Note: Descriptions are shown in the official language in which they were submitted.
~6~47~
-- 1 --
THIS APPLICATION IS A DIVISION OF APPLICATION No. 477,420
The present invention relates to intermediates
useful in a process for the preparation of pyrrolidone
derivatives. The invention also relates to a process for
the production of these intermediates.
More particularly, the present invention relates
to intermediates for preparing 4-hydroxy-2-oxo-1-pyrroli-
dineacetamide (oxiracetam) 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 preparing 4-hydroxy-2-oxo-l-pyrro-
lidine derivatives of structure (1):
, .
~ \
` 30 ~ (1)
\~0
2 ~ ~
: ~ :
. . ~;, ,. ,. .. : , : : ... .
- : ~ . ` :, :- ~
` ~Z6~3472
-. in which Y is NRlR2 or OR, where Rl ~nd R2, which
can be the same or different, are hydrogen or C1 3
alkyl and R is Cl 3 alkyl, which comprises protecting
the hydroxy group of a compoun~ of structure (2):
~ ~0
\ CH - CH2
2x 70 (2)
.~ NHCH2COY
wherei.n X is chloro or bromo, and Y is NRlR2 or OR
where Rl and R2, which can be the same or different,
are hydrogen or Cl 3 alkyl, and R is Cl_3 alkyl, wi
a protecting qroup which is stable under basic conditions
~- 15 and remo.veable under acidic conditions, to give a
`:~ compound of structure~(3)
'~ ` ` .' ~
: ' ' Pro~;-O\
- CH CH
CH2X CO (3)
NHC~2COY
:
in which Prot is a hydroxy-protecting group which is :
; stable under basic conditions and :removeable under acidic
conditions, cyclising the compound: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~
~ 30 ~ ~
:~ ~ \~ (4)
'" C~ CO~ '
:'~' ' .:
~: :
. ~ ;
~L~6~7~
in which Prot is a hydroxy-protecting group which is stable
under basic conditions and removeable under acidic
conditions, and Y is -NR R or OR, removing the group Prot
under acidic conditions, and optionally reacting the
products in which Y is OR with an amine of formula HNR1 R .
The present invention relates to the intermediates
(2) and (3) used in the foregoing process. The structures
(2) and (3) may be represented more generally by the
structure (5) given below.
In summary, the present invention provides a
process for the preparation of a compound of structure (5):
R3~
~ H FH2
CH2X ~O ~5)
HC~COY
in which X is chloro or bromo, Y is NRlR or OR where R and
R2, which can be the same or different, are hydrogen or C1_3
alkyl and R is C1 3 alkyl, and R is hydrogen or a hydroxy-
protecting group which is stable under basic conditions and
removeablP under acidic conditions, comprising reducing a
~ compound of structure (6):
.~ :
XcH2ccH2coNHcH2coy~ (6)
in which X and Y are as defined above, and if desirad,
protecting the resulting hydroxy group (where R3=H) with a
protecting group (R3~H) which is stable under basic condi-
tions and removeable under acidic conditions.
.~
, ~:
12~72
-- 4
The invention also provides a compound of
structure (5) when produced by the above process or by any
obvious chemical equivalent.
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.14
et seq. in "Protective Groups in Organic Chemistry" by T.W.
Greene (John Wiley 1981). The protecting yroup chosen
should not be too sterically bulky to prevent the
cyclisation reaction. It has now been found that the
compound of structure (3) or (5), in which Prot or R3
respectively is trimethylsilyl, cannot be cyclised easily
and it is now believed 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 tetrahydro-
pyranyl, or ~ -ethoxyethyl, particularly preferably tetra-
; hydropyranyl.
Tetrahydropranyl derivatives are prepared by
reaction with dihydropyran and preferably this reaction is
performed at room temperature in a solvent salected from,
for example, methylenechloride, chloroform, tetrahydrofuran,
toluene, benzene etc. and in the presence of an acid
catalyst, preferably pyridine para-toluenesulphonate (PPTS).
Examples of other acid catalysts are p-toluenesulphonic
acid, sulphuric acid, phosphoryl chloride and polyphosphoric
acid. When PPTS is usad, the amount of PPTS used is
preferably 10% with respect to compound (2) on a molar
- 30 basis. Preferably about 1.0 to 1.5 molar equivalents of
`; dihydropyran are used.
Preferably Y is NR1R and preferably Rl and R are
both hydrogen.
:`-`, ~ ; ;~ .:
' ~ .; ~ ~ ` : :
~26~3~7~
When Y is OR preferably it is -OC2H5.
In the cyclisation of structure (3), it is
preferable, that the strong non-nucleophilic base is sodium
hydride or potassium t-butoxide. Preferably the cyclisation
reaction is carried out at a temperature of -10 C to +30C,
preferably at about 0C, in a suitable solvent for example
tetrahydrofuran (THF), toluene, methylene chloride (CH2Cl2)
or dioxane.
The alkyl 4-hydroxy-2-oxo-1-pyrrolidine deri~a-
tives (4) can be deprotected by heating, e.g. at 20 - 70C
in a suitable solvent, for example ethanol, methanol,
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 NRlR by aminolysis with an amine HNRlR in a
solvent such as water, methanol or ethanol at a temperature
between -10 and +50C.
The process accor~ing to the present invention
involves reducing a compound of structure (6)
1l
H2coNHcH2coy (6)
:
Suitable reducing agents are those of the hydride
class. Preferably the reducing agent is sodium borohydride 30 (NaBH4). Preferably the reduction is performed at -10 to
+30C, preferably at about 0C, in a solvent selected for
example from dimethoxyethane, tetrahydrofuran, ethyl ether,
2-methoxyethanol, ethanol, methanol, isopropanol or water.
The compounds of structure (6) can be prepared by
' '
~ '
-` ~26847~
reacting gamma-bromoacetoacetyl bromide or gamma-chloro-
acetoacetyl chloride with a glycine derivative of structure
(7)
NH2CH2COY (7)
where Y is NRlR or OR where R is Cl 3 alkyl. Preferably
the reaction is performed at low temperatures of from -78C
to +10C, preferably -50 to -20C, under anhydrous condi-
tions in a solvent selected from methylene chloride,chloroform, tetrahydrofuran or toluene. Preferably the
bromoacetoacetyl bromide or the chloroacetoacetyl chloride
are prepared in situ by reacting diketine 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 hydro-
20 chloride. Preferably an equimolar ratio of reagents isused, although it is possible to use an excess of one or the
other.
It will be appreciated thAt the compounds of
structures (1~ to (5) have at least one chiral carbon atom
and, for example, when Prot or R is tetrahydropyranyl,
~-compounds of structures (3), (4) and (5) have two chiral
carbon atoms. This invention includes racemic mixtures and
to the resolved optical isomers and diasteroisomeric
mixtures of the compounds described and claimed.
'`~ ~
.~ ;
, :
~ : .. : : . . :
~6~3472
., .
The examples that follow illustrate the invention
but do not limit it.
Example 1
Methyl 2~(4-bromo-3-oxobutanamido)acetate
!
4.8 ml Diketene are dissolved in 30 ml methylene
chloride. The solution is cooled to -50C and a solution
of 3.24 ml bromine dissolved in 20 ml methylene chloride
is added dropwise over 30 min. The mixture is left
stirring for 2h at ambient temperature. At -40 is
- added, all at once, an intimate mixture of 20g finely
ground Na2CO3 and 7.99 glycine methyl ester
hydrochloride. Stirring is continued for 90 min,
allowing ~he mixture to return to ambient temperature.
The salt is filtered quickly, the filtrate is
~ concentrated in vacuo at ambient temperature The
resi~ual oil is purified by chromatography on silica,
eluting with ethyl acetate. The desired compound is
; 20 obtained as a white powder, m.p. 76-77C.
Example 2
Methyl 2-(4-bromo-3-hydroxybutanamido~acetate
l.Sg Methyl 2-(4~bromo-3-oxobutanamido)acetate is
dissolved in 15 rnl dimethoxyethane. The solution is
cooled to 0C and 60mg NaBH4 is added. After 5 minj
the solvent is evaporated in vacuo and the residue is
chromatographed on silica, eluting with ethyl acetate.
0 The title compound is obtained as a white powder, m.p.
60-61C.
, .
~` :
: ~ :
~6~472
Example 3
Methyl 2-(4-bromo-3-hyd~oxybutanamido)acetate
0.76 ml Diketene is dissolved in 3.5 ml methylene
S chloride. The solution is cooled to -30C and a solution
of 0.5 ml bromine in 3.5 ml methylene chloride is added
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 ret~rn to ambient with
continued stirring. After filtering, and evaporating in
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 purifie~ by
chromatography on silica, eluting with ethyl acetate.
~` ` The title compound is obtained as a white powder, m.p.
60-61C.
.
`~ 25 Example 4
.. : , :
Ethyl 2-(4-bromo-3-hydroxybutanamido)acetate
. j .
Proceed as described above, using 1.4g glycine ethyl
ester hydrochloride. A white powder is obtained, m.p.
30 59-61~C.
... .
;
~ ,
: ~ : - ' : ~ ''
~2~47
- Example 5
Methyl 2-(4-bromo-3-(tetrahyd~opyran-2-yloxy)butanamido)-
acetate
. .
To a solution of 300 mg methyl
2-(4-bromo-3-hydroxybutanamido)acetate in S0 ml methylene
chloride a~e added 30 mg pyridinium p-toluenesulphonate
and 1 ml dihydropyran. After stirring at ambient
temperature for 20h, the solvent is evaporated in vacuo
and the residu~ chromatographed on silica, eluting with
ether. A colourless oil is obtained (92%), Rf 0.33
(silloa gel plates, thickness 0.25, eluent diethyl ether).
Example S
Ethyl 2-(4-bromo-3-(tetrahydropyran-2-yloxy)bu~anamido?-
.
acetate
To a solution of 1 g ethyl2-(4-bromo-3-hydroxybutanamido)acetate in 30 ml methylene
chloride are added 100 mg pyridinium p-toluenesulphonate
and 1 ml dihydropyran. Stirring is contlnued for 3h at
ambient temperature, the solvent is evaporated in vacuo
and the residue chromatographed on silica, eluting with
ether. A pale straw-coloured oil is obtained ~91%),
~f. o.5 (silica gel ~lates, th~ckness 0.25 mm eluent ethyl
acetate).
~ . ' :
.; , , :-: .. . :: ~': : ' . :
~LX~8~2
Example 7
Ethyl 2-(4-chloro-3-oxobutanamido)acetate
5.08 ml diketene are dissolved in 40 ml CH2C12. The
S solution is cooled to -300C and chlorine is passed
through it for lh. The solution is then added rapidly
dropwise to a solution of glycine ethyl ester prepared by
suspending 9.30g glycine ethyl ester hydrochloride in
160 ml methylene chloride containing 18.6 ml
triethylamine, the mixture is stirred for 30 min and
cooled to -30C. Stixring is cont;nued for 30 min, the
solvent is evaporated in va~uo, and the residue taken up
in ethyl acetate. The salts are filtered- off, the
solvent is 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
- ` Ethyl 2-~4-chloro-3-hydrox~ tanamido1acetate
`~ 5.08 ml diketene are dissolved in 40 ml CH~C12.
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
CH~Cl~ prepared as in the preceding example. After
stirring for 30 min, the solvent is evaporated in vacuo,
the residue is taken up in ethyl acetate and the ~salts
~`~ filtered off . ~he solvent i8 evaporated9 tho oily re6idue i8
dis~ol~ed in 150 ml ethanol, cooled in ice, and 1.26 g NaB~4
3 i8 addcd in portions. After 30 m~n a ~ew drops of dilute
hydrochloric acid ~rc added, the gcl~nt i8
~,
., .
,`. ' . ~
: ` ~ '' ' - :.:
.-.
- , . , ~ ~ '" .' : '
84~X
evaporated, the residue is taken up in ethyl acetate,
washed with brine and dried. The solvent is evaporated
and the residue chromatographed on silica, eluting With
ethyl acetate. The compound is obtained as a white
powder, m.p. 53-4C.
Example 9
Ethyl 2-(4-chloro-3-(tetrahYdropYran-2-Yloxy)butanamido)-
acetate
lg Ethyl 2-(4-chloro-3-hydroxybutanamido)acetate is
dissolved in 10 ml CH2C12. 100 mg pyridine
p-toluenesulphonate and 0~5 ml dihydropyran are added.
The mixtu~e is stirred for 7h. The solvent is evaporated
`~ 15 and the residue chromatographed, eluting wi~h ethyl
acetate. A colourless oil is obtained, Rf 0.5 (silica
gel plates, thickness 0.25 mm, eluent ethyl acetate).
Example 10
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 su~pension is
added a solution of 2.5 g ethyl
:~ 25 2- (4-bromo-3-(tetrahydropyran-2-yloxy]butanamido)acetate
in 30 ml tetrahydrofuran. 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 hy
ch~omatography on silica, eluting with ethyl acetate. A
colourless oil is obtained, Rf 0.32 (silica gel plates,
~ thickness t).25mm, eluent ethyl acetate).
: : .
:
: ' .
- :. ; .
; .. . ..
`: ~2~847~
11
; Example 11
Ethyl 2-oxo-4-(tetrahYdropyran-2-yl)-1-pyrrolidineacetate . , .
Proceeding as described previously, and using 2.249
5 ethyl 2-(4-chloro-3-(tetrahydropyran-2-yloxy)butanamido)-
acetate, a colourless oil is obtained, Rf 0.32 ~silica
gel plat~s,thickness 0.25 mm, eluent ethyl acetate).
t
Example 12
10 ~thyl 4-hYdroxY-2-oxo-1-pYrrolidineace~ate
A solution of 0.16 9 ethyl
2-oxo-4-~tetrahydropyran-2-yl~-1-pyrrolidineacetate is
dissolved in 5 ml ethanol containing 16 mg pyridinium .
15 p-toluenesulphonate.'~ho ~i~t~r~-is heatod 4 h ~t 35~, the 3
. othsnol i8 evapor~to~ and *he residue chroma~ographed on ~ ~-
silica. The compound iB obtsined as a oolourle~s oil (62%). ~ :
Example 13
4-HydroxY-2-oxo-l-pyrrolidineacetanlide '
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
25 140 ml acetone and the mixtuee is stirred at ambient
temperature until the gum that precipitates solidifies
~:~ into white crystals. On filtering ln vacuo and drying,
4-hydroxy-2-oxo-1-pyrrolidineacetamide is obtained, m.p.
160-162C.
~ .
j .
.
