DD159069A5 - PROCESS FOR PREPARING N- (ZYCLOALKYL) AMINO SAURER COMPOUNDS - Google Patents

Abstract

The invention relates to a process for the preparation of N- (cycloalkyl) amino acid compounds for d. Use as a medicine, in particular for the treatment of hypertension. The aim of the invention is to provide novel compounds which are suitable as inhibitors of angiotensin converting enzyme. According to the invention, compounds of the formula wherein R 1 is hydrogen or a lower alkyl are prepared; R 2 is hydrogen, acetyl or benzoyl; A is cyclopentyl, cyclohexyl or cycloheptile; m is 0 or 1; p is 1 or 2 and DCHA is dicyclohexylamine or zero.

Description

- J- 18.12.1981

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Process for the preparation of IT-cicycloalkyl-amino acid compounds _; _ ___.

Äjwe Mungsgebiet der_ Brfindung

The invention relates to a process for the preparation of compounds of the invention which are useful as medicaments and which are useful as inhibitors of angiotensin I converting enzyme.

Characteristic eris tics of ^ known technically s solutions

It is known that the decapeptide angiotensin I is converted by an enzyme into the octapeptide angiotensin II, which has potent hypertensive action. It is further known that certain compounds capable of preventing this transformation are suitable antihypertensive agents are"

- ¹ o

There is no information available on which compounds have hitherto been used as inhibitors of angiotensin I converting enzyme.

The aim of the invention is to provide novel compounds which are suitable as inhibitors of angiotensin I converting enzyme.

^r invention

The invention has for its object to provide novel compounds with the desired properties and methods for their

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Find production «

According to the invention N- (cycloalkyl) amino acid compounds of the formula

R ₂ -SC CH ₂ ) _p

AR ₁

DCHA

(D

produced, in which

^il 1

^H 2

P DCHA

Wasserstoff.oder a lower alkyl, hydrogen5 acetyl or benzoyl, cyclopentyl, cyclohexyl or cycloheptyl,

0 or 1,

1 or 2 and dicyclohexylamine or nothing

is.

According to the Invention, the compounds of the formula I are prepared in such a way that

a) a compound of the formula:

Hf ¹ .AHCHCOOH

azylated, in which A and R, have the abovementioned meaning, with an acylating agent of the formula:

X (CH ₂ ) _p

CH

CH

COCI

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wherein ρ and m are as defined above and χ is selected from the group consisting of benzoylthio, azetylthio and bromo, thereby enabling benzoylthio to be put on standby by reaction with potassium thiobenzoate. j

b) optional treatment with dicyclohexylamine and c) hydrolysis of the benzoyl or acetoxy component «

Particularly valuable are the following "/" compounds of formula I:

H-Z3-benzoylthio) -1-oxopropyl / cyclohexylglycine / H-cyclohexy1-N- (3-mercapto-1-oxopruby1) -glycine (_§) - (-) - E "- ^ 3-azecththio) - 1-oxopropyl-7-cyclohexyl3: ylalanine7 C ₁ S) - (-) ~ 1 \ F- / 5-acetylthio) -1-oxo-propyl l7-cyclopentyl alanine N-3- (acetylthio) -1-oxo-propyl 1-lM-cyclohepty! alanine> T- / 5 ™ Bens oylthi o ™ 1 »oxo-propyl l / cyclopentyl-glycine N-Z2- (β-monoethylthio) -1-acetyl-T7-cyclohexylglycine-dicyclohexylamine salt

IT ZL3 ~ A2etylthio) -2- "methyl-1 - oxopropyl7-ii-zyklohexylglyzin-dicyclohexylamine salt

U- / 2- (benzoylthio) azety l / -LT-zy klohexy lglysin H-Z3-benzoylthio) -1-oxopropyl- _S -H "~ cycloheptylglycine; l-cyclopentyl-H- (3-mercapto-1 -oxopropyl) -glycine N-cyclohexyl-jPi- (3-mercapto-2-yl-1-yl-1-oxypropyl) -gly-zine.

Obviously, the compounds represented by the formula (I) exist in diastereoisomeric forms or in recombined racemic mixtures, all of which are to be assigned to the scope of the present invention. "Generally, the stereoisomeric form with the absolute

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S (L) -KoniΊguration prefers «

The compounds are powerful inhibitors of this En-

which I is for the conversion of the decapeptide angiotensin responsible for octapeptide angiotensin II ».Angiotensin II is a powerful blood pressure-enhancing agent _s nonmien from being" that it is the causative agent in some forms of hypertension disease "

Some time already it has been determined that a substance _S which has the ability to ₉ the angiotensin II Bntstehungsweg - ~ to interrupt so the above-mentioned conversion, a useful and effective means of combating associated with that pressor agent hypertension represents "

Thus, the compounds of the present invention have been found to possess remarkable activity in the inhibition of angiotensin I converting enzyme. Thus, invitro techniques for detecting such activity of these compounds are highly useful. For example, these compounds inhibit that from rabbits - lung tissue isolated pure conversion enzyme at levels of about O ₃ O41 _y ^ m to 0 ₃ 24S /> m · So these are significant inhibitors of angiotensin I converting enzyme «

The compounds of the present invention are not limited to in vitro inhibition of their conversion enzyme-inhibiting activity. Upon oral administration, a dose-dependent antihypertensive effect is exhibited in acute aortic coarctation of hypertonic rats as a suspension in O _S 5 % Methocel orally doses of 1 mg / kg to 200 mg / kg administered in these rats cause a reduction in mean arterial blood pressure of 30 mm Hg ₄

The compounds of the present. Invention may exist in a variety of dosage forms such as tablet th ", capsules USWE _s solutions to the appropriate administration are prepared;

13JA11982 * ÖÜM92

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being classic. Excipients and adjuvants with which there is no compatibility. Such dosage forms consist of 10 mg of a compound of formula (I) or one of its salts in a unitary dosage form in accordance with the accepted pharmaceutical practice.

embodiment

In order to make the present invention readily apparent to and understood by those skilled in the art, in the following examples, presently preferred methods of preparing the compounds encompassed by the invention are described.

Example_ I

A. l -cyclohexylglycine

Glycine (37-, 5β $ .O ₅ 5 m) was dissolved in a solution of MeOH (400 ml) and ITaOH (20 g, 0.5 m). To this mixture was added cyclohexanone (49 _s O g, 0.5 m), the resulting mixture was stirred for 0.5 h. Thereafter, palladium was added to charcoal (5 %) (15 g); this was hydrogenated on the Parr Schiller for 6 h. Then, another 0 _{s was} added to 5 m cyclohexanone. The mixture was stirred for 0.5 h and then returned to the Parr shaker for the following 8 h * The catalyst was filtered and the solution was evaporated to a slurry which was then dissolved in .HPO (500 ml), extracted with EtOAc (2 × 150 ml), acidified to pH = 5 with 6 × HCl.

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acidified and finally evaporated to a solid. ». Recrystallization with hot H 2 O yielded 22 g (28%). Melting point 217 · · · · 220 ^° C; R _f -7 / ert - · 0 ₅ 4 (silica gel, CHCl ₃ , MeOH, HQAc: 8.5, '1, O ₉ 0.5).

B. 1- / 3- (Benzoylohlo) -1-oxo-propyl17-N-cyclohexyl-glycine N-cyclohexylglycine (11 g, 0.069 m) was dissolved in 1 % TSaOE (69 ml).

θ '

This solution was cooled to 0 ° C. in an E ± s salt bath. This cooled solution was added dropwise and continuously over 15 minutes to 3-bromopropionyl chloride (11.8 g _. O ₈ O69 Bi) and 2 H HaOH (34 _S 5 ml) added «The resulting. Mixture was stirred at room temperature for 4 '. During this time, to the reaction mixture was added dropwise a solution of potassium thiobenzoate (12 ₉ g, O ₃ O 69m) in H 2 O (69 mL). The stirring was continued overnight The reaction mixture was then cooled in an ice-bath and brought to about pH 2 with concentrated HCl. The crude product was oiled and extracted with EtOAc (3 - 200 mL). The EtOAc extra intions were combined, washed - 2x 150 mL 1 1 H 2 O, 2 × 150 mL R 2) ₉ × 150 mL saturated IaOl and 1 × 150 mL H 2 PO 4 - dried (MgSO 4), filtered and evaporated to an oil. The oil was triturated with hexanes, the resulting white solid was filtered and recrystallized with EtOAc / Hezanen to a yield of 3 <> 8 g; melting point 118 "" 120 ⁰ C; thin layer chromatography. R _f O ₃ 55 (75 J 25 toluene ι _acetic?) IR and electron spin resonance showed structural Stabilität®

Analytical calculation for C ₁₃ H ₂₃ IiO ₄ S; C, 61.87%; H, 6 ^ 63 % \

U, 4 ₅ 01 % Findings: C ₅ 61.91 % \ H ₃ 6 _s 7O %;

The solution of the compound of Example I (4 ^ 0 g ₉ 0 _s 01 m) was stirred in concentrated ammonium hydroxide (15 ml) at room temperature under a nitrogen atmosphere for 4 h. The resulting mixture was filtered and washed with ethyl acetate (4x 50 ml) for disposal of the benzamide lift product® The aqueous phase was washed with concentrated hydrochloric acid

brought to pH = 2 and extracted with 3x 50 ml of ethyl acetate. The ethyl acetate was combined, washed with 100 ml of water, dried (MgSO 4) and evaporated to an oil. This oil was dissolved in 5 ml of chloroform; acetic acid (64: 1: 1)! dissolved and replaced by one with 30 g of silica gel in CHCl: MeOHsHOAc (64s1: 1) filled column (1.5 cm 60 cm χ) passed therethrough Then, fractions of 6 ml _eee 7 warden collected * to The fractions found were pooled and evaporated to an oil ₅ which was triturated with hexanes to a solid. The solid was filtered and dried to yield 0 _s 7 g (30 %) ; Melting point 115 ·.-1-16 ⁰ C; R _f = Oj 5 (silica gel CHCl ₃ IMeOHtHOAc, 64: 1: 1); Electron spin resonance and IE gave structural stability,

Analyte · Calculation for C ^ H ^ ISKKS: G ₉ 53 _s 85j H ₅ 7.81; N, 5 * 71

Findings ι C _s 53,93; H ₅ 7.60; IT ₅ 5 * 53

"") - H "·" j ~ 3 * ~ - (acetylthio) -1-oxopropylJ-IT-cyclohexylalanine

Α «Ir-l'-Cyclohexylalanine

Alanine (22 _S 5 g _s O _s 25.m) was added to a solution of MeOH (4OO ml) and ITaOH (10 g _s O ₅₁ 25 m). Then cyclohexanone (24s5 gs 0.25 in) was added and the was mixture 0 _s 5 vice stirred h! Do was added palladium on charcoal (5%) (7 ₅ 5g), the whole was 4 hours was hydrogenated on the Parr shaker "Ss was the addition of further 0 ₅ 25 m Zyklohexa non j, the mixture was stirred again for 0.5 h and then! fanned a.uf the Parr shaker reset _Φ the catalyst was filtered and the solution evaporated to a slurry, which is now in H ^ O (400 ml) with ₉ BtOAc (33C 100 ml) was extracted and acidified to pH = 6 with β-IT-HCl. The precipitate was filtered off to yield 24 g of dried

Consequence product Melting point 275 "* o280 ⁰ C (dele") * The filtrate was evaporated to half its volume and cooled; the Präzipitaf was filtered to give an additional yield of 9 g Folgeprodukt5 melting point 275e * »280 ° C _e The zvsei yields were added to 33 g (77%) combined ι R _f - O _s 35 (silica gel, CHCl (dec."): MeOH: HOAc; 8.5: 1: 0 _s 5) _e

B. (S) (-) - IT. f3 '"(Azetylthio)« 1 »oxopropyl'] ~ H ~ cyclohexylalanine

LH-cyclohexylalanine (10 g _S O _5, 06 m) were dissolved in pyridine (120 ml) aufgelösts This solution was cooled to approximately 15 ° C, then 3-Azetylthiopropanoylchlorid (3 _s 0 _s sil 10 g, O _S .O6 m ) was added dropwise at a rate which kept the temperature in the range of 15eoo18 C _β Sodajin the ice bath was removed and stirred the reaction mixture at room temperature overnight,

The reaction mixture was added to 140 ml of ice-water, acidified to pH 1 _sec.sup.2 with concentrated HCl and extracted with 3s: 150 ml of ether. The combined ether extracts were washed with 2x100 ml of water, dried over MgSO.sub.y, Darco treated and evaporated to a light yellow oil (mass 9 _S 5 g) _Φ

The oil was dissolved in 20 mL of 5 % HOAc / toluene and passed through a column (2.5 x 60 mm) filled with 150 g of silica gel in 5 % H 2 O / Sfoluen. The product was removed from the column with 5 % HOAc / toluene Fractions of around 7 DiI were collected by means of a collector. The fractions were analyzed by thin layer chromatography (g % HOAc / toluene), the product containing fractions were combined and evaporated to an oil, which was transformed into a crystallizate with Crystallize was recrystallized twice with ITitromethane to yield 2.2 g (12 %) ; Melting point 140 _eee 141 C; Thin-layer chromatography R _f -0.1 (silica gel, & % HOAc / toluene); £ cCJ | ° = -0.4 ⁰ C (0 = 1, MeOH); Electron spin resonance and IR yielded structural stability ₄

Analyta calculation for O..H _,? "HO.S; G ₉ 55 _S 78; H ₃ 7 _? 69; H, 4 ₉ & 5

Findings C _s 56 _S O5; H, 7.88 j H ₅ 4.54

i- (Aze tyl thio) - "

A ₀ LH-cyclopentylalanine

Alanine _(22? G _s 5 O ₉ 25 ra) was added to a solution of MeOH (400 ml) and Haoh (10 ß _f 0 * 25 ei) added ,, then cyclopentanone was {21g, 22 ^ 1 ml, 0.25 m ₃₎ and the mixture was stirred for 0.5 h with stirring uncharged palladium on charcoal (5 % f T $ 5 g); this mixture was hydrogenated on the Parr shaker for 4 h. A further addition of 0.25 m cyclopentanone was taken, the 'mixture was stirred _0? 5 h and then laag Retired on the Parr shaker over Geesthacht ~ _Φ sets The catalyst v? Urde removed by filtration ,, the FiItrat to vmrde © The solution vmrde was evaporated to a slurry acidified HCl to pH = 6 crystallized with isopropanol ₃ | evaporated to a slurry, v dissolved / hich in H 0 (500 ml), ethyl acetate (2iz 150 ml) and extracted with _6]? the Xx'istallisat vmrde filtered and dried and yielded a yield of 3β ₅ 5 g (92%); Schmelzpunlct 240 ° 0 (dek _a) R _f - _g 0 38 (silica gel, GHGl _3: MeOHiHOAc; 8.5: 1 : 0.5) ·

B ₈ (S) (-) ~ ϊϊ ^ [3 "" (acetylthio) - '1 ~ oxopropyl "| -l-cyclopentylalanine

L ~ H-Zyklopentylalanin (9 ', 4 g _s 0 ^ 06 m) was dissolved in pyridine (120 ml) "This solution was cooled to 15 C, then 3-Azetylthiopropanoylchlorid (S _s was 0 ml, 10 g ₃ O ₅ oo m) was added dropwise at a rate _s added "stirred, the ice bath was removed soflann _s the reaction mixture at room temperature over vmrde laugh!" in which the temperature between 15 and 18 ° C kept i / vurde

The Reaktionsgemisoh was mixed with 300 ml of ice water, with

concentrated! ⁵ HCl to a pH value of 1 _β "" leavened 2 and extracted with 3x 200 mL of ether _β The collapsed EMier "extracts were washed with 2x 150 ml of water, dried over MgSO, dried 5, treated with Darco, filtered unfezu an oil a which crystallized on standing. This crystallizate was powdered with cold liter of ether, filtered and recrystallized with ethyl acetate, the yield being .1.8 g (10 %) ; Melting point 123 _i> "* 124 ° 0; R-, «0 _? 19 (silica gel, 9% toluene-acetic acid); [jij_ | gn = '- 0.6 (C = 2 * HOAc); Electronnenespin resonance an "" IR ~ yielded "structural stabilization

yt ... Calculation for C ₁₀ H ₂₁ HO ₄ S: 0 _d 54 _S 33; H 7.37 _s; H ₅ 4.87

"^ Findings · C _s 54 _s 36 s H _{s. 7;!} 32 N ₃ 4.83

Α «, L - (+) <~ H ^ cycloheptylalanine

A mixture of ITaOH (20 ^ 0 g _s 0,, 50 mol) and cycloheptanone (56 _s O gj O ₃ , 50 mol) was introduced into methanol (400 ml), this mixture was stirred for 16 h »Then 15 _s 0 g

5% Pd / G was added, this mixture was exposed to the reaction at 40 psi (initial value) on a Parr apparatus

6 h, 24 psi of the theoretical 34 psi were removed, another 35 g (0.31 mol) of cycloheptanone were introduced, the mixture was allowed to stand for 16 h. The mixture was then catalytically reduced for a further 20 h and a further 13 psi was taken _O

The filtered solution was added to a klaren'Sirup.konzentriert © addition "of water laughing (500 ml) was dissolving, the basic solution was extracted with ethyl acetate (500 ml) _β extracted It began a white _f crystalline solid from the aqueous solution to precipitate The pH was adjusted with concentrated ECI and 1 Έ

HaOH on. The thick mass was filtered, the recovered wet solid was stirred in 2-propanol (500 mL), recovered and air dried (82.3 g »89 / S). A 1.0 g sample was made by suspension in refluxing absolute ethanol (50 ml) and with slow addition of water (30 ml) recrystallised "The hot solution was filtered and left to cool", Is a white solid, melting point above 30O ⁰ ; ^ ⁰ = ¹¹ * ⁸ ° (C = ¹ ? °? 5 H

Analyfc »Calculation for C ₁₀ H ₁₉ IO ₂ SC ₅ 64 ₅ 83? H ₃ 1Oj34; H, 7 * 56

Finding: C ₅ 65.15; H _s 10 ₃ 43; H ₅ 7.29

B ", IT-3- (Azetylthio) -1 - o xo per pyl-li" sykl ohe ρ tyl al anin

Sine solution of 1N HaOH (100 mL), (Sj-I-cycloheptylalanine (18j gj 0 _s 10 m) and water (500 mL) was kept at 5 ° C, while acetylthiopropionyl chloride (13j0 mL, 0.10 m ) and 1 H Haoh (100 ml) tO min across added ^ the mixture was diluted to 800 ml, while the solid wurfte separated from the solution. "latriumazetat _(0? 20 m) was added as a solid ,, were likewise more 0.10M Acid Chloride (13j0m) rapidly introduced. "The mixture was stirred without cooling for 6 hours and then filtered." The filtrate was acidified with dilute hydrochloric acid and extruded with ethyl acetate (2x400ml), the combined extract was water (2x 200 ml) and dried (15gS0.) »

The filtered solution was concentrated to an oil which in a filled with 300 g silica gel column (60 χ 6 cm) using toluene / acetic acid (20s1) was fiert chromatogra-Sluant as "The (at R> 0 ₅ 2 Silica gel, same eluant). ÜY-positive material was collected; Evaporation of the eluant gave a solid which was recrystallized with acetonitrile to give a white crystals of 4 »8 g yield _β The fabric sample was stirred in ether (50 ml) and collected

(4.2g _s 13% yield), m.p. 110.. .111 ⁰ G ₅ />] χ ° _{= Q 1Q} (C s10, dimethylformamide) _e

Analyte, calculation for C ₁₅ H ₂₅ IO ₄ Ss 0, 57.12; 'H, 7 _S 99; N ₅ 4.44

findings; C _s 56 _S 92; H ₃ 8 _s 00; Έ ₉ 4 _? 38

As B - cyclopentylglycine

Glycine (18 _S 75 g _s 0.25 m) was dissolved in a solution of MeOH (400 mL) and HaOH (10 g _s O ₅₁ 25 m). To this solution was added cyclopentanone (22.1 g ₅ 0 _f 25 m). added; the so corresponds * stanäene mixture was O ₅ for 5 hours stirred "After that palladium on charcoal was added (5%) (7 g); dmeses thing? The mixture was hydrogenated on the Parr shaker for 6 h. "Bs was a further addition of O ₅ 25 m cyclopentanone; the mixture was stirred for 5 h over 0 _s and then returned to the Parr shaker with a good laugh »The catalyst was filtered, again an addition of 0.25 m cyclopentanone; the mixture was stirred for 0.5 l, another 7 g of 5% palladium on charcoal was added, then the mixture was hydrogenated on the Parr shaker for 4 h (until the H ₂ uptake was complete). The catalyst then became filtered, which was FII appeared evaporated to an oil "to this oil was added 300 ml HPO _# this resulted in a milky solution containing 200 ml EtOAc was washed with 3 ^ * the pH of the aqueous" phase gave was then treated with concentrated HCl ? to pH ~ / ert of 6 placed, the solution was evaporated to a slurry, "the sludge was treated with isopropanol, the resulting crystals were filtered =, broken in pieces with cold nitromethane, filtered, and (at a yield of 22 ₅ 6 g 63%) dried, TLC showed a major spot R _f, '0.29 and two ITebenflecken R "- 0.38 and 0 _s 51 (silica gel CHCl ,, ₃₅ MeOH, HOAc 8 _s 5S1; 0 5) _®?

J U

H-Zyklopentylglyzin (15 _g? O ₅ 1 m) was dissolved in 1 I IaOH (105 ml, Oj1 m) dissolved j then this solution was _β cooled using an ice bath, the cooled solution was added dropwise and uniformly over 15 minutes of time 3-bromopropionyl chloride (10.6 ml j Ogi in), and 2 I Haoh (52 _S 5 mL) * the reaction mixture was 4 stirred h at room temperature, during which time the reaction mixture was added a solution of Kaliumthiobenzoat _(18? 5 g ₉ 0, 1 m) in 100 ml HgO added drop by drop. "Stirring continues over laughing"

The reaction mixture vmrde in an ice bath chilled and acidified with a 100-ml layer EtOAc with concentrated HCl to pH 2 © -were The layers _S separated and the aqueous layer was extracted with 3x 100 mL EtOAc "The combined EtOAc layers were washed (3x 100 ml 10% HCl ± _ge? 1z 100 ml H ₂ O. 2x 100 ml saturated IACL Ix 100 ml HgO) for _{5 5} with MgSO ₁ j dried with Darco, filtered, and to a tacky Peststoff'eingedampft "This Peststoff was kaitem Bt "Ο powdered _s filtered and dried (mass 7 * 2 g) #

Recrystallization from hot nitromethane afforded pale yellow crystals of Eris, - mass -6., 0.g (18%.); Melting point 151 ··· 152 ° C; Thin-layer chromatography ₉ R _f ~ '0.30 (silica gel, -9 I1 _s toluene-10AOc); IR and electron spin resonance gave structural _stability

Analyte * Calculation for C ₁₇ H ₂₁ HO ₄ Ss C ₅ 60 "88; H, 6.31; ^ ₉ 4 ₅ 18

Findings 0

To a solution of H 2 -cyclohexylglycine (15.7 g. Of _{S 5} O ₅ mol) in 100 mL of 1 N HCl was added dropwise chloroethylacetate (8 _s, 0 mL, .0.10 mol) together with 100 mL of 1: 1 6 hours later potassium thiobenzoate was added (17 ₉ 6 g _s 0 _s 10 mol).

quickly added | the mixture was stirred overnight

Eighteen hours later, the solution was at a pH of 8 «The solution was acidified with dilute hydrochloric acid and with ethyl acetate (200 ml)," The organic layer was washed with water (100 ml) and dried (MgSO,) _β

The concentrated residue was treated with 20: 1 ToluenEssigsäure gel (300 g chromatography Qualitätskieselgel, 60-200 grain size) * The UV positive spot at R _f = 0 _s 05 on the thin layer chromatography-silica gel was isolated _s after first three impurities were dissolved out ". The collected product of R "= 0 _s 05 was dissolved in ether; adding dicyclohexylamine afforded the desired pesticide; Melting point 186 _äeo 188 ° C (8 _S 2 g _s 16% yield) ©

Analysis ₀ Calculation for C ₁₇ H ₂₁ NO ₄ SC ₁₂ H ₂ ^ H: C ₃ 67.41; H ₅ 8,5S;

Finding j C _s 67,40; H ₅ 8 _S 64; N, 5,28

Example VIII

Li-cyclohexylglycine (12g, 0.076m) was suspended in pyridine (150ml). This mixture was cooled to 15 ° C with an ice bath, (+) - 3-acetylthio-2-mercaptopropanoylchloride (13% g, O _s O76 in) was dropwise ben ₃ at a Kate added gege ". the temperature at 15 ⁰ C was kept "The mixture was transferred! Fanned feel room temperature vice touched

The reaction mixture was stirred into 50 ml of bis-water and concentrated HCl under a layer of 100 ml of ether

Gesau to pH 2 ert * The layers were separated _s the aqueous (layer was extracted with 2x 200 ml of ether extracted The ether layers were combined, washed (Ix 150 ml H ₀ O ₅ 3 × 100 ml of 10% HGL, 1x 100 ml H ₉ O , 2x 150 ml saturated HaOl ₅ 1x 100 ml HpO) _5, dried (MgSO.), Treated with Darco, filtered and evaporated to an oil,

The dicyclohexylamine salt was prepared by dissolving the oil (20 g ₉ 0.06 m) in 300 ml of ether ₉ cooling the solution in an ice bath and dropwise addition of dicyclohexylamine (13 ml, ₅ O 06 m) generates (pH S) ₀ It "was formed a Peststoff; this was ₃ rinsed with ether and dried ^ mass 7 filtered j 'recrystallized with acetonitrile _S 5 g (20%) | melting point 134e * _o 135 ⁰ _g;? TLC R _f = 0 38 (Iiieselgel _s 10 % HOAc ^ iolene) IR and electron spin resonance are structurally stable.

AnalyU calculation for C ₁ , H ₀ -HO,

ft TT fiT "ip Q Ο * C ₅ 64 , b9j H, 9 , 61; 5 ₉ 8th Findings: 64 _S 39; H ₅ 9 , 71;

The compound from Example VII (6 _s 0 g, O ₅ 012 mol) was stirred in a mixture of 5% potassium bisulfate (100 ml) and ethyl acetate (100 ml) for 0.5 h. The separated aqueous layer became with ethyl acetate (100 mL) _ä. The combined organic layers were washed with water (100 ml) and dried (MgSO 4) _a

Evaporation, under reduced pressure, yielded a clear oil which crystallized on treatment with hexane (200 ml). The solid was recrystallized from toluene to give 2.6 g (65% yield) ι melting point at 115 .. .117 ⁰ C.

Ό O

Calculation for O ^ JEt ^ HO-S: G ₉ 6O ₅ 88; H ₃ 6.31; H, 4,18

findings; C ₃ 60 _? 8δ; H, 6 _s 25j H ₃ 4 »11

(Benzoylthio) -1 - os: opropyl »H-cycloheptylglycine

Sodium hydroxide (20.0 g _s 0.5 mol) was dissolved in methanol (400 ml) "GIysin (37 _S 5 g _{s 0?} 5 mol) and Zykloheptanon (5β <> 0

gg Oj ₁ 5 mol) warns'zugesetzt, and the / solution ... was!, - O ^ h-long .... __

The solution was stirred on a Parr apparatus with 15 ₉ g of 5% palladium on charcoal (50 % HpO) at an initial pressure of 27 psi. Reduced Hach 2 _s 0 h the theoretical hydrogen number was removed. The mixture was filtered concentrated to a muddy material, then dissolved in water (200 ml) and brought to pH 6 _s 0 with concentrated HCl and 1 liter of 1N NaOH solution. After evaporation, a muddy material remained which was dissolved in 2-propanol (400 ml) was stirred and then air-dried yielded 5490 g (63 %) of crude IT-cycloheptylglycine.

Water (100 ml) and 1.0 1 NaOH (100 ml) were added to 17.1 g (0.10 mol) of the amino acid. The solution was cooled to 10 ^° C. _S methylene chloride (200 ml) was added _. with stirring, the temperature was at 5 * »held ο10 ⁰ C, while 3- (benzoylthio) propanoyl chloride (0 080 mol _s, 1.8,2 g) were added rapidly" To the solution at a pH ~ /? ert of 7 "" _e 8 _? 5 to keepj was 1 _? 0 S HaOH added dropwise; In addition, 80 ml of the basic solution were added over 1.0 hour. Stirring was continued for 20 hours. The solutions were separated. The aqueous phase (pH = 7) was discarded, the organic layer was wet "stored." The organic Lösimg was treated mit'1,0 IT HCl (200 ml), _separated? Washed with water (100 ml) and dried (MgSO -), Evaporation under reduced pressure gave an oily residue »

! zl

The oil was dissolved in ethyl acetate (100 ml); Dicyclohecylamine was added dropwise ^ until moist litmus paper showed a bright green parse. "A light yellow pesticide slowly formed, which was collected and recrystallized with Hct.

The rekristaliisierte Peststoff was Ethylaaetat (100 ml) and 5 conclude KHSO ^ stirred for one hour, -, The separated organic layer was washed with water (100 ml), dried (MgSO.) And evaporated under reduced 'pressure au a Peststoff evaporated " This pesticide was stirred in .Ether (50 ml) and collected j. yielded 2 _S 1 g of secondary product (7 _S 2 %, 4 _S 5 % total) ι Melting point 148 _θ »si 49 C _B A sample was recrystallised by acetonitrile to a melting point of 143 ° C * 151 sv

Analyte Calculation for C, qH ^ -ITO ^ S t C, 62.44; H ₅ 7? 45; IT ^ 3 »83

Findings: C ₅ 62 _S 79; H ₉ 6 _S 93; H ₅ 3 _S 85

TT Ai

BeispJ.el

The compound of Example ¥ 1 (2 g, 0 _s 006 ra) was dissolved in concentrated imnaoniumhydroxid ,, .This solution was stirred for 4 hours at ambient temperature, "The resulting Peststoff was removed by filtration _s, the Piltrat% 'urde with Y / This solution was washed with 3 × 50 ml EtOAc. _β The aqueous layer was then acidified to pH = 2 with concentrated HCl. o The aqueous solution was extracted with 3 × 50 ml EtOAc. The pooled extracts were washed (2x50 ml HpO). ₉ dried (MgSO,), treated with Darco, and evaporated to an oil "After pulverization with hexa" newly of Peststoff was filtered (1.0 g, 72%) \ Schmel.zpun.kt _eee 1O5 1O7 ° _C? ι Duimschichtchromatografie B. _f «0 ^ 5 (silica gel, 25 % HOAc / toluene) j IE and electron spin resonance are struk« ·

-ZP-

turbulent _β

Aaalyfc »Calculation for C ₁₀ H ₁₇ ITO ₃ Ss C, 51» 92; Ή, 7 »41; N ₁ 6.06

Findings: O ₅ 52.08? H, 7.49; N, 6.03

H "3-Asetylthio-2-methyl-1-oxopropyl-N-cyclohexylglycine (1.5 gm of Oj ₁ 005 m) was dissolved in 2 * 6 ml (O ₅ 04 m) of concentrated ammonium hydroxide. This solution was allowed to stand for 4 h The solution was diluted with 50 ml of water and washed with 3 × 50 ml EtOAc; the aqueous layer was acidified to pH = 2 with concentrated HCl. This layer was extracted with 3x50 mL EtOAc. The extracts were combined, washed with 2x50 mL HpO, dried (MgSO 4) and evaporated to an oil <,

After crystallization with hexanes the solid was filtered (0 ₉ 6 gj 46 %) \ melting point, 83 » _Θβ 86 ° 0; Thin Layer Chromatography: R _f - O ₉ 63 (75% toluene / HOAc); IR "and electron spin resonance show structural _{stability β}

Analyte · calculation for C ₁₂ H ₂₁ NO ₃ Ss C ₅ 55.57; H 8.16 _s; U, 5 ₃ 4O

findings; C _s 55 _? 48 ^ E ₉ 8.01; IT, 5.27

Claims (1)

Vf 18,12.1981 AP C 07 c / 230 198/8 58 937 11 invention claim 1. A process for the preparation of a compound of the formula , CH A CH 'COU-OHOO H. DCHA wherein. -. ^: .. JL is hydrogen or a lower alkyl; Rp is hydrogen ₅ acetyl or benzoyl; A is cyclopentyl, zyciohexyl or cycloheptil; m is 0 or 1; ρ is 1 or 2 and BGHA is bizyelohexylamine or Hull, characterized in that a) a compound of the formula; HI AICHGOOH azylated, in which A and R have the abovementioned meaning, with an acylating agent of the formula: _m COCL wherein ρ and m are as defined above and χ is selected from the group consisting of benzoylthio, azetylthio and bromo _s , thereby enabling the replacement of benzoylthio by reaction with potassium thiobenzoate; 18,12.1981 AP C 07. c / 230 198/8 58 937 11 b) optionally treatment with dicyclohexylamine and c) Hydrolysis of the benzoyl or acetoxy component * 2 * Process according to item 1, characterized in that the compound is lf- / 3-BenzoyIthio) -1-oxopropyl / cyclohexylglycine produced * 3 * Process according to item 1, characterized in that the compound H-cyclohexyl-S '(3-mercapto-1-osopropyl) -glycine is produced. 4 »Process according to item 1, characterized in that the compound (S) - (-) -I- / 3-acetyl-1-thio) -1-oxypropyl-7-cyclohexylalanine is produced * 5o method according to item 1, characterized in that the compound (S) - (-) - N- / 3 ™ acetylthio) -1-oxopropy Ij cyclopentylalanine is produced * 6 "method according to item 1 _s, characterized in that the compound 1-3 is prepared (AzetyIthio) -1 -" oxopropy1-N-cycloheptyl alanine " 7, "method according to item 1, characterized in that the compound H- / $ ~ benzoylthio-1-oxopropyIjzyklopentyl ™ glycine is produced * Si. Process according to item 1, characterized in that N- / 2 - (benzoylthio) -1-azetyl-7-cyclohexylglycine-dicyclohexylamine salt is produced »   13 18 "12.1981. , ..... A3? C 07. ο / 230 198 / S 58 937 11 9 "method according to item 1, characterized in that H-Zl '3 - Azety Ithio) ~ 2 ~ me thy 1-1« oxopropy IJ-N-syklohexyl · «· glycine Dizyklohexylainin salt is prepared«. 10 »method according to item I _3, characterized in that the compound I- / 2- (benzoylthio) azetyl7-I» cyclohexylglycine is prepared φ 11 «Method according to item .1, characterized in that the compound U-Z3-benzoylthio) -1-0xopropy-17-JT-syklo-heptyl-glycine is produced * 12 »Process according to 'Item 1, characterized in that the compound ϊί-cyclopentyl-N- (3-mercapto-1-oxopropy1) glycine is produced * 13 * Process according to item 1 _}, characterized in that the compound li-Z.yklohexyl »li ~ (3» mercapto-2 ~ ethyl-1 "oxopropyl) -glycine is produced»