FI87645B - FOERFARANDE FOER FRAMSTAELLNING AV KARBAMINSYRADERIVAT - Google Patents

Description

1 87645

Carbamic acid derivatives - Method of preparation for carbamic acid derivatives

The invention relates to a new process for the preparation of carbamic acid derivatives. More specifically, it relates to a process for preparing derivatives of formula R1

N - C - Y

II

0 wherein Y is an alcohol, mercaptan or amine group. These derivatives are thus carbamates, thiocarbamates or ureas.

The most commonly used methods for preparing these compounds, e.g., carbamates and thiocarbamates, are, e.g., the reaction of chloroformate or thiochloroformate with an amine described in Chemical Review, 1964, 64, pages 656-663, or the reaction of carbamyl chloride or isocyanate with alcohol, phenol, or mercaptan. (Grignard: Traite de Chimie Organique, Volume XIV, pp. 20-31).

Urea, on the other hand, is most often obtained by placing isocyanate or,; carbamyl chloride to react with the amine. When these are ··· symmetric, they can also be prepared by treating amii -: ... r nif osgeenil la (Grignard: vol. XIV, pages 85, 30).

. ·. ·. However, these different methods may not always be able to prepare the desired compounds, or are sometimes difficult to perform.

Some of the starting materials are::: - unstable, as is the case with many chloroformates, e.g. furfuryl, tert-butyl and p-methoxybenzyl chloroformates; - toxic, such as isocyanates, phosgene and in particular light carbamyl chlorides, which are carcinogenic; - or contaminating, such as light thiochloroformates.

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Research has tried to find new ways.

A few compounds have been prepared by reacting dimethyl carbonate or ethyl phenyl carbonate with aniline in the presence of a catalyst such as uranyl nitrate. However, the yields are very low, the mixture has to be heated to a high temperature (100 ° C): U.S. Patent 3,763,217) and considerable amounts of by-products are obtained.

Diphenyl carbonate does not react with amines to form a carbamate except in the presence of a catalyst such as 2-hydroxypyridine (Noboru Yamazaki and Todao Igudi, Fukuji Higashi, Journal of Polymer Science Vol. 17, pp. 835-841 (1979)).

Other carbamizing agents have been proposed such as: - azides. The synthesis of these is performed in several steps and the synthesis is cumbersome. They can decompose explosively, such as BOC azide (Angew, Chem., Ind. Ed. Eng. 16, 1977 No. 2), several experiments have been performed with very special carbonates, such as mixed p-nitrophenyl carbonates. The by-products obtained are difficult to remove, - bicarbonates. The synthesis of these is very cumbersome and expensive. This is especially the case for tert-butyl bicarbonate. In addition, the protecting group disappears, • »; . ·. -f shell formats. However, these are difficult to prepare because of the need to use non-commercial starting materials which are difficult to handle, such as CLCOF or BrCOF.

The reaction of some carbamates with amines has been studied. Urea is obtained only after heating to high,. . to temperatures of the order of 150 to 230 ° C, and provided that a catalyst has been used (Phillip Adams and Frank A. Baron, Chemical Review, 1965, page 574).

These different methods always produce an alcohol or phenone, - ·· ’which is often difficult to remove, and the reaction is reversible.

f · · li 3 87645

In some cases, it is completely impossible to make urea. Thus, when ethyl N-imidazole carbamate is reacted with ethylamine, ethyl N-ethyl carbamate and imidazole and not urea are formed.

The use of an α-halogenated derivative of a carbonic acid for the alkoxycarbonylation of an NH group is described in Synthesis, Vol. 11 (1971) pp. 588-90. Page 588 discloses the reaction of chloromethylene carbonate with a secondary amine or a potassium salt of phthalimide and mentions that only the potassium salt of phthalimide causes N-alkyloxycarbonylphthalimide to be formed. In addition, no examples of amines or chloromethylene carbonates are given.

This brief summary shows the limits of conventional methods and the often scarce results obtained through roads.

It was therefore desirable to have a general method for the preparation of carbamic acid derivatives that was easier to perform both because of the less hazardous starting materials and also for the removal of operating conditions and by-products. . regarding.

:: The method of the present invention can be applied: to the preparation of a wide variety of carbamic acid derivatives. It is particularly appropriate when other roads leading to these derivatives are unsuitable.

The present invention relates to a process for the preparation of carbamic acid derivatives having the formula: R1 \

::: - N - C - Y

::: R2 O

. * ··. wherein R 1 and R 2, which may be the same or different, are: - a hydrogen atom, - an aliphatic radical having 1 to 20 carbon atoms, 4 87645 - a cycloaliphatic or araliphatic radical having not more than 50 carbon atoms or together with a nitrogen atom to which they are attached, a piperidino, morpholino, hexamethyleneimino or imidazole ring, wherein the aliphatic, cycloaliphatic, araliphatic radical or said ring may be substituted by an acid, alcohol, ester, ether, mercapto or amino ring. R 3 R 6 Y is OR, SR, -N or O - N = C a group R 4 R 7 wherein R is an aliphatic radical having 1 to 12 carbon atoms and which may be substituted by halogen or a furyl or trimethylsilyl group; a benzyl, nitrobenzyl, phenyl, benzofuranyl group which may be substituted by lower alkyl, or a fluorenylmethyl group; R 1 and R 4, which may be the same or different, are a hydrogen atom, methyl or together with the nitrogen atom to which they are attached an imidazolyl ring, and R 6 and R 7, which may be the same or different, are an aliphatic radical having 1 to 12 carbon atoms or a cyclo- * * * · '- · · aliphatic radical having up to 30 carbon atoms which may be substituted and the lower alkylthio or the other may be a hydrogen atom, a methylthio radical or a lower alkyloxy radical.

In this method, an amino compound of the formula • I »/ R1 is obtained

NH

: Y: XR2 ”* is reacted in the presence of a hydrohalic acid acceptor: at temperatures between -5 and + 150 ° C with an α-halogenated derivative of carbonic acid of formula i; 5,87645 r5-ch-o-c-y

I II

X 0 wherein r 1, R 2 and Y are as defined above, X is a fluorine, chlorine or bromine atom and R 5 is a hydrogen atom or an aliphatic group having 1 to 4 carbon atoms and which may be substituted by halogen atoms.

The reaction can be carried out in the presence or absence of a solvent.

The reaction scheme can be written as follows: R1 R1 \ 5 N-

NH + R5 - CH - 0 - C - Y -> N-C-Y + R5- CHO + HX

S I II S II

R2 X 0 R2 O

Surprisingly, it has been found that HX is eliminated, but that this R1 does not involve the attachment of the amine group _> N- to carbon, where R2

is a halogen atom to form: R5 - CH - O - C - Y

f u i Q} as might normally be expected and as happens e.g.

. . In the reaction of α-chlorinated carbonate with an acid: R '- CH - O'- C - 0 - R "+ R"' COOH -> R'CH - O - C - 0 - R "

1, Il II

::: Cl O O

··. 0 - C - R '"·: · Il 0 (ASTRA - FR patent 2,201,870).

6 87645

In our method, instead, the α-halogenated derivative is cleaved, the Y-C group is attached to the amino compound group and formed

II

o aldehyde R 2 CHO.

R1

As the hydrogen-containing amino-1 starting material of the formula> NH, R 2 can be used ammonia and most of the known primary or secondary amines.

When R · 1 · or R 1 is an aliphatic radical, it preferably contains 1 to 20 carbon atoms. R 1 and R 2 may also be a cycloaliphatic or araliphatic radical which may have up to 50 carbon atoms, e.g. a benzyl radical, or they may together form a heterocycle, e.g. a piperidino, morpholino or imidazolyl ring.

The substituents on R 1 and R 2 may be various groups such as hydrocarbon groups or acid, alcohol, ester, ether, mercapto or amino functional groups.

Useful amines include methyl amine, diethylamine, di-n-butylamine, isobutylamine, n-octylamine, ethanolamine, benzylamine, N-methyl-N-benzylamine, piperidine, imidazole, hexamethyleneimine, morpholine and *. ... "diethanolamine.

Also very suitable are the natural or synthetic optically active or inactive or racemic amino acids used in peptide syntheses.

Examples are L-phenylalanine, L-proline, glycine, L-tyrosine, L-serine, L-aspartic acid, proline, ethyl glycinate and phenylglycine,

The second starting material used may be an α-halogenated carbamate, thiocarbonate or carbamate. It is best ot-chlorinated.

7 87645 The preparation of this compound can be carried out by various known methods, e.g. for chlorinated derivatives, the α-chlorinated chloroformate of the formula R 1 -CH-O-C-Cl,

I II

Cl o is reacted with a hydroxylated compound or mercaptan as described by M. Matzner, R. Kurkjyn, and R.J. In Cotter's article (Chem. Rev. 64, pp. 651-654 (1964)), or with an amine by the method described in EP Application Publication No. 45234 or Application 83 / 401766.7.

α-chlorinated chloroformates, on the other hand, are prepared very simply by the process of EP-A-40153, in which aldehydes are treated with phosgene.

The radical R 1 is preferably a light radical such as an aliphatic radical having 1 to 4 carbon atoms and which may be substituted, most preferably by halogen atoms and especially chlorine atoms. Of particular value are methyl and trichloromethyl radicals.

The radical R of the carbonate or thiocarbonate can be very different. It may be - an aliphatic radical most preferably having 1 to 12 carbon atoms, such as methyl, ethyl or tert. -butyl radical which may be *, 1 substituted, e.g. with a heterocyclic radical such as · ... · furyl, v; an araliphatic radical, e.g. benzyl, a substituted or unsubstituted aromatic ring which may or may not form part of a ring system, such as. , phenyl or 2,3-dihydro-2,2-dimethyl-7-benzofuranyl.

A: The radical R ', whatever its meaning, may be substituted .v. with one or more groups -O-C-O-CH-R5 or -S-C-O-CH-R5 O H I li

O X O X

Φ a · 8 87645

In particular, when the starting amine is an amino acid, it is one of the groups commonly used in peptide synthesis to protect an amino group, such as tert-butyl, benzyl, para-nitrobenzyl, 9-fluorenylmethyl, 2,2,2-trichloroethyl, trimethylsilylethyl or furfuryl. In this case, α-chlorinated and tert-butyl carbonates are very valuable.

those in the α-chlorinated carbamate-1 starting material and R 1 represent, for example, a hydrogen atom or an ethyl radical or together with the nitrogen atom to which they are attached form an imidazolyl ring. Thus, α-chloro-ethoxycarbonyl-imidazole and 1,2,2,2-tetrachloroethyl N-methylcarbamate are particularly valuable.

R 1 and R 7 represent in particular a hydrogen atom, a methyl radical C ± -C 2 aliphatic radical or a cycloaliphatic radical which may contain 30 carbon atoms. The substituents on R6 and R7 may be hydrocarbon radicals or groups having heteroatoms, in particular sulfur.

Since the release of hydrohalic acid HX occurs during the reaction, · ·. From which, to remove this acid, it is necessary to be involved! is an acid acceptor.

• «; The acid acceptor may be an organic or inorganic base.

: Preferred bases include sodium hydroxide or potassium hydroxide, sodium carbonate or bicarbonate or »» · * "· potassium carbonate or bicarbonate, magnesium oxide and sodium sulfite, which are commonly used as aqueous solutions, tertiary amines such as triethylamine, such as triethylamines. or N, N-dime-R1 stylanil and the amine starting material itself -> NH.

Rz • # · · "/ The amount of basic substance added to the medium should be large enough to neutralize any acid released.

<· * ;; · A small excess compared to the stoichiometric amount * ... * is best used.

il 9 87645

The reaction according to the invention is best carried out in a solvent medium. Generally, one or more solvents are used which are inert to the reagents. They are best selected from the following: Chlorinated aliphatic solvents such as dichloromethane or 1,2-dichloroethane, cyclic or acyclic ethers, e.g. tetrahydrofuran or dioxane, acetone, pyridine, acetonitrile, dimethylformamide or an alcohol such as ethanol or tert-butane. . The reaction medium may, if necessary, contain a certain amount of water, e.g. to dissolve inorganic bases.

The reaction temperature 1a depends on the nature of the solvent and the reactivity of the starting materials. It is between -5 and + 150 °. Most often it is between 0 and 30 ° in the reaction of carbonates and thiocarbonate with amines and between 30 and 100 ° in the reaction of carbamates.

The starting compounds are generally used in stoichiometric amounts. It is recommended to use a slight excess of either of these two reagents.

When the amine starting material is used as the acid acceptor, at least two compounds are used per -C-O-CH-R5- group to be converted.

Il I

• V O X

: Y: equivalent of amine.

»· · Y / Reagent addition sequence is not an essential feature of the invention. However, when the amine is primary and is also used as an acid acceptor base, it is recommended to add it after the second starting compound. Many compounds, some of which are very difficult to prepare, can be easily prepared by the process of the invention by conventional methods. These compounds are very useful as pharmaceuticals, pesticides such as carbofuran, 3,4-dimethylphenyl N-methylcarbamate, aldicarp, carbaryl from carbamates, butylate, EPTC, molinate from thiocarbamates and chlortoluron and monuron from ureas *; or as intermediates in peptide synthesis such as amino acid carbamates. Mention should be made, for example, of the synthesis of aspartame (Tetrahedron, vol.

39, No. 24, supra 4121-4126, 1983, B. Yde et al.).

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The invention is illustrated by the following examples.

Example_1_- Preparation of ethyl N, N-di-n-butylcarbamate nC4Hq /

C2H5 ~ C-NH

Il \ o nC4H 9

A solution of 26 g (0.2 mol) of di-n-butylamine in 20 ml of anhydrous tetrahydrofuran (THF) is added dropwise to a solution containing 15.2 g (0.1 mol) of α-chloroethyl ethyl carbonate CH3CH-OCO-CH2-CH3 in 80 ml of tetrahydro-

f I II

furan. Cl O

The addition is filtered with stirring at 20 ° C. The reaction is slightly exothermic and dibutylamine hydrochloride is observed to precipitate. The mixture is stirred for 2 hours at 20 [deg.] C., the precipitate is removed by filtration and the tetrahydrofuran is evaporated.

The residue is taken up in 200 ml of dichloromethane. The solution is washed with 50 ml of aqueous saturated KHCO 3 solution and left in 50 ml of water. The solution is dried over magnesium sulphate, after which the solvent is removed by evaporation and the residue remains. the remaining residue is distilled under reduced pressure.

·· · 15.1 g (75% yield) of the desired carbamate are obtained. Boiling point (b.p.) 78-80 ° C / 40 Pa (0.3 mm Hg).

IR: ν C = O: 1700 cm -1 NMR: 0.9 to 1.7 ppm (17H) complex C-CH 2 -CH 3. ··· 3.2 ppm (4H) triplet N-CH 2 4.1 ppm (2H) Quartet O-CH2 Example 2 - Preparation of ethyl Nn-octylcarbamate C2H5-C-NH nC8H17O

II

11 87645

A solution of 7.6 g (0.05 mol) of α-chloroethyl ethyl carbonate in 10 ml of tetrahydrofuran is cooled to 5-10 ° C and also added to a solution cooled to 5-10 ° C containing 12 .9 (0.1 mol) of n-octylamine in 40 ml of tetrahydrofuran. After the addition is complete with stirring, the mixture is allowed to return to room temperature and kept at this temperature with stirring for 2 hours. The precipitate is removed by filtration, the solvent is evaporated and the residue is taken up in 50 ml of any ethyl ether. The solution is filtered again and the ether phase is washed with 50 ml of water. The solution is dried over magnesium sulfate, the solvent is removed by evaporation and the remaining mixture is distilled under reduced pressure.

8.64 g (yield 86%) of the desired carbamate are thus obtained.

(B.p.) 110 ° C / 40 Pa (0.3 mmHg).

IR: v C = O: 1700 cm-1, v N - H: 3300 cm-1 1 H NMR: 0.1 - 1.7 ppm (18H) complex (CH 2) n CH 3 3.2 ppm (4H) triplet N- CH2 4.1 ppm (2H) quartet O-CH2 5.2 ppm (1H9 complex NH-C-

II

Example 3 - Ethyl Preparation of N-octyl carbamate] ··· * 6.5 g (0.05 moles) of n-octylamine, • * / * 1 30 ml, tetrahydrofuran, 10 ml of water and 10 g of potassium carbonate K2CO3 · The temperature is maintained at 5-0 ° C while 7.6 g (0.05 mol) of α-chloroethyl ethyl carbonate in 5 ml of tetrahydrofuran are added dropwise with stirring.

I .. 'The mixture is allowed to warm to room temperature and kept at this temperature for 1 hour with stirring. Add 50 ml of sodium chloride saturated with water, extract the mixture twice with 40 ml. ethyl ether and the ether phases are combined and dried over magnesium sulfate.

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The solvent is removed by evaporation and distilled under reduced pressure to give 7.4 (74%) of the desired carbamate.

Kp. 110-112 ° C / 40 Pa (0.3 mm Hg).

Example 4 - Preparation of ethyl N, N-di-n-butylcarbamate

To a solution of 6.5 g (0.05 mol) of di-n-butylamine and 5.56 g (0.055 mol) of triethylamine in 40 ml of tetrahydrofuran is added dropwise with stirring and maintaining the temperature at 5-10 8.4 g (0.055 mol) of α-chloroethyl ethyl carbonate dissolved in 10% tetrahydrofuran at [deg.] C.

The mixture is allowed to warm to room temperature and kept at this temperature for 2 hours with stirring.

The precipitate is removed by filtration, after which the solvent is evaporated and distilled off under reduced pressure. 6.3 g (63% yield) of the desired carbonate are recovered.

Kp. 76 ° C / 2 6.6 Pa (0.2 mm Hg).

Example 5 - Preparation of tert-butyl Ν-η-octylcarbamate ch2: CH3-C-O-C-NH nC8H17 ch3 oa) Synthesis of α-chloroethyl tert-butyl carbonate To a reactor cooled to 5 ° C is added 600 ml of trichloromethane. : 43.7 g (0.59 mol) of tert-butanol and 94.7 g (0.66 ·: mol) of α-chloroethyl chloroformate. 57 g (0.72 mol) of pyridine are then added dropwise with stirring. During the addition, the temperature is maintained between 10 and 20 ° C. The mixture is stirred for 4 hours at room temperature.

1: 13 97645

The reaction mixture is washed with 100 ml of 1N aqueous 1N hydrochloric acid solution, 200 ml of saturated Ν32 <20 ^ solution and twice with 100 ml of ice water. The organic phase is collected and dried over magnesium sulfate aa.

After evaporation of the solvent and distillation under reduced pressure, 91.5 g (86%) of α-chloroethyl tert-butyl carbonate are obtained.

Kp. 88 ° C / 2.7 kPa (20 mm Hg).

IR: vC = O: 1750 cm-1 1 H NMR: 1.5 ppm (9H) (CH 2) 3 C-singlet

1.8 pDm (3H) doublet CH -.- C

3 Cl 6.4 ppm (1H) quartet-O CH- C1 b) Reaction of α-chloroethyl · tert-butyl carbonate with n-octylamine

A solution of 52 g (0.4 mol) of n-octylamine in 65 ml of anhydrous tetrahydrofuran is added dropwise to a solution of 36.2 g (0.2 mol) of α-chloroethyl tert-butyl carbonate in 120 ml of tetrahydrofuran. The addition is carried out with stirring. . + 10 ° C. The mixture is stirred for about 15 hours at room temperature; * insoluble compounds are removed by filtration and the tetrahydro-furan is evaporated. The residue is taken up in 400 ml of dichloromethane and the solution is washed with 10 ml of 1N aqueous hydrochloric acid solution, 200 ml of water, 100 ml of saturated aqueous KHCO3 solution and then 100 ml of water.

The solution is dried over magnesium sulfate, then the solvent is evaporated off and the remaining mixture is distilled under reduced pressure.

This gives 36.52 g (yield 80%) of the desired carbamate.

Kp. 142 ° C / 200 Pa (1.5 mm Hg) IR: vC = 0 1690 cm -1 vNH 3340 cm -1 1 87645

II NMR: I), 1 -1,) ppm (Γ3Η) complex C- (CH2ln C1U

1.4 ppm (9H) singlet (CH 2 Cl 2) -C

3.0 ppm (2H) quartet Cll

4.7 ppm (1H) complex NH-C 1 -C) Preparation of chloromethyl tert-butyl carbonate

Proceed in the same way as in Example 5 a). 7.4 g (0.1 mol) of tert-butanol, 15.48 g of chloromethyl chloroformate and 8.1 ml of pyridine are used as starting materials to give 9.2 g (55%) of tert-butyl chloromethyl carbonate.

Kp. 82 ° C / 2 kPa (15 mm Hg) NMR: 1.4 ppm (CH 2 Cl 2 - C singlet 5.8 ppm CH 2 -C 1 singlet IR: vC = 0 1750 cm -1 d) Chloromethyl tert-butyl carbonate reaction with n-octylamine

The procedure is the same as in 5 b), but 1-chloroethyl tert-butyl carbonate is replaced by chloromethyl tert-butyl carbonate. 6.5 g of n-octylamine and 8.5 g are used as starting material. chloromethyl tert-butyl carbonate to give 4.3 g (38%) of tert-butyl N-n-octyl carbomate, which is identical; with the product obtained in (5b) above.

Example j> Fur_i: ury_y 1 i Preparation of N-n-octyl carbamate | T jj _ CH2 - OC - NHnCgH17 '° 0 a) Synthesis of g-chloroethyl furfuryl carbonate. . The procedure is the same as in Example 5 a), but 0.22 mol of α-chloroethyl chloroformate are added dropwise to a solution containing 0.2 mol of furfuryl alcohol and 0.24 mol of pyridine I! is 87645 in 200 ml of dichloromethane.

35.55 g (87% yield) of u-chloroethyl furfuryl carbonate are obtained.

Kp. 94-98 ° C / 13.3 Pa (0.1 mm Hg) IR: vC = 0 1 7 50 rm ~ 1

1 H NMR: 1.8 ppm (3H) dub

5.2 ppm (2H) singlet CH 2 O.

6.3-6.6 ppm (3H) complex H-C = and H-C ^ - Cl 7.5 ppm (1H) complex HCl) b) Reaction of α-chloroethyl furfuryl carbonate with n-octylamine

The procedure is the same as in Example 5 b), but using 10.2 g (0.05 mol) of the above-mentioned carbonate in 30 ml of tetrahydrofuran and 12.9 g (0.1 mol) of n-octylamine in 15 ml of tetrahydrofuran.

11.05 g (yield 87%) of the desired carbamate are obtained.

Kp. 162 ° C / 66.6 Pa (0.5 mm Hg), melting point (m.p.) 29 ° C.

IR: vc = O 1700 cm-1 ', vNH 3 34 0 cm-1 H NMR: 0.7-1.5 ppm (15H) complex (C

• 3.1 ppm (2H) quartet CH2N

4.9 ppm (1H) broad complex NH

5.0 ppm (2H) singlet CH2O

6.4 ppm (2H) complex H-C = 7.4 ppm (1H) complex H-C 2 NO

Example 7 - Preparation of furfuryl N-n-octyl carbamate

6.5 g (0.05 mol) of n-octylamine, 30 ml of tetrahydrofuran and 20 ml of 5M aqueous CO 2 solution are charged to the reactor. temperature; 1a is kept at 5-10 ° C and 11.25 g (0.055 mol) of α-chloroethyl furfuryl carbonate are added dropwise with stirring.

i6 87 645

The mixture is allowed to warm to room temperature and kept at this temperature for 18 hours with stirring. 50 ml of water saturated with sodium chloride are added, the mixture is extracted twice with 40 ml of ethyl ether and the ether phases are combined and dried over magnesium sulphate.

The solvent is removed and distilled under reduced pressure to give 9.5 g (75%) of the desired carbamate.

Kp. 142 ° C / 26.6 Pa (0.2 mm Hg)

Example 8 - Preparation of benzyl N-n-octyl carbamate H 2 O-c - NH n Cg H 17 a) Synthesis of g-chloroethyl benzyl carbonate

Proceed in the same manner as in Example 5 a), but using 200 ml of dichloromethane, 21.6 g (0.2 mol) of benzyl alcohol, 31.6 g (0.22 mol) of α-chloroethyl chloroformate and 0.2 mol of pyridine.

: 40.5 g (94% yield) of α-chloroethylbenzylcarbo- are obtained. carbonate.

Kp. 100 ° C / 166.6 Pa T. · IR: vc = O 1760 cm -1 1 H NMR: 1.8 ppm (3H) doublet CH 2 - 5.2 ppm (2H) singlet CH 2 ·: 6.4 ppm (1H ) quartet O-CH-Cl 7.3 ppm (511) singlet aromatic protons h! b) reaction of α-chloroethyl benzyl carbonate with n-octylamine k '

Proceed in the same way as in Example 5 b), but using 19.4 g (0.15 mol) of n-octylamine in 30 ml of tetrahydrofuran and 16.2 g (0.075 mol) of the above carbonate in 40 ml: in tetrahydrofuran.

17.7 g (90% yield) of the desired carbamate are obtained.

Kp. 180 ° C / 66, b Pa (0.5 mm Hg), melting point 33-34 ° C.

IR: vC = -O 1 6 80 cm -1 NH 3 O 780 cm -1 NMR: 0.7-1.5 ppm (15H) complex (CH 2) n CH 2

3.1 ppm (2H) quartet Cl 2 N

4.8 ppm (1H) singlet NH

5.1 ppm <2H) singlet CH2 to 7.3 ppm (5H) singlet aromatic protons.

Example 9 - Preparation of phenyl N-isobutylcarbamate / -, CH3 V_y q \ Ch3 a) Synthesis of g-chloroethylphenyl carbonate .79 g (0.055 "... moles) of g-chloroethyl chloroformate and 0.5 moles of pyridine.

: 94.23 g (94%) of g-chloroethylphenyl carbonate are thus obtained.

. ·. : Kp. 1 10 ° C / δ 6.6 Pa (10.5 mm Hg) IR: vC = O 1770 cm -1 1 H NMR: 1.7 ppm (3H) doublet CH 2 δ 6.3 ppm (1H) quartet CH- C1 7.0-7.3 ppm (5H) complex of aromatic protons.

- b) reaction of g-chloroethylphenyl carbonate with isobutylamine ιβ 87645

The procedure is the same as in Example 7, but 7.3 g (0.1 mol) of isobutylamine, 35 ml of a 5M aqueous K2CO3 solution and 20.1 g (0.1 mol) of the above carbonate are used.

Removal of the solvent and recrystallization from petroleum ether gives 12.5 g (65%) of the desired product.

Melting point 66-67 ° C IR: vc = O 1710 cm -1 vNH: 3400 cm -1 1H NMR: 0.9 ppm (6H) doublet CH.

^ -Mp

1.8 ppm (1H) multiplet CH

""We

3.1 ppm (2H) triplet Cf 2 -N

5.3 ppm (1H) broad singlet NH

7.0-7.3 (5H) complex of aromatic protons.

Example 10 Preparation of ~ tert-butyloxycarbonylpiperidine CHt, __ 1 (CH - C - OC - N) I. \ / ch3 o

Proceed in the same way as in Example 7, but use ;; 8.5 g (0.1 mol) of piperidine, 60 ml of tetrahydrofuran, 20 ml of saturated aqueous 1 CO 2 solution and 0.11 mol of α-chloroethyl tert-butyl carbonate.

The mixture is stirred for only 2 hours. The desired carbamate is obtained: - r 14.8 g (80%).

Kp · 96-98 ° C / 2 kPa (15 mm I-Ig) IR: vc = O 1690 cm-1 1 H NMR: 1.3-1.6 ppm, (15H) -CH 2 -, CH 3 -

· 3.3 ppm (4 H) CH 2 N

: Example 11 - Preparation of S-c-style N-n-octylthiocarbamate Preparation of N-n-octylthiocarbonate ('' 81-117 19 87645 a) g-clonethyl S-ethylthiocarbonate

25 H I J

0 Cl

The procedure is the same as in Example 5 a), but 31.5 g (0.22 mol) of n-chloroethyl chloroformate are added to a solution of 12.4 g (0.2 mol) of ethanethiol and 15.8 g (0.2 mol). pyridine in 200 ml of dichloromethane.

21.1 g (62.5%) of α-chloroethyl S-ethylthiocarbonate are obtained.

Kp. 110 ° C / 5.86 kPa (44 mmHg) IR: vc = O 1720 cm -1 1H NMR: 1.3 ppm triplet CH 3 1.75 ppm doublet CH 3

2.8 ppm quartet CH2 ~ S

6.5 ppm quartet O-CHCl b) Reaction of α-chloroethyl S-ethylthiocarbonate with n-octylamine

Proceed in the same way as in Example 7, but using 6.5 g (0.05 mol) of n-octylamine, 30 ml of tetrahydrofuran, 20 ml of 5M aqueous K2CO3 solution and 8.43 g (0.05 mol) of the above. ; thiocarbonate.

5.3 g (49%) of the desired thiocarbamate are thus obtained.

• 'Kp. 14-152 ° C / 66.6 Pa (0.5 mm Hg).

IR: vc = O 1650 cm -1 VNH 3300 cm -1 1H NMR: 0.7-1.6 ppm (18H) complex (CH 2) n CH 3

: 2.8 ppm (2H) quartet CH2S

3.1 ppm (2H) pseudo-triplet CH2N

3.2 ppm (1H) broad singlet NH

20 87 645

Examples 12 - 19 - Preparation of various benzyl carbamates In these examples, u-chloroethyl benzyl carbonate is reacted as in Example 7 with various primary or secondary amines.

Temperature conditions and reaction times, physical properties and yields of the products obtained are given in Table I.

i, 2i 87645

'~ G

<D

of

P C

_p φ 0 \ 0 <, v> o \ o ο'ΰ cK> o * P o'.c QJ 1¾ p -H -p ίΠ 1- "O '. r' <3" O ^ Γ- WOO oo co σν a> ao ld γ- oo H + JC Ό -PC jC O 05 3 3 fl α-pw ---------------- -—--—? g OS 0 (dJ <D (0fX OJrQ 0 (05¾ 4J + JCL, 05¾¾ 0-1¾ ww η Οι r- • H -H ro 'rm 00 r- ~ ^

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::: D -h • · - <; 01 O <n m ^ ln vo r ~ co ΕΊ W G <- <- ^ t-r-t- 22 87645

Example 20 - Preparation of S-ethyl N, N-hexamethylene thiocarbamate (molinate) I 2 2 ^ 1 - C-S "C2H5 CH2-CH2-CH2 o

Proceed in the same manner as in Example 11. α-Chloroethyl S-ethylthiocarbonate is reacted with hexamethyleneimine.

"Molinate" is obtained in 70% yield as a distilled product.

(Bp 141 ° C / 1.7 kPa (13 mm Hg)).

Example 21 - Preparation of tert-butyl N-benzylcarbamate Synthesis of CH3 (N, N'-CH2-nhco-c-ch3O CH3 a) 1,2,2,2-tetrachloroethyl tert-butyl carbonate 1,2,2,2-Tetrachloroethyl chloroformate is added in one portion to a solution of tert-butanol (3 g; 0.04 mol) in dichloromethane (50 ml). The mixture is cooled to 0 [deg.] C. and 0.2 g (0.04 mol) of pyridine are added dropwise. The mixture is stirred for 4 hours at room temperature. Then add: Y: 20 ml of ice water and the organic phase is separated and washed with 20 ml of ice water. Dry over magnesium sulfate and evaporate the solvent.

; 11.3 g of a white solid are obtained (yield 99%). The solid is recrystallized from petroleum ether (yield 87%; melting point 70 ° C). 9.9 g of purified carbonate are obtained.

'.Y Kp. 96 ° C / 865 Pa (6.5 mm Hg) ': IR: vC = O 1770 cm -1 1 H NMR: (CDCl 3, TMS): 1.5 (s, CH 3) 6.7 (s, CH ) b) Reaction of the above carbonate with benzylamine 23 87645 1.1 g (0.01 mol) of benzylamine are dissolved in 20 ml of tetrahydrofuran and 3 ml of 5M aqueous potassium carbonate solution are added.

2.9 g (0.01 mol) of tert-butyl tetrachloroethyl carbonate dissolved in 5 ml of tetrahydrofuran are then added at 5 ° C. The mixture is stirred for one hour at 20 [deg.] C. and the organic phase is decanted and washed with 10 ml of saturated aqueous NaCl solution. The organic phase is dried, the solvent is evaporated off and the remaining mixture is distilled: 2.0 g of the desired carbamate are obtained (yield 96%).

Kp. 103 ° C / 6.7 Pa (0.05 mm Hg).

The product is recrystallized from petroleum ether to give 1.84 g of the desired carbamate (89%). Sp. 54 ° C (53-54 ° C).

Example 22 - Preparation of tert-butyloxycarbonylimidazole N = rr \ CH

\ I 3

N-C-O-C-CH

/ 11 10 CH 3 5 g (17.5 mmol) of tert-butyl 1,2,2,2-tetrachloroethyl carbonate dissolved in 10 ml of tetrahydrofuran are added at 0 ° C to a solution of imidazole (1.2 g; 17.6 mmol) in tetrahydrofuran (20 ml) and also 5M aqueous potassium carbonate solution (5 ml). The mixture is stirred for one hour at 20 ° C, the organic phase is decanted and washed with 10 ml of saturated aqueous •; NaCl solution.

The residue obtained after drying the organic phase and evaporating the solvents is distilled to give 2.55 g of product (yield 86%).

Kp. 64 ° C / 133.3 Pa (1 mm Hg), b.p. 43 ° C.

:: Example 23 - Preparation of 2,3-dihydro-2,2-dimethyl-7-benzofuranyl N-methylcarbamate (carbofuran) 24 87645 a) 1-Chloroethyl 2,3-dihydro-2,2-dimethyl-7-benzofuranyl synthesis of carbonate 21.5 g (0.15 mol) of 1-chloroethyl chloroformate are added in one portion to a solution of 2,3-dihydro-2,2-dimethyl-7-benzofuranol (24.6 g; 0.15 mol) in dichloromethane ( 150 ml). The mixture is cooled to between 0 and 5 ° C and 12 g (0.15 mol) of pyridine are added dropwise. The mixture is stirred for three hours at 20 ° C. The organic phase is then washed twice with 50 ml of ice water. Dry over magnesium sulfate and evaporate the solvent. The yellow oil obtained is distilled. 34.1 g (84% yield) of the desired carbonate are recovered.

Kp. 127 ° C / 66.6 Pa (0.5 mm Hg).

b) Reaction of the above carbonate with methylamine 5.4 g (0.02 mol) of the above carbonate are dissolved in tetrahydrofuran (20 ml). 10 ml of an approximately 5M aqueous solution of CO 2 are then added, followed by 1.7 ml (0.02 mol) of a 40% solution of methylamine in water. The mixture is stirred for 15 hours at 20 ° C. The organic phase is decanted and washed with saturated NaCl solution. The solvent is evaporated off and the product is crystallized from methyl-cyclohexane. 3.5 g of the desired carbamate are obtained (yield 79%).

. ‘Melting point 148 ° C.

:: (c) Proceed in the same way as in (a) and then in (b), but substituting N, N-dimethylaniline for the pyridine and not distilling the carbonate intermediate. When 16.4 g of 2,3-dihydro-2,2-dimethyl-7-berizofuranol are used as starting material, . 16.8 g (76%) of carbofuran were melted, m.p. 147 ° C.

Example 24 - Preparation of N, methyl-N1-piperidylurea * a) Synthesis of 1,2,2,2-tetrachloroethyl N-methylcarbamate 34.7 ml (0.4 mmol) of methylamine (40% in aqueous solution) are added dropwise at 0 ° C. to a solution of 49.4 g (0.2 moles) of 1,2,2,2-tetrachlorethyl chloroformate in dichloro-87645 methane (150 ml). The mixture is then stirred for 2 hours at room temperature. The organic phase is washed twice with 100 ml of water and dried over magnesium sulfate.

The product crystallizes on evaporation of the solvent to give 42.6 g of the desired carbamate (yield 88%).

Sp. 10 5-10 6 ° C.

1 H NMR: 2.75 (CH 3 -N) 5.2 (NH) 6.7 (CH-Cl) IR: C = O 1760 cm -1 b) Synthesis of N-methyl-N1-piperidylurea 4.83 g ( 0.02 mol) of the carbamate obtained above are dissolved in a mixture of 30 ml of tetrahydrofuran and 5 ml of water saturated with potassium carbonate, to this solution kept at 10 ° C, 1.7 g (0.02 mol) of piperidine are added and the mixture is stirred for 4 hours. The organic phase is decanted and washed with 50 ml of saturated NaCl water, dried over magnesium sulphate, the solvent is evaporated off and the residue is distilled to give 1.8 g of urea (yield 63%).

Kp. 110 ° C / 6.7 Pa (0.05 mm Hg).

. ·. Example 25 - Preparation of imidazolylcarbonylpiperidine

N = \ / V

Synthesis of N - C - N) L- (±) a) α-Chloroethoxycarbonylimidazole 28.6 g (0.2 mol) of chloroethyl chloroformate are added dropwise to a solution cooled in a water bath containing 27.2 g (0.4 mol) of imidazole. In 200 ml of dichloromethane. The mixture is stirred at room temperature for 4 hours and then 50 ml of ice water are added. The organic phase is washed twice with 50 ml of water and then dried over magnesium sulphate. After evaporation and distillation, 38.1 g (73%) of α-chloroethoxycarbonylimidazole (b.p. 80 ° C / 66.6 Pa (0.5 mm Hg)) are obtained as a colorless liquid which spontaneously crystallizes at room temperature, melting point 50 ° C. Cl UN - CO CH CHO • 1 H NMR: (60 MHz, CDCl 3, TMS): 1.9 (d, CH 3) 6.7 (q, OCH-Cl) 7.05; 7.4; 8.2 (3 pseudo-singlets imidazole) IR: vc = O 1770 cm-1 b) reaction of g-chloroethoxycarbonylimidazole with piperidine

A solution of 8.5 g (0.1 mol) of piperidine in 10 ml of tetrahydrofuran is added dropwise to a solution of u-chloroethoxycarbonyl-imidazole (8.75 g; 0.05 mol) in 50 ml of tet. rahydrof uranium. This solution is cooled to 5 ° C during the addition and then stirred at room temperature.

The piperidine hydrochloride formed is filtered off and the organic phase is washed once with water. It is then dried over * · * · * magnesium sulphate and the solvent is evaporated off, the remaining mixture is distilled off and 6.2 g (yield 70%) of the desired product are obtained. Kp. 1 3 4 ° C / 2 6.6 Pa (0.2 mm Hg): The resulting liquid crystallizes spontaneously in the refrigerator.

: ·. Sp. 38 ° C.

1 H NMR: 1.5 ppm multiplet (CH 2) δ 3.5 ppm multiplet CH 2 -N-CH 2 C = δ 7.0 ppm i 7.15 ppm 't imidazole 7.8 ppm J IR: vc = O 1690 cm -1 1 27 '87645

Example 26 - Preparation of N, N-diethylimidazolecarbouramide

N - C - N

'et

The procedure is the same as in Example 25 b), but the piperidine is replaced by diethylamine 11a. The desired urea is obtained in a yield of 6.5 g (78%).

Kp. 106 ° C / 26.6 Pa (0.2 mm Hg).

Sp. 41 ° C (calc. 38-43 ° C) 1 H NMR: 1.2 ppm (t, CH 3) 3.4 ppm (q, CH 2 N) 7.0 ppm 7.2 ppm Vimidazole 7.8 ppm, IR: vc = O 1690 cm-1

Example 27 - Preparation of 2-methyl-2- (methylthio) propanal O - / (methylamino) carbonyl / oxime (aldicarp) No 10N sodium hydroxide is added successively with 50 ml of toluene and 6.65 g (0.05 mol) of 2-methyl-2 - (methylthio) propanaalioksiimia. The mixture is stirred for a few moments at room temperature and then the water is removed by azeotropic distillation. After that the mixture cool in an ice-water bath and add dropwise 7.15 g (0.05 .mu.m.) of 1-chloroethyl chloroformate. The mixture is stirred for one hour at about 10-15 ° C. 10 ml (about 0.13 mol) of 40 ml of aqueous methylamine are then added dropwise and the mixture is stirred for a further hour at the same temperature. The organic phase is decanted and washed with 10 ml of ice water. The organic phase is dried over magnesium sulphate and evaporated to dryness. 8.7 g of a light brown solid, m.p. 82-90 ° C (70% purity by HPLC), which can be further purified - either by silica gel chromatography or by crystallization from isopropyl ether (yield 63 έ, m.p. 98-100 ° C). ).

1 H-NMR (CDCl 3, 60 MHz): 1.42 ppm, 6H) 1.92 (2.3H).

28 87645

Example 28 - Synthesis of tert-butyloxycarbonyl-L-aspartic acid

To a solution of 1.33 g (10 mmol) of L-aspartic acid in a mixture of dioxane and water (1: 1, 30 ml) is added 4.2 ml (30 mmol) of triethylamine and the mixture is stirred until dissolution is complete (about 10 minutes). 2.85 g (10 mmol) of tert-butyl 1,2,2,2-tetrachloroethyl carbonate are then added and the mixture is stirred for 6 hours at 20 ° C. 50 ml of water are then added and the mixture is extracted twice with 20 ml of ethyl acetate. The aqueous phase is acidified (pH 2-3) with N-hydrochloric acid and then extracted 3 times with 30 ml of ethyl acetate. The extract is washed with saturated NaCl solution, dried over magnesium sulfate and evaporated. The product obtained is crystallized from ethyl acetate and petroleum ether. 1.4 g (60% yield) of the desired acid are obtained. Sp. 116-118 ° C, m.p. 114-116 ° C.

20 20 / a / = -5 (c 1.0 MeOH) / «/ = - 6.2 (c 1.0 MeOH) D D ref.

Example 29 - Preparation of ethyl furfuryloxycarbonylglycinate **. ' 2.05 g (10 mmol) of α-chloroethyl furfuryl carbonate are added to a solution kept between 5 and 10 ° C containing 1.03 g (10 mmol) of ethyl glycinate, 6 ml of tetrahydrofuran and 4 ml of 0.5 M potassium carbonate solution. . The mixture is allowed to warm to room temperature and stirred for 18 hours. 50 ml of water saturated with sodium chloride are added and the mixture is extracted 3 times with 40 ml of ethyl ether. The organic phases are combined and dried over magnesium sulfate. . account. After removal of the solvent and distillation, 1.5 g (yield 66%) of the desired product are obtained.

'·' Kp. 144 ° C / 40 Pa (0.3 mm Hg).

::: IR: vC = O 1680 cm * 1 vNH 3280 cm * 1 ·. 1 H NMR (CDCl 3), TMS): 1.3 ppm triplet CH 3 3.95 ppm doublet N-CH 2 ^ 4.2 ppm quartet Δ2 <ΟΗ3) δ 29 87645

5.1 ppm singlet Ch 2 O-Cl 2 -N

5.2 ppm wide singlet NH

6.4 ppm complex H-C = 7.4 ppm complex 1I-C ^ 0

Example 30 - Preparation of benzyloxycarbonyl-L-proline

To a solution of 1.15 g (10 mmol) of L-proline, 10 ml of methanol and 3 ml of saturated aqueous potassium carbonate at 5 ° C is added 2.36 g (11 mmol) of benzyl α-chloroethyl carbonate. After four hours of reaction, 50 ml of water are added and the mixture is washed twice with 10 ml of ethyl ether. The mixture is acidified to pH 2-3 with 6N hydrochloric acid and extracted with ethyl acetate.

After evaporation of the solvents and recrystallization from a mixture of ethyl acetate and petroleum ether, 2.2 g (yield 88%) of Z- (L) -proline are obtained.

Sp. 7 5-7 6 ° C (m.p. 76-78 ° C).

Example 31 - Preparation of 1,2,2,2-tetrachloroethyl 2-trimethylsilylethyl carbonate (CH3) 3Si - CH2 - CH2 - O-C-O-CH-CCl3: cl. Using 5.91 g of trimethylsilylethanol and 12.35 g of tetrachloro- · '·' ethyl chloroformate as starting material * '* /, 13.6 g (yield 83%) of the desired product are obtained, m.p .: 9 2-94 ° C / 6, 6 Pa.

IR νCO = 1750 cm -1: T: 1 H NMR (CDCl 3, external TMS): 0.1 (s, CH 3 -Si) 1.1 (t, CH 2 -Si) 4.35 (t, CH 2 -Si) O) 6.7 (s, CH-Cl) 30o 87645

Example 32 - Preparation of trimethylsilylethyloxycarbonyl-L-phenylalanine / CH2 - C6H5 (CH-.) Si - Cll - - O - C - NH - Cll

J / J V

o co2 »0.83 g of L-phenylalanine (5 mmol) are dissolved in a mixture of dioxane and water (1: 2; 12 ml) containing 1.4 ml of triethylamine (10 mmol). The mixture is cooled to 0 ° C and 1.8 g (5.5 mmol) of the carbonate obtained above dissolved in 4 ml of dioxane are added in one portion. After 2 hours at 2 [deg.] C., 20 ml of water are added and the mixture is extracted twice with 20 ml of ether. The aqueous phase is then acidified (pH 2-3) with 6N hydrochloric acid and extracted 3 times with 50 ml of ethyl acetate. The extract is dried over magnesium sulfate and evaporated. 1.4 g (100 ") of the desired product are obtained in the form of an oil.

1 H NMR (CDCl 3, TMS) δ (s, CH 3 -Si) 0.9 (t, CH 2 -Si) 3.0 (CH 2 Ph), 4.0 (t, O-CH 2 -C-Si) 4.5 <m, CH-N) 5.2 (s, NH) 7.2 (s, Ph)

1 I

To this oil dissolved in 5 ml of ether is added 2 ml of dicyclohexylamine and, after crystallization, 1.93 g (yield 78%) of the dicyclohexylammonium salt are obtained, m.p. 111-112 ° C.

• »• ·" · 1 4 »1 't» ♦ · 1 · * 1 · · * »·

Claims (11)

A process for the preparation of carbamic acid derivatives of the formula n - c - y 2 2 R 2 where R 1 and R 2, which may be the same or different, are: - a hydrogen atom, - an aliphatic radical of 1 to 20 carbon atoms, - cycloaliphatic or araliphatic radical having a maximum of 50 carbon atoms, or together with the nitrogen atom to which they are attached form a piperidino, morpholino, hexamethylene imino or imidazole ring, the aliphatic, cycloaliphatic, araliphatic radical or said ring may be substituted with an acid, alcohol, ester, ether, mercapto or amino group,. R 3 K 6 ^ / Y is OR, SR, -N or O - N = O group ^ R4 XR6 where R is an aliphatic radical of 1-12 carbon atoms and which may be substituted by halogen or a furyl or trimethylsilyl group ; a benzyl, nitrobenzyl, phenyl, benzofuranyl group which may be substituted with lower alkyl, or a fluorenylmethyl group; R3 and R4, which may be the same or different, are a hydrogen atom, methyl or they form together with the nitrogen atom to which they are attached an imidazolyl ring, and R6 and R7, which may be the same or different, are an aliphatic radical of 1 12 carbon atoms or a cycloaliphatic radical having a maximum of 30 carbon atoms and may be substituted with a lower alkylthio or the other may be a hydrogen atom, methyl radical or lower alkyloxy radical, characterized in that the amino compound of the formula hydrocyanic acid acceptor at a temperature between -5 and + 150 ° C with an α-halogenated derivative of a carbonic acid of the formula R1 2-CH-O-CY I II X 0 where R1, R2 and Y are as defined above, X is a fluorine, chlorine or bromine atom and R 2 is a hydrogen atom or aliphatic group of 1-4 carbon atoms and which may be substituted by a halogen atom. 2. A process according to claim 1, characterized in that X is a chlorine atom. 3. A method according to claim 1 or 2, characterized in that R is a group commonly used in peptide syntheses to protect amino acid amino groups. A process according to claim 3, characterized in that the α-halogenated derivative is α-chloroethyl ethyl carbonate, α-chloroethyl tert-butyl carbonate, α-chloroethyl ethyl furfuryl carbonate, α-chloroethylbenzyl carbonate, α-chloroethylphenyl carbonate or α-chloroethyl , 3-dihydro-2,2-dimethyl-7-benzofuranyl carbonate, 2 1,2,2,2-tetrachlorethyl-tert-butyl carbonate, α-chloroethyl-5-ethylthiocarbonate, α-chloroethoxycarbonylimidazole, 1,2,2, 2-tetrachlorethyl N-methylcarbamate, 1,2,2,2-tetrachloroethyl, 2-trimethylsilylethyl carbonate or 2-methyl-2- (methylthio) propanal O- [α-chloroethyl oxycarbonyl] oxime. 5. A process according to any one of the preceding claims, characterized in that R · and are general radicals of natural amino acids or synthetic amino acids. 6. Process according to any preceding claim, characterized in that the amine is methylamine, diethylamine, di-n-butylamine, isobutylamine, n-octylamine, ethanolamine, benzylamine, imidazole, hexamethylene-imine, morpholine, diethanolamine , n-methyl-n-benzylamine, piperidine, L-phenylalanine, L-proline, glycine-L-tyrosine, L-serine, L-aspartic acid, ethyl glycinate, phenylglycinate or proline. Process according to any of the preceding claims, characterized in that the reaction is carried out in the presence of one or more solvents which are inert to the reagents. Process according to any of the preceding claims, characterized in that the solvents are selected from a group consisting of chlorinated aliphatic solvents, cyclic or acyclic ethers, alcohol, acetone, pyridine, acetonitrile or dimethyl formamide. • 9. A process according to claim 8 or 9, characterized in that the solution medium contains water. 10. A process according to any preceding claim, characterized in that the acid acceptor is an organic or inorganic base. 11. A process according to any of the preceding claims, characterized in that the acid acceptor is sodium hydroxide or potassium hydroxide, sodium sulfite, sodium carbonate or bicarbonate or potassium carbonate or bicarbonate, magnesium oxide, tertiary amine or 38 R 2 - and R 2 are the same as above. Process according to any of the preceding claims, characterized in that the tertiary amine is triethylamine, pyridine or N, N-dimethylamine. IN: