Catalytic hydrogenation for producing amines from carboxylic acid amides, carboxylic acid diamides, di-, tri-, or polypeptides, or peptide amides

Abstract

The present invention relates to a process for the preparation of amines, comprising the following steps: a. reaction of a (i) carboxylic acid amide of the general formula (I), or (ii) carboxylic acid diamide of the general formula (II), or (iii) di-, tri- or polypeptide, or (iv) peptide amide with carboxy-terminal amide function with an alkylating agent, b. addition of a hydrogenation catalyst to the reaction mixture in a molar ratio of from 1:10 to 1:100 000, based on carboxylic acid amide, carboxylic acid diamide, di-, tri- or polypeptide or peptide amide, c. reaction of the reaction mixture with hydrogen, where a hydrogen pressure of from 0.1 bar to 200 bar is established and where a temperature in a range of from 0 C. to 250 C. is established.

Claims

1. A process for the preparation of amines, comprising the steps: a) performing an O-alkylation of one or more compounds by reacting said compounds with an alkylating agent in a reaction mixture, wherein said alkylating agent is selected from the group consisting of: alkyl halides; esters of sulphonic acid; esters of fluorosulphonic acid; esters of trifluoromethanesulphonic acid; esters of chloroformic acid; oxonium salts; dialkyl sulphates; and diazomethane and said compounds are selected from the group consisting of: i) a carboxylic acid amide of the general formula (I): ##STR00061## wherein: R is selected from the group consisting of: H, (C.sub.1-C.sub.24)-alkyl, (C.sub.3-C.sub.20)-cycloalkyl, (C.sub.2-C.sub.13)-heterocycloalkyl, (C.sub.6-C.sub.14)-aryl, (C.sub.3-C.sub.13)-heteroaryl and the acid radical of an amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine; and R.sup.1 and R.sup.2, independently of one another, are selected from the group consisting of: H, (C.sub.1-C.sub.24)-alkyl, (C.sub.3-C.sub.8)-cycloalkyl, (C.sub.2-C.sub.7)-heterocycloalkyl, (C.sub.6-C.sub.14)-aryl or (C.sub.3-C.sub.13)-heteroaryl, where both the radicals R with R.sup.1, R with R.sup.2 and also R.sup.1 with R.sup.2 may, independently of one another, form a saturated or mono- or polyunsaturated (C.sub.2-C.sub.18)-alkylene or (C.sub.2-C.sub.18)-heteroalkylene bridge, such that an aliphatic or aromatic ring having in total 3-20 ring atoms is formed; ii) a carboxylic acid diamide of the general formula (II): ##STR00062## wherein: R is selected from the group consisting of divalent (C.sub.1-C.sub.24)-alkyl radicals, (C.sub.3-C.sub.20)-cycloalkyl radicals, (C.sub.2-C.sub.13)-heterocycloalkyl radicals, (C.sub.6-C.sub.14)-aryl radicals, (C.sub.3-C.sub.13)-heteroaryl radicals; and R and R, independently of one another, are selected from the group consisting of H, (C.sub.1-C.sub.24)-alkyl, (C.sub.1-C.sub.24)-heteroalkyl, (C.sub.3-C.sub.8)-cycloalkyl, (C.sub.2-C.sub.7)-heterocycloalkyl, (C.sub.6-C.sub.14)-aryl or (C.sub.3-C.sub.13)-heteroaryl, where the radicals R with R may together form a saturated or mono- or polyunsaturated (C.sub.2-C.sub.18)-alkylene or (C.sub.2-C.sub.18)-heteroalkylene bridge, such that an aliphatic or aromatic ring having in total 3-20 ring atoms is formed; iii) a di-, tri- or polypeptide, and iv) a peptide amide with a carboxy-terminal amide function; b) adding a hydrogenation catalyst to the reaction mixture, wherein the molar ratio of hydrogenation catalyst to carboxylic acid amide, or carboxylic acid diamide, or di-, tri- or polypeptide or peptide amide, is in a range of from 1:10 to 1:100 000; c) reacting the reaction mixture with hydrogen, at a hydrogen pressure of from 0.1 bar to 200 bar and at a temperature of from 0 C. to 250 C.

2. The process of claim 1, wherein the hydrogenation catalyst comprises at least one active metal.

3. The process of claim 2, wherein the active metal is a metal of group VII B and/or VIII B of the Periodic Table of the Elements.

4. The process of claim 1, wherein, after step a), a base is added to the reaction mixture and wherein a molar ratio of base to alkylating agent of from 1:1 to 1:3 is produced.

5. The process of claim 1, wherein the reaction is carried out in a solvent.

6. The process of claim 5, wherein the solvent is selected from the group consisting of: hydrocarbons; chlorinated hydrocarbons; ethers; esters; and alcohols.

7. The process of claim 1, wherein the reaction is carried out without solvents.

8. The process of claim 5, wherein said alkylating agent is anhydrous and wherein an anhydrous solvent is used.

9. The process of claim 1, wherein said compounds are carboxylic acid amides of the general formula (I): ##STR00063## wherein: R is selected from the group consisting of: H, (C.sub.1-C.sub.24)-alkyl, (C.sub.3-C.sub.20)-cycloalkyl, (C.sub.2-C.sub.13)-heterocycloalkyl, (C.sub.6-C.sub.14)-aryl, (C.sub.3-C.sub.13)-heteroaryl and the acid radical of an amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine; and R.sup.1 and R.sup.2, independently of one another, are selected from the group consisting of: H, (C.sub.1-C.sub.24)-alkyl, (C.sub.3-C.sub.8)-cycloalkyl, (C.sub.2-C.sub.7)-heterocycloalkyl, (C.sub.6-C.sub.14)-aryl or (C.sub.3-C.sub.13)-heteroaryl, where both the radicals R with R.sup.1, R with R.sup.2 and also R.sup.1 with R.sup.2 may, independently of one another, form a saturated or mono- or polyunsaturated (C.sub.2-C.sub.18)-alkylene or (C.sub.2-C.sub.18)-heteroalkylene bridge, such that an aliphatic or aromatic ring having in total 3-20 ring atoms is formed.

10. The process of claim 9, wherein: R is H or a C.sub.1-C.sub.6 alkyl; and R.sup.1 and R.sup.2 are independently: H, a (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.8)-cycloalkyl, (C.sub.2-C.sub.7)-heterocycloalkyl, a (C.sub.6-C.sub.14)-aryl or a (C.sub.3-C.sub.13)-heteroaryl.

11. The process of claim 1, wherein said compounds are carboxylic acid diamides of the general formula (II): ##STR00064## wherein: R is selected from the group consisting of divalent (C.sub.1-C.sub.24)-alkyl radicals, (C.sub.3-C.sub.20)-cycloalkyl radicals, (C.sub.2-C.sub.13)-heterocycloalkyl radicals, (C.sub.6-C.sub.14)-aryl radicals, (C.sub.3-C.sub.13)-heteroaryl radicals; and R and R, independently of one another, are selected from the group consisting of H, (C.sub.1-C.sub.24)-alkyl, (C.sub.1-C.sub.24)-heteroalkyl, (C.sub.3-C.sub.8)-cycloalkyl, (C.sub.2-C.sub.7)-heterocycloalkyl, (C.sub.6-C.sub.14)-aryl or (C.sub.3-C.sub.13)-heteroaryl, where the radicals R with R may together form a saturated or mono- or polyunsaturated (C.sub.2-C.sub.18)-alkylene or (C.sub.2-C.sub.18)-heteroalkylene bridge, such that an aliphatic or aromatic ring having in total 3-20 ring atoms is formed.

12. The process of claim 1, wherein said compounds are one or more of the following: N,N,N,N-tetramethylsuccinic acid diamide; N,N,N,N-tetramethyladipic acid diamide; N,N,N,N-tetramethylsuberic acid diamide, N,N,N,N-tetramethylterephthalic acid diamide and sarcosine anhydride.

13. The process of claim 1, wherein said compounds are di-, tri- or polypeptides.

14. The process of claim 1, wherein said compounds are peptide amides with a carboxy-terminal amide function.

15. The process of claim 1, wherein said alkylating agent is an alkyl halide.

16. The process of claim 1, wherein said alkylating agent is an ester of sulphonic acid; an ester of fluorosulphonic acid; or and ester of trifluoromethanesulphonic acid.

17. The process of claim 1, wherein said alkylating agent is an ester of chloroformic acid.

18. The process of claim 1, wherein said alkylating agent is an oxonium salts.

19. The process of claim 1, wherein said alkylating agent is a dialkyl sulphate.

20. The process of claim 1, wherein said alkylating agent is diazomethane.

Description

WORKING EXAMPLES

(1) The examples below serve to illustrate the invention without limiting it thereto.

Examples 1-4

(2) ##STR00010##

Example 1

(3) Piperidone-2 (5 g, 50 mmol) is admixed with ethyl chloroformate (6 ml, 60 mmol) and stirred under argon for 4 hours at 50 C. Concentration in vacuo is then carried out, and the residue is taken up in absolute ethanol. An autoclave is charged with 5% Pt/C (0.98 g, 0.5 mol %), flushed with argon and filled with reaction solution in ethanol. 40 bar of hydrogen are then injected in, and the mixture is stirred at 25 C. and a constant pressure until hydrogen absorption is no longer evident (5 h). Following separation off from the catalyst, the filtrate is concentrated on a rotary evaporator, the residue is dissolved in 20 ml of water and washed with diethyl ether, the aqueous phase is rendered basic with 2N NaOH solution and etherified out. The organic phase is dried over K.sub.2CO.sub.3; after evaporating off the ether virtually clean piperidine is obtained.

(4) The yield can be found in Table 4.

Example 2

(5) Piperidone-2 (5 g, 50 mmol) is admixed with dimethyl sulphate (5 ml, 50 mmol) and stirred under argon for 3 hours at 80 C., and the product is then taken up in 10 ml of absolute methanol. An autoclave is charged with 5% Pt/C (0.98 g, 0.5 mol %), flushed with argon and filled with the reaction solution in methanol. 40 bar of hydrogen are then injected in, and the mixture is stirred at 25 C. and a constant pressure until hydrogen absorption is no longer evident (5 h). After separation off from the catalyst, the filtrate is concentrated on a rotary evaporator, the residue is dissolved in 20 ml of water and washed with diethyl ether, the aqueous phase is rendered basic with 2N NaOH solution and etherified out. The organic phase is dried over K.sub.2CO.sub.3; after evaporating off the ether virtually clean piperidine is obtained.

(6) The yield can be found in Table 4.

Example 3

(7) Piperidone-2 (5 g, 50 mmol) is admixed, with the exclusion of moisture and cooling on a water bath, with triethyloxonium tetrafluoroborate (10.45 g, 55 mmol). The water bath temperature is then gradually heated to 40 C., and stirring is carried out at this temperature for 1 hour. Then, the ether is drawn off in vacuo, and the residue is taken up in absolute ethanol. An autoclave is charged with 5% Pt/C (0.98 g, 0.5 mol %), flushed with argon and filled with the reaction mixture in ethanol. 40 bar of hydrogen are then injected in, and the mixture is stirred at 25 C. and a constant pressure until hydrogen absorption is no longer evident (5 h). After separation off from the catalyst, the filtrate is concentrated on a rotary evaporator, the residue is dissolved in 20 ml of water and washed with diethyl ether, the aqueous phase is rendered basic with 2N NaOH solution and etherified out. The organic phase is dried over K.sub.2CO.sub.3; after the ether has been evaporated off virtually clean piperidine is obtained.

(8) The yield can be found in Table 4.

Example 4

(9) Piperidone-2 (5 g, 50 mmol) is admixed, with the exclusion of moisture and cooling on a water bath, with triethyloxonium tetrafluoroborate (10.45 g, 55 mmol). Then, the water bath temperature is gradually heated to 40 C., and stirring is carried out at this temperature for 1 hour. Then, the ether is drawn off in vacuo, and the residue is taken up in absolute ethanol. An autoclave is charged with 5% Pt/C (0.98 g, 0.5 mol %) and K.sub.2CO.sub.3 (6.9 g, 50 mmol), flushed with argon and filled with the reaction mixture in ethanol. 40 bar of hydrogen are then injected in, and the mixture is stirred at 25 C. and a constant pressure until hydrogen absorption is no longer evident (5 h). After filtration over Celite, the filtrate is dissolved in 25 ml of 2N hydrochloric acid and washed with diethyl ether, the aqueous phase is rendered basic with 2N NaOH solution and etherified out, the organic phase is dried over K.sub.2CO.sub.3. After evaporating off the ether, virtually clean piperidine is obtained.

(10) The yield can be found in Table 4.

(11) TABLE-US-00004 TABLE 4 Reaction of piperidone-2 to piperidine. Example Alkylating agent Base Yield, % 1 ClCOOEt 80 2 (MeO).sub.2SO.sub.2 86 3 (Et.sub.3O)BF.sub.4 85 4 (Et.sub.3O)BF.sub.4 K.sub.2CO.sub.3 86

Example 5

(12) Pyrrolidone-2 (4.25 g, 50 mmol) is admixed with ethyl chloroformate (6 ml, 60 mmol) and stirred under argon for 4 hours at 50 C. Then, the mixture is concentrated in vacuo, and the residue is taken up in absolute ethanol. An autoclave is charged with 5% Pt/C (0.98 g, 0.5 mol %), flushed with argon and filled with the reaction solution in ethanol. 40 bar of hydrogen are then injected in, and the mixture is stirred at 25 C. and constant pressure for 24 hours. After separation off from the catalyst, the filtrate is concentrated on a rotary evaporator, the residue is dissolved in 20 ml of water and washed with diethyl ether, the aqueous phase is rendered basic with 2N NaOH solution and etherified out. The organic phase is dried over K.sub.2CO.sub.3; after the ether has been evaporated off virtually clean pyrrolidine is obtained. Yield 1.85 g (52%).

Examples 6-9

(13) A carboxylic acid amide (10 mmol) is admixed with dimethyl sulphate (1 ml, 10 mmol) and stirred under argon for 3 hours at 80 C., and then the product is taken up in 5 ml of absolute methanol. An autoclave is charged with catalyst (1 mol %) and 5 ml of 2M sodium methylate solution in methanol, flushed with argon and filled with the reaction solution in methanol. 40 bar of hydrogen are then injected in, and the mixture is stirred at 25 C. and a constant pressure until hydrogen absorption is no longer evident (1-2 h). After filtration over Celite, the filtrate is dissolved in 10 ml of 2N hydrochloric acid and washed with diethyl ether, the aqueous phase is rendered basic with 12 ml of 2N NaOH solution and etherified out. The combined organic phases are dried over K.sub.2CO.sub.3 and admixed with 10 ml of 1M HCl solution in diethyl ether. The solid amine hydrochloride is filtered off, washed with diethyl ether and dried in vacuo.

(14) The catalysts used and yields can be found in Table 5.

(15) TABLE-US-00005 TABLE 5 Exam- Carboxylic Yield ple Catalyst acid amide Product [%] 6 5% Pd/C 60 7 5% Ru/Al.sub.2O.sub.3 60 8 5% Pd/CaCO.sub.3 50 9 [(dppb)Rh (cod)]BF.sub.4 60

Examples 10-28

(16) A solution of carboxylic acid amide (20 mmol) in dichloromethane (10 ml) is admixed with triethyloxonium tetrafluoroborate (4.18 g, 22 mmol) and stirred either (A) overnight at room temperature or (B) for 3 hours on the water bath at 40 C. under argon. Then, the mixture is concentrated in vacuo and the residue is taken up in 20 ml of absolute ethanol. An autoclave cooled in the ice bath is charged with catalyst (1 mol %) and 10 ml of 2M sodiummethylate solution in ethanol, flushed with argon and filled with the reaction solution in ethanol. 40 bar of hydrogen are then injected in, and the mixture is stirred at 25 C. and a constant pressure until hydrogen absorption is no longer evident (1-12 h). After filtration over Celite, the filtrate is dissolved in 11 ml of 2N hydrochloric acid and washed with diethyl ether, the aqueous phase is rendered basic with 14 ml of 2N NaOH solution, the amine is extracted with diethyl ether, and the combined organic phases are dried over K.sub.2CO.sub.3. After drawing off the solvent in vacuo, virtually clean amine is obtained.

(17) The catalysts used and yields can be found in Table 6.

(18) TABLE-US-00006 TABLE 6 Starting Example Catalyst material Product Yield, % 10 [A] 5% Pd/CaCO.sub.3 0 69 11 [A] 5% Pt/C 68 12 [A] [(dppb) Rh (cod) ] BF.sub.4 68 13 [A] 5% Pd/Al.sub.2O.sub.3 62 14 [A] 5% Pt/C 72 15 [B] 5% Pd/C 0 78 16 [B] 5% Pd/CaCO.sub.3 78 17 [B] 5% Pd/Al.sub.2O.sub.3 76 18 [B] [(dppb)Rh(cod)] BF.sub.4 71 19 [B] 5% Pd/C 37 20 [B] 5% Pt/C 0 35 21 [B] 5% Ru/Al.sub.2O.sub.3 39 22 [B] [(dppb)Rh(cod)] BF.sub.4 39 23 [B] 5% Pd/C 83 24 [B] 5% Pd/CaCO.sub.3 98 25 [B] 5% Pd/Al.sub.2O.sub.3 0 98 26 [B] [(dppb)Rh(cod)] BF.sub.4 93 27 [A] 5% Pd/C 34 28 [A] 5% Pt/C 37 Conditions: [A] stirred overnight at room temperature, [B] stirred for 3 h at 40 C.

Examples 29-32

(19) ##STR00057##

(20) A solution of N,N-tetramethylsuccinic acid diamide (20 mmol) in dichloromethane (20 ml) is admixed with triethyloxonium tetrafluoroborate (8.36 g, 44 mmol) and stirred under argon for 3 hours on the water bath at 40 C. The mixture is then concentrated in vacuo, and the residue is taken up in 50 ml of absolute ethanol. An autoclave cooled in the ice bath is charged with catalyst (1 mol %) and 20 ml of 2M sodiumethylate solution in ethanol, flushed with argon and filled with the reaction mixture in ethanol. 40 bar of hydrogen are then injected in, and the mixture is stirred at 25 C. and a constant pressure until hydrogen absorption is no longer evident (1-12 h). After filtration over Celite, the filtrate is worked up as in Examples 10-28.

(21) The catalysts used and yields of N,N-tetramethyl-1,4-butanediamine can be found in Table 7.

(22) TABLE-US-00007 TABLE 7 Conversion of N,N-tetramethylsuccinic acid diamide to N,N-tetramethyl-1,4-butanediamine Example Catalyst Yield, % 29 5% Pd/C 60 30 5% Pd/Al.sub.2O.sub.3 62 31 5% Ru/Al.sub.2O.sub.3 63 32 [(dppb)Rh(cod)]BF.sub.4 67

Example 33

(23) ##STR00058##

(24) A solution of N-Boc-Ala-Pro-OMe (3.0 g, 10 mmol) in dichloromethane (10 ml) is admixed with triethyloxonium tetrafluoroborate (3.80 g, 20 mmol) and stirred under argon overnight at room temperature. Then, the mixture is concentrated in vacuo, and the residue is taken up in 20 ml of absolute ethanol. An autoclave is charged with 5% Pt/C (0.78 g, 2 mol %), trioctylmethylammonium chloride (Aliquat 336, 40 mg, 0.1 mmol) and K.sub.2CO.sub.3 (2.76 g, 20 mmol), flushed with argon and filled with the reaction mixture in ethanol. 40 bar of hydrogen are then injected in, and the mixture is stirred at 25 C. and constant pressure for 16 hours. After filtration over Celite, the filtrate is concentrated in vacuo, and the residue is purified by column chromatography (ethyl acetate/hexane 1:1). 1.42 g (55%) of (2'S,2S)-1-(2-ethoxycarbonylaminopropyl)pyrrolidine-2-carboxylic acid methyl ester (Rf 0.25) are obtained.

(25) .sup.1H NMR (CDCl.sub.3) 5.19 (br. s, 1H), 3.99-4.07 (m, 2H), 3.63 (s, 3H), 3.60 (q, J=6.4, 1H), 3.23 (dd, J=8.6, J=5.1, 1H), 3.09 (ddd, J=8.3, J=8.2, J=3.9, 1H), 2.60 (dd, J=12.4, J=6.0, 1H), 2.50 (dd, J=11.7, J=5.9, 1H), 2.47 (dt, J=8.9, J=7.5, 1H), 2.00-2.05 (m, 1H), 1.81-1.86 (m, 2H), 1.72-1.78 (m, 1H), 1.17 (t, J=7.1, 3H), 1.13 (d, J=6.6, 3H); .sup.13C 174.80, 156.28, 66.50, 60.38, 60.20, 54.44, 51.69, 46.41, 29.39, 23.83, 19.48, 14.64.

Example 34

(26) ##STR00059##

(27) A solution of N-Boc-Phe-Pro-OMe (3.87 g, 10 mmol) in dichloromethane (10 ml) is admixed with triethyloxonium tetrafluoroborate (3.80 g, 20 mmol) and stirred under argon overnight at room temperature. Then, the mixture is concentrated in vacuo, and the residue is taken up in 20 ml of absolute ethanol. An autoclave is charged with 5% Pt/C (0.78 g, 2 mol %), trioctylmethylammonium chloride (Aliquat 336, 40 mg, 0.1 mmol) and K.sub.2CO.sub.3 (2.76 g, 20 mmol), flushed with argon and filled with the reaction mixture in ethanol. 40 bar of hydrogen are then injected in, and the mixture is stirred at 25 C. and constant pressure for 16 hours. After filtering over Celite, the filtrate is concentrated in vacuo, and the residue is purified by column chromatography (ethyl acetate/hexane 1:1). 1.18 g (34%) of (2'S,2S)-1-(2-ethoxycarbonylamino-3-phenylpropyl)pyrrolidine-2-carboxylic acid methyl ester (Rf 0.40) are obtained.

(28) .sup.1H NMR (CDCl.sub.3) 7.20 (t, J=7.6, 2H), 7.12 (t, J=7.8, 3H), 5.46 (br. s, 1H), 4.07 (dq, J=10.6, J=7.2, 1H), 4.02 (dq, J=10.6, J=7.1, 1H), 3.75 (br. m, 1H), 3.61 (s, 3H), 3.18 (br. m, 1H), 3.07 (br. m, 1H), 3.03 (td, J=7.9, J=3.4, 1H),2.58 (dd, J=13.5, J=7.8, 1H), 2.52 (t, J=11.3, 1H), 2.40 (dd, J=12.1, J=3.85, 1H), 2.21 (br. m, 1H), 1.98-2.04 (m, 1H), 1.98-2.04 (m, 1H), 1.66-1.72 (m, 2H), 1.18 (t, J=7.2, 3H); .sup.13C 174.71, 156.84, 138.20, 129.48, 128.29, 126.25, 65.51, 60.54, 56.79, 53.04, 51.81, 51.44, 39.48, 29.21, 23.43, 14.69.

Example 35

(29) ##STR00060##

(30) In a Schlenk vessel cooled in the ice bath, N-(2-cyanoethyl)pyrrolidone-2 (6.9 g, 50 mmol) is admixed with triethyloxonium tetrafluoroborate (10.45 g, 55 mmol) and stirred overnight at room temperature under argon. The ether phase is decanted off and any ether still present is removed in vacuo. The residue is dissolved in dry dichloromethane (40 ml) and added dropwise to a suspension of sodium ethoxide (ethanol-free) in 10 ml of dry diethyl ether at 20 C. Then, the mixture is left overnight to warm to room temperature with vigorous stirring and filtered off from the NaBF.sub.4 under argon. The filtrate is concentrated and dissolved in 10 ml of dry dichloromethane. An autoclave is charged with 5% Pt/C (390 mg, 0.2 mol %), flushed with argon and filled with the reaction solution in dichloromethane. 40 bar of hydrogen are then injected in, and the mixture is stirred at 25 C. and constant pressure for 24 hours. After filtering over Celite, the filtrate is dissolved in 40 ml of ice-cold 2N hydrochloric acid and washed with diethyl ether, the aqueous phase is rendered basic under ice cooling with 42 ml of 2N NaOH solution, the product is extracted with diethyl ether (620 ml), and the combined organic phases are dried over K.sub.2CO.sub.3. After stripping off the solvent in vacuo, 2.6 g (44%) of virtually clean 3-(1-pyrrolidino)propionitrile are obtained.