PROCESS FOR PRODUCING CHIRAL GLYCINE DERIVATIVES

PROCEDE POUR PRODUIRE DES DERIVES CHIRAUX DE LA GLYCINE

English Abstract

ABSTRACT OF THE DISCLOSURE
By a simple enantiomer separation of 1,3-imidazolin-
4-ones produced from glycine esters, primary alkyl amines and
pivaldehyde and having the general formula
<IMG> (II),
wherein R represents a straight-chain or branched C1 to C4 -
alkyl group with a chiral acid, chiral glycine derivatives
having the general formula
<IMG> (I),
wherein R is as above, * represents an asymmetry centre and R1
represents a phenyl or benzyl group, a phenoyl-oxy or benzyl-
oxy group, preferably the phenyl group or a phenyl group mono-
or tri-substituted in any ring portion by a C1 to C4-alkyl or
alkoxy group are readily accessible. On diastereo-selective
.alpha.-alkylation they result in branched and non-branched pro-
teinogenic or non-proteinogenic (R)- and (S)-amino acids.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for producing enantiomer-pure (R)- and
(S)-1,3-imidazolidin-4-ones having the general formula
<IMG> (I),
wherein * represents an asymmetry centre, R represents a
straight-chain C1 to C4-alkyl group and R1 a phenyl or benzyl
group, a phenyl-oxy or benzyl-oxy group or a phenyl group
mono- or tri-substituted in any ring position by a C1 to C4-
alkyl or alkoxy group, in which a racemic 1,3-imidazolidin-4-
one having the general formula
<IMG> (II),
wherein R has the meaning defined above, is converted into a
diastereomeric salt pair by reaction with a chiral acid, said
salt pair is fractionated and crystallized, (R)-II and (S)-II
are isolated on dividing this salt pair and these compounds
are reacted with an acid halide having the general formula
<IMG> (IIIa),
wherein Hal is chlorine or bromine or with an anhydride having
the general formula
<IMG> (IIIb),
wherein R1 has the meaning defined above.

2. A process according to claim 1, in which (R,S)-
2-(t-butyl)-3-methyl-1,3-imidazolidin-4-one is used.
3. A process according to claim 1 or 2, in which
(R)- and (S)-mandelic acid is used as chiral acid.
4. A process according to claim 1 or 2, in which
(-)-diacetone-2-ketogulonic acid is used as chiral acid.
5. A process according to claim 1, in which the
chiral acid is selected from N-acetyl amino acids, Z-protected
amino acids, pyroglutamic acid, tartaric acid, malic acid,
camphor-10-sulphonic acid, dibenzoyl tartaric acid and deoxy
cholic acid.
6. A process according to claim 1, in which the
reaction with the chiral acid is effected at a temperature
from -30°C to 25°C in a solvent.
7. A process according to claim 6, in which the
solvent is an alcohol, a mixture of alcohol with water, a
acetic ester or a chlorinated hydrocarbon.
8. A process according to claim 7, in which the
chlorinated hydrocarbon solvent is methylene chloride or chlo-
roform.
9. A process according to claim 6, in which the
solvent is acetone.
10. A process according to claim 6, in which the
crystallization is effected in a chlorinated hydrocarbon and
reacting with an aqueous solution of caustic soda or potash.

Description

~Z9~733
The present invention relates to a process for pro-
ducing ~R)- and (S)- 1,3-imldazolidin-4-ones.
Heretofore, the chiral 1,3-imidazolidin-4-one having
the general formula I was accessible only by degradation reac-
tions of 1,3-imidazolidin-ones in the 5-position which had
been obtained by means by multistage syntheses starting from
L- or M-methionine and L- or O-benzyl serine (D) Seebach, D.D.
Miller, S. Muller and T Weber, Helv. Chim. Heta 68, 949
(1985).
The present invention provldes a process for produc-
ing compounds according to formula ~I) given hereinafter in
which inexpensive achiral starting products can be used.
The present invention thus provides a process for
producing (R)- and (S)- 1,3-imidazolidin-4-ones having the
general formula
Cl13 / N C~O
l-l3c-c-llc* 1 (1),
c~3 N_ C1l2
~ ~ R1
wherein * represents an asymmetry centre, R represents a
straight-chain or branched Cl to C4 alkyl group and Rl repre-
sents a phenyl or benzyl group, a phenyl-oxy or benzyl-oxy
group, preferably the phenyl group or a phenyl group mono- or
tri-substituted in any ring position by a Cl to C~-alkyl or
alkoxy group in which a racemic 1,3-imidazolidln-4-one having
the general formula
Cl13 ~N C~
113C-C-IIC 1 (11),
C113 \N ~C112
11
wherein R has the meaning defined above, ls converted by reac-
tion with a chiral acid having the general formula
'~ '

~L29~i733
*R2 _ COO~I (IV),
wherein *R2 represents a chiral radical into a diastereomeric
salt pair of, for exampl0, (S)- acid/(S)-II and (S)-acid/(R)-
II.
Fundamentally any compound known from the litera-
ture, such as N-acetyl amino acids, Z-protected amino acids,
pyroglutamic acid, tartaric acid, mallc acid, camphor-10-
sulphonic acid, dibenzoyl tartaric acid and deoxy cholic acid
can be used as chiral acids, but (R)- or (s)-mandelic acid and
(-)-diacetone-2-ketogluonic are preferred.
This is carried out at temperatures from -30C to
25C from solutions of compounds according to ~ormula (II) in
solvents, as for example, alcohols, particularly methanol or
ethanol, mixtures of these alcohols with water, acetic ester
or chlorinated hydrocarbons, particularly methylene chloride
or chloroform.
- Acetone is particularly suitable.
The solvent is always so selected as a function of
the compounds to be separated that the solubility differences
between the two salt pairs are large. ~or example, the salt
form (-)-diacetone-2-gluonic acid and (S)-II and the salt from
(R)-mandelic acid (R)-II in ethanol show the greatest tendency
to crystallize out relative to their antipodes.
On separating the two diastereomeric salt pairs by
fractional crystallization, which is followed by recrystal-
lization for purification, when required, the 1,3-imidazo-
lidin-4-ones (R)-II or (S)-II are obtained by reacting the
salts preferably suspended in a chlorinated hydrocarbon, par-
ticularly methylene chloride or chloroform, wlth an aqueous
solution of caustic soda or a caustic potash solution whose
amount is slightly above~that required stoichiometrically.
Subsequently the (R) and (S)-1,3-imidazolldin-~-ones
-- 2

1~6733
having the general formula (II) are reacted in a conventional
manner, without isolation, with a compound having the general
formula (IIIa)
R - C (IIIa),
\~l a ~
wherein Hal is chlorine or bromine or (IIIb)
C ) 20 ( I I I b),
wherein Rl has the meaning deflned above. in the presence of
trlethyl amine, pyridine or caustic soda or potash solution to
the (R)- and (S)-l,3-imidazolidin-~-ones having the general
formula (I) (see D. Seebach, D.D. Miller, S. Muller and T.
Weber, Helv. Chim. Acta 68, 94~ (1985)1.
The corresponding other antipode can be obtained in
an analogous manner by concentrating the crystallization
mother liquor.
After repeated recrystallization and subsequent dry-
ing at reduced pressure until constant weight is attained the
crystalline (R)- and (S)-1,3-imidazolidin-4-ones having the
formula (I) are thus obtained in good chemical yields and in
optical yields of 98 to 99%. Up to 95% of the applied chiral
acids having the general formula ~IV) can be recovered without
detectable racemization. Therefore, on separating (R)-I and
(S)-I the aqueous phase is acidified with mineral acids, such
as sulphuric acid or hydrochloric acid, and extracted with a
solvent that is not miscible with water, as for example,
acetic ester.
The process according to the present lnvention pro-
vides an excellent access to enantiomer-pure glycine deriva-
tives having the general formula (I) from achiral start:lng

~91~733
products and, as described, for example, by D. Seebach et al.
in DE-OS 3 334 855 or in Helv. Chim. Acta 68, 949 ~1985),
after diasteroselective single or repeated C~-alkylation and
ring cleavage this process provides a favourable basis for the
synthesis of branched and non-branched proteinogenic or non-
proteinogenic (R)- and (S)-amino acids.
For carrylng out the process according to the pre-
sent invention there is first produced in a conventional man-
ner from a glycine amide having the general formula
0
1 ~ 2 1 -- C ~ t V )
wherein R has the meaning defined hereinbefore, and from
pivaldehyde the racemic 1,3-imidazolidin-4-one having the
general formula (II)( (R. Naef and D. Seebach, Helv. Chim.
Acta 68, 135 (1985)). An alternative production process is
evident from the degradation of a side chain in the 5-posi-
tion, starting from DL-amino acids such as methionine or O-
benzyl serine as described by D. Seebach et al. in Helv. Chim.
20 Acta 68, 949 (1985).
The present invention will be described in greater
detail by the following Examples:
a) Production of (R,S)-2-(t-butyl)-3-methyl-1,3-imidazolidin-
4-one
The suspension obtained by adding 125.6 g (l mole)
of glycine methyl ester hydrochloride to ice-cooled 375 ml of
; 8 M ethanolic methyl amine was stirred for 15 hours at room
temperature and concentrated under reduced pressure so as to
form a viscous paste. Said paste was suspended three times
30 using 200 ml of methylene chloride each time and reconcen-
~rated again. The residue was mixed with 1 litre of methylene
chloride, 235 ml (1.5 moles) of pivaldehyde and 209 ml (1.5

~9~33
moles) of triethyl amine and boiled for 10 hours on a water
separator. On filtering, washing the residue with 500 ml of
ether and concentrating the filtrate under reduced pressure a
solution of the oil obtained was mixed in 300 ml of methanol
with 600 ml of HCl-saturated methanol whille cooling with ice,
stirred for 0.5 hour at 0C and 2 hours at room temperature
and again concentrated by evaporation. ,A solution of the
syrup in 800 ml of methylene chloride was washed with 670 ml
of a 3 M solution of caustic soda while cooling with ice and
10concentrated to 107.5 g (69%) of crude (R,S)-2-(t-butyl)-3-
methyl-1,3-imidazolidin-4-one, a yellowish oil which
crystallized in the cold. (For analytics see R. NaeE and ~.
Seebach, Helv. Chim. Acta 68, 135 ~1985).
b) Enantiomer Separation of (RS)-2-(t-butyl)-3-methyl-1,3-
imidazolidin-4-one
~; A mixture of 70 g (0.448 mole) of the (R,S)-2-(t-
butyl)-3-methyl-1,3-imidazolidin-4-one and 70 g of (R)-~-)-
mandelic acid was dissolved in boiling acetone. On cooling to
room temperatures within 6 hours and further 15 hours at 5C
the precipltated crystal cake was filtered off. Upon drying,
54.5 g of a slightly yellow crystallizate of R-mandelic acid
and (R)-2-t-(butyl3-3-methyl-1,3-imidazolidin-4-one was iso-
lated.
c) Production of (S)-(+)-l-benzoyl-2-(t-butyl)-3-methyl-1,3-
imidazolidln-4-one
A suspension of the diastereomeric salt of (R)-(-)-
mandelic acid and ~R)-2-~t-butyl)-3-methyl-(1,3-imidazolidin-
4-one (54.5 g, 0.177 mole) obtained according to b) in 200 ml
of methylene chloride was mixed with g2 ml of a 2 M solution
of caustic soda and shaken. By extracting the water phase
acidlfied with a 50% sul~huric acid with 300 ml of acetic
ethyl ester up to 25.5 g of (R)-(-)-mandelic acid can be
5 _

~96733
recovered.
The 1,3-imidazolidin-4-one remaining in the organic
phase was benzoylated by adding 20.1 ml (0.173 mole) of ben-
zoyl chloride and 195 ml of a 1 M solution of caustic soda
while cooling with ice. The organic phase was separated,
dried over magnesium sulphate and concentrated under reduced
pressure.
45.8 g of yellow crystallizate with ~ c~ ]D = + 107
(c = 1, CH2C12) were obtained. :~
Crystallizing twice from ethanol, precipitating from
methylene chloride with pentane and drying for 12 hours at 0.1
torr and 60C yielded 34.7 g ~60~) of (S)-~)-l-benzoyl-2-(t-
butyl)-3--methyl-1,3-imidazolidin-4-one with [c~]D = ~ 127 (c
1, CH2C12 ) -
By crystallizing a sample three times from an
ethanol and subsequent sublimation (135C/0.01 torr) an ~D
of ~ 127.5C and a melting point of 143 to 144C were
obtained.
The spectroscopic data correspond to those of the
(R,S)-compound described by Seebach et al. in Helv. Chim. Acta
68, 949 (1985).
d) Production of (R)-(-)-benzoyl)-2-(t-butyl)-3-methyl-1,3-
lmidazolidin-4-one
The syrup remaining on concentrating the crystal-
lization mother liquor obtained according to b) was taken up
in 300 ml oE methylene chloride, whereupon - as described
under c)- the mandelic acid was washed out first (140 ml of a
2 M solution of caustic soda~ and the 1,3-imidazolidin-4-one
was then directly benzoylated in the organic phase (30 ml,
(0.258 mole) of benzoyl chloride, 280 ml of a 1 M solution of
caustic soda).
The crude crystal obtained on concentrating the
-6-

~29~733
organic phase under reduced pressure was recrystallized from
45 ml of ethanol.
33.6 g of crystals with [c~]D = --109 (c = l,
CH~C12) were obtained.
Recrystallizing and drying - as described under c) -
yielded 26.4 g (45%) of (R)~ benzoyl-2-(t-butyl)-3-
methyl-1,3-imidazolidin-4-one with [c~]D = -126 (c = 1,
CH2C~
~ 30