NZ216215A - Certain tricyclic aminoacids - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £16215 NO DRAWINGS I • . r Oh-.QJL \Hi-85 OOlo^qq |$g i : . . 3 OMAR 1988 f',c: l.3CXo NEW ZEALAND Patents Act 1953 216215 la:; on C r 'V J Spccificr.cicn hss been ance-dated] CO Inltials N.Z. No.

COMPLETE SPECIFICATION •NEW TRICYCLIC AMINOACIDS AND PROCESSES FOR THEIR PREPARATION" We, HOECHST AKTIENGESELLSCHAFT, a corporation organized under the laws of the Federal Republic of Germany,Of D-6230 Frankfurt/Main 80, Federal Republic of Germany, do hereby declare the invention, for which we pray ^ that a Patent may be granted to us, and the method by which it is to be performed,to be particularly described in and by the following statement:- 1 216215 The present invention relates to compounds of the formula H co2w H 11 CIII) in which A denotes -CH=CH- or -CH^-CH^- and W denotes hydrogen or a radical which can be split off under acidic, basic or hydrogenolytic conditions, in particular a tert.-butyl or benzyl radical. These compounds are useful for preparation of the derivatives of tricyclic amino acids (described and claimed in Patent Specification No. 206236, the disclosure of which is incorporated herein by reference).

The invention relates to compounds of the formula III in which the H atoms on C-2 end C-6 are in the cis~configuration relative to one another, the pyrrolidine ring is orientated in the endo- or exo-position relative to the bicyclic ring system, the group -COgW on C-4 is i ri the cis- or trans-position relative to the hydrogen on C-2, W denotes hydrogen or a radical which can be split off under acid, basic or hydrogenolytic conditions and A denotes a -CH=CH- or -CHj-CHj- group.

These compounds are used according to the inven-ion es starting substances in t!ie synthesis of compounds escribed and claimed in Patent Specification No. 206236 and can be prepared, according to the invention, by the following procedure: 2 16215 In one synthesis variant, a compound of the V*L in which the hydrogen atoms on C-2 and C-6 are in the cis-configuration relative to one another and the cyclo-pentanone ring is orientated either in the endo-position {formulae IX a and b) or in the exo-position (formulae X a and b> relative to the bicyclic ring system, is used as 10 the starting substance.

The compounds of the formulae IX a and X a are known from R.R.Sauer, J. Org. Chem. 39, 1850 (1974), end the compounds of the formulae IX b and X b are described in J. Org. chem. 32, 3120 (1967).

The ketones IX and X are converted by known methods into the oximes or oxime derivatives of the formula XI , Jjiammanfta : r -■ - ■*■*• O 2 16215 (XI) H N ^OR3 1n which the H atoms on C-2 end C-6 are in the cis-configuration relative to one another, the cyclopentane ring is orientated in the endo- or exo-position relative 5 to the bicyclic ring system, A denotes a -CH=CH- or -C^-CHj-group and r' denotes hydrogen, alkyl, aryl, aralkyl, -SO3H, arylsulfonyl or another group suitable for Beckmann rearrangement. is preferably hydrogen, <Cj to C^-slkyl, (C^ to Cp)-aryl, (Cy to C^q)-10 aralkyl, SOjH, ben2enesuIionyL or p-toluenesuIfonyI.

The compounds of the formula XI are converted into a compound of the formula X12 (XII) in which the H atoms on C-2 and C-7 are in the c i s-15 configuration relative to one another, the lactam ring is orientated in the endo- or exo-position relative to the bicyclic ring system and A has the abovementioned meaning, in a Beckmann rearrangement, cf. Organic Reactions 1_1_ (1960) 1-156, by reaction with e mineral acid, 20 such as, for example, sulfuric acid or po lyphosphoric acid, or, if r' denotes H, with benzenesulfonyl chloride or p-toluener.ulfonyl chloride and e base, ruch ar tri- 216215 - 4A - ethylamine, or with an organic acid, such as, for example, formic acid. The regio-isomers which arise after the Beckmann rearrangement can easily be removed by recrysta11ization or by column chromatography over silica gel. The compounds of the formula XII are halo-genated to give a compound of the formula XIII € H Hal rvS lxiin i H in which A has the abovementioned meaning and Hal denotes a halogen atom, preferably chlorine or bromine. Exaxples of suitable halogonating agents ore inorganic acid halides, such as PCI5, SOjC I j>, POCI3, SOClj and PBrj, and halogens, such as bromine. It is advantageous to use PCI5 or POCI3 in combination with SOjjClg.

An imide halide is first formed as en inter mediate, and then reacts further with the halogenating agents mentioned and by subsequent hydrolysis under basic conditions, preferably with aqueous alkali netal carbonate, to- give a compound of the formula XIII.

The compounds of the formula XIII are subsequently catalytica I ly rcduced in a polar protic solvent, such as, for example, an alcohol, preferably ethanol, or a tarboxy-lic acid, such as, for example, acetic acid, with addition cf an acid acccptor, such as, for example, sodiun f - acctatc or triethylemino, to give a cohc l| A* ! formula XIV 9, i 216215 H (XIV) H H in which A and Hal have the abovenentioned meanings. Examples of suitable catalysts are Raney nickel and palladium- or platinum-on-animaI charcoal. 5 If A denotes -CH=CH-, it is necessary to protect the C-C double bonds via a eyelopentadienyl-iron dicarbonyl complex of the formula XV. The iron complex is split off again with Na in acetone after the hydrogenation, as described in J. Alter. Chem. Soc. 97_, 3254 (1975) K.M. 10 Nicholas.

CO I Fe I CO <2> BF e> Jlal 'Hal (XV) Compounds of the formula XIV can also be prepared directly by halogenation of the compounds of the formula XII using smaller amounts of the abovenentioned halogenat- i ng agent s .

Compounds of the formula XIV are converted into a compound of the formula III in which W denotes hydrogen ~Uf "jl h e known Favorskii reaction in the presence of a #"•*£ ft ' in a manner knewn per se base, and* where relevant, the product is esterified/ 20 ojfh^ abovernent i oned Favorskii reaction is carried out in "2 9MAY1987 /an ia I coho I i c solvent, such as methanol, ethariol or tert.- j butanol^ or in w?ter or mixtures thereof ?t temperatures 2162 15 — 6 • in the range from 20°C to 140°C, preferably between 60°C and 100°C. Alkali metal or alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal alcoholates, such as, 5 "for example, sodium methylate or potassium tert.-butylate, are advantageously used as bases. denotes hydrogen which are obtained by the Favorskii reaction arc racemates, and can be obtained in the form 10 of a diastereomer mixture. Thus, starting from the ketones of the formula IX, the aminoacids of the formulae Ilia and Illb together with the mirror image isomers are obtained, and starting from the ketone of the formula X, the efircacids of the formulae IIIc end II!d end the 15 associated mirror image isomers are obtained, W denoting hydrogen and A having the above meaning.

The compounds of the formula III in which W (Ilia) (Illb) Ay. C02VJ (IIIc) C02ltf (Hid) a r> 7 ' 216215 The hydrogen atoms on C-2 and C-6 arc in the ds-configuration relative to one another 1n all four compounds of the formulae llla-IIId; In compounds of the formulae Hla and Illb, the pyrrolidine ring is orientated 5 1n the endo-pos1tion relative to the bicyclic ring system and in the formulae IIIc and Hid, the pyrrolidine ring 1s orientated in the exo-position, the -COjW groups on C-4 in the compounds of the fornulae Ilia end Illd are orientated In the cis-position relative to the hydrogen • 10 atom on C-2, and in the compounds of the formulae Illb and IIIc these groups are correspondingly In the transposition. In the following reactions, the corresponding racemates or diastereomer mixtures can be used. The first racemates can alsoTbe separated into the optical anti- podes by known methods of peptide chemistry, and the di-mixtures into the diasterecmers astereomer I can be separatedTby fractional crystallization, or by column chromatography over silica gel as diastereo- mers or after formation of suitable derivatives.

If desired, the aminoacids can be esterified in a manner known per se.

The preferred tert.-Lutyl esters and benzyl esters of the ami noacids of the formula III (W denotes tert.-butyl or benzyl) are obtained by the conventional methods of peptide chemistry, such as, for example, in the case of the tert.-butyl ester, by reaction of the acids with iso-25 butylcne in an inert organic solvent (for example dioxane) in the presence of acids (such as, for example, sulfuric acid). If A denotes -CH=CHr,the following process has -Mjgjfed to be particularly edvantaoeous: the correspond- .I i ng ' ami no* r i d is scylated on the nitrogen with f» group - 8 - 216215 which can be split off under basic conditions, such as, lor example, the 2-methylsulfonyl-ethoxycarbonyl group <= KSC), Tesser, BaIvert-Geer6, Int. J. Pept. Protein Res. 7, 295 (1975).

The carboxylic add is reacted with tert .-butanol in the neutral to weakly basic pH range in an organic solvent, such as, for example, pyridine, in the presence of propyIphosphonic acid anhydride to give the corresponding tert.-butyl ester. The tert.-butyl ester of the formula III (V denotes tert.-butyl) is obtained by splitting off the HSC protective group with an alkali in the strongly alkaline pH range in an aqueous solvent.

The configurations of the intermediates on the bridge head C-2 and C-6 are In each case retained in the reactions described above for the preparation of the coa-pounds of the formula Illr The compounds of the formula III obtained according to the procedure described above are obtained as a mixture and can be separated from one another by, for example, recrysta11izat ion or chromatography.

The compounds of the formula III are obtained as racemic mixtures.

However, after separation of the racemates into the optical antipodes by conventional methods, for example by salt formation with optically active bases or acids, they can also be used as pure ena'nt ioroer s. The pure enant i on*® r 5 csri plso be obtained. 'i )' 2162 1 5 The examples which follow tfrve to illustrate the Invention, without restricting it to the compound* mentioned as representatives.

A Unless indicated otherwise, the H-NI-lf! data given in the examples which follow were determined by measure-v l«ent in CDCI3 and ere given in S (ppiO .

Fxairple ] 3-[fl- d-S-Carbethoxy-S-phenylpropyU-S-alanyU-lR^R^S^S, 7S-tricytloC5.2.1 .0^*^3-3-a2a-o'ecane""A-carboxylic acid hydrochloride •j 7 a) CO Endo-1 r i cy c I0C6 . 2. 1 .0 * 3-3-aza-A-oxo-undccane 7.8 g of ( + ) endo-t r i eye IoC5 .2.1 .0^ *'3-3 -0>.o-decane (Journ. Org. Chem. 32, 3120, 1967) are dissolved in 52 ml of 95X strength formic acid. 9.1 g of hydroxylamine-0-sulfonic eci d, dissolved in 26 ml of 95X strength forric acid, are added dropwise thereto in the course of 10 tainutes. The nixture is then boiled under reflux for 2 2162 1 5 hours. After cooling, ice Is added, and the mixture Is neutralized with concentrated sodium hydroxide solution, with ice-cooling. The mixture is extracted with methylene chloride and the extract is washed with water, dried 5 and concentrated on a rotary evaporator. Crude yield: 7.4 g of mixture. The mixture, which is composed of endo-1ricyc lot6.2.1,0C• 3-3-aza-4-oxo-undecane and endo- 2 7 tricycloC6.2.1.0 • D-4-aza-3-oxo-undecane is separated into its components ovr silica gel with methylene chloi— 10 1de/methanoI 95:5.

Yield: 4.5 g; melting point: 170°--172cC b) (O Endo-tricycloC6.2.1.0^*^D-3-aza-4-oxo-5,5-di-chloro-unoecane 4.5 c of the lactar from E.ra^pte la ere dissolved 15 in 70 ml of anhydrous chloroform, and 5.6 g of phosphorus pent ach I oride are added at room temperature, while stirring. 7.8 g of sulfuryl chloride in 8 ml of chloroform are added dropwise to this mixture in the course of 30 minutes, and the fixture is then refluxed for 3 hours. 20 Thereafter, it is rendered neutral with saturated pot a s-sium carbonate solution, while cooling. After the chloroforn phase has been separated off, the aqueous phase is extracted with methylene chloride and the organic phases are combined, washed with water, dried and 25 concentrated in vacuo. The crude product is filtered over silica gel with methylene ch I o r i de/rue t h sno I 95:5.

Yield: 3.7 g; melting point: 199-200°C 216215 - 11 ~ c) (♦> Endo-tHeye lcC6.2.1.02*^3-3-aza-4-oxo-5-chloro-undecane 2.9 g of the dichlorolactan from Example 1b and 1.7 ml of triethylarnine are dissolved in 170 ml of ethanol. About 0.7 g of Raney nickel is added thereto molar, and hydrogenation is carried out. After l^equi valent of hydrogen has been taken up, the hydrogenation is interrupted, the catalyst is filtered off with suction and the ethanol solution is concentrated in vacuo. The residue 10 is taken up in ethyl acetate and the mixture is. washed with water, dried and evaporated. The residue is separated into its components over silica gel with methylene chIoride/metha no I 95:5.

Yield: 1.7 g; melting point: 179-181°C d) 1:1 mixture of 1 R ,2R , 4S,6S> ,7 S-1 r i cy c loC5 .2.1 . D2 ' -3- aza-decane-4-carboxyIic acid and 1S,2S,AR,6R,7R-tri- cycloC5.2:1 .02*^D-3-aza-decane-'»-carboxylic acid 1.3 g of the monochlorolactam from Example 1c are added to a boiling solution of 2.2 g of barium hydroxide octahydrate in 39 r. I of water. The nixture is refluxed for 4 hours and tlien adjusted to pH 6.5 with concentrated sulfuric acid and refluxed for 1 hour. After cooling, the precipitate is filtered off with suction. The mother liquor is concentrated to dryness and the residue is crystallized from ethyl acetate.

Yield: 1.1 g; Rf: 0.61 (Si02; CH2Cl2 / CHjOH / CH3C02H / K20 20:15 :2:A> According to the ^H-NMR (270 KHz), a small amount 2 6 of 1S,2s/AS,6R/7R-trieye loC5.2.1.0 ' 3-3-azc-decane-4- Q . 12 . 216215 carboxylic acid and 1R,2R,AR,6S,7S-tricycloC5.2.1.02,6D-3-az a-decane-A-c a r bo xy I i c add, which can be separated off, are formed. e) 1:1 mixture of benzyl 1 R,2R,AS,6S,7S-t r i eye lo-C5 .2.1 . 5 0 • 3-3-aza-decane-A-carboxylate hydrochloride and benzyl lS,2S,AR,6R,7R-tricycloC5.2.1,0^*^D-5-aza-decane-A-carboxyI ate hydrochloride ml of benzyl alcohol are cooled to -5°C and 1.7 g of thionyl chloride are added dropwise. 1.1 g of 10 the racemic aminoacid from Example 1d are added to this solution. The mixture is allowed to come to 0°C and is stirred at 5 ° C for 17 hours. The benzyl alcohol is distilled off in vacuo and the residue is triturated with di i scpropyI ether.

Yield: 1.1 g 1H-NMR (I>r.S0-d6): 1.0-3.0 (n>, 5H), 3.2-A.8 (m CH) 5.2 (s, 2H), 7.A (broad s 5H) and 9.2-10.5 (broad, 2H) f) Benzyl3-{N-< 1-S-carbethoxy-3-phenylpropyl)-S-alanyq-lR,2R,AS,6S,7S-tricycloC5.2.1.0^*^3-3-aza-decane-A- carboxylate 0.96 g of N-(1 -S-carbethoxy-3-phcnyIpropyI)-S-alanine, 0.A6 g of l-hydroxy~lH-bcrizotriazole, 1 g of the benzyl ester -from Example 1e, 0.7 g of dicyclohexylcarbo-diimide and 0.A y of N-et hy I rr.o rpho I i ne are added succes-25 sively to 10 ml of anhydrous dimethyIformamide, with ice-cooling, and the mixture is stirred at room temperature fop 17 hours. It is then diluted with 12 ml of ethyl i1 j! .aestate and the N,N'-dicyclohexylurea which has precipitated is filtered I ■' /of^ with suction. The solvent is distilled off in vacuo. 2162 1 5 O The residue Is taken up 1n ether and the mixture 1s washed with saturated sodium carbonate solution and water, dried and concentrated. The 1.7 g of residue 1s separated into the pure diastereomers over silica gel with cyclohexane/ 5 ethyl acetate 8:?.

The fraction which runs through rapidly contains benzyI 3-[n-<1-S-carbethoxy-3-phenylpropyl)-S-alanyi]-1S,2S, AR#6R,7R-tricyclo-C5.2.1.0^*^D-3-aza-decane-A-carboxylate. 100 mg; m/e: 532; Rf = 0.52 (SiC>2/ eye Iahexene/ethy I 10 acetate 1:1). c The fraction which runs through slowly contains 400 mg of benz y I 3-j^-CI -S-ca rbet ho xy-3-pheny Ipr opy I)-S-alanyl}-lR,2R,AS,6S,7S-tricyclo[5.2.1.0^*'D-3-aza-decane-A-cerboxyI ate. ir/e: 53?; Rf = 0.43 (SiC^; cyclohc-xane/ethyl acetate 1:1) g)3-[N- (1-S-Carbethoxy-3-phenylpropyl)-S-alany^-lR/2R,AS/ 6S,7S-tricycloC5.2.1.02*^3-3-aza-decane-<-"carboxylic acid hydrochloride 20 350 mg of benzy 13-[N-(1 -S-c d rbe t hoxy-3-pheny I- l propyl)-$-alanytJ-lR,2R,4S,6S,7S-tricyclor5.2.1.0^"'D-3- aza-decane-A-carboxyI ate from Example 1f are dissolved in 10 ml of ethanol, 30 mg of 10% strength palladium-on-charcoal are added and hydrogenation is carried out at ^ 25 room temperature. After the catalyst has been filtered off with suction, the solution is concentrated in vacuo, the residue is dissolved in ethyl acetate and the solution is rendered acid with etlianolic hydrogen chloride and concentrated on a rotary evaporator. The residue is 216215 triturated with dllsopropyl ether.

Yield: 270 mg; melting point: 162-165°C (decomposition); Rf B 0.42 (S102# methylene chlor1de/methanoI 8:2) £>mnx>le 2 3-[n-(1 -S-h^rbet hoxy-3-pheny lpropyl)-s-alanyQ-ls/2s,4S^2R, 7R-tricyc lo f3v£. 1.0^*^D-3-aza-decano-4-carboxyl ip-^lTc 1 d hydrochloride 3-[n- (1 - S-Ca rbe tho^c><^3-phcny>fffopy I )-S-alanyQ-1S,2S, 4S,6R,7R-tricyClot5.2.1 za-de c a ne-4-car bo xy I i c acid hydroch lorid*-^Ts obtained in ans^nalogous manner by the proce><cescribed in Example 1e to 1 g t>^i ng 1S,2S,4S, ricycloC5.2.1 .O2*6! -as -the starting substance.

Z xar«p I e 2. 1 5 3-^J- (1-S-Carbethoxy-3-phenylpropyl)-$-alanyi}-1S,2R,4S,6S/ 2 £ 7R-tr1cycloC5.2.1.0 * 3-3-aza-decane-4-carboxylic acid a) (♦_) Exo-1 r i cy c loC6. 2.1 .0^ 3-3-aza-4-o xo-unde c ane The compound is prepared by t!ic process described in Example 1a), starting "from (♦_) exo-trieye lo[5.2.1.0-20 2 *^3-3-oxo-decane (Journ. Org. Chem. 32, 3120 (1967)).

The lactam mixture is separated into its components over silica gel using methylene chloride/methanol 9:1. = 0.49 (SiOj; CHjClp/CHjOH 9:1); melting point: 178-1 80°C ? 7 b) ( + ) Exo-1 r i cyc IoC6 . 2 .1.0 " 3-3-aza-4-0K0-5/5-di ch loro- The compound is prepared by the process described £a, Iting point: 24 0°C; R ^ : 0.49 ( SiO^ ; CH^Clj,/ Example 1b, starting from the lactam of Example , . ■ •• • MMMkCil • I'l+hT © 2 16215 CH3OH 95:5) c) (O Exo-trieye lot6.2.1,Q^*^D-3-aza-A-oxo-5-chloro-undecane.

The compound is prepared by the process described in Example 1c, starting from the dichloroI act am of Examp le Rf = 0.26 (Si02; CH2Cl2 / CHjOH 95:5) d) 1:1 mixture of 1S,2R,AS,6S,7R-1rieye IoC5.2.1.02•^D-3-aza-deeane-A-carboxylic acid and mirror image isomers 10 end 1R,2S,AS,6R,7S-1ricye IoC5.2.1.02■-3-aza-decane-A-carboxylic acid and mirror image isomers The compounds are prepared by the process described in Example 1d, starting from the monochloro 1 actam AV& £ "ll-V Ex.-ple/t.

Rf = 0 .5 A (Si02; CH2 C l2 / CHjOH/C Hj C02H/h'20 20:15 :2: A) NMR (D20) : 0.9-1.6 <m 8H>; 2.1-2.5 (m 3K>; and 3.A-A.0 Cm, 2H) e> 1:1 mixture of benzyl 1S,2R,AS,6S,7R-trieyelo-20 T5.2.1.0 • D-3-aza-decane-A-cerboxylate and mirror image isorers 8nd benzyl 1R,2S,AS,6R,7S-tri eye lo- ? A t5.2.1.0 * D-3-aza-decane-A-carboxyI ate and mirror image i somers The compounds are prepared by the process des- 'w 25 cribed in Example 1e, starting from the amincacid mixture 2.

AA*Ck. of Example sSd.

Tt(4#7 = 0.31, diastereomer I (Si02; CH2Cl2/CHjOH 95:5) Rf = 0.26 diastereomer II The mixture can be separated preparative ly into 2 162 1 5 the two racemic diastereomers chromatograph1caIly over silica gel after N-acylation. f) Mixture of benzy I 3-[n (1-S-c a r be t hoxy-3-pher>y Ip r opy I)-S-alenyl]-lS,2R,4S,6S,7R-tricycloC5.2.1.02,^3-3-aza-decane-5 4-carboxyI ate, benzy I 3-{n (1 - s-carbet hoxy-3-pheny Ip ropy I) - S-alanylJ-lR,2S,AR,6R,7S-t ri eye loC5 .2.1 .02-63-3-aza-© decane-4-ca rboxy late, benzyl 3-[n (1 -S-c a rbethoxy-3- phcnylpropyl3-S~alanylj-lR/2S,4S/6R,7S-tricyclo-C5.2.1.0 * 3-3-aza-decane-4-carboxyI ate and benzyl 3- jjj-(1 S-ca rbe t hoxy-3-pheny Ip ropy I >-S-a I a ny l]-1 S ,2R, 4R, ( 2 A w 6S,7R-tricycloC5.2.1.0 D-3-aza-decane-/»-carboxylate The compounds arc prepared by the process described in Example 1 f, storting from the benzyl ester /M* 2 II|mixture of Example /fie. The diastereomer mixture is 15 separated inic its components over silica gel using methylene chloride/ethyI acetate 99:1 to 8:2.

Diastereomer A Rf = D.134 (Si02; methylene chloride/ethyl acetate 95:5) m/e = 532 D i a st e reone r B Rf = 0.126 (Si02; methylene chloride/ethyl acetate 95: 5) m/e = 532 25 Diastereomer C Rf = 0.105 (Si02; methylene chlcride/ethyl acetate 95:5) p/e = 532 216215 Q U Mastereoncr V Rf ■ 0.074 (SiO^; methylene chloride/ethyl acetate 95:53 m/c = 532 B)3-|n- (1 -S-Co rbethoxy-3-phenylpropyl)-S-alanyl]-lS,2R,4S,, 6S,7R-tricyclot5.2.1.02,®3-3-aza-decane-4-carboxylic acid hydrochlori de, 3-|n-(1 -S-carbethoxy-3-phenylpropyl)- S-alanyl-1R,2S,4R,6R,7S-tri cyclot5.2.1 .02*63-3-aza- decane-4-carboxyIic acid hydroch lor i de, 3-[n-(1 -S-ca rb- ethoxy-3-phenylpropyl)-S-alany^-1R,2S,4S/6R,7S-tri-2 6 cycloC5.2.1.0*3-3-aza-dccane-4-carboxylic acid hydrochloride and 3-{n-(1 -S-c a r bet ho xy-3-phe ny Ip ropy I)-S- alar.y^-lS,2R,4R,6S,7R-tricyc lot5.2.1.02,^3-3-aza-decane- 4-csrbcx>lic acid hydrochloride are formed when the diastereomers A, B, C and 0 of Example 2.

/Sg arc each reacted by the process described in Example ig.

Diastereomer A1 Rf = 0.191 (Si02; methylene chIoride/methanoI 9:1) m/e : 514 as the trimethylsilyl derivative Diastereomer B' Rf = 0.231 (S i 02; methylene chloridc/methiinol 9:1) m/e : 514 as the trimethylsilyl derivative Diastereoner C' Rf = 0.301 C S i 0 ^ ? methylene ch loride/mcthanol 9:1) m/e : 514 as the trinethyIsilyI derivative stereomer D ' Rf = o .358 (G i 0 2; methylene chloride/methanol 9:1) m/e : 514 as the trifliethylsilyl derivative Hmmi

Claims (4)

WHAT WE CLAIM IS:

1 . A compound of the formula III H o,w (*sn i t 2 H H A denotes -CH«CH- or -CH„-CH„- and —1 the H atons on C-2 and C-6 are in the cis-con-figuration relative to one another, the group -COgU on C-A is orientated in the cis- or trans-position relative to the H atom on C-2 end the pyrrolidine ring is orientated in the exo- or endo-position relative to the bicyclic radical, and in which W denotes hydrogen or a radical which can be split off under acid, basic or hydrogcnoly-ticconditions.

2. A process for the preparation of a compound of the formula III as claimed in claim 1 , which comprises rearranging a compound of the formula XI _ 19 _ 21G2I3 (XI) c In which A denotes -CH=CH- or -CH^-CH^-, R-* denotes hydrogen, alkyl, »ryl, aralkyl, -SOjH, benzenesulfonyl or p-toluenesulfonyl, the H atoms on C-2 and C-6 are In the c1s-configuration relative to one another and the cyclopentane ring is orientated in the endo- or exo-position relative to the bicyclic ring systers, to give a compound of the formula XII (XII) .sfcriT r in which A has the above meaning, the H atoms on C-2 and C-7 are in the cis-configuration and the lactam ring is orientated in the exo- or endo-position relative to the bicyclic radical, halogenating this compound to give a compound of the formula XIII EC1987* (XIII) Hal denotes a halogen atom in which A h&s the above meaning,jand the stereochemistry corresponds to the formula XII, catalyticslly reducing flb - 2$ - 216215 the compound of the formula XIII to give a compound of the formula XIV (XIV) and the stereochemistry corresponds to the formula XII in which A end Hal have the abovementioned meanings/and, if A de no t e s * C H = C H-> this double bond is transiently protected as a eyelopentadienyl-iron dicarbonyl complex, reacting the resulting compound of the formula XIV in the presence of a base in a manner which is known per se to give a conpound of the formula III in which U'denotes hydrogen end, if desired, cstcrifying this compound to give a compound of the formula 111 in which W denotes a radical which can be split off under acid, basic or hydrogenolytic conditions.

3. A compound according to claim 1 substantially as herein described or exemplified.

4. A process according to claim 2 substantially as herein described or exemplified. HOECHST AKTIENGESESSLSCHAFT By Their Attorneys HENRY HUGHES LIMITED