Note: Descriptions are shown in the official language in which they were submitted.
- 1 335293
This invention relates to a multistep process for
the production of 5-alkyl tetramic acids from 4-alkyloxy-
or 4-benzyloxy-3-pyrrolin-2-ones and aldehydes or ketones.
The invention further relates to novel 5-alkyl tetramic
5 acids, which are obtainable in this manner.
5-Alkyl tetramic acids are valuable intermediate
products useful for the production of beta-hydroxy-gamma-
amino acids, such as statine, which, for its part, plays an
essential role as a structural element of renin inhibitors,
10 such as pepstatin or analogs thereof modified in the side
chain. Renine inhibitors exhibit promising physiological
effects and, therefore, are suitable for therapeutic
purposes, especially as antihypertensive agents [H.J.
Altenbach, Nachr. Chem. Tech. Lab. 36, 756 (1988)].
15 Depending on the conditions and the substituents, the
tetramic acid can be present in the dione form, i.e., as
pyrrolidine-2,4-dione, or in the enolone form, i.e., as 4-
hydroxy-3-pyrrolin-2-one, or as mixture of the two forms.
For brevity, only the dione form will be depicted below in
20 each case regardless of the actual conditions.
Hitherto, there has been lacking simple and cost-
favorable processes for the production of variously
substituted 5-alkyl tetramic acids.
Thus, from Jouin et al., J. Chem. Soc. Perkin
25 Trans. I, 1987, 1177, it is known to condense N-protected
alpha-amino acids, after activation with chloroformic acid
isop ropenyl ester in the presence of 4-
dimethylaminopyridine with Muldrum's acid, to form the
corresponding (l-hydroxyalkylidene) Muldrum's acids, which
30 on heating in solution eliminate acetone and C02 and are
converted into the N-protected 5-substituted tetramic
acids. Such process does yield optically active tetramic
acid derivatives, if optically active natural alpha-amino
acids are employed as starting materials, but a whole
35 series of expensive starting materials is needed that are
in some instances difficult to obtain or highly toxic,
which in practice rules out a technical application.
1 335293
Another drawback of such prior process is the
limitation on the possibilities of variation of the
substituents in the end product, which results from the
fact that, with the alpha-amino acids only a limited choice
5 of substituents is available.
The same drawbacks are exhibited by an order
process, which starts from alpha-amino acid esters, which
are first reacted with malonic acid ester chlorides to form
the corresponding N-(alkoxycarbonylacetyl)-alpha-amino acid
10 esters. The latter are cyclized to the 3-alkoxycarbonyl
tetramic acids, which are converted into the corresponding
5-substituted tetramic acids by hydrolysis and
decarboxylation. (T.P.C. Mulholland, R. Foster and D.B.
HaYdock, J. Chem. Soc. Perkin Trans. I 1972, 2121).
The main object of the invention is to provide a
process which does not exhibit the above-mentioned
drawbacks and makes available a broad spectrum of
differently substituted tetramic acids.
Accordingly,one aspect of the invention provides
20 a process for the production of a substituted tetramic acid
of the formula:
Rl ~,
~ ~ N ~
R H (I)
or a tautomer thereof, wherein:
(a) Rl is a straight-chain or branched alkyl
group having from 1 to 6 carbon atoms or a cycloalkyl group
having from 4 to 7 carbon atoms or a group of the formula-
~CH2]n~Q, wherein n is 1 or 2 and Q is one of the above-
mentioned cycloalkyl groups or a phenyl group, and R2,
35 independently therefrom, is hydrogen or a straight-chain
alkyl group having from 1 to 4 carbon atoms; or
(b) Rl and R2 together form an optionally
branched alkanediyl group,which, in conjunction with the
- 1 3352q3
linking carbon atom, forms a 4- to 7-member ring optionally
substituted by one or more lower alkyl groups.
In a first step of the process of the invention,
a 3-pyrrolin-2-one of the formula:
R30
N (II)
H
wherein R3 is a straight-chain or branched alkyl group
having from 1 to 4 carbon atoms or a benzyl group
optionally substituted with one or more lower alkyl groups,
15 is reacted with an aldehyde or ketone of the formula:
R2 - C - R1 (IIIa)
20 or
o
R2 - C - R4 (IIIb)
wherein R1 is a straight-chain or branched alkyl group
25 having from 1 to 6 carbon atoms, a cycloalkyl group having
from 4 to 7 carbon atoms or a group of the formula -[CH2]n-
Q in which N is 1 or 2 and Q is one of the above-mentioned
cycloalkyl groups or a phenyl group;
R2, independently therefrom, is hydrogen or a
30 straight-chain alkyl group having 1 to 4 carbon atoms; and
R4 is a group which differs from R1 only by the
presence of one or more double or triple bonds not
belonging to any aromatic system and not conjugated with
the carbonyl group. The reaction takes place in solution
35 in the presence of a base and leads to a 5-alkylidene-3-
pyrrolin-2-one of the formula:
4 1 3352~3
R30
Rl~
R (IVa)
or
R30
R )~
~{~ N
R2 H (IVb)
wherein R1, R2, R3 and R4 have the above-mentioned
15 meanings.
The 4-alkoxy or 4-benzyloxy-3-pyrrolin-2-one of
formula (II) can be obtained according to known processes.
4-Alkoxy-3-pyrrolin-2-one can be produced according to
European Published Patent Application 0216324 from 4-
20 haloacetic acid esters with orthoformic acid esters andammonia. 4-Benzyloxy-3-pyrrolin-2-one can be produced
according to European Published Patent Application 0252363
from 4-methoxy-3-pyrrolin-2-one and the corresponding
benzyl alcohol. As the radical R3, the 3-pyrrolin-2-ones
25 suitably contain an alkyl group with up to 4 carbon atoms,
for example, methyl, ethyl, propyl, isopropyl or butyl, or
a benzyl group, which can be optionally substituted with
one or more alkyl groups having up to 4 carbon atoms, such
as, o-methylbenzyl, m-methylbenzyl, p-methylbenzyl, 2,4-
30 dimethylbenzyl, 3,5-dimethylbenzyl, p-ethylbenzyl, p-
isopropylbenzyl, p-butylbenzyl or p-tert-butylbenzyl.
Preferred meanings for group R3 are methyl, ethyl, propyl,
isopropyl and benzyl; methyl is especially preferred.
Useful aldehydes or ketones of general formula
35 (IIIa) or (IIIb) include saturated aliphatic aldehydes
having from 2 to 7 carbon atoms, namely straight-chain such
as acetaldehyde, propionaldehyde, butyraldehyde,
valeraldehyde, caproaldehyde or enanthaldehyde, or branched
1 3352~3
such as isobutyraldehyde, isovaleraldehyde, pivalaaldehyde,
isocaproaldehyde, 2-methylvaleraldehyde or 2-
ethylbutyraldehyde, or saturated alicyclic aldehydes having
to 8 carbon atoms, such as cyclobutanecarbaldehyde,
5 cyclopentanecarbaldehyde, cyclohexanecarbaldehyde or
cycloheptanecarbaldehyde, or cycloalkylacetaldehydes, such
as cyclohexylacetaldehyde, cycloalkylpropionaldehydes, such
as 3-cyclohexylpropionaldehyde, arylacetaldehydes, such as
phenylacetaldehyde, arylpropionaldehydes, such as 3-
10 phenylpropionaldehyde, or aliphatic ketones, such asacetone, ethyl methyl ketone, isopropyl methyl ketone,
diethyl ketone, isobutyl methyl ketone, 2-heptanone, 3-
heptanone, 4-heptanone, 2-octanone or 5-nonanone, or
alicyclic ketones, such as cyclobutanone, cyclopentanone,
15 cyclohexanone or cycloheptanone. It is within the scope of
the invention to use unsaturated aldehydes or ketones
instead of the corresponding saturated ones, for example 3-
cyclohexenecarbaldehyde instead of cyclohexanecarbaldehyde.
A requirement in this case is that the multiple bonds not
20 be in conjugation with the carbonyl group, since otherwise
other reaction paths come to the fore. In these cases, the
double or triple bonds in the last process step, i.e. the
catalytic hydrogenation, are also hydrogenated.
If aldehydes or unsymmetrical ketones are used,
25 two geometric isomers, namely the Z and E forms of the
corresponding 5-alkylidene-3-pyrrolin-2-one, are formed.
Which of the two forms is formed or whether both are
produced concurrently, depends on the radicals R1 or R4 and
R2. For the further course of the reaction it is not
30 critical whether the Z or E form or a mixture results.
The reaction of the 3-pyrrolin-2-one with the
aldehyde or ketone is performed with a base as catalyst in
solution. Preferably an alkali hydroxide, especially
preferably sodium hydroxide, is used as the base.
Polar protic solvents, such as water or lower
alcohols, are suitable as solvents, preferably water alone
or in admixture with a lower alcohol. The reaction is
suitably performed at a temperature of from 20 to 100C,
-
6 1 3~5;~93
preferably from 30 to 50C. The reaction period is
suitably from 5 minutes to 5 hours. The molar ratio of 3-
pyrrolin-2-one (II) to aldehyde or ketone (III) is suitably
from 1:1 to 1:5, preferably from 1:1 to 1:1.5.
In the following step the 5-alkylidene-3-
pyrrolin-2-one of formula (III) is converted, by cleavage
of radical R3 under acid catalysis, into a 5-alkylidene
tetramic acid of the formula:
o
R2 H (Va)
o
~= o
{ N
R2 H (Vb)
This step can be omitted if R3 is a benzyl group or a
25 substituted benzyl group, since benzyl groups are also
cleavable under conditions of catalytic hydrogenation (see
European Published Patent Application 0252363). This is
particularly advantageous if such compounds according to
the invention are to be produced which, under conditions of
30 acid-catalyzed cleavage, tend to experience side reactions.
The acid-catalyzed cleavage can be performed with strong
acids in polar protic solvents, such as water or aqueous
solvent mixtures or lower carboxylic acids. In a preferred
embodiment, hydrogen chloride or hydrogen bromide in acetic
35 acid is used, hydrogen chloride being especially preferred.
Another preferred embodiment uses sulfuric acid in aqueous
tetrahydrofuran or dioxane. The reaction temperature is
suitably from 20 to 100C, preferably from 20 to 60C.
7 l 335293
In the last process step, the exocyclic double
bond as well as, optionally, other double or triple bonds
present in radical R4 are hydrogenated on a palladium
catalyst. At the same time, if radical R3 is a benzyl
5 group or substituted benzyl group and was not cleaved by
acid, R3 is removed by hydrogenolysis. Thus, a chirality
center is formed in position 5 of the pyrroline or
pyrrolidine ring and, if R2 is different from Rl and is not
hydrogen, also in the alpha-position of the side chain, so
10 that the resulting tetramic acid is obtained as an
enantiomeric or diastereomeric mixture.
The catalyst can be applied to a support
material, such as activated carbon or aluminum oxide. The
hydrogenation is suitably performed in a solvent, such as
15 methanol or ethyl acetate. For this purpose, all solvents
usual for catalytic hydrogenation can be used. The
hydrogen pressure in the hydrogenation is not critical and
is preferably from 1 to 50 bars. Preferably hydrogenation
is performed at a temperature of from 10 to 60C with room
20 temperature being especially preferred.
Another aspect of the invention provides a
substituted tetramic acid of the formula:
Rl
~ ~ (I)
30 or a tautomer thereof, wherein
(a) Rl is a straight-chain or branched alkyl
group having from 2 to 6 carbon atoms, a cycloalkyl group
having 4 to 7 carbon atoms or a group of the formula
-~CH2]n~Q in which n is l or 2, and Q is one of the above-
35 mentioned cycloalkyl groups or a phenyl group, and R2,
independently therefrom, is hydrogen or a straight-chain
alkyl group having from 1 to 4 carbon atoms; or
8 l 335293
(b) R1 or R2 together comprise an optionally
branched alkanediyl group, which, in conjunction with the
linking carbon atom, form a 4- or 7-member ring optionally
substituted by one or more lower alkyl groups, other than
5 5-benzyl tetramic acid, 5-(2-butyl) tetramic acid, 5-
isobutyl tetramic acid or 5-n-hexyl tetramic acid.
The following Examples illustrate embodiments of
the process according to the invention. In the Examples,
all 1H NMR spectra were taken in CDCl3 at 300 MHz.
Example 1
(Z)-4-methoxy-5-isobutylidene-3-pyrrolin-2-one
(IV, R2 = H, R3 = Me, R4 = isopropyl)
35.9 g of 4-methoxy-3-pyrrolin-2-one (II, R3 =
Me) was dissolved in 2000 ml of 4 n aqueous sodium
15 hydroxide solution and mixed at 50C over 30 minutes with a
solution of 24.0 g of isobutyraldehyde in 675 ml of
methanol. After 1 hour, 675 ml of water was added and the
reaction mixture was cooled to 0C. The resulting product
was filtered off, washed with water and dried in a vacuum
20 at 40C. The filtrate was extracted with dichloromethane.
The yield was 39.7 g plus 10.1 g from the dichloromethane
extract (99.4 percent total yield). Other data for the
product were:
Melting point: 139 to 141C, colorless crystals
1H-NMR: ~ = 8.64 (br.s, lH), 5.30 (d, lH),
5.1 4 (d, lH), 3.85 (s, 3H), 2.67
(m, lH), 1.11 (d, 6H)
Example 2
(Z)-4-methoxy-5-(cyclohexylmethylene)-3-pyrrolin-2-one
30 (IV, R2 = H, R3 = Me, R4 = cyclohexyl)
23.9 g of 4-methoxy-3-pyrrolin-2-one (94.6
percent) in 1360 ml of 4 n sodium hydroxide solution and
27.5 g of cyclohexanecarbaldehyde (90 to 95 percent) in 330
ml of methanol were reacted as described in Example 1.
35 Data for the product were:
Yield: 39.8 g (96.1 percent)
Melting point: 134 to 136C, colorless crystals
9 1 3352'~3
H-NMR: ~= 9.07 (br.s, lH), 5.32 (d, lH),
5.14 (d, lH), 3.83 (s, 3H), 2.40 (m,
lH), 1.09-1.81 (m, lOH)
Example 3
5 (Z)-4-methoxy-5-propylidene-3-pyrrolin-2-one
(IV, R2 = H, R3 = Me, R4 = Et)
23.9 g of 4-methoxy-3-pyrrolin-2-one (94.6
percent) in 1360 ml of a 4 n sodium hydroxide solution and
13.2 g of propionaldehyde (97 percent) in 330 ml of
10 methanol were reacted as described in Example 1. Data for
the product were:
Yield: 18.0 g (58.8 percent)
Melting point: 119 to 127C, colorless crystals
lH-NMR: ~= 8.62 (br.s, lH) 5.43 (t, lH),
5.12 (d, lH), 3.84 (s, 3H), 2.27 (m,
2H), 1.12 (t, 3H)
Example 4
(Z)-4-methoxy-5-(2-ethYlbutylidene)-3-pyrrolin-2-one
(IV, R2 = H, R3 = Me, R4 = 3-pentyl)
The synthesis was carried out as described in
Example 1, except that 2-ethylbutyraldehyde was used as the
carbonyl compound. Data for the product were:
Yield: 73.5 percent
Melting point: 128 to 130C, colorless crystals
lH-NMR: ~ = 8.38 (br.s, lH), 5.20 (d, lH),
5.13 (d, lH), 3.85 (s, 3H), 2.17 (m,
lH), 1.25-1.65 (m, 4H), 0.89 (t, 6H)
Example 5
(i)-(Z)-4-methoxy-5-(2-methylpentylidene)-3-pyrrolin-2-one
30 (IV, R2 = H, R3 = Me, R4 = 2-pentyl)
The synthesis was carried out as described in
Example 1, except that 2-methylvaleraldehyde was used as
the carbonyl compound. Data for the product were:
Yield: 73.3 percent
Melting point: 83 to 87, colorless crystals
H-NMR: ~= 8.05 (br.s, lH), 5.25 (d, lH),
5.12 (d, lH), 3.85 (s, 3H), 2.45 (m,
1 335293
lH), 1.20-1.50 (m, 4H), 1.09 (d,
3H), 0.90 (t, 3H).
ExamPle 6
(Z)-4-methoxy-5-isopentylidene-3-pyrrolin-2-one
5 (IV, R2 = H, R3 = Me, R4 = isobutyl)
The synthesis was carried out as described in
Example 1 except that isovaleraldehyde was used as the
carbonyl compound. Data for the product were:
Yield: 92.8 percent
Melting point: 90 to 92C, colorless crystals
H-NMR: ~= 8.60 (br.s, lH), 5.46 (t, lH),
5.13 (d, lH), 3.84 (s, 3H), 2.14
(dd, 2H), 1.79 (m, lH), 0.97 (d, 6H)
Example 7
lS (Z)-4-Methoxy-5-r2,2-dimethylproPYlidene)-3-PYrrolin-2-one
(IV, R2 = H, R3 = Me, R4 = tert-butyl)
The synthesis was carried out as described in
Example 1, except that pivalaldehyde was used as the
carbonyl compound. Data for the product were:
Yield: 54.5 percent
Melting point: 165 to 167 , colorless crystals
H-NMR: ~= 6.92 (br.s, lH), 5.37 (s, lH)
5.08 (d, lH), 3.84 (s, 3H), 1.22
(s, 9H)
Example 8
4-MethoxY-5-isopropylidene-3-pyrrolin-2-one
(IV, R2 = R3 = R4 = Me)
The synthesis was carried out as described in
Example 1, except that three equivalents of acetone were
30 employed as the carbonyl compound and methanol was not
added. Data for the product were:
Yield: 75.8 percent
Melting point: 246 to 248C, colorless crystals
1H-NMR: ~ = 8.27 (br.s, lH), 5.19 (d, lH),
3.84 (s, 3H), 2.11 (s, 3H), 1.93
(s,3H)
- 1 335293
11
Example 9
4-Methoxy-5-(1-methylpropYlidene)-3-pyrrolin-2-one (E/Z
mixture)
(IV, R2 = R3 = Me, R4 = Et)
The synthesis was carried out as described in
Example 8, except that 2-butanone was used as the carbonyl
compound. Data for the product were:
Yield: 34.7 percent
Melting point: 119 to 122C, colorless crystals
lH-NMR:~ = 7.29 (br.s, lH), 5.18 (d, lH),
3.82 (s, 3H), 2.52 (q, lH), 2.25 (q,
lH), 2.08 (s, 3H), 1.95 (s, 3H),
1.11 (t, 3H), 1.07 (t, 3H)
Example 10
15 (+)-(Z)-4-Methoxy-5-(3-cyclohexen-1-yl-methylene)-3-
pyrrolin-2-one
(IV, R2 = H, R3 = Me, R4 = 3-cyclohexen -l-yl)
The synthesis was carried out as described in
Example 1, except that 3-cyclohexen-1-aldehyde (1,2,3,6-
20 tetrahydrobenzaldehyde) was used as the carbonyl compound.
Data for the product were:
Yield: 97.1 percent
Melting point: 152 to 162C, colorless crystals
1H-NMR:~ = 7.87 (br.s, lH), 5.62-5.79
(m, 2H), 5.40 (d, lH), 5.13 (d, lH),
3.84 (s, 3H), 2.58 (m, lH), 1.44-
2.29 (m, 6H)
Example 11
(Z)-4-BenzYloxY-5-isobutylidene-3-pYrrolin-2-one
30 (IV, R2 = H, R3 = benzyl, R4 = isopropyl)
This synthesis was carried out as described in
Example 1, except that 4-benzyloxy-3-pyrrolin-2-one (II, R3
= benzyl) was used in place of 4-methyoxy-3-pyrrolin-2-one.
Data for the product were:
Yield: 57.6 percent
Melting point: 159 to 161C, colorless crystals
lH-NMR:~ = 8.17 (br.s, lH), 7.30-7.45 (m,
~ ~5~9~
12
5H), 5.38 (d,lH), 5.20 (d, lH), 5.03
(s, 2H), 2.62 (m, lH), 1.11 (d, 6H)
ExamPle 12
(Z)-5-Isobutylidenepyrrolidine -2,4-dione ((Z)-
5 isobutylidene tetramic acid)
(Va, Rl = isopropyl, R2 = H)
39.7 g of (Z)-4-methoxy-5-isobutylidene-3-
pyrrolin-2-one (produced according to Example 1) was
dissolved in 390 ml of acetic acid. The solution was
10 saturated with hydrogen chloride gas at 40 to 45C over 10
hours and then concentrated by evaporation in a vacuum.
Data for the product were:
Yield: 49.3 g
Melting point: 140 to 142 (from water),
yellowish crystals
H-NMR: ~ = 9.68 (br.s, lH), 5.58 (d, lH),
3.12 (s, 2H), 2.55 (m, lH), 1.12 (d,
6H)
Examples 13 to 20
The compounds listed in Table 1 were produced
analogously to Example 12. The yields are almost
quantitative (more than 95 percent); all of the compounds
are yellow.
I
Table 1
Fe~J~I I Melting
Example Ha e Structure Fro Point ~H-~R-Spectru
Exa~ple t-C]
13 (Z~-5-~Cyclohexylmethylene)- Va, Rl = Cyclohexyl, 2 168-170 9.37 (br.s, 1H), 5.61 (d, 1H), 3.12
pyrrolidin-2,4-dione (s, 2H), 2.22 (m, 1H), 1.13-1.82 (m,
R2 = H 10H)
14 (Z)-5-Propylidene-pyrrolidin-2,4- Va, R' = Et, 3 134-136 10.07 (br.s, 1H), 5.72 (t, 1H), 3.13
dione (s, 2H), 2.20 (m, 2H), 1.13 (t, 3H)
R2 = H
(Z)-5-(2-Ethylbutylidene)- Va, R' = 3-Pentyl, 4 127-129 9.78 (br.s, 1H), 5.51 (d, 1H), 3.13
pyrrolidin-2,4-dione (s, 2H), 2.12 (m, 1H), 1.25-1.68 (m,
R2 = H 4H), 0.89 (t, 6H)
16 (~)-(Z)-(1-Methyl pentylidene)- Va, RI = 2-Pentyl, 5 115O-117 9.40 (br.s, 1H), 5.53 (d, 1H), 3.12
pyrrolidin-2,4-dione (s, 2H), 2.38 (m, 1H), 1.25-1.53 (m, ~,
R2 = H 4H), 1.09 (d, 3H), 0.91 (t, 3H)
17 (Z)-5-lsopentylidene-pyrrolidin- Va, R' = Isobutyl, 6 114-115 9.97 (br.s, 1H), 5.76 (t 1H), 3.12
2,4-dione (s, 2H), 2.09 (dd, 1H), ;.82 (m, 1H),
R2 = H 0.97 (d, 6H)
18 (Z)-5-(2,2-Dimethyl-propylidene)- Va, R' = tert-Butyl, 7 106-108 8.42 (br.s, 1H), 5.67 (s, 1H), 3.04
pyrrolidin-2,4-dione (s, 2H), 1.22 (s, 9H) ~_~J
R = H ~_r~
19 5-lsopropylidene-pyrrolidin-2,4- Va, R' = R2 = Me 8 187-188 9.43 (br.s, 1H), 3.11 (s, 2H), 2.20 ~_
dione (s, 2H), 1.89 (s, 3H) r~
(t)-(Z)-5-(3-Cyclohexene-1-yl- Vb, R2 = H, 10 5.60-5.80 (m, 3H), 3.13 (s, 2H), 2.55 ~_rJ
methylene)-pyrrolidin-2,4-dione (m, 1H), 2.45-2.30 (m, 6H)
R4 = 3-Cyclohexen-1-yl
`- 1 335293
14
ExamPle 21
(+)-5-Isobutyl-~Yrrolidine-2,4-dione~(+)-5-isobutyl
tetramic acid~
(1, Rl = isopropyl , R2 = H)
10.0 g of (Z)-5-isobutylidene-pyrrolidine-2,4-
dione (raw product from Example 12) was dissolved in 200 ml
of ethyl acetate and mixed with 1.0 g of
palladium/activated carbon (5 percent Pd). The mixture was
hydrogenated at room temperature and 20 bars of hydrogen
10 pressure in an autoclave with stirring for four hours, then
the catalyst was filtered off and the solvent was distilled
off. The yield was 7.4 g of raw product (98 percent based
on the 5-isobutylidene-4-methoxy-3-pyrrolin-2-one). Other
data for product were:
Melting point: 113 to 117 (from ethyl
acetate/hexane), yellowish crystals
H-NMR: ~= 8.05 (br.s, lH), 4.04 (dd, lH),
3.04 (s, 2H), 1.44-1.89 (m, 3H),
0.97 (dd, 6H)
Examples 22 to 26
The compounds listed in Table 2 were produced
analogously to Example 21. The yields are based in each
case on the corresponding compound V; all compounds are
colorless.
Table 2
r~J~ Melting
Example Mame Structure Fro Point rield ~H-MMR-Spectrum
Example [-C] oa
22 (1)-5-(Cyclohexylmethyl)- 1, R1 = Cyclohexyl,13 169-171 83.2 7.00 (br.s, 1H), 4.07 (dd,
pyrrolidin-2,4-dione 1H), 3.04 ~s, 2H), 0.85-1.80
R2 = H (m, 13H)
23 (I)-5-(2-Ethylbutyl)-pyrrolidin- 1, R' = 3-Pentyl, 15 78-80 71.7 7.30 (br.s, 1H), 4.04 (W,
2,4-dione 1H), 3.03 (s, 2H), 1.22-1.84
R2 = H (m, 7H), 0.82-0.97 (m, 6H)
24 (~)-5-Propyl-pyrrolidin-2,4-dione 1, R1 = Et, 14 101-103 97.6 7.20 (br.s, 1H), 4.03 (W,
1H), 3.03 (s, 2H), 1.32-1.90
R2 = H (m, 4H), 0.98 (t, 3H)
(~)-5-lsopentyl-pyrrolidin-2,4- 1, R~ = Isobutyl, 17 124-126 88 7 09 (br s, 1H), 4.01 (dd,
R2 = H (m, 5H), 0.92 ( W,6H) ~'
26 (') 5-(2-Methylpentyl)-pyrrolidin- 1, R~ = 2-Pentyl, 16 98-101 73 6 98 (br s 1H) **
(Diastereomeric mixture) R2 = H 4.00-4.10 (m, 1H) ***
3.03 (s, 2H) ***
0.85-1.90 (m, 13H) *** ~_rJ
* : Diastereomer A (_
** : Diastereomer B
*** : Diastereomers A+B
~O
16 1 335293
Example 27
(+)-5-Isobutyl-PYrrolidine-2~4-dione
(I, R1 = isopropyl, R2 = H)
4.0 g of (Z)-4-benzyloxy-5-isobutylidene-3-
5 pyrrolin-2-one (produced according to Example 11) was
dissolved in 50 ml of ethyl acetate and mixed with 0.4 g of
palladium/activated carbon (5 percent Pd). The mixture was
hydrogenated at room temperature and 20 bars of hydrogen
pressure in an autoclave with stirring for 7 hours, then
10 the catalyst was filtered off and the solvent was distilled
off. The yield was 2.6 g of colorless crystals. The
physical data were identical with those for the product
according to Example 21.
