U.S. patent application number 11/067044 was filed with the patent office on 2005-08-25 for process for the production of n-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)p- henyl]-n-ethylacetamide (zaleplon).
Invention is credited to Feher, Erika, Korodi, Ferenc, Magyar, Erika.
Application Number | 20050187225 11/067044 |
Document ID | / |
Family ID | 23147125 |
Filed Date | 2005-08-25 |
United States Patent
Application |
20050187225 |
Kind Code |
A1 |
Korodi, Ferenc ; et
al. |
August 25, 2005 |
Process for the production of
N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)p-
henyl]-N-ethylacetamide (zaleplon)
Abstract
The present invention provides a process for the production of
N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide
(zaleplon), an active ingredient that is approved for the treatment
of insomnia. The process involves reacting
N-[3-[3-(dimethylamino)-1-oxo-2-p- ropenyl]phenyl]-N-ethylacetamide
or a salt thereof with 3-amino-4-cyanopyrazole or a salt thereof
under acidic conditions in a reaction medium comprising a mixture
of water and a water-miscible organic compound.
Inventors: |
Korodi, Ferenc; (Debrecen,
HU) ; Feher, Erika; (Debrecen, HU) ; Magyar,
Erika; (Debrecen, HU) |
Correspondence
Address: |
KENYON & KENYON
ONE BROADWAY
NEW YORK
NY
10004
US
|
Family ID: |
23147125 |
Appl. No.: |
11/067044 |
Filed: |
February 25, 2005 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
11067044 |
Feb 25, 2005 |
|
|
|
10170673 |
Jun 12, 2002 |
|
|
|
6884888 |
|
|
|
|
60297635 |
Jun 12, 2001 |
|
|
|
Current U.S.
Class: |
514/259.3 ;
544/281 |
Current CPC
Class: |
A61P 25/22 20180101;
A61P 25/20 20180101; C07D 487/04 20130101 |
Class at
Publication: |
514/259.3 ;
544/281 |
International
Class: |
A61K 031/519; C07D
487/04 |
Claims
1-24. (canceled)
25.
N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-5-yl]-N-ethylacetamide.
26-29. (canceled)
30. A method for assaying zaleplon comprising the steps of: a.
providing a sample solution of a zaleplon sample in
acetonitrile:water (1:1) diluent, b. loading the sample solution
onto an RP-18, 3 mm, HPLC column, c. eluting the column using a
mixture of ammonium-format buffer and acetonitrile with determined
flow rate, and d. measuring the zaleplon content of the relevant
sample at 245 nm wavelength with a UV detector and appropriate
recording apparatus.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of provisional
application Ser. No. 60/297,635, filed Jun. 12, 2001.
FIELD OF THE INVENTION
[0002] The present invention relates to an improved process for
producing
N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide.
BACKGROUND OF THE INVENTION
[0003] Zaleplon, whose systematic chemical name is
N-[3-(3-cyanopyrazolo[1-
,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide, possesses anxiolytic,
antiepileptic, sedative and hypnotic properties. It is approved by
the U.S. Food and Drug Administration for short-term treatment of
insomnia.
[0004] Zaleplon and a process for preparing it are disclosed in
U.S. Pat. No. 4,626,538, which is incorporated herein by reference.
In the '538 patent process, shown in Scheme 1,
N-(3-acetylphenyl)ethanamide is condensed with dimethylformamide
dimethyl acetal to form
N-[3-[3-(dimethylamino)-1-oxo-2-propenyl)]phenyl]acetamide. The
primary amide of the acetamide is then alkylated with ethyl iodide,
forming
N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylacetamide
1. To prepare zaleplon in the last step, ethylacetamide 1 is
condensed with 3-amino-4-cyanopyrazole 2 by refluxing the reactants
in glacial acetic acid for eight hours. 1
[0005] U.S. Pat. No. 5,714,607 discloses an improvement upon the
'538 patent process. According to the '607 patent, zaleplon can be
obtained in improved yield and purity if the final step of the '538
patent process is modified by adding water to the acetic acid
solvent at about 10% to about 85% (v/v). It is also reported that
the reaction is faster when water is added. As stated in the '607
patent, the improved conditions shorten the reaction time from
about 3-3.5 to about 1-3.5 hours. According to Table 1 of the '607
patent, zaleplon was obtained in yields ranging from 81.7-90% and
in HPLC purity ranging from 98.77 to 99.4%.
[0006] Nevertheless, development of a more advantageous procedure
for production of zaleplon under acidic conditions starting from
ethylacetamide and 3-amino-4-cyanopyrazole in high yield and purity
and in a short time is still desirable.
[0007] In order to obtain marketing approval for a new drug
product, manufacturers have to submit to the regulatory authorities
evidence to show that the product is acceptable for human
administration. Such a submission must include, among other things,
analytical data to show the impurity profile of the product to
demonstrate that the impurities are absent, or are present only a
negligible amount. For such a demonstration there is a need for
analytical methods capable of detection of the impurities and
reference markers for identification and assaying thereof.
SUMMARY OF THE INVENTION
[0008] The present invention provides a process for producing
zaleplon by reacting N-[3
-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylacetami- de and
3-amino-4-cyanopyrazole in a liquid reaction medium of water and a
water-miscible organic compound under acidic conditions. The
reaction proceeds through an imine intermediate that is prone to
precipitate from water. The imine intermediate remains dissolved in
the reaction media of this invention. The process proceeds rapidly
at ambient temperature to produce highly pure zaleplon in high
yield. The process is suitable for small or large-scale production
of pure zaleplon.
[0009] In another embodiment, the present invention relates to pure
zaleplon having a purity, as determined by HPLC, of at least
98.5%.
[0010] In yet another aspect, the present invention relates to pure
zaleplon having a purity of at least 99% as determined by HPLC.
[0011] In another aspect, the present invention relates a method
for preparation of a novel chemical compound,
N-[3-(3-cyanopyrazolo[1,5-a]pyr-
imidin-5-yl)phenyl]-N-ethylacetamide, which is the regioisomer and
main process impurity of zaleplon. This new compound, which is
characterized by NMR and MS investigations, can be used as a
reference marker in analysis of zaleplon.
[0012] In still a further aspect, the present invention relates to
analytical methods for testing and show the impurity profile of
zaleplon. These methods are also suitable for analyzing and
assaying zaleplon and its main impurity which, in the methods of
the invention, serves as reference marker.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] FIG. 1 shows a typical HPLC chromatogram for zaleplon
produced by the method of the present invention.
[0014] FIG. 2 shows the HPLC chromatigram of the novel compound
N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-5-yl)phenyl]-N-ethylacetamide
produced by the method of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0015] The present invention is based on a mechanistic study and
new observations concerning the reaction of
N-[3-[3-(dimethylamino)-1-oxo-2-p- ropenyl]phenyl]-N-ethylacetamide
1 with 3-amino-4-cyanopyrazole 2 leading to zaleplon. Our
observations include identification of a reaction intermediate,
imine 3 by high performance liquid chromatography-mass
spectroscopy. Our results, including the identification of the
imine intermediate, are consistent with a reaction mechanism that
is set forth in Scheme 2. 23
[0016] According to Scheme 2, ethylacetamide 1 undergoes
Michael-type addition of the 3-amino group of pyrazole 2.
.alpha.-Elimination of dimethylamine from a transient
charge-separated intermediate restores the double bond, which
rearranges to form imine intermediate 3. The 2-nitrogen atom of the
pyrazole ring cyclizes onto the keto group with elimination of
water forming zaleplon.
[0017] Both the addition and cyclization reactions occur in the
presence of acid. The dimethylamine liberated in the first
elimination step binds an equivalent of acid. Consequently an
excess of acid is required for this sequence of acid catalyzed
conversions to go to completion.
[0018] The starting materials, imine intermediate, and product have
significantly different polarities. It became apparent during the
course of our study that while aqueous mineral acid is a good
solvent for both starting materials 1 and 2, it is not a good
solvent for imine intermediate 3 or zaleplon. Imine intermediate 3
tends to separate from aqueous mineral acids that do not contain a
significant amount of a water-miscible organic co-solvent and forms
an oily precipitate, thereby preventing the reaction from going to
completion. The starting materials and imine intermediate are
soluble in a variety of protic and polar aprotic organic solvents.
Unfortunately, the rate of the reaction is solvent dependent and is
much slower in the organic solvents we tried than it is in
water.
[0019] Overcoming the above-mentioned solubility problems, the
present invention provides a process for producing zaleplon whereby
ethylacetamide 1, or an acid addition salt thereof, is reacted with
3-amino-4-cyanopyrazole 2, or an acid addition salt thereof, in a
reaction medium of water and at least one water-miscible organic
compound in the presence of an acid. The quantity of water, organic
solvent, and acid can be adjusted independently. The water-miscible
organic solvent can tend to solubilize imine intermediate 3. As
stated previously, an equivalent or more of an acid must be present
in order to maintain acidic conditions throughout the course of the
reaction. By including at least one water-miscible organic
compound, the solvating power in the reaction medium is decoupled
from the choice of acid. This flexibility is advantageous because
it enables optimization of the production process simultaneously
for yield and reaction rate. Such flexibility is not possible in
prior art processes. In the process described in the '607 patent,
varying the amount of acid is the only means of altering the
solvating properties of the reaction medium.
[0020] In particular, the reaction medium for production of
zaleplon from compounds 1 and 2 according to this invention is a
mixture of water and at least one water-miscible organic solvent
(organic co-solvent). Organic co-solvents suitable in the practice
of the present invention include organic compounds that do not bear
carboxylic acid groups, such as C.sub.1-C.sub.6 monohydroxyl and
polyhydroxyl alcohols (e.g. methanol, ethanol, propanol), nitriles
(e.g. acetonitrile, propionitrile), ethers (e.g. tetrahydrofuran,
dioxane), nitro compounds (e.g. nitromethane, nitroethane), amides
(e.g. formamide, dimethylformamide, acetamide, dimethylacetamide,
hexamethylphosphoramide and hexamethylphosphortriamide- ,
sulfoxides (e.g. dimethylsulfoxide), and other water-miscible
organic compounds that are inert to the reagents and/or the
product. Any of the above recited co-solvents can be used alone, or
any of them can be used in any combination.
[0021] The ratio of organic co-solvent to water in the reaction
medium is preferably from about 10% to about 90% (v/v) organic
co-solvent in water, more preferably from about 30% to about 40%
(v/v) organic co-solvent in water. Most preferably, the reaction
medium is a mixture of about 36% (v/v) methanol in water.
[0022] As used herein in connection with the composition of water
and organic co-solvent in a reaction medium, volume % (vol-%), %
v/v, and N % v/v (where N is a number from 1 up to and including
100) are synonymous and calculated as follows (illustrated for
species A):
Vol-%.sub.A=Wt.sub.A.times..rho..sub.A/(Wt.sub.A.times..rho..sub.A+Wt.sub.-
B.times..rho..sub.B)
[0023] where:
[0024] Wt.sub.A and Wt.sub.B are the weights in grams of species A
and B, respectively, and
[0025] .rho..sub.A and .rho..sub.B are the densities, in g./ml. of
species A and B, respectively.
[0026] Suitable acids for use in the practice of the method of the
present invention include inorganic acids, such as hydrochloric
acid, hydrobromic acid, sulfuric acid, phosphoric acid and boric
acid, and water-miscible organic acids, such as formic acid, acetic
acid, propionic acid, oxalic acid, malonic acid and tartaric acid.
The acid should be used in at least an amount capable of
protonating all of the liberated dimethylamine, thereby maintaining
an at least moderately acidic environment for ring closure of imine
intermediate 3 and completion of the zaleplon-forming reaction. An
acid may be added individually as such to the reaction mixture.
Alternatively, the acid may be added as the proton donating
component of an acid addition salt of ethylacetamide 1 or pyrazole
2. Thus, it will be appreciated by those skilled in the art that up
to about two equivalents of acid may be added by using acid
addition salts of the starting materials. Therefore, separate
individual addition of an acid as such is not strictly necessary to
establish acidic conditions.
[0027] Preferred acids include hydrochloric acid and phosphoric
acid, either of which is preferably present in the reaction mixture
in an amount of from about one to about two molar equivalents with
respect to the limiting reagent. Starting materials 1 and 2 may be
used in any ratio. The one present in the lesser molar amount
constitutes the limiting reagent to which the amount of acid should
be compared. The starting materials are preferably used in
approximately equimolar amounts due to their cost.
[0028] In accord with especially preferred sets of production
parameters used in Examples 1, 3-5, 13, 14, 19 and 20, the reaction
goes to completion within several hours at ambient temperature,
without external heating or cooling. The process according to the
present invention is preferably conducted at a temperature in the
range of from about 20.degree. C. to about 25.degree. C. The
reaction also may be conducted at elevated temperature, up to the
boiling point of the reaction medium (e.g. Examples 16-18), as well
as at lower temperatures (e.g. Example 21).
[0029] The reaction time necessary for complete conversion is about
2 to about 8 hours at a temperature in the range of from about
20.degree. C. to about 25.degree. C., depending upon the
composition of the reaction mixture. The time required for the
reaction to go to completion may be decreased to about 0.2 hours at
an elevated temperature of about 50.degree. C. Reactions performed
with cooling require more time to reach completion (about 6 to
about 8 hours) but yield a product of somewhat higher purity
(compare Examples 13 and 21).
[0030] By following the preferred embodiments of the invention, the
zaleplon product precipitates from the reaction mixture by the end
of the reaction or may be induced to precipitate by cooling. The
precipitate may be recovered by filtration. Cooling the reaction
mixture before collecting the product may increase the yield.
[0031] This process produces pure
N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7--
yl)phenyl]-N-ethylacetamide (zaleplon) in the highest yield
currently reported. The process of this invention achieves a higher
reaction rate at lower temperatures than is possible using known
processes for producing zaleplon.
[0032] The purity of the product, as isolated, is very high (above
98.5%). However, if desired, pure zaleplon obtained by the process
of the present invention and having a purity of at least 98.5%,
preferably at least 99%, as determined by HPLC, can be
recrystallized from a solvent, preferably from methanol, ethanol,
or a reaction medium of water and a co-solvent such as methanol,
ethanol, acetonitrile and the like in order to produce a drug
substance that complies with regulatory requirements.
[0033] Formation of
N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-5-yl)phenyl]-N-e-
thylacetamide (4), regioisomer of zaleplon, has been discovered as
a main impurity in the synthesis of zaleplon starting from
3-amino-4-cyanopyrazole and
N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phen-
yl]-N-ethylacetamide. The amount of this impurity has been found to
be strongly dependent on the reaction conditions.
[0034] According to the reaction conditions claimed in the U.S.
Prov. Pat. Appl. 60/297,635 the amount of this impurity is in the
range of 0.2-0.5% (HPLC) in the crude product.
[0035] In another embodiment the present invention provides a
method for the preparation of the novel
N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-5-yl)p-
henyl]-N-ethylacetamide (4) starting from 3-amino-4-cyanopyrazole
and
N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylacetamide
by reacting them in water or in the mixture of water and a water
miscible organic solvent in the presence of an acid. The amount of
this impurity can be increase by up to 5% (HPLC) be use of a high
concentration of a strong acid. This facilitates the isolation and
characterization of this new compound. 4
[0036] The reaction can be performed at 20.degree. to 30.degree. C.
or at higher temperature up to the boiling point of water. A
temperature of 20.degree. to 30.degree. C. is preferred. As a water
miscible organic solvent both polar protic (acetic acid, methanol,
ethanol i-propanol) or aprotic (acetonitrile, tetrahydrofuran,
dimethylformamide) solvents can be applied. As an acid, both
mineral (hydrochloric, sulfuric, phosphoric) and organic (acetic,
trifluoroacetic, methanesulfonic) can be used. Hydrochloric acid is
the preferred preferred acid.
[0037] In a preferred embodiment of the present invention the
reaction is performed in water in the presence of hydrochloric acid
at about 25.degree. C. The isolation of the mixture of zaleplon and
its regioisomer 4 can be performed by evaporation, filtration,
extraction and by combination of this methods.
[0038] In a particularly preferred embodiment of the present
invention, after completion of the reaction, the reaction mixture
is diluted with water and the precipitated zaleplon is removed by
filtration. Then the filtrate is neutralized to precipitate the
mixture of zaleplon and its regioismer 4. A further crop of the
mixture can be obtained by extraction of water phase with water
inmiscible organic solvents such as ethylacetate, dichloromethane,
chloroform and like.
[0039] Isolation of compound 4 can be performed by chromatography.
Column chromatography, preparative TLC or HPLC can be applied.
Column chromatography is preferred. As a packing, silica gel or
aluminium oxide can be used. Silica gel is preferred. As an eluent,
different organic solvents or mixtures of them can be used.
Mixtures of dichloromethane and acetone are preferred. The isolated
2 was characterized with .sup.1H-nmr and .sup.13C-nmr spectroscopic
as well as mass spectrometric investigations to prove its
structure.
[0040] In a further embodiment, the present invention provides
novel HPLC methods for determination of the impurity profile and
assay of zaleplon.
[0041] In one such embodiment, suitable for complete resolution
(separation) of the peak of zaleplon (1) from the peak of
structurally very similar compound (4) as well as the other
impurities, the present invention provides a method for HPLC
including the steps of:
[0042] a, dissolving zaleplon sample in acetonitrile:water (1:1)
diluent,
[0043] b, injecting the sample solution onto an RP-18, 5 .mu.m,
HPLC column,
[0044] c, gradient eluting with a mixture of ammonium-formate
buffer and acetonitrile, and
[0045] d, measuring of the amounts of each impurity at 245 nm
wavelength with a UV detector and appropriate recording device.
[0046] In another embodiment, particularly suitable for analysis
and assay of zaleplon and its main impurity 4 in a drug substance
and pharmaceutical compositions containing zaleplon, the present
invention provides an HPLC method including the steps of:
[0047] a, dissolving zaleplon sample in acetonitrile:water (1:1)
diluent,
[0048] b, injection the sample solution onto an RP-18, 3 .mu.m,
HPLC column,
[0049] c, eluting the sample from the column using a mixture of
ammonium-format buffer and acetonitrile with determined flow rate,
and
[0050] d, measuring the zaleplon content of the relevant sample at
245 nm wavelength with a UV detector and appropriate recording
apparatus
[0051] Having thus described the various aspects of the present
invention, the following non-limiting examples are provided to
illustrate specific embodiments.
EXAMPLES
Example 1
[0052]
N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylacetamide
(2.6 g, 0.01 mol) and 3-amino-4-cyanopyrazole (1.08 g, 0.01 mol)
were dissolved in the mixture of water (35 cm.sup.3) and methanol
(20 cm.sup.3). Phosphoric acid (85%) (0.67 cm.sup.3, 0.01 mol) was
then added and the mixture was stirred at room temperature for
about 4 hours. The reaction mixture was then cooled to about
5.degree. C. and the crystalline product that formed was collected,
washed with water and dried at about 60.degree. C. to yield
zaleplon (2.79 g, 91.5%) in 98.83% purity as determined by
HPLC.
Example 2
[0053]
N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylacetamide
(2.6 g, 0.01 mol) and 3-amino-4-cyanopyrazole (1.08 g, 0.01 mol)
were dissolved in the mixture of water (35 cm.sup.3) and ethanol
(20 cm.sup.3). Phosphoric acid (85%) (0.67 cm.sup.3, 0.01 mol) was
then added and the mixture was stirred at room temperature for
about 8 hours. The reaction mixture was then cooled to about
5.degree. C. and the crystalline product that formed was collected,
washed with water and dried at about 60.degree. C. to yield
zaleplon (2.95 g, 96.7%) in 99.09% purity as determined by
HPLC.
Example 3
[0054]
N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylacetamide
(2.6 g, 0.01 mol) and 3-amino-4-cyanopyrazole (1.08 g, 0.01 mol)
were dissolved in the mixture of water (35 cm.sup.3) and methanol
(20 cm.sup.3). Concentrated (37%) hydrochloride acid (1.0 cm.sup.3,
0.012 mol) was then added and the mixture was stirred at room
temperature for about 2 hours. The reaction mixture was then cooled
to about 5.degree. C. and the crystalline product that formed was
collected, washed with water and dried at about 60.degree. C. to
yield zaleplon (2.80 g, 91.8%) in 98.69% purity as determined by
HPLC.
1TABLE 1 The effects of different reaction conditions are
illustrated in Table 1 Moles of Temp. Volume of Co-solvent Acid
Time Yield Purity.sup.3 Ex. ethylacetamide 1 (C) Water (cm.sup.3)
Co-solvent Volume (cm.sup.3) Acid Moles Equivalents (h) (%) (%) 4
0.01 23 35 MeOH 20 H.sub.3PO.sub.4 0.015 1.5 4 94.5 98.82 5 0.01 23
35 MeOH 20 H.sub.3PO.sub.4 0.020 2 4 93.0 98.80 6 0.01 23 15 MeOH
40 H.sub.3PO.sub.4 0.015 1.5 36 90.0 99.40 7 0.01 23 ... MeOH 55
H.sub.3PO.sub.4 0.015 1.5 >72 ... ... 8 0.01 23 35 EtOH 14
H.sub.3PO.sub.4 0.015 1.5 8 96.1 98.40 9 0.01 23 35 DMF 20
H.sub.3PO.sub.4 0.015 1.5 10 87.9 98.57 10 0.01 23 35 ACN 20
H.sub.3PO.sub.4 0.015 1.5 20 78.2 99.74 11 0.01 23 35 THF 20
H.sub.3PO.sub.4 0.015 1.5 72 89.2 98.40 12 0.01 23 35 MeOH 20 HCl
0.010 1.0 24 82.0 98.95 13 0.01 23 35 MeOH 20 HCl 0.015 1.5 2 92.1
98.9l 14 0.01 23 35 MeOH 20 HCl 0.020 2.0 2 95.1 99.12 15 0.01 23
35 ... ... AcOH 0.260 26 5 85.0 98.97 16 0.01 50 35 MeOH 20
H.sub.3PO.sub.4 0.015 1.5 0.25 90.2 99.25 17 0.01 50 35 MeOH 20 HCl
0.015 1.5 0.2 88.9 99.16 18 0.01 65 ... MeOH 55 H.sub.3PO.sub.4
0.015 1.5 16 79.0 98.71 Determined as percent area of the peak
corresponding to zaleplon in an HPLC chromacogram of the crude
reaction mixture.
Example 19
[0055]
N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylacetamide
(26.0 g. 0.1 mol) and 3-amino-4-cyanopyrazole (10.8 g, 0.1 mol)
were dissolved in the mixture of water (350 cm.sup.3) and methanol
(200 cm.sup.3). Concentrated (37%) hydrochloric acid (12.5
cm.sup.3, 0.12 mol) was then added and the mixture was stirred at
room temperature for about 2 hours. The reaction mixture was then
cooled to about 5.degree. C. and the crystalline product formed was
collected, washed with water and dried at about 60.degree. C. to
yield zaleplon (29.8 g, 97.7%) in 99.08% purity as determined by
HPLC.
Example 20
[0056]
N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylacetamide
(2.6 g, 0.01 mol) and 3-amino-4-cyanopyrazole-hydrochloride (1.44
g, 0.01 mol) were dissolved in the mixture of water (35 cm.sup.3)
and methanol (20 cm.sup.3). Concentrated (37%) hydrochloric acid
(0.83 cm.sup.3, 0.01 mol) was then added and the mixture was
stirred at room temperature for about 2 hours. The reaction mixture
was then cooled to about 5.degree. C. and the crystalline product
formed was collected, washed with water and dried at about
60.degree. C. to yield zaleplon (2.93 g, 96.1%) in 99.16% purity as
determined by HPLC.
Example 21
[0057]
N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylacetamide
(2.6 g, 0.01 mol) and 3-amino-4-cyanopyrazole (1.08 g, 0.01 mol)
were dissolved in the mixture of water (35 cm.sup.3) and methanol
(20 cm.sup.3). Concentrated (37%) hydrochloric acid (1.25 cm.sup.3,
0.015 mol) was then added and the mixture was stirred at about
15.degree. C. for about 8 hours. The reaction mixture was then
cooled to about 5.degree. C. and the crystalline product formed was
collected, washed with water and dried at about 60.degree. C. to
yield zaleplon (2.87 g, 94.1%) in 99.5% purity as determined by
HPLC.
Example 22
Preparation of
N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-5-yl)phenyl]-N-ethyl--
acetamide
[0058]
N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylacetamide
(5.2 g, 0.02 mol) and 3-amino-4-cyanopyrazole (2.16 g, 0.02 mol)
were dissolved in the mixture of water (50 ml) and concentrated
hydrochloric acid (40 ml) and the mixture was stirred at room
temperature for 8 h. The reaction mixture was then cooled to
5.degree. C. and the precipitate was removed by filtration. The
filtrate was neutralized by concentrated aqueous ammonia solution
to precipitate 380 mg of the mixture of zaleplon and its
regioisomer 4 which was collected by filtration. The filtrate was
extracted with 100 ml of ethylacetate to give 100 mg of the mixture
of the above two compounds upon evaporation. The two crops combined
were put to a silica gel column (100 g) and the elution was
performed by the solvent mixture of chloroform and acetone 3:1
(v/v) to yield as a second crop 240 mg (4%) of 4; mp
194-196.degree. C.; .sup.1H-NMR (CDCl.sub.3) .delta. (ppm) 1.143
(t, 3H), 1.876 (s, 3H), 3.804 (q, 2H), 7.361 (d, 1H), 7.532 (d,
1H), 7.613 (t, 1H), 8.018 (s, 1H), 8.159 (d, 1H), 8.375 (s, 1H),
8.805 ((d, 1H); .sup.13C-NMR (CDCl.sub.3) .delta. (ppm) 12.89,
22.68, 43.84, 83.17, 107.71, 112.84, 127.17, 127.48, 130.62,
131.63, 136.67, 137.46, 144.10, 148.31, 149.99, 158.60, 169.90; MS
(EI, 70 EV) m/z (%) 305 (M.sup.+, 18), 248 (59).
* * * * *