PROCESS FOR PRODUCING SUBSTITUTED AMINO ALCOHOLS

Abstract

A process for producing a compound of the formula (I)

##STR00001##

involves at least reacting a compound of the formula (II)

##STR00002##

with hydrogen and water in the presence of at least one homogeneous transition metal catalyst TMC 1.

Claims

1: A process for producing a compound of the formula (I) ##STR00048## wherein in the formula (I) R.sup.1 is hydrogen or an organic radical having from 1 to 40 carbon atoms, R.sup.2 is an organic radical having from 1 to 40 carbon atoms, or R.sup.1 and R.sup.2 together with the atoms connecting them, form a divalent organic group having from 1 to 40 carbon atoms, the process comprising: reacting a compound of the formula (II) ##STR00049## wherein in the formula (II) R.sup.1 and R.sup.2 have the same meaning as in formula (I), and R.sup.3 is hydrogen or an organic radical having from 1 to 40 carbon atoms, with hydrogen and water in the presence of at least one homogeneous transition metal catalyst (TMC 1) comprising a transition metal selected from the group consisting of Ru and Rh.

2: The process according to claim 1, wherein a ligand of the at least one homogeneous TMC 1 is selected from the group consisting of CO, H, Cl, and mono-, bi-, tri-, and tetra-dentate phosphines of the formulae (IV) and (V) ##STR00050## wherein n is 0 or 1; R.sup.4 to R.sup.12 are, independently of one another, unsubstituted or at least monosubstituted C.sub.1-C.sub.10-alkyl, C.sub.1-C.sub.4-alkyldiphenylphosphine (—C.sub.1-C.sub.4-alkyl-P(phenyl).sub.2), C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocyclyl comprising at least one heteroatom selected from the group consisting of N, O, and S, C.sub.5-C.sub.14-aryl, or C.sub.5-C.sub.10-heteroaryl comprising at least one heteroatom selected from the group consisting of N, O, and S, wherein a substituent of R.sup.4 to R.sup.12 is selected from the group consisting of F, Cl, Br, OH, CN, NH.sub.2, and C.sub.1-C.sub.10-alkyl; A is i) a bridging group selected from the group consisting of unsubstituted or at least monosubstituted N, O, P, C.sub.1-C.sub.6-alkane, C.sub.3-C.sub.10-cycloalkane, C.sub.3-C.sub.10-heterocycloalkane comprising at least one heteroatom selected from the group consisting of N, O, and S, C.sub.5-C.sub.14-aromatic, and C.sub.5-C.sub.6-heteroaromatic comprising at least one heteroatom selected from the group consisting of N, O, and S, wherein a substituent of the bridging group is selected from the group consisting of C.sub.1-C.sub.4-alkyl, phenyl, F, Cl, Br, OH, OR.sup.16, NH.sub.2, NHR.sup.16, and N(R.sup.16).sub.2, wherein R.sup.16 is selected from the group consisting of C.sub.1-C.sub.10-alkyl and C.sub.5-C.sub.10-aryl; or ii) a bridging group of the formula (VI) or (VII): ##STR00051## wherein m, q are, independently of one another, 0, 1, 2, 3, or 4; R.sup.13, R.sup.14 are, independently of one another, selected from the group consisting of C.sub.1-C.sub.10-alkyl, F, Cl, Br, OH, OR.sup.15, NH.sub.2, NHR.sup.15, and N(R.sup.15).sub.2, wherein R.sup.15 is selected from the group consisting of C.sub.1-C.sub.10-alkyl and C.sub.5-C.sub.10-aryl; X.sup.1, X.sup.2 are, independently of one another, NH, O, or S; X.sup.3 is a bond, NH, NR.sup.16, O, S, or CR.sup.17R.sup.18; R.sup.16 is unsubstituted or at least monosubstituted C.sub.1-C.sub.10-alkyl, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocyclyl comprising at least one heteroatom selected from N, O and S, C.sub.5-C.sub.14-aryl, or C.sub.5-C.sub.10-heteroaryl comprising at least one heteroatom selected from the group consisting of N, O, and S, wherein a substituent of R.sup.16 is selected from the group consisting of F, Cl, Br, OH, CN, NH.sub.2, and C.sub.1-C.sub.10-alkyl; R.sup.17, R.sup.18 are, independently of one another, unsubstituted or at least monosubstituted C.sub.1-C.sub.10-alkyl, C.sub.1-C.sub.10-alkoxy, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-cycloalkoxy, C.sub.3-C.sub.10-heterocyclyl comprising at least one heteroatom selected from N, O, and S, C.sub.5-C.sub.14-aryl, C.sub.5-C.sub.14-aryloxy, or C.sub.5-C.sub.10-heteroaryl comprising at least one heteroatom selected from the group consisting of N, O, and S, wherein a substituent of R.sup.17 or R.sup.18 is selected from the group consisting of F, Cl, Br, OH, CN, NH.sub.2, and C.sub.1-C.sub.10-alkyl; and wherein in the formulae (IV) and (V) Y.sup.1, Y.sup.2, Y.sup.3 are, independently of one another, a bond, unsubstituted or at least monosubstituted methylene, ethylene, trimethylene, tetramethylene, pentamethylene, or hexamethylene, wherein a substituent of Y.sup.1, Y.sup.2, or Y.sup.3 is selected from the group consisting of F, Cl, Br, OH, OR.sup.15, CN, NH.sub.2, NHR.sup.15, N(R.sup.15).sub.2, and C.sub.1-C.sub.10-alkyl, wherein R.sup.15 is selected from the group consisting of C.sub.1-C.sub.10-alkyl and C.sub.5-C.sub.10-aryl.

3: The process according to claim 1, wherein a ligand of the at least one homogeneous TMC 1 is selected from the group consisting of CO, H, Cl, PPh.sub.3, binap, PMe.sub.3, PEt.sub.3, Pn-Pr.sub.3, Pn-Bu.sub.3, Pn-Octyl.sub.3, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), 1,1,1-tris(diphenylphosphinomethyl)ethane (Triphos), 1,2-bis(diphenylphosphino)ethane (dppe), P(Ph.sub.2)-Et-N-Et-P(Ph.sub.2), P(Cy-)-Me-acridine-Me-(Cy.sub.2)P, and P(tBu.sub.2)-Me-pyridine-Me-P(tBu.sub.2).

4: The process according to claim 1, wherein R.sup.3 is hydrogen.

5: The process according to claim 1, wherein the at least one homogeneous TMC 1 is selected from the group consisting of [Ru(PPh.sub.3).sub.3(CO)(H)Cl], [Ru(PPh.sub.3).sub.3(CO)Cl.sub.2], [Ru(PPh.sub.3).sub.3(CO)(H).sub.2], [Ru(binap)(Cl).sub.2], [Ru(PMe.sub.3).sub.4(H).sub.2], [Ru(PEt.sub.3).sub.4(H).sub.2], [Ru(Pn-Pr.sub.3).sub.4(H).sub.2], [Ru(Pn-Bu.sub.3).sub.4(H).sub.2], [Ru(Pn-Octyl.sub.3).sub.4(H).sub.2], [Ru(Pn-Bu.sub.3).sub.4(H).sub.2], [Ru(PnOctyl.sub.3).sub.4(H).sub.2], [Ru(PPh.sub.3).sub.3(CO)(H)Cl], [Ru(PPh.sub.3).sub.3(CO)(H).sub.2], Ru-MACHO, Ru-milst-acridine, Ru-milst-pyridine, and [Ru(PPh.sub.3).sub.3(CO)(H)Cl], in combination with 1,1,1-tris(diphenylphosphinomethyl)ethane (Triphos) or bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos).

6: The process according to claim 1, wherein the at least one homogeneous TMC 1 is used in an amount of 0.001 mol % to 20 mol %, calculated as transition metal and based on the amount of the compound of the formula (II) used in the process.

7: The process according to claim 1, wherein the reaction between the compound of the formula (II), water, and hydrogen is performed at a pressure in the range from 10 to 180 bar.

8: The process according to claim 1, wherein the reaction between the compound of the formula (II), water, and hydrogen is performed at a temperature in the range from 50° C. to 180° C.

9: The process according to claim 1, wherein the reaction between the compound of the formula (II), water, and hydrogen is performed in the presence of a solvent selected from the group consisting of an ether and an alcohol.

10: The process according to claim 1, wherein the at least one homogeneous TMC 1 is recycled by removing the compound of the formula (II) and other volatile compounds of a reaction mixture obtained after the reaction between the compound of the formula (II), water, and hydrogen, via distillation.

11: The process according to claim 1, wherein the reaction between the compound of the formula (II), water, and hydrogen is carried out at different H.sub.2 pressures, wherein a lower H.sub.2 pressure in the range from 1 to 80 bar is used at first to reduce the nitrile group of the compound of the formula (II), and afterwards H.sub.2 pressure is increased to a pressure in the range from 90 to 200 bar to reduce the amide group of the compound of the formula (II).

12: The process according to claim 1, wherein the nitrogen-carbon bond of the amide group —N(H)—C(═O)— of a compound of the formula (III), which is formed as an intermediate product in the reaction between the compound of the formula (II), water, and hydrogen, ##STR00052## is cleaved by converting the amide group —NH—C(═O)—R.sup.3 into an amino group —NH.sub.2 or its corresponding ammonium group —NH.sub.3.sup.+ by hydrolysis or by hydrogenation of the amide group —NH—C(═O)—R.sup.3 to form an amino group —NH.sub.2 and a primary alcohol HO—CH.sub.2—R.sup.3.

13: The process according to claim 9, wherein the solvent is selected from the group consisting of dioxane, tetrahydrofuran, glyme, methanol, and ethanol.

Description

GENERAL

[0185] All chemicals and solvents were purchased from Sigma-Aldrich or ABCR and used without further purification.

[0186] .sup.1H and .sup.13C NMR spectra were recorded on Bruker Avance 200 MHz spectrometer and were referenced to the residual proton (.sup.1H) or carbon (.sup.13C) resonance peaks of the solvent. Chemical shifts (6) are reported in ppm.

1. Synthesis of the Protected Aminonitriles, the Compounds of the Formula (II)

1.1 Synthesis of N-(1-cyanocyclohexyl)formamide

[0187] ##STR00028##

[0188] A ca. 20 mL pressure tube (Ace tube) was charged with 1-hydroxycyclohexane-1-carbonitrile (1.252 g, 10.0 mmol), formamide (1.19 mL, 30 mmol), and acetic acid (0.57 mL, 10 mmol). The tube was then flushed with argon and closed. It was then placed into a 120° C. pre-heated oil bath and the mixture was stirred at this temperature for 4 h. The crude material was purified by flash chromatography (SiO.sub.2, DCM/MeOH 1:0 to 50:1) to yield 1.439 g (95% yield) of desired product as an off-white solid (96% purity by GC analysis). .sup.1H NMR in CDCl.sub.3-d show a 3.5:1 mixture of isomers. Major isomer: .sup.1H NMR (200 MHz, CDCl.sub.3) δ 8.18 (s, 1H), 5.65 (s, 1H), 2.52-2.29 (m, 2H), 1.92-1.62 (m, J=6.0 Hz, 8H). Minor isomer: .sup.1H NMR (200 MHz, CDCl.sub.3) δ 8.51 (d, J=11.8 Hz, 1H), 6.11 (s, 1H), 2.27-2.09 (m, J=6.4 Hz, 2H), 1.92-1.62 (m, J=6.0 Hz, 8H).

1.2 Synthesis of N-(1-cyanocyclohexyl)-acetamide

[0189] ##STR00029##

[0190] To a stirred solution of aminonitrile (474 mg, 3.62 mmol) and trimethylamine (0.6 mL, 4.28 mmol) in anhydrous Et.sub.2O (6 mL) cooled in an ice bath was added dropwise acetyl chloride (0.3 mL, 4.28 mmol) by syringe. The bath was removed and the reaction was stirred at rt for 3.5 hours. Then, the mixture was filtered through a fritted-glass funnel (medium porosity), and the Et.sub.2O was discarded. Using a second filter flask, the filter cake was washed 4 times with EtOAc. The EtOAc extracts were collected and evaporated to yield 311.7 mg (52% yield) of target compound as a white solid that did not require purification for subsequent reactions, .sup.1H NMR (200 MHz, CDCl.sub.3) δ 7.08 (s, 1H), 2.40-2.19 (m, 2H), 1.96 (s, 3H), 1.80-1.40 (m, 8H).

1.3 Synthesis of N-(1-cyano-1-methyl-ethyl)acetamide

[0191] ##STR00030##

[0192] A 100 mL dried two-necked round bottom flask was charged with 2-amino-2-methyl-propanenitrile (300 mg, 3.57 mmol) and dissolved in anhydrous EtOAc (14 mL). K.sub.2CO.sub.3 (615 mg, 4.44 mmol) was added followed by Ac.sub.2O (0.4 mL, 4.28 mmol). The heterogeneous mixture was stirred for 20 hours at room temperature under argon atmosphere. Then, the crude was filtered and the residue was washed with EtOAc. The resulting solution was concentrated under vacuum. Purified by flash chromatography (SiO.sub.2, petroleum ether/EA/Acetone 10:10:1) to yield 150.7 mg (33% yield) of desired product as an off-white solid. .sup.1H NMR (200 MHz, CDCl.sub.3) δ 5.78 (s, 1H), 2.01 (s, 3H), 1.70 (s, 6H).

1.4 Synthesis of N-(1-cyano-1-methyl-ethyl)formamide

[0193] ##STR00031##

[0194] A ca. 20 mL pressure tube (Ace tube) was charged with acetone cyanohydrin (2.55 g, 30.0 mmol), formamide (4.05 g, 90 mmol), and acetic acid (1.7 mL, 30 mmol). The tube was then flushed with argon and closed. It was then placed into a 125° C. pre-heated oil bath and the mixture was stirred at this temperature for 4 h. The reaction was cooled to room temperature, 30 mL of benzene were added and the resulting mixture was concentrated under vacuum and purified without further treatment by flash chromatography (SiO.sub.2, CH.sub.2Cl.sub.2/MeOH 1:0 to 50:1) as an eluent. The product was dried under vacuum to remove residual volatiles and isolated as an yellow oil to yield 1.837 g (91% yield, 9:1 mixture of isomers). .sup.1H NMR (200 MHz, CDCl.sub.3) δ 8.17 (s, 1H), 6.00 (s, 1H), 1.74 (s, 8H). The signals of the minor isomer are all overlapped with the exception of .sup.1H NMR (200 MHz, CDCl.sub.3) δ 8.48 (d, J=11.8 Hz, 1H).

1.5 Synthesis of N-(1-cyano-1,2-dimethyl-propyl)formamide

[0195] ##STR00032##

1.5.1 Standard Procedure for the Formyl Protected Aminonitriles of Formula (II)

[0196] Freshly prepared acetic-formic anhydride” (1.44 mL, 10 mmol) was added to a stirred solution of the amino-nitrile (2 mmol) in THF (9 mL) at rt under argon atmosphere. The resulting mixture was stirred under these conditions for 65 h. Then, the reaction was treated with aqueous saturated sodium bicarbonate solution (2×30 mL) and subsequently extracted with dichloromethane (3×50 mL). The organic extracts were dried over Na.sub.2SO.sub.4, evaporated, and the residue was purified by flash column chromatography over silica gel using MeOH/CH.sub.2Cl.sub.2 (4%) as eluent.

[0197] “Acetic-formic anhydride: A MW vial equipped with a stirring bar was charged with 2 mL of Ac.sub.2O and 0.88 mL of formic acid, sealed and put under argon. The resulting solution was stirred at 60° C. for 1.5 h. The mixture was cooled down to room temperature and used without further treatment in the subsequent step.

[0198] Starting form 2-amino-2,3-dimethylbutyronitrile (224.3 mg, 2 mmol); isolated as a pale-yellow oil (243 mg, 87% yield), as a 3:1 mixture of isomers. Major isomer: .sup.1H NMR (200 MHz, CDCl.sub.3) δ 8.20 (s, 1H), 5.64 (s, 1H), 2.37 (app dt, J=13.6, 6.8 Hz, 1H), 1.68 (s, 3H), 1.20-1.02 (m, 6H). Minor isomer: .sup.1H NMR (200 MHz, CDCl.sub.3) δ 8.48 (d, J=11.7 Hz, 1H), 6.13 (s, 1H), 2.00 (app dt, J=14.6, 7.4 Hz, 1H), 1.61 (s, 3H), 1.20-1.02 (m, 6H).

1.6 Synthesis of N-(1-cyano-1-ethyl-propyl)formamide

[0199] ##STR00033##

[0200] Synthesized following the “Standard procedure for the formyl protected aminonitriles of formula (II) of example 1.5.1.

[0201] Starting from 2-amino-2-ethylbutanenitrile (224.3 mg, 2 mmol); isolated as a pale-yellow oil (245 mg, 88% yield), as a 3:1 mixture of isomers. Major isomer: .sup.1H NMR (200 MHz, CDCl.sub.3) δ 8.19 (s, 1H), 5.73 (s, 1H), 2.06 (app qd, J=7.8, 6.7 Hz, 4H), 1.20-0.99 (m, J=10.8, 7.4 Hz, 6H). Minor Isomer: .sup.1H NMR (200 MHz, CDCl.sub.3) δ 8.44 (d, J=11.7 Hz, 1H), 6.54 (s, 1H), 1.97-1.76 (m, J=19.4, 10.9.6.3 Hz, 4H), 1.20-0.99 (m, J=10.8, 7.4 Hz, 6H).

2. Synthesis of Compounds of the Formula (I) by Reductive Hydrolysis of Compounds of the Formula (II)

2.1 Protocol for the Reductive Nitrile Hydrolysis of Protected Aminonitriles of Formula (II)

2.1.1 Synthesis of (1-aminocyclohexyl)methanol

[0202] ##STR00034##

[0203] A ca. 40 mL Premex autoclave (equipped with Teflon insert) was charged with RuHCl(CO)(PPh.sub.3).sub.3 (47.6 mg, 0.05 mmol), the nitrile (152.2 mg, 1 mmol), 1,4-dioxane (7.0 mL) and H.sub.2O (7.0 mL) under air. After closing the reaction vessel, the system was purged first with nitrogen (3×) and then with hydrogen (3×). Finally, the autoclave was pressurized with hydrogen (45 bar) and heated at 140° C. Note: At this temperature the internal pressure rises up to 60 bar. The mixture was stirred under these conditions for 20 h. Then, the reaction was cooled-down on a water bath and depressurized carefully, the organic phase was extracted with EtOAc (3×25 mL), washed with brine and dried over Na.sub.2SO.sub.4. Filtered through a short cotton pad and concentrated under vacuum. .sup.1H-NMR analysis in CDCl.sub.3-d showed exclusive formation of deprotected product (>99% conversion). .sup.1H NMR (200 MHz, CDCl.sub.3) δ 3.32 (s, 1H), 2.09 (br. s, 2H), 1.59-1.31 (m, J=19.1, 11.0 Hz, 8H).

2.2 Evaluation of Conditions for the Preparation of 2-amino-2-methyl-propanol (2-AMP)

2.2.1 Standard Procedure

[0204] A ca. 40 mL Premex autoclave (equipped with Teflon insert) was charged with RuHCl(CO)(PPh.sub.3).sub.3 (3 mol %), the nitrile 1 (1 mmol) and indicated solvent (7.0 mL) under air. After closing the reaction vessel, the system was purged first with nitrogen (3×) and then with hydrogen (3×). Finally, the autoclave was pressurized with the indicated hydrogen pressure (× bar), and heated at 140° C. The mixture was stirred for the indicated time under the same conditions. Then, the reaction was cooled-down on a water bath and depressurized carefully, the crude mixture was collected in a round bottom flask and concentrated under vacuum. The ratio between the mixtures of products was determined by .sup.1H-NMR using MeOD-d.sub.4 as solvent.

##STR00035##

TABLE-US-00001 H.sub.2 Time Conv Ratio Overall yield Solvent (bar) (h) (%) (2/3/4) (%) MeOH 45 18 >99 c.m. — EtOH 45 18 <5 traces — 1,4-dioxane/H.sub.2O 45 18 >99 2.7/1/— 89 (6:1) 1,4-dioxane/H.sub.2O 55 18 >99 3.5/1/— 72 (6:1) 1,4-dioxane/H.sub.2O 55 65 >99 1/tr/tr 57 (6:1) c.m. = complex mixtures, primary and secondary amines also detected; tr = traces

2.2.2 Evaluation of Ligands

[0205] A ca. 40 mL Premex autoclave (equipped with Teflon insert) was charged with the ruthenium complex (5 mol %) and a corresponding ligand (10 mol %) respectively, the nitrile 1 (1 mmol) and dioxane (7.0 mL) under air. After closing the reaction vessel, the system was purged first with nitrogen (3×) and then with hydrogen (3×). Finally, the autoclave was pressurized with the indicated hydrogen pressure (45-50 bar), and heated at 140° C. The mixture was stirred for 18 h. Then, the reaction was cooled-down on a water bath and depressurized carefully, the crude mixture was collected in a round bottom flask and concentrated under vacuum. The ratio between the mixtures of products was determined by .sup.1H-NMR using MeOD-d.sub.4 as solvent with hexamethylbenzene as an Internal standard.

##STR00036##

TABLE-US-00002 Overall Conv. Yield 2 3 4 Complex Ligand (%) (%) (%) (%) (%) RuHCOCl(PPh.sub.3).sub.3 Xantphos 90 46 46 <1 <1 RuHCOCl(PPh.sub.3).sub.3 dppe <5 <1 <1 <1 <1 RuHCOCl(PPh.sub.3).sub.3 triphos >99 36 29 7 <1 Ru-MACHO ® — 85 10 10 <1 <1 Ru-milst-pyridine — 46 6 6 <1 <1 Ru-milst-acridine — >99 24 24 <1 <1

##STR00037##

2.2.2.1 Evaluation of Different Metals and Ligands for the Reductive Nitrile Hydrolysis

[0206] ##STR00038##

[0207] An approximately 40 mL Premex autoclave (equipped with a Teflon insert) was charged with the catalyst, ligand, additive, the protected amino nitrile 1 (0.5 mmol) and solvent. After closing the reaction vessel, the system was purged first with nitrogen (5×) and then with hydrogen (3×). Finally, the autoclave was pressurized with hydrogen (55 bar) and heated at the specified temperature (140° C.). The mixture was then stirred under the same conditions for 18 h. Then, the reaction was cooled-down on a water bath and depressurized carefully. Finally, the crude was analyzed by .sup.1H NMR using hexamethylbenzene as internal standard for quantification (0.05 M In CDCl.sub.3).

##STR00039##

TABLE-US-00003 Caltalyst Additive Base Conversion NMR Yield [%] Entry [mol %] [mol %] [mol %] [%] 2a 2b other RK 1.1-1 Rh(PPh.sub.3).sub.3Cl [5] — — >99  — 10 14 RK 1.1-2 [Rh(COD)Cl].sub.2 [5] Xantphos [10] — >99  — 24 47 (6 species) RK 1.1-3 [Ir(COD)Cl].sub.2 [2.5] PPh.sub.3 [10] — .sup. 86.sup.[a] — — 12 RK 1.1-4 [Ir(COD)Cl].sub.2 [2.5] Xantphos [10] —  8 — —  8 RK 1.2-1 Mn-PNP [5] — .sup.tBuOK [10] 18 — — — RK 1.2-2 Co.sub.2CO.sub.8 [2.5] PPh.sub.3[10] — 38 — 31 RK 1.2-3 CoCl.sub.2 [5] PNN [10] NaOEt [10] 23 — — 22 RK 1.2-4 CoCl.sub.2 [5] PPh.sub.3 [10] 41 — — ? RK 1.2-5 CoCl.sub.2 [5] Xantphos [10] 23 — — — RK 1.2-6 CoCl.sub.2 [5] P.sup.PhNP.sup.Ph [6] NaOEt [20] 21 — — — RK 1.2-7 — — NaOEt [20] 20 — — — RK blank — — — <1 — — — .sup.[a]Conversion after aqueous work-up

2.2.3 Evaluation of Pressure Effect

[0208] For experiments under higher pressure, a 160 ML stainless steel autoclave without teflon lining, equipped with a magnetically coupled overhead stirrer with inclined blades, electrical heating mantle and H.sub.2-inlet was used. A solution of 0.6 g (0.005 mol) nitrile 1 in 25.7 g dioxane and 4.3 g water was put into the autoclave beaker, 0.153 g of RuHCl(CO)(PPh.sub.3).sub.3 (3 mol %) were added, the autoclave was closed and flushed with argon. Then, the autoclave was pressurized at room temperature to 20 bar with hydrogen and with stirring, the autoclave was heated to 150° C. The pressure was adjusted to 55 bar at this temperature by charging hydrogen to the autoclave and the mixture was stirred for 24 h. After this time, it was allowed to cool to room temperature and depressurized. A sample was taken and analyzed as described below (sample 1). After this, the autoclave was pressurized to 20 bar again, heated to 150° C. and the pressure increased to 135 bar. The mixture was stirred under these conditions for another 24 h after which a further sample was taken in a similar way as before (sample 2).

[0209] The samples were analyzed by gas chromatography using a column of type RTX5 Amine, length 30 m, with diameter 0.32 mm and layer thickness 1.5 μm, FID detector. Temperature program: injection at 60° C., heating up with 4° C./min to 280° C., holding 15 minutes at 280° C. Results given in area percent, solvent signal was excluded and water was not detected.

TABLE-US-00004 Sample 2-AMP Nitrile 1 N-formyl-2-AMP 1 58.3 3.9 22.0 2 74.3 1.5 7.8

[0210] The purity by GC of the starting nitrile 1 was 84% (area-%). Thus, a maximum of about 84% of desired product peak area would be expected, which compares well with the amount found (74.3% of 2-AMP). The calculated selectivity based on the initial peak area of 84% for starting material would amount to 89% for sample 2. Sample 2 was also analyzed using an internal standard (diglyme) in order to quantify the mass of product formed. The crude product solution was found to contain 1.16 mass-% of 2-AMP, which corresponds to a molar yield of 73% of product 2-AMP, and 0.16% of N-formyl-2-AMP which corresponds to a molar yield of 8% of N-formyl-2-AMP.

[0211] Thus, it was shown that higher pressure favorites the deprotection of the amino group as the ratio of 3 to 2 was far higher than that achieved before at higher yield (about 9.5:1 at a combined yield of 81%).

[0212] In the same set-up and according to the same procedure, the triphos and xantphos ligands were also tested using 3 mol-% of catalyst (RuHCl(CO)(PPh.sub.3).sub.3/ligand 1:1) at two different pressure levels. The experiments were run at 140° C. for 24 h. The purity of the starting nitrile (95% with triphos and 91% with xantphos) was accounted for in the calculation of the yield.

Triphos:

[0213]

TABLE-US-00005 Molar yield N-formyl- Molar yield N-formyl- Sample 2-AMP Nitrite X 2-AMP 2-AMP 2-AMP 1 41.0 0.74 33.7 45.9 28.6 2 71.6 0 13.0 69.8 16.0

Xantphos

[0214]

TABLE-US-00006 Molar yield N-formyl- Molar yield N-formyl- Sample 2-AMP Nitrile X 2-AMP 2-AMP 2-AMP 1 55.8 0 15.50 48.9 10.3 2 61.3 0 4.2 57.2 3.0

[0215] Thus, it was shown again that higher pressure favorites the deprotection of the amino group also in the case of multidentate ligands as the ratio of 3 to 2 was far higher than that achieved before at higher yield (about 5.5:1 at a combined yield of 85% for triphos and 14.6:1 at a combined yield of 60% for xantphos).

2.2.4 Evaluation of Salt Effect

[0216] Standard procedure: A ca. 40 mL Premex autoclave (equipped with Teflon insert) was charged with indicated additive (1 equiv.). RuHCl(CO)(PPh.sub.3).sub.3 (X mol %), the nitrile 1 (1 mmol), dioxane (6.0 mL) and H.sub.2O (1.0 mL) under air. After closing the reaction vessel, the system was purged first with nitrogen (3×) and then with hydrogen (3×). Finally, the autoclave was pressurized with hydrogen (55 bar), and heated at 140° C. Note: At this temperature the internal pressure rises up to 70 bar. The mixture was stirred for 17 h. Then, the reaction was cooled-down on a water bath and depressurized carefully, the crude mixture was collected in a round bottom flask and concentrated under vacuum. 0.3 mmol of hexamethylcyclotrisiloxane or 1 mmol of Cl.sub.2CH.sub.2CH.sub.2Cl.sub.2 (used as internal standard) were added to the crude mixture to determine the .sup.1H-NMR yield in MeOD-d.sub.4.

##STR00040##

TABLE-US-00007 Conv 2 3 4 mol % [Ru] Additive (%) (yield, %) (yield, %) (yield, %) 2 — 90 86  3 — 2 NaCl 83 28 — 57 3 (NH.sub.4).sub.2SO.sub.4 >99 53 — 30 3 Na.sub.2SO.sub.4 >99 50 28 — 3 (NH.sub.4)H.sub.2PO.sub.4 >99 60 — 29 3 Yb(OTf).sub.3* <75% 70 — — *In this case, only 5 mol % of additive was used.

##STR00041##

[0217] .sup.1H NMR (200 MHz, MeOD) δ3.28 (s, 21H), 1.06 (s, 6H).

##STR00042##

[0218] Isolated as a 2.5:1 mixture of isomers: Major isomer: .sup.1H NMR (200 MHz, MeOD) δ 7.92 (s, 1H), 3.58 (s, 2H), 1.30 (d, J=0.6 Hz, 6H). Minor isomer: .sup.1H NMR (200 MHz, MeOD) δ 8.21 (s, 1H), 3.39 (s, 2H), 1.27 (d, J=0.7 Hz, 6H).

##STR00043##

[0219] .sup.1H NMR (200 MHz, MeOD) δ 3.48 (s, 1H), 1.29 (s, 1H).

2.2.5 Isolation as an HCl Adduct

[0220] Method A)

##STR00044##

[0221] A ca. 40 mL Premex autoclave (equipped with Teflon insert) was charged with RuHCl(CO)(PPh.sub.3).sub.3 (3 mol %), the nitrile 1 (1 mmol), dioxane (6.0 mL) and H.sub.2O (1.0 mL) under air. After closing the reaction vessel, the system was purged first with nitrogen (3×) and then with hydrogen (3×). Finally, the autoclave was pressurized with hydrogen (45 bar) and heated at 140° C. Note: At this temperature the internal pressure rises up to 60 bar. The mixture was stirred for 18 h. Then, the reaction was cooled-down on a water bath and depressurized carefully, the crude mixture was collected in a round bottom flask and concentrated under vacuum. Subsequently, it was dissolved in 1 mL of EtOH, 0.1 mL of concentrated HCl (36%) were added to the solution. The resulting mixture was stirred at room temperature for 18 hours. Then, the mixture was concentrated under reduced pressure and it was washed with Et.sub.2O (×3) and dried under vacuum. The product was isolated as an off-white solid (67.1 mg, 54% yield over two steps). .sup.1H NMR (200 MHz, D.sub.2O) δ 3.55 (s, 2H), 1.31 (s, 6H).

[0222] Method B)

##STR00045##

[0223] A ca. 40 mL Premex autoclave (equipped with Teflon insert) was charged with RuHCl(CO)(PPh.sub.3).sub.3 (3 mol %), the nitrile 1 (1 mmol), dioxane (6.0 mL) and H.sub.2O (1.0 mL) under air. After closing the reaction vessel, the system was purged first with nitrogen (3×) and then with hydrogen (3×). Finally, the autoclave was pressurized with hydrogen (55 bar) and heated at 140° C. Note: At this temperature the internal pressure rises up to 60 bar. The mixture was stirred for 18 h. Then, the reaction was cooled-down on a water bath and depressurized carefully, the crude mixture was collected in a round bottom flask and concentrated under vacuum. Subsequently, it was dissolved in 2.5 mL of MeOH. To the solution, 2.5 mL of a 2 M HCl aqueous solution were added. The mixture was stirred at 80° C. for 18 hours. Then, the mixture was concentrated under reduced pressure and it was washed with Et.sub.2O (×3) and dried under vacuum. The product was isolated as an off-white solid (74.2 mg, 59% yield over two steps). .sup.1H NMR (200 MHz, D.sub.2O) δ 3.55 (s, 2H), 1.31 (s, 6H).

2.2.6 Isolation as an HCl Adduct, Substrate Scope

[0224] The corresponding formyl-protected aminonitriles were prepared according to the procedures 1.3 or 1.4, 1.51. The reactions on the substrate scope were performed as followed: A ca. 40 mL Premex autoclave (equipped with Teflon insert) was charged with RuHCl(CO)(PPh.sub.3).sub.3 (5 mol %), the formyl protected aminonitrile (1 mmol), dioxane (6.0 mL) and H.sub.2O (1.0 mL) under air. After closing the reaction vessel, the system was purged first with nitrogen (3×) and then with hydrogen (3×). Finally, the autoclave was pressurized with hydrogen (55 bar) and heated at 140° C. Note: At this temperature the internal pressure rises up to 60 bar. The mixture was stirred for 18 h. Then, the reaction was cooled-down on a water bath and depressurized carefully, the crude mixture was collected in a round bottom flask and concentrated under vacuum. Subsequently, it was dissolved in 2.5 mL of MeOH. To the solution, 2.5 mL of a 2 M HCl aqueous solution were added. The mixture was stirred at 80° C. for 18 hours. Then, the mixture was concentrated under reduced pressure and it was washed with Et.sub.2O (×3) and dried under vacuum to obtain the corresponding amino alcohols in the form of their HCl-salts.

[0225] The product yields were determined by .sup.1H-NMR spectroscopy in CDCl.sub.3.

##STR00046##

2.2.3 Comparative Examples

[0226] Stability of non-protected aminonitriles at elevated temperatures in the presence of water: 2-amino-2-methyl-propanenitrile was dissolved in D-O/MeOH-d.sub.4 (1:1) in an J-young NMR-tube and heated for 2 hours at 140° C. The reaction mixture was analyzed by .sup.1H-NMR. It was detected, that the aminonitrile is hydrolyzed to the ketone, HCN and NH.sub.3, which showed that unprotected aminonitriles are not stable under the conditions required for the reductive nitrile hydrolysis. Therefore the amine function has to be protected.

##STR00047##

[0227] A ca. 40 mL Premex autoclave (equipped with Teflon insert) was charged with RuHCl(CO)(PPh.sub.3).sub.3 (48.1 mg, 0.05 mmol), 1-aminocyclohexane-1-carbonitrile (124.2 mg, 1 mmol), 1,4-dioxane (7.0 mL) and H.sub.2O (7.0 mL) under air. The mixture was degassed gently with argon. After closing the reaction vessel, the system was purged first with nitrogen (3×) and then with hydrogen (3×). Finally, the autoclave was pressurized with hydrogen (43 bar) and heated at 140° C. Note: At this temperature the internal pressure rises up to 60 bar. The mixture was stirred under these conditions for 17.5 h. Then, the reaction was cooled-down on a water bath and depressurized carefully, the organic phase was extracted with EtOAc (3×25 mL), washed with brine and dried over Na.sub.2SO.sub.4. Filtered through a short cotton pad and concentrated under vacuum. .sup.1H-NMR analysis in CDCl.sub.3-d showed no formation of expected product.

[0228] Thus, this experiment suggests that the reductive hydrolysis of nitrile group occurs faster than the deprotection of formyl amino group.