FI77037C - New enantioselective synthesis for N-substituted proline derivatives - Google Patents

Description

<77037

New enantioselective synthesis for N-substituted proline derivatives - New enantioselective syntheses for N-substituted proline derivatives

N - [(2s) -3-mercapto-2-methylpropionyl] -5-proline of formula I

O ° 0H

J (I>

O X

A

H CH3 where X is an SH group, a new enantio-selective synthesis starting from cyclic compounds of formula II <"> y \ n / \ (II) H CH3 where Y may be sulfur or oxygen.

The compound of formula I wherein X is mercapto is an inhibitor of the enzyme (ACE) which converts angiotensin I to angiotensin II. It is commonly known as captopril (International Non-proprietary Name) and can be used as a hypotensive agent, especially for angiotensively dependent hypotension. reduction (see MA Ondetti et al. Science, 196, 441, 1977; RK Ferguson et al., Lancet, 1977, 775; RC Heel et al. Drugs, 20, 409, 1980). The compound of formula I has been prepared by various methods, but none of them involves the enantio-selective synthesis of a chiral thiocarboxyacyl moiety attached to the N atom of the L-proline core (see U.S. Patent 4,046,889; DT-OS 2,703,828; European 2,77037 Application Publication 8831; Japanese Patent Publication (not studied) 80/09058). Other synthetic routes involve the hydrolytic opening of a thiazepinone ring of a compound of formula II (Y = S), as a mixture of two possible diastereoisomers. This compound, in turn, is prepared by a series of non-stereospecific reactions starting from 2-methyl-L-propylthiopropanoic acid having the formula cx <°

H S-CH2-CH-COOH

ch3 and using excipients and protecting groups known in the peptide chemistry at various stages (see U.S. Patent 4,192,945, pages 2-4, and U.S. Patent 4,225,495, pages 2-5). However, in all of these methods, diastereoisomeric mixtures must be separated when the racemic β-methyl-β- (S-protected) thiopropion group is attached to the L-proline ring (both the nitrogen atom and the carboxyl group) or complex separation of the chiral acid enantiomers must be performed before With L-proline.

It has now surprisingly been found that these disadvantages are eliminated by the use of readily available chiral intermediates of formula III.

/ \ * H °? 'y (III) (Y = S, O) ch2 3 77037 which can be converted to compounds of general formula IT enantio-selectively by asymmetrically inducing a C2-Chiral center on the L-proline moiety. The new chiral center of the compounds of formula II has the best, or even exclusively, S-configuration.

The pre-chiral part, i.e. carbon-carbon double bond, is shown in the previous formula III by a dashed circle, while the induced center of chirality is indicated by a solid line.

With respect to compound III, the pre-chiral moiety is stereospecifically hydrogenated from the less sterically hindered cC side to give compounds of formula II (Y = O, S) (a more thorough study of the highly diastereospecific endo- and exocyclic hydrogenation of 6-membered ring double bonds is disclosed in JP Vigneron et al., Tetrahydron Letters, 5681, 1968; V. Sunjid et al., J. Org. Chem., 43, 1355, 1978 and J. Org. Chem., 4Λ, 4423, 1979).

The compounds of formula II are valuable chiral intermediates which make it possible to prepare the compounds of formula I in one step when Y represents sulfur in the compounds of formula II; this transformation is at the same time the shortest and most economical chiral route to the compound of formula I wherein X is SH, i.e. captopril. When Y in the compounds of formula II represents an oxygen atom, its conversion to compound I (X = SH) first involves a tosylation reaction, after which the mercapto group is nucleophilically attached. Also in this last way, although it has 2 additional steps, there are significant advantages from a chiral-economic point of view, as all intermediates are formed in high yield and can be easily isolated.

4,77037

The following examples further illustrate the methods of preparation and use of the compounds mentioned in this invention.

Example 1 (9aS) -Hexahydro-4-methylidene-1H, 4H, 5H-pyrrolo [2,1-c] [1,4] oxazepine-1,5-dione 2.62 g (0.01 mol) N - ((3-bromo) -methylacryloyl- (S) -proline is dissolved in 30 ml of methanol and the resulting solution was added dropwise at 0 ° C to a solution of Q56 g (0.01 mol) of potassium hydroxide in 20 ml of methanol. . The solvent was evaporated in vacuo at room temperature, after which the resulting residue was dissolved in any dimethylformamide, the mixture was heated at 80 ° C for 6 h and then the dimethylformamide was evaporated off. The residue was dissolved in 5% water and the aqueous portion was extracted with 150 mL (3 x 50 mL) of ethyl acetate. The organic extracts were dried over sodium sulfate, and the solvent was evaporated to give 1.7 g of the title compound as an oil.

Infra Red Spectrum (membrane) t

Characteristic absorption peaks (cm-1) s 2980, 1720, 1640, 1590 cm-1 were observed at the following frequencies.

The resulting oil was as such a useful starting material for e.g. hydrogenation.

Example 2 (9aS) -Hexahydro-4-methylidene-1H, 4H, 5H-pyrrolo [2,1-c] [1,4] oxazepine-1,5-dione 3.93 g (0.015 mol) of (9aS) - hexahydro-4-bromomethyl-1H, 5H-pyrrolo [2,1-c] - [1,4] -oxazepine-1,5-dione and 1.0 g of lithium bromide dissolved in 20 ml of hexamethylene phosphorus-5,77037 triamide (HMPTA) was heated at 120 ° C for 4 h. The solvent was evaporated in vacuo, then the resulting residue was dissolved in 20 ml of water, the aqueous solution was saturated with sodium chloride, the pH was adjusted to one with concentrated hydrochloric acid, and the whole was finally extracted with 60 ml (3 x 20 ml) of ethyl acetate. The organic extracts were collected, the ethyl acetate was evaporated and the resulting residue was crystallized from diethyl ether. Yield: 2.33 g (96% of theory) of the title compound.

Example 3 (9aS) -Hexahydro-4-methylidene-1H, 4H, 5H-pyrrolo [2,1-c] [1,4] oxazepine-1,5-dione 26.6 g (0.1 mol) were used as starting material. the potassium salt of N - ((3-bromo) methylacryloyl- (S) -proline prepared according to Example 1. The cyclization was performed using dimethyl sulfoxide as a solvent. 16.6 g (92% of theory) of pure title compound were obtained, which was purified by silica gel column chromatography (elution system: ethyl acetate / methanol: 9/1).

Example 4 (4S, 9aS) -Hexahydro-4-methyl-1H, 5H-pyrrolo [2,1-c] [1,4] oxazepine-1,5-dione 0.9 g (0.005 mol) (9aS) -hexahydro-4-methylidene-1H, 4H, 5H-pyrrolo [2,1-c] - [1,4] -oxazepine-1,5-dione was dissolved in 50 ml of ethanol and catalytically hydrogenated at atmospheric pressure and room temperature using 0.2 g Pd / carbon as catalyst. The hydrogenation reaction was complete in 8 h to give 0.9 g (98% of theory) of the title compound.

77037 6

Example 5 (4S, 9aS) -Hexahydro-4-methyl-1Hf 5H-pyrrolo [2,1-c] [1,43-oxazepine-1,5-dione 0.9 g (0.005 moles) of (9aS) - Hexahydro-4-methylidene-1H, 4H, 5H-pyrrolot2,1-c] - [1,4] -oxazepine-1,5-dione was hydrogenated in 200 ml of benzene for 24 h at 6 atmospheres at room temperature using 200 g of catalyst as the catalyst. mg of RhCl (PPh3) 3 ~ catalyst obtained from JA Osbornin et al., J. Cern. Soc.

(A), 1711, 1966 from 1.2 g of triphenylphosphine and RhCl 3 -3H 2 O (0.1 g).

After filtration, evaporation of the solvent and crystallization from ethyl acetate, (4S, 9aS) -hexahydro-4-methyl-1H, 5H-pyrrolo [2,1-c] [1,4] oxazepine-1,5-dione was obtained in enantioselectively pure form. in terms of. Yield: 0.82 g (91% of theory).

NMR spectrum (CDCl 3): 1.42 ppm (d, 3H), no decomposition of the peaks was observed with the addition of the "optishift" reagent.

Elemental analysis C9H13NO3 MP = 183.21

Calc .: C 59.00%, H 7.15%, N 7.64%

Found: 59.05%, 6.91%, 7.88%

Example 6 N - [(2S) -3-mercapto-2-methylpropionyl] - (S) -proline 3.98 g (0.02 moles) of (4S, 9aS) -hexahydro-4-methyl-1H, 5H-pyrrolot2 1,1-c] - [1,4] -thiazepine-1,5-dione was dissolved in 15 ml of a 5 N solution of ammonia in methanol. Here the solution was stirred for 3 h at room temperature under nitrogen gas.

7 77037

The solvent was evaporated in vacuo and the oily residue was crystallized from a mixture of ethyl acetate and n-hexane to give 3.73 g (86% of theory) enantioselectively of N - [(2S) -3-mercapto-2-methylpropionyl] - (S) -proline.

M.p .: 104-105 ° C [α] 20 D = -134 ° (c = 1.6 in ethanol).

Elemental analysis C9H15NO3 MP = 217.18

Calculated: C 49.73%, H 6.96%, N 6.45%

Found: 49.81%, 6.74%, 6.59%

Example 7 N - [(2S) -3-mercapto-2-methylpropionyl] - (S) -proline

1.99 g (0.001 mol) of (4S, 9aS) -hexahydro-4-methyl-1H, 5H-pyrrolo [2,1-c] [1,4] thiazepine-1,5-dione were dissolved in a mixture of 8 ml. water and 12 ml of concentrated ammonia. The resulting solution was stirred for 2 h at 0 ° C under nitrogen. Diluted with water, and the insoluble matter was separated by filtration, after which the filtrate was extracted with ethyl acetate. The aqueous phase was adjusted to pH 1 with concentrated hydrochloric acid, saturated with sodium chloride and re-extracted with 120 ml (3 x 40 ml) of ethyl acetate. The organic extracts were collected, the solvent was evaporated and the resulting residue was crystallized from ethyl acetate / n-hexane. Yield: 1.78 g (82% of theory) of the title compound. M.p .: 102-104 ° C

Example 8 N - [(2S) -3-hydroxy-2-methylpropionyl] - (S) -proline 7.32 g (0.04 moles) of the enantiomerically pure (4S, 9aS) -hexahydro-4 prepared according to Example 5 or 6. -methyl-1H, 5H-pyrrolo [2,1-c] - [1,4] -oxazepine-1,5-dione was dissolved in 50 ml of methanol and treated at 0 ° C with a solution containing 2 .35 g (0.042 mol) of potassium hydroxide in 50 ml of ethanol. The pH was adjusted to one with concentrated hydrochloric acid, then saturated with sodium chloride and the aqueous phase was extracted with 150 ml of ethyl acetate (3 x 50 ml). Crystallization gave 7.15 g (89% of theory) of the chemically and enantioselectively pure title compound.

Elemental analysis C9H15NO4 MP = 201.22

Calc .: C 53.72%, H 7.50%, N 6.96%

Found: 53.49%, 7.36%, 7.08%

Example 9 N - [(2S) -3-p-toluenesulfoxy-2-methylpropionyl] - (S) -proline p-toluenesulfonyl chloride (2.09 g, 11.0 mmol) was added portionwise to a solution cooled to 0 ° C which contained N - [(2S) -3-hydroxy-2-methylpropionyl] - (S) -proline (2.01 g, 10.0 mmol) in anhydrous pyridine (12 mL). The reaction mixture was kept under ice-cooling overnight, water (50 ml) was added, the pH was adjusted together with concentrated hydrochloric acid and extracted with ethyl acetate (3 x 50 ml). The organic extracts were washed with 5% hydrochloric acid. The resulting oil was crystallized by adding ether. Yield 94% (3.34 g)

Example 10 N - [(2S) -3-mercapto-2-methylpropionyl] -S-proline

To a solution of N - [(2S) -2-p-toluenesulfoxy-2-methyl-propionyl] - (S) -proline (1.77 g, 5.0 mmol) in methanol / N 2 O (3: 1 10 ml), NaSH (2.0 g) was added. The reaction mixture was stirred under nitrogen for 1 h at 20 ° C and then for 3 h at 50 ° C. A portion of the reaction mixture was evaporated and an additional 20 mL of water was added. The pH was adjusted together with concentrated hydrochloric acid and the mixture was extracted with ethyl acetate (4 x 20 mL). The organic extracts were dried over sodium sulfate and the solvent was evaporated. The crude residue (1.09 g; quantitative yield) was crystallized from ETOAc / n-hexane to give the product,

M.p .: 102-103 ° C [α] 20 D = -130 ° (c - 1.1, EtOH).

Example 11 e * - (N-tert-Butoxycarbonyl-S-proline) -thiomethacrylic acid

A solution of ethyl chloroformate (0.54 g, 5.0 mmol) in absolute tetrahydrofuran (5 mL) was added dropwise to a cooled solution of N-tert-Boc-S-proline (1.08 g, 5.0 mmol) and triethylamine (0.505 g, 5.0 mmol) in absolute tetrahydrofuran (10 mL). After stirring for 1 h at room temperature, the triethylamine hydrochloride was filtered off and the filtrate was added to a cooled solution of NaSH (0.28 g, 5.0 mmol) in absolute tetrahydrofuran (10 mL). After 30 minutes, a solution of β-bromomethacrylic acid (0.82 g, 5.0 mmol) and triethylamine (0.505 g, 5.0 mmol) in methanol (10 mL) was added with stirring. After stirring at room temperature for 2 h, the pH was adjusted to 5 and the reaction mixture was evaporated. The residue was dissolved in water (50 mL) and extracted with methylene chloride (3 x 50 mL). The organic extracts were dried over sodium sulfate and evaporated. The resulting oily residue (1.6 g, quantitative yield) could be used as described in Example 12 without further purification. A pure sample could be obtained by chromatography on silica gel using AcOEt-EtOH 8: 2 as eluent. After crystallization from ether, the melting point is 85-86 ° C.

IR: 2980, 1725, 1690, 1645, 1410, 1370 cm-1.

1. 77037

Elemental analysis for C14H21NO5S (315.39)

Calc .: C 53.32%, H 6.70%, N 4.44%

Found: 52.97%, 6.80%, 4.59%

Example 12 o <- (S-Thioprolyl) -methacrylic acid hydrobromide

The N-Boc derivative obtained as described in Example 11 (1.04 g) was dissolved in glacial acetic acid (9 ml) and 48% hydrobromic acid (1 ml) in acetic acid was added dropwise. After stirring for 2 h at room temperature, toluene (20 ml) was added and the solvent was evaporated. the oily residue was crystallized by adding acetone and recrystallized from acetonitrile. M.p .: 167-168 ° C. IR: 3380 (broad peak), 2600-30000 (broad peak), 1708, 1680, 1642, 1535, 1385 cm-1.

Elemental analysis for c9H14NO3BrS (296.19)

Calculated: C 36.49% H 4.76% N 4.72%

Found: 36.66% 4.96% 4.39%

Example 13 (9aS) -Hexahydro-4-methylidene-1H, 4H, 5H-pyrrolo [1,2-c] [1,4] thiazepine-1,5-dione d- (S-prolyl) -thiomethacrylic acid (2, 15 g, 10.0 mol) solution of dichloromethane (100 ml) was added dropwise to a solution of dicyclohexylcarbodiimide (2.10 g, 11.0 mmol) and 4-dimethylaminopyridine (1.34 g, 11.0 mmol). in dichloromethane (150 ml). Stirring was continued at room temperature for 12 h, the precipitate was filtered off, the filtrate was evaporated and the oily residue was purified on a silica gel column using AcOEt as eluent. The pure product (1.4 g, yield 78%) was obtained as a glassy solid which did not crystallize.

IR: 2880-2980 (multiplet), 1700, 1630, 1420, 815 cm-1 UV (1 x 10-4 M / MeOH) λmax: (E) 220 (6800).

Elemental analysis for C9H11NO2S (197.26)

Calc .: C 54.82% H 5.56% N 7.10%

Found: 54.60% 6.01% 6.88%

Example 14 (4S, 9aS) -Hexahydro-4-methyl-1H, 5H-pyrrolo [2,1-c] [1,4] -thiazepine-1,5-dione 0.6 g of palladium / carbon was added (9aS ) -hexahydro-4-methyl-diene-1H, 4H, 5H-pyrrolo [2,1-c] [1,4] -diazepine-1,5-dione (1.16 g, 6.0 mmol) solution in ethanol (40 ml). The hydrogenation reaction was performed at about 60 atmospheres and 50 ° C.

When the reaction was complete, the catalyst was filtered off and the filtrate was evaporated to dryness. The residue (1.92 g, yield 98%) was crystallized from chloroform to give pure product.

M.p .: 101-103 ° C.

IR: 1670, 1601, 1465, 1410 cm-1.

NMR (CDCl 3): δ $ 1.35 (d, 3H); 1.7 - 2.15 (m, 3 H); 2.50 - 2.90 (m, 1 H); 2.90 - 3.80 (m, 5 H); 4.74 - 5.10 (m, 1 H).

[α] 20 ° c = -114.9 ° (c = 0.835; EtOH 99.8%).

D

Claims (2)

77037 Intermediate (9aS) -hexahydro-4-methylidene-1H, 4H, 5H-pyrrolo [2,1-c] [1,4] -azepine-1,5-dione of formula (III) OY I y dii) CH 2 wherein Y is oxygen or sulfur. The process uses an intermediate according to claim 1 for the preparation of optically pure (4s, 9aS) -hexahydro-4-methyl-1H, 5H-pyrrolo [2,1-c] [1,4] oxazepine-1,5-dione, characterized in that (9aS) -hexahydro-4-methylidene-1H, 4H, 5H-pyrrolo [2,1-c] [1,4] oxazepine-1,5-dione is catalytically hydrogenated in the presence of homogeneous or heterogeneous achiral catalysts such as Pt / carbon, Pt / C, Pd / BaSO 4 or rhodium-triphenylphosphine complex and in an inert organic solvent such as ethanol, dioxane or benzene under a hydrogen pressure of between about 1 and about 50 atmospheres.