CA1268472A - Intermediates for the preparation of pyrrolidine derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE:

A process for preparing compounds (1) (1) where Y is NR1R2 or OR, R1 and R2 are hydrogen or C1-3 alkyl, and R is C1-3 alkyl, comprises protecting the hydroxy group of a compound (2)

Description

~6~47~

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 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.
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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~

; 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 .

.

Claims (10)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of a compound of structure (5):
(5) in which X is chloro or bromo, Y is NR1R2 or OR where R1 and R2, which can be the same or different, are hydrogen or C1-3 alkyl and R is C1-3 alkyl, and R3 is hydrogen or a hydroxy-protecting group which is stable under basic conditions and removeable under acidic conditions, comprising reducing a compound of structure (6):
(6) in which X and Y are as defined above, and if desired, 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.

2. A process according to claim 1, wherein R3 is hydrogen or tetrahydropyranyl, and Y is methoxy or ethoxy.

3. A process according to claim 2, wherein (i) Y is methoxy or ethoxy, X is bromo and R3 is hydrogen; or (ii) Y is methoxy or ethoxy, X is bromo and R3 is tetrahydropyran-2-yl; or (iii) Y is ethoxy, X is chloro and R3 is hydrogen; or (iv) Y is ethoxy, X is chloro and R3 is tetrahydropyran-2-yl.

4. A process according to claim 1, carried out in the presence of a hydride.

5. A process according to claim 4, wherein the hydride is sodium borohydride.

6. A process according to claim 1, carried out at a temperature in the range from -10° to 30°C.

7. A process according to claim 1, carried out in a solvent selected from: dimethoxyethane, tetrahydro-furan, ethyl ether, 2-methoxyethanol, ethanol, methanol, isopropanol and water.

8. A compound of structure (5) (5) in which X is chloro or bromo, Y is NR1R2 or OR where R1 and R2, which can be the same or different, are hydro-gen or C1-3 alkyl and R is C1-3 alkyl, and R3 is hydrogen or a hydroxy-protecting group which is stable under basic conditions and removeable under acidic conditions.

9. A compound according to claim 8 in which R3 is hydrogen or tetrahydropyranyl, and Y is methoxy or ethoxy.

10. A compound according to claim 9 selected respectively from:

(i) methyl or ethyl 2-(4-bromo-3-hydroxybutanamido)-acetate (ii) methyl or ethyl 2-(4-bromo- 3-(tetrahydropyran-2-yloxy)butanamido)acetate (iii) ethyl 2-(4-chloro-3-hydroxybutanamido)acetate (iv) ethyl 2-(4-chloro-3-(tetrahydropyran-2-yloxy)-butanamido) acetate.