NL8202153A - NEW ENANTIO-SELECTIVE SYNTHESIS OF N-SUBSTITUTED PROLINE DERIVATIVES. - Google Patents

Description

m1 ----

^ -SI

»VO 3394

New enantio-selective synthesis of N-substituted proline derivatives.

The compound of formula 1, wherein X represents a mercapto group, is an inhibitor of angiotensin I to angiotensin XI converting enzyme (ACE). It is commonly known by the name captopril (I®, International Non-proprietary Name) and is used as an antihypertensive agent, particularly for lowering angiotensin-dependent hypertension (see M.A. Anddetti et al.

Science, 196, 44l, 1977j R.K. Eerguson et al, Lancet, 1977, 775; R.C. Heel et al., Drugs, 20, 409, 1910). The compound of formula 1 has been prepared by various methods, but in no case by an enantio-selective synthesis for the chiral thiocarbomycyl group attached to the nitrogen atom of the L-proline nucleus (U.S. Patent 4,046,889; Offenlegungsschrift 2,703,828 European Patent Application 8831; and Japanese Patent Publication 80/09058). Other synthetic methods include a hydrolytic opening of the thiaze-15 pinon ring of the compound of formula 2 (Y = S), as a mixture of the two possible diastereoisomers, which in turn are through a series of non-stereospecific reactions starting from 2- methyl L-prolyl-thiopropanoic acid of the formula IV is prepared using various auxiliary reagents and protecting groups known from the chemistry of the peptides. (U.S. Pat. Nos. 4,192,945, 2-4, and 4,225,495. 2 - 5) However, all these methods require a breakdown of diastereoxomeric mixtures when the racemic ct-methyl / 3- (S-protected) -thiopropionic acid group is introduced into the L-prolination (both with nitrogen atom and the carboxyl function), or arduous separations of the enantiomers of the chiral acid must be performed before coupling to the L-proline.

It has now surprisingly been found that all these disadvantages can be avoided by using readily available chiral intermediates of the formula 3 (Y = S, O) which in the compounds of the formula 2 have an enantio - can be introduced selectively via an asymmetric induction of the Cg-chiral center of the L-proline piece. The new chiral center of the compounds of the formula II preferably or even exclusively has the S configuration.

In formula 3 shown above, the pro-chiral stretch, i.e. the carbon-carbon double bond, is indicated by a dotted circle, while the inducing chiral center is indicated by a continuous circle line.

As far as compound 3 is concerned, the pro-chiral piece undergoes a stereospecific hydrogenation of the less sterically hindered

M

the Qf side, giving rise to the compounds of formula 2 (Y = 0, S) (for a more extensive study on the very diastereospecific endo and exo-cyclic hydrogenation of double bonds in six-rings see JPVigneron et al ., Tetrahedron Letters, 5681, 1968; V. Sunjic et al., J. Org. Chem., * 3, 1355s 1978 and J. Org. Chem., 1, 23, 1979)

The compounds of formula 2 are valuable chiral intermediates which make it possible to prepare the compounds of formula 1 in one step when Y is sulfur in the compounds of formula 2; this conversion thus constitutes the shortest and most economical chiral preparation of the compounds of formula I, wherein X = SÉ,. t.w. captopril. When in the compound of formula 2 Y is oxygen, its conversion to compound 1 (X = SH) first involves a tosylation reaction followed by a nucleophilic introduction of the mercapto group.

This latter reaction, although requiring two additional steps, also has clear advantages in terms of chiral economy, since all intermediates are obtained in high yields and are easily isolated.

The invention is further elucidated by means of the following examples.

Example I

(9 aS) -hexahyor o-U-me thylydene-ΙΗ, UH, 5H-pyrrhene / "* 2,1-c-7 - / * 1,1 * -oxaze-pine-1,5-dione.

2.62 g (0.01 mol) of N - (--bromo) -methyl-acryloyl- (S) -proline, 82ΌΠ53 ----------- 3 - 3 - was dissolved in 30 cm of methanol and the solution obtained endowed dropwise at 0 ° C with a solution of 0.56 g (0.01 mol) KOH in 20 cm 3 of methanol. After distilling off the solvent in vacuo at room temperature, the resulting residue was dissolved in 20 cm @ 3 of methyl formmid, this mixture was heated at 0 ° C for 6 hours and the dimethylformamide distilled off. The residue was taken up in 50 ml of water and this water-3. phase extracted with 3 x 50 cm ethyl acetate. The organic extracts were dried with sodium sulfate, the solvent was distilled off and 1.7 g of an oily residue were obtained, which was then hydrogenated. Infrared spectrum (film): characteristic absorption bands at the following frequencies in cm ”: 2980, 1720, 16 ^ 0 and 1590.

Example II

* ..............

(9aS) -hexahy dro-U-methylidene-1H, 4I, 5H-pyrrole 2, l-c-7-ZT1 sb, 7-oxaze-pine-1,5-dione.

15 3.93 g (0.015 mol) (9aS) -hexahydro-Bromomethyl-1H, 5H-pyrrole-C2,1-c J-jT 1, b J7-oxazepine-1,5-dione and 1.0 g lithium bromide dissolved in 20 cm-3 HMPTA (hexamethylene phosphor triamide) was heated at 120 ° C for 4 hours. After distilling off the solvent in vacuo, the resulting *3 residue was dissolved in 20 cm of water, this aqueous phase saturated with sodium chloride 20, the pH adjusted to 1 with concentrated hydrochloric acid and the whole extracted with 3 x 20 cm of ethyl acetate. The organic phases; ; collected, the ethyl acetate distilled off and the residue obtained recrystallized from diethyl ether. Yield 2.33 g (86 # of theory) of the title compound.

Example III

(9aS) -hexahydro-1-methylidene-1H, 1H, 5H-pyrrole 2,1 2.1-0 ^ 7- ¾ 19 ¾-oxaze-pine-1,5-dione.

From 26.6 g (0.1 mol) of the potassium salt of N- (3-bromo) -methyl-aeryloyl- (S) -proline, prepared according to example I and using dimethyl sulfoxide as solvent for the cyclization, ΐβ, β g (92 #) of the pure title compound obtained, purified and passed over a column of silica gel with the elution system ethyl acetate / methanol 9: 1 · Example IV

(bS, 9aS) -hexahydro-1-methyl-1H, 5H-pyrrole-2,1-c-7-Z-1-7-oxazepine-1,5-dione.

- & 2-Ö-2T5 3 --——---- - 4 - 0.9 g (0.005 mol) (9aS) -hexahydro-4-methylidene-1H, 4I, 5H-pyrrol-^ 2,1 -C7-7.1-7-oxazepine-1,5-dione was dissolved in 50 ml of ethanol and it was catalytically hydrogenated at atmospheric pressure and room temperature using 0.2 g of Pd / carbon as catalyst. The hydrogenation ended after 8 hours to yield 0.9 g (98%) of the title compound.

Example V

(4S, 9aS) -hexahydro-4-methyl-1H, 5H-pyrrole-T 2,1,1-7-Z * 1,4,7-oxazepine-1,5-dione.

10.9 g (0.005 mol) of (9aS) -hexahydro-4-methylidene-M, 4H, 5H-pyrido -C2 1,4-oxazepine-1,5-dione was hydrogenated in 200

O

cm 2 of benzene at 6 at 24 hours at room temperature using 200 mg of RhCl 3 PPH 4) as catalyst obtained from 1.2 g of triphenylphosphine and EhCl 2 -SHgO (0.1 g) according to Osborn in J. Chem. Soc. (A), 15, 1711, 1966.

j

After filtering, distilling off the solvent and crystallizing from ethyl acetate, the desired end product was obtained in an enantio-selectively pure form. Yield 0.82 g (91%) - Nuclear Magnetic Resonance Spectrum (CdCl 3): 1.42 ppm (3.3 H); no peak cleavage was observed after addition of an optishift reagent. Elemental analysis for C 1 H H NO N (mg = 183.21) calculated: C 59.00, H 7.15, N 7.64%; found: C 59.05 »H 6.91, N 7.88%.

Example VI

25 Ν- / Γ (2S) -3-mercapto-2-methylpropionylJ- (S) -proline.

• 3.98 g (0.02 mol) (4s, 9aS) -hexahydro-4-methyl-1H, 5H-pyrrole-C2,1-c-7- / T1 »4 J7-thiazepine-1,5-dione was dissolved in 15 ml of a 5 N solution of ammonia in methanol and stirring this solution under a nitrogen atmosphere for 3 hours at room temperature. After distilling off the solvent in vacuo, the oily residue was recrystallized from a mixture of ethyl acetate / n-hexane to 3.73 g (86%) of the title compound in an enantio-selectively pure form. Mp. 104-105 ° C. j = -134 ° (c = 1.6 in ethanol).

Elemental analysis for C 1 H H NO N (mg = 217.18) calculated: C 49.73, H 6.96, N 6.45%; found: C 49.81, H 6.74, N 6.59% »8202153 V '- 5 -

Example VII

N-Z ”(2S) -3-merc apt o-2-methylpropionyl-7- (S) -proline.

1.99 g (0.01 mol) (US, 9aS) -hexahydro-k-methyl-1H, 5H-pyrrole-C 2, 1-c 7- / T 1, 7-thiazepine-1,5-dione was dissolved in a mixture of 3-3-8 cm of water and 12 cm of concentrated ammonia, after which the resulting solution was stirred at 0 ° C for 2 hours under a nitrogen or atmosphere. After diluting with water and filtering off insoluble material, the filtrate was extracted with ethyl acetate, the aqueous phase adjusted to pH 1 with concentrated hydrochloric acid, saturated with sodium chloride and re-filtered.

O O

Extracted with 120 cm3 (3x0.0 cmJ) ethyl acetate. The organic extracts were combined, the solvent distilled off and the resulting residue crystallized from ethyl acetate / n-hexane. Yield 1.78 g (82%) of the title compound with Smp. 102-10l; oC.

Example VIII

15 v N- (2S) -3-hydroxy-2-methyl-propionyl-7- (S) -proline.

7.32 g (0.04 mol) enantiomerically pure (i + S, 9aS) -hexahydro-4-methyl-1Ξ, 5H-pyrrole- / 72,1-c J-C1, H „7-oxazepine-1, 5-dione, obtained as described in Example V or VI, was dissolved with 50 cm of methanol and treated at 0 ° C with a solution of 2.35 g (0.0 ^ 2 mol) Κ0Ξ in 50 cm ^ 20 ethanol. After adjusting the pH to 1 with concentrated hydrochloric acid and saturating with NaCl, the aqueous phase was extracted with

O

3 x 50 cm ethyl acetate. Upon crystallization, 7.15 gb (89%) of tannophene was obtained chemically and enantio-selectively pure title compound.

Element air analysis for C H 2 NO N (m. G = 201.22) calculated: C 53.72, H 7.50, N 6.96 #; found: C 53, 9, H 7.36, N 7.08.

Example IX

(- (2S) -3-p-toluenesulfoxy-2-methylpropionyl-7- (S) -proline.

To a solution of H-C (2S) -3-hydroxy-2-methylpropionylJ7- (S) -

30 proline (2.01 g, 10.0 mmol) in 12 cm 3 anhydrous pyridine, which is at 0 ° C

was cooled, 2.09 g '(11.0 mmol) of p-toluenesulfonyl chloride was added portionwise. The reaction mixture was kept cold in ice overnight, then 50 cm of water added, the pH adjusted to 3 with concentrated hydrochloric acid and extracted with 3 x 50 cm of ethyl acetate. The organic extracts were washed with 5% hydrochloric acid to give an oil 8207153 "- 6 -

which crystallized on addition of ether. Yield 9k% or 3.3 ^ g. Example X.

C-C (2S) -3-mercapto-2-methylpropionyl-7-S-proline.

To a solution of 1.77 g (5.0 mmol) N- / 7 (2S) -3-p-toluenesul-5-phoxy-2-methylpropionyl_7- (S) -proline in methanol / HgO (3: 1; 10 cm 2) 2.0 g NaSH was added. The reaction mixture was stirred under nitrogen at 20 ° C for 1 hour, then at 50 ° C for 3 hours. * The reaction mixture was ... partially evaporated and 20 cm more water added. The pH was adjusted to 1 with o concentrated hydrochloric acid and the mixture was extracted with 1 x 20 cm @ 3 ethyl acetate. The organic extracts were dried with sodium sulfate and the solvent distilled off. The crude residue (1.09 g; quantitative) was recrystallized from EtOAc / n-hexane to yield a product, mp 102-103 ° C, -130 ° (c = 1.1, EtOH).

15, Example XI

f ° C- (N-tert-butoxycarbonyl-S-prolyl) -thiomethacrylic acid.

To a cooled solution of 1.08 g (5.0 mmol) N-tert-Boc-S-

O

proline and 0.505 g (5.0 mmol) of triethylamine in 10 cnr of absolute THF

O

a solution of 0.5 µg (5 * 0 mmol) ethyl chloroformate in 5% abso-20 l of THF was added dropwise. After stirring for 1 hour at room temperature, the triethylamine hydrochloride formed was filtered off and the filtrate added to a cooled solution of 0.28 g (5.0 mmol) NaSH in 10 cm absolute THF. After stirring for 30 minutes, a solution of β-bromomethacylic acid (0.82 g, 5.0 mmol) and 0.505 g of triethylamine 3 m 10 ml of methanol was added. After stirring for 2 hours at room temperature, the pH was adjusted to 5 and the reaction mixture was evaporated to dryness. The residue, 3, was dissolved in 50 cm H 2 O and extracted with 3 x 50 cm methylene chloride, after which the organic extract was dried with sodium sulfate and evaporated to dryness. The resulting oily residue (1.6 g; quantitative) was used without further purification as described in Example XEX. A pure sample could be obtained by chromatography on silica gel with AcOEt-EtOH 8: 2 as an eluent. After crystallization from ether, the melting point was 85 - 86 ° C.

IE: 2980, 1725, 1690, 16U5, 11HO and 1370 cm-1.

Elemental Analysis for C H 2 NO N S (315.39) 8202153; \ \ \ -7-.

calculated: C 53.32, H 6.70, IT k9kk% \ found: C 52.97, H 6.80, H Example XII

oC - (s-thioprolyl) -methacetic acid hydrobromide.

The H-Boc derivative obtained as described in Example XI

O O

(1.0 µg) was dissolved in 9 cm glacial acetic acid and 1 cnr KB% hydrogen bromide in acetic acid was added dropwise. After stirring for 2 hours at room temperature, 20 cm of toluene was added and the solvent was distilled off. The oily residue crystallized on addition of .10 acetone and was recrystallized from acetonitrile. Mp. 167-168 ° C.

IE: 3380 (wide band), 2600 - 3100 (wide band), 1T08, l680, 16 ^ 2, 1535, 1385 cm "1. *

Elemental Analysis for C 1 -H-NO-BrS (269.19) Calculated: C 36 ^ 9, H U, 76, ff ^ 72JE; 15 ‘found: C 36.66, H ^ 96, N k939%

Example XIII

(9aS) -hexahydro-1-methylidene-1H, UH, 5H-pyrrole-IT 2, 1-cJ 7 "Z" 1, 1, J 7-thiaze-pine-1,5-dione.

A solution of 2.15 g (10.0 mmol) <K- (S-prolyl) -thiomethacryl-3 · 20 acid m 100 cm dichloromethane was added dropwise to a solution of 2.10 g (11 mmol) dicyclohexylcarbodiimide and 1 , 3¾ g (11.0

O

mmol) ^ dimethylaminopyridine in 150 ml of dichloromethane. After stirring for 12 hours at room temperature, the precipitate formed was filtered off, the filtrate evaporated to dryness and the oily residue purified on a column of silica gel with ethyl acetate as eluent. The pure product (1.1 g; 78 / ¾) was obtained as a glassy solid which was not crystallizable.

IE: 2880 - 2980 (multiplet), 1700, 1630, 1520, 815 cm "1.

ÜV (i x 10 "^ M / MeOH) Λ: (£): 220 (6800).

max. 30 Elemental analysis for C 1 H H Hg 5 (197.26) calculated; C 5¾, 82, H 5.56, H 7.10; found: C 5 ^ 60, H 6.01, N 6.88 $.

Example XIV

(9aS) -hexahyr dro-h-thy thy-1H, 5H-pyrrole- / 2,1,1-C 7- / 1,5-thiazepine-1,5-dione.

—Xittfrtry ------ V \ * - 8 -

To a solution of (9aS) -hexahydro-1 * -methylidene-1H, 1H, 5H-pyrrole-2,1-ci <7-1,1,1 * J7,1-thiazepine-1,5 -dione (1.16 g, 6.0 mmol) in

O

ethanol (1 * 0 cm) was added 0.6 g palladium on charcoal and the hydrogenation reaction was carried out at about 60 at and 50 ° C. After the reaction was completed, the catalyst was filtered off and the filtrate evaporated to dryness. The residue weighed 1.92 g (98 $) and was crystallized from chloroform to give the pure product, mp 101-105PC.

IR: 1670, 1601, 11 * 65, 11 * 10 cm ”1.

10 NMR (CDCl 3): f 1.35 (d, 3H); 1.7-2.15 (m. 3H); 2.50-2.90 (m, 1H); 2.90-3.80 (m, 5H); 1 *, 75 - 5.10 (m, 1H).

-ll! *,? ° (c 0.835; Et OH 99.8 #). * --- r? o rrsz -------

Claims (5)

Process for preparing compounds of the formula 1 of the formula sheet, wherein X represents OH, SH or a p-toluenesulfonyl group, characterized in that the CO-Y bond of compounds of the general formula 2, wherein Y is oxygen or sulfur, with be. Aid of aqueous sodium hydroxide, ammonia, potassium hydroxide in methanol, ammonia in methanol, dissolving in mineral acids mixed with solvents or solvent systems selected from what is stripped / methanol and water / dioxane or the like. 2. Process according to claim 1, characterized in that the reaction 10 is carried out at a temperature between 0 ° C and the boiling temperature of the reaction mixture, preferably between 0 and 20 ° C * * 3. Process according to claim 1 or 2, characterized in that the isolation of the enantiomerically pure compound of formula 1 (X = SH) is carried out by crystallization from ethyl acetate, diisopropyl-15 ether, acetone, n-hexane, acetonitrile, dioxane or mixtures thereof. Process for the preparation of optically pure (^ S, 9aS) -hexa -hydro-i -methyl-1H, 5H-pyrrole-Z "2, lr-c_7" Z "i - ^ - 7" oxazepine-1 5-dione, characterized in that (9aS) -hexahydro-1-methylidene-1H, 5H-pyrrole- / 72,1-c Jl 1 J-oxazepine-1,5-dione is catalytically hydrogenated at presence of homogeneous or heterogeneous achiral catalysts in the form of Pd / carbon, Pt / C, Pd / BaSO4, rhodium triphenylphosphine complexes and the like, in inert organic solvents in the form of ethanol, dioxane, benzene and analogues , under a hydrogen pressure between 1 and about 50 at. 25 5 · The compound (9aS) -hexahydro-V-methylidene-1H, te, 5H-pyrrole-C 2,1-c J-L1 «7-oxazepine-1 , 5-dion. 6. The compound (9aS) -hexahydro-k-methylidene-1H, te, 5H-pyrrole-2,1-cJ-Γ1,6,7-thiazepine-1,5-dione. 7 * The compound (, 9aS) -hexahydro-1-methyl-1H, 5H-pyrr-O- / l2,1-C-7 30 / T1, -7-oxazepine-1,5-dione. 8. The compound y ^ '- dibromo-isobutyl-isj-thioproline. 9. The compound H- {/ $ -bromomethylacryloyl) - (S) -thioproline, 8.