CA1255326A - 2-(4-halo-3-oxobutanamido)acetic acid derivatives as intermediates in 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

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):

110~
: ( 1 ) \
CHzCOY

.' ''' '` ~ .
. . .
:' , , : ~; . .
,~ .

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

(4 . ' ' , , .

. .

..

~5;~

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.

'.~,, .

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~

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 :: .
. .
.

:: : :
:: :
:. , ' :
., ~ .
... . , - . ~ :.. ::.... .

- 5a -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.

.~ .
"' ~
'" ~; ' '~ :

53~

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.

: : ' ,:
. ,~
. ., .~, , .. .

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 ., , i;
. ~

:`~
-~ :

~5~

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).

~' : .. , , : ~ . ' . .
.
':: `' ~. :- .-:, ~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.
.

' ,::
:~ ' .: .

Claims (10)

1. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
   
   l. A process for the preparation of a compound of structure (6):
   
   (6) in which X is chloro or bromo and 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, comprising: reacting gamma-bromoacetoacetyl bromide or gamma-chloro-acetoacetyl chloride with a glycine derivative of structure (7):
   
   NH2CH2COY (7) where Y is NR1R2 or OR where R is C1-3 alkyl, at a temperature of from -78 to 10° C under anhydrous conditions.
2. 2. A process according to claim 1, carried out at a temperature in the range from -50° C to -20° C.
3. 3. A process according to claim 1, wherein the bromoacetoacetyl bromide or the chloroacetoacetyl chloride are prepared in situ by reacting diketene respectively with bromine or chlorine.
4. 4. A process according to claim 3, wherein the halogen added to the diketene is dissolved in a solvent, either as a solution or by bubbling it as a gas, and then the glycine derivative of structure (7) is added in the presence of an organic or inorganic base.
5. 5. A process according to claim 1, carried out in a solvent selected from methylene chloride, chloroform, tetrahydrofuran or toluene.
6. 6. A process according to claim 2 or 3, carried out in toluene as solvent.
7. 7. A process according to claim 1, wherein Y is OR, said glycine derivative being liberated in situ from a salt thereof.
8. 8. A process according to claim 7, wherein said salt is the hydrochloride.
9. 9. A process according to claim 1, wherein an equimolar ratio of reagents is used.
10. 10. A compound of structure (6):
    
    (6) in which X is chloro or bromo and 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.