Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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The present invention relates to a p~ocess for the
manufacture of 3-amino-isoxazoles. More parti~ularly, the invention
relates to an improved process ~or the manufac~ure of 3-amino-5-
methylisoxazole (hereafter referred to as 3-AMI) at high yields.
EUCX~OUND oF ~HE DNUENTI
The compound 3-AMI is known aq an important raw material fo~
the preparation of sulfonamide derivatives which are widely used as
antibacterical agents. Thus for example, by condensation of 3-AMI
with N-protected p-aminohenzenesulfonyl chloride, sulfamethoxazole
is obtained which is one of the most effective sulfa drugs. 3-AMI
is mentioned as a new compound in the U.K. Patent No. 814,276 as a
starting material for the manufacture of sulfa drugs. According to
the patent, 3-AMI is obtained by the hydrolysis of ethyl-5-methyl-
isoxazole-3-carbamate.
The literature is quite abundant with methods dealing with
the manufacture of derivatives o~ 3-amino-isoxazoles having the formula:
- NH2 wherein: R represents: hydrogen, an
I alkyl group containing l-S
R
~ O ~ carbon atoms and aryl groups.
The general scheme of these methods involves the reaction between a
hydroxylamine, or derivatives thereof, with sultable nitrile compounds
and the cyclization of the resulting intermediate product
~'
~3q~
usiny alkali hydroxide solutions. One of the maln disadvantages
of the known methods is the relatively poor yields which are in
the range of 50 - 76% only. Attempts to lmprove the yields of the
methods, based on the above scheme, were unsuccessful and
S accordingly other routes, which are more complicated or are
requiring more expensive starting materials were suggested. Thus
for instance accoxding to C.A. 98, 126062, it is suggested to cæry
out this synthesis by starting with 3-carbamoyl-5-methylisoxazole
and a mixture of sodium hydroxide and ~odium hypochlori~e.
It is an object of the present invention to provide an
improved process for the manufacture of 3-amino-5-methylisoxazole.
It is another object of the present invention to provide an
improved process for the manufacture of 3-amino-5~methylisoxazole at
high yields. It is yet another object of the present invention to
provide an improved process for the manu~acture of 3-amino-5-methyl-
isoxazole (3-AMI) which is ot a high purity.
The invention consists of an improved process for the
manufac~ure o~ 3-AMI, by reacting a nitrile compound selected from
the group consisting of 2,3-dibromobutyronitrile (DBBN),
2-bromo-3-methoxybutyromtrile (BMBN), 2-bromocrotononitrile
(2-BCN), tetrolonitrile (TN) and mixtures thereof with
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hydroxyurea in an alkali metal hydroxide medium, the pH
during the reaction being maintained in the range o 10.1 - 13.
It was unexpectedly found that by carrying out the reaction of the
nitrile-hydroxyurea compound under a controlled pH range, the
most preferred being between 10.5 - 12.5, the yields obtained are
considerably imp~oved being akove 90%. Moreover, the 3-AMI product
is substantially fxee of the 5-amino-3-methylisoxazole (5-AMI)
which is one of the main impurities present in the prior ar~ methods.
Another advantage of the process according to the pxesent
invention, is the relatively short reaction time required in the
cyclization step producing the 3-AMI. Whereas the prior art methods
are mentioning long periods up to 24 hours, according to the present
invention even less than 4 hours were found to be sufficient to
obtain the high yields of 3-AMI. This enables to carry out the
process even in a continuous manner.
According to a preferred embcdiment, the reaction in the
alkali metal hydroxide mediu~, is carried out in the presence of an
inert organic solvent for example primary alcohols, dioxane,
tetrahydrofuran and the like or any mixture thereof. Spedfic
examples of alcohols are methanol, ethanol etc.
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Suitable alkali me~al hydroxides to be employed during the
cyclization step are sod~um, potassium and lithium hydroxide, the first
one being most preferable being also the less expensive. The alkali
metal hydroxide is added generally in the form of an aqueous solution,
the preferred concentration ran~e being ketween 30~ to 50% by wt.
The reaction temperature is not critical, generally being from about
room temperature to the reflux temperature of the solvents utilized.
The first step of the process consists of the reaction between
a nitrile, and hydroxyureaO This reaction is carried out under vigorous
stirring. The nitrile is selected from DBBN, BMBN, 2-BCN and rLN or any
mixture thereof, prepared according to the methods known in ~he art.
The sMBN see~s to be a new compound which is not described in the
literature. It is Qbtained by the bromination o~ crotononitrile(CN)
in methanol.
The hydroxyurea can be added either in its pure form or produced
in-situ without any isolation or purification. Thus for instance,
hydroxyurea can be prepared by mixing alkyl carbamates and hydroxylamine
salts in basic aqueous medium. The hydroxylamine may be in the form
of a free base or an acid addition salt such as hydrochloride,
hydrosulfate and the like. In the latter case, the hydroxylamine
will be formed in-situ, by reacting the acid salt with sodium hydroxide
in the presence of alkyl carbamates as known in the art.
The main feature of the present lnvention, is the product:Lon
of the 3-AMI by the reaction of the suitable nitriles and hy~roxyurea
in the presence of alkali metal hydroxide in a critical narrow pH
range. It was found that the high yields are achieved only when the
S reaction is produced under a pH ranging from 10.1 to 13 and most
preferable at a pH range of between 10.5 to 12.5. When the F*l is
below 10.1 or above 13, a sharp decrease occurs in the yield being
accompanied by an increase o~ 5~AMI known as the main impurity.
This will cleæly appear from the Examples presented below. The
inventors are not yet in a position to give a definite explanation of
this phenomena.
The control o~ ~he ~H in the a~ove narrow range can be
obtained by adding continuously small portions of alkaline metal
hydroxide, using a conventional pH electrode as monitoring device.
Of course a person skilled in the art may utilize any other
expedients for monitoring the pH at the above range.
The invention will be hereatter illustrated by the ~ollo~ing
Examples without being limited thereto. A person skilled in the
art after reading the specification, will be in a position ~o
appreciate the gist o~ the invention and many variations might be
conceivecl and incorporated therein~
~30:17~6
EXAMPLES 1 to 5
A solution contaimng 53.6 gr (0.8 moles) of crotononitrile
and 42.5 ml of absolute methanol was mixed vigorously in a ~hree-
necked flask. 128 gr (0.8 moles) o~ bromine were introduced
dropwise into the solution. After the addition was completed the
solution was lett for 24 hours aging and was ~ound to consist of
about 79% DBBN.
o an amount o~ 130 mls of cold solution from the above
resulted DBEN solution, it was added under vigorous stirring a
solution consisting of 20 g sodium hydroxide dissolved in 75 ml
water.
The solution was stirred ~or five minutes after the addition
was completed, the organic layer was separated and dried over
anhydrous MgS0 . 69.66 gr of a pale yellow mixture was obtained.
According to NMR spectrum, using tetrachloroethane as internal
standard, the solution contained 85% of 2-BCN, 10.5% of B~EN and
1.1% of tetrolonitrile (TN).
Aqueous hydroxyurea (HXU) solution was prepared from 95 gr
hydroxylammonium hydrochloride and 129 gr ot ethyl carbamate in a
basic medium. 130 gr of the mixture ~repared above was introduced
dropwise to the cold vigorously stirred HXU solution, while the pH
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was kept between certain limits by occasional addition
of 50% NaOH solution. After the addition was completed,
the reaction mixture was mixed ~or 1 hr at room
temperatur~ and then refluxed for about 3 hours.
The solution was cooled, filtered and extracted
with 3 x 250 ml o~ ethyl acetate. The combined organic
layer was dried over anhydrous MgS04 and evaporated.
The resulting oil was analyzed by HPLC using a Bio-Rad*,
Aminex* HPX-72-0, 300 mm x 7 mm column; 0~01 ~ NaOH was
used as eluant.
The experiment was repeated under the same
conditions, the difference being the pH range maintained
during the NaOH addition. The results are summarized in
the following Table 1:
Table 1~ Yields of 3-AMI produced at various~ es
usLnq crude 2-BCN as a nitrile s~Dxe
~1 Ex.2E~.3 Ex.4Ex.5
pH limits 9-10 10-1111-12 12-1313-14
3-AMI yield70.9 85.683.0 79.552.1
20 5-AMI yield3.4 2.1 1.5 1.1 2.0
-
From the above Table 1, it appears clearly the improved
results of the 3-AMI obtained according to the present
invention. When the pH is kept in the range of 10.1-13,
the yields are in the range of 79.5% to 85.6% compared
with 70.9% and 52.1% when the pH ranges are between 9-10
and 13-14, i.e., below or above the optimal range
* - Trademarks
,~ ..~,
~3~.1L'7~6
discovered acco~ding to the present invention. Also, the 3-AMI
product i5 purer than that obtained in the pH xanges outside the
range of the present invention, containing less 5~AMI, which is
the main impurity co-produced in the process.
EXA~PLES 6 to 8.
An amount of 214 mls of a methanolic solution of D~BW,
obtained as in Examples 1 - 5, was added dropwise under vigorous
stirring to an ice cooled solution of aqueous HXU (prepared as in
Example 1 - 5) present in a 3 1 three-neclced flask. To the mixture,
a solution of NaOH (50% concentration by wt.) was added, maintaining
strictly the pH range. When the addi~ion was completed the crude
mixture was worked up as described in Examples 1 - 5. Thxee
experiments were repeated under the same conditions, the difference
being the pH ranges kept during the sodium hydroxide addition.
The results are summarized in the following Table 2.
T~ELE 2 Yields of
crude DBBN as a nitrile source.
Fx. 6 Ex. 7 Ex 8
pH ran~e 9-10 12-12.5 13.5-14
20 3-AMI yield 65.01 82.3% 21%
5-AMI yield 4.10 >0.1% not measured
_ . . _ . . .. , .. .... _
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From the above Table 2, it again appears the improv~l resllts
concerning yield ~nd purity of the 3-AMI produced according to the
present invention.
F~UU~PLE 9,
2-~romocrotoni~rile ~2-ECN) was obtained by deh~drobromination
of the DçæN obtained as in Examples 1-5, using a solution of NaOH.
The 2-~CN was distilled under vacuum ~50 degrees C/8 mm Rg). The
procedure for obtaining the 3-A~I was the s~ne as in Examples 1-5,
using ;~n amount o~ 147 g of the distilled 2-BCN. The pH during the
reaction, was maintained by the addition of NaOH (50% concentration ~y
wt.) in the range of 11 - 12~ An amount o~ 88.15 g of 3-AMI was
produced ~Yield = 90%) the S-AMI impurity being less than 0.7%, as
determaned by the ~.PLC analysls (as mentioned in Ex~nples 1 - 5).
It should be pointed out that Examples 1, 5, 6, 8 do not
illustrate the present invention a~d are presented for ~omparison
purposes only.
