WO1994007841A1

WO1994007841A1 - Process for reducing carboxylic acids or carboxylic acid derivatives, and novel compounds

Info

Publication number: WO1994007841A1
Application number: PCT/EP1993/002617
Authority: WO
Inventors: Karlheinz Drauz; Michael Schwarm; Albert I. Meyers; Marc Mckennon
Original assignee: Degussa Aktiengesellschaft
Priority date: 1992-09-29
Filing date: 1993-09-25
Publication date: 1994-04-14
Also published as: DE4232505A1

Abstract

Carboxylic acids and their derivatives, especially amino acids and their derivatives, are reduced to the corresponding amines or amino alcohols or diamines by expensive and complicated reducing agents and processes. The novel process is designed to facilitate economical reduction in gentle conditions while retaining any chirality centres and permit implementation on a technical scale. In addition, carboxylic acid derivatives like amides are to be reduced. Carboxylic acids or their derivatives of formula (I) are reduced to a compound of general formula (II) or (III), in the presence of an alkaline boron hydride and a halogen. Suitable halogens are in particular chlorine and iodine. The amines, β-amino alcohols and diamines are versatile synthesis structural units and may be used as racemate splitting reagents, structural units for peptide analogues and also as pharmaceutical raw materials.

Description

Process for the reduction of carboxylic acids or

Carboxylic acid derivatives and new compounds

description

The invention relates to a process for the reduction of carboxylic acids or carboxylic acid derivatives of the general formula I.

according to the preamble of claim 1 and new connections that can be produced with this method.

Amines and β-amino alcohols and also oiamines

versatile synthetic building blocks. Corresponding chiral compounds are particularly important

Components, for example to display optically active connections.

An overview for amino alcohols is given by G. M. Coppola, H.F. Schuster, Asymmetry Synthesis, John Wiley and Sons, New York 1987; M. Nogradi, S tereoselective

Synthesis, Verlag Chemie, Weinheim 1987. The β-amino alcohols are used for the production of chiral

Catalysts with which enantioselek t ive

Cyclopropanations, reductions, hydrolysations, Oiels-Alder reactions and other reactions can be carried out, gives an overview

C. Bolm, Angew. Chem. 1991, 103, 556. The β-amino alcohols are often important

Synthesis intermediates built in to

Subsequent reactions due to steric or

electronic influences the formation of

To induce asymmetry centers, the enantio- or diastereomer excesses often achieved

are extraordinarily high. As examples

4-substituted oxazolidin-2-one (J.R. Gage,

D. A. Evans, Org. Synth. 1989, 68, 77 and there

quot. Lit.) and the bicyclic lactams (D. Romo, A.I. Meyers, Tetrahedron 1991, 47, 9503).

β-amino alcohols can be integrated into peptide isosteres, products with high physiological

Activity, for example enkephalin analogues with stronger and longer-lasting analgesic effects (Y. Kiso, M. Yamaguchi, T. Akita,

H. Moritoki, M. Takei, H. Nakamura,

Natural Sciences 1981, 68, 210; J. Pless, W. Bauer, F. Cardinaux, A. Closse, D. Hauser, R. Huguenin,

D. Roemer. H. H. Buescher, R. C. Hill, Helv. Chim.

Acta 1979, 62, 398). Β-Amino alcohols are also suitable as C-terminal protective groups in peptide synthesis (C. Kashima, K. Harada, Y. Fujioka, T. Maruyama,

Y. Omote, J. Chem. Soc. Perkin Trans. I 1988, 535). For the cleavage of racemates, β-amino alcohols were used, either by fractionally crystallizing the tereomeric salts of N-alkyl-β-amino alcohols (M. Tukamoto, T. Sawayama, Dainippon Pharma ceutical Co., EP 0 105 696 AI. April 18, 1984 F. Horiuchi, M. Matsui, Agric. Biol. Chem. 1973, 37, 1713) or diastereomeric addition compounds were separated chromatographically (K. Ogura, M. Ishida, H. Tomori,

M. Fujita, Bull. Chem. Soc. Jpn. 1989, 62, 3531). For those derived from β-amino alcohols

1,3,2-oxazaphospholidine-2-sulfide became insecticide

Activity demonstrated (S. Wu, R. Takeya, M. Eto,

C. Tomizawa, J. Pesticide Sei. 1987, 12, 221).

Various methods exist for the preparation of the optically active β-amino alcohols. You can e.g. B. are obtained by racemate resolution, either as a conventional fractional crystallization of diastereomeric salts as in the case of

(S} -2-aminobutanol, the precursor of

Tuberculosis drug Ethambutol (F. Lanzendörfer, G. Fritz, H. Siegel, BASF AG, DE 35 17 108 A1.

November 13, 1986, and cited there. Lit.), or by

enzymatic cleavage of suitable derivatives can be carried out (F. Francalani, P. Cesti, W. Cabri,

D. Bianchi, T. Martinengo, M. Foa, 3. Org. Chem. 1987, 52, 5079, and cited there. Lit., H. S. Bevinakatti,

R.V. Nevadkar, Tetrahedron: Asym. 1990, 1, 583).

Reductive are fundamentally different

Method. Optically active β-amino alcohols were obtained for the first time by reducing optically active amino acid esters, although with considerable

Racemization (P. Karrer, W. Karrer, H. Thomann,

E. Horlacher, W. Mäder, Helv. Chim. Acta 1921. 4, 76). Later, this reaction could also be made using Lithium aluminum hydride (P. Karrer, P. Portmann,

M. Suter, Helv. Chim. Acta 1948, 31, 1617) or

Sodium borohydride (H. Seki, K. Kogo, H. Matsuo,

S. Ohki, I. Matsuo, S. Yamada, Chem. Pharm. Bull.

1965, 13, 995), it being possible to show that these and other hydride reductions proceed practically without racemization

(G. S. Poindexter, A.I. Meyers, Tetrahedron Lett. 1977, 3527). Because of the time-consuming two-step process of reducing the amino acid esters

However, sodium borohydride has established itself as the standard method of reducing the free optically active amino acids with lithium aluminum hydride (D.A. Dickmann, A.I. Meyers, G.A. Smith, R.E. Gawley, Organic

Syntheses Coll. Vol. VII, p. 530. John Wiley & Sons, New York 1990). A borane-dimethyl sulfide complex with activation by boron trifluoride etherate can also be used (J.R. Gage, D.A. Evans, Org.

Synth. 1989. 68, 77; G.A. Smith, R.E. Gawley, Org. Synth. 1985, 63, 136). It has recently been shown that with suitable activation also

Lithium borohydride (with trimethylchlorosilane: A. Giannis, K. Sandhoff, Angew. Chem. Int. Ed. Engl. 1989, 28, 218) or sodium borohydride (with trimethylchlorosilane: R. Dharanipragada, A. Alarcon, VJ Hruby, Org. Prep. Proc. Int. 1991, 23, 396; with boron trifluoride etherate: WHJ Boesten, CHM Schepers, MJA Roberts (Stamicarbon BV) EP 0 322 982 A2, 05.07.1989) for the direct reduction of amino acids. However, all of the methods mentioned have disadvantages which have hitherto prevented use on a larger scale. So the two-step reactions are about that

Intermediate stage of the esters from the outset time consuming and too expensive. Reductions with lithium aluminum hydride can be carried out quickly and efficiently on a laboratory scale

slight flammability of LiAlH ₄ but special

Precautions. In addition, the reagent is uneconomical due to its high price. The use of a borane-dimethyl sulfide adduct is one

considerable odor nuisance. In the methods that use boron trifluoride etherate as an activator, this reagent is used in molar amounts, which increases problems with the

Disposal of fluoride-containing residues are conditional. An addition of alkylhalosilanes to

Activation of the alkali borohydride leads to the formation of unusable silanes or siloxanes.

The preparation of amines by reduction of the corresponding amides is also generally known and can be carried out using a large number of reducing agents. Provide reviews: J. March, Advanced Organic Chemistry, 3rd Ed., John Wiley and Sons, New York 1985, pp. 1093 ff .; B. C. Challis, J. A. Challis, in: The Chemistry of Amides (Ed .: J. Zabicky),

Interscience Publishers, London 1970, pp. 795 ff. Because of their great power of reduction, the use of different ones is particularly widespread

Aluminum hydrides, however, are the use of these

On a larger scale, reagents often have the high price and safety problems due to the easy flammability. The use of borane complexes such as borane-tetrahydrofuran (ME Jung, JC Rohloff, J. Org. Chem. 1985, 50. 4909) or borane-dimethyl sulfide (KA Parker, CA Coburn, J. Org. Chem. 1992, 57, 97) is problematic for the same reasons, with the latter reagent additionally because of the unpleasant smell. The two step process of conversion to thioamide and

subsequent desulfurization with Raney nickel

(M.E. Kuehne, J. Am. Chem. Soc. 1964, 86, 2946;

E. Pfammatter. D. Seebach, Liebigs Ann. Chem. 1991, 1323) appears because of the complex

Reaction management, the expensive Raney nickel, the

Production of waste containing nickel and

Odor nuisance is also technically unattractive.

Aminoborohydrides made from a borane amine complex and a strong base are also

successfully used in the reduction of amides, but with sodium aminoborohydrides

(R. O. Hutchins, K. Liam, F. El-Telbany,

Y. P. Stercho, J. Org. Chem. 1984. 49. 2438), the reaction times were mostly very long, and mixtures of the amine and the corresponding alcohol were often obtained due to reductive cleavage of the amide.

Lithium pyrrolidinoborohydride, an obviously very powerful reducing agent, gave the corresponding alcohol in the reaction with a tertiary amide

(G. 8. Fischer, J. Harrison, J. C. Füller,

CT Goralski, B. Singaram, Tetrahedron Lett. 1992, 33, 4533). Therefore there have been attempts for some time

Alkali metal borohydrides that are technically easier to control, but on their own

Reduction of amides are generally not reactive enough to be activated by suitable additives. This is how the reaction with sodium borohydride is successful with the addition of cobalt (II) chloride (T. Satoh, S. Suzuki,

Y. Suzuki, Y. Miyaji, Z. Imai, Tetrahedron Lett. 1969, 4555). Titanium (IV) chloride (S. Niwa, K. Soai, J. Chem. Soc. Perkin Trans. I 1991. 2717; K. Soai, H. Hayashi, H. Hasegawa, Heterocycles 1986, 24, 1287),

Tin (IV) chloride (Y. Tsuda, T. Sano, H. Watanabe, Synthesis 1977, 652) or dialkyl selenium dihalides (S. Akabori, Y. Takanohashi, S. Aoki, S. Sato,

J. Chem. Soc. Perkin Trans. I 1991, 3121). However, there is a technical application here

unavoidable production of large quantities of metal-containing waste. The use of the system

Sodium borohydride acetic acid is limited to the reduction of primary and secondary amides, while for tertiary amides the toxic and significantly more expensive one

Trifluoresic acid must be used (N. Umino, T. Iwakuma, N. Itoh, Tetrahedron Lett. 1976, 763). The reduction of amides with sodium borohydride in acidic dimethyl sulfoxide (S. R. Wann, P. T. Thorsen,

MM Kreevoy. J. Org. Chem. 1981, 46, 2579) as well as an activation of sodium borohydride by thiols (Y. Maki, K. Kikuchi, H. Sugiyama, S. Seto, Chem. Ind. 1976, 322) due to the at work with sulfur compounds almost unavoidable unpleasant smell on a technical scale hardly possible. The The same argument applies to the reduction. of amides with sodium borohydride and pyridine (Y. Kikugawa, S. Ikegami. S. Yamada, Chem. Pharm. Bull. 1965, 13 394; ibid. 1969, 17, 398). With the help of

Phosphorus oxychloride (M.E. Kuehne, P.J. Shannon, J. Org. Chem. 1977, 42, 1977) or

Phosphorus pentachloride (A. Rahman, A. ßasha, N. Waheed, S. Ahmed, Tetrahedron Lett. 1976, 219) can be obtained from amides, the corresponding chloriminium salts, which can be reduced with ethanolic sodium borohydride. In similar experiments to

However, reduction of amino acids led to the formation of poorly soluble polymeric and phosphine-like

malodorous products were observed, dimers were also isolated (Kuehne and Shannon), so that this variant is also used in technical tests

Difficulties can be expected.

A significant step forward was the activation of alkali borohydrides with boron trifluoride etherate

(U. Groth, L. Richter, U. Schöllkopf, Tetrahedron 1992, 48, 117) or chlorotrimethylsilane (A. Giannis, K. Sandhoff, Angew. Chemie. 1989, 1091, 220). When used on a larger scale, the toxicity of boron trifluoride and the production of fluoride-containing waste or the relatively high price of chlorotrimethylsilane must be considered. A special case is a method in which lithium borohydride with catalytic amounts

Lithium triethyl borohydride to reduce a

N-protected imidazolidin-4-one is used

(Pfammatter and Seebach). From Tetrahedron Lett. 33, 5517-8, 1992

Various reduction methods based on NaBH ₄ for free or N-protected amino acids are known, including the NaBH ₄ -I _{2 system} . It is reduced

only the carboxylic acid, in some systems, despite simple amino acids (e.g. L-valine)

Yields very low.

The object of the invention is to provide a process for reducing carboxylic acids or carboxylic acid derivatives

Show presentation of amines, especially β-amino alcohols and diamines, the reduction under mild conditions and while preserving any

Chirality centers should be feasible. The

Reaction should be carried out with inexpensive and easily and safely manageable reagents, with a slight workup and an unproblematic table after the end of the reaction

Disposal of the residues should be guaranteed.

This object is achieved in the process described at the outset by the use of an alkali borohydride and a halogen as a reducing agent.

The reduction of alkyl or aryl carboxylic acids to the corresponding alcohols by means of sodium borohydride and activation by iodine is known in principle

(M. Periasamy, J.V. Bhaskar Kanth, J. Org. Chem.

1991, 56, 5964), but this method has so far been restricted to structurally relatively simple and in particular optically inactive compounds. According to the invention, it has now been found that this reducing agent system is suitable for reactions of sensitive compounds which have hitherto been difficult or expensive and costly, for example

Amino acids that can be used. The compounds to be reduced according to the invention are in particular optically active and become optical while maintaining them

Reduced activity. It is particularly advantageous that the process according to the invention can also be used to reduce the amides which are generally difficult to reduce with complex hydrides.

Suitable halogens are especially chlorine and iodine and bromine. The reduction is on a laboratory scale

performed with iodine because of the easier dosing. The iodide present at the end of the reaction can, if desired, with a

Oxidizing agents can be converted back into iodine by known methods. Particularly preferred

especially for free amino acids, is the cheaper chlorine, which is directly gaseous to activate the

Alkali borohydride can be used. The resulting chloride is not serious

Disposal problem. The reaction in a suitable solvent, in particular an ether, such as tetrahydrofuran or is advantageous

Ethylene glycol dimethyl ether. As

Alkali borohydrides are particularly suitable

inexpensive, safe to use and relatively easily soluble compounds in sodium and ether

Lithium borohydride as well as the potassium compound.

According to the invention, a large number of carboxylic acids or carboxylic acid derivatives can be added to the corresponding ones

Alcohols, amino alcohols. Amines or diamines can be reduced. The reaction is preferred - despite the

relatively insensitive reagents - carried out under protective gas, in particular a noble gas such as argon. As a result, the yield can be increased in some cases up to -100.

The compounds to be reduced according to the invention can be converted into a general formula I.

summarize what

R ¹ for H. is an alkyl or aryl radical, each with

up to 20 carbon atoms, and

X represents a group which increases the carbonyl carbon by one oxidation state.

Particularly suitable radicals for X are OR ² or NR ² R ³ , the radicals R ² and R ^{3 being} independently of one another

H, alkyl and / or aryl radicals each having up to 20 carbon atoms. In the case of OR ² , hydrogen or an alkyl radical having up to 6 carbon atoms is preferred. All alkyl or aryl radicals can be functional groups which optionally contain heteroatoms

Groups substituted and / or via one or more

Heteroatoms can be multiplied by

Multiple compounds of the formula I can also be multiplied with one another via the radicals R ¹ to R ³ connected, such as in the case of a

Peptides. Heteroatoms over which the alkyl or

Aryl radicals can be multiplied, in particular O, N and S. Particularly interesting substituents are, for example, OR ', NR'R'',PR'R'', P (O) R'R'', P (OR') ( OR "). P (O) (OR ') R'', P (O) (OR') (OR ''), SR ', S (O) R', S (O) ₂ R ', S ( O) ₂ OR ', F, Cl, Br, I, CN, CHO, C (O) R', C (O) OR ', C (O) Cl, C (O) NR'R'', alkenyl or Be alkynyl, where R 'and R''can independently be hydrogen or an alkyl or aryl radical having up to 20 C atoms.

The substituents can themselves be reducible groups. The reduction is not limited to the acid group shown in Formula I.

The compound of the formula I preferably has at least two C atoms, advantageously at least three C atoms, ie at least one of the radicals R ¹ to R ³

advantageous not H.

The alkyl and / or aryl radicals can be linked to one another, an example of such

Ring structure is, for example, proline. If that

Carboxylic acid derivative is an amide (X = NR ² R ³ ), then R ¹ can be freely selected as indicated above. In the case of carboxylic acids or other carboxylic acid derivatives of the general formula I, R ¹

, , , R ⁴ to R ⁷ can, independently of one another, like R ² and R ³ H, be an alkyl or aryl radical which is substituted and / or via one or more

Heteroatoms can be multiplied.

For all radicals R, the heteroatoms can be incorporated in the chain and / or in the aryl radical (heteroaromatics). The alkyl radicals can be straight-chain, branched-chain and / or cyclic, and can contain unsaturated bonds.

The compounds of formula I can be achiral, racemic or optically active. The method is particularly suitable for optically active amino acids and

Amino acid derivatives are suitable since the reduction according to the invention can be carried out while maintaining the optical activities and the resulting ones

Amino alcohols and diamines of considerable

commercial and scientific interests. If X = NR ² R ³ , the reduction according to the invention leads to a compound of the general formula III

R ¹² -CH ₂ NR ¹³ R ¹⁴ (III) otherwise to compounds of the general formula II.

In the formulas II and III, the radicals R ⁸ to R ^{11 are} identical to the radicals R ⁴ to R ⁷ and the radicals R ¹² to R ^{14 are} identical to the radicals R ¹ to R ³ or are derived from these by reducing any functional groups which may be present which are also reduced under the given conditions.

Compounds of the general formulas IV, VI, VIII and X which are reduced to the corresponding compounds of the general formulas V, VII, IX and XI are particularly preferably used.

... The general formulas VI and X show compounds in which the basic element of the two

general formula I is included.

The inventive method can advantageously be carried out so that the connection of the

general formula I and the borohydride are suspended or dissolved in a suitable solvent which dissolves the reactants sufficiently well, for example an ether, and

then, if necessary with cooling, the

Halogen is metered in, preferably in dissolved form or as a gas. The development of hydrogen and heat indicates the progress of the reaction. The reaction can in principle be carried out between very low and elevated temperatures, with the

Reactants preferably together at a temperature between -20 ° C and room temperature, in particular between 0 ° C and room temperature. Since the reaction is always more or less exothermic, cooling is usually advisable. Subsequently, it can advantageously be heated up to the boiling point of the solvent used to accelerate or complete the conversion.

Working up is carried out according to known methods, with excess initially being advantageous

Reducing agent is destroyed by the careful addition of alcohol or water. Occasionally, particularly stable boron-amine complexes are left for hydrolysis

However, organic solvents illate one

Treatment of the reaction mixture with the aqueous solution of an acid is appropriate. Then becomes Example based, the reaction product extracted with a suitable organic solvent and by distillation, crystallization or

Chromatography further purified if necessary.

Theoretically, the amounts of the reagents to be used result from the reactions taking place. The halogens turn the boronates into more reactive

Conveyed borane species, whereby to reduce the

Halogens X ₂ to halides 2 X- two hydride equivalents are consumed, so that each used

Equivalent halogen X _{2 in} principle two equivalents of boranate are to be used. The boranes then presumably bring about the actual reduction, whereby to

Conversion of an amide to an amine two

Hydride equivalents, for the conversion of a carboxylic acid into an alcohol also two hydride equivalents, for each acidic proton present in the molecule, one equivalent again for its neutralization and

Reduction of any further reducible functional groups that may be present, possibly additional ones

Hydride equivalents are necessary. So requires

for example the reduction of an N-acylated

Amino acid to the corresponding N-alkylamino alcohol-2 hydride equivalents to reduce the amide to

Amine,

- 2 hydride equivalents to reduce the acid to

alcohol

- 2 hydride equivalents to neutralize the

Carboxyl and the amide proton as well

- 2 hydride equivalents for the reduction of one halogen

X ₂ to two halides X-, with 2 equivalents of active borane species. However, since amides are often difficult to reduce and the last reacting hydride functions of the boranes have only a weakened reducing power compared to the first reacting ones, it is often necessary to use a sometimes significant excess of reducing agent in order to achieve the most complete conversion possible. The suitable proportions of the reactants can be determined in a few suitable experiments because of the broad applicability of the reactions.

Overall, this new process offers one

interesting access to especially optically active amino alcohols and amines, since it uses inexpensive and technically relatively unproblematic raw materials such as α-amino acids and primary, secondary or tertiary amines and the reactions are easy and safe to set up and easy to work up. The quality of the process is underlined by the high quality

achievable yields and maintaining optical activity during the reaction; the rotation values of most products correspond to the literature data, insofar as these exist.

With the process according to the invention, the compounds L-tyrosinol hydroiodide, N-ethyl-D-phenylalaninol, (S) -2-amino-1 - [(2-methylpropyl) amino] -3-phenylpropane, (S) -2 -Isopropylpiperazine dihydrochloride are prepared, which also belong to the invention. The compounds can be used as racemate resolution reagents. Building blocks for peptide analogs and also as pharmaceutical

Raw materials.

The process is illustrated by the following examples. Examples:

1. L-tert-leucinol

6.92 g (183 mmol) of sodium borohydride and 10.0 g (76 mmol) of L-tert-leucine were added to 200 ml of THF under argon. A solution of 19.3 g (76 mmol) of iodine in 50 ml of THF was then added dropwise at 0.degree. C., with vigorous evolution of hydrogen starting. After the addition had ended, the mixture was heated to the reflux temperature for 18 h and then cooled to room temperature and methanol was carefully added dropwise until the reaction solution became clear. The mixture was then stirred for 30 minutes, the solvent was distilled off, the residue was taken up in 150 ml of 20% strength aqueous potassium hydroxide solution and the mixture was stirred for 4 hours. The mixture was then extracted three times with 150 ml of methylene chloride, the extract was dried over sodium sulfate, evaporated and the residue (100%) was distilled in a Kugelrohr oven.

Yield: 7.53 g (84%) colorless solid

Bp: 90 ° C / 0.2 mm

[α] _D ²⁰ : + 37 ° (c = 1, EtOH)

(Lit .: [α] _D ²⁵ : + 37.24 ° (c = 1.02, EtOH), H. Nishiyama, H. Sakaguchi, T. Nakamura, M. Norihata, M. Kondo, K. Itoh, Organometallics 1989, 8, 846)

2. L-valinol

The presentation was carried out analogously to Example 1.

Yield: 100% colorless solid (crude product)

Bp: 75 ° C / 6 mm

[α] _D ²⁰ : +17 ° (c = 10, EtOH)

(Lit.: [α] _D ²¹ : +17 ° (c = 10, EtOH), Aldrich catalog 1990-1991)

3. D-phenylglycinol

The presentation was carried out analogously to Example 1.

Yield: 91% colorless solid (crude product)

M.p .: 69 - 71 ° C (from toluene)

[α] _D ²⁰ : -32 ° (c = 0.75, 1N HCl)

(Lit .: [α] _D ¹⁹ : -31.7 ° (c = 0.76, 1N HCl), Aldrich catalog

1990-1991)

4. L-phenylalaninol

The presentation was carried out analogously to Example 1.

Yield: 95% colorless solid (crude product)

M.p .: 86 - 88 ° C (from toluene) [α] _D ²⁰ : -22 ° (c = 1, 2, 1 N HCl)

(Lit .: [α] _D ²⁰ : -22.8 ° (c = 1.2, 1N HCl), Aldrich catalog

1990-1991)

5. L-prolinol

The representation. was carried out analogously to Example 1.

Yield: 96% colorless liquid (crude product)

Bp: 80 ° C / l mm

[α] _D ²⁰ : + 30 ° (c = 1.6, toluene)

(Lit .: [α] _D ²⁰ : + 31º (c = 1, toluene), Aldrich catalog 1990-1991)

6. L-isoleucinol

The presentation was carried out analogously to Example 1.

Yield: 8.78 g (75%) colorless crystal mass

Bp: 100-101 ° C / 5 mm

M.p .: 38 - 40 ° C

[α] _D ²⁰ : + 3.5 ° (c = 1, EtOH)

(Lit .: [α] _D ²² : + 5.4 ° (c = 1.6, EtOH), Aldrich catalog 1990-1991; [α] _D ²⁵ : -3.6 ° (c = 1.776, EtOH) , H. Seki, K. Koga, H.

Matsuo, S. Ohki, I. Matsuo, S. Yamada, Chem. Pharra. Bull

1965, 13, 995; [α] _D ²⁵ : -3.62 ° (c = 3.35, EtOH), S. Itsuno, A.

Hirao, S. Nakahama, N. Yamazaki, J. Chem. Soc. Perkin Trans.

I 1983, 1673)

7. L-methioninol

The presentation was carried out analogously to Example 1.

Yield: 8.73 g (65%) colorless liquid

Bp: 140 ° C / 1 mm

[α] _D ²⁰ : -14.0 ° (c = 1, EtOH)

(Lit .: [α] _D ²⁴ : -12.7 ° (c = 1, 4, EtOH), Aldrich catalog 1990-1991)

8. L-tyrosinol hydroiodide

9.10 g (0.10 mol) of sodium borohydride, then 18.1 g of L-tyrosine were first added to 500 ml of THF at room temperature. A solution of 25.4 g (0.10 mol) of iodine in 75 ml of THF was then added dropwise at 8-10 ° C. and the mixture was then heated under reflux overnight. After cooling to room temperature, 50 ml of methanol was added dropwise. The solvent was then evaporated off, the residue was dissolved in 100 ml of 2N hydrochloric acid and evaporated again, followed by two 200 ml portions of ethanol. stilled and the residue was stirred at 40 ° C. with 300 ml of ethanol. After filtration, the mixture was concentrated until the crystals formed, left overnight at 5 ° C., the solid was filtered off with suction, washed with ethanol, dried, taken up in 43 ml of ethanol, filtered hot and, after distilling off about 20 ml of ethanol, left at 5 ° C. overnight . The crystallized solid was filtered off, washed with a little ethanol and dried at about 50 ° C. in a vacuum drying cabinet.

Yield: 13.4 g (45%) colorless crystals

M.p .: 220-223 ° C (dec.)

[α] _D ²⁰ : -13.6 ° (c = 2, water)

C9H19INO2 calc. C 36.63 H 4.78 N 4.75 I 43.00

295.13 found C 36.79 H 4.82 N 4.69 I 42.40

(Traces Cl 0.55)

9. L-phenylalaninol

First, 16.52 g (0.10 mol) of L-phenylalanine, then 9.10 g (0.24 mol) of sodium borohydride were firmly introduced into 250 ml of THF. With ice cooling, 7.09 g (0.1 mol) of chlorine were passed into this solution over the course of 1 h, with vigorous evolution of hydrogen and a vigorous exotherm occurring. After stirring for 1 day under reflux, the mixture was hydrolyzed at room temperature with 30 ml of methanol, evaporated to dryness, taken up in 150 ml of 20% potassium hydroxide solution, extracted three times with 200 ml of methyl tert-butyl ether and evaporated to dryness again (residue 14.92 g ( 99%) colorless solid). After recrystallization from toluene twice, the product was filtered off, washed with a little toluene and dried in a vacuum drying cabinet at 50 ° C.

Yield: 8.36 g (55%) colorless solid

[α] _D ²⁰ : -23.4 ° (c = 1, EtOH)

(Lit .: [α] _D ²⁰ : -22.8 ° (c = 1.2, 1N HCl), Aldrich catalog 1990-1991)

10. N-methyl-L-phenylalaninol

9.10 g (0.24 mol) of solid sodium borohydride were added with stirring to a solution of 19.32 g of N-formyl-L-phenylalanine (0.10 mol) in 250 ml of tetrahydrofuran (THF), with vigorous gas evolution starting . A solution of 25.40 g (0.10 mol) of iodine in 100 ml of THF was then added dropwise at a temperature of 25-40 ° C and then stirred under reflux overnight, forming a thick suspension. After dripping After hydrolysis with 30 ml of methanol at room temperature, the reaction mixture was spun in at 40 ° C. and the colorless residue was taken up in 100 ml of 20% potassium hydroxide solution. This solution was extracted three times with 150 ml each of methyl tert-butyl ether (MTBE) and, after drying over sodium sulfate, the extract was evaporated to dryness to give a pale yellow oil which was crystallized with 200 ml of hot n-hexane. After filtration and drying, 13.88 g of a colorless solid were obtained. Recrystallization from 20 ml of toluene again gave a colorless, crystalline solid. A second batch was obtained by rotating the mother liquors in both crystallizations and recrystallizing the residue from 5 ml of ethyl acetate. Both batches of N-methyl-L-phenylalaninol were combined.

Yield: 12.04 g (73%) of colorless crystals

M.p .: 70.5-73.5 ° C

[α] _D ²⁰ : + 21.8 ° (c = 1, EtOH)

(Lit .: [α] _D ²⁰ : + 17.1 ° (c = 2, chloroform), A. Karim, A. Mortreux, F. Petit, G. Buono, G. Pfeifer, C. Siv, J. Organomet.

Chem. 1986, 317, 93)

C10H15NO calc. C 72.69 H 9.15 N 8.48

165.23 found C 72.36 H 9.28 N 8.36

11. N-ethyl-D-phenylalaninol

20.70 g (0.10 mol) of solid N-acetyl-D-phenylalanine were added to a suspension of 9.10 g (0.24 mol) of sodium borohydride in 250 ml of THF with stirring. 25.40 g (0.10 mol) of iodine, dissolved in 75 ml of THF, were then added dropwise over 45 minutes while cooling with ice at 10-13 ° C. After stirring overnight under reflux, the mixture was hydrolyzed dropwise at room temperature with 20 ml of methanol and the reaction mixture was evaporated. The residue was taken up in 200 ml of 20% potassium hydroxide solution and extracted three times with 150 ml of MTBE. After drying over magnesium sulfate, the mixture was evaporated in a rotary evaporator and the residue, 22.9 g, was recrystallized from 200 ml of n-hexane, giving N-ethyl-D-phenylalaninol as a colorless solid.

Yield: 14.9 g (83%)

M.p .: 82-84 "C.

[α] _D ²⁰ : -11.6 ° (c = 1, EtOH)

C11H17NO calc. C 73.70 H 9.56 N 7.81

179.26 found C 73.51 H 9.69 N 7.91 12. N-ethyl-L-prolinol

15.72 g (0.10 mol) of N-acetyl-L-proline and 9.10 g (0.24 mol) of sodium borohydride were firmly introduced into 250 ml of THF, with a clear development of heat and gas occurring. A solution of 25.40 g (0.10 mol) of iodine in 100 ml of THF was added dropwise to the resulting suspension, the suspension being thicker and a clear exotherm and gas evolution being observed. After heating under reflux overnight, the mixture was hydrolyzed at room temperature with 30 ml of methanol, concentrated in a rotary evaporator, the residue was taken up in 200 ml of water, stirred for 2 h, the solution was made basic with 100 ml of 20% strength potassium hydroxide solution, extracted four times with 150 ml of MTBE and the extract evaporated after drying over sodium sulfate. The pale yellow oil obtained was taken up in 50 ml of water, the solution was stirred for 30 min, mixed with 50 ml of 5% hydrochloric acid, stirred for a further 90 min, made basic with 50 ml of 20% potassium hydroxide solution, extracted four times with 150 ml of methylene chloride each time Extract dried over sodium sulfate and evaporated. The pale yellow oil obtained (8.31 g) was then distilled in a bulb tube.

Yield: 7.39 g (57%) colorless oil

Sdp .: 80 - 85 ° C / 0.4 mm

[α] _D ²⁰ : -84.8 ° (c = 1, EtOH)

(Lit .: [ɸ] _D : -110.4 ° (c = 1.9, MeOH), CF Hammer, JD Weber, Tetrahedron 1981, 37, 2173)

C7H15NO calc. C 65.08 H 11.70 N 10.84

129.20 found C 64.72 H 12.12 N 11.14

13. N-benzylaminoethanol

18.2 g (0.48 mol) of sodium borohydride were added to a suspension of 35.8 g (0.20 mol) of hippuric acid (N-benzoylglycine) in 500 ml of THF under argon, gas evolution and a clear exotherm being observed. A solution of 50.8 g (0.20 mol) of iodine in 150 ml of THF was then added dropwise at 8-10 ° C. in the course of 1 hour and the mixture was then refluxed overnight. After cooling to room temperature, excess hydride was destroyed by dropwise addition of 50 ml of methanol and the reaction mixture was evaporated. The residue was taken up in 100 ml of water and 30 ml of concentrated hydrochloric acid, the solution was stirred for 30 min, then made basic by adding 400 ml of 20% potassium hydroxide solution and extracted three times with 150 ml each of methyl tert-butyl ether. The extract was Triumsulfat dried, filtered, evaporated to dryness and the resulting oil distilled twice in a Kugelrohr.

Yield: 19.4 g (64.1%) colorless oil

Bp: 86-88 ° C / 0.4 mm

n _D ²⁰ : 1.544

(Lit: n _D ²⁰ : 1.5435, Aldrich catalog 1990 - 1991)

C9H13NO calc. C 71.49 H 8.67 N 9.26

151.21 found C 71.14 H 8.82 N 10.30

14. (S) -1-tert-butoxycarbonyl-2-tert-butyl-3-methyl-1,3-imidazolidine

A solution of 25.6 g (0.10 mol) of (S) -1-tert-butoxycarbonyl-2-tert-butyl-3-methyl-1,3-imidazolidin-4-one in 150 ml of THF was stirred 7.56 g (0.20 mol) of solid sodium borohydride were added. After 15 minutes, a solution of 12.7 g (0.05 mol) of iodine in 50 ml of THF was added dropwise at 5 ° C. over 1 hour and then heated under reflux for 44 hours. The mixture was then carefully hydrolyzed at 5 ° C. with 250 ml of saturated ammonium chloride solution, stirred at 50 ° C. until the evolution of gas ceased, the precipitate was dissolved by adding aqueous sodium hydroxide solution, the organic phase was separated off and the water phase was extracted four times with 150 ml of MTBE each time. After drying the extract and spinning in a colorless oil was obtained which slowly crystallized. It was taken up in 150 ml of n-hexane, an insoluble residue was filtered off and concentrated to 42 g. Large, colorless crystals were obtained in the freezer. Successive concentration of the mother liquor provided further crystals, which were combined with the first batch.

Yield: 14.79 g (61%) colorless crystals

M.p .: 50.5-52.0 ° C

[α] _D ²⁰ : +22.5 ° (c = 1, chloroform)

(Lit .: [α] _D : -22.8 ° (c = 1.22, chloroform) for the (R) -enantiomer; E. Pfammatter, D. Seebach, Liebigs Ann. Chem. 1991, 1323)

C13H26N2O2 calc. C 64.30 H 10.81 N 11.56

242.0 found C 64.57 H 11.05 N 11.58

15. (S) -2-Amino-1 - ((2-methylpropyl) amino] -3-phenylpropane To a thin suspension of 5.50 g (25 mmol) L-phenylalanine isobutylamide in 75 ml THF were initially 2.275 g (60 mmol) of solid sodium borohydride and then 6.275 g (25 mmol) of iodine, dissolved in 25 ml of THF, were added dropwise, one steady gas evolution and a moderate exotherm was observed. The mixture was then stirred under reflux for 2 d, then hydrolyzed at room temperature with 50 ml of methanol, evaporated in a rotary evaporator, the residue was dissolved in 200 ml of 1N sodium hydroxide solution, this solution was extracted four times with 100 ml of methylene chloride and the extract was evaporated after drying over sodium sulfate. The remaining yellowish oil was then distilled in a bulb tube.

Yield: 2.34 g (45%) colorless oil

Bp: 150-160 ° C / 0.4 mm

[α] _D ²⁰ : + 10.7 ° (c = 1, EtOH)

C13H22N2 calc. C 75.67 H 10.75 N 13.58

206.32 found C 74.93 H 10.74 N 14.16

16. (S) -2-isopropylpiperazine dihydrochloride

15.12 g (0.40 mol) of solid sodium borohydride were added to a suspension of 15.62 g (0.10 mol) of cyclo-glycyl-L-valine in 250 ml of THF with stirring, resulting in a low gas and Heat development came. A solution of 25.40 g (0.10 mol) of iodine in 100 ml of THF was then added dropwise, initially there being a clear exotherm and gas evolution, but finally the iodine was hardly decolorized. Thereafter, the mixture was stirred at room temperature for 1 h, then under reflux, hydrolyzed at room temperature with 50 ml of methanol, stirred for 1 h, concentrated in a rotary evaporator, taken up in 50 ml of water, made basic with 50 ml of 2N sodium hydroxide solution, extracted four times with 100 ml of methylene chloride, the extract is dried over sodium sulfate and evaporated. The residue (12.78 g of almost colorless oil) was dissolved in 125 ml of MTBE, filtered clear and 30 g of a 29% solution of hydrogen chloride in MTBE were added dropwise. The fluffy white precipitate was filtered off, dried (14.31 g) and recrystallized from 300 ml of ethanol. Yield: 6.14 g (31%) of fine, long, colorless needles

[α] _D ²⁰ : -3.1 ° (c = 1, water)

17. L-phenylalaninol

A solution of 25.40 was added to a suspension of 5.30 g (0.24 mol) of lithium borohydride and 16.50 g (0.10 mol) of L-phenylalanine in 250 ml of THF within 1 h at 5-12 ° C g (0.10 mol) iodine added dropwise in 75 ml THF. After heating to reflux overnight, 30 ml of methanol were carefully added dropwise at room temperature, the solvent was spun off, the remaining one Residue taken up in 170 ml of 20% potassium hydroxide solution and the solution extracted three times with 150 ml of MTBE. After drying over sodium sulfate, the extract was evaporated, the residue was recrystallized from toluene, filtered off, washed with a little toluene and dried in a vacuum drying cabinet at 50 ° C.

Yield: 10.50 g (70%) colorless crystals

M.p .: 92-94 ° C

[α] _D ²⁰ : - 24.2 ° (c = 1, EtOH)

(Lit .: [α] _D ²² : -22.8º (c = 1,2, 1N HCl), Aldrich catalog 1990-1991)

Claims

1. Process for reducing a carboxylic acid or a carboxylic acid derivative of the general formula

wherein

R ^{1 is} H, an alkyl or aryl radical each having up to 20 carbon atoms, and

X for one the carbonyl carbon one

Group which increases the oxidation level,

where X up to two H atoms, alkyl and / or

Aryl radicals R ² or R ³ , each with up to

Can carry 20 carbon atoms;

wherein each alkyl or aryl radical is substituted and / or via one or more heteroatoms

can be multiplied;

where alkyl and / or aryl radicals can be linked to one another;

where R is ¹ ,

if X is not -NR ² R ³ , wherein R ⁴ to R ⁷

independently have the meaning of R ² or R ³ including H. to a compound of general formula II

or to a compound of general formula III

wherein

R ⁸ to R ¹¹ with R ⁴ to R ⁷ and

R ¹² to R ^{14 are} identical to R ¹ to R ³ or from these by reducing reducible

functional groups have emerged «

characterized in that the reduction with an alkali borohydride and a halogen

is carried out.

A method according to claim 1, characterized in that an α-amino acid or its ester of

general formula IV

in which

* possibly represents an asymmetry center R ^{2 is} H or a C ¹ to C ⁶ alkyl radical which may optionally also be substituted and / or interrupted by one or more heteroatoms,

R ^{1 is} preferably H.

to a β-amino alcohol of the general formula V

is implemented

A method according to claim 1 or 2, characterized in that an N-acyl amino acid or its ester of the general formula VI

to an n-alkylated β-amino alcohol

general formula VII

is implemented.

4. The method according to claim 1, characterized in that an α-amino acid amide of the general formula VIII

to a diamine of the general formula IX

is implemented.

5. The method according to claim 1 or 4, characterized

characterized in that an amine nitrogen

acylated amino acid amide of the general formula X

to a diamine of the general formula XI

is reduced in which

R ³ 'and R ¹⁴ ' independently of R ³ and R ^{14 have} their general meaning.

6. The method according to any one of the preceding claims, characterized in that lithium, sodium or potassium borohydride is used as the alkali borohydride.

7. The method according to any one of the preceding claims, characterized in that chlorine, bromine or iodine is used as halogen.

8. The method according to any one of the preceding claims, characterized in that the reduction is carried out in a solvent, in particular in an ether.

A method according to claim 8, characterized in that the reactions between -20ºC and

Boiling temperature of the solvent used is carried out.

10. The method according to any one of the preceding claims, characterized in that the reaction mixture after the end of the reaction with an alcohol or water hydrolyzed, mixed with a base and

then the reaction product is extracted with a suitable organic solvent.

11. The method according to any one of claims 1-9, characterized in that the reaction mixture after the end of the reaction with an alcohol or water

hydrolyzed, mixed with an acid and

then a salt of the reaction product is extracted with a suitable solvent.

12. New connections, producible after a

Method according to one of claims 1-11,

L-tyrosinol hydroiodide, N-ethyl-D-phenylalaninol, (S) -2-amino-1 - [(2-methylpropyl) amino] -3-phenylpropane, (S) -2-isopropylpiperazine dihydrochloride.