Note: Descriptions are shown in the official language in which they were submitted.
THI~ APPLICATION IS A DIVISION OF APPLICATION No. 477,420
The present invention relates to 2-(4-halo-3-
oxobutanamido)acetic acid derivatives and to a process for
their preparation. These derivatives may be used to prepare
intermediates useful in a process for the preparation of
pyrrolidone derivatives. More particularly, in a process
for preparing 4-hydroxy-2-oxo-1-pyrrolidineacetamide (oxi-
racetam) and its N-derivatives which are useful psychotropic
compounds because they restore cognitive function in animals
and man damaged as a result of various pathologies.
Several processes exist at present for preparing
oxiracetam and its analogues. One process which starts from
gamma-amino-beta-hydroxybutyric acid is described in the
British Patent 1588074, and another process which starts
from a protected glycinamide and an epoxybutanoate is
described in Canadian Patent Application No. 474,316. The
aim of the present invention is to provide an alternative
process for the preparation of oxiracetam and its N-alkyl
analogues using different starting materials which are
commercially available at economically interesting costs.
The invention claimed in parent application No.
477,420 is a process for pxeparing 4-hydroxy-2-oxo-1-pyrro-
lidine derivatives of structure (1):
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: ( 1 )
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CHzCOY
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in which Y is NRlR or OR, where Rl and R2, which
can be the sam~ or di~fererlt, are hydrogen or Cl 3
alkyl and R is Cl 3 alkyl, which comprises protecting
the hydroxy group of a compound of structure (2):
S
HO
\ CH--CH2
c~x fo (2)
NHCH~COY
wherein X is chloro or bromo, and Y is NRlR2 or OR
~here Rl and R2, which can be the same or different,
are hydrogen or Cl 3 alkyl, and R is Cl 3 alkyl, with
a protecting group which is stable under basic conditions
~5 and removeable under acidic conditions, to give a
compound of structure (3)
Prot-O\
fH fH2
~ 20 C~2X ICO (3)
NlICH 2COY
:
in which Prot is a hydroxy-protecting group which is
stable under basic conditions and removeable under acidic
conditions, cyclising the cvmpound of structure (3) in
the presence of a strong non-nucleophilic base formed
from an alkali metal to give a compound of structure (4)
Prot-O
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in which Prot is a hydroxy-protecting group which is
stable un~er basic conditions and removeable under acidic
conditions, and Y is -NRlR2 or OR, removing the group
Prot under acidic conditions, and optionally reacting the
products in which Y is OR with an amine of formula
HNRlR2
Hydroxy-protecting groups which are stable under
basic conditions and removeable under acidic conditions
are generally known in the art and are described in
standard textbooks for example various ether groupS
described at p.l4 et seq. in 'Protective Groups in
Organic Chemistry' by T.W Greene (John Wiley 19813. The
protecting group chosen should not be too sterically
bulky to prevent the cyclisation reaction. We have found
that the compound of struct~re (3) in which Prot is
trimethylsilyl cannot be cyclised easily and we believe
that this is probably due to unfavourable steric
hinderance caused by the protecting group shielding
carbon atoms adjacent to the carbinol group from
nucleophilic attack. Preferably Prot is
tetrahydropyranyl, or ~ -~tho~yethyl, part~cula~ly
preferably tet~ahydropyranyl.
Tetrahydropyranyl derivatives are prepared by
reaction with dihydropyran and preferably this reaction
is performed at room temperature in a solvent selected
from for example methyleneohloride, ch~c-l3form, tetr~hydro-
furan, toluene, benzene etc~ and in the presence of an acid
catalyst9 p~eferably pyridine para-toluenesulphonate
(PPTS~. Examples of other acid catalysts are
p-toluenesulphonic acid, sulphuric acid, phosphoryl
chloride and polyphosphoric acid. When PPTS is used the
amount of PPTS used is preferably 10% with respect to
compound (2) on a molar basis. Preferably about 1.0 to
1.5 molar equivalents of dihydropyran are used.
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Preferably Y is NR R and preferably R and R are
both hydrogen.
When Y is OR preferably it is -OC2H5.
Preferably the strong non-nucleophilic base is
sodium hydride or potassium t-butoxide. Preferably the
cyclisation reaction is carried out at a temperature of
-10C to +30C, preferably at about 0C, in a suitable
solvent for example tetrahydroEuran (THF), toluene,
methylene chloride ~CH2C12~ or dioxane.
The alkyl 4-hydroxy-2-oxo-1-pyrrolidine deriva-
tives (4) can be deprotected by heating, e.g. at 20 - 70 C
in a suitable solvent, for example ethanol, methanol,
lS isopropanol or water, in the presence of an acid catalyst.
Preferably the acid catalyst is pyridine p-toluenesulphonate
(PPTS), p-toluenesulphonic acid, hydrochloric acid or
;~ sulphuric acid.
The alkyl 4-hydroxy~2-oxo-1-pyrrolidineacetates
((4) Y = OR) can be converted to compounds of Structure (4~
~; in which Y is NR1R2 by aminolysis with an amine HNR1R2 in a
solvent such as water, methanol or ethanol at a temperature
between -10 and +S0C.
The compounds of structure (2) can be prepared by
reducing a compound of structure (6)
O
XCH2CCH2CONHCH2COY (6)
Suitable reducing agents are those of the hydride
class. Preferably the reducing agent is sodium borohydride
(NaBH~). Preferably the reduction is performed at -10 to
+30C, preferably at about 0C, in a solvent selected for
example from dimethoxyethane, tetrahydrofuran, ethyl ether,
: ~
.
~,12S~
- 5 -
2-methoxyethanol, ethanol, methanol, isopropanol or water.
The present invention xelates to the compounds of
structure (6).
In summary, the present invention provides a
process for the preparation of a compound of structure (6):
XCH2CC~2CONHCH2COY (6)
in which X is chloro or bromo and Y is NRlR2 or OR where Rl
and R , which can be the same or different, are hydrogen or
Cl_3 allcyl and R is C1 3 alkyl, comprising:
reacting gamma-bromoacetoacetyl bromide or gamma-chloro-
acetoacetyl chloride wi-th a glycine deriva-tive of structure
(7):
2 2 ( )
where Y is NR1R2 or OR where R is C1 3 alkyl, at a
temperature of from -78 to 10 C under anhydrous
conditions.
The invention also provides a compound of
structure (6).
Preferably the reaction is performed at low
temperatures of from -50 to -20 C and in a solvent
selected from methylene chloride, chloroform,
tetrahydrofuran or toluene. Preferably the bromoacetoacetyl
bromide or the chloroacetoacetyl chloride are prepared in
si-tu by reacting diketene with bromine or chlorine.
Preferably the halogen is added to diketene dissolved in a
solvent, either as a solution or by bubbling it as a gas,
and then the glycine ester or amide of structure (7) is
added in the presence of an organic or inorganic base. When
a glycine ester is used preferably it is liberated in situ
-~ from one of its salts, e.g. the hydrochloride. Preferably
an equimolar ratio of reagents is
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used, although it is possible to use an excess of one or the
other.
It will be appreciated that the compounds of
structures ~1), (2), (3) and (4) have a-t least one chiral
carbon atom and, for example, when Prot is tetrahydro-
pyranyl, compounds of structures (3) and (4) have two chiral
carbon atoms. This description relates to racemic mixturas
and to the resolved op-tical isomers and diasteroisomeric
mixtures of the compounds described.
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The examples that follow illustrate the invention
but do not limit it.
Example 1
Methyl 2-t4-bromo-3-oxobutanamido~acetate
4.8 ml Diketene are dissolved in 30 ml methylene
chloride. The solution is cooled to -50C and a solution
o~ 3.24 ml bromine dissolved in 20 ml methylene chloride
is added dropwise over 30 min. The mixture is left
stiering for 2h at ambient temperature. At -40 is
added; all at once, an intimate mixture of 20g finely
ground Na2C03 and 7.9g glycine methyl ester
hydrochloride. Stirring is continued for 90 min,
allowing the mixture to return to ambient temperature.
The salt is ~iltered quickly, the filtrate is
concentrated in vacuo at ambient temperat~re. The
resi~ual oil is purified by chromatography on silic~,
eluting with ethyl acetate. The desired compound is
obtained as a white powder, m.p. 76-77C.
Example 2
Methyl_2-~4-bromo-3-hydroxybutanamido)acetate
1.59 Methyl 2-~4-bromo-3-oxobutanamido)acetate is
dissolved in 15 ml dimethoxyethane. The solution is
cooled to 0C and 60mg NaBH4 is added. After S min,
the solvent is evaporated in vacuo and the residue is
chromatographed on silica, eluting with ethyl acetate.
~; 30 The title compound is obtained as a white powder, m.p.
60 61C.
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Example ~
Methyl 2-l4-bromo-3-hydroxybutanamido)acetate
0.76 ml Diketene is dissolved in 3.5 ml methylene
S chloriae. The solution i5 cooled to -30C and a sol~tion
of O.S m~ bromine in 3.5 ml methylene chloride is addea
slowly dropwise, after which stirring is continued at
30C for 10 mins. This solution is added quickly
dropwise to a solution of glycine methyl ester prepared
by suspending 1~25g glycine methyl ester hydrochloride in
20 ml methylene chloride containing 2.8 ml triethylamine,
stirring for 30 min and cooling to -30C. The
temperature is allowed to return to ambient with
continued stirring. After filtering, and evaporating in
lS vacuo at ambient temperature, the oil remaining is
dissolved in 20 ml ethanol, cooled to 0C and treated
with 100 mg NaBH4. After 5 min the excess hydride is
destroyed with dilute acid, the ethanol is evaporated and
the residue taken up with ethyl acetate; the solution is
washed with brine, dried, evaporated, and purified by
chcomatography sn silica, eluting with ethyl acetate.
The title compound is obtained as a white powder, m.p.
60-61C.
~xample 4
~thyl 2-(4-bromo-3-hydroxybutanamido)acetate
Proceed as described above, using 1.4g ylycine ethyl
ester hydrochloride. A white powder is obtained, m p
30 59-61C.
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Example S
Methyl 2-(4-bromo-3-~tetrahydropyran-2-yloxy)butanamido3-
acetate
To a solution of 300 mg methyl
2-(4-bromo-3-hydroxybutanamido)acetate in 50 ml methylene
chloride are added 30 mg pyridinium p-toluenesulphonate
and l ml dihydropyran. After stirring at ambient
temperature for 20h, the sol~ent is evaporated in vacuo
and the residue chromatographed on silica, eluting with
ether. A colourless oil is obtained (92%), Rf 0~33
(~ilica gel plate~, thic~nes~ 0.25, elllent diethy7 ~ther)~
Example 6
Ethyl 2-(4-bromo~3 (tetrahydropyran-2-yloxy)butanamid
acetate
To a-solution of l g ethyl
2-(4-bromo-3-hyd~oxybutanamido)acetate in ~0 ml methylene
chloride are added lO0 mg pyridinium p-toluenesulphonate
and l ml dihydropyran~ Stirring is contin~ed for 3h at
ambient temperature, the solYent is evaporated in vacuo
and the residue chromatographed on silica, eluting with
ether. A pale straw-coloured oil is obtained (91%),
~f. oO5 ¦silica g~l plates~ thicknes~ 0.25 mm eluent ethyl
acetate3.
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Exampl_
Ethyl 2-(4 chloro-3-oxobutana~ido)acetate
5.08 ml diketene are dissolved in 40 ml CH2C12. The
solution is cooled to -30C and chlorine is passed
through it for lh. The solution is then added rapidly
dropwise to a solution of glycine ethyl ester prepared by
s~spending 9.30g glycine ethyl ester hydrochloride in
160 ml methylene chloride c~ntaining 18.6 ml
triethylamine, the mixture is stirred for 30 min and
cooled to ~30C. Stirring is continued for 30 min, the
solvent is evaporated in vacuo, and the residue taken up
in ethyl acetate. ~he salts are ~iltered off, the
solvent i5 evaporated and the residue chromatographed on
silica, eluting with ethyl acetate. The compound is
obtained as a white powder, m.p. 96-7C.
Example 8
~thyl 2-(4-chloro-3-hydroxy~utanamido)acetate
5.08 ml diketene are dissolved in 40 ml C~2C12.
The solution is cooled to -30C and chlorine is passed
through for 90 min. The solution is then added rapidly
dropwise to a solution of glycine ethyl ester in 160 ml
~H2C12 prepared as in the preceding exa~ple. A~ter
stirring for 30 min, the solvent is evaporated n vacuo,
the residue is taken up in ethyl acetate and the salts
f iltered of f . ~he solvent i8 evaporated, the oily res~due i8
dissolved in 150 ml ethanol, cooled in ice, and 1~26 g NaBH4
30 i~; add~d in portions. After 30 min a fe~ drops of dilut~
hydrochloric acid are added, th~ 801~ent ls
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evaporated, the residue is taken up in ethyl acetate,
washed with brine and dried. The solvent is evaporated
and the cesidue chromatographed on silica, eluting With
ethyl acetate. The compound is obtained as a white
S powder, m p. 53-4C.
Example 9
Ethyl 2-~4-chloro-3-(tetrah~dropYran-2-yloxy3butanamid
acetate
lg Ethyl 2-(4-chloro-3-hydroxyb~tanamido~acetate is
dissolved in 10 ml CH2C12. 100 mg pyridine
p-toluenesulphonate and 0.5 ml dihydropyran are added.
The mixture is stirred for 7h. The solvent is evaporated
and the residue chromatographed, eluting with ethyl
a~etate. A colourless oil is obtained, Rf 0.5 (silica
gel plates, thickness 0.25 mm, eluent ethyl acetate).
Example 10
~0
Ethyl 2-oxo-4-(tetrahydropyran-2-yl)-1-pyrrolidineacetate
150 mg NaH are suspended in 20 ml tetrahydrofuran,
and the mixture is cooled in ice. To this suspension is
added a solution of 2.5 g ~thyl
2-(4-bromo-3-(tetrahydropyran-2-yloxy)butanamido)acetate
in 30 ml tetx-ahydrofuran. The mixture is stirred 40 min,
then poured with stirring into a solution of 1 ml acetic
acid in 10 ml water at 0C. The solution is extracted
with ether, the organic phase is washed with a saturated
solution of NaHCO3, then washed with brine, dried and
- evaporated. The crude oil obtained is purified by
chromatography on silica, eluting with ethyl acetate.
colourless oil is obtained, Rf 0~32 ~silica gel plates,
' thickness 0.25mm, eluent ethyl acetate).
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~ample 11
Ethyl 2-oxo-4-ttetrahydropyran-2-yl)-1-pyrrolidineacetate
Proceeding as described previously, and using 2.24g
ethyl 2-(4-chloro-3-(tetrahydropyran-2-yloxy)buta~amido)-
acetate, a colourless oil is obtained, Rf 0.32 (silica
gel plate89 thickness 0.25 mm~ eluent ethyl acetate).
Example 12
Ethyl 4-hydroxy-2-oxo-1-pyrrolidineacetate
A solution of 0.16 g ethyl
2-oxo-4-(tetrahydropyran-2-yl3-1-pyrrolidineacetate is
dissolved in 5 ml ethanol containing 16 mg pyridinium
p-toluenesulphonate. T~e mlxture i8 heated 4 h at 35, the
ethanol i~ evaporated and the residue chro~atogTaphed on
sil~ca. The co~pound ls obtained as ~ colourles~ o~l (62%3.
:;
Example 13
4-Hvdroxv-2-oxo-1-pyrrolidineacetamide
A solution of 7.1 g ethyl
4-hydroxy-2-oxo-1-pyrrolidineacetate obtained in Example
12, in 7.1 ml ammonia solution (d25=0~90~ is stirred at
- ambient temperature for 15 h. It is then diluted with
140 ml acetone and the mixture is stirred at ambient
temperature until the gum that precipitates solidifies
into white crystals. On filtering in vacuo and drying,
4-hydroxy-2-oxo-1-pyrrolidineacetamide is obtained, m.p.
160-162~C.
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