HU187129B - Process for the production of primary amino-alcohols by the reduction of primary amino acid amides - Google Patents

Abstract

The present invention relates to a process for the preparation of primary amino alcohols by reduction of primary amine amides in liquid ammonia by means of metal sodium, to a solution of the primary amine amino acid to be reduced to a solution of the primary amine in liquid ammonia. and then reacting the sodium with an amount of an ammonium salt equivalent to the said amount of sodium to the reaction mixture and repeating this two-step reaction cycle at least 5 times, preferably 10-15 times, or b) 15-50 molar equivalents of 1- Comosoltolt alkanol and - preferably, in portions of 5 to 20 g of atomic metal sodium equivalent, and after sodium reaction, an amount of ammonium salt equivalent to the amount of sodium in the reaction mixture is added to the reaction mixture, except when starting out in the primary amino acid amide used as the starting material, the groups to be reacted with sodium in addition to the amide group to be reduced are added, so in the first step of the process, an additional amount of metal sodium is added to the solution of the primary amide to be reduced and after the reduction is complete. in this case, said groups are liberated from sodium salt.

Description

The present invention relates to a novel process for the preparation of primary amino alcohols by reduction of primary amino acid amides with sodium, in liquid ammonia, with or without an external proton donor.

The simpler aliphatic carboxylic acid amides (Chabley, E., Compte rendre 154, 1962) and Ann. chim., 8, 201 (1917)], as well as carbamoyl-containing amino acid derivatives and peptides such as asparagine and glutamine derivatives (ÜberhardtT et al., Hungarian Patent Application Publication No. T / 29070), partially to simple aliphatic alcohols. and leads to hydroxyamino acid and / or β-amino alcohol derivatives. In liquid ammonia, the salt formation and reduction of the carbamoyl group to alcohol are competitive reactions, so that alcohol formation is never complete. Therefore, Chabley (i. M.) Obtained the corresponding alcohols from simple aliphatic carboxylic amides in about 20% yield.

It is also known that alkyl and dialkylamides can not, or only poorly, be reduced to aldehydes by sodium ethanol ammonia (so-called Birch) reduction (Birch, A.J., et al., Austr. J. Chem., 1955, 8, 512; Weygand, F. and Eberhardt, C., Angew. Chem., 64, 458 (1952); Brown, H.C. and Subbakao, B.C., J. Am. Chem. Soc., 1958, 80, 5377 (1958).

Various metal hydrides and complex hydrides have been widely used for the reduction of the carbamoyl group (Hajós, A., Methoden Der Organischen Chemie, Vol. 4 / 1b, Georg Thieme Verlag, Stuttgart-New York, 1981, 1-486). Depending on the hydride used, the reduction leads to aldehyde, alcohol, amine, but in most cases only to a mixture thereof, and is therefore not very selective. Hydrides are highly reactive compounds such as the carbamoyl group and the carboxyl group is also reduced. In addition, the industrial applicability of hydrides is limited by their high cost.

It has been found that the primary carbamoyl-containing amino acid amides can be completely converted to the corresponding alcohol derivative under the conditions of sodium ammonia reduction by liberating the carboxamidate salt formed in a competitive reaction with alcohol formation by addition of the ammonium salt (which acts as a proton donor). The cycle of adding sodium and then liberating the carboxamidate salt is repeated (5-15 times) until the starting carboxylic acid amide is completely converted to the alcohol (Method A). It is not necessary to wait for the complete reaction of the sodium, i.e. the disappearance of the blue color of the reaction mixture, during each reduction step. In the first cycles, sodium reacts in 5 to 15 minutes, and then it takes longer and longer.

In each cycle, sodium equivalent to the carbamoyl group is used followed by an equivalent ammonium salt (e.g., ammonium chloride). The reduction step of the first cycle determines the time taken for the sodium to react (5-15 minutes), and for subsequent cycles this duration is maintained in each reduction step.

If the starting material contains a functional group other than the carbamoyl moiety which forms a salt with sodium (e.g., hydroxyl, carboxyl, mercapto, etc.), initially the amount of sodium required to convert these to the salt is added to the reaction mixture. an equivalent amount of sodium in the sodium is added only in the final cycle.

In a preferred embodiment of the process, a solution of 10 mg of N-tert-butyloxycarbonyl-L-asparagine in anhydrous liquid ammonia is sprayed with 20 mg of sodium. The resulting white slurry is converted to a clear solution by the addition of 10 mmol of ammonium chloride. Subsequent ciklusok- ₁ Ban, 10 mg sodium was reacted 10-12percig atom, then the reaction mixture was treated with 10 mM ammonium klroriddal that always clears the ammonium salt is added. In the final cycle, 20 mmol of ammonium chloride was added to the reaction mixture, after evaporation of the ammonia, the residue was dissolved in water, the solution was acidified and extracted with ethyl acetate. The organic phase is evaporated and the residue is dissolved in ether and the addition of dicyclohexylamine gives 8.4 mmol of chromatographically uniform N-tert-butyloxycarbonyl-L-homoserine dicyclohexylammonium salt.

Furthermore, we have found that in the presence of the ammonium salt of the primary amino acid amides, they can be reduced to the corresponding alcohol with good yields under Birch reduction conditions (his method). In this case, the compound to be reduced is dissolved in anhydrous ammonia in the presence of 15 to 50 equivalents of alcohol, preferably methanol, ethanol or propanol. Sodium is added in portions to the reaction mixture and in each case the reaction mixture is allowed to disappear in blue. Alcohol formation is completed with 5-20 grams of sodium equivalent; at this time, an equivalent of sodium salt (e.g. ammonium chloride) is added to the reaction mixture.

In a preferred embodiment of the method, the reduction of the carboxylic acid amide is carried out in the presence of 30 equivalents of methanol by adding 15 equivalents of sodium in 15 portions. The reaction mixture is worked up in the same manner as in Method A described above. N-t-butyloxycarbonyl-asparagine as starting ^'7 5 -8O% isolated yield of N-t-butyloxycarbonyl-L-homo-serine dicyclohexylamine salt.

Because of its simplicity, Method B is generally preferred for the reaction. In some cases, however, the resulting product is converted into a high volume gelatinous precipitate due to alcoholate formation which makes it difficult or impossible to stir the reaction mixture. In this case, it is preferable to use Method A, which produces a clear solution after each addition of the ammonium salt.

The present invention thus provides a novel process for the preparation of primary amino alcohols by reduction of primary amino acid amides in liquid ammonia with metal sodium, wherein the desired primary

To a solution of 187,129 alcohol-reducible primary amino acids in liquid ammonia, add up to an equivalent amount of metal sodium relative to the amide group to be reduced, and then, after reacting the sodium, add an equivalent of said ammonium salt to said reaction mixture and or (b) 15 to 50 molar equivalents of C 1 -C 4 alkanol and, preferably in portions, 5 to 20 g atomic equivalent of metal sodium, followed by reaction of the sodium with an ammonium salt. an amount equivalent to said sodium amount is added to the reaction mixture, and if there are groups reacting with the sodium to form a salt in the primary amino acid amide starting material which is to be reduced in the first step of the process, an equivalent amount of metal sodium is added to a solution of the primary amino acid amide to be reduced, and upon completion of the reduction said groups are liberated from the sodium salt.

The process according to the invention has the advantage that the reduction of the carbamoyl group to an alcohol, unlike the processes known hitherto, is complete and unambiguous. For the reduction, readily available and inexpensive reagents are used; the reaction can easily be carried out in large sizes in industrial Birch reduction devices. A further advantage of the process is the selectivity of the reduction. The alcohol and phenolic hydroxyl, mercapto, carboxyl, amino, N-tert-butyloxycarbonyl, N-t-amyloxycarbonyl and the like which may be present in the starting material are not or only negligibly damaged by the reaction, but the aromatic groups which may be present similar to Birch reduction, they may suffer partial reduction.

Because of this selective nature of reduction, for example, monoamides of optically pure N-tert-butyloxycarbonyl or N-t-amyloxycarbonylaminodicarboxylic acids can be selectively reduced without changing the optical purity. Optically pure N-tert-butyloxycarbonyl or N-tertiary-amyloxycarbonylhydroxy amino acids have so far only been obtained by complex stepwise synthesis and resolution. Some of the amino acid derivatives obtainable by the process of the invention are novel compounds and are obtained in protected form by reduction selectivity in such a pure state that they can be incorporated directly into peptides upon activation.

Our procedure is suitable for. Reduction of unprotected amino acid amides of amino groups such as Lalaninamide to L-alaninol, L-phenylalaninamide to 2 (S) -amino-3-cyclohexa-1,4-dienylpropan-1-ol. These compounds are preferably isolated in the form of their salts.

The following examples illustrate the practice of the present invention in more detail.

Abbreviations used in the examples to denote amino acid derivatives are recommended by IUPAC-IUB [J. Biol. Chem., 247, 977 (1972)]. Further abbreviations: Boc = N-tert-butyloxycarbonyl, Hse = Lhomoserine.

Melting point determinations were made by dr. They were made in a Tottoli apparatus (Büchi, Switzerland).

Thin layer chromatography was performed on a precast silica gel adsorbent (DCFertigplatten, Merck) in the following solvent mixtures:

1. ethyl acetate:

(pyridine: acetic acid: water = 20: 6: 11) = 9: 1

2. ethyl acetate (pyridine: acetic acid: water = 20: 6: 11) = 4: 1

3. ethyl acetate (pyridine: acetic acid: water = 20: 6: 11) = 1: 1

Chromatograms were obtained with ninhydrin and after chlorination with potassium iodide tolidine.

Specific optical rotation was measured on a Perkin Elmer 141-digit photoelectric polarimeter.

Infrared spectra were taken with a Perkin Elmer 250 and 700 spectrophotometer.

1 H-NMR spectra were obtained on a Varian EM 360 and XL 100 and a Bruker WM 250 instrument using TMS internal standard. ¹³ C-NMR spectra were recorded on a Varian XL 100 and a Bruker WM 250 instrument.

UV spectra were recorded on a Unicam SP 1800 ultraviolet spectrophotometer.

Example 1 (Method A)

N-tert-butyloxycarbonyl-L-homoserine dicyclohexylamine salt

Boc-Asn-OH (2.32 g, 10 mmol) was dissolved in anhydrous liquid ammonia (300 mL), distilled from sodium, and reacted with 0.46 g (20 mmol) of sodium at the boiling point of ammonia. After 4 minutes of reaction the color of the opalescent solution turns deep blue and the mixture begins to foam. After 15 minutes, the reaction mixture is converted to a white suspension. Then 0.535 g (10 mmol) of ammonium chloride was added to the reaction mixture, which was converted to a clear solution . The latter cycle (repeated addition of the same amount of sodium or ammonium chloride under the same conditions) is repeated ten times, but in the last cycle 1.07 g (20 mmol) of ammonium chloride is liberated from the sodium salt. The ammonia was then evaporated using a water bath at 40 ° C. The residue was dissolved in water (100 mL), adjusted to pH 3 with 18% hydrochloric acid, and extracted with ethyl acetate (5 x 50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and the residual oil dissolved in 50 mL of anhydrous ether. Dicyclohexylamine (1.96 mL, 10 mmol) was added with stirring. The resulting suspension was allowed to stand in a refrigerator. The precipitate was filtered the next day and washed well with ether. Thus 3.37 g (84.2%) of Boc-HSe3

187 129

OH.DCHA is obtained. M.p. 147-149 ° C, Rf = 0.40 (dicyclohexylamine 0.15), [α] D = -3.85 ° (c = 2, dimethylformamide). M. Manning et al. (Peptides, Proc. 5th Am. Peptide Symp. M. Goodman and J. Meienhofer, eds. John Wiley and Sons, New York, 1977, p. 201), m.p. 148-149 ° C. [%] J ^{= 2} 'dimethylformamide) by A. Touran et al. Med. Chem., 20, 1169 (1977)], m.p. 149-150 ° C and an optical tensile strength of [α] 25 D ⁼ -3.5 ° (c = 2, dimethylformamide).

Example 2 (Method B) N-tert-Butyloxycarbonyl-L-homoserine dicyclohexyl ammonium salt

2.32 g (10 mmol) of Boc-Asn-OH in 300 ml of sodium distilled anhydrous liquid ammonia and

Dissolve in 11.4 mL (300 mmol) of anhydrous methanol and stir with 3.76 g (163 mmol) of sodium at the boiling point of ammonia. Sodium was added in 0.2-0.3 g portions, waiting for the blue color of the suspension to disappear. At the end of the reaction, ammonium chloride (10.7 g, 200 mmol) was sprayed onto the mixture and the ammonia was evaporated in a water bath at 40 ° C and the residue was worked up according to Method A (Example 1). 3.13 g (77.5%) of Boe-Hse-OH.DCHA are obtained. 147-149 ° C, [α] D = -3.75 ° (c = 2.0, dimethylformamide).

Example 3

Dicyclohexylammonium salt of L-2- (tert-butyloxycarbonylamino) -5-hydroxyvaleric acid (N-terbutyloxycarbonyl-5-hydroxy-L-norvalindicyclohexylammonium)

Boc-Gln-OH (2.46 g, 10 mmol) was reduced according to Method A (Example 1) and the reaction mixture was reduced to

Work up as in Example 1. This gives 3.15 g (75.8%) of the dicyclohexylammonium salt of 2- (tert-butyloxycarbonyl-L-amino) -5-hydroxy-valeric acid. 131-132 ° C, Rf 0.40 (dicyclohexylamine 0.15). A small sample was recrystallized from ethanol-ether by clarification. 133-134 ° C, [α] D = + 8.4 ° (c = 1.01, ethanol). The structure of the compound is confirmed by its IR and 1 H-NMR spectra.

Analysis: Calculated for C ₂₂ H ₄₂ O ₅ N ₂ (M: 414.57);

Calculated: C, 63.73; H, 10.21%; N, 6.76%; Found: C, 63.43; H, 10.50%; N, 6.95%.

Example 4

Dicyclohexylammonium salt of DL-2- (tert-Butyloxycarbonylamino) -5-hydroxy-valeric acid,

Boc-DL-Gln-OH (2.46 g, 10 mmol) was reduced according to Method A (Example 1). 3.24 g (78.3%) of the dicyclohexylammonium salt of 2- (tert-butyloxycarbonyl-DL-amino) -54 are obtained. 147-150 ° C, Rf 0.25, RJ 0.40. The structure of the compound is confirmed by its IR and 1 H-NMR spectra.

Example 5

3-Cyclohexa-4-dienyl-L-aminolem hemimaleinate [2- (S) -amino-3-cyclohexa-1,4-dienylpropan-1-ol hemimaleinate]

9.80 g (40 mmol) of H-Phe-NH, · HBr are reduced according to Method A (Example 1). After the ammonia was evaporated, the residue was dissolved in water (200 mL) and extracted with ethyl acetate (6 x 80 mL). The combined organic phases are dried over anhydrous sodium sulfate, decolorized with charcoal and then concentrated in vacuo after filtration. The residual oil was crystallized from ether-diisopropyl ether. The suspension was left in the refrigerator and the next day the precipitate was filtered off and washed with diisopropyl ether. There was thus obtained 4.45 g (72.3%) of 3-cyclohexa-1,4-dienyl-L-alaninol. M.p. 60-62 ° C, RJ 0.55, [α] D 20 -20.9 ° (c = 1.2.1 M hydrochloric acid), [α] D = -9.15 ° (c = 5.0, ethanol).

3-Cyclohexa-1,4-dienyl-L-alaninol (4.0 g, 26 mmol) was dissolved in ethyl acetate (50 mL) and the maleinate salt was separated by adding a solution of maleic acid (3.5 g, 30 mmol) in ethanol (10 mL) and ethyl acetate (50 mL). . The suspension was kept in the refrigerator for the next day, and the precipitate was filtered off and washed with ethyl acetate. 6.93 g of 3-cyclohexa-1,4-dienyl-L-alaninol hemimaleinate are obtained. M.p. 138-139 ° C, [α] D = + 5.95 ° (c = 1.08 in ethanol). Its structure is confirmed by its IR, C H ¹³ C-NMR spectrum.

Analysis: Calculated for C ₁₃ H ₉ O ₅ N (M: 269.29);

Calculated: C, 57.98; H, 7.11; N, 5.20; Found: C, 58.17; H, 7.02; N, 5.38%.

Example 6

3-Cyclohexa-1,4-dienyl-L-alaninol hemimaleinate

H-Phe-NH ₂ · HBr (2.45 g, 10 mmol) was reduced according to Method B (Example 2) and worked up as described in Example 5. 1.18 g (77.0%) of 3-cyclohexa-1,4-dienyl-L-alaninol are obtained. 58-59 ° C,

Mp ~ 20.9 ° (c = 1.2.1 mol / L hydrochloric acid). From 1.08 g of base, 1.08 g of maleic acid is prepared to form maleic acid. 1.81 g of 3-cyclohexa-1,4-dienyl-L-alaninol hememaleinate are obtained. M.p. 38-139 ° C.

Example 7

L-A laninol hemioxalate

0.88 g (10 mmol) of L-alaninamide was reduced according to Method B (Example 2). After evaporation of the ammonia and methanol, the residue is suspended in ether, the sodium chloride is filtered off and the residue is evaporated. Wash thoroughly with 187129 ether. To the filtrate was added a solution of oxalic acid dihydrate (1.26 g, 10 mmol) in ethanol (10 mL). The resulting slurry was allowed to stand in a refrigerator and the next day the precipitate was filtered off and washed with ether. 1.31 g (79.3%) of L-alaninol hemioxalate are obtained. 135-136 ° C. A small sample was recrystallized from methanol. 139-141 ° C; R f = 0.35; Mp ⁼ + 18.2 ° (c = 1.0, 80% ethanol). P. Karrer et al., Helv. Chim. Acta, 31, 1617 (1948)], m.p. 140-141 ° C.

Claims (4)

Patent claims CLAIMS 1. A process for the preparation of primary amino alcohols by reduction of primary amino acid amides in liquid ammonia with metal sodium, characterized in that a solution of the desired primary amino acid amide in liquid ammonia can be reduced. a) adding up to an equivalent amount of metal sodium per amide group to be reduced, and after reacting the sodium, add an equivalent amount of an ammonium salt to said amount of sodium, and repeat the two-step reaction cycle at least 5 times, preferably 10-15 times. , obsession b) 15 to 50 molar equivalents of C 1 -C 4 alkanol and, preferably in portions, 5 to 20 g of atoro equivalents of metal sodium are added, and after reaction of the sodium, ⁵ equivalents of said ammonium salt is added to said sodium salt. while reacting with the sodium to form a reductive amide group in the primary amino acid starting material, an additional amount of metal sodium equivalent to these salt-forming groups is added in the first step of the process, followed by after completion of the reduction, if desired, the said tube ⁵ ports liberated from the Na salt. 2. A process according to claim 1 wherein the primary amino acid amide is a racemic or optically active amino acid amide. 3. A process according to claim 1 wherein the primary amino acid amide is a racemic or optically active aminodicarboxylic acid monoamide. 4. A process according to claim 1 wherein the primary amino acid amide is a racemic or optically active N-tert-butyl or N-t-amyloxycarbonyl amino acid amide.