CA1335293C - 5-alkyl-tetramic acids and process for their production - Google Patents
5-alkyl-tetramic acids and process for their productionInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/38—2-Pyrrolones
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Abstract
A process is disclosed for the production of 5-alkyl tetramic acids, some of which are novel, from 4-alkoxy-3-pyrrolin-2-ones and aldehydes or ketones. By basic catalysis, 5-alkylidene-4-alkoxy-3-pyrrolin-2-ones are first formed, which are converted into the target compounds by cleavage of the alkoxy group and catalytic hydrogenation.
Description
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.
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:
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 Rl~
R (IVa) or 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, 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) 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~
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 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
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.
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.
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:
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 Rl~
R (IVa) or 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, 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) 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~
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 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
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.
Claims (29)
1. A process for the production of a substituted tetramic acid of the formula:
(I) or a tautomer thereof, wherein (a) R1 is a straight-chain or branched alkyl group 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, and R2, independently therefrom, is hydrogen or a straight-chain alkyl group having from 1 to 4 carbon atoms; or (b) R1 and R2 together comprise an optionally branched alkanediyl group, which, in conjunction with the linking carbon atom, forms a 4- to 7-member ring optionally substituted by one or more lower alkyl groups, which process comprises reacting a 3-pyrrolin-2-one of the formula:
(II) wherein R3 is a straight-chain or branched alkyl group having from 1 to 4 carbon atoms or a benzyl group optionally substituted by one or more lower alkyl groups, with an aldehyde or ketone of the formula:
(III) wherein either R2 and R4 have the meanings defined above for R2 and R1 or R4, or the optionally substituted alkanediyl group, formed by R2 and R4 together, differs from R1 or from the alkanediyl group formed by R1 and R2 together by the presence of one or more double or triple bonds not constituting part of an aromatic system and not conjugated with the carbonyl group, in the presence of a base in solution to form a 5-alkylidene-3-pyrrolin-2-one of the formula:
(IV) wherein R2, R3 and R4 have the meanings defined above, cleaving radical R3 from compound (IV) and catalytically hydrogenating the exocyclic double bond as well as the multiple bonds optionally present in radical R4.
(I) or a tautomer thereof, wherein (a) R1 is a straight-chain or branched alkyl group 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, and R2, independently therefrom, is hydrogen or a straight-chain alkyl group having from 1 to 4 carbon atoms; or (b) R1 and R2 together comprise an optionally branched alkanediyl group, which, in conjunction with the linking carbon atom, forms a 4- to 7-member ring optionally substituted by one or more lower alkyl groups, which process comprises reacting a 3-pyrrolin-2-one of the formula:
(II) wherein R3 is a straight-chain or branched alkyl group having from 1 to 4 carbon atoms or a benzyl group optionally substituted by one or more lower alkyl groups, with an aldehyde or ketone of the formula:
(III) wherein either R2 and R4 have the meanings defined above for R2 and R1 or R4, or the optionally substituted alkanediyl group, formed by R2 and R4 together, differs from R1 or from the alkanediyl group formed by R1 and R2 together by the presence of one or more double or triple bonds not constituting part of an aromatic system and not conjugated with the carbonyl group, in the presence of a base in solution to form a 5-alkylidene-3-pyrrolin-2-one of the formula:
(IV) wherein R2, R3 and R4 have the meanings defined above, cleaving radical R3 from compound (IV) and catalytically hydrogenating the exocyclic double bond as well as the multiple bonds optionally present in radical R4.
2. A process according to claim 1, wherein the cleavage of radical R3 is effected by treatment with a strong acid and the catalytic hydrogenation is then performed.
3. A process according to claim 1, wherein R3 is an optionally substituted benzyl radical and cleavage of R3 together with catalytic hydrogenation of the exocyclic double bond and optionally of multiple bonds present in radical R4 takes place in one step in the presence of a palladium catalyst.
4. A process according to claim 3, wherein the condensation of the 3-pyrrolin-2-one with the carbonyl compound is performed, in aqueous or aqueous alcoholic solution at a temperature of from 20° to 100°C.
5. A process according to claim 4, wherein an alkali hydroxide is used as the base.
6. A process according to claim 5, wherein the condensation of the 3-pyrrolin-2-one with the carbonyl compound is performed at a temperature of from 20° to 50°C.
7. A process according to claim 2, wherein the cleavage of group R3 is performed with an acid selected from hydrogen chloride, hydrogen bromide and sulfuric acid, in a solvent selected from water, acetic acid, aqueous tetrahydrofuran, aqueous dioxane and mixtures thereof.
8. A process according to claim 7, wherein the cleavage of the group R3 is performed with hydrogen chloride in anhydrous acetic acid at a temperature of from 20° to 60°C.
9. A process according to claim 8, wherein palladium on activated carbon is used as the catalyst.
10. A process according to claim 9, wherein the hydrogenation is performed under a pressure of from 1 to 50 bars in a solvent which is inert toward catalytic hydrogenation.
11. A process according to claim 10, wherein 4-methoxy-3-pyrrolin-2-one is used as the starting material of formula (II).
12. A process according to claim 1,wherein the condensation of the 3-pyrrolin-2-one with the carbonyl compound is performed in aqueous or aqueous alcoholic solution at a temperature of from 20° to 100°C.
13. A process according to claim 1, wherein the alkali hydroxide is used as the base.
14. A process according to claim 13, wherein the condensation of the 3-pyrrolin-2-one with the carbonyl compound is performed at a temperature of from 20° to 50°C.
15. A process according to claim 1, wherein palladium on activated carbon is used as the catalyst.
16. A process according to claim 1, wherein the hydrogenation is performed under a pressure of from 1 to 50 bars in a solvent which is inert toward catalytic hydrogenation.
17. A process according to claim 1, wherein 4-methoxy-3-pyrrolin-2-one is used as the starting material of formula (II).
18. A substituted tetramic acid of the formula:
(I) or a tautomer thereof, wherein (a) R1 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 1 or 2, and Q is one of the above-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 (b) R1 and 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-benzyl tetramic acid, 5-(2-butyl) tetramic acid, 5-isobutyl tetramic acid or 5-n-hexyl tetramic acid.
(I) or a tautomer thereof, wherein (a) R1 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 1 or 2, and Q is one of the above-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 (b) R1 and 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-benzyl tetramic acid, 5-(2-butyl) tetramic acid, 5-isobutyl tetramic acid or 5-n-hexyl tetramic acid.
19. A substituted tetramic acid according to claim 18, wherein R2 is hydrogen.
20. 5-(Cyclohexylmethyl) tetramic acid.
21. 5-(2-ethylbutyl) tetramic acid.
22. 5-propyl tetramic acid.
23. 5-isopentyl tetramic acid.
24. 5-(2-methylpentyl) tetramic acid.
25. A compound according to claim 18, wherein R1 is a straight-chain or branched alkyl group having 2 to 6 carbon atoms.
26. A compound according to claim 18, wherein R1 is a cycloalkyl group having 4 to 7 carbon atoms.
27. A compound according to claim 18, wherein R1 is a group of the formula -[CH2]n-Q where n is 1 or 2, and Q is a cycloalkyl group having 4 to 7 carbon atoms or a phenyl group.
28. A compound according to claim 18, wherein R2 is a straight-chain alkyl group having 1 to 4 carbon atoms.
29. A compound according to claim 18, wherein R
and R2 together comprise an optionally branched alkanediyl group, which, in conjunction with the linking carbon atom, forms 4 to 7 carbon member ring.
and R2 together comprise an optionally branched alkanediyl group, which, in conjunction with the linking carbon atom, forms 4 to 7 carbon member ring.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA 609740 CA1335293C (en) | 1988-09-06 | 1989-08-29 | 5-alkyl-tetramic acids and process for their production |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH333788 | 1988-09-06 | ||
| CH3337/88 | 1988-09-06 | ||
| CA 609740 CA1335293C (en) | 1988-09-06 | 1989-08-29 | 5-alkyl-tetramic acids and process for their production |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1335293C true CA1335293C (en) | 1995-04-18 |
Family
ID=25672987
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 609740 Expired - Fee Related CA1335293C (en) | 1988-09-06 | 1989-08-29 | 5-alkyl-tetramic acids and process for their production |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1335293C (en) |
-
1989
- 1989-08-29 CA CA 609740 patent/CA1335293C/en not_active Expired - Fee Related
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