U.S. patent application number 09/852265 was filed with the patent office on 2001-12-27 for process for the preparation of (e,z) 3-(2-aminoethoxyimino)-androstane-6,1- 7-dione and its analogues.
Invention is credited to Carzana, Giulio, Gobbini, Mauro, Sputore, Simona.
Application Number | 20010056182 09/852265 |
Document ID | / |
Family ID | 11454735 |
Filed Date | 2001-12-27 |
United States Patent
Application |
20010056182 |
Kind Code |
A1 |
Gobbini, Mauro ; et
al. |
December 27, 2001 |
Process for the preparation of (E,Z)
3-(2-aminoethoxyimino)-androstane-6,1- 7-dione and its
analogues
Abstract
An improved process is described for the preparation of
compounds with general formula (I) and particularly for the
preparation of the compound (E,Z)
3-(2-aminoethoxyimino)-androstane-6,17-dione, in which n=1 and
R.sup.1=R.sup.2=H. 1
Inventors: |
Gobbini, Mauro; (Marcallo,
IT) ; Carzana, Giulio; (Milan, IT) ; Sputore,
Simona; (Meda, IT) |
Correspondence
Address: |
NIXON & VANDERHYE P.C.
1100 North Glebe Road, 8th Floor
Arlington
VA
22201-4714
US
|
Family ID: |
11454735 |
Appl. No.: |
09/852265 |
Filed: |
May 10, 2001 |
Current U.S.
Class: |
540/112 ;
552/520 |
Current CPC
Class: |
C07J 41/0016 20130101;
C07J 51/00 20130101 |
Class at
Publication: |
540/112 ;
552/520 |
International
Class: |
C07J 043/00; C07J
041/00 |
Foreign Application Data
Date |
Code |
Application Number |
May 17, 2000 |
IT |
RM2000A000266 |
Claims
1. Procedure for the preparation of compounds with general formula
(I) 6in which: n=1-3; R.sup.1 and R.sup.2, which may be the same or
different, are hydrogen or alkyl C.sub.1-C.sub.6 or together form a
5 or 6 term saturated heterocycle, optionally containing a second
heteroatom selected from the group consisting of oxygen, sulphur or
nitrogen. according to the following reaction diagram: 7comprising
the steps of: (a) introducing a hydroxyl group in position 6.alpha.
of the steroid skeleton and at the same time reducing the ketone
function in position 17, obtaining derivative 9 from
dehydroepiandrosterone; (b) oxidating simultaneously the three
hydroxyl groups present in derivative 9, obtaining derivative 10;
(c) selectively oximating the ketone group in position 3 of
derivative 10 with hydroxylamine, optionally in salified form, with
general formula (II) 8in which n=1-3; R.sup.1 and R.sup.2 are as
defined above.
2. Process according to claim 1, in which the oximation step (c) is
done using 2-aminoethoxy-amine, optionally in salified form) to
yield (E,Z)-3-(2-aminoethoxyimino)-androstane-6,17-dione.
3. Process according to claim 1 or 2, in which the product is
obtained in salified form.
Description
[0001] The subject matter of the invention described herein is an
improved process for the preparation of compounds with general
formula (I) and in particular of compound (E,Z)
3-(2-aminoethoxyimino)-androstane-6,17-dione (hereinafter referred
to as PST 2744) and their pharmaceutically acceptable salts, 2
[0002] in which:
[0003] n=1-3; R.sup.1 and R.sup.2, which may be the same or
different, are hydrogen or alkyl C.sub.1-C.sub.3 or together form a
5 or 6 term saturated heterocycle, optionally containing a second
heteroatom selected from the group consisting of oxygen, sulphur or
nitrogen.
[0004] The formula (I) compound in which n=1 and R.sup.1=R.sup.2=H
is PST 2744; it is a known compound, endowed with positive
inotropic activity at the cardiovascular system level, and is
therefore a useful agent in the treatment of heart failure.
[0005] European Patent Application EP 0825197 (Sigma-Tau Industrie
Farmaceutiche Riunite) discloses PST 2744 and its analogues
included in formula (I) above and in addition describes a process
for their preparation; PST 2744 is described in the example of
preparation no. 7.
[0006] The process for the preparation of PST 2744 according to the
method described in EP 0825197 is indicated in the following
reaction diagram.
DIAGRAM 1
[0007] 3
[0008] where: TBS=t-butyldimethylsilane; Ac=acetyl
[0009] Diagram 1 shows that the process for the preparation of PST
2744, which is done using dehydroepiandrosterone as the starting
product, involves as many as 9 steps with the formation of 8
intermediate compounds. This process involves such a large number
of steps because protection/deprotection reactions are used for the
potentially reactive functional groups present in the molecule.
[0010] Such protection is a well-known practice (see, for example:
Greene, T. W. and Wuts P. G. M., Protective Group in Organic
Synthesis, 3rd ed., Wiley, New York, US, 1999) and is often
unavoidable in the field of organic chemistry, but with the
drawback that the introduction and subsequent removal of each
protective group means lengthening the synthesis process by two
steps, with obvious increases in terms both of execution times and
costs.
[0011] The PST 2744 preparation process described in EP 0825197 is
carried out by performing chromatographic purifications of the
intermediate products.
[0012] An improved process has now been found, and this is the
subject matter of the invention described herein, for the
preparation of compounds with general formula (I), particularly PST
2744, which avoids the use of protective groups in the various
synthesis steps, with a substantial reduction of the number of
steps and purifications, and with a substantial reduction of
production costs.
[0013] The process according to the invention described herein is
indicated in the following reaction diagram by way of an example as
far as PST 2744 is concerned.
DIAGRAM 2
[0014] 4
[0015] This process comprises the steps of:
[0016] (a) introducing a hydroxyl group in position 6.alpha. of the
steroid skeleton and at the same time reducing the ketone function
in position 17, obtaining derivative 9 from
dehydroepiandrosterone;
[0017] (b) oxidating simultaneously the three hydroxyl groups
present in derivative 9, obtaining derivative 10;
[0018] (c) selectively oximating the ketone group in position 3 of
derivative 10 obtaining PST 2744, preferably in a salified
form.
[0019] It is perfectly clear that the process according to the
invention described herein applies to all formula (I) compounds,
which differ from one another in the aminoalkyl chain bound to the
oxime group in position 3. Given that the addition of the amine
aminoalkoxy chain to ketone group 3, to yield the corresponding
oximic derivative is analogous to the reaction described in EP
0825197, the process according to the invention, as exemplified for
PST 2744 and regarding the transformations on the steroid nucleus,
is applicable by analogy to all formula (I) compounds, as described
above. Any minor changes made to the reactions exemplified
(solvents, molar ratios, reaction controls) are thoroughly obvious
and immediate to the technician with average experience in the
sector, on the basis of his or her own general knowledge alone.
[0020] The advantage of the process according to the invention
indicated in Diagram 2 can be immediately perceived on comparing it
with the process described in EP 0825197 and indicated in Diagram
1.
[0021] Moreover, the process according to the invention described
herein takes place with optimum selectivity of oximation of the
ketone group in position 3, to yield the compound desired, despite
the presence of two other ketone groups in positions 6 and 17.
[0022] As has been said, the process according to the invention
described herein is characterised by the lack of the use of
protective groups. In fact, Diagram 2 shows that from the starting
compound, dehydroepiandrosterone, intermediate 10 is obtained in
two steps, completely skipping intermediates 1-7 indicated in
Diagram 1, in which the protective groups are introduced in steps A
and D to yield intermediates 1 and 4, and are then removed in steps
E and G to give intermediates 5 and 7.
[0023] The reaction conditions used in the process which is the
subject matter of the invention described herein, with reference to
Diagram 2, are:
[0024] Step A: ation of the double bond present in position 5 and
reduction of the ketone in position 17 of the
dehydroepiandrosterone. For this reaction we use borane (both as a
monomer and as the diborane dimer), 9-BBN, disiamylborane or
texylborane, both in the free form and as complexes with other
substances such as, for example, tetrahydrofuran, dimethylsulphur
or bases such as, for example, ammonia, dimethylamine,
tnethylamine, and pyridine. In particular, the borane can be added
to the reaction mixture in the form of a complex with
tetrahydrofuran or dimethylsulphur, or can be generated in situ by
reaction between sodium borohydride and acetic acid or between
sodium borohydride and a Lewis acid, such as, for example,
borotrifluoride etherate; or, lastly, it may be generated, in the
way previously described, in an environment external to the
reaction mixture and can be introduced into said mixture. The
reaction is done at a temperature ranging from -10.degree. C. to
the boiling temperature of the reaction mixture, for a period of
time ranging from one to five hours.
[0025] The subsequent oxidation of the alkylboranes obtained can be
accomplished, for example, with H.sub.2O.sub.2/NaOH, with sodium
perborate or other alkaline perborates added in aqueous solution to
the reaction mixture. The reaction is done at a temperature ranging
from -10.degree. C. to the boiling temperature of the reaction
mixture, for a time period ranging from 10 to 24 hours. The final
product is purified by crystallisation by solvents such as ethyl
acetate, methanol, ethanol, isopropanol, acetone, water or mixtures
of the same.
[0026] Step B. oxidation of the three hydroxyl functions present in
compound 9. This oxidation is carried out with oxidants such as
chromium oxide in the presence of sulphuric acid and water (Jones
reagent) in acetone, at a temperature ranging from -10.degree. C.
to the boiling temperature of the reaction mixture; with
tetrapropylammonium perruthenate as the oxidant in catalytic
amounts and N-methylmorpholine N-oxide as the stoichiometric
oxidant, in ethylene chloride or acetonitrile or mixtures of these
solvents, optionally in the presence of molecular sieves, at a
temperature ranging from -10.degree. C. to the boiling temperature
of the reaction mixture; ruthenium tetroxide as the oxidant in
catalytic amounts, generated in situ from a stoichiometric oxidant,
which can be sodium bromate, sodium hypochlorite or an alkaline
periodate, such as sodium periodate, starting from ruthenium
hydrate dioxide or ruthenium chloride, in solvents such as acetone,
acetonitrile/carbon tetrachloride/waters
acetonitrile/chloroform/water, acetonitrile/methylene
chloride/water, ethyl acetate/acetonitrile/water in variable
proportions, at a temperature ranging from -10.degree. C. to the
boiling temperature of the reaction mixture.
[0027] This oxidation reaction described in step B is carried out
for a period of time ranging from 0.5 to 24 hours, also depending
on the type of oxidant used.
[0028] Step C: reaction between triketone 10 and
2-aminoethoxyamine. The reaction is carried out adding the base in
salified form or as a free base dissolved in a mixture of solvents
such as dioxane, tetrahydrofuran, water or homogeneous mixtures of
the same to the reaction mixture containing the triketone in the
same solvents as for the base, optionally in the presence of buffer
solutions; the pH of the solution may range from approximately 2 to
approximately 10 depending on whether or not buffer solutions are
used; the reaction temperature ranges from -10.degree. C. to the
boiling temperature of the reaction mixture and the time period
ranges from 0.5 to 12 hours.
[0029] The reaction product is isolated for treatment with solvents
such as tetrahydrofuran, ethyl alcohol, isopropyl alcohol, ethyl
acetate or mixtures of the same. The reaction product can be
isolated as a free base or, preferably, as a salt with inorganic
acids such as hydrochloric or sulphuric acid or with organic acids
such as oxalic acid, fumaric acid or other pharmaceutically
acceptable acids. 2-aminoethoxyammine is a known product (Bruno, I.
et al. Helv. Chim. Acta, 1962, 45, 358).
[0030] On varying the hydroxylamine used, in the last step,
compounds of general formula (I) described in the previously cited
patent application are obtained.
[0031] In this case, the hydroxylamine used has general formula
(II): 5
[0032] in which: n=1-3; R.sup.1 and R.sup.2 have the meanings
described previously.
[0033] The hydroxylamines with general formula (II) can be used as
free bases or in forms salified with inorganic acids such as
hydrochloric acid or sulphuric acid.
[0034] The hydroxylamines with general formula (II) are known
products, which are often available commercially or can be prepared
from commercially available products using standard methods.
[0035] The advantages in terms of costs and time which can be
achieved with the process that is the subject matter of the
invention are therefore obvious.
[0036] The process which is the subject matter of the invention
described herein is further illustrated by the following
examples.
EXAMPLE 1
Step A
[0037] To a solution of dehydroepiandrosterone (30.0 g) in 450 mL
of THF maintained under a nitrogen atmosphere and at a temperature
of -10.degree. C. was added the complex BH.sub.3THF 1M in THF (260
mL). On completing the addition, the temperature was allowed to
rise once again to ambient temperature; after 3 h 500 mL of
H.sub.2O were added and then NaBO.sub.3.4H.sub.2O (31.4 g).
[0038] The reaction was left to stir for one night.
[0039] The precipitate formed was filtered, washed with THF and
eliminated. The aqueous and organic phases were separated, NaCl was
added to the aqueous phase and this was re-extracted with THF
(3.times.200 mL). The merged organic phases were anhydrified with
NaCl and Na.sub.2SO.sub.4 and evaporated under reduced pressure to
obtain the crude product, which was crystallised by AcOEt/MeOH and
then filtered and washed with AcOEt. Approximately 21 g of
androstane-3.beta.,6.alpha.,17.beta.-triol 9 were obtained (known
product: Nicholson, S. H., Turner, A. B. J. Chem. Soc., Perkin
Trans. 1, 1976, 1357).
[0040] The analytical results are in agreement with those reported
in the literature.
EXAMPLE 2
Step B
[0041] To a solution of androstane-3.beta.,6.alpha.,17.beta.-triol
9 (18.6 g) in 335 mL of acetone, was added an excess of Jones
reagent (74 ml), maintaining the temperature below 40.degree. C.
under stirring.
[0042] Five minutes after completing the addition, the excess
oxidant was eliminated with 10 mL of i-PrOH; after a few minutes
the suspension was filtered, the salts were washed with acetone and
the washings added to the main filtrate. The solution was then
evaporated dry and the solid residue treated with H.sub.2O and
extracted with AcOEt (300 mL and 3.times.100 mL). The merged
organic phases were washed with H.sub.2O (100 mL), a 5% NaHCO.sub.3
solution (100 mL), H.sub.2O (100 mL), anhydrified with NaSO.sub.4
and vacuum concentrated. 13.6 g of androstane-3,6,17-trione 10 were
obtained (known product: Amendolla C. et al., J. Chem Soc., 1954,
1226).
[0043] The analytical results are in agreement with those reported
in the literature.
EXAMPLE 3
Step C
[0044] To a solution of androstane-3,6,17-trione 10 (10,0 g) in 200
mL of THF was added drop-wise by rapid drip a solution of
2-aminoethoxyamine dihydrochloride in H.sub.2O (3.92 g, in 50 mL).
The mixture was left to react at ambient temperature for 1.5 h. The
reaction was washed adding NaCl and maintaining it under stirring
for approximately 10 minutes; the phases were separated and the
aqueous phase was re-extracted with THF (2.times.100 mL).
Anhydification was done with Na.sub.2SO.sub.4 and the solvent was
evaporated, obtaining an oily residue which was treated with
CH.sub.2Cl.sub.2 (200 mL circa) and washed with a saturated
solution of NaCl (3.times.30 mL). The reaction mixture was
anhydrified again with Na.sub.2SO.sub.4 and the solvent evaporated,
obtaining a crude product (13.8 g approx.), which was crystallised
by AcOEt (55 mL) to yield 7.0 g of the product desired, (E, Z)
3-(2-aminoethoxyimino)-androstane-6,17-dio- ne (PST 2744) as a
hydrochloride, with a melting point of 208-210.degree. C.
* * * * *