Process for the preparation of ramipril

Abstract

An enantioselective process for the production of (2S,3aS,6aS)-cyclopenta[b]pyrrole-2-carboxylic acid and its conversion into Ramipril is provided.

Claims

1. A process for preparing a compound of formula (VI) ##STR00066## wherein: R1 is CO.sub.2R4 or CN; R2 is (C1-C4)alkyl; R3 is (C1-C4)alkyl, wherein one, two or three hydrogen atoms are optionally replaced by fluorine, (C1-C4)alkoxy, or phenyl; R4 is (C1-C4)alkyl; and Ar is phenyl, optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, (C1-C4)alkoxy and (C1-C4)alkyl, or 1-naphthyl; comprising reacting a chiral amine of formula (IV) ##STR00067## wherein: R1 is CO.sub.2R4 or CN; R4 is (C1-C4)alkyl; and Ar is phenyl, optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, (C1-C4)alkoxy and (C1-C4)alkyl, or 1-naphthyl; with a 2-acylamino-acrylic acid ester of formula (V) ##STR00068## wherein: R2 is (C1-C4)alkyl; and R3 is (C1-C4)alkyl, wherein one, two or three hydrogen atoms are optionally replaced by fluorine, (C1-C4)alkoxy, or phenyl, to produce the compound of formula (VI).

2. A compound of formula (VI) ##STR00069## wherein: R1 is CO.sub.2R4 or CN; R2 is (C1-C4)alkyl; R3 is (C1-C4)alkyl, wherein one, two or three hydrogen atoms are optionally replaced by fluorine, (C1-C4)alkoxy, or phenyl; R4 is (C1-C4)alkyl; and Ar is phenyl, optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, (C1-C4)alkoxy and (C1-C4)alkyl, or 1-naphthyl.

3. The compound according to claim 2, wherein the carbon atom bearing the R1 group is in the (S) configuration.

4. A compound of formula (VIIa) ##STR00070## wherein: R2 is (C1-C4)alkyl; R3 is (C1-C4)alkyl, wherein one, two or three hydrogen atoms are optionally replaced by fluorine, (C1-C4)alkoxy, or phenyl; and R4 is (C1-C4)alkyl.

5. The compound of claim 4, wherein the carbon atom bearing the CO.sub.2R4 group is in the (S) configuration.

6. A compound of formula (VIIb) ##STR00071## wherein: R2 is (C1-C4)alkyl; and R3 is (C1-C4)alkyl, wherein one, two or three hydrogen atoms are optionally replaced by fluorine, (C1-C4)alkoxy, or phenyl.

7. The compound of claim 6, wherein the carbon atom bearing the CN group is in the (R) configuration.

8. The compound according to claim 2, wherein R1 is CO.sub.2R4.

9. The compound according to claim 2, wherein R2 is methyl or ethyl.

10. The compound according to claim 2, wherein R3 is methyl, ethyl, propyl, butyl, trifluoromethyl, methoxy, ethoxy, propoxy, butoxy, or phenyl.

11. The compound according to claim 2, wherein R4 is methyl or ethyl.

12. The compound according to claim 2, wherein Ar is phenyl, 4-methoxyphenyl, 4-chlorophenyl or 1-naphthyl.

13. The compound according to claim 4, wherein R2 is methyl or ethyl.

14. The compound according to claim 4, wherein R3 is methyl, ethyl, propyl, butyl, trifluoromethyl, methoxy, ethoxy, propoxy, butoxy, or phenyl.

15. The compound according to claim 4, wherein R4 is methyl or ethyl.

16. The process of claim 1, further comprising steps (B-1a), (B-1b), (C), and (D): (B-1a) hydrolysing the chiral imine moiety in the compound of formula (VI) to produce a chiral ketone of formula (VII), ##STR00072## wherein: R1 is CO.sub.2R4 or CN; R2 is (C1-C4)alkyl; R3 is (C1-C4)alkyl, wherein one, two or three hydrogen atoms are optionally replaced by fluorine, (C1-C4)alkoxy, or phenyl; and R4 is (C1-C4)alkyl; followed by (B-1b) hydrolysing the chiral ketone of formula (VII) to produce a chiral amino acid of formula (VIII), or a salt thereof, ##STR00073## which is in equilibrium with a chiral bicyclic amino acid of formula (IX), or a salt thereof, ##STR00074## and (C) converting the chiral bicyclic amino acid of formula (IX) or salt thereof, from the mixture of the chiral amino acid of formula (VIII) or salt thereof, and the chiral bicyclic amino acid of formula (IX) or salt thereof, by catalytic hydrogenation into a compound of formula (IIIa), or a salt thereof, ##STR00075## and (D) converting the compound of formula (IIIa) or salt thereof into a compound of formula (I) ##STR00076##

17. The process of claim 1, further comprising steps (B-2), (C), and (D): (B-2) hydrolysing the chiral imine in the compound of formula (VI) to produce a chiral amino acid of formula (VIII), or a salt thereof, ##STR00077## which is in equilibrium with a chiral bicyclic amino acid of formula (IX), or a salt thereof, ##STR00078## and (C) converting the chiral bicyclic amino acid of formula (IX) or salt thereof, from the mixture of the chiral amino acid of formula (VIII) or salt thereof, and the chiral bicyclic amino acid of formula (IX) or salt thereof, by catalytic hydrogenation into a compound of formula (IIIa), or a salt thereof, ##STR00079## and (D) converting the compound of formula (IIIa) or salt thereof into a compound of formula (I) ##STR00080##

Description

EXAMPLES

Abbreviations

(1) ca. circa h hour(s) i. vac. in vacuum LC-MS liquid chromatography-mass spectrometry M molar MTBE methyl-tert.-butylether NMR nuclear magnetic resonance DCM dichloromethane Ar aryl Bn benzyl Me methyl Et ethyl

(2) The invention is described in more detail by the examples that follow. These examples are designated to illustrate the invention, but do not limit its scope. Each step of the process described in the present invention may be operated either batch by batch or as a continuous process, or semi-continuous mode, and is scalable on larger amounts than described here.

(3) The NMR assignments are for illustration only based on analysis of the one-dimensional and multi-dimensional .sup.1H and .sup.13C NMR spectra as done by those skilled in the art. A more detailed analysis of the spectra may lead to minor reassignments of some NMR peaks, which obviously does not change the overall assignment. NMR spectra were recorded on 500 MHz and on 600 MHz instruments, shifts are relative to TMS in [ppm]; the solvent is always DMSO-d.sub.6 if not denoted otherwise.

Preparation of Compounds of Formula (IV) Incl. (IVa) and IVb)

Example 1

2-[(S)-1-phenyl-ethylamino]-cyclopent-1-ene-carbonitrile (compound (IVb) wherein Ar=phenyl)

(4) ##STR00050##

(5) 9.80 g (85.3 mmol) of 2-oxo-cyclopentane-carbonitrile (Ark Pharm Inc., purity 95%) were dissolved in 20 ml of toluene and 10.4 g (85.3 mmol) of (S)-1-phenyl-ethylamine (>99%, BASF) were added under cooling at 20 C. to 30 C. After stirring for 4 hours, water and crystals deposited in the reaction vessel, and water was completely removed by distillation with toluene on a rotary evaporator. The remaining crystalline mass was stirred in cold MTBE, filtered and dried to give 16.7 g (92%) of the title product as bright yellow crystals. LC-MS: MH.sup.+ 213,

(6) .sup.1H NMR: 1.39 (d, 3H, Me), 1.72 (m, 2H, H-4), 2.30-2.48 (m, 4H, H-3, H-5), 4.93 (m, 1H, CHN), 7.23 (m, 2H, ArH), 7.33 (m, 3H, ArH).

Example 2

2-[(S)-1-(4-methoxyphenyl)-ethylamino]-cyclopent-1-ene-carboxylic acid methylester (compound of formula (IV) wherein Ar=4-methoxyphenyl, R1CO2Me)

(7) 10.37 g (70.0 mmol) of 2-oxo-cyclopentane-carboxylic acid methylester (purity 96%, Aldrich) were dissolved in 30 ml of toluene and 10.00 g (65.5 mmol) of (S)-1-(4-methoxyphenyl)-ethylamine (purity>99%, BASF) were stirred under argon for 12 hours at ca. 25 C. Water was completely removed by evaporation of toluene (350 ml) and the product was dried at 80 C./1 mbar to give 18.1 g (100%) of the title product as yellow oil.

(8) LC-MS: MH.sup.+ 276;

(9) .sup.1H NMR: 1.40 (d, 3H, Me), 1.65 (m, 2H, H-4), 2.25, 2.37, 2.62 (3m, 4H, H-3, H-5), 3.57 (s, 3H, CO.sub.2Me), 3.73 (s, 3H, OMe), 4.60 (m, 1H, CHN), 6.90, 7.20 (2m, 4H, ArH), 7.70 (d, 1H, NH).

Example 3

2-[(S)-1-(1-naphtyl)-ethylamino]-cyclopent-1-ene-carboxylic acid methylester (compound (IV) wherein Ar=1-naphtyl, R1CO2Me)

(10) The title compound was prepared in an analogous manner as described in Example 2 from 3.89 g (26.3 mmol) of 2-oxo-cyclopentane-carboxylic acid methylester and 4.50 g (25.8 mmol) of (S)-1-(1-naphtyl)-ethylamine (purity 98.5%, BASF) in quantitative yield (7.60 g yellow oil).

(11) LC-MS: MH.sup.+ 296;

(12) .sup.1H NMR: 1.57 (d, 3H, Me), 1.56, 1.67 (2m, 2H, H-4), 2.05, 2.40, 2.65 (3m, 4H, H-3, H-5), 3.61 (s, 3H, CO.sub.2Me), 5.50 (m, 1H, CHN), 6.90, 7.20 (2m, 4H, ArH), 7.10-8.20 (m, 7H, ArH).

Example 3a

Preparation of 2-[(S)-1-(phenylethylamino]-cyclopent-1-ene-carboxylic acid methylester (IV) (Ar=4-phenyl, R1CO2Me)

(13) The title compound was prepared in an analogous manner as described in Example 2 from 63.51 g (0.43 mol) 2-oxo-cyclopentane-carboxylic acid methylester (purity 96%, Aldrich) and 50.0 g (0.41 mol)(S)-1-phenylethylamine (purity>99%, BASF) in almost quantitative yield (97.0 g, 97%).

(14) LC-MS: MH.sup.+ 246; .sup.1H NMR: 1.41 (d, 3H), 1.70 (m, 2H), 2.20 (m, 1H), 2.41 (m, 2H), 2.62 (m, 1H), 3.57 (s, 3H), 4.65 (m, 1H), 7.20-7.40 (m, 5H), 7.75 (d, 1H).

Example 4

2-[(S)-1-(4-chlorophenyl)-ethylamino]-cyclopent-1-ene-carbonitrile (compound (IVb) wherein Ar=4-chlorophenyl)

(15) The title compound was prepared in an analogous manner as described in example 1 from 2-oxo-cyclopentane-carbonitrile and (S)-1-(4-chlorophenyl)-ethylamine (purity>98%, BASF): The yield was 94% of bright yellow crystals.

(16) LC-MS: MH.sup.+ 247; .sup.1H NMR: 1.38 (d, 3H, Me), 1.73 (m, 2H, H-4), 2.30-2.50 (m, 4H, H-3, H-5), 4.92 (m, 1H, CHN), 7.28 (d, 1H, NH), 7.35, 7.40 (2d, 4H, ArH).

Preparation of Compounds of Formula (VI), Incl. (VIa) and (VIb)

Example 5

Methyl (2S)-2-acetamido-3-[(1S,2E)-1-cyano-2-[(1S)-1-phenylethyl]imino-cyclopentyl]propanoate (Compound of Formula (VI) (Wherein Ar=Phenyl, R1CN, R2=Me, R3=Me) from Compound of Formula (IVb) (Wherein Ar=Phenyl, R1=CN) and Compound of Formula (V) (Wherein R2=Me, R3=Me)) (Step A))

(17) ##STR00051##

(18) 3.00 g (14.13 mmol) of 2-[(S)-1-phenyl-ethylamino]-cyclopent-1-ene-carbonitrile (IVb, Ar=phenyl, Example 1), 2.12 g (14.84 mmol) of 2-acetylamino-acrylic acid-methylester (V, R.sup.2=Me, R.sup.3=Me) (Aldrich), and 0.05 g of hydroquinone were mixed with 5 ml of acetonitrile and heated under stirring at 65 C. (bath temperature) for 65 hours. The solvent was evaporated and the semi-solid mass was diluted under stirring with 20 ml of MTBE. After cooling to room temperature, the mixture was filtered. The crude solid product was dissolved in a minimum amount of hot dichloromethane and the hot solution was diluted with MTBE. A small amount of solid was removed by filtration. Then the filtrate was evaporated, the residue taken up again in a minimum amount of hot dichloromethane. The vast bulk of dichloromethane then was slowly evaporated using a rotary evaporator while adding successively MTBE. After some time the product separated as sparkling crystals. The suspension was stirred for about two hours while cooling to room temperature. The crystals were filtered, washed with MTBE and dried i.vac. Part of this was used as seeding crystal for making a larger amount of the title compound (see next experiment)

(19) X-ray crystallographic analysis: A specimen was used for the X-ray crystallographic analysis. The X-ray intensity data were measured. The total exposure time was 13.71 hours. The frames were integrated with the Bruker SAINT software package using a narrow-frame algorithm. The integration of the data using an orthorhombic unit cell yielded a total of 7602 reflections to a maximum 8 angle of 69.74 (0.82 resolution), of which 2303 were independent (average redundancy 3.301, completeness=63.7%, R.sub.int=1.71%, R.sub.sig=1.29%) and 2230 (96.83%) were greater than 2(F.sup.2). The final cell constants of a=9.1247(7) , b=11.7442(8) , c=18.9593(14) , volume=2031.7(3) .sup.3, are based upon the refinement of the XYZ-centroids of 5717 reflections above 20 (I) with 8.857<2<136.6. Data were corrected for absorption effects using the multi-scan method (SADABS). The ratio of minimum to maximum apparent transmission was 0.859. The structure was solved and refined using the Bruker SHELXTL Software Package, using the space group P 21 21 21, with Z=4 for the formula unit, C.sub.20H.sub.25N.sub.3O.sub.3. The resulting absolute configuration was as drawn above and in Scheme 3.

(20) 16.70 g (78.6 mmol) of 2-[(S)-1-phenyl-ethylamino]-cyclopent-1-ene-carbonitrile (IVb, Ar=phenyl, Example 1), 11.82 g (82.6 mmol) of 2-acetylamino-acrylic acid-methylester (V, R.sup.2=Me, R.sup.3=Me) (Aldrich), and 0.10 g of hydroquinone were mixed with 20 ml of acetonitrile and heated under stirring at 60 C.-65 C. An orange-yellow solution formed within 30 minutes. After ca. 24 hours, a seeding crystal of the title product was added whereupon some product crystallized out. The reaction mixture thickened while most of the solvent was evaporated, and after 48 hours 50 ml of MTBE were added under stirring to the hot suspension. After cooling at room temperature, a first crop of product (12.4 g) was obtained by filtration and washing with MTBE. A second crop (6.00 g) was obtained after a repeated treatment of the concentrated filtrate (without additional acetonitrile and for another 48 hours under the same conditions) to give in total 18.6 g (65%) of the title compound as colorless crystals. The mother liquor still contained the starting compounds and some additional product in a ratio of about 1:1:1 and in principle allowed for a repeated reaction/isolation procedure to obtain a further crop of the title product. (LC peak areas were calibrated).

(21) LC-MS: MH.sup.+ 356.

(22) .sup.1H NMR: 1.33 (d, 3H, H-15), 1.76, 1.95 (m, 2H, H-4), 1.86 (s, 3H, H-12), 1.95, 2.19 (m, 2H, H-3), 1.92, 2.46 (m, 2H, H-6), 2.45 (m, 2H, H-5), 3.66 (s, 3H, H-13), 4.52 (q, 1H, H-14), 4.59 (m, 1H, H-7), 7.23 (m, 1H, H-19), 7.33 (m, 2H, H-18), 7.37 (m, 2H, H-17), 8.44 (d, 1H, H-9); .sup.13C NMR: 21.39 (C-4), 22.33 (C-12), 24.04 (C-15), 27.34 (C-5), 34.86 (C-3), 36.55 (C-6), 45.94 (C-2), 49.54 (C-7), 52.08 (C-13), 61.00 (C-14), 120.89 (C-10), 126.29 (C-17), 126.60 (C-19), 128.22 (C-18), 144.89 (C-16), 169.30 (C-11), 171.92 (C-8), 173.31 (C-1).

Example 6

Methyl (2S)-2-acetamido-3-[(1S,2E)-2-[(1S)-1-(4-chlorophenyl)ethyl]imino-1-cyano-cyclopentyl]propanoate (Compound of Formula (VI) (Wherein Ar=4-Chlorophenyl, R1CN, R2=Me, R3=Me) from Compound of Formula (IV) (Wherein Ar=4-Chlorophenyl, R1CN) and Compound of Formula (V) (Wherein R2=Me, R3=Me)) (Step A)

(23) ##STR00052##

(24) 5.00 g (20.3 mmol) of compound (IV) (Ar=4-chlorophenyl, R.sup.1CN, Example 4) and 3.05 g (21.3 mmol) of compound (V) (R.sup.2=Me, R.sup.3=Me) were converted in an analogous manner as described in Example 5, using 10 ml of MTBE as a solvent, into 5.05 g (63%) of the title compound (yellow solid).

(25) LC-MS: MH.sup.+ 390

(26) .sup.1H NMR: 1.32 (d, 3H, H-15), 1.75, 1.94 (m, 2H, H-4), 1.86 (s, 3H, H-12), 1.95, 2.20 (m, 2H, H-3), 1.90, 2.45 (m, 2H, H-6), 2.46 (m, 2H, H-5), 3.67 (s, 3H, H-13), 4.53 (q, 1H, H-14), 4.60 (m, 1H, H-7), 7.33-7.46 (m, 4H, H-17, H-18), 8.43 (d, 1H, H-9)

Example 7

Methyl (1S,2E)-1-[(2S)-2-acetamido-3-methoxy-3-oxo-propyl]-2-[(1S)-1-phenylethyl]imino-cyclopentanecarboxylate

(27) (compound (VI) (wherein Ar=phenyl, R.sup.1CO.sub.2Me, R.sup.2=Me, R.sup.3=Me) from compound (IV) (wherein Ar=phenyl, R.sup.1CO.sub.2Me) and compound (V) (wherein R.sup.2=Me, R.sup.3=Me)) (step A)

(28) ##STR00053##

(29) 20.00 g (81.53 mmol) (2-[(S)-1-phenyl-ethylamino]-cyclopent-1-ene-carboxylic acid methylester (IV) (Ar=phenyl, R.sup.1CO.sub.2Me, Example 3a), 12.50 g (85.60 mmol) of 2-acetylamino-acrylic acid-methylester (V) (R.sup.2=Me, R.sup.3=Me) and 0.18 g of hydroquinone were mixed with 10 ml of acetonitrile and heated under stirring at 50 C.-60 C. After ca. 3 days, the crystallized product was isolated, after addition of 30 ml of diisopropylether and stirring for 2 hours at 10 C. Yield of this fraction: 17.59 g (56%). The filtrate was evaporated and the same reaction and isolation procedure was repeated once to give a combined yield of 23.51 g (74.2%) of the title product.

(30) LC-MS: MH.sup.+ 389.

(31) .sup.1H NMR: 1.32 (d, 3H, H-15), 1.82 (m, 2H, H-4), 1.83 (s, 3H, H-12), 1.84, 2.26 (m, 2H, H-3), 1.74, 2.62 (m, 2H, H-6), 2.23, 2.38 (m, 2H, H-5), 3.52 (s, 3H, H-20), 3.58 (s, 3H, H-13), 4.44 (q, 1H, H-14), 4.44 (m, 1H, H-7), 7.18 (m, 1H, H-19), 7.25 (m, 2H, H-17), 7.28 (m, 2H, H-18), 8.32 (d, 1H, H-9);

(32) .sup.13C NMR: 21.62 (C-4), 22.29 (C-12), 24.35 (C-15), 27.90 (C-5), 32.72 (C-3), 36.72 (C-6), 49.39 (C-7), 51.67 (C-13), 51.76 (C-20), 56.68 (C-2), 60.44 (C-14), 126.06 (C-17), 126.27 (C-19), 128.03 (C-18), 145.45 (C-16), 168.97 (C-11), 172.39 (C-8), 172.66 (C-10), 176.76 (C-1).

Example 8

Ethyl (1S,2E)-1-[(2S)-2-acetamido-3-methoxy-3-oxo-propyl]-2-[(1S)-1-phenylethyl]imino-cyclopentanecarboxylate (Compound (VI) (Wherein Ar=Phenyl, R1=CO2Et, R2=Me, R3=Me) from Compound (IV) (Wherein Ar=Phenyl, R1=CO2Et) and Compound (V) (Wherein R2=Me, R3=Me) (Step A)

(33) ##STR00054##

(34) 32.0 g (0.123 mol) of 2-[(S)-1-phenyl-ethylamino]-cyclopent-1-ene-carboxylic acid ethylester (IV) (Ar=phenyl, R.sup.1=CO.sub.2Et), prepared in a strictly analogous manner as described in Example 2 from 2-oxo-cyclopentane-carboxylic acid ethylester (purity 96%, Aldrich) and (S)-1-phenyl-ethylamine (purity>99%, BASF), and 18.0 g (0.125 mol) of 2-acetylamino-acrylic acid-methylester (V) (R.sup.2=Me, R.sup.3=Me) were reacted in an analogous manner as described in example 7 to give 25.0 g of the title compound as a first crystallization fraction. Further product contained in the mother liquor was not isolated.

(35) .sup.1H NMR: 1.02 (t, 3H, H-17), 1.33 (d, 3H, H-15), 1.82 (m, 2H, H-4), 1.81 (s, 3H, H-12), 1.84, 2.25 (m, 2H, H-3), 1.72, 2.62 (2dd, 2H, H-6), 2.23, 2.38 (m, 2H, H-5), 3.58 (s, 3H, H-13), 3.98 (q, 2H, H-17), 4.43 (q, 1H, H-14), 4.43 (m, 1H, H-7), 7.18 (m, 1H, H-21), 7.25 (m, 2H, H-19), 7.28 (m, 2H, H-20).

(36) X-Ray Crystallographic Analysis:

(37) A specimen of the title compound was used for the X-ray crystallographic analysis. The X-ray intensity data were measured. The total exposure time was 12.01 hours. The frames were integrated with the Bruker SAINT software package using a narrow-frame algorithm. The integration of the data using an orthorhombic unit cell yielded a total of 8017 reflections to a maximum 8 angle of 49.94 (1.01 resolution), of which 2249 were independent (average redundancy 3.565, completeness=98.7%, R.sub.int=2.37%, R.sub.sig=2.32%) and 2026 (90.08%) were greater than 2(F.sup.2). The final cell constants of a=9.2601(4) , b=13.3630(6) , c=18.2369(8) , volume=2256.68(17) .sup.3, are based upon the refinement of the XYZ-centroids of 2561 reflections above 20 (I) with 8.202<2<91.28. Data were corrected for absorption effects using the multi-scan method (SADABS). The ratio of minimum to maximum apparent transmission was 0.910. The structure was solved and refined using the Bruker SHELXTL Software Package, using the space group P 21 21 21, with Z=4 for the formula unit, C.sub.22H.sub.30N.sub.2O.sub.5. The resulting absolute configuration was as drawn above and in Scheme 3.

Example 9

Methyl (1S,2E)-1-[(2S)-3-methoxy-3-oxo-2-[(2,2,2-trifluoroacetyl)amino]propyl]-2-[(1S)-1-phenylethyl]imino-cyclopentanecarboxylate (Compound (VI) (Wherein Ar=Phenyl, R1CO2Me, R2=Me, R3CF3) from Compound (IV) (Wherein Ar=Phenyl, R1CO2Me) and Compound (V) (Wherein R2=Me, R3CF3) (Step A)

(38) ##STR00055##

(39) 4.13 g (16.84 mmol) of 2-[(S)-1-phenyl-ethylamino]-cyclopent-1-ene-carboxylic acid-methylester (IV), (Ar=phenyl, R.sup.1CO.sub.2Me, Example 3a), 0.06 g of hydroquinone, 3.32 g (16.84 mmol) of 2-trifluoroacetylamino-acrylic acid-methylester (V) (R.sup.2=Me, R.sup.3CF.sub.3, Darses et al. JAGS, 2008, vol. 130, no. 19, p. 6159-6169) and 1.5 ml of acetonitrile were heated at 60 C. under argon atmosphere. Conversion within seven hours was 75% according to LC-MS analysis and the mixture was evaporated i.vac. to afford 7.59 g of a crude product containing the title compound and some unreacted starting material. LC-MS: MH.sup.+ 443.

(40) .sup.1H NMR: 1.32 (d, 3H, H-15), 1.82 (m, 2H, H-4), 1.84, 2.26 (m, 2H, H-3), 2.00, 2.73 (m, 2H, H-6), 2.23, 2.38 (m, 2H, H-5), 3.56 (s, 3H, H-20), 3.67 (s, 3H, H-13), 4.45 (q, 1H, H-14), 4.69 (m, 1H, H-7), 7.18 (m, 1H, H-19), 7.25 (m, 2H, H-17), 7.28 (m, 2H, H-18), 9.90 (d, 1H, H-9);

Example 10

Dimethyl (2S)-1-formyl-6a-[[(1S)-1-phenylethyl]amino]-3,4,5,6-tetrahydro-2H-cyclopenta[b]pyrrole-2,3a-dicarboxylate (Compound (VI) Wherein Ar=Phenyl, R1CO2Me, R2=Me, Scheme 4), Respectively, from Compound (IV) (Wherein Ar=Phenyl, R1CO2Me) and Compound (V) (Wherein R2=Me, R3H) (Step A)

(41) ##STR00056##

(42) The synthesis was performed in an analogous manner as described in example 7. The following NMR data refer to the major stereoisomer of the bicyclic reaction product (content according to NMR data ca. 90%) in the crude product mixture.

(43) .sup.1H NMR: 1.21 (d, 3H, H-15), 1.54, 2.16 (m, 2H, H-5), 1.39, 1.58 (m, 2H, H-6), 1.61, 1.94 (m, 2H, H-7), 2.19 (m, 1H, H-13), 2.33, 2.52 (m, 2H, H-3), 3.70 (s, 3H, H-11), 3.71 (s, 3H, H-10), 3.96 (q, 1H, H-14), 4.46 (dd, 1H, H-2), 7.18 (m, 1H, H-19), 7.28 (m, 2H, H-18), 7.33 (m, 2H, H-17), 8.47 (s, 1H, H-12);

(44) .sup.13C NMR: 21.46 (C-6), 26.36 (C-15), 32.82 (C-5), 33.27 (C-3), 34.02 (C-7), 52.06 (C-10, C-14), 52.22 (C-11), 55.90 (C-2), 63.45 (C-4), 91.03 (C-8), 126.31 (C-17), 126.36 (C-19), 128.02 (C-18), 147.63 (C-16), 160.35 (C-12), 172.42 (C-9), 172.51 (C-1).

(45) NMR spectra show the content of non-cyclized structure of formula (VI), wherein Ar=phenyl, R.sup.1CO.sub.2Me, R2=Me) to be below 3%. Equilibrium is in favor of compound VI as shown in scheme 4).

Example 11

Methyl (1S,2E)-1-[(2S)-2-acetamido-3-methoxy-3-oxo-propyl]-2-[(1S)-1-(4-methoxyphenyl)ethyl]imino-cyclopentanecarboxylate (Compound (VI) (Wherein Ar=4-Methoxyphenyl, R1CO2Me, R2=Me, R3=Me) from Compound (IV) (Wherein Ar=4-Methoxyphenyl, R4CO2Me) and Compound (V) (Wherein R2=Me, R3=Me)) (Step A))

(46) ##STR00057##

(47) The title compound was prepared in an analogous manner as described in example 7 from 3.00 g (10.9 mmol) of compound (IV) (Ar=4-methoxyphenyl, R.sup.1CO.sub.2Me, Example 2) and 1.64 g (11.4 mmol) of compound (V) (R.sup.2=Me, R.sup.3=Me) using 10 ml of MTBE as a solvent. 3.00 g (66%) of the title product were obtained as viscous orange oil after washing the crude product three times with diisopropylether.

(48) LC-MS: MH.sup.+ 419

(49) .sup.1H NMR: 1.30 (d, 3H, H-15), 1.82 (m, 2H, H-4), 1.83 (s, 3H, H-12), 1.84, 2.25 (m, 2H, H-3), 1.74, 2.62 (m, 2H, H-6), 2.23, 2.38 (m, 2H, H-5), 3.52 (s, 3H, H-20), 3.59 (s, 3H, H-13), 3.73 (s, 3H, H-19), 4.38 (q, 1H, H-14), 4.43 (m, 1H, H-7), 6.85 (d, 2H, H-17), 7.15 (d, 2H, H-18), 8.33 (d, 1H, H-9);

Preparation of Compounds of Formulae (VII), Incl. (VIIa), (VIIb), and of (VII), Incl. (VIIa) and (VIIb)

Example 12

Methyl (2S)-2-acetamido-3-[(1R)-1-cyano-2-oxo-cyclopentyl]-propanoate (compound (VII) (R1CN, R2=Me, R3=Me) from compound (VI) (wherein Ar=phenyl, R1CN, R2=Me, R3=Me) (step B-1))

(50) ##STR00058##

(51) 18.00 g (50.64 mmol) of compound (VI) (Ar=phenyl, R.sup.1CN, R.sup.2=Me, R.sup.3=Me, Example 5), 5.00 g (83.3 mmol) of acetic acid and 40 ml of water were heated under stirring at 50-55 C. The suspension became clear within 45 minutes and the reaction was complete after 90 minutes (LC-MS). The product partially crystallized from the reaction mixture upon cooling. The crystals were washed with small portions of cold water. The filtrate was acidified with 25 ml of 2N hydrochloric acid, and the combined aqueous phases were concentrated to ca. 30 ml and extracted 5 times with ethyl acetate. The combined extracts were evaporated and the product crystallized from a small volume of hot dichloromethane and MTBE to give a total of 12.13 g (95%) of the title compound.

(52) LC-MS: MH.sup.+ 253.

(53) .sup.1H NMR: 1.86 (s, 3H, H-12), 1.92 (m, 2H, H-3), 1.99, 2.25 (2dd, 2H, H-7), 2.00, 2.15 (2m, 2H, H-4), 2.37 (m, 2H, H-2), 3.64 (s, 3H, H-13), 4.47 (ddd, 1H, H-8), 8.45 (d, 1H, H-10).

(54) The chiral auxiliary (S)-1-phenyl-ethylamine can be recovered from the alkalinized aqueous phase by extraction and distillation.

Preparation of Compounds of Formula (VIIa) and (VIIa)

Example 13

Methyl (1S)-1-[(2S)-2-acetamido-3-methoxy-3-oxo-propyl]-2-oxo-cyclopentane carboxylate (Compound (VII) (Wherein R1CO2Me, R2=Me, R3=Me) from Compound (VI) (Wherein Ar=Phenyl, R1CO2Me, R2=Me, R3=Me)) (Step B-1)

(55) ##STR00059##

(56) 17.10 g (44.02 mmol) of compound (VI) (Ar=phenyl, R.sup.1CO.sub.2Me, R.sup.2=Me, R.sup.3=Me; Example 7), 3.17 g (52.82 mmol) of acetic acid and 27 ml of water were heated under stirring at 50 C. The reaction was complete after 5 hours (LC-MS). The reaction mixture was acidified with dilute hydrochloric acid and extracted exhaustively with ethyl acetate. The combined extracts were washed with a small amount of dilute hydrochloric acid, dried over MgSO.sub.4 and evaporated. The product crystallized from a mixture of MTBE/acetone (ca. 5/1, 50 ml) to give a total of 11.20 g (89%) of the title compound.

(57) LC-MS: MH.sup.+ 286.

(58) .sup.1H NMR: 1.81 (s, 3H, H-14), 1.78 (dd, 1H, J=14.3, 8.7 Hz, H-7), 2.41 (dd, 1H, J=14.3, 5.9 Hz, H-7), 1.90, (m, 2H, H-3), 1.99, 2.43 (2m, 2H, H-4), 2.30 (m, 2H, H-2), 3.58 (s, 3H, H-12), 3.60 (s, 3H, H-11), 4.39 (ddd, 1H, J=8.7, 8.4, 5.9 Hz, H-8), 8.25 (d, 1H, J=8.4 Hz, H-10).

(59) .sup.13C NMR: 19.28 (C-3), 22.26 (C-14), 31.84 (C-4), 36.68 (C-2), 34.65 (C-7), 48.77 (C-8), 51.85 (C-12), 52.44 (C-11), 58.54 (C-5), 169.14 (C-13), 170.01 (C-6), 213.45 (C-1).

Example 14

Ethyl (1S)-1-[(2S)-2-acetamido-3-methoxy-3-oxo-propyl]-2-oxo-cyclopentane carboxylate (Compound (VII) (Wherein R1=CO2Et, R2=Me, R3=Me) from Compound (VI) (Wherein Ar=Phenyl, R1=CO2Et, R2=Me, R3=Me)) (Step B-1)

(60) The compound was prepared in an analogous manner as described in Example 13 from compound (VI) (Ar=phenyl, R.sup.1=CO.sub.2Et, R.sup.2=Me, R.sup.3=Me) as prepared in Example 8.

(61) ##STR00060##

(62) .sup.1H NMR: 1.16 (t, 3H, J=7.1 Hz, H-12), 1.81 (s, 3H, H-15), 1.76 (dd, 1H, J=14.4, 9.0 Hz, H-7), 2.41 (dd, 1H, J=14.4, 5.6 Hz, H-7), 1.90, (m, 2H, H-3), 1.99, 2.42 (2m, 2H, H-4), 2.30 (m, 2H, H-2), 3.58 (s, 3H, H-13), 4.05 (q, 2H, J=7.1 Hz, H-11), 4.41 (ddd, 1H, J=9.0, 8.4, 5.6 Hz, H-8), 8.25 (d, 1H, J=8.4 Hz, H-10).

(63) .sup.13C NMR: 19.32 (C-3), 22.26 (C-15), 31.84 (C-4), 36.64 (C-2), 34.60 (C-7), 48.79 (C-8), 51.82 (C-13), 58.62 (C-5), 61.09 (C-11), 169.13 (C-14), 169.49 (C-6), 213.51 (C-1).

Example 15

Methyl (1S)-1-[(2S)-3-methoxy-3-oxo-2-[(2,2,2-trifluoroacetyl)-amino]propyl]-2-oxo-cyclopentanecarboxylate (Compound (VII) (Wherein R1CO2Me, R2=Me, R3CF3) from Compound (VIa) (Wherein Ar=Phenyl, R1CO2Me, R2=Me, R3CF3) (Step B-1)

(64) ##STR00061##

(65) 2.00 g of crude compound (VI) (wherein Ar=phenyl, R.sup.1CO.sub.2Me, R.sup.2=Me, R.sup.3CF.sub.3) obtained in Example 9 were dissolved in a mixture of acetic acid (0.35 ml), water (1 ml) and acetonitrile (2 ml) and were heated under stirring at 50 C. The reaction was complete after one hour (LC-MS). The reaction mixture was acidified with dilute hydrochloric acid and extracted twice with MTBE. The combined extracts were washed with a pH 5 buffer solution and brine, dried over MgSO.sub.4 and evaporated to give 1.47 g of yellow oil which was composed of ca. 70% of the target compound and ca. 20% of the enaminoester (IV) (wherein Ar=phenyl, R.sup.1CO.sub.2Me). The crude product was subjected to column chromatography on silica gel (heptane/ethylacetate) to afford 1.23 g of the pure title compound as colourless oil. LC-MS: MH.sup.+ 340.

(66) .sup.1H NMR: 1.80-2.04 (m, 4H, H-3, H-4), 2.23-2.47 (m, 3H, H-2, H-7), 2.57 (dd, 1H, H7), 3.60 (s, 3H, H-12), 3.65 (s, 3H, H-11), 4.57 (m, 1H, H-8), 9.88 (d, 1H, H-10).

Example 16

Dimethyl (2S)-1-formyl-6a-hydroxy-3,4,5,6-tetrahydro-2H-cyclopenta[b]pyrrole-2,3a-dicarboxylate (Compound (VII) Wherein R1CO2Me, R2=Me)) (Step B-1)

(67) ##STR00062##

(68) The synthesis of the title compound was performed analogously as described in Example 13 starting from compound (VI) (wherein Ar=phenyl, R.sup.1CO.sub.2Me, R.sup.2=Me) obtained in Example 10 (partly containing compound (VI) wherein Ar=phenyl, R.sup.1CO.sub.2Me, R.sup.2=Me, R.sup.3H). The following NMR data refer to the major stereoisomer (ca. 90%) of the bicyclic reaction product contained in the crude product mixture (1.80 g, yield 69%).

(69) .sup.1H NMR: 1.45, 1.75 (m, 2H, H-6), 1.63, 2.26 (m, 2H, H-5), 2.21, 2.29 (m, 2H, H7), 2.16, 2.48 (m, 2H, H-3), 3.62 (s, 3H, H-10), 3.64 (s, 3H, H-11), 4.29 (dd, 1H, H-2), 6.58 (s, 1H, 8-OH), 8.39 (s, 1H, H-12).

(70) .sup.13C NMR: 21.41 (C-6), 33.13 (C-5), 34.06 (C-3), 38.17 (C-7), 51.86 (C-11), 52.01 (C-10), 56.58 (C-2), 61.56 (C-4), 101.03 (C-8), 161.22 (C-12), 170.96 (C-1), 172.49 (C-9).

(71) The crude title compound was subjected to acid hydrolysis (aqueous HCl) according to step B-3 as described in the subsequent example 17. The crude amino acid of formula (VIII)

(72) ##STR00063##
was obtained as a hydrochloride salt in quantitative yield and analysed by .sup.1H NMR spectroscopy (DMSO-d.sub.6): 1.20-2.45 (m, 9H), 3.93 (m, 1H, CHN), 8.50 (s, 3H, NH3.sup.+).

Preparation of Compounds (IIIa), (IIIb), (II), (IX) and (I)

Example 17

Preparation of the hydrochloride of (2S,3aS,6aS)-cyclopenta[b]pyrrole-2-carboxylic acid (IIIa) from compound (VII) (wherein R1CO2Me, R2=Me, R3=Me) (steps B-1b+C in one vessel)

(73) ##STR00064##

(74) 20.0 g (70.1 mmol) of compound (VII) (R.sup.1CO.sub.2Me, R.sup.2=Me, R.sup.3=Me, Example 13) were heated at ca. 100 C. with 140 ml of 1 M hydrochloric acid until LC-MS indicated the complete conversion into a product with MH.sup.+ 172 (ca. 14 h). In the course of this hydrolysis process, some distillate was collected and replaced by the same volume of 1 M HCl. The reaction mixture was concentrated, diluted with 100 ml of water and concentrated again to give 23.4 g of oily product. Subsequent hydrogenation of this material was performed in the same vessel in water at pH1 at 90-100 C. using 400 mg of a 5% Pd on carbon catalyst until LC-MS indicated the complete conversion into the target product with MH.sup.+ 156. The catalyst was filtered off, the filtrate was evaporated and the residue was evaporated again two times with acetone. The solid residue was stirred in acetone, filtered, washed with acetone and dried to give 10.0 g (74.4%) of the pure title compound which was proven to be identical with an authentic sample.

(75) 1H NMR (D.sub.2O): 1.43-2.00 (m, 7H), 2.60 (m, 1H, H-3), 2.95 (m, 1H, H-3), 4.15 (m, 1H, H-6a), 4.30 (m, 1H, H-2).

Example 18

Preparation of (2S,3aS,6aS)-cyclopenta[b]pyrrole-2-carboxylic acid (IIIa) from compound (VII) (wherein R1CN, R2=Me, R3=Me) (step B-1b and then C)

(76) 1.00 g (3.96 mmol) of compound (VII) (R.sup.1CN, R.sup.2=Me, R3=Me, Example 12) were heated at 100 C. with 5 ml of concentrated hydrochloric acid until LC-MS indicated the complete conversion into a product with MH.sup.+ 172 (ca. 24 h). The solution was concentrated to ca. 3 ml and diluted with 20 ml of acetone under stirring. The supernatant was decanted and the insoluble washed again twice with acetone and dried i.vac. to yield a glassy residue (ca. 0.80 g) which was redissolved in 10 ml of water containing 0.31 g (3.75 mmol) of sodium hydrogen-carbonate. Subsequent hydrogenation was performed at 50 C. (balloon) using 10% Pd on Charcoal (50 mg) until products with MH.sup.+ 172 were completely transformed into the title compound with MH+ 156, as shown by LC-MS analysis. The catalyst was removed by filtration and the filtrate was concentrated to ca. 3 ml and stirred with a mixture of acetone/isopropanol (10/1). The insoluble material was dried i. vac. to give 0.61 g (68% corr. yield) of the crude title compound as colorless solid which was contaminated with ca. 0.21 g of sodium chloride. For analytical data see the preceding example.

Example 19

Preparation of Ramipril (I) from (2S,3aS,6aS)-cyclopenta[b]pyrrole-2-carboxylic acid (IIIa) and the anhydride of the formula (X) (step D-1)

(77) 2.43 g (12.67 mmol) of the hydrochloride of (2S,3aS,6aS)-cyclopenta[b]pyrrole-2-carboxylic acid (IIIa) as prepared in Example 17 were dissolved in 10 ml of water, then a solution of 3.87 g (12.67 mmol) of the anhydride of the formula (X) was added. Aqueous 2N NaOH was added at a temperature of 10-15 C. until a pH of 9.0 was obtained, and then additional aqueous NaOH was added dropwise under stirring while keeping the pH at 8.5-9.5. The turbid mixture turned into a clear solution within ca. 30 minutes after the addition of ca. 19 ml of 2N NaOH solution. The solution as acidified to pH 5.2 using concentrated hydrochloric acid and extracted three times with ethyl acetate and brine. Evaporation of solvents provided a colourless oil which crystallized from cold diisopropylether. Yield: 3.90 g (74%) of Ramipril with >98.7% purity (LC peak area).

(78) LC-MS: MH.sup.+ 417,

(79) .sup.1H NMR (2 rotamers) 1.06 (d, 3H, Me), 1.19 (t, 3H, Me), 1.30-2.05 (m, 8H), 2.27-2.47 (m, 1H), 2.57 (m, 2H), 2.72 (m, 1H), 3.13, 3.19 (m, 1H), 3.30 (m, 1H), 3.63 (m, 1H), 4.08 (q, 2H, OCH.sub.2CH.sub.3), 4.30, 4.50 (m, 2H), 7.12-7.30 (m, 5H ArH).

Example 20

Preparation of the hydrochloride of (2S,3aS,6aS)-cyclopenta[b]pyrrole-2-carboxylic acid benzylester (IIIb) from (2S,3aS,6aS)-cyclopenta[b]pyrrole-2-carboxylic acid (IIIa) (step D-2a)

(80) ##STR00065##

(81) 5.00 g (26.09 mmol) of the hydrochloride of (2S,3aS,6aS)-cyclopenta[b]pyrrole-2-carboxylic acid (IIIa) as prepared in Example 17 were suspended in 30.0 ml (0.29 mol) of benzylalcohol at 0 C. and 5.0 ml (68.9 mmol) of thionylchloride were added slowly at <5 C. The mixture was slowly warmed up to room temperature. After ca. 2 days stirring, the mixture was diluted with 120 ml of MTBE. The solid was isolated by filtration, washed with MTBE and dried to obtain 7.06 g (96%) of the hydrochloride of the title compound as a grey-white powder. Peak area LC-MS>99%,

(82) LC-MS: MH.sup.+ 246.

(83) 1H NMR: 1.40-1.83 (m, 6H, H-4, H-5, H-6), 1.95 (m, 1H, H-3), 2.48 (m, 1H, H-3) 2.82 (m, 1H, H-3a), 3.98 (m, 1H, H-6a), 4.45 (m, 1H, H-2), 5.25 (dd, 2H, OCH.sub.2), 7.40 (m, 5H, Ar), 8.80-10.50 (brm, 2H, NH)

(84) Chiral HPLC analysis: Column Chiralpak IA/124, dimensions 2504.6 mm with eluent mixture of heptane/ethanol/methanol 20/1/1+0.1% diethylamine. The retention times were 7.60 minutes for (2R,3aR,6aR)-cyclopenta[b]pyrrole-2-carboxylic acid benzylester (peak area<0.01%) and 8.05 minutes for (2S,3aS,6aS)-cyclopenta[b]pyrrole-2-carboxylic acid benzylester (>99.9%). The enantiomeric excess was ee>99.8%. For comparison, a commercial sample of the all-S isomer purchased from Aldrich Chemicals showed a ratio all-S/all-R of 98.61/1.39% (ee 97.2%) by using the same assay.

Example 21

Preparation of Ramipril-benzylester (XI) from (2S,3aS,6aS)-cyclopenta[b]pyrrole-2-carboxylic acid-benzylester (IIIb, R=Bn) and the anhydride of the formula (X) (step D-2b-1)

(85) 1.90 g (6.74 mmol) of the hydrochloride of (2S,3aS,6aS)-cyclopenta[b]pyrrole-2-carboxylic acid-benzylester (111b, R=Bn, Example 20) were added to a stirred mixture of 0.83 g (9.83 mol) of sodium hydrogencarbonate in 5 ml of water and 20 ml of ethyl acetate at 15 C. After 5 minutes, a solution of 2.00 g (6.55 mmol) of the anhydride of the formula X in 5 ml of ethyl acetate was added dropwise within 5 minutes. Stirring was continued at ambient temperature for 60 minutes, the organic phase was separated, washed twice with saturated aqueous sodium hydrogen carbonate, dried and evaporated to dryness i.vac. (ca. 30 C./up to 1 mbar) to give 3.30 g (99%) of the title compound as colorless oil. LC-MS purity was >98% (peak area) (MH.sup.+ 507). The .sup.1H NMR data of this product were undistinguishable from the data obtained with the product being prepared in Example 22.

Example 22

Conversion of N-[1-(S)-(ethoxycarbonyl)-3-phenylpropyl]-L-alanine (II) into Ramipril-benzylester (XI) using the Vilsmeier reagent (XII) (step D-2b-2)

(86) 0.70 ml (9.62 mmol) thionylchloride were added dropwise under argon and cooling to 0.67 g (9.17 mmol) dry N,N-dimethylformamide. The mixture was stirred for one hour at 40 C. and then another two hours at 40 C. i.vac. (up to 1 mbar). A viscous semi-crystalline mass (1.17 g, 100%) formed upon cooling in an ice-bath. At a temperature of 10 C., this material was combined under an argon atmosphere with a suspension of 2.39 g (8.56 mmol) of N-[1-(S)-(ethoxycarbonyl)-3-phenylpropyl]-L-alanine (II) in 25 ml of dry DCM containing 10 mmol of dry HCl. The mixture became a clear solution within ca. 10 minutes and was stirred further 15 minutes in a temperature range from 10 C. to 5 C. The cold solution was then transferred within ca. 3 minutes into a vigorously stirred mixture of water (5 ml), sodium bicarbonate (3.4 g), DCM (5 ml) and 2.00 g (8.15 mmol) of (2S,3aS,6aS)-cyclopenta[b]pyrrole-2-carboxylic acid-benzylester (IIIb, R=Bn, Example 20). The organic phase was separated, washed 3 times with 5 ml of water, dried over sodium sulfate and carefully concentrated at 25 C./1 mbar to yield 4.11 g (99.5%) of crude Ramipril-benzylester (XI) as a clear oil. LC-MS purity was 96.6% (peak area) (MH.sup.+ 507).

(87) .sup.1H NMR (2 conformers) 1.03 (d, 3H, Me), 1.18 (t, 3H, Me), 1.25-2.45 (m, 10H), 2.57 (m, 2H), 2.73 (m, 1H), 3.13 (m, 1H), 3.62 (m. 1H), 4.08 (q, 2H, OCH.sub.2CH.sub.3), 4.33 (m, 1H), 4.47, 4.73 (m, 1H), 5.10 (q, 2H, OBn), 7.10-7.40 (m, 10H ArH).

Example 23

Preparation of Ramipril (I) from Ramipril-Benzylester (XI) (Step D-2c)

(88) 4.1 g (8.09 mmol) of Ramipril-benzylester (XI) obtained in Example 21 were hydrogenated at 15-20 C. in 30 ml of methanol with a 10% Pd on charcoal catalyst (ca. 100 mg) at atmospheric pressure (balloon). After complete consumption of the starting material, as detected by LC-MS, the catalyst was filtered off and the solvent was evaporated i.vac. In this manner, crude Ramipril was obtained as viscous oil in almost quantitative yield (3.35 g).

(89) A sample was crystallized from acetone and exhibited >99.9 purity (LC-MS peak area at 220 nm). Analytical datasame as in Example 19.