FR2881425A1 - Process for preparing amino-alcohols or alcohols from amino-acids, carboxylic acids or their esters, comprises reduction of carboxylic acid or ester groups to give alcohol group in the presence of a reducing agent - Google Patents

Abstract

Preparation of amino-alcohols or alcohols from the amino acids, carboxylic acids or their esters, comprises reduction of carboxylic acid or ester groups to give alcohol group in the presence of a reducing agent. Preparation of amino-alcohols or alcohols from the amino-acids, carboxylic acids or their esters, comprises reduction of carboxylic acid or ester groups to give alcohol group in the presence of a reducing agent of formula (ZnXBH4) (where X is chlorine, bromine, iodine or fluorine).

Description

The invention relates to a process for the simple and cost-effective preparation of

  aminoalcohols and alcohols by direct reduction of the corresponding amino acids, carboxylic acids and esters using a new non-hazardous reducing entity.

  Processes for the preparation of amino alcohols or alcohols described in the literature generally use metal hydrides and can be classified into two main categories: processes requiring the prior obtaining of intermediates and direct processes.

  Processes requiring the prior obtaining of intermediates, such as protected esters or amino acids, are of a more complex implementation and require a greater number of operations. They are therefore less productive.

  Direct processes make it possible to reduce the carboxylic function or the ester function as a function of alcohol, without it being necessary to protect the reactive groups. Thus, these methods make it possible in particular to directly convert an amino acid to aminoalcohol, without it being necessary to protect the amino acid. The direct processes known from the prior art require for the most part dangerous reagents, such as LiAlH4, DiBAH (diisobutyl aluminum hydride), and BH3 complexed, or generate in situ versatile reagents such as diborane, thus there are combinations of sodium borohydride (NaBH4) with 12, concentrated H2SO4, TmsCl (trimethylsilylchloride), AlCl3, BF3.

  Red-Al (sodium bis (2-methoxyethoxy) aluminum hydride) makes it difficult or very difficult to obtain amino alcohols by direct reduction of the amino acids (see Aldrichimica Acta, 31, (1), 21-22). and J. Org Chem., (1993), 58, 3568 for a summary of the methods of amino acid reductions by hydrides). Only one method, using zinc borohydride (Zn (BH4) 2, allows the synthesis of amino alcohols under acceptable safety and yield conditions but under unproductive conditions (S. Narasimhan, S. Madhavan and K. GaneshwarPrasad, Synthetic Communications, 26 (4), 703-706 (1996) and Aldrichimica Acta, 31, (1), 19-26) In this process, the amino acid is reduced by a solution of 1 equivalent of Zn ( BH4) 2 0.28 M in THF (tetrahydrofuran) (30 volumes) Zn (BH4) 2 can be prepared beforehand by the reaction of ZnCl 2 + 2 NaBH 4 and is free of chlorine. THF for 5 hours However, the process described has low productivity In addition, the amount of NaBH4 required for the reduction is 2 equivalents for 1 equivalent of amino acid and Zn (BH4) 2 is unstable and is destroyed by Finally, the process only describes the production of unpurified amino-alcohols.

  Finally, there is also a process for direct reduction of amino acids by catalytic hydrogenation (WO9938838), but this process uses metal catalysts in large quantities (up to 1 gram of catalyst per gram of aminoalcohol obtained) and requires the use of high pressures (from 150.105 to 200.105 Pa).

  There is also a need for a high efficiency process which uses low-hazard reagents.

  However, the inventor has discovered, surprisingly, that by using as a reducing entity a halogenated derivative of zinc borohydride, a simple, productive process which does not use dangerous reagents and does not need to be passed is obtained. by an intermediary limiting the yield.

  The subject of the invention is therefore a process for the preparation of amino alcohols or alcohols from corresponding amino acids, carboxylic acids or esters respectively, characterized in that the reduction step of the carboxylic acid or ester function in the alcohol function is carried out in the presence of a reducing agent of formula ZnXBH4, where X represents Cl, Br, I or F. In the context of the present invention, the amino acid may be any known natural or synthetic amino acid of the skilled person.

  By natural amino acid are meant the amino acids selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, hydroxylysine, hydroxyproline, methionine, phenylalanine, proline, selenocysteine, serine, threonine, tryptophan, tyrosine and valine .

  Synthetic amino acids are especially those compounds which have an amine function, which may be substituted, and a carboxylic acid function. The amino acids for which the amine and carboxylic acid functions are carried by the same carbon are called α-amino acids. In the same manner, there may be mentioned α, β, β3-amino acids, for which, respectively, the acid function is in the β, β or β position of the amine function.

  Examples of synthetic amino acids that may be mentioned include (2 or 3) -aminoadipic, 2 (or 4) aminobenzoic, 2-aminobutyric, 4-aminobutyric acid (GABA), 2 (or 6) aminocaproic acid, amino-1-cyclohexane carboxylic acid, 1-amino-1-cyclopentane carboxylic acid, 8-amino-3,6-dioctanoic acid, 1-aminoindanecarboxylic acid, 2-aminoisobutyric acid, 3 (or 4) -aminomethylbenzoic acid, aminooxyacetic acid, 4-aminopyrollidinecarboxylic acid, 2- aminovaleric, azetidine-2-carboxylic, diaminobutyric, indoline-2-carboxylic, isonipecotic, nipecotic, phenyl-2-pyrrolidinecarboxylic, pipecolic, tetrahydroisoquinoline carboxylic, amino-1-carboxymethylpiperidine, tert-leucine, 4-carboxymethylpiperazine, 4-carboxymethylpiperidine, cyclohexylalanine, cyclohexylglycine, 3, 4-dimethoxyphenylalanine, homoleucine, homophenylalanine, hydroxyproline, naphthylalanine, 4-methylphenylalanine, 4-nitrophenylalanine, norleucine, norvaline, ornithine, phenylglycine or sarcosine.

  According to an advantageous variant of the invention, the amino acid corresponds to the formula (I) ## STR1 ## in which: - R is a hydrogen atom or a linear or branched alkyl radical; C1_C12, C6-C11 aryl, C7-C17 aralkyl, C5-C11 heteroaryl or C6-C17 heteroaralkyl, said radicals being capable of being substituted by one or more -NR3R4, alkyl, nitro (-NO2), hydroxy radicals (- OH) or halogen and may contain heteroatoms selected from the group consisting of N, O, Se and S, R1 and R2, independently of each other, represent a hydrogen atom, a linear or branched alkyl radical. C1-C12 or C3-C8 cycloalkyl, or R1 and R2 may together form, with the nitrogen atom which carries them, an aliphatic or aromatic ring of 5 to 8 members, said ring may be substituted by one or more radicals -NR3R4, alkyl, nitro, hydroxy or halogen and may contain heteroatoms selected from the group consisting of N, O, Se and S, or R and R1 together with the carbon and nitrogen atom carrying them respectively, form an aliphatic or aromatic ring of 5 to 8 members, said cycle being able to be substituted by a or more -NR3R4, alkyl, nitro, hydroxy or halogen radicals and which may contain heteroatoms chosen from the group consisting of N, O, Se and S, and R2 represents a hydrogen atom, a linear or branched C1-alkyl radical; C12 or C3-C8 cycloalkyl, and R3 and R4, independently of each other, represent a hydrogen atom, a linear or branched C1-C12 alkyl or C3-C8 cycloalkyl radical, or R3 and R4 together with the atom carrying them may form an aliphatic or aromatic ring of 5 to 8 members, said ring possibly comprising heteroatoms selected from the group consisting of N, O, Se and S, and n is a whole number ranging from 0 to 10, advantageously from 0 to 9. n is even more advantageously 0 or 1.

  According to an advantageous variant of the invention, the carboxylic acid corresponds to the formula R'-COOH or the ester corresponds to the formula R "-COO-R", in which R ', R "and R"' independently from each other, represent a linear or branched C1-C12 alkyl, C7-C12 aralkyl, C6-C11 aryl, C4-C10 heteroaryl or C5-C11 heteroaralkyl radical, which may be substituted by one or more radicals. -OH.

  In the context of the present invention, the term "alkyl" denotes a straight or branched chain hydrocarbon residue containing from 1 to 12 carbon atoms, advantageously from 1 to 6 carbon atoms, even more advantageously from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl and butyl.

  In the context of the present invention, the term "aryl" denotes an aromatic carbocyclic residue containing from 6 to 11 carbon atoms and the term "heteroaryl" denotes an aromatic carbocyclic residue containing from 6 to 11 carbon atoms, one or more of which may be carbon atoms. be replaced by heteroatoms selected from the group consisting of N, O, Se and S. Examples of aryl radical include phenyl and naphthyl, advantageously phenyl. As an example of a heteroaryl radical, imidazole, indole, furan, thiophene and pyrrole, advantageously indole and imidazole, may be mentioned in particular.

  In the context of the present invention, the term aralkyl designates a hydrocarbon residue containing from 1 to 6 carbon atoms bonded to an aryl radical, as defined above. As an example of an aralkyl radical, there may be mentioned in particular benzyl and phenethyl.

  In the context of the present invention, the term heteroaralkyl denotes a hydrocarbon residue containing from 1 to 6 carbon atoms bonded to a heteroaryl radical, as defined above. As an example of a heteroaralkyl radical, there may be mentioned pyridylmethyl and quinolin-3-ylmethyl.

  In the context of the present invention, the term cycloalkyl refers to a cyclic alkyl group containing from 3 to 8 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

  In the context of the present invention, the term halogen denotes chlorine, bromine, fluorine or iodine.

  The process advantageously comprises the following successive steps: a) formation of a complex (amino alcohol or alcohol) / borane by reaction between an amino acid or a carboxylic acid or an ester and said reducing agent in a suitable solvent; b) hydrolyzing the complex obtained in step a) to obtain the aminoalcohol or the desired alcohol; c) if appropriate, elimination of the mineral salts formed during step b); d) removing the solvent from the reaction and recovering the desired amino alcohol or alcohol.

  In the context of the present invention, the expression "reducing agent" denotes the compound of formula ZnXBH4, where X represents Cl, Br, I or F. The solvent of step a) is advantageously chosen from the group comprising THF, alkyl ethers, such as dimethyl ether, glycol ethers, such as diglyme and triglyme, and methyl THF.

  During step b), the complex may be hydrolysed either in an acid medium or in a basic medium. The hydrolysis is advantageously carried out by means of an organic or inorganic base, of greater basicity than said amino alcohol or alcohol, in a proportion of at least 2 equivalents, advantageously from 2 to 5 equivalents, of base with respect to the molar amount of reducing agent engaged.

  In the context of the present invention, the upper basic expression defines a base which has a pKb value lower than the pKb value of the amino alcohol or alcohol in question (or a pKa value greater than the value pKa of the amino alcohol or alcohol considered). The base used is therefore a stronger base than the amino alcohol or the alcohol in question, it thus has a stronger attraction of protons.

  For the hydrolysis step b), the complex obtained following step a) can be cast on the organic or inorganic base (reverse flow) or the organic or mineral base can be cast on the complex resulting from the step at). We prefer the reverse flow.

  The base used during this hydrolysis step is advantageously sodium hydroxide or potassium hydroxide in a concentration of 5 to 50% by weight in water, preferably 30 to 50% by weight in water.

  The concentration of the sodium hydroxide or potassium hydroxide solution used determines the water content of the organic solution of the amino alcohol or of the alcohol obtained following step b). Thus the use of a solution of sodium hydroxide or potassium hydroxide at 30% by weight leads to the production of a solution of the amino alcohol or alcohol measured at about 12% by weight of water. The use of a sodium hydroxide or potassium hydroxide solution at 50% by weight advantageously makes it possible to obtain a solution of the aminoalcohol or of the alcohol at approximately 4% by weight of water; the water is thus much more easily separated from the aminoalcohol or alcohol during the distillation of the solvent since it co-distills therewith.

  The amount of sodium hydroxide or potash required may be between 2 equivalents and 5 equivalents and more precisely and advantageously is fixed at 2 equivalents exactly with respect to the molar amount of reducing agent employed. The apparent pH of the medium is then advantageously between 9 and 14, preferably between 11 and 14. Under these stoichiometric conditions, there is no soda or free potash in the reactor, and the amino alcohol or The alcohol formed is readily recovered as a solution in the selected solvent without the need for additional steps of decantation and phase separation.

  During step b), the medium is advantageously heated to a temperature between 30 C and the reflux temperature of the solvent used in step a). In addition to allowing the destruction of the excess of hydride, this heating makes it possible to make the reaction medium very stirrable by stabilizing the formation of the mineral compounds and thus provides easy extraction of the inorganic salts. In the case of an excess of base, it may be removed by decantation and withdrawal after squeezing the inorganic salts, amino alcohol or alcohol remaining in solution in the solvent used.

  Hydrolysis of the reduction medium with sodium hydroxide or concentrated potassium hydroxide in an exactly stoichiometric amount relative to the molar amount of reducing agent employed, advantageously makes it possible to form easily-filterable salts, and to avoid any decantation and separating a possible aqueous phase, thus considerably improving the productivity and the necessary handling.

  If necessary, the formed inorganic salts are eliminated. To do this, the suspension obtained after step b) is filtered to recover these salts. The cake obtained is then rinsed with the solvent chosen so as to entrain and recover the amino alcohol or the alcohol in solution in the solvent. This solvent is advantageously chosen from the group comprising THF, glycol ethers, methyl THF, alkyl ethers. This solvent is advantageously the same solvent that was used in step a).

  The recovered inorganic salts are advantageously in the form of a very easy to handle powder, which can either be removed as such, or solubilized in water, optionally after neutralization, or even acidification.

  Then, in a simple manner, the solvent, if its boiling point is lower than that of the aminoalcohol or alcohol, is removed at atmospheric pressure or under vacuum, and the amino alcohol or the The desired alcohol is distilled under higher vacuum or at atmospheric pressure if its physical characteristics permit.

  In some cases, the solvent may be selected to co-distill with the amino alcohol or alcohol and thus prevent the latter from crystallizing too quickly during the distillation.

  In some cases it may be useful to choose a solvent with a higher boiling point so as to be able to constitute a distillation stand.

  The solvent can be recycled by dehydration with pearl soda following a simple technique and then re-distillation. In this case, a mass of pearl soda equal to the weight of water contained in the solvent is mixed with the solvent to be recovered, the 50% by weight sodium hydroxide solution obtained is stirred and then decanted, and the sodium hydroxide solution is withdrawn. it is possible to recycle and then the solvent is distilled at atmospheric pressure. Recyclable solvent is thus recovered with a water content of about 0.2% by mass.

  According to a variant of the invention, said reducing agent is formed beforehand.

  Step a) then advantageously comprises the following successive steps: i) adding 1 to 2 equivalents of said reducing agent (relative to the molar amount of amino acid, carboxylic acid or ester) to a suspension amino acid, carboxylic acid or ester in a suitable solvent; and ii) heating the solution obtained following step i) at a temperature between 30 ° C. and the boiling point of the solvent for 1 to 50 hours, advantageously 6 to 20 hours.

  In step i), 1 to 1.5 equivalents of said reducing agent are advantageously used, still more preferably 1.25 equivalents of said reducing agent, relative to the molar amount of amino acid, carboxylic acid or ester.

  When the amino acid, the carboxylic acid or the committed ester has two carboxylic acid functions or two ester functions, the amount of reducing agent introduced is doubled.

  The solution comprising said reducing agent is advantageously slowly poured onto the suspension comprising the amino acid or the carboxylic acid or the ester and a suitable solvent. The solution comprising said reducing agent is advantageously poured at a rate limited by the measurement of the evolution of hydrogen. The amount of hydrogen released at time t measures the progress of the reaction at this time. The casting can be carried out continuously, can be stopped without inconvenience and then resume depending on the gas evolution or the exotherm of the reaction.

  Step i) is advantageously carried out at a temperature of between 20 and 80 ° C., still more advantageously between 20 and 50 ° C. The solvent used in step i) is advantageously chosen from the group comprising THF and glycol ethers. , methyl THF, alkyl ethers. It is advantageously the same as that used for the formation of the reducer. In the case of a mixture of solvents, the boiling point is that of the most volatile solvent, except in the case of azeotropes (the boiling point is that of the azeotrope). In an advantageous embodiment, the same solvent is used in all stages.

  Following step ii), the aminoalcohol or alcohol is formed as a borane complex.

  Halogenozinc borohydride ZnXs: BH4, where X represents a halogen, can be formed by the stoichiometric mixture of ZnCl2 or any other zinc halide (bromide, iodide, etc.) and NaBH4, KBH4, LiBH4, Zn (BH4). 2, or other borohydrides; however, sodium borohydride will be preferred.

  In the context of the present invention, the reducing agent is advantageously chlorozinc borohydride.

  Chlorozinc borohydride or ZnC1BH4 is described in the book Reduction with complex metal hybrids of Norman G. GAYLORD, Interscience Publishers Inc., NEW YORK 1956, in parallel with zinc borohydride Zn (BH4) 2.

  The chlorozinc borohydride formed beforehand is advantageously synthesized by casting a solution of zinc chloride, solubilized in 2 to 10 volumes of the chosen solvent (solvent of step a)), advantageously 3 to 4 volumes of solvent, relative to with zinc chloride, on a suspension of sodium borohydride in the same solvent as that of step a). The mixture obtained is advantageously left in contact at a temperature of between 30 and 50 ° C., and is then cooled to ambient temperature.

  In practice, it will be preferred to introduce a small excess of borohydride with respect to zinc chloride, since part of the borohydride is degraded in contact with the free acidity of zinc chloride, an advantageous proportion being 1.25 equivalents of NaBH4 for 1 to 1.25 equivalent (s) of ZnC12.

  When zinc chloride is used in stoichiometric equivalence with borohydride, the excess of the reagents will advantageously be at least equal to 1.25 equivalents for 1 equivalent of amino acid, or carboxylic acid or ester, to be reduced. According to another variant, at least 1.25 equivalents of sodium borohydride, or of another metal, and at least 1 equivalent of zinc chloride, relative to the committed molar amount of amino acid, may be used, or carboxylic acid or ester.

  Halogenozinc borohydride can also be obtained by the following methods: addition of NaBH4 powdered or suspended in a compatible solvent, to a solution or mixture of ZnCl2 and the product to be reduced, addition of ZnCl2 to a mixture of the product to reduce and NaBH4, addition of NaBH4 to a solution or a suspension of ZnCl2 in a compatible solvent, then adding the product to be reduced on the suspension obtained, etc ... but these solutions are more difficult and more random from the point of view process safety. The methods described in detail above in the description will be preferred as being safer and more easily industrializable since they do not involve the addition of solids to a medium which releases hydrogen in a flammable solvent.

  According to another variant of the invention, said reducing agent is formed in situ.

  Step a) then advantageously comprises the following successive steps: 1) mixing an amino acid having a free NH 2 function with 1 to 2 equivalents of a zinc halide ZnX 2, relative to the molar amount of amino acid in a solvent to form an amino acid / zinc halide complex; 2) casting the amino acid / zinc halide complex on a suspension containing 1 to 2 equivalents of borohydride, relative to the molar amount of amino acid, in a solvent (preferably identical to that of step 1) ), said borohydride being in molar excess with respect to the zinc halide,; 3) at the end of the casting, heating the reaction medium to a temperature between 30 C and the boiling point of the solvent for 1 to 50 hours, to form an amino-alcohol-borane complex.

  In the formula ZnX2, X represents Cl, Br, I or F. The amino acid / zinc halide complex obtained following step a) is generally soluble.

  In accordance with the present invention, and in the case where the reductant is made active in situ, the amino acid is first suspended in a solvent, selected from the group consisting of THF, alkyl ethers, such as dimethyl ether, glycol ethers, such as diglyme and triglyme, and methyl THF. Then, the zinc halide is added to the previous suspension.

  The amount of zinc halide can vary from 0.5 to 2 equivalents and more preferably is advantageously between 1 and 1.25 equivalents relative to the molar amount of committed amino acid; the quantity needed to obtain a complete solution and then a complete reduction of at least 1 equivalent.

  The solvent used in step 1) is advantageously chosen from the same group as the solvent used to suspend the amino acid. In an advantageous embodiment, the same solvent is used in all stages.

  In step 2), the amount of borohydride used is between 1 and 2 equivalents, relative to the committed molar amount of amino acid, and more particularly 1.25 equivalents, relative to the molar amount involved. amino acid, and is advantageously in excess relative to the zinc halide, advantageously from 1 to 1.25 equivalents of borohydride for 1 equivalent of zinc halide. Similar optimal yields are obtained when 1.25 equivalents of zinc halide and 1.25 equivalents of borohydride, for one equivalent of amino acid, or 1 equivalent of zinc halide and 1.25 equivalents of zinc are used. borohydride, for 1 equivalent of amino acid. The borohydride used is advantageously sodium borohydride. The reducing agent used is advantageously chlorozinc borohydride.

  When the committed amino acid has two carboxylic acid functions, the amounts of zinc halide and borohydride introduced are doubled.

  In step 3), the medium is advantageously heated to a temperature of between 30 and 80 ° C., and more advantageously inks between 30 and 65 ° C. The medium is advantageously heated for 6 to 20 hours.

  Thus, thanks to the process according to the invention, pure alcohols and amino-alcohols are easily obtained with molar yields advantageously ranging from 70 to 85%.

  The yields of aminoalcohols vary from one amino acid to another: Lleucine leads to L-leucinol with a yield of 85% (distillation at 64 ° C. under 2 mmHg); L-alanine leads to L-alaninol with a yield of 78% (distillation at 57 ° C. under 2 mmHg), L-proline leads to L-prolinol with a yield of 73% (distillation at 62 ° C. under 2 mmHg), L-phenylglycine leads to L-phenylglycinol with a yield of 81% (distillation towards 116 ° C. under 3 mmHg, crystallization towards 70/75 ° C.), L-valine leads to L-valinol with a yield of 75 to 80% (distillation at 58 ° C. under 3 mmHg) Similarly, phenylalanine is reduced to phenylalaninol. D-serine is reduced to D-serinol.

  Under similar conditions of stoichiometry and procedure, the benzoic acid is reduced to benzyl alcohol. In this case, the amount of hydrogen released is two times less than for the reduction of an amino acid having a free amine function.

  In the same way, methyl 2-N, N-dimethylamino-2-phenyl butanoate, an intermediate of trimebutine, is reduced to 2-N, N-dimethylamino-2-phenyl butanol.

  The method according to the invention makes it possible to limit the necessary amount of NaBH 4, which can advantageously be reduced to 1.25 equivalents for 1 equivalent of amino acid, carboxylic acid or ester. It also allows a decrease in the maximum volume, which can advantageously be reduced to 11 volumes relative to the volume of amino alcohol or alcohol obtained.

  In addition, halogenozinc borohydride, especially chlorozinc borohydride, is much more stable than zinc borohydride Zn (BH4) 2 already described.

  The following examples illustrate the invention without limiting it.

  EXAMPLE 1 Preparation of L-valinol by Prior Preparation of the L-Valine / ZnCl2 Complex Formation of the Reducing Entity in Situ In a 1-liter equipped reactor, 200 grams (1.7 mol) of Lvaline, 600 ml of THF, then 232 grams of zinc chloride (1.7 mol, 1 equivalent), so as to obtain a clear solution of complex.

  In a second reactor, 2 liters equipped, is introduced 80.5 grams (2.13 mol, 1.25 equivalent) of sodium borohydride powder, and: 150 ml of THF.

  The solution of L-valine complex + zinc chloride is suspended over the borohydride suspension in 4 hours and the temperature is allowed to rise to 30-40 C. It is heated at 60-65 ° C overnight and then the medium is cooled to 25-30 ° C. A total evolution of hydrogen of 2.2 equivalents with respect to. the committed amino acid.

  The medium is poured on 272 grams (3.4 mol) of 50% by weight sodium hydroxide in water and then heated for 1 hour at 60-65 C with rapid stirring. The pH is close to 12.

  The inorganic salts are filtered off and washed with 2 × 200 ml of anhydrous THF. The THF is distilled at atmospheric pressure up to 80 ° C. in the mass and then under a slight vacuum at 50 mmHg. L-Valinol is distilled under high vacuum at 80 ° C. at 7 mmHg.

  132.5 grams of L-valinol are obtained in the form of a colorless oil crystallizing at room temperature, with a mass yield of 75% relative to the molar amount of L-valine employed.

  Chiral purity> 99.9%; water rate = 0.09%; Perchloric determination = 99.2%, GC purity = 99.45%. EXAMPLE 2 Preparation of L-Leucinol by Prior Preparation of the L-Leucine / ZnCl 2 Complex Reducing In Situ Entity In a 1 liter reactor equipped, 200 grams (1.52 moles) of L-leucine, 500 ml of THF and then 207 grams (1.52 moles) of zinc chloride are introduced. It is heated to reflux so as to obtain a solution, which is cooled to a temperature of 25-30 C.

  In a 2 liter reactor equipped, 71.8 grams (1.9 mole, 1.25 equivalents) of sodium borohydride powder and 150 ml of THF are introduced.

  The solution of complex L-leucine + ZnCl 2 is poured onto the borohydride suspension in 9 hours and the temperature is allowed to rise to 35 ° C. and then to maintain it at this temperature of 35 ° C. The medium is then heated to 68 ° C. and maintains at this temperature for 12 hours. Cooled to room temperature.

  The medium obtained is cast on 243.2 grams (3.04 mol - 2 equivalents) of 50% by weight sodium hydroxide in water, allowing the temperature to rise to 50-55 ° C. and then refluxing the THF for one hour. It is cooled to 25 ° C. and the inorganic salts are filtered off and the cake is washed with 2 × 200 ml of THF. The THF is distilled at atmospheric pressure and then under a slight vacuum. The L-leucinol is distilled under high vacuum at 63/64 C under 2 mm Hg.

  151.7 grams of pure L-leucinol are obtained, with a molar yield of 85%.

  Example 3: Preparation of L-valinol by the technique of prior preparation of the chlorozinc borohydride solution.

  In a 3 liter reactor equipped, 1580 ml of THF and then 464 grams (3.4 mol - 1 equivalent) of zinc chloride are introduced, the mixture is heated to 50-60 C so as to complete the solubilization of zinc chloride. then cooled to about 25 ° C.

  In a second reactor equipped with 3 liters, 161 grams (4.25 mol-1.25 equivalents) of sodium borohydride powder and then 320 ml of THF.

  The zinc chloride solution is poured onto the sodium borohydride suspension in 1 hour, allowing the temperature to rise to 50 ° C. and then keeping it at 50 ° C. for 1 to 2 hours so as to obtain a complete reaction. A fine white slurry is obtained which is cooled to room temperature.

  In the first reactor of 3 liters, 400 grams (3, 4 mol1 equivalent) of L-valine and then 600 ml of THF are introduced, and then the suspension is heated to a temperature of 50-55 C.

  The reductant solution is poured slowly in about 10 hours and maintaining the temperature at 50-60 ° C., by cooling during the first half of the casting and then by heating during the second half of the casting. A gas meter can display the evolution of hydrogen, 2 equivalents relative to the amino acid. Optionally, distilled 600 ml of THF that can be reused later.

  The medium is then heated to 60-68 ° C and left in contact with stirring for 12 hours. Cooled to room temperature.

  In the second reactor of 3 liters, 544 grams of 50% by weight sodium hydroxide solution (6.8 mol - 2 equivalents) are introduced.

  The gray suspension of the first reactor is poured into the second reactor containing the sodium hydroxide in 2 to 3 hours and the temperature is allowed to reach 50-55 ° C. and then it is maintained at this value by cooling. The medium is then heated to 65 ° C. and kept in contact with good stirring at this temperature for two hours. At this stage, the apparent pH of the medium is 11.2. It is cooled to a temperature of 10-15 ° C. and the pH is adjusted to 13 by adding a little sodium hydroxide.

  The inorganic salts are filtered through a porous porcelain filter and the cake washed with 1 liter of THF. The THF is distilled at atmospheric pressure and then under a slight vacuum at 50 mmHg. The L-valinol is distilled under reduced pressure at 57.5 ° C. under 2 mmHg. 264 grams of L-valinol is obtained, ie a molar yield of 75%.

  Example 4: Preparation of L-phenylglycinol by the technique of prior preparation of chlorozinc borohydride.

  In a reactor of 1 liter equipped, is introduced 535 ml of THF then 153 grams (1.124 mol - 1 equivalent) of zinc chloride. The mixture is then heated at 50 ° C. for 30 minutes in order to solubilize the zinc chloride.

  53.1 grams (1.405 mol - 1.25 equivalents) of sodium borohydride powder and 100 ml of THF are introduced into a second reactor.

  The ZnCl 2 solution is poured onto the suspension of NaBH 4 in 1 hour and the temperature is allowed to reach 50 ° C. It is then maintained for 2 hours at 50 ° C. and then cooled to room temperature.

  In the first reactor of 1 liter, 170 grams of Lphenylglycine (1.124 mol -1 equivalent) and 250 ml of THF are introduced. Then heated to 50 C.

  The solution of the reducing agent is poured in 4 hours on the suspension of L-15 phenylglycine while maintaining a temperature of 50-55 C.

  The mixture is left in contact for 15 hours at 55-65 ° C. while distilling 400 ml of THF. Cooled to room temperature.

  In the second 1-liter reactor, 180 grams of 50% sodium hydroxide (2.25 mol-2 equivalent) are introduced and then the suspension of the phenylglycinol complex is poured onto the sodium hydroxide solution in 2 hours, allowing the temperature to reach 50 ° C. and then keeping it at this temperature by cooling. The suspension obtained is heated at 65 ° C. for 2 hours and then cooled to a temperature of 10 ° C. The inorganic salts are filtered off and the cake is washed with 3 × 116 ml of recovered THF.

  The THF is distilled at atmospheric pressure and then under a slight vacuum. Finally, L-phenylglycinol is distilled at 115 ° -118 ° C. at 3 to 4 mmHg, the refrigerants being supplied with hot water (crystallizes towards 70 ° C.).

  125 grams of L-phenylglycinol are obtained, ie a molar yield of 81%.

  Example 5: Preparation of benzyl alcohol by reduction of benzoic acid via the preliminary preparation of chlorozinc borohydride.

  In a reactor of 0.5 liter equipped, 334 ml of THF and then 98.2 grams (0.72 mol -1 equivalent) of zinc chloride are introduced, then heated to 50 C for complete solubilization. Cooled to room temperature.

  In a second reactor of 0.5 liter equipped, is introduced 34 grams (0.9 mol - 1.25 equivalents) of NaBH4 and 68 ml of THF.

  The zinc chloride solution is poured onto the sodium borohydride suspension, allowing the temperature to rise to 50 ° C. and keeping it there for 2 hours. Then cooled to room temperature.

  In the first reactor, 88 grams (0.72 mol -1 equivalent) of benzoic acid and 160 ml of THF are introduced. The suspension is heated to 50 C.

  The reducing solution is poured onto the benzoic acid suspension in 2 hours while maintaining the temperature at 50 ° C., 16 liters of hydrogen (0.714 mol -1 equivalent) are evolved.

  It is heated to 65 ° C. and left in contact at this temperature for 12 hours and then cooled.

  The heterogeneous medium obtained is cast on 115 grams of a 50% sodium hydroxide solution (1.44 mol - 2 equivalents), the medium is heated at 65 ° C. for 1 hour and then cooled to 15 ° C.

  The inorganic salts are filtered and the cake is washed with 170 ml of THF. The THF is distilled at atmospheric pressure and then under a slight vacuum. The benzyl alcohol is distilled under reduced pressure.

  66 grams of benzyl alcohol are obtained, a molar yield of 85%.

Claims (17)

  A process for the preparation of amino alcohols or alcohols from the corresponding amino acids, carboxylic acids or esters respectively, characterized in that the reduction step of the carboxylic acid or ester function in the alcohol function is carried out in the presence of a reducing agent of the formula ZnXBH4, where X is Cl, Br, I or F. 2. Process according to claim 1, characterized in that the amino acid corresponds to the formula (I) R CH (CH 2) n -OHOH N R 1 / R 2 (I) in which either R represents a hydrogen atom or a linear or branched C1-C12 alkyl, C6-C11 aryl, C7-C17 aralkyl, C5Cl11 heteroaryl or C6-C17 heteroaralkyl radical, which radicals may be substituted by one or more --NR3R4, alkyl, nitro radicals; , hydroxy or halogen and may contain heteroatoms selected from the group consisting of N, O, Se and S, R1 and R2, independently of each other, represent a hydrogen atom, a linear or branched alkyl radical C1-C12 or C3-C8 cycloalkyl, or R1 and R2 may together with the nitrogen atom carrying them form an aliphatic or aromatic 5-8 membered ring, which ring may be substituted by one or more -NR3R4 nitro, hydroxy or halogen radicals and may contain heteroatoms selected from the group consisting of N, O, Se and S, - or R and R1 together with the carbon and nitrogen atom carrying them respectively, form an aliphatic or aromatic ring of 5 to 8 members, which ring may be substituted by one or more -NR3R4 nitro, hydroxy or halogen radicals and possibly containing heteroatoms selected from the group consisting of N, O, Se and S, and R2 represents a hydrogen atom, a linear or branched C1-C12 alkyl radical or C3-C8 cycloalkyl, and R3 and R4, independently of each other, represent a hydrogen atom, a linear or branched C1-C12 alkyl radical or a C3-C8 cycloalkyl radical, or R3 and R4 may form together with the atom carrying them, an aliphatic or aromatic ring of 5 to 8 members, said ring may comprise heteroatoms selected from the group consisting of N, O, Se and S, and n is an integer ranging from 0 to 10.   3. Process according to claim 1, characterized in that the carboxylic acid corresponds to the formula R'-COOH or the ester corresponds to the formula R "-COO-R", in which R ', R "and R" , independently of one another, represent a linear or branched C1-C12 alkyl, C7-C12 aralkyl, C6-C11 aryl or C4-C10 heteroaryl or C5-C11 heteroaralkyl radical, which may be substituted by a or more -OH radicals.   4. Method according to any one of claims 1 to 3, characterized in that it comprises the following successive steps: a) formation of a complex (amino alcohol or alcohol) / borane by reaction between an amino acid or a carboxylic acid or an ester and said reducing agent, in a suitable solvent; b) hydrolyzing the complex obtained in step a) to obtain the aminoalcohol or the desired alcohol; c) if appropriate, elimination of the mineral salts formed during step b); D) removal of the reaction solvent and recovery of the aminoalcohol or desired alcohol.   5. Method according to claim 4, characterized in that the solvent used in step a) is selected from the group consisting of tetrahydrofuran, alkyl ethers, glycol ethers and methyl tetrahydrofuran.   6. Process according to any one of claims 1 to 5, characterized in that during step b), the hydrolysis is carried out using an organic or inorganic base, of higher basicity than said amino-alcohol or alcohol, at least 2 equivalents, preferably 2 to 5 equivalents, base based on the molar amount of reducing agent employed.   7. Process according to claim 6, characterized in that the base used is sodium hydroxide or potassium hydroxide in a concentration of 5 to 50% by weight in water.   8. Method according to any one of claims 2 to 7, characterized in that during step b), the medium is heated to a temperature between 30 C and the reflux temperature of the solvent used in step a ).   9. Method according to any one of the preceding claims, characterized in that said reducing agent is formed beforehand.   10. The method of claim 9, characterized in that step a) comprises the following successive steps: i) adding 1 to 2 equivalents of said reducing agent, relative to the molar amount of committed amino acid, of carboxylic acid or ester, to a suspension of amino acid, carboxylic acid or ester in a suitable solvent; and ii) heating the solution obtained following step i) at a temperature between 30 ° C. and the boiling point of the solvent for 1 to 50 hours, advantageously 6 to 20 hours.   11. Process according to claim 10, characterized in that step i) is carried out at a temperature of between -20 and 80 ° C.   12. Method according to any one of claims 1 to 8, characterized in that said reducing agent is formed in situ.   13. The method of claim 12, characterized in that step a) comprises the following successive steps: 1) reaction of an amino acid, having a free NH 2 function, with 1 to 2 equivalents of a zinc halide ZnX2, based on the molar amount of amino acid, in a solvent to form an amino acid / zinc halide complex; 2) casting the amino acid / zinc halide complex on a suspension containing 1 to 2 equivalents of borohydride, relative to the molar amount of amino acid, in a solvent, preferably identical to that of step 1) said borohydride being in molar excess relative to the zinc halide; 3) at the end of the casting, heating the reaction medium at a temperature of between 30 ° C. and the boiling point of the solvent for 1 to 50 hours, advantageously 6 to 20 hours, to form an aminoalcohol-borane complex.   14. The method of claim 13, characterized in that in step 1) is used 1 to 1.25 equivalents of zinc halide relative to the molar amount of amino acid.   15. The method of claim 13 or 14, characterized in that the solvent used in step 1) is selected from the group consisting of tetrahydrofuran, ethylene glycol, dimethyl ether, glycol ethers and diethyl ether. alkyl.   16. Process according to any one of Claims 13 to 15, characterized in that, during steps 1) and 2), 1 to 1.25 equivalents of zinc halide and 1.25 equivalents of borohydride are used, relative to the molar amount of amino acid.   17. Process according to any one of the preceding claims, characterized in that said reducing agent is chlorozinc borohydride.