-tr- ihydro-6-aza-3-oxapentalen-2-one
(R.sub.1=H, R.sub.2=H, R.sub.3=phenyl, R.sub.4=methyl,
R.sub.5=methyl, Y=CO, m=1, n=0).
EXAMPLE 87
4,6-Dimethyl-5-(2'-Thenoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0654] (A) Ethyl 5-(2'-thenoyl)-1,4-dimethylpyrrole-2-acetate The
Friedel-Crafts acylation procedure of Example 83D is followed
except that an equivalent quantity of 2'-thenoylchloride is
substituted for the p-fluorobenzoyl chloride used therein to yield
ethyl 5-(2'-thenoyl)-1,4-dimethylpyrrole-2-acetate.
[0655] (B) 1,4-Dimethyl-5-(2 '-thenoyl)-pyrrole-2-acetic acid
[0656] The ester of part A of this Example is hydrolyzed in
accordance with the procedure of Example 83E to yield
1,4-dimethyl-5-(2'-thenoyl)-py- rrole-2-acetic acid.
[0657] (C)
4,6-Dimethyl-5-(2'-thenoyl)-1,3,6-trihydro-6-aza-3-oxapentalen--
2-one
[0658] 1,4-Dimethyl-5-(2'-thenoyl)-pyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
4,6-dimethyl-5-(2'-thenoyl)-
-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R.sub.1=H, R.sub.2H,
R.sub.3=2'-thiophenyl, R.sub.4=methyl, R.sub.5=methyl, Y=CO, m=1,
n=0).
EXAMPLE 88
4,6-Dimethyl-5-(5'-Methyl-2'-Thenoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-
-One
[0659] (A) Ethyl
5-(5'-methyl-2'-thenoyl)-1,4-dimethylpyrrole-2-acetate
[0660] The Friedel-Crafts acylation procedure of Example 83D is
followed except that an equivalent quantity of 5'-methyl-2'-thenoyl
chloride is substituted for the p-fluorobenzoyl chloride used
therein to yield ethyl
5-(5'-methyl-2'-thenoyl)-1,4-dimethylpyrrole-2-acetate.
[0661] (B) 1,4-Dimethyl-5-(5'-methyl-2'-thenoyl)pyrrole-2-acetic
acid
[0662] The ester of part A of this Example is hydrolyzed in
accordance with the procedure of Example 83E to yield
1,4-dimethyl-5-(5'-methyl-2'-t- henoyl)pyrrole-2-acetic acid.
[0663] (C)
4,6-Dimethyl-5-(5'-methyl-2'-thenoyl)-1,3,6-trihydro-6-aza-3-ox-
apentalen-2-one
[0664] 1,4-Dimethyl-5-(5'-methyl-2'-thenoyl)pyrrole-2-acetic acid
is subjected to the procedure of Example 1, part C to produce
4,6-dimethyl-5-(5'-methyl-2'-thenoyl)-1,3,6-trihydro-6-aza-3-oxapentalen--
2-one (R.sub.1=H, R.sub.2=H, R.sub.3=5'-methyl-2'-thiophenyl,
R.sub.4=methyl, R.sub.5=methyl, Y=CO, m=1, n=0).
EXAMPLE 89
4,6-Dimethyl-5-(4'-Trifluoromethylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapenta-
len-2-One
[0665] (A) Ethyl
5-(p-trifluoromethylbenzoyl)-1,4-dimethylpyrrole-2-acetat- e The
Friedel-Crafts acylation procedure of Example 83D is followed
except that an equivalent quantity of 4'-trifluoromethylbenzoyl
chloride is substituted for the p-fluorobenzoyl chloride used
therein to yield ethyl
5-(p-trifluoromethylbenzoyl)-1,4-dimethylpyrrole-2-acetate.
[0666] (B)
1,4-Dimethyl-5-(p-trifluoromethylbenzoyl)pyrrole-2-acetic acid
[0667] The ester of part A of this Example is hydrolyzed in
accordance with the procedure of Example 83E to yield
1,4-dimethyl-5-(p-trifluoromet- hylbenzoyl)pyrrole-2-acetic
acid.
[0668] (C)
4,6-Dimethyl-5-(4'-trifluoromethylbenzoyl)-1,3,6-trihydro-6-aza-
-3-oxapentalen-2-one
[0669] 1,4-Dimethyl-5-(p-trifluoromethylbenzoyl)pyrrole-2-acetic
acid is subjected to the procedure of Example 1, part C to produce
4,6-dimethyl-5-(4'-trifluoromethylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapent-
alen-2-one (R.sub.1=H, R.sub.2=H, R.sub.3=4'-trifluoromethylphenyl,
R.sub.4=methyl, R.sub.5=methyl, Y=CO, m=1, n=0).
EXAMPLE 90
4,6-Dimethyl-5-(3',4'-Dimethoxybenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-
-2-One
[0670] (A) Ethyl
5-(3',4'-dimethoxybenzoyl)-1,4-dimethylpyrrole-2-acetate
[0671] The Friedel-Crafts acylation procedure of Example 83D is
followed except that an equivalent quantity of
3',4'-dimethoxybenzoyl chloride is substituted for the
p-fluorobenzoyl chloride used therein to yield ethyl
5-(3',4'-dimethoxybenzoyl)-1,4-dimethylpyrrole-2-acetate.
[0672] (B) 1,4-Dimethyl-5-(3',4'-dimethoxybenzoyl)-pyrrole-2-acetic
acid
[0673] The ester of part A of this Example is hydrolyzed in
accordance with the procedure of Example 83E to yield
1,4-dimethyl-5-(3',4'-dimethox- ybenzoyl)-pyrrole-2-acetic
acid.
[0674] (C)
4,6-Dimethyl-5-(3',4'-dimethoxybenzoyl)-1,3,6-trihydro-6-aza-3--
oxapentalen-2-one
[0675] 1,4-Dimethyl-5-(3',4'-dimethoxybenzoyl)-pyrrole-2-acetic
acid is subjected to the procedure of Example 1, part C to produce
4,6-dimethyl-5-(3',4'-dimethoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxapentale-
n-2-one (R.sub.1=H, R.sub.2=H, R.sub.3=3',4'-dimethoxyphenyl,
R.sub.4=methyl, R.sub.5=methyl, Y=CO, m=1, n=0).
EXAMPLE 91
4,6-Dimethyl-5-(2',3',5'-Tribromobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapental-
en-2-One
[0676] (A) Ethyl
5-(2',3',5'-tribromobenzoyl)-1,4-dimethylpyrrole-2-acetat- e
[0677] The Friedel-Crafts acylation procedure of Example 83D is
followed except that an equivalent quantity of
2',3',5'-tribromobenzoyl chloride is substituted for the
p-fluorobenzoyl chloride used therein to yield ethyl
5-(2',3',5'-tribromobenzoyl)-1,4-dimethylpyrrole-2-acetate.
[0678] (B)
1,4-Dimethyl-5-(2',3',5'-tribromobenzoyl)pyrrole-2-acetic acid
[0679] The ester of part A of this Example is hydrolyzed in
accordance with the procedure of Example 83E to yield
1,4-dimethyl-5-(2',3',5'-tribr- omobenzoyl)pyrrole-2-acetic
acid.
[0680] (C) 4,6-Dimethyl-5-(2',3
',5'-tribromobenzoyl)-1,3,6-trihydro-6-aza-
-3-oxapentalen-2-one
[0681] 1,4-Dimethyl-5-(2',3',5'-tribromobenzoyl)pyrrole-2-acetic
acid is subjected to the procedure of Example 1, part C to produce
4,6-dimethyl-5-(2',3',5'-tribromobenzoyl)-1,3,6-trihydro-6-aza-3-oxapenta-
len-2-one (R.sub.1=H, R.sub.2=H, R.sub.3=2',3',5'-tribromophenyl,
R.sub.4=methyl, R.sub.5=methyl, Y=CO, m=1, n=0).
EXAMPLE 92
4,6-Dimethyl-5-(2'-Methylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0682] (A) Ethyl
5-(o-methylbenzoyl)-1,4-dimethylpyrrole-2-acetate
[0683] The Friedel-Crafts acylation procedure of Example 83D is
followed except that an equivalent quantity of 2'-methylbenzoyl
chloride is substituted for the p-fluorobenzoyl chloride used
therein to yield ethyl
5-(o-methylbenzoyl)-1,4-dimethylpyrrole-2-acetate.
[0684] (B) 1,4-Dimethyl-5-(o-methylbenzoyl)pyrrole-2-acetic
acid
[0685] The ester of part A of this Example is hydrolyzed in
accordance with the procedure of Example 83E to yield
1,4-dimethyl-5-(o-methylbenzoy- l)pyrrole-2-acetic acid.
[0686] (C)
4,6-Dimethyl-5-(2'-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapen-
talen-2-one
[0687] 1,4-Dimethyl-5-(o-methylbenzoyl)pyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
4,6-dimethyl-5-(2'-methy-
lbenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R.sub.1=H,
R.sub.2=H, R.sub.3=2'-methylphenyl, R.sub.4=methyl, R.sub.5=methyl,
Y=CO, m=1, n=0).
EXAMPLE 93
4,6-Dimethyl-5-(4'-Cyanobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0688] (A) Ethyl
5-(p-cyanobenzoyl)-1,4-dimethylpyrrole-2-acetate
[0689] The Friedel-Crafts acylation procedure of Example 83D is
followed except that an equivalent quantity of 4'-cyanobenzoyl
chloride is substituted for the p-fluorobenzoyl chloride used
therein to yield ethyl
5-(p-cyanobenzoyl)-1,4-dimethylpyrrole-2-acetate.
[0690] (B) 1,4-Dimethyl-5-(p-cyanobenzoyl)pyrrole-2-acetic acid
[0691] The ester of part A of this Example is hydrolyzed in
accordance with the procedure of Example 83E to yield
1,4-dimethyl-5-(p-cyanobenzoyl- )pyrrole-2-acetic acid.
[0692] (C)
4,6-Dimethyl-5-(4'-cyanobenzoyl)-1,3,6-trihydro-6-aza-3-oxapent-
alen-2-one
[0693] 1,4-Dimethyl-5-(p-cyanobenzoyl)pyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
4,6-dimethyl-5-(4'-cyano-
benzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R.sub.1=H,
R.sub.2=H, R.sub.3=4'-cyanophenyl, R.sub.4=methyl, R.sub.5=methyl,
Y=CO, m=1, n=0).
EXAMPLE 94
4,6-Dimethyl-5-(4'-Aminobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0694] By using an equivalent amount of
4,6-dimethyl-5-(4'-nitrobenzoyl)-1-
,3,6-trihydro-6-aza-3-oxapentalen-2-one in place of
5-(p-nitrobenzoyl)-1-methylpyrrole-2-acetonitrile in the
hydrogenation procedure of Example 85C, the product,
4,6-dimethyl-5-(4'-aminobenzoyl)-1-
,3,6-trihydro-6-aza-3-oxapentalen-2-one is obtained. (R.sub.1=H,
R.sub.2=H, R.sub.3=4'-aminophenyl, R.sub.4=methyl, R.sub.5=methyl,
Y=CO, m=1, n=0).
EXAMPLE 95
Rac-1,4,6-Trimethyl-5-(4'-Fluorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentale-
n-2-One
[0695] (A) Ethyl
1,4,.alpha.-trimethyl-5-(p-fluorobenzoyl)-pyrrole-2-aceta- te
[0696] The methylation procedure of Example 77A is repeated, except
that an equivalent quantity of ethyl
1,4-dimethyl-5-(p-fluorobenzoyl)-pyrrole-- 2-acetate (from Example
83) is methylated instead of the ethyl
5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example
77A, to yield ethyl
1,4,.alpha.-trimethyl-5-(p-fluorobenzoyl)-pyrrole-2-acetate.
[0697] (B)
1,4,.alpha.-Trimethyl-5-(p-fluorobenzoyl)-pyrrole-2-acetic acid
[0698] The hydrolysis procedure of Example 77B is followed in
transforming the ester from part A of this Example into
1,4,.alpha.-trimethyl-5-(p-flu- orobenzoyl)-pyrrole-2-acetic
acid.
[0699] (C)
Rac-1,4,6-trimethyl-5-(4'-fluorobenzoyl)-1,3,6-trihydro-6-aza-3-
-oxapentalen-2-one
[0700] 1,4,.alpha.-Trimethyl-5-(p-fluorobenzoyl)-pyrrole-2-acetic
acid is subjected to the procedure of Example 1, part C to produce
rac-1,4,6-trimethyl-5-(4'-fluorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapental-
en-2-one (R.sub.1=methyl, R.sub.2=H, R.sub.3=4'-fluorophenyl,
R.sub.4=methyl, R.sub.5=methyl, Y=CO, m=1, n=0).
EXAMPLE 96
Rac-1,4,6-Trimethyl-5-(3'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentale-
n-2-One
[0701] (A) Ethyl
5-(m-chlorobenzoyl)-1,4,.alpha.-trimethylpyrrole-2-acetat- e The
methylation procedure of Example 77A is repeated, except that an
equivalent quantity of ethyl
5-(m-chlorobenzoyl)-1,4-dimethylpyrrole-2-ac- etate (from Example
84) is methylated instead of the ethyl
5-(m-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example
77A, to yield ethyl
5-(m-chlorobenzoyl)-1,4,.alpha.-trimethylpyrrole-2-acetate.
[0702] (B)
5-(m-Chlorobenzoyl)-1,4,.alpha.-trimethylpyrrole-2-acetic acid The
hydrolysis procedure of Example 77B is followed in transforming the
ester from part A of this Example into
5-(m-chlorobenzoyl)-1,4,.alpha.-tr- imethylpyrrole-2-acetic
acid.
[0703] (C)
Rac-1,4,6-trimethyl-5-(3'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-
-oxapentalen-2-one
[0704] 5-(m-Chlorobenzoyl)-1,4,.alpha.-trimethylpyrrole-2-acetic
acid is subjected to the procedure of Example 1, part C to produce
rac-1,4,6-trimethyl-5-(3'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-oxapental-
en-2-one (R.sub.1=methyl, R.sub.2=H, R.sub.3=3'-chlorophenyl,
R.sub.4=methyl, R.sub.5=methyl, Y=CO, m=1, n=0).
EXAMPLE 97
Rac-1,4,6-Trimethyl-5-Benzoyl-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One
[0705] (A) Ethyl
5-benzoyl-1,4,.alpha.-trimethylpyrrole-2-acetate
[0706] The methylation procedure of Example 77A is repeated, except
that an equivalent quantity of ethyl
5-benzoyl-1,4-dimethylpyrrole-2-acetate (from Example 86) is
methylated instead of the ethyl
5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example
77A, to yield ethyl
5-benzoyl-1,4,.alpha.-trimethylpyrrole-2-acetate.
[0707] (B) 5-Benzoyl-1,4,.alpha.-trimethylpyrrole-2-acetic acid
[0708] The hydrolysis procedure of Example 77B is followed in
transforming the ester from part A of this Example into
5-benzoyl-1,4,.alpha.-trimethy- lpyrrole-2-acetic acid.
[0709] (C)
Rac-1,4,6-trimethyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentale-
n-2-one
[0710] 5-Benzoyl-1,4,.alpha.-trimethylpyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
rac-1,4,6-trimethyl-5-be-
nzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-2-one (R.sub.1=methyl,
R.sub.2=H, R.sub.3=phenyl, R.sub.4=methyl, R.sub.5=methyl, Y=CO,
m=1, n=0).
EXAMPLE 98
Rac-1,4,6-Trimethyl-5-(2'-Thenoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-On-
e
[0711] (A) Ethyl
5-(2'-thenoyl)-1,4,.alpha.-trimethylpyrrole-2-acetate
[0712] The methylation procedure of Example 77A is repeated, except
that an equivalent quantity of ethyl
5-(2'-thenoyl)-1,4-dimethylpyrrole-2-acet- ate (from Example 87) is
methylated instead of the ethyl
5-(m-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example
77A, to yield ethyl
5-(2'-thenoyl)-1,4,.alpha.-trimethylpyrrole-2-acetate.
[0713] (B) 5-(2'-Thenoyl)-1,4,.alpha.-trimethylpyrrole-2-acetic
acid
[0714] The hydrolysis procedure of Example 77B is followed in
transforming the ester from part A of this Example into
5-(2'-thenoyl)-1,4,.alpha.-tri- methylpyrrole-2-acetic acid.
[0715] (C)
Rac-1,4,6-trimethyl-5-(2'-thenoyl)-1,3,6-trihydro-6-aza-3-oxape-
ntalen-2-one
[0716] 5-(2'-Thenoyl)-1,4,.alpha.-trimethylpyrrole-2-acetic acid is
subjected to the procedure of Example 1, part C to produce
rac-1,4,6-trimethyl-5-(2'-thenoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-2-o-
ne (R.sub.1=methyl, R.sub.2=H, R.sub.3=2'-thiophenyl,
R.sub.4=methyl, R.sub.5=methyl, Y=CO, m=1, n=0).
EXAMPLE 99
Rac-1,4,6-Trimethyl-5-(5'-Methyl-2'-Thenoyl)-1,3,6-Trihydro-6-Aza-3-Oxapen-
talen-2-One
[0717] (A) Ethyl
5-(5'-methyl-2'-thenoyl)-1,4,.alpha.-trimethylpyrrole-2-a-
cetate
[0718] The methylation procedure of Example 77A is repeated, except
that an equivalent quantity of ethyl
5-(5'-methyl-2'-thenoyl)-1,4-dimethylpyrr- ole-2-acetate (from
Example 88) is methylated instead of the ethyl
5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example
77A, to yield ethyl
5-(5'-methyl-2'-thenoyl)-1,4,.alpha.-trimethylpyrrole-2-aceta-
te.
[0719] (B)
5-(5'-Methyl-2'-thenoyl)-1,4,.alpha.-trimethylpyrrole-2-acetic
acid
[0720] The hydrolysis procedure of Example 77B is followed in
transforming the ester from part A of this Examples into
5-(5'-methyl-2'-thenoyl)-1,4,- .alpha.-trimethylpyrrole-2-acetic
acid.
[0721] (C)
Rac-1,4,6-trimethyl-5-(5'-methyl-2'-thenoyl)-1,3,6-trihydro-6-a-
za-3-oxapentalen-2-one
[0722]
5-(5'-methyl-2'-thenoyl)-1,4,.alpha.-trimethylpyrrole-2-acetic acid
is subjected to the procedure of Example 1, part C to produce
rac-1,4,6-trimethyl-5-(5'-methyl-2'-thenoyl)-1,3,6-trihydro-6-aza-3-oxape-
ntalen-2-one (R.sub.1=methyl, R.sub.2=H,
R.sub.3=5'-methyl-2'-thiophenyl, R.sub.4=methyl, R.sub.5=methyl,
Y=CO, m=1, n=0).
EXAMPLE 100
Rac-1,4,6-Trimethyl-5-(4'-Trifluoromethylbenzoyl)-1,3,6-Trihydro-6-Aza-3-O-
xapentalen-2-One
[0723] (A) Ethyl
5-(p-trifluoromethylbenzoyl)-1,4,.alpha.-trimethylpyrrole-
-2-acetate
[0724] The methylation procedure of Example 77A is repeated, except
that an equivalent quantity of ethyl
5-(p-trifluoromethylbenzoyl)-1,4-dimethyl- pyrrole-2-acetate (from
Example 89) is methylated instead of the ethyl
5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example
77A, to yield ethyl
5-(p-trifluoromethylbenzoyl)-1,4,.alpha.-trimethylpyrrole-2-a-
cetate.
[0725] (B)
5-(p-Trifluoromethylbenzoyl)-1,4,.alpha.-trimethylpyrrole-2-ace-
tic acid
[0726] The hydrolysis procedure of Example 77B is followed in
transforming the ester from part A of this Example into
5-(p-trifluoromethylbenzoyl)-1-
,4,.alpha.-trimethylpyrrole-2-acetic acid.
[0727] (C)
Rac-1,4,6-trimethyl-5-(4'-trifluoromethylbenzoyl)-1,3,6-trihydr-
o-6-aza-3-oxapentalen-2-one
[0728]
5-(p-Trifluoromethylbenzoyl)-1,4,.alpha.-trimethylpyrrole-2-acetic
acid is subjected to the procedure of Example 1, part C to produce
rac-1,4,6-trimethyl-5-(4'-trifluoromethylbenzoyl)-1,3,6-trihydro-6-aza-3--
oxapentalen-2-one (R.sub.1=methyl, R.sub.2=H,
R.sub.3=4'-trifluoromethylph- enyl, R.sub.4=methyl, R.sub.5=methyl,
Y=CO, m=1, n=0).
EXAMPLE 101
Rac-1,4,6-Trimethyl-5-(3',4'-Dimethoxybenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxap-
entalen-2-One
[0729] (A) Ethyl
5-(3',4'-dimethoxybenzoyl)-1,4,.alpha.-trimethylpyrrole-2-
-acetate
[0730] The methylation procedure of Example 77A is repeated, except
that an equivalent quantity of ethyl
5-(3',4'-dimethoxybenzoyl)-1,4-dimethylpy- rrole-2-acetate (from
Example 90) is methylated instead of the ethyl
5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example
77A, to yield ethyl
5-(3',4'-dimethoxybenzoyl)-1,4,.alpha.-trimethylpyrrole-2-ace-
tate.
[0731] (B)
5-(3',4'-Dimethoxybenzoyl)-1,4,.alpha.-trimethylpyrrole-2-aceti- c
acid
[0732] The hydrolysis procedure of Example 77B is followed in
transforming the ester from part A of this Example into
5-(3',4'-dimethoxybenzoyl)-1,4- ,.alpha.-trimethylpyrrole-2-acetic
acid.
[0733] (C)
Rac-1,4,6-trimethyl-5-(3',4'-dimethoxybenzoyl)-1,3,6-trihydro-6-
-aza-3-oxapentalen-2-one
[0734]
5-(3',4'-Dimethoxybenzoyl)-1,4,.alpha.-trimethylpyrrole-2-acetic
acid is subjected to the procedure of Example 1, part C to produce
rac-1,4,6-trimethyl-5-(3',4'-dimethoxybenzoyl)-1,3,6-trihydro-6-aza-3-oxa-
pentalen-2-one (R.sub.1=methyl, R.sub.2=H,
R.sub.3=3',4'-dimethoxyphenyl, R.sub.4=methyl, R.sub.5=methyl,
Y=CO, m=1, n=0).
EXAMPLE 102
Rac-1,4,6-Trimethyl-5-(2',3',5'-Tribromobenzoyl)-1,3,6-Trihydro-6-Aza-3-Ox-
apentalen-2-One
[0735] (A) Ethyl
5-(2',3',5'-tribromobenzoyl)-1,4,.alpha.-trimethylpyrrole-
-2-acetate
[0736] The methylation procedure of Example 77A is repeated, except
that an equivalent quantity of ethyl
5-(2',3',5'-tribromobenzoyl)-1,4-dimethyl- pyrrole-2-acetate (from
Example 91) is methylated instead of the ethyl
5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example
77A, to yield ethyl
5-(2',3',5'-tribromobenzoyl)-1,4,.alpha.-trimethylpyrrole-2-a-
cetate.
[0737] (B) 5-(2',3
',5'-Tribromobenzoyl)-1,4,.alpha.-trimethylpyrrole-2-ac- etic
acid
[0738] The hydrolysis procedure of Example 77B is followed in
transforming the ester from part A of this Example into
5-(2',3',5'-tribromobenzoyl)-1-
,4,.alpha.-trimethylpyrrole-2-acetic acid.
[0739] (C)
Rac-1,4,6-trimethyl-5-(2',3',5'-tribromobenzoyl)-1,3,6-trihydro-
-6-aza-3-oxapentalen-2-one
[0740]
5-(2',3',5'-Tribromobenzoyl)-1,4,.alpha.-trimethylpyrrole-2-acetic
acid is subjected to the procedure of Example 1, part C to produce
rac-1,4,6-trimethyl-5-(2',3',5'-tribromobenzoyl)-1,3,6-trihydro-6-aza-3-o-
xapentalen-2-one (R.sub.1=methyl, R.sub.2=H,
R.sub.3=2',3',5'-tribromophen- yl, R.sub.4=methyl, R.sub.5=methyl,
Y=CO, m=1, n=0).
EXAMPLE 103
Rac-1,4,6-Trimethyl-5-(2'-Methylbenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentale-
n-2-One
[0741] (A) Ethyl
5-(2'-methylbenzoyl)-1,4,.alpha.-trimethylpyrrole-2-aceta- te
[0742] The methylation procedure of Example 77A is repeated, except
that an equivalent quantity of ethyl
5-(2'-methylbenzoyl)-1,4-dimethylpyrrole-- 2-acetate (from Example
92) is methylated instead of the ethyl
5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example
77A, to yield ethyl 5-(2'-methylbenzoyl)-1,4,
.alpha.-trimethylpyrrole-2-acetate.
[0743] (B)
5-(2'-Methylbenzoyl)-1,4,.alpha.-trimethylpyrrole-2-acetic acid
[0744] The hydrolysis procedure of Example 77B is followed in
transforming the ester from part A of this Example into
5-(2'-methylbenzoyl)-1,4,.alph- a.-trimethylpyrrole-2-acetic
acid.
[0745] (C)
Rac-1,4,6-trimethyl-5-(2'-methylbenzoyl)-1,3,6-trihydro-6-aza-3-
-oxapentalen-2-one
[0746] 5-(2'-Methylbenzoyl)-1,4,.alpha.-trimethylpyrrole-2-acetic
acid is subjected to the procedure of Example 1, part C to produce
rac-1,4,6-trimethyl-5-(2'-methylbenzoyl)-1,3,6-trihydro-6-aza-3-oxapental-
en-2-one (R.sub.1=methyl, R.sub.2=H, R.sub.3=2'-methylphenyl,
R.sub.4=methyl, R.sub.5=methyl, Y=CO, m=1, n=0).
EXAMPLE 104
Rac-1,4,6-Trimethyl-5-(4'-Cyanobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxapentalen-
-2-One
[0747] (A) Ethyl
5-(p-cyanobenzoyl)-1,4,.alpha.-trimethylpyrrole-2-acetate
[0748] The methylation procedure of Example 77A is repeated, except
that an equivalent quantity of (from Example 93) is methylated
instead of the ethyl
5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example
77A, to yield ethyl
5-(p-cyanobenzoyl)-1,4,c-trimethylpyrrole-2-acetate.
[0749] (B) 5-(p-Cyanobenzoyl)-1,4,.alpha.-trimethylpyrrole-2-acetic
acid
[0750] The hydrolysis procedure of Example 77B is followed in
transforming the ester from part A of this Example into
5-(p-cyanobenzoyl)-1,4,.alpha.- -trimethylpyrrole-2-acetic
acid.
[0751] (C)
Rac-1,4,6-trimethyl-5-(4'-cyanobenzoyl)-1,3,6-trihydro-6-aza-3--
oxapentalen-2-one
[0752] 5-(p-Cyanobenzoyl)-1,4,.alpha.-trimethylpyrrole-2-acetic
acid is subjected to the procedure of Example 1, part C to produce
rac-1,4,6-trimethyl-5-(4'cyanobenzoyl)-1,3,6-trihydro-6-aza-3-oxapentalen-
-2-one (R.sub.1=methyl, R.sub.2=H, R.sub.3=4'-cyanophenyl,
R.sub.4=methyl, R.sub.5=methyl, Y=CO, m=1, n=0).
EXAMPLE 105
Rac-1-(n-Propyl)-4,6-Dimethyl-5-(4'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3--
Oxapentalen-2-One
[0753] (A) Ethyl
5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-prop-
yl)-acetate
[0754] The alkylation procedure of Example 77A is performed upon
ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate (from
Example 84), using an equivalent quantity of n-propyl iodide
instead of methyl iodide used in Example 77A to yield ethyl
5-(p-chlorobenzoyl)-1,4-dimethylpyrrol-
e-2-(.alpha.-n-propyl)acetate.
[0755] (B)
5-(p-Chlorobenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-propyl)-ac-
etic acid
[0756] The hydrolysis procedure of Example 77B is followed in
transforming the ester from part A of this Example into
5-(p-chlorobenzoyl)-1,4-dimeth- ylpyrrole-2-(.alpha.-propyl)-acetic
acid.
[0757] (C)
Rac-1-(n-propyl)-4,6-dimethyl-5-(4'-chlorobenzoyl)-1,3,6-trihyd-
ro-6-aza-3-oxapentalen-2-one
[0758]
5-(p-Chlorobenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-propyl)-acetic
acid is subjected to the procedure of Example 1, part C to produce
rac-1-(n-propyl)-4,6-dimethyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3-
-oxapentalen-2-one (R.sub.1=n-propyl, R.sub.2=H,
R.sub.3=4'-chlorophenyl, R.sub.4 methyl, R.sub.5=methyl, Y=CO, m=1,
n=0).
EXAMPLE 106
Rac-1-(n-Propyl)-4,6-Dimethyl-5-(4
'-Nitrobenzoyl)-1,3,6-Trihydro-6-Aza-3-- Oxapentalen-2-One
[0759] (A) Ethyl
5-(p-nitrobenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-propy-
l)-acetate
[0760] The alkylation procedure of Example 77A is performed upon
ethyl 5-(p-nitrobenzoyl)-1,4-dimethylpyrrole-2-acetate (from
Example 85), using an equivalent quantity of n-propyl iodide
instead of methyl iodide used in Example 77A to yield ethyl
5-(p-nitrobenzoyl)-1,4-dimethylpyrrole-2-(.-
alpha.-n-propyl)-acetate.
[0761] (B)
5-(p-Nitrobenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-propyl)-ace-
tic acid
[0762] The hydrolysis procedure of Example 77B is followed in
transforming the ester from part A of this Example into
5-(p-nitrobenzoyl)-1,4-dimethy-
lpyrrole-2-(.alpha.-n-propyl)-acetic acid.
[0763] (C)
Rac-1-(n-propyl)-4,6-dimethyl-5-(4'-nitrobenzoyl)-1,3,6-trihydr-
o-6-aza-3-oxapentalen-2-one
[0764]
5-(p-Nitrobenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-propyl)-acetic
acid is subjected to the procedure of Example 1, part C to produce
rac-1-(n-propyl)-4,6-dimethyl-5-(4'-nitrobenzoyl)-1,3,6-trihydro-6-aza-3--
oxapentalen-2-one (R.sub.1=n-propyl, R.sub.2=H,
R.sub.3=4'-nitrophenyl, R.sub.4=methyl, R.sub.5=methyl, Y=CO, m=1,
n=0).
EXAMPLE 107
Rac-1-(n-Propyl)-4,6-Dimethyl-5-Benzoyl-1,3
6-Trihydro-6-Aza-3-Oxapentalen- -2-One
[0765] (A) Ethyl
5-benzoyl-1,4-dimethylpyrrole-2-(.alpha.-n-propyl)-acetat- e
[0766] The alkylation procedure of Example 77A is performed upon
ethyl 5-benzoyl-1,4-dimethylpyrrole-2-acetate (from Example 86),
using an equivalent quantity of n-propyl iodide instead of methyl
iodide used in Example 77A to yield ethyl
5-benzoyl-1,4-dimethylpyrrole-2-(.alpha.-n-pro- pyl)-acetate.
[0767] (B)
5-Benzoyl-1,4-dimethylpyrrole-2-(.alpha.-n-propyl)-acetic acid
[0768] The hydrolysis procedure of Example 77B is followed in
transforming the ester from part A of this Example into
5-benzoyl-1,4-dimethylpyrrole-- 2-(.alpha.-n-propyl)-acetic
acid.
[0769] (C)
Rac-1-(n-propyl)-4,6-dimethyl-5-benzoyl-1,3,6-trihydro-6-aza-3--
oxapentalen-2-one
[0770] 5-Benzoyl-1,4-dimethylpyrrole-2-(.alpha.-n-propyl)-acetic
acid is subjected to the procedure of Example 1, part C to produce
rac-1-(n-propyl)-4,6-dimethyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentale-
n-2-one (R.sub.1=n-propyl, R.sub.2=H, R.sub.3=phenyl,
R.sub.4=methyl, R.sub.5=methyl, Y=CO, m=1, n=0).
EXAMPLE 108
Rac-1-(n-Propyl)-4,6-Dimethyl-5-(2'-Thenoyl)-1,3,6-Trihydro-6-Aza-3-Oxapen-
talen-2-One
[0771] (A) Ethyl
5-(2'-thenoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-propyl)-a-
cetate
[0772] The alkylation procedure of Example 77A is performed upon
ethyl 5-(2'-thenoyl)-1,4-dimethylpyrrole-2-acetate (from Example
87), using an equivalent quantity of n-propyl iodide instead of
methyl iodide used in Example 77A to yield ethyl
5-(2'-thenoyl)-1,4-dimethylpyrrole-2-(.alpha.--
n-propyl)-acetate.
[0773] (B)
5-(2'-Thenoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-propyl)-acetic
acid
[0774] The hydrolysis procedure of Example 77B is followed in
transforming the ester from part A of this Example into
5-(2'-thenoyl)-1,4-dimethylpyr- role-2-(.alpha.-n-propyl)-acetic
acid.
[0775] (C)
Rac-1-(n-propyl)-4,6-dimethyl-5-(2'-thenoyl)-1,3,6-trihydro-6-a-
za-3-oxapentalen-2-one
[0776]
5-(2'-Thenoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-propyl)-acetic acid
is subjected to the procedure of Example 1, part C to produce
rac-1-(n-propyl)-4,6-dimethyl-5-(2'-thenoyl)-1,3,6-trihydro-6-aza-3-oxape-
ntalen-2-one (R.sub.1=n-propyl, R.sub.2=H, R.sub.3=2'-thiophenyl,
R.sub.4=methyl, R.sub.5=methyl, Y=CO, m=1, n=0).
EXAMPLE 109
Rac-1-(n-Propyl)-4,6-Dimethyl-5-(5'-Methyl-2'-Thenoyl)-1,3,6-Trihydro-6-Az-
a-3-Oxapentalen-2-One
[0777] (A) Ethyl
5-(5'-methylthenoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-pro-
pyl)-acetate
[0778] The alkylation procedure of Example 77A is performed upon
ethyl 5-(5'-methyl-2'-thenoyl)-1,4-dimethylpyrrole-2-acetate (from
Example 88), using an equivalent quantity of n-propyl iodide
instead of methyl iodide used in Example 77A to yield ethyl
5-(5'-methyl-2'-thenoyl)-1,4-dimethylp-
yrrole-2-(.alpha.-n-propyl)-acetate.
[0779] (B)
5-(5'-Methyl-2'-thenoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-propy-
l)-acetic acid
[0780] The hydrolysis procedure of Example 77B is followed in
transforming the ester from part A of this Example into
5-(5'-methyl-2'-thenoyl)-1,4-d-
imethylpyrrole-2-(.alpha.-n-propyl)-acetic acid.
[0781] (C)
Rac-1-(n-propyl)-4,6-dimethyl-5-(5'-methyl-2'-thenoyl)-1,3,6-tr-
ihydro-6-aza-3-oxapentalen-2-one
[0782]
5-(5'-Methyl-2'-thenoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-propyl)-a-
cetic acid is subjected to the procedure of Example 1, part C to
produce
rac-1-(n-propyl)-4,6-dimethyl-5-(5'-methyl-2'-thenoyl)-1,3,6-trihydro-6-a-
za-3-oxapentalen-2-one (R.sub.1=n-propyl, R.sub.2=H,
R.sub.3=5'-methyl-2'-thiophenyl, R.sub.4=methyl, R.sub.5=methyl,
Y=CO, m=1, n=0).
EXAMPLE 110
Rac-1-(n-Propyl)-4,6-Dimethyl-5-(4'-Trifluoromethylbenzoyl)-1,3,6-Trihydro-
-6-Aza-3-Oxapentalen-2-One
[0783] (A) Ethyl
5-(p-trifluoromethylbenzoyl)-1,4-dimethylpyrrole-2-(.alph-
a.-n-propyl)-acetate
[0784] The alkylation procedure of Example 77A is performed upon
ethyl 5-(p-trifluoromethylbenzoyl)-1,4-dimethylpyrrole-2-acetate
(from Example 89), using an equivalent quantity of n-propyl iodide
instead of methyl iodide used in Example 77A to yield ethyl
5-(p-trifluoromethylbenzoyl)-1,-
4-dimethylpyrrole-2-(.alpha.-n-propyl)-acetate.
[0785] (B)
5-(p-Trifluoromethylbenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-p-
ropyl)-acetic acid The hydrolysis procedure of Example 77B is
followed in transforming the ester from part A of this Example into
5-(p-trifluoromethylbenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-propyl)-ace-
tic acid.
[0786] (C)
Rac-1-(n-propyl)-4,6-dimethyl-5-(4'-trifluoromethylbenzoyl)-1,3-
,6-trihydro-6-aza-3-oxapentalen-2-one
[0787]
5-(p-Trifluoromethylbenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-propy-
l)-acetic acid is subjected to the procedure of Example 1, part C
to produce
rac-1-(n-propyl)-4,6-dimethyl-5-(4'-trifluoromethylbenzoyl)-1,3,6-
-trihydro-6-aza-3-oxapentalen-2-one (R.sub.1=n-propyl, R.sub.2=H,
R.sub.3=4'-trifluoromethylphenyl, R.sub.4=methyl, R.sub.5=methyl,
Y=CO, m=1, n=0).
EXAMPLE 111
Rac-1-(n-Propyl)-4,6-Dimethyl-5-(3',4'-Dimethoxybenzoyl)-1,3,6-Trihydro-6--
Aza-3-Oxapentalen-2-One
[0788] (A) Ethyl
5-(3',4'-dimethoxybenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-
-n-propyl)-acetate
[0789] The alkylation procedure of Example 77A is performed upon
ethyl 5-(3',4'-dimethoxybenzoyl)-1,4-dimethylpyrrole-2-acetate
(from Example 90), using an equivalent quantity of n-propyl iodide
instead of methyl iodide used in Example 77A to yield ethyl
5-(3',4'-dimethoxybenzoyl)-1,4--
dimethylpyrrole-2-(.alpha.-n-propyl)-acetate.
[0790] (B)
5-(3',4'-Dimethoxybenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-pro-
pyl)-acetic acid The hydrolysis procedure of Example 77B is
followed in transforming the ester from part A of this Example into
5-(3',4'-dimethoxybenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-propyl)-aceti-
c acid.
[0791] (C)
Rac-1-(n-propyl)-4,6-dimethyl-5-(3',4'-dimethoxybenzoyl)-1,3,6--
trihydro-6-aza-3-oxapentalen-2-one
[0792] 5-(3
',4'-Dimethoxybenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-propyl-
)-acetic acid is subjected to the procedure of Example 1, part C to
produce
rac-1-(n-propyl)-4,6-dimethyl-5-(3',4'-dimethoxybenzoyl)-1,3,6-tr-
ihydro-6-aza-3-oxapentalen-2-one (R.sub.1=n-propyl, R.sub.2=H,
R.sub.3=3',4'-dimethoxyphenyl, R.sub.4=methyl, R.sub.5=methyl,
Y=CO, m=1, n=0).
EXAMPLE 112
Rac-1-(n-Propyl)-4,6-Dimethyl-5-(2',3',5'-Tribromobenzoyl)-1,3,6-Trihydro--
6-Aza-3-Oxapentalen-2-One
[0793] (A) Ethyl
5-(2',3',5'-tribromobenzoyl)-1,4-dimethylpyrrole-2-(.alph-
a.-n-propyl)-acetate
[0794] The alkylation procedure of Example 77A is performed upon
ethyl 5-(2',3',5'-tribromobenzoyl)-1,4-dimethylpyrrole-2-acetate
(from Example 91), using an equivalent quantity of n-propyl iodide
instead of methyl iodide used in Example 77A to yield ethyl
5-(2',3',5'-tribromobenzoyl)-1,-
4-dimethylpyrrole-2-(.alpha.-n-propyl)-acetate.
[0795] (B)
5-(2',3',5'-Tribromobenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-p-
ropyl)-acetic acid
[0796] The hydrolysis procedure of Example 77B is followed in
transforming the ester from part A of this Example into
5-(2',3',5'-tribromobenzoyl)-1-
,4-dimethylpyrrole-2-(.alpha.-n-propyl)-acetic acid.
[0797] (C)
Rac-1-(n-propyl)-4,6-dimethyl-5-(2',3',5'-tribromobenzoyl)-1,3,-
6-trihydro-6-aza-3-oxapentalen-2-one
[0798]
5-(2',3',5'-Tribromobenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-propy-
l)-acetic acid is subjected to the procedure of Example 1, part C
to produce
rac-1-(n-propyl)-4,6-dimethyl-5-(2',3',5'-tribromobenzoyl)-1,3,6--
trihydro-6-aza-3-oxapentalen-2-one (R.sub.1=n-propyl, R.sub.2=H,
R.sub.3=2',3',5'-tribromophenyl, R.sub.4=methyl, R.sub.5=methyl,
Y=CO, m=1, n=0).
EXAMPLE 113
Rac-1-(n-Propyl)-4,6-Dimethyl-5-(2'-Methylbenzoyl)-1,3,6-Trihydro-6-Aza-3--
Oxapentalen-2-One
[0799] (A) Ethyl
5-(o-methylbenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-prop-
yl)-acetate The alkylation procedure of Example 77A is performed
upon ethyl 5-(o-methylbenzoyl)-1,4-dimethylpyrrole-2-acetate (from
Example 92), using an equivalent quantity of n-propyl iodide
instead of methyl iodide used in Example 77A to yield ethyl
5-(o-methylbenzoyl)-1,4-dimethy-
lpyrrole-2-(.alpha.-n-propyl)-acetate.
[0800] (B)
5-(o-Methylbenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-propyl)-ac-
etic acid
[0801] The hydrolysis procedure of Example 77B is followed in
transforming the ester from part A of this Example into
5-(o-methylbenzoyl)-1,4-dimeth-
ylpyrrole-2-(.alpha.-n-propyl)-acetic acid.
[0802] (C)
Rac-1-(n-propyl)-4,6-dimethyl-5-(2'-methylbenzoyl)-1,3,6-trihyd-
ro-6-aza-3-oxapentalen-2-one
[0803]
5-(o-Methylbenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-propyl)-acetic
acid is subjected to the procedure of Example 1, part C to produce
rac-1-(n-propyl)-4,6-dimethyl-5-(2'-methylbenzoyl)-1,3,6-trihydro-6-aza-3-
-oxapentalen-2-one (R.sub.1=n-propyl, R.sub.2=H,
R.sub.3=2'-methylphenyl, R.sub.4=methyl, R.sub.5=methyl, Y=CO, m=1,
n=0).
EXAMPLE 114
Rac-1-(n-Propyl)-4,6-Dimethyl-5-(4'-Cyanobenzoyl)-1,3,6-Trihydro-6-Aza-3-O-
xapentalen-2-One
[0804] (A) Ethyl
5-(p-cyanobenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-propy-
l)-acetate
[0805] The alkylation procedure of Example 77A is performed upon
ethyl 5-(p-cyanobenzoyl)-1,4-dimethylpyrrole-2-acetate (from
Example 93), using an equivalent quantity of n-propyl iodide
instead of methyl iodide used in Example 77A to yield ethyl
5-(p-cyanobenzoyl)-1,4-dimethylpyrrole-2-(.-
alpha.-n-propyl)-acetate.
[0806] (B)
5-(p-Cyanobenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-propyl)-ace-
tic acid
[0807] The hydrolysis procedure of Example 77B is followed in
transforming the ester from part A of this Example into
5-(p-cyanobenzoyl)-1,4-dimethy-
lpyrrole-2-(.alpha.-n-propyl)-acetic acid.
[0808] (C)
Rac-1-(n-propyl)-4,6-dimethyl-5-(4'-cyanobenzoyl)-1,3,6-trihydr-
o-6-aza-3-oxapentalen-2-one
[0809]
5-(p-Cyanobenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-propyl)-acetic
acid is subjected to the procedure of Example 1, part C to produce
rac-1-(n-propyl)-4,6-dimethyl-5-(4'-cyanobenzoyl)-1,3,6-trihydro-6-aza-3--
oxapentalen-2-one (R.sub.1=n-propyl, R.sub.2=H,
R.sub.3=4'-cyanophenyl, R.sub.4=methyl, R.sub.5=methyl, Y=CO, m=1,
n=0).
EXAMPLE 115
Rac-1-(n-Hexyl)-4,6-Dimethyl-5-(4'-Chlorobenzoyl)-1,3,6-Trihydro-6-Aza-3-O-
xapentalen-2-One
[0810] (A) Ethyl
5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-hexy-
l)-acetate
[0811] The alkylation procedure of Example 77A is performed upon
ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate (from
Example 84), using an equivalent quantity of n-hexyl iodide instead
of methyl iodide used in Example 77A to yield ethyl
5-(p-chlorobenzoyl)-1,4-dimethylpyrrol-
e-2-(.alpha.-n-hexyl)acetate.
[0812] (B)
5-(p-Chlorobenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-hexyl)-ace-
tic acid The hydrolysis procedure of Example 77B is followed in
transforming the ester from part A of this Example into
5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-hexyl)-acetic
acid.
[0813] (C)
Rac-1-(n-hexyl)-4,6-dimethyl-5-(4'-chlorobenzoyl)-1,3,6-trihydr-
o-6-aza-3-oxapentalen-2-one
[0814]
5-(p-Chlorobenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-hexyl)-acetic
acid is subjected to the procedure of Example 1, part C to produce
rac-1-(n-hexyl)-4,6-dimethyl-5-(4'-chlorobenzoyl)-1,3,6-trihydro-6-aza-3--
oxapentalen-2-one (R.sub.1=n-hexyl, R.sub.2=H,
R.sub.3=4'-chlorophenyl, R.sub.4=methyl, R.sub.5=methyl, Y=CO, m=1,
n=0).
EXAMPLE 116
Rac-1-(n-Hexyl)-4,6-Dimethyl-5-(4'Nitrobenzoyl)-1,3,6-Trihydro-6-Aza-3-Oxa-
pentalen-2-One
[0815] (A) Ethyl
5-(p-nitrobenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-hexyl-
)-acetate
[0816] The alkylation procedure of Example 77A is performed upon
ethyl 5-(p-nitrobenzoyl)-1,4-dimethylpyrrole-2-acetate (from
Example 85), using an equivalent quantity of n-hexyl iodide instead
of methyl iodide used in Example 77A to yield ethyl
5-(p-nitrobenzoyl)-1,4-dimethylpyrrole-2-(.alp-
ha.-n-hexyl)-acetate.
[0817] (B)
5-(p-Nitrobenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-hexyl)-acet- ic
acid
[0818] The hydrolysis procedure of Example 77B is followed in
transforming the ester from part A of this Example into
5-(p-nitrobenzoyl)-1,4-dimethy- lpyrrole-2-(.alpha.-n-hexyl)-acetic
acid.
[0819] (C)
Rac-1-(n-hexyl)-4,6-dimethyl-5-(4'nitrobenzoyl)-1,3,6-trihydro--
6-aza-3-oxapentalen-2-one
[0820]
5-(p-Nitrobenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-hexyl)-acetic
acid is subjected to the procedure of Example 1, part C to produce
rac-1-(n-hexyl)-4,6-dimethyl-5-(4'nitrobenzoyl)-1,3,6-trihydro-6-aza-3-ox-
apentalen-2-one (R.sub.1=n-hexyl, R.sub.2=H,
R.sub.3=4'-nitrophenyl, R.sub.4=methyl, R.sub.5=methyl, Y=CO, m=1,
n=0).
EXAMPLE 117
Rac-1-(n-Hexyl)-4,6-Dimethyl-5-Benzoyl-1,3,6-Trihydro-6-Aza-3-Oxapentalen--
2-One
[0821] (A) Ethyl
5-benzoyl-1,4-dimethylpyrrole-2-(.alpha.-n-hexyl)-acetate
[0822] The alkylation procedure of Example 77A is performed upon
ethyl 5-benzoyl-1,4-dimethylpyrrole-2-acetate (from Example 86),
using an equivalent quantity of n-hexyl iodide instead of methyl
iodide used in Example 77A to yield ethyl
5-benzoyl-1,4-dimethylpyrrole-2-(.alpha.-n-hex- yl)-acetate.
[0823] (B) 5-Benzoyl-1,4-dimethylpyrrole-2-(.alpha.-n-hexyl)-acetic
acid
[0824] The hydrolysis procedure of Example 77B is followed in
transforming the ester from part A of this Example into
5-benzoyl-1,4-dimethylpyrrole-- 2-(.alpha.-n-hexyl)-acetic
acid.
[0825] (C)
Rac-1-(n-hexyl)-4,6-dimethyl-5-benzoyl-1,3,6-trihydro-6-aza-3-o-
xapentalen-2-one
[0826] 5-Benzoyl-1,4-dimethylpyrrole-2-(.alpha.-n-hexyl)-acetic
acid is subjected to the procedure of Example 1, part C to produce
rac-1-(n-hexyl)-4,6-dimethyl-5-benzoyl-1,3,6-trihydro-6-aza-3-oxapentalen-
-2-one (R.sub.1=n-hexyl, R.sub.2=H, R.sub.3=phenyl, R.sub.4=methyl,
R.sub.5=methyl, Y=CO, m=1, n=0).
EXAMPLE 118
Rac-1-(n-Hexyl)-4,6-Dimethyl-5-(2'-Thenoyl)-1,3,6-Trihydro-6-Aza-3-Oxapent-
alen-2-One
[0827] (A) Ethyl
5-(2'-thenoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-hexyl)-ac-
etate
[0828] The alkylation procedure of Example 77A is performed upon
ethyl 5-(2'-thenoyl)-1,4-dimethylpyrrole-2-acetate (from Example
87), using an equivalent quantity of n-hexyl iodide instead of
methyl iodide used in Example 77A to yield ethyl
5-(2'-thenoyl)-1,4-dimethylpyrrole-2-(.alpha.--
n-hexyl)-acetate.
[0829] (B)
5-(2'-Thenoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-hexyl)-acetic
acid
[0830] The hydrolysis procedure of Example 77B is followed in
transforming the ester from part A of this Example into
5-(2'-thenoyl)-1,4-dimethylpyr- role-2-(.alpha.-n-hexyl)-acetic
acid.
[0831] (C)
Rac-1-(n-hexyl)-4,6-dimethyl-5-(2'-thenoyl)-1,3,6-trihydro-6-az-
a-3-oxapentalen-2-one
[0832]
5-(2'-Thenoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-hexyl)-acetic acid
is subjected to the procedure of Example 1, part C to produce
rac-1-(n-hexyl)-4,6-dimethyl-5-(2'-thenoyl)-1,3,6-trihydro-6-aza-3-oxapen-
talen-2-one (R.sub.1=n-hexyl, R.sub.2=H, R.sub.3=2'-thiophenyl,
R.sub.4=methyl, R.sub.5=methyl, Y=CO, m=1, n=0).
EXAMPLE 119
Rac-1-(n-Hexyl)-4,6-Dimethyl-5-(5'-Methyl-2'-Thenoyl)-1,3,6-Trihydro-6-Aza-
-3-Oxapentalen-2-One
[0833] (A) Ethyl
5-(5'-methylthenoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-hex-
yl)-acetate
[0834] The alkylation procedure of Example 77A is performed upon
ethyl 5-(5'-methyl-2'-thenoyl)-1,4-dimethylpyrrole-2-acetate (from
Example 88), using an equivalent quantity of n-hexyl iodide instead
of methyl iodide used in Example 77A to yield ethyl
5-(5'-methyl-2'-thenoyl)-1,4-dimethylp-
yrrole-2-(.alpha.-n-hexyl)-acetate.
[0835] (B)
5-(5'-methyl-2'-thenoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-hexyl-
)-acetic acid
[0836] The hydrolysis procedure of Example 77B is followed in
transforming the ester from part A of this Example into
5-(5'-methyl-2'-thenoyl)-1,4-d-
imethylpyrrole-2-(.alpha.-n-hexyl)-acetic acid.
[0837] (C)
Rac-1-(n-hexyl)-4,6-dimethyl-5-(5'-methyl-2'-thenoyl)-1,3,6-tri-
hydro-6-aza-3-oxapentalen-2-one
[0838]
5-(5'-Methyl-2'-thenoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-hexyl)-ac-
etic acid is subjected to the procedure of Example 1, part C to
produce
rac-1-(n-hexyl)-4,6-dimethyl-5-(5-methyl-2'-thenoyl)-1,3,6-trihydro-6-aza-
-3-oxapentalen-2-one (R.sub.1=n-hexyl, R.sub.2=H,
R.sub.3=5'-methyl-2'-thi- ophenyl, R.sub.4=methyl, R.sub.5=methyl,
Y=CO, m=1, n=0).
EXAMPLE 120
Rac-1-(n-Hexyl)-4,6-Dimethyl-5-(4
'-Trifluoromethylbenzoyl)-1,3,6-Trihydro-
-6-Aza-3-Oxapentalen-2-One
[0839] (A) Ethyl
5-(p-trifluoromethylbenzoyl)-1,4-dimethylpyrrole-2-(.alph-
a.-n-hexyl)-acetate
[0840] The alkylation procedure of Example 77A is performed upon
ethyl 5-(p-trifluoromethylbenzoyl)-1,4-dimethylpyrrole-2-acetate
(from Example 89), using an equivalent quantity of n-hexyl iodide
instead of methyl iodide used in Example 77A to yield ethyl
5-(p-trifluoromethylbenzoyl)-1,-
4-dimethylpyrrole-2-(.alpha.-n-hexyl)-acetate.
[0841] (B)
5-(p-Trifluoromethylbenzoyl)-,4-dimethylpyrrole-2-(.alpha.-n-he-
xyl)-acetic acid
[0842] The hydrolysis procedure of Example 77B is followed in
transforming the ester from part A of this Example into
5-(p-trifluoromethylbenzoyl)-1-
,4-dimethylpyrrole-2-(.alpha.-n-hexyl)-acetic acid.
[0843] (C)
Rac-1-(n-hexyl)-4,6-dimethyl-5-(4'-trifluoromethylbenzoyl)-1,3,-
6-trihydro-6-aza-3-oxapentalen-2-one
[0844]
5-(p-Trifluoromethylbenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-hexyl-
)-acetic acid is subjected to the procedure of Example 1, part C to
produce
rac-1-(n-hexyl)-4,6-dimethyl-5-(4'-trifluoromethylbenzoyl)-1,3,6--
trihydro-6-aza-3-oxapentalen-2-one (R.sub.1=n-hexyl, R.sub.2=H,
R.sub.3=4'-trifluoromethylphenyl, R.sub.4=methyl, R.sub.5=methyl,
Y=CO, m=1, n=0).
EXAMPLE 121
Rac-1-(n-Hexyl)-4,6-Dimethyl-5-(3',4'-Dimethoxybenzoyl)-1,3,6-Trihydro-6-A-
za-3-Oxapentalen-2-One
[0845] (A) Ethyl 5-(3
',4'-dimethoxybenzoyl)-1,4-dimethylpyrrole-2-(.alpha-
.-n-hexyl)-acetate
[0846] The alkylation procedure of Example 77A is performed upon
ethyl 5-(3',4'-dimethoxybenzoyl)-1,4-dimethylpyrrole-2-acetate
(from Example 90), using an equivalent quantity of n-hexyl iodide
instead of methyl iodide used in Example 77A to yield ethyl
5-(3',4'-dimethoxybenzoyl)-1,4--
dimethylpyrrole-2-(.alpha.-n-hexyl)-acetate.
[0847] (B)
5-(3',4'-Dimethoxybenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-hex-
yl)-acetic acid
[0848] The hydrolysis procedure of Example 77B is followed in
transforming the ester from part A of this Example into
5-(3',4'-dimethoxybenzoyl)-1,4-
-dimethylpyrrole-2-(.alpha.-n-hexyl)-acetic acid.
[0849] (C)
Rac-1-(n-hexyl)-4,6-dimethyl-5-(3',4'-dimethoxybenzoyl)-1,3,6-t-
rihydro-6-aza-3-oxapentalen-2-one
[0850]
5-(3',4'-Dimethoxybenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-hexyl)--
acetic acid is subjected to the procedure of Example 1, part C to
produce
rac-1-(n-hexyl)-4,6-dimethyl-5-(3',4'-dimethoxybenzoyl)-1,3,6-trihydro-6--
aza-3-oxapentalen-2-one (R.sub.1=n-hexyl, R.sub.2=H,
R.sub.3=3',4'-dimethoxyphenyl, R.sub.4=methyl, R.sub.5=methyl,
Y=CO, m=1, n=0).
EXAMPLE 122
Rac-1-(n-Hexyl)-4,6-Dimethyl-5-(2',3',5'-Tribromobenzoyl)-1,3,6-Trihydro-6-
-Aza-3-Oxapentalen-2-One
[0851] (A) Ethyl
5-(2',3',5'-tribromobenzoyl)-1,4-dimethylpyrrole-2-(.alph-
a.-n-hexyl)-acetate
[0852] The alkylation procedure of Example 77A is performed upon
ethyl 5-(2',3',5'-tribromobenzoyl)-1,4-dimethylpyrrole-2-acetate
(from Example 91), using an equivalent quantity of n-hexyl iodide
instead of methyl iodide used in Example 77A to yield ethyl
5-(2',3',5'-tribromobenzoyl)-1,-
4-dimethylpyrrole-2-(.alpha.-n-hexyl)-acetate.
[0853] (B)
5-(2',3',5'-Tribromobenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-h-
exyl)-acetic acid
[0854] The hydrolysis procedure of Example 77B is followed in
transforming the ester from part A of this Example into
5-(2',3',5'-tribromobenzoyl)-1-
,4-dimethylpyrrole-2-(.alpha.-n-hexyl)-acetic acid
[0855] (C)
Rac-1-(n-hexyl)-4,6-dimethyl-5-(2',3',5'-tribromobenzoyl)-1,3,6-
-trihydro-6-aza-3-oxapentalen-2-one
[0856]
5-(2',3',5'-Tribromobenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-hexyl-
)-acetic acid is subjected to the procedure of Example 1, part C to
produce
rac-1-(n-hexyl)-4,6-dimethyl-5-(2',3',5'-tribromobenzoyl)-1,3,6-t-
rihydro-6-aza-3-oxapentalen-2-one (R.sub.1=n-hexyl, R.sub.2H,
R.sub.3=2',3',5'-tribromophenyl, R.sub.4=methyl, R.sub.5=methyl,
Y=CO, m=1, n=0).
EXAMPLE 123
Rac-1-(n-Hexyl)-4,6-Dimethyl-5-(2'-Methylbenzoyl)-1,3,6-Trihydro-6-Aza-3-O-
xapentalen-2-One
[0857] (A) Ethyl
5-(o-methylbenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-hexy-
l)-acetate
[0858] The alkylation procedure of Example 77A is performed upon
ethyl 5-(o-methylbenzoyl)-1,4-dimethylpyrrole-2-acetate (from
Example 92), using an equivalent quantity of n-hexyl iodide instead
of methyl iodide used in Example 77A to yield ethyl
5-(.alpha.-methylbenzoyl)-1,4-dimethyl-
pyrrole-2-(.alpha.-n-hexyl)-acetate.
[0859] (B)
5-(o-Methylbenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-hexyl)-ace-
tic acid
[0860] The hydrolysis procedure of Example 77B is followed in
transforming the ester from part A of this Example into
5-(o-methylbenzoyl)-1,4-dimeth-
ylpyrrole-2-(.alpha.-n-hexyl)-acetic acid.
[0861] (C)
Rac-1-(n-hexyl)-4,6-dimethyl-5-(2'-methylbenzoyl)-1,3,6-trihydr-
o-6-aza-3-oxapentalen-2-one
[0862]
5-(o-Methylbenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-hexyl)-acetic
acid is subjected to the procedure of Example 1, part C to produce
rac-1-(n-hexyl)-4,6-dimethyl-5-(2'-methylbenzoyl)-1,3,6-trihydro-6-aza-3--
oxapentalen-2-one (RI =n-hexyl, R.sub.2=H, R.sub.3=2'-methylphenyl,
R.sub.4 methyl, R.sub.5=methyl, Y=CO, m=1, n=0).
EXAMPLE 124
Rac-1-(n-Hexyl)-4,6-Dimethyl-5-(4'-Cyanobenzoyl)-1,3,6-Trihydro-6-Aza-3-Ox-
apentalen-2-One
[0863] (A) Ethyl
5-(p-cyanobenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-hexyl-
)-acetate
[0864] The alkylation procedure of Example 77A is performed upon
ethyl 5-(p-cyanobenzoyl)-1,4-dimethylpyrrole-2-acetate (from
Example 93), using an equivalent quantity of n-hexyl iodide instead
of methyl iodide used in Example 77A to yield ethyl
5-(p-cyanobenzoyl)-1,4-dimethylpyrrole-2-(-n-h- exyl)-acetate.
[0865] (B)
5-(p-Cyanobenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-hexyl)-acet- ic
acid
[0866] The hydrolysis procedure of Example 77B is followed in
transforming the ester from part A of this Example into
5-(p-cyanobenzoyl)-1,4-dimethy- lpyrrole-2-(.alpha.-n-hexyl)-acetic
acid.
[0867] (C)
Rac-1-(n-hexyl)-4,6-dimethyl-5-(4'-cyanobenzoyl)-1,3,6-trihydro-
-6-aza-3-oxapentalen-2-one
[0868]
5-(p-Cyanobenzoyl)-1,4-dimethylpyrrole-2-(.alpha.-n-hexyl)-acetic
acid is subjected to the procedure of Example 1, part C to produce
rac-1-(n-hexyl)-4,6-dimethyl-5-(4'-cyanobenzoyl)-1,3,6-trihydro-6-aza-3-o-
xapentalen-2-one (R.sub.1=n-hexyl, R.sub.2=H,
R.sub.3=4'-cyanophenyl, R.sub.4=methyl, R.sub.5=methyl, Y=CO, m=1,
n=0).
EXAMPLES 125-136
4,6-Dialkyl-5-Aroyl-1,3,6-Trihydro-6-Aza-3-Oxa-Pentalen-2-One
[0869] (A) By repeating the procedure of Example 76B, except that
an equivalent amount of ethylamine and n-butylamine is substituted
for the methylamine employed therein, there are obtained, as
respective products, ethyl
3-ethoxycarbonyl-1,4-diethylpyrrole-2-acetate and ethyl
3-ethoxycarbonyl-1-n-butyl-4-ethylpyrrole-2-acetate.
[0870] (B) Similarly, by following the procedure of Example 76B,
except that an equivalent amount of chloromethyl n-butyl ketone is
substituted for the 1-chloro-2-butanone used therein, ethyl
3-ethoxycarbonyl-4-n-buty- l-1-methylpyrrole-2-acetate is
obtained.
[0871] (C) The procedure of Examples 83A through 83C are repeated,
except that an equivalent amount of each of the products obtained
in paragraphs A and B of this Example is substituted for the ethyl
1,4-dimetyl-3-ethoxycarbonylpyrrole-2-acetate initially employed in
Example 83A, to yield, as respective final products: ethyl
1,4-diethylpyrrole-2-acetate; ethyl
1-n-butyl-4-ethylpyrrole-2-acetate; and ethyl
4-n-butyl-1-methylpyrrole-2-acetate.
[0872] (D) The Friedel-Crafts procedure of Example 83D is followed
using an equivalent amount of the appropriate ester obtained in
paragraph C of this Example and an equivalent amount of an
appropriate Aryl chloride as the acylating agent to yield the
following products: ethyl
5-(p-chlorobenzoyl)-1,4-diethylpyrrole-2-acetate; ethyl
5-(2-thenoyl)-1,4-diethylpyrrole-2-acetate; ethyl
5-(p-methylsulfonyl)-1-- n-butyl-4-ethylpyrrole-2-acetate; ethyl
5-(p-trifluoromethylbenzoyl)-1-n-b- utyl-4-ethylpyrrole-2-acetate;
ethyl 5-(p-nitrobenzoyl)-4-n-butyl-1-methyl- pyrrole-2-acetate;
ethyl 5-(p-cyanobenzoyl)-4-n-butyl-1-methylpyrrole-2-ac- etate; and
ethyl 5-(3',4'-dimethoxybenzoyl)-4-n-butyl-1-methylpyrrole-2-ac-
etate.
[0873] (E) Each of the esters obtained in paragraph D of this
Example is hydrolyzed in accordance with the procedure of Example
83E to yield the corresponding 5-aryl derivatives of
1,4-dialkylpyrrole-2-acetic acid.
[0874] (F)
4,6-dialkyl-5-aroyl-1,3,6-trihydro-6-aza-3-oxa-pentalen-2-one
[0875] The acids from part E are subjected to the procedure of
Example 1, part C to produce the corresponding
4,6-dialkyl-5-aroyl-1,3,6-trihydro-6-- aza-3-oxa-pentalen-2-ones
(R.sub.1=H, R.sub.2=H, R.sub.3=aryl, R.sub.4=alkyl, R.sub.5=alkyl,
Y=CO, m=1, n=0).
* * * * *