Note: Descriptions are shown in the official language in which they were submitted.
gl2S6B83
THIS APPLICATION IS A DIVISION OF CANADIAN PATENT APPLICA-
-
TION NO. 474,316
The present invention relates to in~ermediates and to
their acid addition salts useful in a pxocess for
preparing pyrrolidinone derivatiYes, more specifically
2-oxo-1-pyrrolidineacetamide deriYatives, which may also
be called l-carbamoyl~ethyl-2-pyrrolidinon~ derivatives.
Ie is known that 4-su~stituted deriYa~ives of
2-oxo-1-pyrrolidineacetamide are valued psychotropic
agents that, in animals and man, restore cognitive
function that has been damaged as a result of various
lo pathologies~ These drugs are described for example in
Pharm.Res.Commun. 16,67(1984) by Banfi et al, or in Drug
Development ~es 2, 447 ~1982) by TM Itil et al.
~nown processes for preparing the abo~e pyrrolidinone
1~ derivatives which are described in,G~ 1588074 and 1588075
start from gamma-amino-beta-hydroxybutyric acid, and
involve several steps such as protection with a
silylating agent~ alkylation, cyclisation and final
aminolysis to give the carbamoylmethyl group attached to
the heterocyclic nitrogen atom. This kind of knoun
process involves the use of particular anhydrous solvents
and of bases or of acid-accepting compounds, which
require special equipment and precautions in order to
maintain an anhydrous environment.
'~
-- 2
The main ai~ of the invention claimed in parent
application no. 474,316 is to provide a process for the
preparation of 2-oxo-1-pyrrolidine-acetamides which does not
require the use of anhydrous conditions, nor, therefore, the
equipment and precautions that would otherwise be necessary.
A further aim of the invention claimed in that application
is to provide a process that makes use of cheap and readily
available starting materials~ Another aim of the invention
claimed in the parent application is to provide a process
that permits the desired 2-oxo-1-pyrrolidine-acetamide
derivatives to ~e obtained with good selectivity.
In meeting these and other aims, the parent
invention provides a process for preparing a pyrrolidinone
derivative of general structure (1):5
no 7
~ tl)
Cl~2coNl~2
in which R is hydrogen, straight or branched alkyl of 1 to 4
carbon atoms, or acyl containing 1 to 10 carbon atoms,
comprising: -N--deprotecting a compound of general structure
25 t2):
R30
\ Ct~ - C~ -C02X
CH ~
R ~ N ~H2 t2)
~ - HN - C0
~254~ 33
-- 3 --
- where R1 is hydrogen and R2 is benzyl or R1 and R can
together form a group CR4R , where ~4 and R are
independently hydrogen, alkyl containing 1 to 4 carbon
atoms, phenyl or together are 1,4-butylene or 1,5~pentylene
(-(CH2)5~-; R3 is hydrogen or straight or b:ranched alkyl of
1 to 4 carbon atoms; and X is straight o:r branched alkyl
containing 1 to 10 carbon atoms; to give a compound of
general structure ~3):
R ~
CH--CH2--COzX
~ Cl~2 (3)
IS2N--CO
which is subjected to an intramolecular cyclisation
reaction; and optionally when R3 is hydrogen the product is
converted into a compound in which R is acyl or alkyl.
The present invention is directed towards the
intermediates of structures (2) and (3).
The present invention therefore provides a
compound of general structure (2/3):
R~
f~ C~2 C~2X
~ N - C~z (2/3)
A/
B - HN - CO
and acid addition salts thereof, in which R3 is hydrogen or
-- 4 --
straight or branched alkyl of 1 to 4 carbon atoms and X is
straight or branched alkyl containing 1 to 10 carbon atoms;
A and B are either both hydrogen or A is R and B is R
where R is hydrogen and R2 is benzyl or R and R can
together form a group = CR4R5, where R and R5 are
independently hydrogen, alkyl containing 1 to 4 carbon
atoms, phenyl or together are 1,4-butylene or 1,5-pentylene
( (CH2)5)
More particularly the present invention provides a
compound of structure (3):
R3 ~
Cll - Cll C02X
I
lS ~ I!N ~ 1ll2 ( )
112N--CO
and acid addition salts thereof, in which R3 is hydrogen or
straight or branched alkyl of 1 to 4 carbon atoms and X is
straight or branched alkyl containing 1 to 10 carbon atoms,
R is preferably hydrogen.
The present invention also provides a compound of
structure (2):
R
f,~ C~lz COzX
~ 2 (2)
R . HN CO
~;~5~ 33
- 4a -
wherein:
R is hydrogen and R2 is benzyl or R and R2 can together
form a group CR4R5, where R4 and R5 are independently
hydrogen, alkyl containing 1 to 4 carbon atoms, phenyl or
together are 1,4-butylene or 1,S-pentylene (-~CH2)`5)-;
R is hydrogen or straight or branched alkyl of 1 to 4
carbon atoms; and X is straight or branched alkyl containing
1 to 10 carbon atoms.
In compound (2) R1 and R together preferably form
a 2-methyl-propan-l,1-diyl group (CHCH(CH3)21, and R3 is
preferably hydrogen.
In the process for which the compounds of the
present invention are useful intermediates, and when R2 is
benzyl, the compound of structure(2) can be deprotected via
catalytic hydrogenation using for instance a 5% Pd/C
/
9~ 2S~33
s
catal~st at tem~eratures between n~ and 40C an~ at
pressures between ambient and ~0 Torr. The reaction is
performed in a s~itable s~lvent, e.g. alcoh~l, an
aliphatic or aromatic hydrocarb~n, water, or mixture of
S these. Preferably the solvent is a mixture o~ formic
acid and methanol. The subsequent cyclisation takes
place at 0 to 120~C, preferably 60 to 80C, with or
without solvent. The svlvent, if used, is selected from
those mentioned above f~r the hydrogenation, or is
acetonitrile.
When Rl and R together form a group ~C \
R4 R
deprotection and intramolecular cyclisation can be
15 efected by heating with water at temperatures between
90~ and 160C, preferably betwee~ 100 and 130C. It is
conYenient to use water or mixtures of solvents and water.
PreEerably the solvent is a 95% mixture of an ~or~anic
solvent with water (5~). As organic co-solvents may be `
used dimethylformamide (DMF3 , dimethylsulphoxide (DMSO),
dimethylaceeamide ~MA), acetonitrile and alcohols such as
ethanol9 etc. Preferably the reaction is carried out in
the presence of a carboxylic acid, e.g. acetic acid or
benzoic acid. Although catalytic quantities of carboxy1ic
25 acids are effective preferably about one molar equivalent
of a carboxylic acid is used.
: The co~pound of structure (1) in which ~ is hydrogen
: is oxiracetam and is a particularly useful p~oduct of this
3 invention~
The compounds of structure ~1~ in which R is
hydrogen can be converted into a compound in which R is
acyl or alky~ by reaction with an acyl halide (prefera~ly
35 a chloride) or acid anhydride using conventional
~Z5~ 3
procedures. or b~ using an alkyl halide (preferably a
bromide or iodidel or sulphat~ using conventional
procedures.
S The c~mpounds prepared by ~e process of the parent
invention have a centre of asymmetry at the carbon ato~
in the 4-position, where the OR substituent is
attached . hence it is possible to obtain them as separate
enantiomers or as a racemic mixture thereo~.
If desired the deprotected intermediates of structure
: (3) ~ay be isolated in the form of a salt with an acid
selected from organic or inorganic acids such as
hydrochloric, hydrobromic, sulphuric, p-toluenesulphonic,
15 acetic, oxalic, maleic, malic acids etc. A preferred
intermediate of structure (2) is that wherein R3 is
hydrogen and Rl and R2 together form a
2-methyl-propan-1,1-diyl group, which may be conveniently
isolated as an oxalate or maleate salt.
.
The intermediates of structure (2) can be prepared
by reacting
CH2Co2x ~ H~ -CH
R HN - C0
-~ 30 an al~yl 3,4-epoxybutanoate of the structure (4) where
X is alkyl of 1-10 car~on atoms, with a glycineamide
derivative of structure (5) (in which Rl and R2 are
as defined in structure (~)) to form a compound of
structure (Z) in which R is hydrogen; and optionally
reacting the product with an alkyl halide ~preferably a
~2~ 3
bromide or iollide~, dialkyl sulphate, acyl halille
(preferably a chloride) or acid anhydride to form a
compound of structure (2) in ~hich R~ is other than
hydrogen .
The condensation reaction be~ween (4) and (S) may
take plac~ without the use of sol~ents or in the presence
of organic solvenes, water or mixtures of these in
proportions of from 1:5 to ZO:l, preferable from 1:1 to
1~3 of organic solYent and water. As organic solvent may
be used a wide variety of inert solvents e.g
acetonitri}e, alcohols such as isopropanol, acetone etc.
The condensation is performed at a temperature of
lS 20 ~o 120C, preferably 70-100C. In the condensation
phase the two reagents may be used in stoichiometric
proporéions~ or an excess of one of them may be used,
preferably a ratio of from 1:1 to 1:1.1 of the amine
deriYati~e t5) and the epoxyester (4).
The intermediate of structure (23 in which R3 is
hydrogen that results from the condensation may be
isolated and purified, or ~ay be converted at once into
compound I, by deprotection and cyclisation. These
reac~ions may be carried out in the same mixture as the
condensation reaction, in the absence of solvent, with
the same solvent, or by replacing the initial solvent
with one or more high-boiling solvents.
The alkyl 3,4-epoxybutanoates (4) can be prepared by
known methods described in the literature, for instance
from alkyl 3,4-butenoates by epoxidation with peroxide
compounds such as organic and inorganic peracids,
hydrogen peroxide etc, (e~g. by the general procedure of
- 35 ~. ~enturello et al. J.Org.Che~. 48 ~831(19~3) or by
dehy(lrohaloRenation of 3-halo-4-hvdroxvbutyra~es (cf R
Rambaud and S T)ucher, P~ull.Soc.Chim.Fr., 466 (1966)).
The imidazolidinones of structure (S) in which Rl
and R together form a group ~ C may be prepared
R4 \ R~
from glycineamide a~d suitable carbonyl compounds~ or
: from alkyl alkylidenaminoacetates and ammonia, by ~ethods
described in the literature, e.g A.C. Davis and A.L.
Levy, J.Chem.Soc,, 3479 (1951); P.G. Wiering and ~.
Steinberg, Rec.Trav.Chim. Pays-Bas lll, 284 (1971~.
The invention is illustrated by the following Preparations
and Examples: -
15Preparat iOIl 1
_-Methylpropyl-3,4-epoxybutanoate
Sodium tungstate dihydrate ~0.85?g , 2.5 mmol), 8S%
phosphoric acid (0.850 ml, 5 mmol) 36.3S hydrogen
peroxide (5.6 ~1, 60 mmol) were dissolved in 20 Ml o~
water and the pH ~as adjusted to 1.6 by 10% sulphuric
acid. The solution was heated to 70C, and under
vigorous stirring a solution of 2-methylpropyl
3-butenoate (7.1 g, 50 mmol), trimethylcaprylammoniu~
chloride (0.41 g) in 1,2-dichloroethane ~15 ml) was
added. After 6 hours the mixture was cooled, then the
layers were separated. The aqueous phase was washed
with 30 ml of dichloroethane. Organic layers were
collected, washed with 2 x 40 ml of saturated solution
of sodium sulphite, dried and distilled. The title
co~pound was obtained as a colourless vil, b.p.
104-108 30 mmHg,
~2 5~ ~3
rre~arati~n 2
(a) A stream oF hydrogen uas bubbled into a solution o~
2-methylpropyl-4-lN-(aminocarb~nylmethyl) ben2ylamino]-
3-hydroxybutanoate (18) in ethanol (30 ~1) containing
Pd/C 5% (100 mg) for 1 hr. The catalyst was filtered and
oxalic acid (O. 2B 8) was added, The resulting solution
was chilled overnight and th~ precipitate was collected
to give ~00 mB Of 2-meth~lpropyl
4-(aminocarbonylmethylamino~-3- hydroxybutanoate o%alate.
m.p. 145C dec.
(b) In the sa~c way, from ~Q of 2-methylpropyl 4-1N-
(a~inocarbonylmet~l)benzyla~inol-3 hydroxybut~noate (~B)
lS ~nd malclc ~cid t2.168) 210 ~g of 2-~cth~ Prl-4-
aminocarbonylmethy~amino)-3- hydroxybutanoate maleate
(~m.p. 109C dec.) were obtained.
:~; . Example 1
: 20
1.3g o~ 1,4-diazaspirol4,~]dec~n-2-one ~(5); R4
S = -(CH2~5-) (8.4 mmoles) are heated and stirred
with magnetic stirring, with 1. Sg 2-methylpropyl
3,4-epoxybutanoate ~(4)~ X = isobutyl) (9.S mmoles) up to
110 (external temperature~ for 24h. The mixture is
cooled, and the dark mass o~tained is washed with 10 ml
boiling ethyl acetate. This is decanted, and the solid
obtained is crystallised from methanol to give oxiracetam
as a crystalline white powder, m.p. 167-70C.
3o
Ex ampl e 2
lg o~ ~,2-dimethyl-4-imidazolidinone ((S);
R4~R5-CH3) (8-76 mmoles) is dissol~ed in 5 ml
3~ acetonitr~le. lg 2~methylpropyl 3,4-epoxybu~anoate ((4);
1~
X ~ isobutyl ) ( 6. 32 mmoles) is ah~1ed and th~ inixture is
boiled for 30h uith stirring. The mixture is cooled, the
solvent is decanted o~, the resulting ~ark solid mass is
taken up in ethanol, and the solid oxiracetam obtained is
filtere~ off~ m.p. 167-70C.
Example 3
D.650~ ~,2-dime~hyl-4-imidazolidinone (~S);
R4~RS-CH3) ~5.7 mmoles) is dissolved in 5 ml
isopropanol. lg 2-~ethylpropyl 3,4-epoxybutanoate ((4);
X ~ isobutyl) (6.32 mmoles) is added. The mixture is
boiled for 9h. A further lg of epoxyester is added and
boiling is continued for a further 9h~ A~ter cooling,
the solvènt is decanted and the dark mass obtained is
taken up in ethanol The solid obtained is ~iltered. to
give oxiracetam, m.p. 167-70C.
~xample 4
lg of ~,2-dimethyl-4-i~id~zolidinone ((5);
R4~5YCH3~ (~.76 ~moles) are heated at 16SC
(external temperature3 for lh 30min with Zg
2-methylprQpyl 3,4-epoxybutanoate ((4); X = isobutyl)
(12.64 ~moles). 0.17 ml of water and 5 ml ethanol are
added, and boiling is continued for a further 2h. The
mixture is cooled and filtered. Oxiracetam is obtained
as a ~hite crystalline pow~er, m.p. 167-70C.
Example S
. lg o~ 2,2-di~ethyl-4-i~idazolidinone (~S);
R4=R5=CH3) (8.70 mmoles) is dissolved in I ml
water. 1.5~ 2-methylpropyl 3,4-epoxybutanoate ~(4~;
X = isobutyl) (9:48 mmoles) are added and the mixture is
~:5~3
1 1
heated at 50~ for 11~ ~ith ~tirrin~ h~ a ma~netic
stirrer. H~atin~ is then continued at the boilin~ point
for a further llh. The mixture is conled, 10 ml acetone
is added, stirring is perform~d ~or 30 min and the mixture
is filtered: The product obtained is crystallised from
methanol .to giYe oxiracetam of ~.p. lb7-70~C as a ~hite
crystalline po~der.
xam~ 6
0 58 2,2-dimethyl-4-imidazolidinone ((S);
R4~R5~CH~) (4.38 mmoles) are heated at 115C
(external temperature) for 12h with stirring by a
magnetic stirrer~ with 0.578 ethyl 3,4-epoxybutanoate
15 ((4~; X-CzH5) t4.38 mmoles). The mixture is cooled,
taken up with methanol and filtered. Oxiracetam is
obtaine~, m.p. 167-70C.
: E~ample 7
~: 20
lg 2,2-dimethyl-4-i~idazolidinone ~4~;
R4~R5~CH3) ~8.76 mmoles) is dissolved in 1 ml
wa~er, 2g 2-~ethylpropyl 3,4-epoxybutanoate is added and
stirring is continued at ambient temperature for 10 days.
Z5 The oil ohtained is chromatographed on silica, eluting
with 1:1 acetone/methanol. The main Çraction is
collected, dehydrated using MgS04, and evaporated. An
oil is obtained, which solidifies on rubbing, is taken up
in hexane and filtered. 1.8g 2-methylpropyl
2,2-di~ethyl-4-oxo~ idazolidine-B-hydroxybutyrate is
obtained ~(2); R3~H, R4-R5sCH3, X ~ isobutyl~, ~ p,
76-8C, a white solid ~75 5S). This compound is dissolved
in 3 ~1 acetonitrile and 1 ml water, and boiled for 72h.
After evaporating, the product is taken up with ethanol
and filtered, oxiracetam is obtained as a ~hite
crystalline powder, m.p. 167-70C.
~5~3
1 2
Example 8
6.52g 2-(1-methylethyl)-4-imidazolidinone
hydrochloride (~5); R4-H, Q5~isopropyl) (0.04 ~oles)
S 5 are dissolved in 40ml water and treated with 2.8g
potassium carbonate (O.OZ ~ole). 7g 2-methylpropyl
3,4-epoxrbutanoate are added ~(4)-, X ~ isobutyl) (0.044
mole~ and 25 ml acetone. The mixture is heated at bOC
for 48h with stirring. The mixture is reduced to a small
1 10 volume, the solid ls filtered and ~ashed with ether.
: 3 Sg of a white solid, m.p. 1}5-40C is obtained. The
liquor ~rom which this solid was separated is eYaporated
to dryness and chromatographed on silica, eluting ~ith
8:2 ethylacetate/methanol. The main ~ractions are
1 15 collected and evaporated to give a further ~.9g compound
of m.p. 135-40C, giving a total of 6.4g 2-methylpropyl
2-(1-methylethyl)-4-oxo-1-i~idazolidine-B-hydroxybutanoate
~(2); R3=R4=H, R5=isopropyl, X=isobutyl). lg of
this co~pound ~3.5 mmoles~ is heated to boiling for 8h in
6 ~1 dimethyl sulfoxide ~ 2 ml ~ater. After evaporation,
the residue is taken up with acetone, filtered, dried in
vacuo and crystallised ~rom methanol~ 0.32g Vxiraceta~
is obtained as a white crystalline powder, m.p. 167-7aC
(yield 57.8S).
~xampl~ 9
5.8g of 2-(l-methylethyl~-4 imidazolidinone
hydrochloride ((5); R4=H, R5=isopopyl3 ~0.0~5 moles)
3 30 are shaken in 10 ml water and treated with ?,4g po~assium
carbonate (0~0174 moles). 4.5g ethyl 3,4-epoxybutanoate
and 6 ml acetone are added, and stirring is main~ained
for 4Sh at 70C. After evaporation, the residue is
chromatographed on silica, eluting with 8:2 ethyl
3 35 acetate~methanol. The main fractions are collected and
~ 3
13
e~a~orate~ The oil that ~emains is tak~n up with eth~l
acetatc~ ~fter being left to stand overni~ht the white
compound obtained is filtered : 1.38 ethyl
2-(1-methylethyl)-4-oxo-1-imidazolidine-B-hydroxybutanoa~e
m.p. 118-122C. 0.95g of this compound (3.7 mmoles~ are
heated to boiling for 15h in 4 ml DMF and 1 ml water.
After evaporation in vacuo. the residue is taken up with
methanol, and the solution is ~iltered. 0.378 oxiracetam
is obtained as a white crystalline powder, ~.p. 167-70C
(63.2%).
E% ampl e 10
l9g Z-(l-Methylethyl)imidazolidinone (~S); R4=H,
R5=isopropyl) tO.15 moles) are dissolYed in lOOml water
and lSOml acetone. 2-Methylpropyl-3,4-epoxybutanoate
(0.15 moles3 are added and the mixture is heated and
stirred for 48h at 70C. The acetone is evaporated in
; vacuo and 100 ml DMF are added, followed by boiling for
21h. ~he mixture is reduced to a small volume in vacuo,
the residue is taken up with 40ml water and washed with
2x40 ml methylene chloride. The aqueous phase is
evaporated to dryness and redissolved in 15 ml methanol.
This is left to stand for 3h at 0C, filtered and dried
- 25 to give oxiracetam as a white crystalline powder, m.p.
167-70C.
Example 11
12g 2-~1-methylethyl)-4-imidazolidinone
hydrochloride ((5); R4=H, R5=isopropyl~ (0.073 moles)
are shaken ~ith 20 ml water and treated with Sg potassium
carbonate (0.036 moles). 8.5g methyl 3,4-epoxybutanoate
(0.073 moles~ and 12 ml acetone are added. The mixture
is stirred for 45h at 70C. After evaporating, the
14
resi(lue is chromatoRraphed on si~ica, elu~in~ h P.:~
ethyl acetate/methanol. The main fractions are com~in~d
and evaporated~ Z.5~ of a compound, m.p. 109-122C, are
obtained as a ~hite powder (14.4%). 2.0g of this
compound (0.008Z mole~ are heated to boiling for lSh with
8.8 ml DMF and 2.2 ml uater. After eYaporation in vacuo,
the residue is taken up with methanol~ and filtere~.
0-748 oxiracetam is obtained as a white crystalline
po~der, mOp. 167-70C (57.4~).
Example 12
A mixture of 0.7g Z-phenylimidazolidine-4-one and lg
Z-methylpropyl 3,4-epoxybutanoate are heated for 12h at
7~ (external temperature) in 2 ml water and 2 ml acetone.
After evaporating, the residue is taken up with ether and
the white solid obtained is filtered, and recryst~llised
from ethyl/acetate. . 2-Methylpropyl-2-phenyl-4-
oxoimidazolidine-~-hydroxybutanoate is obtained as a
white powder, m.p. 126-1~8C.
Examele 13
A solution of 0.65g 2-methylpropyl 2-phenyl-4-
oxoimidazolidine-~-hydroxybutanoate in l.S ml dilDethyl
sulfoxide and 0.5 ml water is heated at reflux for 16h.
After evaporating D the residue is chromatographed on
silica, eluting ~ith 7:3 ethyl acetate/methanol.
Oxiracetam is obtained as a white powder, m.p. 167-70C.
Ex~ple 14
A. 2-Methylpropyl 4-~N-~car~amoylmethyl)
~enzyla~inoJ-B-hydroxybutalloate {~2); R~=CHzC6H5,
35 R3=H, X ~ isopropyl3.
2~
A mi~ture of ben~vlaminoacetami-le ((5) Kl-H,
R2~C~l2~6~3s) (1~64~) and ~-methylpropyl
3,4-epoxybutanoat~ (1.588) are heated for ~oany hours a~
30C with magneti~ stirring. The reac~}on mixture is
5 taken up with li~roin and the resulting solid is
filtered. Recrystallisation is from ether/ligroin.
2.7g of title compound m.p. 99-100C are obtained.
B. 4-Hydro~y-2-oxo-1-pyrrolidineacetamide
~oxiracetam).
A solution of compound A (lg~ in Z5 ml ethanol
is hydrogenated at ambient temperature and pressure in the
presence of 100 mK 5% Pd/C. The catalyst is ~iltered off
lS and the solvent evaporated to give 0.728 2-methylpropyl
4-(carbamoylmethylamino)-3-hydroxybutanoate. This
compound is dissol~ed in situ in 10 ml acetonitrile and
- heated at reflux for 8h. After evaporation of the
solYent9 the residue is crystallised from ethanol.
0xiraceta~ is -obtained as a white cryseall-ine pouder
of m.p. 167-70C.
Example lS
25 1-Carbamoylmethyl-4-acetoxy-2-pyrrolidone,
A mixture of 5.53g oxiracetam and 44.3 ml acetyl
chloride is heated at reflux for lS min. After cooling,
the solvent is evaporated in vacuo and the oil remaining
is taken up in a little aqueous sodium bicarbonate, and
solid sodium bicarbonate is added wi~h stirring until
neutrality is achieved~ Most of the water present is
removed by treating with methyl iso~utyl ketone in vacuo,
the residue is taken up with ~ethylene chloride, dried
with sodium sulphate and eYaporated in vacuo. The ~il
- 16 -
remaining is triturated in isopropyl alcohol/diethyl ether
and recrystallised from 20:80 isopropyl alcohol/isopropyl
ether to give l-carbamoylmethyl-4-acetoxy-2-pyrrolidone
which when purified by chro~atography melts at 84-86 C.
EXAMPLE 16
4-Hydroxy-2-oxo-1-pyrrolidineacetamide (oxiracetam).
A solution of 2-methylpropyl 2-(1-methylethyl)-4-
oxoimidazolidine-~-hydroxybutanoate (15 g, 52.4 mmol),
benzoic acid (6.4 g, 52.4 mmol) and water (3.75 ml,
208 mmol) in n-pentanol (90 ml) was refluxed under nitrogen
for 6 hr. After cooling the mixture was extracted twice
with water (35 ml). The aqueous extracts were evaporated
to dryness and the residue was crystallized from methanol to
give 5.15 g (62.1%) of the title compound, m.p. 167-70 C.
The description above illustrates how the process
claimed in the parent application achieves its stated aims,
permitting the use, as starting material of an easily and
cheaply available glycinamide derivative, and allowing the
use of aqueous solvents without the need to ensure anhydrous
conditions.
This process can be worked with good selectivity
for the desired compound and little formation of by-
products, thanks to the use of the starting amine
derivatised as a secondary amine.
