ES2291101A1 - Valacyclovir and its pharmaceutical salts preparation method, involves carrying out reaction of activated derivative of acyclovir with enamine of L-valine amino acid - Google Patents

Abstract

The valacyclovir and its pharmaceutical salts preparation method involves carrying out reaction of activated derivative of acyclovir with enamine of L-valine amino acid, which has a formula. The enamines of the L-valine amino acid having a formula, are new compounds. The formula includes a carboxyl group of the amino acid connected with a base selected between a group composed of quaternary ammonium, bicyclic amidines, linear amidines and phosphazenes. Independent claims are also included for the following: (1) compounds of enamines of the L-valine amino acid (2) a method for obtaining the compounds of enamines of the L-valine amino acid.

Description

Procedure for the preparation of valacyclovir.

Technical field

The present invention relates to a new procedure for the preparation of valacyclovir and its salts pharmaceutically acceptable.

Prior art

Valacyclovir is the common denomination L-valinato international 2 - [(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl) methoxy] ethyl of formula:

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one

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and it is a prodrug of the principle active antiviral acyclovir, which is usually used in the form of hydrochloride

Valacyclovir and its antiviral properties were first described in EP-A-308065.

In EP-A-308065 the production of valacyclovir by a reaction of esterification between the aliphatic hydroxyl group of acyclovir and the carboxylic group of L-valine. Optionally acyclovir may have hydroxy and amino groups protected attached to the purine ring, and the amino acid valine can also have the protected amino group.

In Example 1 of said patent application, the preparation of valacyclovir by reaction of the acyclovir with the N-benzyloxycarbonyl-L-valine within dimethylformamide and in the presence of dicyclohexylcarbodiimide and 4 dimethylaminopyridine. After the condensation reaction the valine protective group is removed by hydrogenolysis in the presence of palladium on carbon as catalyst.

One of the disadvantages of this procedure is that to obtain the monohydrate of the valacyclovir hydrochloride with a yield of 55% a 35% molar excess of N-benzyloxycarbonyl-L-valine and 63% molar excess of dicyclohexylcarbodiimide. The bass obtained performance and the need to use excesses of expensive compounds makes such a procedure unfeasible industrially.

In WO-A-98/03553 a procedure for the preparation of valacyclovir is described in which reacts an activated acyclovir derivative with a enamine of the amino acid L-valine, which responds to the General Formula:

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2

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where M is an alkali metal, R 1 a C 1 alkyl group a C_ {10}.

The acyclovir activated derivative mentioned is prepared by replacing the aliphatic hydroxyl group of acyclovir by a leaving group, for example, methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate, chlorine or bromine

The preparation of the amino acid enamine L-valine is based on a reaction known from many years ago between amino acids and a dicarbonyl compound, in presence of a base of the MOH type, which results in enamines of said amino acids with their carboxylic group salified by the metal corresponding to the base.

In the procedure described in WO-A-98/03553 obtains the valacyclovir hydrochloride in the form of monohydrate with a maximum yield of 62% in the case of using the p-toluenesulfonate as leaving group, so The returns cannot be considered satisfactory. In bliss patent application, no indication on the purity of the product obtained.

There is therefore a need to have a procedure that allows obtaining valacyclovir and its salts Pharmaceuticals with better yields.

The authors of the present invention have discovered a new procedure to prepare valacyclovir and its salts, which is based on new intermediate compounds, so that the performance is better than that described in the state of the technique, and the product has a purity that makes it appropriate for be used as an active ingredient in formulations Pharmaceuticals

Object of the invention

The object of the invention is a process for the preparation of valacyclovir and its pharmaceutical salts with Better performance

Another object of the invention are the new intermediate compounds used to prepare valacyclovir.

An object of the invention is also a procedure for the preparation of intermediate compounds new.

Detailed description of the invention

The authors of the present invention have discovered a procedure for the preparation of valacyclovir and its pharmaceutically acceptable salts comprising

to)

do reacting an activated acyclovir derivative of the general formula (I)

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3

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where Z select from the group consisting of methanesulfonyloxy, p-toluenesulfonyloxy, or trifluoromethanesulfonyloxy, with an enamine of the amino acid L-valine of formula general (II)

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4

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where R a C 1 to C 8 alkyl or linear or branched arylalkyl, and Y + is the cation corresponding to a base selected from the group consisting of quaternary ammonium compounds, amidines bicyclics, linear amidines, and phosphazenes,

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within a organic solvent to obtain the compound of formula (III)

5

where R is a C1 or C8 linear or branched alkyl or arylalkyl

b)

remove the protective group from compound (III) by treatment with an acid to obtain the salt of valacyclovir with said acid, and, if desired,

C)

convert valacyclovir salt into the corresponding free base.

The activated acyclovir derivative of the formula General (I) is formally an acyclovir ester with acid corresponding sulfonic acid: methanesulfonic acid, acid p-toluenesulfonic acid or acid trifluoromethanesulfonic. Such esters are usually referred to as acyclovir mesylate, acyclovir tosylate or triflate acyclovir respectively.

The compound (I) can be prepared by procedures described in the prior art, as per example in the patent application WO-A-98/03553. In examples 4 and 8 the preparation of tosylate and acyclovir mesylate is described using p-toluenesulfonyl chloride and the methanesulfonyl chloride, respectively.

It has been observed, that when the derivative activated of acyclovir is prepared using a sulfonic acid chloride, the presence of chloride ions leads to the formation of a compound of formula (I) where Z is chlorine, which impurifies the final product, valacyclovir or its pharmaceutical salts.

Preferably, according to the procedure of the invention, the acyclovir activated derivative is prepared from a sulfonic acid anhydride.

In the process of the invention, the sulfonic acid anhydride is selected from the group formed by methanesulfonic acid anhydride, acid anhydride p-toluenesulfonic acid, or acid anhydride trifluoromethanesulfonic.

More preferably the anhydride is selected. of methanesulfonic acid.

The reaction for the preparation of the derivative Activated acyclovir is preferably carried out in the breast of an organic solvent, and in the presence of an organic base strong.

The organic solvent is selected preferably between the group formed by acetonitrile, chloride methylene, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, and / or their mixtures

The strong organic base is preferably heterocyclic More preferably the 4-N-dimethylaminopyridine.

The reaction is usually carried out at a temperature between room temperature and reflux temperature of the solvent used, for a period between 3 and 5 hours.

The reaction yield to prepare the Compounds of formula (I) from acyclovir are generally is between 80% and 90% with respect to acyclovir

The amino acid enamines L-valine of formula (II) that are reacted with the activated acyclovir derivative to prepare the compound (III), they are new.

The difference of amino acid enamines L-valine of formula (II) with respect to enamines described in the patent application WO-A-98/0553, resides in the base that salify the carboxylic group of the amino acid.

The enamines of the present invention have the carboxylic group salified with a base selected from the group consisting of quaternary ammonium compounds, amidines bicyclics, linear amidines, and phosphazenes, while the enamines described in WO-A-98/03553 they have the carboxylic group salified with a hydroxide alkaline.

The use of these new enamines of L-valine in the process of the invention allows the preparation of valacyclovir and its pharmaceutical salts with a higher performance than described in the patent application WO-A-98/03553, and with a bass impurity content.

The quaternary ammonium compounds, the bicyclic amidines, linear amidines and phosphazenes are compounds well known to those skilled in the art, and a large Number of them are commercially available.

In the case of ammonium compounds quaternary the Y + cation present in the compound of formula (II) responds to the general formula (IV):

6

where R 1, R 2, R 3 and R 4 are alkyl or arylalkyl groups C_ {1} to C_ {24}, may be the same or different

The Y + cation in the case of amidines bicyclic, linear amidines and phosphazenes is the species formed by protonation of said bases with the carboxylic hydrogen of the L-valine:

7

The quaternary ammonium compound preferably it is selected from the group consisting of: hydroxide of tetraethylammonium, tetrabutylammonium hydroxide, hydroxide of methyltributylammonium, tetrahexylammonium hydroxide hydroxide tetrapropylammonium, dodecyltrimethylammonium hydroxide, and hydroxide of diethyldipropylammonium. More preferably, the tetrabutylammonium hydroxide.

The bicyclic amidine is selected preferably from the group formed by the 1,5-diazabicyclo [4.3.0] non-5-eno, also known as DBN, and the 1,8-diazabicyclo [5.4.0] undec-7-eno, also known as DBU. More preferably, the 1,8-diazabicyclo [5.4.0] undec-7-eno (DBU)

Linear amidine is preferably selected from pentamethylguanidine, and 2- tert -butyl-1,1,3,3-tretramethylguanidine.

The phosphazene is preferably selected from the group consisting of 2- tert- butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diaza-phosphaine, tert- butyliminotri (pyrrolidin) phosphorane (BTPP), and the tert -butylimino-tris (dimethylamino) phosphorane. More preferably, tert- butyliminotri (pyrrolidin) phosphorane (BTPP) is selected.

The reaction between the activated derivative of acyclovir and the L-valine enamine of formula (II) for the preparation of compound (III), according to the procedure of The invention is carried out in an organic solvent. Preferably an organic solvent selected from among the group consisting of dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, and / or mixtures thereof.

Preferably a molar excess of the valine enamine of formula (II) with respect to the activated derivative of acyclovir of formula (I). More preferably a molar ratio between the enamine of L-valine formula (II) and the activated acyclovir derivative of formula (I) which It is between 1.25: 1 and 3: 1.

Said reaction is carried out at a temperature. generally between 30 ° C and 75 ° C, during a period of Time between 2 and 4 hours.

The new enamines of L-valine, object of the invention, allow the reaction to be carried out in mild temperature conditions, which reduce the content in impurities of valacyclovir obtained according to the procedure of the invention.

The compound (III) is isolated by procedures conventional well known to the expert, for example, as the described in the patent application WO-A-98/03553.

Usually, through the procedure of invention the compound of formula (III) is obtained with a yield between 80% and 90%.

In a preferred embodiment of the procedure of the invention, the amino acid enamine L-valine of formula (II) is not isolated and reacted directly with the activated acyclovir derivative of formula (I), therein reactor where the enamine has been prepared under the conditions of reaction already described. This type of procedure is called "one pot ", and allows to avoid the isolation of the products and Take better advantage of production resources.

The elimination of the enamine protective group that found in compound (III) is carried out by the treatment with an acid, for example according to the procedure described in Example 6 of the patent application WO-A-98/03553.

In a preferred embodiment, the deprotection it is carried out for example in the system formed by water, acetone and hydrochloric acid. The product you get in these conditions is the salt of valacyclovir with hydrochloric acid, also called valacyclovir hydrochloride.

The deprotection reaction usually allows to obtain valacyclovir salt with a yield between 85% and 90% in isolated product.

The overall performance of the procedure of the invention is usually between 72% and 75%, while the yield described in the application for WO-A-98/03553 patent is from 62%

In addition, valacyclovir obtained by The process of the invention has a low content in impurities, which do not usually exceed 0.5% by weight, with except for acyclovir, which is usually below 0.7% in weigh.

Obtaining valacyclovir or its salts Pharmaceutically acceptable with reduced impurity content it is an advantage of the process of the invention, since the valacyclovir is an active substance that is difficult to purify by usual industrial procedures such as, by example, extraction, or crystallization.

The objects of the present invention are also enamines of the L-valine of general formula (II) already mentioned, which are new.

The procedure for the preparation of L-valine enamines of general formula (II) comprises reacting the amino acid L-valine with a linear or branched C 1 alkyl or arylalkyl ester C 8 of acetoacetic acid, in the presence of a base selected from the group formed ammonium compounds quaternary, bicyclic amidines, linear amidines, and phosphazenes, in an organic solvent.

The amino acid L-valine that is preferably uses a low impurity content of so that the formation of impurities analogous to valacyclovir as are, for example, leuciclovir, and isoleuciclovir.

Preferably used L-Valine that has a low impurity content isoleucine and leucine, mainly; in an amount below 0.10% by weight of each of them, more preferably, below 0.05% by weight.

The impurity content of isoleucine and Leucine in L.Valina can be determined by the procedures common in the art. For example, using HPMC and gas chromatography.

Preferably used as a compound dicarbonyl a C 1 to C 4 alkyl ester of the acid acetoacetic More preferably, the acetoacetate of methyl.

The organic solvent used in the procedure to prepare the enamines of L-valine of formula (II) is selected from the group consisting of C 1 to C 4 aliphatic alcohols, chloride of methylene, dimethylformamide, and / or mixtures thereof.

The reaction is usually carried out at a temperature between 25ºC and 65ºC, for a time between 5 and 10 hours.

L-valine enamine can be isolate by evaporation under reduced pressure of the solvent of the reaction and the water formed due to the formation of the enamina.

Amino acid transformation L-valine in your salted enamine is usually quantitative, and has an appropriate purity to be used in subsequent steps of the process of the invention.

Surprisingly the employment of new intermediate compounds, that is, the enamines of Salted L-valine with a selected base among the group consisting of quaternary ammonium compounds, bicyclic amidines, linear amidines, and phosphazenes, for the Preparation of valacyclovir and its pharmaceutical salts according to procedure object of the invention, allows to obtain the product with higher yields than those described in the state of the technique.

Valacyclovir in the form of free base can be obtain from valacyclovir hydrochloride by procedures described in the prior art, as in the example 7 of the patent application WO-A-98/03553.

Examples Example 1 Preparation of salted L-valine enamine with tetrabutylammonium hydroxide

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In a reactor under nitrogen atmosphere loaded 128 g (1.1 mol) of L-valine, 190 ml of methanol, 780 ml of 40% tetrabutylammonium hydroxide in methanol and stirred at room temperature.

Then 142 ml (1.3 moles) of ethyl acetoacetate and the solution was heated to reflux temperature for 9 hours.

After this period of time, he concentrated the solution under reduced pressure, and 367 g of the L-valine enamine salified with hydroxide tetrabutylammonium, with sufficient purity to be used in the next stage

The yield was quantitative.

Example 2 Preparation of salted L-valine enamine with 1,8-diazabicyclo- [5.4.0] undec-7-eno (DBU)

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In a reactor under nitrogen atmosphere loaded 50 g (0.43 mol) of L-valine, 250 ml of methanol, 65 g (0.43 mol) of 1,8-diazabicyclo [5.4.0] undec-7-eno (DBU) and stirred at room temperature.

Then, 60 g (0.52 mol) were added of methyl acetoacetate on the solution, and heated to reflux temperature for 8 hours.

After this period of time, the dissolution it was concentrated under reduced pressure, and 156 g of the L-valine enamine salted with DBU, which had Enough purity to be used in the next stage.

The yield was quantitative.

Example 3 Preparation of the enamine of L-valine salified with tert -butylimino-tri (pyrrolidino) phosphorane (BTPP)

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2 grams (0.017 mol) of L-valine, 10 ml of methanol and 5.5 ml (0.018 mol) of tert- butylimino-tri (pyrrolidino) phosphorane were charged in a nitrogen atmosphere reactor.

It was stirred at room temperature until solution, and 2.3 g (0.020 mol) of acetoacetate were added methyl.

The solution was heated to reflux, and once complete the reaction was concentrated under reduced pressure to remove the solvent from the reaction and the water formed.

8.9 g of the enamine of L-valine salified with BTPP, which had purity appropriate to be used in the next stage.

The performance was practically quantitative.

The amino acid L-Valine used in examples 1, 2 and 3 it has a low impurity content isoleucine and leucine, in an amount below 0.10% by weight of every one of them.

Example 4 Preparation of acyclovir mesylate

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In a reactor under nitrogen atmosphere loaded 12 g of 4-N-dimethylaminopyridine, 35 ml of acetonitrile and cooled to a temperature between -5 ° C and 5 ° C.

Then, 11.9 g (0.068) were added moles) of methanesulfonic anhydride. The temperature between 15 ° C and 35 ° C, and 6.15 g (0.027 mol) of acyclovir

The suspension was heated to a temperature between 35 ° C and 45 ° C. At 3 hours the suspension at a temperature between 15 ° C and 25 ° C. Be filtered the solid and washed with acetonitrile. 7.45 g of acyclovir mesylate, which represented a yield of 90%.

Example 5 Preparation of compound (III) with R = Me

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12

63 ml of dimethylformamide were added on 36.5 g (0.1 mol) of L-valine enamine salified with DBU obtained in Example 2. The solution obtained it was heated to a temperature between 30 ° C and 40 ° C, and above 12 g (0.04 mol) of acyclovir mesylate were added obtained in Example 4.

The reaction mixture was then heated. at a temperature between 65 ° C and 70 ° C and was maintained between 2 and 4 hours until the reaction is complete.

After the reaction is over, the reaction mixture is added about 315 ml of water at a temperature between 65 ° C and 75 ° C.

The suspension obtained was filtered, and the solid Isolated washed with hot water.

14.3 g of compound (III) were obtained with R = Me, which represented a yield of 85%.

Example 6 Preparation of compound (III) with R = Me according to single reactor procedure

13

In a reactor under nitrogen atmosphere loaded 50 g (0.43 mol) of L-valine, 175 ml of dimethylformamide, 65 g (0.43 mol) of 1,8-diazabicyclo [5.4.0] un-dec-7-eno (DBU) and stirred at room temperature.

Then, 60 g (0.52 mol) were added of methyl acetoacetate on the suspension, and heated to a temperature between 80ºC and 85ºC for about 8 hours.

After this time, the reaction mixture at a temperature between 50 ° C and 55 ° C, and 51.8 g (0.17 mol) of compound (I) was added thereto obtained in Example 4.

Once the reaction is complete, after a period of time between 2 and 4 hours, the solid was isolated by precipitation in 875 ml of water at a temperature included between 65ºC and 75ºC.

The suspension was filtered and the isolated solid was washed with hot water.

61.3 g of compound (III) were obtained with R = Me, which represented a yield of 85%.

Example 7 Preparation of valacyclovir hydrochloride

14

In a 250 ml flask 12.8 g were added (0.03 mol) of the compound (III) obtained in Example 5, 90 ml of acetone and cooled to a temperature between -10 ° C and 0 ° C

Then, at that temperature was added a solution formed by 7.8 ml of water and 2.6 ml acid 35% hydrochloric.

The suspension obtained was maintained between 20 ° C and 25 ° C under stirring for 6 hours.

The pH was adjusted to a value between 4.5 and 5.5 with triethylamine.

The suspension obtained was filtered and the solid isolated washed with acetone, and dried.

9.8 g of hydrochloride were obtained from valacyclovir in the form of monohydrate, which represented a yield of 86%.

The overall performance, according to the procedure of the invention, from acyclovir mesylate, compound of formula (I), until valacyclovir monohydrate hydrochloride was 73%, better than the performance described in the patent application WO-A-98/03553, which was 62%.

The product obtained had all impurities below 0.05% by weight, with the exception of acyclovir, whose content was less than 0.7% by weight.

Claims (29)

1. Procedure for the preparation of valacyclovir and its pharmaceutically acceptable salts characterized in that it comprises

to)

do react an activated acyclovix derivative of general formula (I)

fifteen

where Z select from the group consisting of methanesulfonyloxy, p-toluenesulfonyloxy, or trifluoromethanesulfonyloxy,

with an enamina of the amino acid L-valine of general formula (II)

16

where R is a C 1 to C 8 alkyl or linear or branched arylalkyl, and Y + is the cation corresponding to a base selected from the group consisting of quaternary ammonium compounds, amidines bicyclics, linear amidines, and phosphazenes,

within a organic solvent to obtain the compound of formula (III)

17

where R is a C1 or C8 linear or branched alkyl or arylalkyl

b)

remove the protective group from compound (III) by treatment with an acid to obtain the salt of valacyclovir with said acid, and, if desired,

C)

convert valacyclovir salt into the corresponding free base.

2. Method according to claim 1, characterized in that the activated acyclovir derivative of formula (I) is prepared from a sulfonic acid anhydride. 3. Method according to claim 2, characterized in that the sulfonic acid anhydride is selected from the group consisting of methanesulfonic acid anhydride, p-toluenesulfonic acid anhydride, or trifluoromethanesulfonic acid anhydride. 4. Method according to claim 3, characterized in that the sulfonic acid anhydride is methanesulfonic acid anhydride. 5. Process according to claims 1 to 4, characterized in that the quaternary ammonium compound is selected from the group consisting of tetraethylammonium hydroxide, tetrabutylammonium hydroxide, methyltributyl ammonium hydroxide, tetrahexylammonium hydroxide, tetrapropylammonium hydroxide, dodecyltrimethylammonium hydroxide, and hydroxide of diethyldipropylammonium. Method according to claim 5, characterized in that the quaternary ammonium compound is tetrabutylammonium hydroxide. Method according to claims 1 to 4, characterized in that the bicyclic amidine is selected from the group consisting of 1,5-diazabicyclo [4.3.0] non-5-ene, and 1,8-diazabicyclo [5.4.0 ] undec-7-eno. Method according to claim 7, characterized in that the bicyclic amidine is 1,8-diazabicyclo [5.4.0] undec-7-ene. 9. Method according to claims 1 to 4, characterized in that the linear amidine is selected from pentamethylguanidine, and 2- tert -butyl-1,1,3,3-tretramethylguanidine. 10. The method according to claims 1 to 4, characterized in that the phosphazene is selected from the group consisting of 2- tert -butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diaza-phosphaine, tert -butyliminotri (pyrrolidin) phosphorane, and tert -butylimino-tris (dimethylamino) phosphorane. 11. Method according to claim 10, characterized in that the phosphazene is tert- butyliminotri (pyrrolidin) phosphorane. 12. Process according to claims 1 to 11, characterized in that the organic solvent is selected from the group consisting of dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, and / or mixtures thereof. 13. Method according to claims 1 to 12, characterized in that a molar excess of the L-valine enamine of formula (II) is used with and with respect to the activated acyclovir derivative of formula (I). 14. Method according to claim 13, characterized in that a molar ratio of the L-valine enamine of formula (II) with respect to the activated acyclovir derivative of formula (I) between 1.25: 1 and 3: 1 is used . 15. Method according to claims 1 to 14, characterized in that the L-valine enamine of formula (II) is not isolated, and reacted directly with the activated acyclovir derivative of formula (I). 16. Method according to claims 1 to 14, characterized in that the L-valine enamine of formula (II) is prepared from the amino acid L-Valine with an impurity content isoleucine and leucine, below 0.10% by weight of every one of them. 17. Compounds of formula (II) 18

where R is a C 1 to C 8 alkyl or linear or branched arylalkyl, and Y + is the cation corresponding to a base selected from the group consisting of quaternary ammonium compounds, amidines bicyclics, linear amidines, and phosphazenes.

18. Compound according to claim 17, characterized in that the quaternary ammonium compound is selected from the group consisting of tetraethylammonium hydroxide, tetrabutylammonium hydroxide, methyltributyl ammonium hydroxide, tetrahexylammonium hydroxide, tetrapropylammonium hydroxide, dodecyltrimethylammonium hydroxide, and diethyldipropylammonium hydroxide . 19. Compound according to claim 18 characterized in that the quaternary ammonium compound is tetrabutylammonium hydroxide. 20. Compound according to claim 17, characterized in that the bicyclic amidine is selected from the group consisting of 1,5-diazabicyclo [4.3.0] non-5-ene, and 1,8-diazabicyclo [5.4.0] undec -7-eno. 21. Compound according to claim 20, characterized in that the bicyclic amidine is 1,8-diazabicyclo [5.4.0] undec-7-ene. 22. Compound according to claim 17, characterized in that the linear amidine is selected from pentamethylguanidine, and 2- tert -butyl-1,1,3,3-tretramethylguanidine. 23. Compound according to claim 17, characterized in that the phosphazene is selected from the group consisting of 2- tert -butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diaza-phosfarin, tert - Butyliminotri (pyrrolidin) phosphorane, and the tert -butylimino-tris (di-methylamino) phosphorane. 24. Compound according to claim 23, characterized in that the phosphazene is tert- butyliminotri (pyrrolidin) phosphorane. 25. Process for the preparation of the compounds of claims 17 to 24, characterized in that it comprises reacting the amino acid L-valine with a linear or branched C 1 to C 8 alkyl or arylalkyl ester of the acetoacetic acid, in the presence from a base selected from the group consisting of quaternary ammonium compound bicyclic amidines, linear amidines, and phosphazenes, within an organic solvent. 26. Method according to claim 25, characterized in that the amino acid L-Valine contains an impurity content isoleucine and leucine, below 0.10% by weight of each of them, determined by HPLC. 27. The method according to claim 25, characterized in that the ester of acetoacetic acid is a C 1 to C 4 alkyl ester. 28. Method according to claim 27, characterized in that the ester of acetoacetic acid is methyl acetoacetate. 29. Method according to claim 28, characterized in that the organic solvent is selected from the group consisting of C 1 to C 4 aliphatic alcohols, methylene chloride, dimethylformamide, and / or mixtures thereof.