SE448376B - PROCEDURE FOR THE PREPARATION OF (ALFAS, 55) -ALFA-AMINO-3-CHLORO-2-ISOXAZOLINE-5-ETHIC ACID (AT-125) AND ANALOGS THEREOF - Google Patents

Description

448 376 e o b ' > I! II -C0R6, -C-VR., or where they together with the nitrogen atom form the group ///// fi \\\ and 7 N e 1o¶ í í n o n FU where R 6 represents alkyl of 1-8 carbon atoms, halogenated alkyl with 1-5 kplatoms and 1-3-halogenaphomes, where R7 represents al- refrigerator with 1-12 carbon atoms and where Rs represents the group (a) 15 R 7 'R 9 ', 11 ,, I- e IV e-c ~ v _-- c_-e 20 Z n_ Z _ í Rw y Ru where R9, É10, Ri% óçh Ríå represent hydrogen and alkyl with 1É5 carbon atoms; (b) 7An * Z '* 25 I - I i, - "CHZ I ¶ \\ CH /// \ ÉH and L 1? CH - ~ CH / J \\ CH 2 n ¶ e 2 30 ' (c) ortointeffenylenerurf 35 * ' 1 In the above-mentioned terms for the variables, "lower- Alkyl "methyl, ethyl, pxopyl, butyl; pentyl, hexyl, heptyl, _ 'octyl and isomeric forms thereof, I' ' .i-: ï lO 15 25 30 35 448 3766 3 g g c Halogenated alkyl having 1-5 carbon atoms and 1-3 halogen atoms in include methyl, ethyl, propyl, butyl, pentyl and isomeric forms. more thereof substituted by 1, 2 or 3 bromine, fluorine, chlorine or iodine atoms.

Halogen denotes bromine, chlorine, fluorine and iodine.

The present invention relates to a chemical process for the preparation position of AT-125 and analogues thereof.

The method of the present invention is advantageous in and in that it involves a complete chemical synthesis of AT-125, which until now could only be produced on micro- biological pathway. It involves the preparation of the compound dl- -trans-3-amino-4-hydroxy-cyclopentene, which in turn converts via a series of reactions to form tricholomers. Acid derivatives, AT-125 and bromine, fluorine and iodine analogues thereof These halogen compounds are then converted to other analogs.

Tricholomic acid, which was first isolated by Takemoto and co- workers, see Yakugaku Zasshi, 84, 1183 and 1230 (1964), is one amino acid with the structure _O: HN- .c 0 co H IHIU : dlyzí get now This compound is known to be flycidal and has a taste which appeals to man.

In addition to the work of Takemoto, other procedures for «Position of tricholomic acid described. These include Äïwa- saki and co-workers, Chem. Pharm. Bull. 17 (5) 866-872 (1969 [7, [iwasaki gochgmedarbetare, cnem, Pnarm. Bull. 1745) 873-878 usesnj, / gïamiï / a, fr., chem. Pharm. ßu11..17 (, s) sve-ses (196911, 4498 376 'j '4 Líamiya; mgchem. pharmfßull. 17 (»s) 886-889 (1969) _7, Lh- niya, T., chem. Pharm, Bull-_ 1 ~ 7 '(s) 890-894 nasagj, [í T. And chem. Pharm. Bq11.v17 (5¶) 895-900 (1969¿7. FATÉ125 or (qS, 5S) -afamino-3-chlorophe-oxoxoline-5-acetic acid _ is an antitumor teoehea fl timicrobial agent of the formula * cl _ N j109 _ _, CQZH F ”H2 Vu production was via tricholomic acid and its derivatives Qch ekan is represented schematically in the following way: . g; - d) Cp 5¶ \ sfeg 1¶ v Step 2 Step 3 - S * i _ Hu 'i ¶_1o 15 » 20 25 ' ¶3o 35 É44s? 376 if, NCOCHZCCl 3 ¶IVb ~ - -: va ' 1 Step 4. Step --- @ - »* ~ + --- + @ 0 "_ 7 O 7 NCOCHZCC l 3 IYIZN COCH2CCl 3 1V 'in 1 stëq GÄA ¶ 'steg 7 _ I ou u 'o ~ ln ¶ "H CH ocNo. _NÉc_> cH2_cc13 CHZOCN _ NH; IIC 10 15 20 25 30 í "as 448 3? ¿¶_- Iib. (skin . .v 14- * t, OUT 10 ' 20 .25 30 35 40 of 448 376- 7 Another aspect of the present invention is the use. of new intermediates in the procedure indicated above for .preparation of compounds of formula I, These intermediates products include 7 (i) compounds selected from the group consisting of racemic mixtures and optically active isomers of the compounds with the formula O f ~ R and R1p3 ^ NR14R15 * f Con cozR / 11 f i '_ - peace NRMR 15 where R represents alkyl having 1-8 carbon atoms, halogenated alkylp with T-5 carbon atoms and 1-3 halogen atoms, where R13 represents hydrogen , alkoxycarbonyl, halogenated alkoxycarbonyl and aralkoxycarbonyl carbonyl, VR14 and R represent hydrogen, _15 o. I o '_ The 'll' fCOR¿,: -C-R7 'or together with the nitrogen atom group -N _ R where R 1 represents alkyl having 1-Q carbon atoms, nalogenated alkyl - É 6 with 1-5 carbon atoms and 1-3 halogen atoms, where R7 represents end 2 * * group consisting of alkyl of 1-12 carbon atoms, and where R8 is draws a group consisting of 7 a _; Ts fllfn »C C ..

.I V I R1o R12 ïc44st375 , d ~~ R '_ V' 7 l. - i V> i å * 9 9, R 11, R 12 are selected from a group consisting of hydrogen and alkyl of 1-5 carbon atoms, ' ~ l - CH * en e ce2 S »n 'c c \ n. , CH CH. l \ l Iz vcng .cn2g_ . / CH 7 orthointerphenyls V ' ', (ii) compounds selected from the group consisting of racemic 15k ¿mixtures and optically active isomers of the compounds with the formula '" fRn 20 _ / 4 N \ ¥ \ - _ - I _ .i _VIV c dnRsd d _ where R3 is selected from the group consisting of hydrogen and c i to. zf c -c- - ~ _ ° || n RaS ~ , HRS O Ra represents alkyl of 1-8 carbon atoms and halogenated alkyl 30g with TFS carbon atoms and 1-3 halogen atoms and R 4 and R5 are the same or different and denotes hydrogen, d g I Ü * _0 "O 7_ I I K 'I u II,, If ', i i, _' _ . R "6OC-, eg R" 7C, where R66 and R "7 represent alkyl of 1-8 carbon 35 atoms, halogenated alkyl having 1-5 carbon atoms and 1-3 halogenator more and when they together with the nitrogen group denote ef ” (in we" , J " U! 10 V15 èo 25 30 135 40 ddår, R 448 376 " 8dbetecknar »(á) _ 9 ddf dÉ11 IN "_C¿; ¿__; Q_CQ_ r to ' .R1o _ R12 where Éà, dRí0} .R1í.ochVRTå denote hydrogen, alkyl of 1-5 carbon atoms. more, (bl . . T fl z Go; / "d dgd c fi ái" d f \ ¿f ~, / ¿'g \\ r CH I ooh (c) orthointerphenyl, compounds from the group consisting of racemic mixtures and optically active isomers of compounds of the formula eR4 'g r III $ \ Ranf t g Én r d e e n gon OH where Rc represents amino, -di-alkylamino, R "6Oë§ ooh R" 7ëàff where R "6 and R" j represent alkyl of 1-8 carbon atoms, halogenated alkyl of 1-5 carbon atoms and 1-3 halogen atoms and the group where RB denotes1 (if a grnpp_ which consists of UI 10 d 15 20 25 ' sou 35, 40 d44sus76 '7kolatQmer;' (p where R "6, _ RJ '1 10 Fa d ÉHQ r w + C7 7 _ Q- jilno än I 'i' where Rgr, MR10, R1 1 'ocïh 3-12 lroeteeknar wrate oeh -alkyl with 1-5 and '= '(cY.ortointerfeñyleu,: there dRÅ'eeh R5 is the same or different and represents hydrogen, ro-_o _ í RÜGOE- RP7C- or together with the nitrogen group do rd / J! ' ... Nf ', _ \ 72 d ßf and R 8 is as previously defined, wherein the group R 3 7 r and NR R are not equal at the same time. 4 5 wüpeíinhihgeu submits associations selected from the group that consists' of racemic> haemorrhages and optically active isomers of pre- enihgar med forñeln K 'where R3 has been previously defined; IN,\: .um Th fi) 10 15 20 hrs) U l 448_576 11 DETAILED ßEsKR1vN1Ns By uPPF1NNINeENo ÅT; 125 and new derívof dömov kon 'be presented in enlígmef with the procedure provided by ovon ongovš.

Sfeg 1_genomFöre $ on off of the fre sweet somvisos in follow ~ ischemic diagram C, Q m¶¶ NE ' In the preferred pathway is shown as sieg o, the epoxycyclopentene V, »Ïillgöhgligneñlígt vod as described, for example, by Crundoll obh medcrbeïoïe, J. Org. Chem., 33: 423 (1968), react with a solution of ammonia in a protic solution medium, such as water, métono, efonol or other alcohols or in eff'icke-profiskt , f \ 44si376nffï 12 solvents such as diethyl ether, dimethylformamide, tetrahydrofuran or dimethoxyethane The reaction in the detaprotic solvent takes place Now most effective in the presence of a catalyst, such as a dry basic aluminum hydroxide, which is described for similar reactions of Posner and Rogers, J. Am. Chem. Soc ;, 99: 8214 (1978l, Reactions> = Protic solvent is generally carried out at -50 to + 50 ° C and at a concentration of epoxide from 0.01 M to 2 M. Molför- The ammonia to eoxide ratio is usually 1: 1 to 50: 1, before 10 15 _20 25 30 treadily in the area l fi gl to 20il. in non-brittle solution means the reaction generally takes place at ¿20 to TOQOC. The concentration, of epoxide in these solvents is usually 0,01 to 2M and molfarhaliqnaef qmmcniuk fill epoxide ar usually 1 = 1 fill 20 1, preferably 1:] to 5r1._Åmínen_med formula IVb, prepared Z on this sweet, is usually isolated by evaporation in a super- 7 shot_ammonia and solvents to form a crystalline salt of the arena remaining amine. These salts can be formed with use of a solution of an acid, such as toluenesulfonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid and other acids in a solvent agents such as water, methanol, ethanol, ether, 1,2-dimethoxy- ethane or p-dioxane, The salts are isolated by filtration and the compound is crystallized directly or by evaporation of solvent followed by subsequent crystallization per soluble solvent.

Alternatively, the crude dmine IVb can be purified by adsorption on a column with an acidic ion exchange resin, such as Dowex 50W-X2 (H +) or Amorlite 1R4120: (H +) followed by elution with a solution agents such as water, methanol, ethanol, ether, tetrahydrofuran, 1,2- edimethoethylene or p-dioxane, containing a volatile amine, such as ammonia, methylamine, diethylamine or triethylamine followed by Introduction of the volatile amine and solvent. .w fi 10 15 25 solar 448 dfóe ß Similarly, the salts of the hydroxyamine can be converted back to the free amine by allowing a solution of ointment in ef? loose-_ agents such as weapons, methanol, ethanol, tetrahydrofuran or 1,2-dimethoxyphane is passed through a basic ion exchange resin, such as Üowex 1-X8 (OH_) or Amberlite lRA-4Ö0 (0Hf) and evaporation of eluafef containing the amine.

The saline of the amine of formula IVb can also be converted to 'the free amine-genome treatment of an aqueous solution of the salt with a light molecular weight deafening cup of a base, such as sodium or potassium hydroxide containing the resulting aqueous solution with a salt, such as sodium chloride or sodium sulfate and For a constant solvent extraction with ' a solvent such as methylene chloride or chloroform. Amines of formula IVb is then isolated by evaporation of solvent. let.

In a breath path to the amine of formula IVb, as shown therein the schematic diagram as sfeg b, gets the epoxide of formula V react with a mixture of hydrazo acid and 1,1,3,3-feframephyl gudnidin i ef? solvents, such as mephylene chloride.

Def there are many references for opening epoxides with ezidine Gene. se J.iofg; ich¿m. 37, 1268 (197a); J. Am. chem. soc, 93, 1813 (1971); J. org. chem.:s2,g1452 (19ß7>; Med. chem. 15, 175 (1972) and J, Am. ch@m.1s§=§ 94, 7098 (1972). however, the garden is re- the activity of acyclic epoxides in the foot. Use of l, l, 3,3- tetramethylguanidine for off solbilisate the azide ion in organic solvent is described by Papa, J, Org. Chem. 31, 1426 (1966). However, it has the special opening of the epoxides to hydroxy oxides- with the reactants, HN3 and 1,1,3,3 = tetramethyl- 10 15 Ä 20 30 _44s% 376 m from, 1:] to 5; 1 and from 1:] 0O to 1: 1. The reaction can take place I 1¶4 some methylene chloride not previously known to the applicant rroppoiferofs.

The molar ratio of hydrazo acid to iguanidine to epoxide shall be: HP ' at femoeroturef between # 50 and TOOOC in concentrations from O, Beer to 2M.íUndef these conditions are d 1-3,4-epoxycyclopentene extfemt reactive. Solvents, such as methylene chloride, which may be used include tetrahydrofuron, dimethylformamide-p-dioxane and alym..The azide with Fo: me1n VI can be removed from the reukfion mixture The use of conventional separafionsiekník, e.g. filtering, ' 7 extrokfion, chromatography and combinations thereof.

An alternative step for step b can be repiesenieros sohematis as a companion; I I I Z Z I I lNUN i i \ I -sot kafalysat r _ i _ ° In this reaction.dl-3, ÄÅepoxícyk1openfen.meas react with a blending of sodium and an acidic cotalysaphor, such as boric acid In a suspended solubilizer such as dimethylformamide, dimethylformamide sulfoxide or acionionfril, About l ~ 5 mol_not; íumazíd per moi epoxide ooh 1-5 moles of boric acid per mole of epoxide were used; The reaction , can be stored between% temperatures 0 and 125 ° C for a period of, Eel-10 days. The desired compound DLÅirans ~ 3-azido-44hydroxycyclo-_ penien VI uivinne; gr the reaction mixture on conventional soff, fâ; such as by extraction and chromography as combinations die; of, .ID Ä) 3 IN 10 20 J ' 25 448 37eo _15 With extended storage at room temperature and faster at heating the azide of formula VI and formula VIa is partially rearranged to the other azide. The two isomers VI and VIa can be separated. chromatographic race.

Step c comprises the reduction of the dl-trans-3-azido-4-hydroxy- cyclopenfen of formula VI to dl-trans-3 # aminof4-hydroxy-cyclo- penfen of the formula IV§, This type of reaction is well known) It is _ however, it is likely that one will obtain superior results in polar solvents, which dissolve the highly polar dl-i ViTrons-3-amino-4-hydroxycyclopentenes. Suitable solvents in- * nefoiro tetrahydrofuran, β-diocan and 1,2-dimethoxyene. Reactional one can be carried out at temperatures between -78 and 50 ° C and conc years between 0.01 To ZMQ The amounts of formula IVb can be obtained from the reaction mixture on the sweet described above for step a. 7 In a rredfe path fill the compound of formula IVb, step d, sheep the epoxide with the formula V reacts with phthalimide in the presence of a analyzer, such as potassium phthalimide or a ferric amine in your solvent agents such as dimephylformamide; dimethyl sulfoxide, ether hydro- furan or occronítríll Zero conditions fralimid and caralysaror to epoxide can be 1: 1 to 10: 1 and ~ 1: 10 fill lzl, respectively.

The reaction can be carried out at 0-125 ° C for 1 hour to 20 days. whereby the higher ion moiety corresponds to the shorter reaction time. derna. The hydroxyphalimide of formula IVd can be obtained from the reaction. the ion mixture by conventional separation technology, e.g. exfracrion chromatography_and combinations thereof. In which the phthalimide of formula IVd is converted to the hydroxyamide of formula IVb by treatment with hydrazine or hydroxy omín in a manner known per se, Suitable solvents for the , ,, .-. 10 l 15 25 30 448 376m 16 reactions include olconols, such as methanol and ethanol, Irohydrofuran, dioxane, dimephylformamide and acefonifril. Molför- I r.ha11 @ nde5 @ ffuiimía maa føímeln Ivà fill hydruzin-e11er hydroxyl- o ~ 5 amine is usually 1: 1 fill li10 and the reaction can be carried out at -20 ~ 100 ° C7 before {redness at or near room temperature; Amino- m, the alcohol of formula IVb can be isolated on the juices described in connection with step a above ..

Step 2 involves the reaction between dl-trans-3-amino-4-hydroxy- the cycloent of formula IVb in trichloroethyl chloroylmate. I detfuç In step 7, the amino group is blocked by the free chloro-ethoxycarbonyl group. fpenna reaction is carried out on per se known sweet for conversion. amines to areians.oReaction occurs using ' a mole-containing trichloroethyl chloroformate to the compound with of formula IVb of about 1: 1 to 1011 and at a temperature of from about -20 to 50oC spirit: a fíd of 20 minoier fill 24 fimmor.

The reaction is usually carried out in solvents such as wafers. methanol, methylene chloride, dterahydrofuran and dioxane containing they a Read or suspended base; -Such as sodium or potassium- carbonate or a ~ amtidr amine which can take up the liberated acid.l The reaction can also be carried out in your solvent which acts as its own base, such as pyridine. The preferred solvent the vaft containing sodium carbonai. Urefanen with the formula IY '.can be recovered from the reaction mixture on conventional juice, as by crystallization, filtration, distillation, exfraction, chromiography.and combinations thereof; Other halogen-substituted alkyl halogenates can be used for gatt_block the amino group, ef.eX.ljodetylchloroformate. Amino- the group may also be blocked by an aralkyloxycarbonyl group or an alkyloxycarbonyl group, for example benzyloxycarbonyl and t- 'IJ 1) 10 15 m x. 30 448m 376 17 Butyloxycarbonyl. Procedures for using these groups for to block amine are well known. Background information regarding preparation and removal of phthalimide, p-nitrobenzyl esters * of carbobenzyloxy and carbo-tert-butyloxy derivatives from amino acids is described, for example, by R.Å. Boissanas Chapter, "ßelectively Removable Amina Protective Group used in the Synthesis of Pepe ltides ", in Advances in Organic Chemistry, 31159-190 (1963). information on the use of t-butyloxycarbonyl groups to blocking amines is described in the ALDRICH Technical Information Bulletins designated BOC-ON (September 1976); Information on use of ethriklarethoxycarbonyl to block amines is disclosed in Windholi and co-workers, Tetranedron Letters, 2555 (1967). However: 1 has the particular sequence used for the present invention. as far as these know not previously used.

The urethane of formula IVa can also be prepared from salts of -e dl-trans-3-amine-4-hydroxycyclopentene, formed by reaction mele lan amine and a protonic acid, The reaction is carried out by upp-r dissolving the salt in water and then treating the reading with sodium carbonate and trichloroformate or other blocking agents 'of the_tyn described in step 2 above. Urethanes of formula IVa i can be recovered from the mixture in a conventional manner.

Step '3 is carried out by reacting the urethane of formula IVa with a slight excess of N-hydraxyfthalimide, diethyl azadicarboxyá lat and trifenvlfpsfin in a solvent. The reaction is carried out at a temperature of # 50 to 5Û ° C; Suitable solvents include includes tetrahydrofuran, ether, 1,2-dimethoxyethane and p-diaxane, The preferred solvent is tetrohydrofuran. It can be noted night a reversal occurs during step 3 and that the urethane with The formula IIIe is obtained as a cis isomer. ? 44s% z7e?% *nine With a löÉt'modífíkofíon, other förèhíngär, bíldoäe ur ominen with other Hulogenšubstítuerode olkylhdlogenformiut, used in instead of the d Ureiiun _¿í sfeg 3., _Vídure ku fi before fl in§or where dmínogruppeñ ör is blocked by a urol- coxycarbonyl group fi is used in s% gg 3. Example§ís (LI 11.1 .Qy v (\ A) .MF 10 * KU \ _; \ so 49 l.

:O N (3 imif ' 44a% 376 n, mí mo 30 448,376 'o2o The reaction and the extraction procedure are essentially the same as in step 3 above;: - w l sfeg 4 transform; Phthalimide compound of the formula IIIe fill the hydroxylamine compound of formula IIId by reaction with light Eyewitness of hydrogen hydrate, This reaction is carried out in the presence of of your solvent at a lemperafur of between -20 and 10 ° C spirit: about 1 rhyme to 2 days. The loan fund that can be used vandae lnnefattar'ferrahydrofuran,: efahol, methanol, water, pe dlaxane oah dimethylformamide. The hydroxylamine of formula IIId can be removed from the reactant mixture in a conventional manner, such as by extraction, crystalline chromatography and nations dörav.l In step 5, the hydrokylamine base is the compound of formula IIId protected by reaction thereof with an alkoxychloropformate, haloalkoxychlorobromate or aralkoxy halogenate, such as f: benzylaxychloroformate 'to give carbams of formula IIIC; The reaction is carried out using an ethole ratio of aralkoxyhalogenformíar_till en Compound of formula IIIg on amšea around Tzl to 10; 1 in a solvent such as tefrahydrofuran, 1,2-dimethoxyene, p4-dioxane, acetonitrile or dimerylformamide, containing a tertiary amine base, such as triethylamine or in solvent agents, such as pyridine) which act as their own base. Def the preferred solvent is pyrldin. The reaction usually takes place at a temperature of ¿20 to 50 ° C, ' Conventional lining such as chrysanthemum, exfracrion, chromium fografí and combinations thereof can be used for aff urvínna the product from the reaction mixture.

In sfeg a amlögenas den.ekYddande group from the amino group in colors' Z .gm e R) Q. 10 15 '20 30 448 376 ' 'v21 _, ._i- the compound of the formula IIIc by reaction with zinc, The amino carbomer of formula IIIb. This reaction can be carried out .and processed reach several sweet.

The preferred method involves combining the reaction in be of methanesulfonic acid and methanol. The reaction is carried out at a temperature between 0 and 50 ° C for a further 30 minutes 5 hours using a molar ratio of zinc acid to a compound of formula IIIc of about 2: 1 to 50: 1. In reaction 7, the aminocarbamate of formula IIIb is converted to Phthalimide of formula IIIq by reaction with 2-methoxy » carbonylbenzoyl chloride and triethylamine in the presence of a solution average; thereby obtaining the tthalimide product of formula IIIa. Reak = the reaction is carried out at a temperature between -20 ° C and 50 ° C below. a time period of 10 minutes to 5 hours using moifsfhallunaef 1 = 1 fill 1o @ 1 av be @ z @ y1k1 @ »id¿n och 1 = 1 f¿11 20t1 of triethylamine to: the compound of the formula TIIC. Suitable ' solvent in which tetrahydrofurant fatty acids, 1,2-dimethoxy- goat, p + dioxane, dimethylformamide, and methylene chloride. The product with The formula Iïlo is recovered from the reaction mixture in a conventional manner sweet, such as extraction, crisis bankruptcy, chromatography and combination itioner darav. The preferred process for extracting extracts fion fæljf av krqmufpgrufí or krisfollisqfiøn; The starting material Zemethoxycarbonylbenzoyl chloride can be prepared 1 in the manner described by Hoogwater and co-workers, Recueil, 92, 819 (197s) ._ e _ In step 8, the alkenphthalimide, formula IIIa, is reacted with a route. nium compound, such as urothenium trichloride in the presence of an oxidated f * , 10l 15 25 _3Q ? 44s * 576 22 agents such as potassium or sodium iodate and a solvent, thereby obtaining the benzyloxycarbonyl divalent of free cholomic acid with formula Ilb, This reaction_conduct; with the introduction of mol- the content of ruthenium chloride and sodium iodate in the compound with the formula IIIa on amking 1: 10 0 to 1:10 and 14; 1 to 10: 1 - oeh did femperafures on amkrlng O to SOQC for a period of 20 mines to 24 hours. Lemnllga solvent includes vafien with aée {one, lmethylacetaf} ^ nitromephane or 1-butyl alcohol.

The preferred solvent is acephanate. Pfodukfen med Fafmelnulïb may atvínnaš nr the reaction mixture on the tíonell {'sütt.

A product with farmmel * _ vïïdle form; ockeå during reaction 8; Istear? Eframstölleerföreninaen of the formula Ilb by removal an de sk§ddande glup fi emna från Föreningen med formulen Ilc. The spe-g eíellagmíllkor eam * anVöndee at ßorftagande-ay these protective * -e groups now depend on the epecialalaxycarbonyl groups, the group (RTS) which is the most abundant form of kvüveafomen íef: ícholomsyraríngen.¿ n'Nur this group is Benzylaxy or aralkoxycarbanyl can removal _ of the protective gçapnerna åke genom uppläsonde aå föreningen í¶ett, e: solvents and treatment of the solution with hydrogen in the presence of * leeward* leeward , 10 15 25 30 35 448 376. rzsl a conventional catalyst at a temperature between 0 and 50 ° C and atmospheric pressure over a period of 20 minutes for 2 hours. Suitable solvents include ethyl acetate, ethanol, toluene and tetrahydrofuran. Suitable catalysts includes palladium pieces, 5% palladium-on-carbon and palla-1 dium on barium carbonate. " The product of formula IIa can be recovered in a conventional manner, Such as by extraction, crystallization, chromatography and combinations thereof; _ '> Alternatively, removal of protecting groups from pre-H the compounds wherein R 13 represents alkoxycarbonyl or aryloxy- carbonyl, occurs in the presence of an acid in a solvent such as * nitromethane and methylene chloride.V I When R13 represents amino analog alkoxycarbonyl, removal of the protecting groups suitably take place in the presence of zinc.

In step 10, the tricnolomic acid derivative of the formula IIbb is converted:> to the ester of formula IIa in a manner well known per se for Esterification, For example, the acid can be treated with diazoalkane or arylated diazomethane, for example diphenyldiazomethane or by treating the compound of formula IIa with an inhibitor series of tertiary amines, such as N, N-diisopropyl-N-ethylamine, followed by a benzyl halide such as diphenylmethyl chloride or p-methoxy In benzyl bromide in a solvent such as tetrahydrofuran, ethyl Acetate, acetonitrile or dimethylformamide.

In step 11 comprising the method according to the invention The tricholomic acid ester of formula IIa for chlorination, phthalimide-isooxazole-acetic acid ester of formula Ia is obtained.

The preferred method of chlorination involves reaction between the compound of formula II and hexamethylphosphoric triamide : - 44s 376 'v24' f - dichloride in the presence of a solvent. This reaction can be carried out 10 15i ? 0 i25 30 K, is carried out at a temperature between 25 and 60 ° C for a period of time of about 24 - 72 hours. Molecular Acquisitionshehexamethylphosphoric triamide dichloride to a compound of formula IIa may be from 1-3. I I wolkaff, CAN. J, c fi en. voL. 53, P. 1333 (19? 5) shows effiförfqr- conversion of the benzoyl hydrogen to their corresponding hydrogens. zonylhologenides. Émellertíd is trying to convert trichloro- _. syra¿_which contains an oxiamide group, fill moievaret hydrae zonyl halide compound according to this method has not been walking; In step_T2, the sphere of formula ïc is converted to the compound with Formula 1b by introducing or adding it protecting group from the amine., Preferred procedures include first_deforesiríng¿_f The reaction of the compound of formula Ib includes reaction: lan this and a new drohologenide gas in the presence of a solution ~ The reaction is carried out at a femperafur from about 5 to 30 ° C for a period of about 1 to 4 hours. Suitable solvents include nifromane; icy_acid_and methylene chloride.

The preferred solvents for nitromone are the halogen moiety Xi be-f * is derived from the specíella.vdieha1ogeníd used. For example - when using hydrogen bromide, hydrogen chloride, hydrogen fluoride and hydrogen iodine is obtained compounds with fermeln 1b da; -x] befecknur ßrøm, chlorine, fldor ooh iodine. .K '.Deposition of the Phthalimidamino Acid Protective Group,' caused by defoating the ether of formula lc takes place nom air deföresiríngsprodukfen may react with_hydrazine hydrate in fvartenfeller alcohol. Products (aS, 5S) faEomino-cyclo-4,5-di » m, d * n 'Il we' we: * 44sss76 } 25> ¶ hydro-5-isozozoleic acid or AT-125 (when X1 represents chlorine) ufvinnes_UT rçokiíonsblcndníngen in conventional sweet, such as by exfrckfion, fkrísfullisophion, chromophore and combinion hence. " Compounds of formulas IIa and 1a3 are prepared from compounds 'ings with formèin lo ellef IIQ on conventional söff under replacement of hqlogennfomer'ñot dndrq parts, exemnelvís: - V «-v ._...__._ T ....__....-..___ ..,., _- m ' 10 TS V20 ' zàa 30 ' e44sd37sse 26_ _Step The reaction of the compound of formula Iaii methanol with a equivalent of sodium methoxide in an inert atmosphere at room temperature 1 for 1-40 hours gives the compound of formula Ia, wherein R denotes methyl¿ * 7 * 'I “ Treatment of a compound of formula IIa with diazomethane in an ether solvent with a catalytic amount. etherate gives Ia1 with R1- = 1methyl. 7 The method of the invention comprises a selective removal of removal of different protecting groups in the presence of different In general, the ease of removal depends on one group on the presence of other groups and on the special turn the readenset. In this regard, the protecting groups can arranged in the order least difficult to remove to most difficult a to remove i_Taoell7I; W I We" 44sÉs76 27 ' c «N0nw> I_ in.

O »¶Hw @ ° @ ~ u» fl fm1w «; HRS _. H> cønnUx W fi xox fi ouø wuHm: «fi + wm: m . H> conHux. _w fl xUxHU vonmcwmo fi cï ^ HH¶ «@EV x @% N. .cwH> xmHoE u% m; > o mwcunwwwnww nov: wccmmmH> o mxo fi vcnEHAufcox_ æ H> conHmxv¶uHmcwmoHrI »¶ @>: ° @ M @ ¥ wx ° x fi < H> LonHuxHx0xHøH4 ~>: onHuxmxo & HuHo wnuwaw fi wwßam ^ NIv @ ~ @> X ^ ¿>: Qnßnx fl xo «wouoHx« u «.. wfuw _x .fi>: c, no 1> m. _ 7 »_, n xwxox fi u wcnwcw o fl uïï .,. ^ H> c ° @ Hu ¥ | wXo fl> Ncu fl ,. w> nVwxconHøx fl Xox fl on <_ ^ H> conHux 1HxoA>% an | + .. w> v «.«> CoßHoxmxo ¥ H < ~ H>: oanoxw «xoH> N: mn fl xoæwßrm_.w> wv .N ., _. ~ \. __. fi>: oßHox fi XoxHuHo woHmJ + fi «wßam_« ~ ^ + Iv.ow> W 10 N Un 30 ifi44s 376 In the preferred method for dissolving DL-amino acids therein, while the compound of formula I of the present invention "see Each of the above procedures may be implemented by the above: 1 on facemic Älandings of alíka¶reactants or a solution can be carried out at any of the steps in the procedure and C111 The regenerative steps are performed on the optically active reactant. ü? I 4 + hydroxy ~ cyclopentene down foi fi eln lVb or after protoniàkf syrafv "salt dd: av_and then lead the remnants of the procedure on-opiískt _: active ísomerei av-reakfanterna.

Dissolution of the raçeniska mixture can be done down obvious, K madífíkaiíoner av de könda.f $ rfarandena'med utilning av kända uppldafanden for uppldshing. For example, the association with for; The IVB melts are dissolved to form a salt with fish active acids such as D or »L-wine wrap L - (+) ~ šyfan give the antipose, which leads to AT-125 down natuilíg kanfígurafion. Respective ointments 'is obtained inexplicably clean by oncrisfallisafion several aånger from solvents such as ethanol. This is a particularly efficient process for the exhalation of optically pure isanei of formula IVb as the compound fill formation of nafurligt AÜ + l25 is off treat it: ocemic För- the compound of formula IVb in a solvent somneiol first and then ded deoxíçholsyfa, which kfistallísefar out essentially anfipoden, the leading fill enanfiomer AT-125. The mother liquor from the .na crisis crisis is converted to the free amine on any of the juices as beskfevs.befröffande-steg d above. This Unprocessed Amine, _ now essentially enriched on the desired anfípod, then transferred to fish purity by formation and recrystallization of LÅ vinesyrasalfef.'Vl is an amphoteric compound, they may form salts with acids, alkalis, w 10 20 dw 448 376- 29 ' ¿Metals1, (including ammonia) alkaline earth metals (including magnesium and aluminum) and amines. Metal salts »¶ 'can be prepared by dissolving them in water and adding hav, en: sown metal hash until the pH of the solution is 7 to 8¿ Metal salts including sodium, potassium and calcium- V the salts, Åmin salts include those with organic bases such as primary, secondary and tertiary, mono-, di- and polyamines oche _can also_ be formed by the use_of the above described or others 7 common procedures. Furthermore, ammonium salts can be prepared on " well known sweet. Other salts are obtained with therapeutically effective bases, which provide a further therapeutic effect to the Farening len. Such bases are, for example, purine bases such as theophylline, bramine, caffeine or derivatives of such pyrine bases, antihistamines bases, which have the ability to form salts with weak acids, pyridine compounds such as nicotinic acid amide} isonicotinoic acid hydrogens zid oçh similar f.Fenylalkylamines¿som adrenaline, ephedrine _ and similar; chloin and others.

Acidic salts can be prepared by neutralizing the compounds of formula I with a suitable acid to a pH below 7.0, preferably to about pH ~ 2 to pH 6. Lëmplie ' Acids for this purpose include hydrochloric acid, sulfuric acid, 'acid, tartaric acid, hydrobromic acid and the like. Acidic and alkaline salts of the compounds can be used For the same biological purpose¿ 'goal as-the original association.

The compounds of formula I and YIIId inhibit the growth of micro- organisms in varying_environment, For example, AT-125 is active against Esaherichia coli and can be used to reduce, inhibit and prevent slime production in pulp systems, caused by .its antibacterial action food this microorganism ÅT-l25 fi. " UI 10 15 so) 'gelafine capsules' of suitable siorlek. Soft gelatin capsules can 448 s7a_fi ii i 36k can alsoVan¶ündas'f $ r to prolong the life of cultures of in Trichomonas' foetUs¿'Tríchomonas hominis and Trichomonas vagi- (f: nglise by freeing them from the coniamination of Escherichia ggli. Furthermore, AT-ÄÉS can be used as an antifungal agent in l shoe wear, which is disclosed in U.S. Pat. No. 3,130, ÉÖ5.

Furthermore, AT-125 can be active mother Bocíllus subtílis be used to reduce or prevent the lactation of fish or - fish limit causes aV this organism or ~ AÃ-125 can be used. for ctr wash laboraioriebünkar and Equipment in mycological laboraiorier.

The compounds of formula I ürh also effective for prevent air bacterial infections.oah¿ium killers in mammals, including humans.

The compounds of the present invention are utilized for administration. Sirafion for humans and animals in unit dosage form, such as fab1effer, _ capsules, pills, powders, granules, sterile parenieral solutions, or suspensions, eye drops, oral solutions or suspensions ions and hydrophene oil emulsions ~ containing suitable quantities g title of the compound of formula I.

För_aral adminisfratibn can either iasTKeller.flyfande unhets- dosage forms are prepared. Prior to the preparation of phase compositions, such as fables, compounds of forneln I can be mixed with con- __ conventional ingredients such as talc, magnesium stearaphecalcium- 4 phosphate, magnesium-aluminosilicate, ukalaium sulphate, ice cream, lactose, acacia gum, methylcellulose_ach functionally similar _ moferial as ~ pharmaceutical preservative ach_börare. Chaos is prepared by mixing the compounds with an etherified pharmaceutical - organic fertilizer and filling of the mixture into hard 117 *. \) 10 15 20 N ' Um 30 448 376 31A is prepared by medical encapsulation of a slurry of compound one with an acceptable vegetable oil, liquefied petrolatum or other inert oils.

Liquid unit dosage forms for oral administration, such as syrups, Elixels and suspensions can also be prepared. Water-soluble precursor more can be dissolved in an aqueous solution together with sugar; aromatic flavors and preservatives to form an elixir can be prepared using hydroal alcohol (ethanol) carriers and suitable sweeteners such as sugar and saccharin together with an aromatic taste.

Suspensions may be prepared with an aqueous vehicle with the aid of of pension agents such as acacia, tragacanth, methylcellulose and the like , similar.

Floating unit farms are used for parenteral administration * of the Compound and a sterile carrier) with water being preferred.l The compound, depending on the carrier and the concentration used, can be used antíngen.suspended or Read out in börarenl Vid preparation of solutions, the compound can be dissolved in water for injection and filter sterilized before filling into appropriate containers or ampoules And törsegllng. Appropriately, additional agents AS local anesthetics, preservatives and buffering agents dissolves in the carrier.-In order to solder the stability, the composition- » The ion is frozen after filling into the containers and water is removed in a vacuum. Dry lyophilized powders are then sealed in the container and an accompanying container 'with water for injection is used for fek0 fl SfIUkfí0n GV liquid before use. Paren ~ terala lasnínaar can be produced on essentially the same sweet with except that the associations are suspended in the borrower instead .fl- S. .ïø _ 15 - 1 30 , ._....._._ .., .., .. É -....__..._..._ ~~ .._......-. .__ __ _ _. . . ii44s; 376.ar 'for off facilitate even distribution of the compoundl7 32 to be dissolvedVoah7aft sterilization_infe can be done by filtering freringß The compounds can be sterilized by exposure to erylene oxide before suspension in the sterile vehicle.7 m » In this way, agents or agents are introduced into the composition Furthermore, a recalcitrant suppository can be used for administration »Ra the active compound¿.This dosage form is of particular interest ' where the mammal cannot be treated in a conventional manner other dosage forms, such as orally or by snus or in cases 'with small children or debilitated persons. The active association can be introduced into each kdnd suppository base on a per se known basis page. Examples of such bases are cocoa butter, polyethylene glycols (carbovaxes), polyethylene sorbent titanium monosarea and mixtures of deåta with other miscible materials that modify: smälrpunkf and dissolution hasrignei {These recalcitrant suppositories may weigh from m1 2,5-gi-dm; Uiiryçkei Üennefsdosiorm "was used in the description for air beteckf g Physically discrete units suitable as a single dose for human league paiienier ash animals, each containing a contaminated _match of okfivf material, calculates for air give the desired terapeu-'A Fishing the effects in conjunction with the necessary pharmaceutical diluents means or carriers The description of these new unit dosage forms according to the present invention relates directly to (a) it 'unique property of the active material and the special ef? effects that one wishes to achieve and (b) inherent limitations if the mixing possibilities of such materials for use on 7 people oah djar, which in deïalj is shown in the description. Example - on suitable unit dose farms_in accordance with the present invention ning are fableiier, capsules, pills; suppositories, powders, Iql * Ü 448 376 33 pointers, biscuits, granules, capsules, teaspoonfuls, tablespoons, 7 dropwise, ampoules, containers, aerosols and metered doses, different mulfiplar of any of the preceding and other forms which described here.

An effective amount of the compound is utilized in the treatment.

The dose of the compound prior to treatment depends on many factors ka are well known to the faokman. These include, for example, "_ Mini-sirraphy route and effect of the special association. Eff 'I To 20 25 _30 ,, human dosages of from about 2 to 200 mg of compound in one. single dose is administered parenterally or in a composition according to The present invention is effective in treating tumors 7 and bacterial_infections. More detailed are single doses from about 5 to 50 mg of the compound. Oral and rectal doses from 5 μl 500 mg as a single dose can be used. Especially referred to , single doses from TO to about 100 mg of the compound.

The following description of the preparation of AT-125 and analogs hence the scope of the belvserzupbfinníngen but is not intended to be limiting., The person skilled in the art can realize variations in the production both av_AT-l2É and analogous precursors as well as the relevant reaction vinkof Qch fekam. __ FfaAnsirÄLlLuïßssvl / áxl / RACEMISKA BLANDNINQAR l * Proposition; l: vdi # 3,4-epoxycyclopentene cnßcoánr I g: i iCHZ-Cl-Zfg ~ _> ig4Na2çO3g 4480376 A34 A manga of 45 g (0.6s0m§1) cyclopene fudis fi pupal plaque 1,750 m1 -.methylene chloride to Vílksn was added 290 g of anhydrous sodium redfish 10 20 30 bonat. The vigorously stirred mixture was treated for a long time for 40 minutes_msd l10 ml 6¿3 mal peracetic acid (to which Sodium diethate was added to neutralize any traces of sulfuric acid) spirit: dat that the temperature was kept below 20? on an ice bath. The reaction mixture was then further stirred * S hours wide; 20-25PC} Thereafter, the reaction mixture was filtered 1-2 g of sodium carbonate were added to the filtrate. The filtrate distilled from 35 mm Hg pressure and sealed stood at 20 mm Hg with a distillation temperature approximately mlika with SOOC (calf temperature never above 40§459C) to give 21.8 g dl-3,4-epaxycyclopentene. 0 '0 Nuclear spin rate (CDCl3, ¿;): 2.122f7 '(m, _2H), 3, óv4.1 (m, 2H), 5.7 - 6, s (m. 2H). preparation 2 dlÅtrans¿azído-Åéhydroxylcyclopentene (a) ¿HN? , m0 a 2 s (Me2Nv2ç = NH - ”;>. <:::: L \ scHzclz 0 m (150 M3 s livs pp: '<0 .l p r - 1 p »VI En manga G9'9o¿gs (1,3asm ° 1) 'fi qff1um @ z1d fílïsuæfes fill 9orm1 H 2 O and 300 ml of methylene chloride. The mixture was stirred vigorously, chilled deS to. <; 109C ochrbeßandladgs with 19 ml of sulfuric acid. After 'I 30 minutes decant the methylene phase and dry over sodium salted. The solution was treated with 0 g (0.07 mal) of 1,1,3,3-tetra- methylguanidine dissolved in 30 ml of methyl chloride; The resulting solution-- (H4 m NB 10 15 ' 25 30 35 _ ningen behdndlødes ned óren.metvlenchloride solution uv.3,4 ~ epoxy- çykldpçnien produced from O, Ö8'mol cyclopentodíen. After 2%? * timme índunsfqdés solvent in vacuo, spring dimension obtained DL + trons-uzido-4-hydroxycyclophefen. 7c > dl-Fruns-azido-2-hydroxycyclopentene Na É / i / l v - l ¶ l - VL l v10 I etf olternotívf förforónde ïrdmsfüllde; the oreno methylene chloro- - lausníngen.cv DL ~ É, 4 ~ §poxícyÉlopenfen ur 36,6 mmol cyclopenfodín concentrated under a pressure uv approx. 50 mm Hg øch- <1 20 ° C..Åier- sf§den ~ Saff @ s fill én blondning qv s 9 (123 mmol) n fl friumuzidn 8'g (129 mmol) boric acid * suspended in 200 ml of dry dimethyl ~ formumid. Blondníng§n_omr $ rdés'víd.25 ° C below 17 fímmor. Reactive The thionate mixture was partitioned between water and ethyl acetate. oceiotfosen tvötfndos med water 'Torkudes over mc nesíumsulfuf _ I 9 . . . 0 och ~ 1ndun; fodes 1 vokuum v1d 25 C. Den impure återsfoden summan- -dlpgs with what was obtained from previous driving with 10 mmol and chromectogrofeyodes over 2 linearly unlucky E. Merck ~ coloners of size B with silica gel 60. The column was eluerges with 40-60 eïylocèici-Skellysolve B and 30 ml fruit fions Uppsumludes. Fruit K: tíonernd 10-13 upnscm1udes.ocn lndünstudes, whereby obtained 7 2, ó4lg_dl-truns-uzídoÄ4-hydroxycyclopenfen as a pale yellow oil.

The follow-up yield of the cyclopentudine was 45%.

Since the reoktídnsblondníngen got so omurrungerudes dl-trans-oiido fi n nl44s sval 0 "? 44s 3760f 'Z (7376 Z '4 ~ hydroxycyclopeñt0n partially till0 dl ~ fr0n $ ¥ a2Åd0} 2¿hydro # ícykIo-_ penfçnL_ f The two isómçrernozseppreyodes kroÜGtogfofí§kf'ö¶er 2 linear un-0_ _ 5 glutno columns of tyß Merck stLrl§k B with kís§l§el 60. Columns n «nu _ i In eluerodes: with (40-6Ö) ethyl acetate ~ Skèllyso1ve B and 30 ml fractions : íívpps fl ml fl des- I (¶ “í í 'í í _ _ '(šll-jciggèç; S-omino-Åfhydroxi-cykïópen * ceh A _ _ 10 xa; ns_p_ann; e; onuns (00013, å) ¿Å1,9s-a, o5 (m, C52), 0s, 5 .. (oH), ¿ 0 0 4, o-4,5 (m, çHou, cHNB), 5,6_6 _, _ 2 ( 0 (m, cHO = CH>; 1 JR (film, cmH / l (, _3300 (oH), 209001213) 15 _ ¶ ¶ ~ í (0 0 * 'dl {ï5gQ§¿3 ~ omino-2 + hydroxy-cyclopentene , 0KörnSpinhr§soncns' (CQC13f§ ~) 71.9 - É, 2 (mg GH2), 3.85-4.2 (OH) "> 0.4, -2s-_4,7 and 4.7_5,1 (m, cHQH), . ¶ 0 cHN3), 5.75_ß, 2 (m, cH = _cH) _ ( 20 0 __z_a _ (_ f__¿; _f fl, mik; 0 - 0000 (01), - 2090 (C210) 'TunnskiÉfskromciouroFí¶ (kíseluelóü) 1 Rf ~ vörde på ísomeren IVc '' "is 0.00 and Rf is av _ gfomefe fi v: ar 0,39 i (4040) 005 (efylaçefaf- * skellysolve s. (' Frcmst fi llníng 3_ dl ~ frqn3-3, q fi íng-4fHydroxiÄçyklo0eñten 0 0 Im 0 (0 0 ._ a 0 ~ - f Ü - - NH w 00 00 i 0 0 0 0 2 2 2 0 ¶ ¶ 0 0¶ IQH "XII i 0 -" Ivbf q » in? 31 10 15 202 30 448 576 237, ' (6) 2.2 g (57.9 mmol) of lithium dluminium hydride are softened to 90 ml eïer oéh the stirred suspension was cooled on eft'isbod. To above suspension list 3.62 g of DL-ircns-czido-4-hydroxy-1 cyclopenfen dissolved in 5 ml of efe; during l5.minufer (exothermic reokå tion with strong cuddle development). After stirring for 2 hours, lhondlddes teckiíonsblqndningen'föfsíkiígt med 2.2 ml voifen, 2.2 ml of 15% sodium hydroxide and 2.2 ml of water (to begin with) very strong exothermic reaction with crude eruption), After stirring for 15 minutes, the phase was removed smoleriolet by filtration. The filtrate was evaporated in vacuo to give 1.96 g of dl-trons-3-uminoo4; hydroxycyclopenia, e.l. what soul nude to eft low smolfunde fixed mofefiul, then dei I Got to stand. This material was extremely votin soluble, Kdrnspinniesonons (CDCl3, '8): _' 1.8 ~ 2.9 lm, CH2), 3.5-4.2 2 -, g eg, (m, cHoH, CHNHZ), 5.4 ~ 5.9 (m, cH = cH), Tunnskíkfskromuiogfcfí (silica gel 60): Rf = 0.24 í, (1-20-80) conc. "'2 NH, oH-M @ oH_cH¿c1 2. (bl The whole amount.oren dl-T: ons-ozído-4-hydroxycyclopentene from.. a 0.68 mol, 1,1,3,3 ~ teffomefy1gpanidin supported zoside formation (Preparation 2u) is dissolved in 100 ml of tetrohydrofuran and solution en_tillsöttes under 30_mínufe; to a suspension of 25.8 g (0.68, mol) lithium aluminum hydride in 1 liter of petrohydrofuran. Tem-I the peroiure at the redkioion is kept below 5 ° C with a is salt ice booth finds iíllsoTsenÄ_Reukiionen Allowed onlu femperciur of 25 ° C for 18 hours, the reaction was cooled sedon back to 0 ° C and Ut; säites efter vorfonnbf for 25 ml voften (exothermic and krofïig gosu + fold), fl25 ml 15 fl-ig, sodium hydroxide and 25 ml vofien, gEffer stirring ytferligore¿1å hour filter rod mixture; The Fosie material was wefted with feirenydrofuron. The sum- / ~. 10¶ 20 N) (_11 30, í44a 576? ¶33__ šlagno filfruief ošh fyöffv§tškornc'índunsfcs i vckuum, varvid 47 g of crude dichloron-3-omino-4-hydrocyclopentene were obtained. Precipitation 4 [dl-phrons-3-amineb-4-hydroxycyclopentene ~ tólüenšulfonofsalf V i _ V. V V V i - _ 7. V _ 0 _ íí ¶ë>? + 1? -¿1n ~ | j ¶ ~ ._OH I 'Å - »I HQ i : vb ¶ ¶ '¶¶ ¶¶' * Ivb] ' 22.17 g ßren.dl-trans-3-qmínq ~ 4Åhydfoxí ~ cyclopenten; §U 200 ml tetfuhydrofu; dn_, bè fi c fl dludeš Imed e fi saturated fetrohydroï furønlösníng in fl èhålld fi de 40 g (0, 21 mQl) _p-foluè fi sulfonic acid- I I monohyUrqï., crisis foals formed; Quickly. These uvlöggnodes through Filtration for 5 minutes to give 14.5 g of dl-truns. 3-Amino-4-hydrocyclic fi phenfoluenesulfonoisult Ée fl ed smölppunkf at 180ff82 ° C. Mßdérlytcrno koncenfrerodeš och kylÄes {whereby er-f hölls yíïçrlígørè ÜSQ9 g_dlÄfruns-Ü-omín§f4-hydroxycyklopenfen- tnluensulfonof.so fi 'krí§full§r fi éd en smälfpunkf på 177 ~ 181 ° C. ímed eff fofulf yield of_33¿4 g.

Preparation of dl-3-cmino-4-hydroxy-cyclo- penien_ur déšå toluensulfbnotsult.

M Ku q, 10 '__ 1vb¿e _39 Åmberlíf 'ln' \ “\ = 1RA_4oo i 04 .ïVb 150: ml_ambe; lifelIRA-400; haçfš in chloride form was doubled on one In a ground glass slurry after warping with 6 x 150 ml of sodium hydroxide, 3 x 150 ml Vaiten ooh 3 x_1É0 ml mefanol.mHar1set was suspended 448 576% _och oockodes i en.chromdfagrafiko1onn containing me% anol} 10.95 g (40.4 mmol) was dissolved in a minimal amount of methanol and then filtered to the column. and the column was eluted with 750 ml of ethanol. Evaporation Kïav the total eluaief gdv 4.2 g of an oil, which sfelnade se- "dun it was obtained s {å ~ öVer_na% ten ~ i vdkuum, whereby dl-3-amino was obtained. 20 30 W e TUnnsk1k + skr0m fl f0gf @ fi (k1Seigè1.6o); Rf_o, 24 i (1_2o_so) coma.

FramsiöllgiQ3_§g = A4 ~ hydïo§i§cyclopenfen with a melting point of 47-50 ° C_ Nuclear Magnetic Resonance Resonance (CDtl3¿ <§): 1.8-2; 9 »(m, CH2), 3,2- (OH, NH2), e 3; 5-4.2- (m, cHoH; CHNHZ), 5.4-5.9 * (m, c fi = cH). in NH 3 OH ~ MeOH-CH 2 Cl 2. called with KMnO4 spray- Fïam- reagent. dl-trons-3-omino = 4-hydroxycyclopeniene (IYb) * _och desšÄp ~ tdlaensulfona {salt - 448 376 1 40A I w i 1. N fl wrlneènl> _ Z, pTsÅ K Rv _] Ol; 4O ml't6rf.metq fi ol_k§ldçs på ett isbdd oßh uhmoníukgoš ßubbludés _ through to obtain a müftod solution. To this fi ommoníaklösninèw iscttes 5OÖ mg fi cyclopentenepoxide. Reokflonen was held at Oo for 24 * I 'fíhm fi y and vid-25bC'Undèr 64 fí fi mcf. ReuÉlíonencentrerudes še- Dilute in vacuo and reflux with 5-10 ml of tefrohydro-1 I T5V fufqn. Def olöslíèa_moferiulef cvlögsnodes'geQ§m cenfrífugering to give a solution of the hydroxyamine of formula IVb. This behondlódes mèd_en-möffad låsning u¶'p-foluensulfonyrc í ïefrqÄ hydrofulun fill dešs en lausníñg iñnèhållande omlnen blev sour.

Den volumínö§c'k; ísf @ llinc fell fi íngen Qppsuml fi dés genom fílfrerí fi g and føfk fi dés. osfeffèlferhails ósolmgl dmmns-sëqminødx-hydrbxi- 'cyklšpenfeñ-ïoluehsulfonutsqlf.

Prcm§É§llninq_§§ dl; tr fi ns ~ 3-cmino-4-hydroxycyclopentene IVb Koch des fi p-toluengulfonotsult 'l ~ 1 “.lNH¿0Hl l l - l “, V ..;. Fl; msll .__ .. š - _- 0 - ' . »Q. l ll L” NH I '- ~ * nu Q 2. p-1sA l __ ~ ¶ ¶ 3 -oñ Q 3 ¶ ._ ¶ï _¶ OH ¶ (i _ ¶ v ¶ g _ _f * 'Ivby _ n "T, 9f 9 (24 mmol) desfillerdde épdxicyklöpenten sctïes fill en is ~ kqll solution of ï; §7, g'K39,4fmmÖl) ommohlpmklofi fl í12O ml koncenf w) p \ 10 151 207 25 30A H 448 376 41 ' free ammonium hydrexide.-Éfferromrörinè å timme vürmdes reuktdons- mixture at 25 ° C and stirring for a further 8 hours. wall; Reukfionsbldndníngen'exffuherodes then with efer for of; soldering of more nel fi fe contaminants. Voftenfcsen möffudes ned no% ríumklóríd¶echeufsaftet for continuous extrusion with mephylene chloride. The methylene chloride was boiled over sodium sulfate and "cbncentrerodes in vdkuum, vøryid was obtained 1.15 g dl-truns-3-emino- 4> hydroxycyclopeniene, which was treated with 1, §4 g (8.1 mmol) telueneulfonic acid dissolved in iefrohydrofuron, 'vrrvid was obtained 1 {47 g dl ~ frun; -Saumine-4-hydroniccyclopentene ~ tolueneulfonuf.

With ntnynfjonde dy eit similar föffurande as in production 5e men ned ufbyfe dv lömnlígu ~ protonic acids instead of to- luensulfensyyo obtained chemical mixtures of I In di-p ~ tolfieL ~ Qínsyrusoifet, down a melting point of 185-190 ° C ¶7 (decomposition) _ d 7 7 di-benioyl-Lvvinsytusclfet with a melting point of 181-18306 (šöndetdelníng) _ V I I I 1-oral acid relief with a melting point of T16-117 ° C- K ': 2 ~ pyrrblidone-5ekørbcXylšy; osc1tet with a melting point of 164- 172 ° C. '~ *' Precipitation 6 .'- dl ~ trcn; ~ 4-hydroXí ~ 34ffolímído ~ cyclcpenfen ° Ivbí '~; "“; 1 * É ~ _ * ¶¶ ¶: va f-ffn 110 20 125 ao k 44seà76 A42 ”1Ee_ fi öpgd * dl-freHs-4-hQdrpxi¿3-omino-eyklopenfen Dissolved in f 45Ö mi fetrchydrofuíun qc fi 87 hg (0¿6Ö mel) friefy1omin._Lös- _ * Z niñgèn kyldes tíiï, Q ° C beh was added dropwise with 59,6.g 7 , (0.3 ml) e-mefo fi ífkarßeñylbenzpylchlorid for 50 minutes. "_Reekfíbnen ~ fil1öts sedan ontd ehífemperqtqe av 25 ° C. Effer 66 Vfímmor föçdeludes redktionsblcndningen mellan efylacetqt cçh -vaften. Éiylcpetoffuse fi ffbxkcdes over magqesíqmsulfuf och , Vdesfíílerddes Å yekeqm] vdrvid, efHöll; ¿62, Ä ~ g of remaining Koljd. Dened kroñutegyeferqdes övee 3 kg silica gel 60, elüerc- A s-des med 6 lífef (10_9o) ¿-2; 5s1 '(1s4s5) gch 11 liter (zosso) aceionemethyleneclofí fl, Frckfioner at 250 ml_uppscmludes. ”Pro-, Û - 'dukten' Éferfdnns í Frukfíonerna 38-61. These Érgkfioser krísfclf .liserudes_sedun dé "få ¥ f sfå, whereby 2É, 9 g dl-trans was obtained; _ [ r_hydr @ x1; 3-ffølidscykløpeqfeh.s' -Eff procedure: f's'ffqmsföllning u¶_O-mefçxí-carbonylbenzç¶l- Élórídl is described by dvrHooQQdter and employees, Rec. Trdv; Chimsf ¶P @ yS; B @ §, 92 (197e); ¿I i, '' ' fïdmsfell fi íng óof ïdl-tyuhsë4 ~ fi ydrQxi-3fftclímído-eykiope fl te fi 'f I s ¶e e s *} '¶. 1 s'e9 ”e , IVbí v ::: ~ .V - @ 7:: ø_IVd " 31.3 9 (o, 115 malå al-ffunS-säuminp: 44hydr @ xycyklopenfen-foluenf. sulfsndf was dissolved in 240 ml fsfruhydàofuran beh 47.m1_ (ø, 46 mQ1) ¶e (0 lf-H ef) 10 15 ¶¶ 20 25 ”So 44s z76 . 43¶ triethylamine. The resultant Wbmrördc »solution was cooled to 596 Wf 'pch Behdndl§dçs dropwise with 22; 8 g (0.15 mol) ø ~ me% oxicurbonyl_ vbenzoyl chloride._Reuktí§hen was then allowed onio a temperature of 25 ° C; After ÄB hours, the reaction mixture is divided between ethyl acetate and water. The ethyl acetate is dried over magnesium _ ~ sülfaT §ch koñcenfrercdes i vckpum, varvid efhölls, 29,6 g av §N_återštod; Üèñno remained chromutogruferodes over silica gel 60¿feluerodes with 5_l. (10-90) 7.5 1, (20 ~ 80) ocefon-mefylen- chloride.¶Frok {ions of 300 ml are collected§íPfodukten isoludes in frcktíonernø 25-35, which since they have had to stand krístollíserude __with an exchange of TÅQZ g dl-trons-4 pent with a melting point of 114-T169C.

Fyomsfàllníng ób I-_dl ¥ fruhs-4 ~ hydroXí-É-ftnlimídocyklopenfen An amount of β-epoxycyclopenene was added to a suspension. @ v'7,2'g (49 mmq1) ~ ff§11m1dv @ = h 1.43 g (7.7 mmol) of potassium phalimide fl 23 ml dry dimethiIfo; mumid. After stirring at 259 DEG C. for 114 hours mqr behænd1 @ aesfreugfaønsblunaningen with 0.5 ml (s; s mmol) affik- acid and stirred for another hour., Reuktíonsblondníngen _ índunšfddes'seddn i vdkuum och återsïoden kromufbgroferudes över 3OOf9'ki $ elgel 60, eluted with (10-90) acetone-CH2Cl2 {Frcktíon fi r __f§_ 10 ¶: ¶AnolysisL Bèf fi node for C H N03; 'I 15 20 25 ¶ V30 448 m , 44V ¶ _pa¶5o ml u§ps¿m1qd§s; P: §duk: è fi ŧ¿ha11s¶i_frqk fi iç fi ginq 26-ao, which šeÄun7de, received sfå krístcllíserdde, vqrvíd obtained 0.58 g dl ~ trcnsÅhydroxy-3-ftclidpëcyklo fi enfén.

Kai fi špï reg nrego fi qng (cDc1¿¿š $ = 2f1§3; 4 (m, cH2) h 3,7 (on), 4,6; 5, o ¶ ¶ ¶ ï¶ï (m, = cH = cH),; 7.7 (S, Aru). ' Tunnškíktgkfomutogfqfiu (kišélgélA6O): Rffšöpdef š] 0, Ö2 i (40-60) ¶¶Etylocétut ~ Skellysolve B ¶¶ and Rf-varae = 0.71 1 > (15fss) ucephene-cH2c12. ._ HI 4:80 » 1s¶11 ¶ ¶ ~~~ ¶c; 65.19; H, ¿@ se, Efhaldetg Éö§ ¥ arondet¶en% F; añstö1lning 6 was used but instead üfnyttju-¶ ' deš on appropriate? Sweet š¶b; tituérud9 0-metexifcdrbonylbenióylchloride - ïler 3 + mèfQxíkcrb§ny1F§fó @ onylkloIid i stöll fi trför O-methoxy- karb§nyIbenzoylkl§fíd:; 'V§fQí fl_ erhö1ls§ K' f 1 i dl ¥% runs-4-hydrbxÅÅ3 + (3Ånifrqftólimíd§) -cyclozenia dl-trcñsÄ4-hyd: oxi ¥ 3f (Åmethyl-f% olímído) + cQk1opénfen : dlffr fl6 sÅÅáhyd; §Xí-3; succíní fi idéc & klópenteh: V 1dlQtruñš ~ 4-hydr§xíÄ3 ¥ (2¿3fäímethylsUcçínímido ~ ¿yklopehten- d1_ffuns; 4_hydr¿: 1-a; he¿ @ hydr @% fd11mia ° §¿yg1Qpè5fen Representation 6 c ' Mwmo-¶ -¶¶. 2 2 »2¶ - í? 15 f 20 25 30 n ~ I gm Wclclocnzccls 443576 45 4.07 g (17.67 mmol) of dl-iran-4-hydroxy-3-phytolidoecyclopenfen was dissolved in 65 ml of fetrahydrafuran and 65 ml of ethyl alcohol. Solution was treated with 0.94 ml, (0.97 g, 19.44 mmol) of hydrazine hydraph. After After 10 minutes a precipitate formed. tionshlandhíngen in vukuum (<: 25 mm-och -3006). Åfersfoden frífu- rerudes with methylene chloride and filtered to remove olöslígdffalhydraildr The filtrate was concentrated in vacuo, varying obtained dl-frans-Gfamino-4-hydraxy-cyclopenfen as eff solid ma-_ fericl.

Framsfüllníng_Z dlëfrans ~ 3 ~ amlno ~ 4 ~ hydroxycyclopenten-N- Hll 5? Ho ïriklgretyl-Urefan x 'g g 2 N CO. g Ncocnzccla on ° 2 es : vb h. e I Ivu 9.9 g are the di-trans-3-amino-4H-hydroxy-cyclopentene (precipitated as The mixture was dissolved in 75 ml of water and the mixture was boiled. was treated with 10.6 g (TQO mmol) of sodium carbonate. The mixture is cool 7 was then taken on an ice bath to <ÄlOQC and treated dropwise vigorous stirring with 10.6 g (50 mmol) of trichlorethyl chloroformate 'under 30 minutes. After 3 hours, the reaction solution was acidified cold kanaenterate hydrochloric acid. Vaffenblcndníngen extracted three times with methylene claride. The methylene chloride solution was fluffed with The mixture was filtered over sodium sulfate and concentrated in vacuo. to give 13.2 g of a brown oil. This oil chromoragrafe- over 750 glycine dioxide, eluting with (10-90) 448 376? 46 enchloride. fractions of 50 ml were summed, -Produkfen appeared K_víd tunnskíkfskromdtogrofí present in fractions of 55 ~ 85.Con- 1o¶ 20 N ..

UI ' 30 ïtorkudes över ñctrig fi sulfoi och koncenffepuäes í_vokUUm. Krisfol- centrifuge of these fractions: gave 5.0 g of trøns fl3-omíno¿4 ~ hydroxy-cyclo ~ pentene-N-triclofethylureaap on a crystalline solid and smalfpunkf pa 1oo ~ 1o3 ° c. «¶ u, Karnspin¿I @ s ° n @ ns¶ (coC1¿, ¿$): ¶ 1.9-3.1 (m, cH2), ¶4, o _ 4.65 (m, sH), 4.74 (s, OCH 2), 5.45-6.1 (m, CH = CH) 6.5-7.0 (NH).

Tunnskíkfskromdfo§rofi '(silicon gel 60): Rf value is 0.5 i (10-90) I I 7 I ocetone; methylene chloride. IN §§G¶§ï§§lQ§gg¿§g1 dlfíruns ~ 3-umíno ~ 4 ~ hydroxíçyklo§enten-N- - friklorefyl @ urefan _ "Q_N., ~ @ __._ w§? ' V _ - »HH ¿_ (: :). «. CH3 ¶ 5; Ncøc fi cc1. (b) '“¶ // \ ~ \ Iåš 3 Ö Hø 2 3 in ïv5¶¶¶ _ _ ¶ Å: vu 13.55 g (50: mmói) frohs ~ 3-cmino-4 ~ hy fl roxycyclopenten-foluenesulfonuf 1 up to 75 ml of solution, solution for treatment with 10.6 g (10.0 m) mol) hofríumkorbonuf kyl? på etf ísbud obh behond; odes droppvis 7 with 10,6 (§ 50 mmol) of tricyclic ethyl chloroform under vigorous stirring. 'ín§. After 75 minutes, the fraction of water is mixed with water and heïylenkíoríd.fV fi tfen phase separated and extrqherodes two times with mefylenkloršd; ~ De summunslughu mefylenklorídfcsernu 'U 10 20_ hrs) UI '_30 448 376 l 47 clay of trons-3-cm-4-hydro-cyclopentene-N-free chloroethyl-urethane bildddesg'unde; koñcentrutíeg. These Oppsumlcdes fre times, each time washing the crystals with ether; skara 1, 5,12 9, $ ma1fpunkf 105,5 _ 1os ° c; crowd 2, 4.35 9, 2 gmalfpunkf 1o5,1o69c; skara 3, 1,25 9, smalfpunkf 104-1o5 ° c.

With the procedure of preparation 7 but with substituted for suitable halogen substituent alkyl halogen precursors or ukfiverode glkylkofbonufer instead of trichlorophyllformiote «Received dl-trons-Éfcmínb-Åefydroxy-cyclopenten-N-t-butyl-Uretun, Diphtron-5-omino-4-hydroxy-cyclopenene-N-p-methoxybenzyl urethane, dl-trons-Bfomino-4-hydroxy-cyclopentene-N-diphenylmethyl urethane, dl-trons-3-omino-4-hydroxycyclopene {en-N- [2-iodophyllyl urethone.

Using the same preamble as in Frumstöllning 7 but with using GV benzyloxychloroformict, dl-trons-3- (O-benzyl- corbumoyl) 54-hydroxybyclopenfen effer chromotogrophy on silica gel with 85% mephylene chloride-ocefon. 3) = 2.12.9 (m, cH2), 3.8-4.5 (m, SH), 5.02 (5, ocH 2), 5, a_6, 6 (m, sH) 7.22 (S, Ph) .5 TUnnskikfskr ° meæagf @ fi = RfI = 0,53 (15% ecefon / mefylenchloride).

Körñsginnresónods (CDCI In total, sweet diphosphate (d) throne-5- (O-benzyl) was prepared. kurbomoyl) ~ 4fhyd: oxy-cyclopentene by ufbyfunde of the rucemisko ufgångshoïeríolet mot d-ufgångsmcferial.

Frumstöllnípg 8l. dlÅ2,2,2FTricloroethyl-cis-5- (pholimidoxy) ~ K 2¿cyclopenten-1-kurbumct _ .. 10 _; LT! 70 PO UI 30 _448 376 43 > ¶ ¶ ¶0 __ Qñg ¿; o _ N_ H2cc13 Ho_ - .o o _ o (° 6 "5) aP 1v¿o o __ * _ (= Nco2c2H5) ¿L? 'o THFo o Hi o oNAocH2cc13 Iïïe 11.75 g (42.8 mmol) ol-frooš-3-omínoå4-hydroxy-cyclopenten-N- trichloroethyl urea, 7.86 g (4E, 3 mmol) of N-hydroxypholimide and 12¿63 g (4s, s> m¿ @ 1) "f; ifeny1f0sfin upplasfes 1 210 ml forr tetra- hydrofuran¿ To the stirred solution sdffeš dropwise under 15 minufer 9.21 g (5311 mmol) of diethylluzodicoroxylcfef under Set cïi tempe: øtuIen was kept below 35 ° C in an ice cream parlor. Reukfionen omå .. *. . o o ' was then stirred under 1 flmme at 25 C, after which it was concentrated in vqkuum (ïomkrinš (25 mm Hg and around SOQC). dog solder with co'1OO ml (100Q60) efylocetot-Skellysolve B and the completed triphenylphosphino fi íden ovlögsnodes by filtration efter omkfing 15AoinuterQ Äterstodeo tíllsot1es * fill_toppen av a 1 kg silica gel 60 colon J yíiken eluerodos med 3 1. (40-60) followed by (50-50) “Ethylocephalus-Skellysolve B; 300 ml fractions Sections 14-19 were found to contain pure dl-2,2,2- free chloroethyl-cis-E- (phylimidoxy) -2-cycloponphene-1-kurbomut at -ü 44823262 _49 barrel disc chromatography.¿Kahcenfraiian gave 6.24 g of crisis as ..a first harvest, smülfaunkf ~ l38,5-l39,5 ° C, 2.8 g as a second 2 10 '20 30 fÃnalvs, Berakhat for C H iCl N O cut with a narrow point of 138.5-1s9.5 ° c and 2.13 g'afersf ° d, was obtained by inhalation to forrhef. Fractions 20-24 showed šig ihnehalen vid thinskikfskromafagrafí en more polar pollution. These Fraktianef combined with 2.13 g of a re-foot from above and chromatographed on 75 DEG C. silica gel 60, eluting with Krades med- (lOÄ9O) efvlacefaf-benZen. Frakfíaner of 300 ml up in gathered. Frakiíoneena 8413 showed by thin layer chromatography ° contain the product. The concentration fraction of these fractions gave two an additional ör-2,2,2-trichloroethyl-cis-5- (phthalimidaxyl) - ~ 2-cyclapenin ~ lekarbamate-crisiallef with 2.75 g and 2.62 g with smölfpu fi kt hå 138.5-139.5 oeh 137.5-138.5. Toialf ufbyfe 14.4] g. I I Kainepinnresananedafa, (CDCl3, ^ §) 2.65-3.0 (m, CH2), 4.77 (s, §CH2) 4.7 - 5.2 (m, 2H), 5.7 - 6.1 (m, cH = cH), 5.35- f6.75 (NH), 7.83 (s, ÅrH).

Thin layer chromatography (silica gel 60): 4 Rf = 0.55 (40 ~ 60) ethyl ~ -5 _ eeefqf-skellysolve B and Rf = 0.47 1 (10- 90) efylacefaf-benzene. c, 45.79; H, 3.12; N, 5.68; cl, 25.35 iErhå11ef = 2.5 c, 45.92; H, 3.13; 2 N, 6.62; cl, 25.47. ï6f13 3 2 5 * The same procedure as in Preparation 8 was used but in the case suitable dl-trans-3-amino-4-hydroxy; cyclopentene-N- I fl ? Ü? 44s¶376 50 Éologen @ lkylÅurefun1i_ $ töllèf ~ för dl-tæcnsàß-dmínof4-hydroxy- .cyclopenfen-N§ifiklorethylEurethane, yurvíd efhöllsr; _10 ” ¶15 í- ?O so ¶ _ dl ~ p-mèfoxíßehzyl-císf fi f (ftulímídçxif2ècyklopenfenÄ1-kcrbumut, dl-diphenylmethyl-cis-5- (Fiulimideoxy) -Zycyclopenefehèl-korbomaf, dl-t-butyl4cís ~ 5 + (ffulimidoxy) Q2-cyclopenfenfïÄkøzbumot, “Using sdm fi u procedure garbage in ïrumsföllníng 8 men instead of ohvühdnihq of suitable N ¥ hydroxyfÉulimíder and N-hydf0X1$uc¿imid@r.fi-šfallef for N-hyaroxifrølimia was obtained dl- (212.2-cycloethyl; petyl) -cis-5- (3-nitrophthulimidoxy) + 2-cyclo-. penien-1-kqfbomuf, ¿í f V I a1 ~ (2,2,2ffr1k1 ° I0efy1) + ¿is-5- (3_n1fr ° ff @ 1imid °) _2- @ yk1Qpen- f§n41 ~ kurbumof, I _ V dl- (2,2,2-trichioethyl) -cisÅ5- (succinimidoxy) -2-cyclopenophen- Z 1 dl- (2,2,2-frichloroethyl) -cis-5- (2,3 ¥ diethyl ~ succinimidoxy) -¶ 2-cyclopenephene-1-carbum, : Mèd'unvöñdning uv'somño procedure set out in Frumstëllníng 8 but with nnQöhdning of olíkdznlkylmethanes and subsfífuerude n- hydroxy-phthalimides and n-hydroxy-phthalimides fi $ lls dl-benzyl (cis-5- (3-pitoxophyllimidoxy) ~ 24-cyclopentene-1-kurbamate dl-p-mephoxybenzyl-cis45- (4-methylphthulimidoxy) -cyclocenien-1- , karbcmqff Initial 9 'dlQbenzyl-cis-5¿ (ftqli fiidoxy) -2-cyclopenten- 1-kurbnmdf; KK 'K "' ' fb ((1 10. f ÉO solar 448 376 51 Cm ¶¿F - NcocH2ç¿H5 _ d d§ Ho - 0 l l 'l * (c6H5) 3P¶ (= Nco2E¿) 2 'THF IVe O Hn 1 _ Ncocuzc 61+ 5 IIIf f A quenlifet qv 1, Å6 g (6.2É mmol) dv trcns-3-umino-cyclppen- fep-N-benyl-urephone, 1.12 Q (6; 88 mmol) N-hydroxytolimide and 1.8 g (6.88 mmol) of triphenylphosphine were dissolved in 25 ml before: furun. The solution bedqndlodeš droppvíd unde; 5 mines with l; 32 g (7.6 mmol) diefylczodíkdrboxylcf íK5 ml felrchydlofurun. The ur ~ The brittle red solution was mixed after starting the application. so {§en fill yellow ihom 10 minutes. After 16 hours koncenfrerodes the reaction mixture in humidity (<125 mm Hg at optimum temperature 30 ° C) - øch åferstoden kromøfogrcferudes över 150 g kíselgel. Columns eluerodes with 4D ml (20-80) followed by (25-75) ethylocetct-benzene. 25 ml drops were collected. The product appeared at thin- f sklktskromutøgfufi vard i frgktionerna 13-20. Concentration av these fractions give 1.76 g of dl-benzyl-cis-5- (ffulimidoxy) -2-cyclo- penfen-l-korßumct'sdm'en plju, which is then crystallized a, '10 Elemental analysis for C 44s * 376f 52 fåft sfå. Circulating precipitates from 50 '% * efylocetot ~ hexone gave one product with a melting point of 120 ~ 122 ° C, Karnspi fi nresqnunsdqfuí (coc13, áï) = 2; e5-2,95 (m, cH2), 4, s_5,1o n * (m, zu), 5.15 (g, ocH 2), ¿S, ss_6.1 (m, cH = cH>, 6.1_6.4 (f) (NH); 7.7 (S, 5, AlH), 7.78 (S, 4, ÅrH) Ä _, _ Il] discovery chromium chromatography (silica gel 160): Rf value of 0.65 in (25-75) ethyl "I '> 7 7' I ocetot-benzen och Rf ~ vürde = 0, 72 _ "i_ (5-95) ocetone ~ methylene chloride. 21H1sN2 ° 5 = Bexöknotz C, 66L65; H, 4.79; N, 7.41 _Erha11 @ f: ¶ c, 66.16; H, 4.84; N; 7.32, Using this method, d-benzylαcis-5 - (fTcl- (Indoxy) -2-cyclopenophen-1-carbumute is prepared by exchange thereon dën rocemiskc mixture against eft ufgångsmdteríul in d-form. §2,2,2-trichloroethyl-cjs-5- (uminooxy) -2- In cyclopenfen-1-kurbomut: } .NH2NH2H2o O Wm ní n N AND CCI 2 3 HZNO IIId u) å ' ÅO 15 20 25: + e44s 376 53 7.42-9 (1å, e7 mmel) d1_2,2,2efrik1ereefy1-frene_5¿ (f + e1im1dex1) e 2-Cyclopentene-I-kurbohot'löstee'i 65 ml fefruhydrofurah and I K65 in ethyl ulced. The solution was treated with 0.94 ml (0.97 g; ¶19,44'mme1) hyaeeziehydref; Effee 10 minutes pictured a fall- ¶Níng; ¿ÉfTef 2 hours inäunstodes redkfíonsblundníhgen i vckuum (Å: 25 mm Hg and ~ f 3OQC) e The residue is trífurerodes with mephylene- kløríd and fílt; efddes for ovlögšnande of insoluble ftdlhydruzide. 7 The filtrate was concentrated in vacuo to give 6.68 g of dl-2, E, 2-trikIor- ethylethis-5- (omíQo ~ oXí) -2-cycloenylene-1-corbamot eom en oil.

Nuclear Piphronsonation (CDCl3, ÉÜ: 2.35-2.65 (m¿ÖCH2), 4.1 ~ 4.95 (m; s, NH, NH 3; (cH = cH).

Thin disc chromophogrophy (silica gel 60): Rf value = 0; 41 i (5-95) "I" "I" mefonol-benzene and Rf-ver- de e o, 41¶1 (4o_6o) efyl- ucefef-Skellysolve B.

Med qnvöndning av förfarcndef i Ffomstöllníng 10, men í sföllet for dl-2,2,2-tricyclone (phthalimidooxy) -2-cyclopentene-1- driving force used dihydrogenolkyl-trans-5- (phylimidoxy) -2- cyclopentene-1-kørbamuter growth was obtained corresponding to Chyl cis-5 - (aminooxy) -2-cyclopenophen-1-hydrocarbon.

Med unvöndniñg qv.fö: fc; onde% enlígf.Frumsiöllníng 10 men med 7 'Development of el or @ -ben7yl ¥ cis-5- (phthulimidoxy) -2-cyclopene- 1, '- CIL » phenol-1-carbomethyl moiety dl or d reepectivebenzyl-cis-5-umium- nooxy) -2-cyclopentene-1-kurbumcf.7Rf ~ value = 0.40 (50% ethyl) ccetut-hexene) _ (initial mutefíul Rf value 0.71). e '(m, "2H), 4.78 (e, ocH2), ¶5, s5_6.1e 10 ' 15 ' '20 lsø - (2.0 mmol) benzyloxyclbroformate solution 1 2 = ml CH 44sss7ss s ., 54 Frsmsïëllning ll 7dl42,2Åfríklor§fyl-sis- [I [(benzyloxy) ~ or- * C7bonyl] amino] oX1] -2-cycloo [x-1] -corbum fw (fl \ 'l ~ ° llmlcllocfiíallc J l O _ CH _ z 6 5> _O, H NO s co 2cc13 s s UH. Ncoc fi zcclß 2 s s H H cH ocN s s _ 6 5 2 _ Lnd s ¿} mc Acid-2,2,2-Tichloroethyl-cis-5-umboxylic acid 2-acyclopentene-1-carbo mut (1.6, mM) ffumsfölld i frbmslàllní fi g TO was dissolved in 10 ml pyri- _ The solution was cooled on an ice bath and treated with 0.34 g 7 7 2Cl2. Eftes 1.5 five cfslgs reoction bluntnípgeh in water and mephylene chloride and treated with ammonium clofid until it showed acidic odor. iíonl Meïylçnklcridfcsen sepurerødèslyforkbdes över ñufríumsülfut and concentrated in vacuo Qorví 76 766 mg of a clju ..

The oil chromutogrufçtuåesïfiver 55-§ silica gel 60, el fi erudes with ÅO + ÉO efylucefot-Skellysolve B. Frukfionef at 10 hl uppsumludes.

Frqkfionernu 10-13.) Vilku'Víd'tunnskíkfskrsmotogrufi vise sig 'Contain the product, summansldgs and concentric rods in vacuum,' , yorvíd received 535 mg sv en återsfød. After the addition of iso- propylefer fill åfeçstodèp osh skrdpñíng ¿.krisfolliserodes the material to give dl-2,2,2-trichloroethyl-cis - [[[(benzyl) oxylarbonyl] qm1 fi o] -cxí] -2 ~ cyclbpehten¿1-carbumd punkff spa 'ss_s9 ° c.l' 'i' I (IN W .

I 15 * 25 30 '-Tuhhskíkt $ krdmotografi ? l44s 575 i -5.5_ KötnsplnnrçsonqnåtÅCDÉlè; É;) 2.2 ~ 2.9 (m, 2H), 4.2-5.0 (m, C fi N, I ego), 4.67A (s, ocH2ccI3), 5.16 (S, oc fl àø), 5.4-6.2 (m, cH = cH), 7.37 (S, ø), 7, s_8, o (m, NH), 8.47 (š, ~ NH>. (kisçlgel §O): g Rf-value O¿73 i (40-60) efyløce- I I i fat-Skellys fi lve B.

Föffårondet enlígf petition 11 ohvündes men i sföllet för fl èn där o fi vönäd'förç fi ínQén_med formeln Illd uñvündes dl eller 7 (1R, 55) -benzyl-β1-5β (uminooxy) -2-cyclopenphene-1-carbonate and i šfüllet för bènzyloxíklóroformídt?, 2,2firíkloroefylklorc ~ formio, where dl or d (respectively) benzyl ~ cis- § ([2,2,2-trichloroethoxy) kurbonyl) ominooxy] 2-cyclopentene ITIÜf. i V * I: V i _ Grain Spin Resonopsis (CDCl 3) {7.3Q (s, pH), 5Lo ~ -ol (m, 2H), 5I10 } (5.10H2H), 44-5; cm, 2H), 4.72 (S, c13cH2), ¶2.4-2, s (m, 2H).

Tuh fi layer chromatography: Rf ~ §örde 0,83 (50% -ethylucetof / hexun) 71Preformation9; 1Z7β-dyl-benzyl-cis - [(2-omino-3-cyclopenienyl}} '1_§xi] korbqmut I II ll. II. NH .f I ål c lil _ \ __-_ l ~ _ * ë> 4 / * IIÛ 2 ¶ N ocH2 c 3 n NCOCH2C7H 6 5 III; I 'I' 'I I IIIb : and Msn 1376 t t10ï ï5 e zoo t 3o¶ 72t, 3É_§ (50.4 mmol) edlf2,2-trichloroethyl-cisL [{[(ben2ylaxy}} zinh and 10.7 g Å 2 O 2 (mmol) ammonium chloride. The resulting 7TunnškiktskromotoOrafi7 (híeelgel 60): 7 56- eo) Zinc! ammontamkiortd, 'the methanol process di c. 'w carbanyl] amino-oxy] -2-cyclopentene-carbonate 425 ml of methanol and the solution was treated with 21.3 g (326 mmol) 4). The mixture was stirred vigorously for 16 minutes for some time 1 dental chromatography, showed that the reaction was complete.

The reaction was slightly exothermic and heated from a starting at a temperature of -25 ° C to a temperature of 35 ° C during the reaction. The reaction mixture was filtered and the filtrate was concentrated in vacuum The filtered dense material was washed with about 20 ml of an aqueous solution of 5% sodium hydrogen sulphate and this "Wash water" was added to the residue to evaporate the methanol.

The resulting water mixture was partitioned between methylene chloride and the methylene chloride phase are separated. The aqueous phase was done Bosic to pH value ß with concentrated ommonium hydroxide etc. 7 were treated with 4 g of sodium cyanide and the resulting solution The mixture was extracted 73 times with 200 ml of methylene chloride.

The combined methylene chloride solutions were dried over sodium hydroxide solution. sulfate and concentrated in vacuo to give 9.6 g (77 Å) benzyl-cis- [2-amino-3-cyclopenten-1-yl) oxy] carbamate som'en'olja.

Nuclear Resonance (CDCl 3, ET): 2.2Å2.7 ° (m; -3¿6-5.5 (m), 5.08 ¶¶ (s, ocH¿), 5.5-5.9 (m, cH = cH), je e7.2a ~ (s, 5A: -H). * ' I R; yaIq¿Vo, 41 (1_1o; 9o) commonium hydroxide-methanol- methylene chloride. <1 ai: 143 ~ 15 20 '25 30 448 576 S7 The reaction gave zinc complex with the product dl-benzyl-cis-[(2- Vamino-3-cyclopenten-1-yl) exi] carbamate, which was soluble in MeOH and in most other organic solvents. These can dissolved in an aqueous acid, The compound Díldade in basic pH values strong complexes with zinc, The product can be extracted from an aqueous solution only if the complexes are broken up. EDTAphetetrasodium salt also worked but A not as good as sodium cyanide. b) Zinc, ammonium chloride, methanol, sodium hydroxide reprocessing Zinc, ammonium chloride reduction in methanol was run as above in faTandeV (a) of 17,67 mmol / dl-2,2,24trichloroethyl-cis- [[[(benzyl- oxy) carbonyl] amino] oxy] -2-cyclopentene-1-carbamate. After extraction of the acidic mitten solution to remove dichlorobitic acid. the product, the aqueous solution was basified to pH 14 with 50% sodium hydroxide solution (using ice to hold At the pH value of 8-10 a voluminous one was formed precipitation of zinc hydroxide but this was redissolved at higher pH. and gave the zinc salt of the desired product. This salt 'insoluble in' most solvents with the exception of solutions of syrof. The resulting precipitate was filtered and tarkades. This zinc salt of dl-benzyl-cis [(2-amino-3-cyclapen- ten-1-ylsaxicarbamate was dissolved in a minimal amount of ammonium chloride. rid.For obtaining solution. This was then freeze-dried and the residue was used in Preparation 13a. c) Zinc, methanesulfonic acid methanol process i 1o g (2336 mmoi) digz, 2,2_fr1k1 ° r @ fy1- = 1s [[{(benz0y1 °> <1) k @ r- bonyl] amino] oxy-2-cyclopentene-1-carbamate and was dissolved in 200 ml .., ...___..___.- f ~ - ._, _..._. e _..._- vé-wr, -åmn ~ “Ld44sez7¿l 110 15 20 25 SO 'see methanpl. The solution was treated with 10 g (155 mmol) of zinc powder.

To this mixture was added for 25 minutes and under vigorous stirring 47ml methonsulfonic acid. Thin layer chromatography showed that the reaction was complete on the smaller island one_hour; Reaction mixture-- _ ningen-filtered; then and the solid zinc was washed with methanol. The filtrate and the combined washing water.concentrateÅ was used in vacuo and the residue was used directly in preparation 13 ,; f 'W 1 d) Zinc acetic acid, the water precursor., 1.0 g (2.36 mmol) of 2,2,2-Zichloroethyl ethyl cis [[[(benzoyloxy) redfish bonyl] ammono] oxy] cyclopentene-1-carbomate was dissolved in 10 ml (9: 1) of acetic acid. acid: water and the solution was treated with a total of 1.0 g (15.4 m lmal) zinc added in * 5 batches at 45 minute intervals; After a total of 6 hours after the initial addition, the sklktskromotografí that the reaction was complete. Reaction mixture The filtrate was partitioned between 5% and 5%. triium hydrogen sulfate solution and methylene chloride. The aqueous phase separates was made and canned to pH 9-10 with concentrated ammonium hydroxide using ice to maintain the mixture cold. The resulting aqueous solution was extracted three times with methylene chloride..The combined methylene chloride solutions dry was concentrated over sodium sulfate and concentrated in vacuo to -516 mg (88%) of di-benzyl-ais - [(2-amino-3-Cyclopenten-T- yl) oxy] carbamate as an oil.

At Gttíkeyrdkörníngehlfare, NH4OH falls to be suitable for to break up the zinc salts. NH 4 OH is not sufficient for products according to procedures 12 (a) and 12 (a). u » U! a? in! 10 15 * 20 30 448 37É 59 Ešggšiëll fl igg 131väl-bengyl-cis- (Zëffulímí fl o-3e (ycyklopeqfen-1Äyl) K '' 1 ^ qxí] karbumoÉ (30) 1 IIH H 1 l H5CH2OCNO7 g c6H5cH2ocNo l gCó Iïïb 1 1 _ IIIG (a) 11.6-g (46.6 mmol) of crude benzyl-cis - (] 2-amino-3-cyclopentene- The 1-yl oxyaccharide from step 34 (0) was dissolved in 250 ml. ~ tefrohydrofUron. For duct dysphysis 1115 g (58.3 mmol) 2-mefoXi- carbonylbenzoyl chloride dissolved in 250 ml of fephydrofurun. To dqtid sctfes 11.5 g (58.3 mhbl) Zfmethoxy-carbonylbenzoyl chloride and 31 ml (23.5 g, 232 mmol) in free ethylamine. Reukfíonsblcndníngen was heated to 5006 for 72 hours at which time the discovery layer chromium fogrqfi ontyddé_dft_reukTionen vdr complete; Reconstruction con- .çænåreradès l vacuum, Ãfersfeden-was distributed between etylocefuï and ammonium chloride. Étylocetgtfdsen ~ fvötiodes och sepurerudes .fñed a 5% -íg'not: iumvöfešulfut and water and fofkodes öVer magnesium sulfate. Concentration with ethyl acetate solution in vacuo gave 22.9 g aren åiersfod. Aferfodgn chromutogrcferudes over 2 kg 'silica gel, óO, eluerodes mea (40,60) ethyl acetate-Skellysolve B. 400 ml fractions are added after a pre-drip of 2 liters.

Product fi Viewed? in frokfionernu_16-24 at thin-layer chromophore grøfl; Concentration of these fractions gave 13.5 g (75%) of -cis-12-ftclcmido-3- (cyclopenophenyl) oXi] carbonate. f- I 10 15 20 25g 30 ' n% 44äg376% ^ g 6o'¶ Nitrogen spin coagulation (COCl 3, Åf): 2.4-3.2 (m, CH 2), 4.5 + 5.5 (m, 4), 5.00 (g, ÖCHZ), 5.5_6.2 í¿-g g - n _ ' (m, cH = cH); 7.27 (; 5ArH), 7; 5-s, o_ (n, 4 ArH); 1 Tunnskíkfškromufggrgfí (kí; e1gel: 60) Rf-v fi fde 0,48 i (40-60) étylocetgtfSkeI1ysqlve B.7 í (b) Using GV šgmmd förfurnnde as in (0) above gave 17.67 g o; en¿dl-benzylßcíšf [(2ÅamÅnof3-cyclopenfenphyl) nxi] -crbumot- zinc sulf, a; 23 9 (4a%)} ice; [2-ffq11m1d @; a_cyk1 ° penfen ~ 1_y1) ° xi_¶ kuibunafå, (C) Using.Summu föffurcnde as in (G) and (b) oven gave 23; 6 mmol dl-ben2yl-ei; [f2-umino-3 + cyclopenten-1-yl) -oxy] 4 Carbide 6.9 g (77% Yield) dl-cis - [(2-cycloimido-3-cyclopenic) ïén-1-yi) oxijku: bamuf {.n T I "' The seamless steps 12 (c): and T3 (c) are the fßíednggnc for-I fopcndèí för ømyunålíng gv dl ¥ 2¿2} 2-fríklnroefylfcís - [[[(ben ~ « zyloxy) kornonylEgmín0] o fi i] -2-cyclopentene-1-corbomut-to dl- benzylecycl [2β-cyclofenac-3-yl] nxi] kgrbumuf. oessufom k @ n_b $ a @ di- och a; c1s- (2-ffQ; im; d¿-3- [¿yk1 ° penfen- 1- (2,2,2-ÉríkløréfoxíkurbonyL) dmínopXí] -kurbamuf'fromsföllcs med ' I.qnvöndníng'ov ”Frcmstgl1níng 13 men ned-utbyfé mot dl- eller d-I 712; 2,2-Triclonethyl-cis-6i; - [(2-fumino-43-cyclopenten-1-yl] -oxy] - I kurbomuf. This unchanged output motor can be represented by _beh§5a1¿ng av dl éxler a rèspekfiv§ benzyl-Ci; [(2,2,2_frik1 ° r0ef_. -Oxy] kurbony1) uminoooxy] -2-cyclopenephene-1-corbumut use GQ * preparation 1ï * with'gHBr_ -foot isüttiksyro for one hour at room temperature. The reflux solution is concentrated in vacuo Ü ___... ._ .........__._.._..., _-___._._......_..._.__.__ .., V '._ ,, .. % ~ ,, +,? %},%%, 44s 576 61 , Ŷ7vurvíd a product was obtained which could be used directly as above wa-q fi sfallning 13. f ',, Ä Kamspi fi nr-esønungj (vcnçla) = 7, s_s, o (m, 4H), 8.45 (m, NH), s, s__ V, 6.2 (m, 2H), 4.3-5.5 (m, 4H), 4.69 (5, CCl3CH2), '5 i' 2 ', 6-3, o (m, 2H). í Barrel chromoto§rophy: fRf ~ vürde 6,67 (50% efylooétot / hexun) , i gylfgiggf fi ng 14 ¶ (us, s§s och fm, sam-Ubenzy1 °> <1) s <@ fb ° ny1] _a_ Oxo-afffolimido-5-isoxyczolidine-acetic acid IQ Û 44s¶à7e, llla ' ¶ 62 ' »U 10; 15 lucky ~ acid. 448 3760 1.0 g (26.5 mmol) (dlecis-β-2-phthulimido-3-cyclopenten-1-yl) - oxíjkøfbnmqï Illq Dissolve in 250 ml of acetone and 180 ml of vutfen.V The resulting solution was treated with 28 g (130 mmol) of sodium hydroxide solution. _fIí0Hj @ a0f AND 100 mg of rufnium chloride hydruf (1_s H20) 1 5 H1 V01; ten; The reaction mixture was stirred vigorously for 1 hour. Effer During the first 15 minutes, a slight exotherm occurred. lwtíon ofšukdd_uv off temperoturen _ $ {eg from around room temperature (about 23 ° C) at 35 ° C. Reuktíonsblondníngen 7 víndunàfødes then at smaller island 30 mm Hg oçh less than 3006 , for removal dv ucetpH. ^ Deñ vuftenhultígu residue distributed des melloñ efylueefoi and moistened acidified with co 10 ml M sulfur Votfenfosen'seporerddes ech exfruherodeš twice med etylovetot. De summdnslogno_eïyloceloflösníngornu fvöffudes with saturated nuïríumk1orídldsníng, Vtorkudes with mcgneeíumsulfut and concentrated in vacuo (less than 30 mm Hg, less than 30 ° C) varvid eíhölls et? gldnsoqde foam. The residue is chromofogrcferodes 1 kg of CC-4 silica gel elutes with a linear gradient. sfölld Uf 5 l (4OÉ6O) ethylqcetcf-Skellysolve B and 5 l (80-20) Äe fi ylccetatefSkellysolve B. Fractionation (400 ml) 16-19 guv 7.48 g of substantially pure (as, 55 and 2R, 5R) -2 [(ben2yloxy) - 47-Ethylphonyl] -3β-dimethyl-5-isoxuzoline-ophyric acid with a melt- 25l so, punk at 113 DEG-110 DEG C. (from etomol), 7 Körnšpínnresoncns d¿focefd fl, cg) § 3,16 (d, J = 7,5, CH2), 5,25 0 (S, §CH2), 5.1_s, 7 (H, 2), 7.09 (S, 5) 7.92 (5.4).

I 0 ,, 21H16N2 ° s _ Beraknuf; c, 59.43; H, 3.00; N, 6.60 Erhallefill c, 50.79; H, 3.80; N, 6.53.

Elemenförunolysz Calculated for C : Froktion014 gay 0.93 g 2-f (benzyloxy) -cduconyl] -Sphoxo-4-phtholimine : ___ 10 15, k) U: 30 = 44s576ljv , 64 Ido-5-isoxic foil with a pour point of 160-162 ° C (efyluse dl / hsxun, lzl).

Kæ @ fi m @ w @ ß,% @ æßm6 »ap6 @ ¿J¿ascäysßs (S, ocH2), 5.1, 2.5, e (m, 2), 7.45 (m, 5) 7.88 (s, 4), 21 16 2 a _2 _ _ H vc, 57.01; H, 4, jo; N, 6.33 7 Ejhålletzf C, 57.24; H, 3.98; 1N, 6.45 7 'Elèmehialbn fi lysz Befükhct fö: C ¶H Nv0 .H O' Calculated: A mixture dv dé two syfornu was obtained in 'Fraction lä, Using sum fërforo fi de sqm l production 14 men med ípsëffunde-cv.dl¿ ellef d-císf (2 ~ ffølímído) -3-fcyklopenfen- 11 ~ (2,2,2-trichloroefoicuronyl) uminooxy] kurbomct gav (as, 55 och_V ß aR, '5R) ~ 2 - [(2,2,24% ríkl9ro§toxl) kdfBonyl} -3 ~ oxo 5-Isoxaczolidine-acetic acid (57s% byte), m.p. 208-210 ° C. ' Körnspinnresonuns (ocefo fi- d6); 3.27 (d, J = 7.5 H2, CH2), s s "A 'A' 4.92 (S, cc13cH2), 5.1_5.7 (m, 2H), 7.91 (S, 4H). slvu fifi skikfskfomdfsgrqfi5-Rf_varde = 6.41 (A xx) An fl lysz Calculation number for 7 C H Cl N, 0 -16 11 3 2 a.,, .7 Calculus "f 7C, '41, 27; _ H, .2.38; N, 6.02 , ï_ fi rha11 @ t; ~ s c, 41.33; H, 2.36; N, 6.04.

The isomer (ÅS, 55 Qch 4R, 5R) -2- (2,2,2-cyclohexethoxy) carbonyl] f 3-Oxo-4-fulimido-5-isoxydzolidine-acetic acid was also prepared with etf Ufbyfe of 22%; Û 10 15 20 30 4481375 , 65 Kürnspíhnresonuns (oceton¿d¿) i_3,1Ö (d, Jc5,5 Hè, 2H1, - '1 o 1 s, os¶ (5, cc13cH2), s, 1_s, s ¶ (m, 2H), 7.90 (s, 4H).

KTunnskíkfskromoíogrofí: Rf ~ vörde = 0,52.

Kfgpštü1lnín9 15 »(aS, 5S and aR, 5R) + 3-oxo-α-phthalimido-5-ice oxozoidine-oxy acid : IC 1 fo o »c5 1 c: Ib 7.48 9 (17.6 fi molå (as, ss and QR, 5R) _2 _ [(ben1y10Xi) k @ fb ° ny11- Dissolve 3-oxoea-Phtholimido-5-isoxozolinoic acetic acid in 150 ml ethyl acetate and 75 ml of 95% ethanol. The solution was treated with 115-gloollodium black and hydrated at 25 ° C with off Pressure 7 cv 1 atmosphere. The reaction was interrupted after 165 minutes, after which, The filtration rod filter and filtrate mixture were used directly for preparation (asl 55 and aR, 5R) -3-oxo-α-phthalimido-5- isoxozolidine-affixic acid.

With the exception of the sum procedure as above in the case of another -sók ínounstudes filfrutet in vacuo varvid obtained (aS, 5S och αR, 5R) -3-oxo-α-phthalimido-5-icoxozolidine-acetic acid as a feed. _. »= 15 N) 11 ' 30 0448376 2 I Tumnskíktskromutogfufí, (k§selgel 60); RfÅvörde = 0.36 in it -motemiqlef hdde, eft R HBr / CH 2 Cl 2 and trifluoroacetic acid could also be used. 66 Karmspimmiesmmmms. (coqon fl å) 2.92 (deivissp11ffrmf.d, m2), Δ f 5.1_5.7, (m, 2), 7.850 (s, 4 Arn), upper phase eV (9: 2: 5: 10) efylocephot- öftíksyrcecyklohexonévotten, I summa 0Üsysfem hode Ufgångsmoteríulet ett Rf- Value of 0.46, I I -> Sdmmd förfpronde som i Fromstöllníng 15 onvöndes_med dl eller d- fåreníngdrno with formula VIIId guy dl or d (respectively) isofríc fi olomsyfa-ffclimid of formula VIIc as a whipped foam med eft Rf ~ §örde på 0,54 Vid tunnskíkfskromdfogrofi. Initial fëyärde på Q, 64 ,: "Nuclear Spin Resonance (Ocetone): 9.1 (s, CO 2 H), 7.83 (S, 4H), s, ~ o_s, s (m, 2H), 02.9s (m, 211); in Alternatively, the benzyloxycarbonyl group may be the nucleoside of the compound with IIc for the image of the compound of formula IIb (or with _ ¥ ormlerno VIId_Tíll'YIIc) with acid; For example, 424 mg is dissolved (1 mmol) of the compound of formula IIb in 5 ml of glacial acetic acid nitrogen atmosphere oehjtorr bromväie bubblos into reokfíonsblundning- _ and undef 10_minuier. After stirring for 4 hours at room temperature rufur "kpncentrerodes solution and chromiumfogroferudes of 50 g CC + Å silica gel with 70% ethyl phylophate / hexane, Detfo procedure gave 170 mg- (59%) of a product as our idea fish with the product as was obtained hydrogenolymic (in the case of nuclear spin resomes and chromiumfogrufi). Other acids and solvents, such as HBr / CH 3 NO, f? vr) 0 s ~ 1 101 1 15 25 448 376 '67 Ftam§täl} ning¿l§_ï (uS, 55 and aR, 5R) e3 ~ oXo-u-ftalimídoÅ5- isoxazalidine acetic acid-benihydryl ester co2cH (C6H5) 2 IIQ 5.2 9 126.5 nmol) benzophenone hydrazone was dissolved in 125 ml of ethyl solution ether. The solution was treated with 10 g of sodium sulfate, 11.1 g (51 mmol1 of yellow mercury oxide and 0.2 ml of a saturated potassium 'hydroxide solution in ethyl alcohol; The reaction was stirred for 60 minutes and the resulting deep bourgonge ~ gurgled mixture was filtered. The resulting solution was added directly to the reaction medium. the solution from a 17.6 mmol hydrogenation in which (aS, 55 and QR, 5R1 ~ 3 + oxa-q-phthalimide-5-isoxazalidine-acetic acid preparation, 'Tooth layer chromatography showed that the reaction was complete on' 1 VmindIe ”Ön 1 hour. The reaction then treated a sufficient * amount of 3N hydrochloric acid under vigorous stirring to destroy this surplus of baurgonge-förgadadíazo associations. Reuktian The mixture was then evaporated in vacuo (below 30 mm Hg and below) S®QC) and chromatographed over 500 g of CC-4 silica gel, and eluent was treated with (40-60) ethyl acetate / toluene. Fractions of 200 ml were collected. Éasç 55 och aR, 5R) ~ 3-oxophthalimido-5 ~ i5oxazolidine- acetic acid-benzhydryl ester was found in fractions 10-14 (3.05 g, Qßßfutbyte).

Körnsg1nnresonans_ (CDClà šli 2,75 (d, J = 11,5, CH2), 5,15-5,7 0 0 (m, 2), 6.93 (S, cH (c 6 H 5) 2), 7.13 - (S, c5H5), 7.28 (S, c6H5), 7.5-8.0 , (m, 4, ArH). ,. 10 15 zol 30 7Nuclear spin resonance (CDCl 3): 7.81 (mf 4H), 7.05 (A 1? 448376 e 68 I * Tunnsklkfskromotogrufl.lklselgel 60):> * R? Åvürde: š ~ Q, 42 í (40-60) ethyl cefut-folU- ~ en. The Iso product from compound 33 head an Rf-1 value of 0.59 in sum sysfem.- A fi edfuinytijonde ev ett fëíforonde similar to that in fremsföllnlno 16 but with ufbyte ev dífenyldíezometcn moi RN2 where R could mean ~ no mefyl¿ ethyl} benzyl and the like give mofsvoronde estrors with the formula lIb¿ With these more reoktívo dlkyldíozoeföreníngur it is more effective off treated acid of formula IIb in a non- 7 pmotic solvents, such as pseudohydrofuron, in addition eåunol.

Alfernofivf can be estrone of formula IIb precipitated by alkyl- ¿_Efíng ev syron i en Bas med e fi reuctivef olkyleríngsmedel. 87 mg (0.3 mmol) of a compound of formula IIb was treated, for example in 3 ml of dry ocetonitrile in a nitrogen atmosphere with 50 .mu.l of diisopropyl- ethylamine and eQ mg pemethoxybenzyl bromide. After 16 hours, the solution was placed between the efyloceåuf and the water and the organic phase seporexodes oeh precoded_with'noiríumsUl§oi and concentrated rodes. Preporofív; foundskromtskromutogfefí '(50% efylocetet i nexone) gave 55 mg (45%) of possible pfmefoxylbenzyl spheres. 2s2,4H>, 5,1- ¶ 5.7 (, 2H), 5.13 (S, 2H), s, 76 (S, 3H; cH3o), 2, a1 (d, J = 7, s, H3, e ' 2H); Utilizing the preamble which are described in detail above but with ufbyfunde ov the compound of formula IIc against dl ~ orl (IN G1 10 '15 20 25 f 30 n¶44sns76 69 H-id # is6tfícholomsy; c ¥ ffolínid med forneln VIIc ger respe fi fíve 'dl- nch d-Compound of formula VIIIb, isofricholomic acid i f {qlÅmiåèsferQf f5gm§tÉ11n§gg4lZ: dl-trons-3 # ftblimid§ ~ 4 ~ fluoromethane- sulfonyloxycyclopents sfg (2118 mmol) 4-hydroxy-34-dimethyl-cyclopeniene and 1.72 g (21.8 mmol) pyridine was dissolved in 6 ml of methylene chloride and the solution a drop of juice for 40 minutes until an ice-cold stirred solution is added. 4.6 g (2T, 8 mmol) of free fluoromethanesulfonic anhydride i '15 ml mephylene chloride in nitrogen atmosphere. The solution was stirred evenly. 'ligore 15'minufer och työttudes dörreffer med vcffen, precodes The concentrated trophy of the mephylene chloride solution gave dl- Trons-3-diflimimido-4-trifluoromefunsulfonyloxycyclopenfen. Fig. 18 dl-benzyl (cis- [I2-phtholimido-3-cyclopentene- 'yl) oRi] kurbcmøf7 I ~% 44ß% a76} 10 15 ? cf 25 30. , j7o 21,8 m fi ol * d1_fruns_3_ffaiimia ° _4_fI¿f1p0romèf¿nsU1fonyloxi- cyclosenfen was dissolved in 50 ml of methylene chloride and the solution hondiodçs with 21.8 mmol of potassium solv mV N-hydroxy-benzylurethane Eff§r_omröring 24'tímmu§ í kvöveufmosför éxtrcherodes reaktions- blending with 5% yotfen solution of nufríumvëïek bon fbonut och Vofién dch Tork fi this. Disfillufion of mefuñÉlofiden gave a siod which k; omofogruFerodés over silica gel, eluèrudès with (40-60) Ethyl acetoSkel1¶solve'B.-After concentration of fruit- ¶Tíonen sçm vid funnskíktskromatbgrofí vísodè sig ihnehållu p: o¿ukten, .gov? d-benzyl-cis - [(2-fiølímíåo ¥ 3fcyklopénten ~ yl) - cxíjkcrbamdf.

Ffomgíëšà fi ínq av opfiskt aktiva ísomerer E; 9 @ §fÉlLQ§EQ_lZ Dissolution cv dI-ions-3-cmino-4-hydroxy ~ _ 7 K 'In the cyclopentene (5): Initial filling of (+) - de- oxícholcf 6b'och (-) tur% raf 6c n), 10É 448 376 7: 1 ' 1-, deoxycholic acid »Yug. > 'i. .i 2.- Årnb§r1ït8 ¥ RÅ440O '¶ í (OH) _ Ö.> LU), vinsyro | vb ¶ï _ I co2H NH2 I ¶HcoH H AND CUEH _ 10 15 20 25 30 448 376 0 L - (+) - vinsyfe, ¿pp1asf.í zoo ml 9s% _ig efønol; De b1 @ nauae 135- _72 1) 49.5 g (0.50 gmol / dl-trons-3-umind-new coxycyclopentene _ Dissolve 200-200 ml of methanol and 98 g (0.25 mol) of deexicholic acid dissolved in about 200-300 ml mefqnel eeh blundqdes oeh allowed me " krlsfullisero during several fims. Kfísfellerne av fruns-3- cmino «Å4hyHroxí-Qyklopenlen uppsumlqdeswgenbm'flltreríng och, fvöttedesrtfe times mee some share? meiunol._DörVid received _ I ", 7105 g are needed 3-omino-4-hydrocyclopenene-phenoxyoxy as light I 'eígegegude ktlsfeller with a melting point of 195-197 ° C (dec. , delníng) .VMederlulen spuredes fill sfeg 2. 2) 500 ml of Ambe; lífeilRÅ-400 (Cl_folm) was added to 600 ml of slípod lrott eeh tvettodes six times with 200 ml sufser of e {f¿ N-noirium chloride, three times with votfen (3 X 200 ml), with 200 ml _ sufser water fre times with methaneql. 250 ml of deflo hydroxy heels and the mother body from sfeg 1 QQcn blqndudes and stirred 2 tímmcí i.kvöyeu% mesfä; .lßlundníngen was then beaten on top of extract 250 ml of Hurlszpockul in a cytophrographic column in The mixture is eluted with mephanol and 250 ml fractions collected. Prodnkten §ísude sig vid funnskikfskromcfogrofíy 7 is ílfrukfionernc 106; The evaporation of these fractions gave 32 g (3E, 4R) of 3-amino-4-hydroxycyclopenfen.

.Tnnnskíklsksomutogrufí (silica gel 00): Rf value = 0.24 i 7 _ 0 0 'I 7' 'K' 7 (l ~ 20-00) ummonium hydroxide- I melcnol - CH2Cl2. Was found by kuliumpermungøndtbe- 'sprp {ning; 3) The supernatant from step 2 was dissolved in 300 ml of 95% strength ethanol. and the solution was mixed with a solution cv 37.5 g (0.25 mol) .Q 10 ' 15 020 ” FJ IJ ' 30 f (c = 3.20), 448 576 '0 0730 Inoculated with previously dissolved salt. After 2-3 hours The crystals were collected by filtration and pre-coated. Thereby "obtained ~ 54.5 g kri $ 1 @ 11er with a narrow punkf of s4fs6 ° c. Krisf fl l- 1ëfnU00mkf1Sf @ 11ise; qaes ur 700 m1 95% _1g efunol. whereby obtained 43.5 9 krisføliin çsR, 4R); 3fqm1n ° _4_hydfQx1 = yk10penfen L (+) - vin- " syrošolf with a melting point of 86.5-88.50 [alzor = -37.80 ' 0 0 0 0 'o 578 4) 2000 ml of Amber.iRA ~ + 40 DEG C. (OH-phosphorus) and 300 ml of methanol. 'tíllsoffès 25¶g dissolved furfrofsolt from steg_3Å Blondníngen om- was stirred.in nitrogen osmosi under 1 fimme.'Ytte: Iigore 100 ml Amber- The IRO-40O (OH form) forms a chromatographic group and V above mixture of foriorsoltef, .Amberlíte hurts and öyerstående meíonollösning fíllsoftet on top. Mefonolen0ut- iogs0from kola nen and förs fl mefonol had to pass thereby fill its an ioful amount of 1500 nl of methanol was collected. Methunol- The mixture was evaporated in vacuo to give 10.18 g of crystalline êters + oo, (SR, 4R) å3Åomino-4-hydroxycyclopenfen with a melting point pa s7_75 ° cin {@] 2 ° '=, - 1a9 ° (@ = 1.0, M @ oH). 578 5¿9 @ ¿¿g¿; Q¿¿¿¿gg_ (] R, sR) §2,2,2-friklorefyl-s_hydr ° x1 ~ 2_cyk10- penten-1 + kurbqmot <0) 0 "00 n ~ ^ 0 '0 »0 0 0. O <+> o / š 0 ~~~ clï í ~ 7 <+> än; _ 0 \\, // L \\ NH c; cocH2cc1G 5- NC ° çH2CCl3 0'§§ 2 -. ° H 0 OH _ I Nqzcos. 0 <+>: vb ¶ ï. '(+>: vc - «fn% 44s 376L ¶1o¶ '15 20 30 74 ' 1, 18 (ICQ mmol) orene (3R, 4R) - 3-quinino-4-hydroxycyclopfen (ffun $ tölld.§om íïfromstöllníng 19, sfeg 4> upplösfeš i 75_ml water and the mixture was treated with 10.6 g (100 mmol) of sodium hydroxide solution. triunkurbonot. Bldndníngen kyldeš sedan på etf-ísbëd till under 7 TOQC och.bebcndlqdesndroppvís nnder k; qftíg omföríng med 24 g (} 10-nmšl) -Éríklošçfylklórofofmiof under 3Q'mínufçr._Efter 3 ~ tim fi u; 7filfre ¥ udes reakfíonsblqndnínçen och den Uppscmlode fcs {c1nrb§uktèn tväítudèš carefully with vuiten. When drying is fi total 2a, 439 (TR, 5R) f2,2,2-trichloroethyl§5-hydroxy-2-cyclopene- Kfen-1§korbamut.som, eft'krís {nllínt fast muferíal-méd en smält-. ppnkt reach 82 ~ 84 ° C, Omkïistullísofíon av eft Iitef prov ur iso- * 7nrqpylefér-Skçllysplve B Quv etf material with a melting point on 87-s7¿59cn [a]; 92 ° n (ç = o, 14, M @ óH); _ Tun fi sk¿kfSkf0m @ {0gr @ f1 (silica gel 60): R¿ ~ vafd§ 0,5 1 (1o_9o) 'f ocefon4methylene chloride. g¿9m; f§¿¿pin9_g¿ ¶n (1R, ss) _z, 2,2_fr1k1 ° r ° efy1-sf (ff @ 1imia ° x1) _ '* 7 2-Äyklbpenten-1 ~ korbomcT' in 1 Q (f) ¶ _ n ï = _II; & _ - <: \ n HU nn ¿: _ N NcocH2cc13¶ _Ho n: _ ¶ () ¶ '_ ¶ (C6H5> sP ¶ + _: vc _ _n .¿ f ' .¶-: ¶ 1 ¶ I (_Nco2c2H5) 2 L_ O 7 Q ~ THF Wmn ¶¶ / u \, -.Ncoc fi cci - n No -n. 2 3 /. . Ü Q 'ni (+) IIIQ W: ri- 15 25 30 É 448 376 »75 ldzj 9- (76, s fnmol) (m, 5R), 2,2, mriklowefyps-hydmlxy-z-cyclo- pgnfe fi-1; kqIb @ mqf; 13.7¿ 9 (s4.4 mmol) N_hydr ° x1ffo1im1q and "VK22, 1Zg '(84 @ 4 mmol) of triphenylphosphine was dissolved in 400 ml of hydrofuruñß To the stirred solution tíllsctfes dropwise below lm¶minierd16¿12 g (92, ¿”mmo1) diethyl azodicarboxylate, varvid , the fempercture was kept below_35 ° C with eft isbdd. The reaction was stirred fseddn 1 hour fi e.vídl25 ° C qureffer den koncenirerudes i vokuum I (ómkríngj d l jnedloknkfíing 100 m1 '(_ 1o, 6o) efylucèfuf-skellysølvelß çcdh fan-_ l In the process of triphenylphosphine oxide pigeon nodes by filtration after : oñkrlñg 15 míquåer; Åferefoden sctfes to the races of a 2 kg In silica gel 5Ö ~ column, which eluted with 3 l (40-60), followed by (50-5 °) fetylucetut-Skellysolve B. Fraklions of 300 ml collection iledeef Frokfidnernc 19-27 víeade sig lnnehållu ren (lR, 5S) -2,2,2 ~ fri ~ chloroethyl-cis-5- (phthulimidoxy) -2-cyclopentene-leak detergent 'chromophography. Upon cone frosion, they gave 26.9 g (1R, 5S) -2,2,2- frichlorophyll-54 (ffulimidoxy) F2-cyclopentene-1-turmeric crystals, 117_ng ° c Mo = ¿26 ° (c_ = o, 5 βgg (1R, 5S) -2,2,2-frichloro-ethyl-5- (cminooxy) - 2-eyklopenfen-1-kørbumot NH2NH2H2O im: u , NQQCH C51 COCH CCI ^ No 2 3 '»e H2No 2 3 . y V * O : ned -l * l d e md 044sf376 , 76 24,9 (17, e7 mmçl) (1R; ss) -2,2,2- {I1k1¿} efyi_s_ (ff @ 1i @ 1d ° xi) _2- 0 10 the cyclopenten-1acorbdmut was dissolved. in 230 ml of tefruhydrofurcn and 230 ml of ethyl alcohol; The solution was treated with 3.3 ml (3.4 §8'mmol) 1hydrczínhy fl íof. After 10 mlnuier-bíldbdes a fall.

After 2> fímmár1índUnsïqdés'reuktíonsßlondningen i vukuum 'ß (<1 25 mm Hš och, §o 30 ° C), Åsterstøden> trífÜrçrqdes med methylene_ chloride and filfreroöég for aV1ögsn0nde'§v fl an olö $ 1ígo7Ffo1-A1 hydruzides. FilTfafet_kohcentrer @ des i vukuu fi 1 whereby _ 20.3 g of a hclvf§stfm0teríøl.'D§flo mutefídl trif fl reradeš mèd 100 ml efylocefcf oc fi fíltrerudes.-Dçf filfrepude-fasta moferíul- '1 ei tyäïtbde $ med 100 ml mefylenkloridl Detsommunslogno fíltrufef Z 15 20 ¶ 250 30 Il fi dunsfßaes i vokgum1 Vorvíd obtained 18.51 g (1R; 5S) -2,2,25 frikI @ roefyl ~ 5-fåminbçxí) -2-cyclopenfenÄ1 ~ kurbcmut som en olio.

'Tunnskikf $ krcmafogrufi (silicon 60): RF value = 0.41 i (5-95'-metunol-benzene pch Rf = 0.41 Ii (40-60) efylošelof-Skellyšolve B.

By d änd vändnlng of the same claim as in fromsfüllníng 23 men with use of hclogenolkyl - (Ür, 5S) -5 (ffulimidoxy) ~ 2- _ cyk10p @ nf @ n ~ 1-knfbqmuf i stallet far. (1R, 5s) _2,2, z_ffik10r-_1 Ielyl-5 - (phthulmiooxy) -2-cyclopenene-1-corbamaler, wherein hölls mofsvdrcnde hçlóQenølkyl-5- (omínoxy) -24cyklßpentén ~ 1- kçrbomuf, I I 1 f (1R; ss) _2,2,2_frik1 ° I0 @ fy1_s - {[[(benzyI0x1) - '-Carbonyl] dmino1o # í1-2-cyclbpenTen-1-kurbcmof' fš9Es% öllQåEq'23 'm Q 10 ._ | ' CH {\ 'J Uw 30 ne448 376 17 * ä c1cocH2c H 'd. . --6 ~ fi ä Q RH Hhn 3 _ e e n Ncocn ccl ¶D e cón5cH5cH2ocNbd 2 3 IIIC 1s§5 9 ev ån Oren (íR} 55) _2,2,2 = fr1k1Qrefy1_5; @ m15q @ xi ~ 2_ cyclopentene ~ 1-kcfbomof; frdmstdlld in accordance with frqmsfüllníng 10_Uppiösfes Å 175 ml pyridine and the solution was cooled on eff ice ~ " bed and treated with 11.6 g (67.7 mmol) of benzyloxychloroformic unpidsí in 15-ml mephylene chloride; After 1.5 hours, treated The reaction mixture was mixed with 10 ml of vivo, stirred for 10 minutes and The compound was beaten in the medium and methylene chloride and treated charged with ommonium clprid f ll until it became acidic. Methylene chloride-L phase seporerudes_dch preceded by nufrium sulfof and concentrated tferodes in vacuo, vdrvíd obtained 22.6 g dv en oil. This oil_ crystalline acid ether to give 5.2 g (1R, 5S) -2,2,2-free cloifyl. {((beneylexi) carbonyl) omino) oxy] -2-cyclopenphene-1-cortyl _ bemot with a melting point of 89.5 - 90.5. A dndro harvest on 779.17 g with a melting point of 89-90 and a third harvest of 1.54 g with a melting point of 8Ö-85 were obtained by crisis foliage of nmderluten from the first harvest of isopropyl lefer. í @] D = -ss ° (c; o} o2, Neon). funnekíktakrometogrofi, (kieelgel dO): 'Rf ~ vördet = 0.73 í I J (40ê60) eTyloceïdï-Skelly- solve B. _ ...----. w-í-qw-pv-v-e-f 1o¶ 15 25 30 44s% s761: ¶ vs íïgmstêlggåig fi ggg (IR, 5S) ¿2,2,2- fi riklooroethyl ~ 5- [f [(f- 7 I b fi tylqxí) korbony1] omíno] oXí¿ ~ 2-cyclopenfe ¶ _en; 1_k @ rbdm ° f ¶ ä 7, Ég * oren * (1É; 5S) -2; 2,2-freechloroethyl-5- (minipoxy) -2-cycloo [en- The ten-1-corbum was dissolved in 25 ml of hydrogen hydroxide and 6.15 g (25 mmol) . \ ' 2- (fert-butoxycophsophenyloxymino) -2-phenylucetanenifril and dormant The mixture was stirred at 22 hours: room temperature, 20 hours at 50 ° C and 72 hours at room temperature; vcreffer the in- * dunsfodes_í vokuum.'ÅferšfodenIkrßmdfógrcferodes övér QOO g kísçlgel, _éluerodes mèd '(15-85) efylocçfof-fdluen. Frøkfioner of 300 ml ßbpscmlades.'The product showed šíg available in pocket tíonernu 10 ~ Ä2. Indun $ tni fi g_och pmkrísfollísotíon-av återstoden from Skellysolve B gave (TR, 5S) ~ 2,2,2> ïrÅk1orQ-efyl-5 - [[[(t ~ buTóxi) - karEon§] fdñinßloxi] É2-cyclopenfen-1 ~ kurbamof med en smölfpunki ïpå 83 ~ 84OC'som ett yíff, fast majçriol.

Body spin resonance du sdufu (CDCl3, É;) f, 45 (5.9) 2.45: 2.7 (m, 2), 4.3- ¶4.9 (m, 2) 4.75 (S, 2), 5, e_6.1 (m, sH); 7.7_7, a (b, 1). _f§gg§j§Åš§¿ggA2í. (] S, ZR) -benzylt (2 ~ o fi íno-3-cyclopenfen- 'I T-yl) oXi] kurbumat , _ n 7 ¶ \\% 7 I ¶_, / ”NH2 7 I ? - »- ~> f» Oí \ /: 'W; "HU in NC °° H2 ° C1 ¶ “oNcocH2c¿H5 c H cH and fi åi H 3 “¶ V6 5 2 _ ¶¶ ¶ ¶ .life .II »¶ f ¶, Iïïb wa, (Ü 10 15 20 30 * 3 ~ cyclopénfen ~ T-y1) oXí] kurB§mQf { ~ 448f376 79 7.12'g (16, s m fi ol) É (iR, 5S) ~ 2,2,2_fr1k10r0 @ fy1_s - [[[(b @ nzy1 ° Xi; ~ chrbonyï] uñíno1pxi-2-cyclopenfen-1-kurbomuf was dissolved in 75 ml methanol; The solution was treated with 7 g (108 mmHg) of zinc powder ¶Till dénno mixture soften for 10 minutes under vigorous _mnöríng_2,1Z ml mefdnsulfonicro, KTunnskíktskromofogrofí vise ótt¿reak {íonen voi fullsiündíg i fi om minder ön 90 minutes. 'fReEktíoñsblohdningçn fíltferodes óch fl en festa zinken tvätte- I dçsf @ ed methanol. Filtycfef and the såmmchslogno fvöffvöfskorno fkßhçenfrerodes i vcküum, vo; vÅd erhölls É, 8_g oren (1S, 2R) Ibenzyl-f (2-amino-3-cyclopenphen-1-yl) oxy] kurbumof, which is 'vëndesidírekf vid ffomstöllníng 23.

With the habit of the same.förfcrunde sam-i fyumsföllning 24 months 1 Sfallef for (1R, ss) _2; 2,2_fr1k1 @ f0efy1_5 _ [[[(benzy10xi) _ kurbonyl} umino] oxy-2-cyclopene {cn41 «korbcmat used (1R, 5S) ~ 2,2,2§trichlorophyll ~ 5Q [[[(beniyloxy] carbonyl] omEno] oxy ~ 2- Cyclope-feh-1-carbon dioxide was obtained (15.2R) -f-buphyl-5 - [(2-omino- §¿9¶§i§ ;; fl iEQwgä_ (15,2R) ~ behzyl- (2-ffolimid§-3- (cyclopenten- 1Äyl) oXí] koIboHof HW ¶ n? _ * fo C¿H5CH20CN ° - -.c6H5cH2ocNo 0 ('- 1115. * 7 _ _ I11 @ ¶ 10 25 30 44s ^ s7s > w 5A518 (16.8 mmHg) forene (fR, 5R) -benzyl-f (2-amino-3-cyclopentene) 1-yl) oxy] cornmeal solution precipitating 23 g dissolved in 90 ml tetrohydrqfuron. To this §ofte; .4,95 Q (25 mmol) 2-methogif carbonylbenzoyl chloride and 10 ml (7.3 g, 72 mmol) of triethylumin.

The reaction solution is heated to 50 ° C for 72 hours; get. iunn§kikfskrQmàt0gÉcfí Qíš fi dé gif reuktioheñ-vqf'fullsföndíg.

Reukfionsblondningen konsèntrerodçsÅí0vgkuum ošh föpdélodes between ethyl acetate and quinonium chloride, Efylucetotfusén separe- K rudeš and fvütfodeš with a 5% 4ig0nctríumvöfesulfu & solution in véfien bch_tQrkodes över mugnesíumsuïfof. Concentration of The liquid solution in vacuum gave 7.4 g of crude residue. The reaction kÉomofógroferdd§s öyér 600 g silica gel, éluérodes med (40 ~ 60) eiyldcèfot-Skellysolve B. Fraktíqner of 50 ml uppscmlqdes.

Produkfen-turned out to be present in the fraction 16 «24 víd_fUnn- layer chromate fl grøfí., Co fifi entrenchion QQ its fi fractions guv 5.2 g (75%) (13.2R) Ebenzyl [2-phtholimido-3- (cyclophenienyl) xylkurbamut * som eff krís fi ollint fcsf material-med en sm§lïpunkt på 89-92, ï @] D = _143 ° (C = 0.7, ÛMeoH) ._ 0 Tunnskikiéchromciogídfi '(silica gel '60): Rf> =' 0; Ä8 i (40-60) ethyl- 0 oceíufÅSkellysolve B. progeny fi QÉ (QS, 5S) Ã2 {Kbenz¶lox¿) kq; bonyl] -3-oxo-a- _ 'ffqlimído-5-isocozozolidine ~ acetic acid now å ' mg; P HH _ 07 _ å- ~ -; - í ~ = - ~ f> / 0 > .co.cH¿ CßH5_ 1 ¶ 448 .S76- <: ~ N_ ' V. çugcsus 0 N 0 _ » 16 f . 15 ízlof 25 30 I tíoneblondníngenVíndQnsTade5'víd less than 30 mm Hg and míndye 448 376 10.0dg_ (2ó} 5 mmol) :( 2R, 3S) -benzyl- [2-phthlimido-3-cyclopenphene ~ 1_ yl) oxy] Rorbomof of the formula IIIo 'was dissolved in 250 ml of ocetone and 180 ml of vofin. The resulting solution was treated with 28 g m (13 mmol) of noffium iodide and 100 mg of ruthenium Elofidhyd; (1-3 H 2 O) l 5 * mlKyof & cn.-Reøkfíonenzomrördes kruffíg {'undeI-1 hour. Reck- ön 30? C For ovlögendnde-dv oceton. The votienholtígo remains partitioned between ethyl acetate and water, diluted with 10 ml of cd 1 M cyclic acid; Vottenfqsen sepdmerdes two dånger_med efyluce- Foot. The co-soldered ethyl acetate solution is hydrated with saturated nofrium chloride solution, .torkodes öyer mognesíumeulfot och kon- centrifuges in vacuo (less than G0 mm Hg, less than 30 ° C) 'vld efï glcnsídf skpm erhöllsl Ãïersíoden saffes fill top _ ay 1 kg CC¿Å silica gel column of 80 g CC-Å silica gel column of _ »Vllken the nveoftš genomiindonsfnlng of methylene chloride solution and eluerodes.'F: okfíonef-oåv400 ml uppsomlodes. Indunsfníng of íroktíonerno 16-19 gay 7; 48 g essentially pure (uS, 55) -2- (benyloxy) carbonyl] -3-oxo-u-fiolimido-5-isoxozolin4-hydroxy acid ïmeuf en esmèslfpuf fi áf 'på 11af116 ° c', ¿MD; _57 ° (c = 2.0 l Meomj ' Frokfion'14 gave Ö, 93 gf (4É (ÉS) 2 ~ [(benzyloxy) ~ corbonyl} -3- oXoÅ4-fiolímido-5-ispxozolididine öphilic acid, with a melting point of 160-2 ° C_ (efyldeetot / heXon: 1:13. 7Enblonding of the two šyrorno found in Froktíon 15; In _With the use of the procedure as in the presentation, 26 men where (ZR, 35) -beniyl-ZZeffolimido-3-cyclopenphen-1-yl) oxy] kurbo- » _ mot ufbyfies mot (.2R¿3S); {4butyIÅ [2-phtholimido-3-cyclopenephene- yl) oxi} koïbomof, vorvid¿Éi1dodes, (aS, 5S) ¥ 2 - [(t-butyloxy) - koibonyl] = Û-eco-α-f% ulimido-5-isoxozolidine-acetic acid and (ÄS, 5S) 4 ' 19 p -1o¶ 30 448 376 83 ' ¶ zff fl f-bufogi) _kurbQny1] fs; ° x ° -4fff @ 11míd ° »s-i $ ° x @; ° 1id1n-aff1k_ SyTQ, - Grain Spin Resonance (CDCl3.1§): ¿1.35 (s, Q), 2.7-3.0 (m, 2), 4.55- 1 ¶¶ 5.0 (m, 1), 5.1s-5.55 (m, 1), 5.55-6.25 (m, 2) 7.2 or 7.4 (1), 7: 6-8.0 (m, 4). f¿gmsfa11ni @ ¿_27 ¿v¶ '(qs¿5s) _a; ° X; ~ a_ffqlimi fl q-5_1g0x @ z @ 1idin- 3 ütfiksyro 7.48 g (T7.6 mol) (cS, 5Si 2- (b? Yl $ xi) carbonyl] -3-oxo-α-ffol- imido-5-isoxazolidine-acetic acid solution in 150 ml of ethyl acetate and 7š ml 95% -íg¶é% fi nol; The solution was treated with 1.5 g of pulludium. -black and hydrègenerudes at 25 ° C and a uimosphere fear. Reck- .ííoñen avbröts èftgr 165 míhutér, varefter feokfíonsblundníng- än filfrerodes och filtrotet índun fi iodes í vukuum, varvid er ~ 3-Oxo-Q-folimido-5-isocyclozolidine-acetic acid was retained as a sfødu Grain spin pesonone (CD3QD,): 2.92 (partially divided d, CH2), 5.1-5.7 (m, 2), V7.85 (S, 4 ÅIH), dd1o I 15_ 25 d30 d 44sds76 ds4d V ~ Tunn§ÄíkíßK§ómufngrdfi (kínnlgpl ÖOÖ: Rf: 'O; 3d i den dvre fasen i of (9: 2: 5: 10) ethyl acetate _. _ _ öftíksyro-cyclohexun-vattenÅ In the same system, an RF value of 0.46 and the hydfógenerdd§ piqduRfen, fiån_3É etf Rf value of Ö, 54 and pre- .díngèn med fqrmeln 33 etf: Rf ~ vdrde då 0.64. - §¿gm; fai1n1 fi9 28- (as, 5š) ~ 3_0x °> «= ffal¿mid ° ~ 5_1s @ xqz ° 1id1n- ffüffiksyrd-benzhydpylésier'medïfoimelh 15b d 0 H d d dd i} d Co2cH (c6H5) 2 I} 2 U _ _ _ L d> 0 d ~ Ä, yes. .f. _ ¶ d §ï :: ø:] f / Iïb} d 1 - íd dd d oou 2.8 g (14.3 mmol) of Bepzophenone Hydrogen were dissolved in 80 ml of ethyl acetate.

Dissolve dissolved solution with 5 g of nitrous oxide, 6.02 g (28 mmol) yellow mercuric oxide and 0.2 ml of muffod 'potassium hydroxide solution in efylulkdhol. The reoccion was stirred for 60 minutes and the resultf .end deep? bourgogne-föfgude blundnídgen filfrerudes. The re- sulfefonde ldsníngenzsdffes direkf fill rgckfionslösníñgen ur - an 8.45 mmol hydrogen bond, in which (αS, 5S) -3-oxo-α-phthul- imid-5-isoxozolidine sweeteners are prepared. After I hour be- _d acted reukfíónšbldndníngen-med'fíllröcklig mö fi gd 3N self-. acid unde: strong ompdríng for uti f $ r; föfu_överskotfef av (get KN 10 15 ' 20 30 'E value of about 3,5 with 6 N sqltsic acid (by dropwise addition), 448 '576 fa5 lbojgougne ~ fërgud§ uzoföreníngcr. Reqktínnsblbndningen índunstos sedqn in Qukuüm (less than 30 mm Hg and less than 30 ° C) and k fi dmqfagfuferodes over 300 Q CC ~ 4-silica gel, eluerodes'med. (40 ~ 60) etylocétot-foluen.lF§aktiooner of 35 ml uppsumlodes. (dS, 5S) _ 3-Nxofafffullmido-5-Isoxylglidine-acetic acid-benzhydrylesphere -aferfønnš i ffqkfionernq 10-14, {a] ¿; + 2 ° (cl: 0.70), lßag fi spin concentration (cDCl3, <5) = 2.75 (q, J = 11.5, cH2), 5.15-5.7, n * i (m, 2), 6.93 (s, cH (co fl fgz), 2.18, (s, COH5), 7.28 (s, C6H5), 7.5-8.0 (m, 4 AIH).

Tnnhškíkfskromafógrqfi (silica 60): Rf ~ vörde = 0.42 i (40-60) ethyløcefuf-foluen. Isopro- ¿ * f>, dukfen from compound VIIb had elf Rf »vürde on, 0.59 in total systems, Eï2m§ïälln¿ns, Z2 Tfißhvlomsyr fl l Cl ' \ l 0 f ba,> HN, "\ co" 2 + NH3 To 1.20 g (6.75 mmol) of (αS, 55) -α; amino-3-chloro-4,5-dihydro- n 5¿í $ @ x @ 2 @ 1_affiksyr @, ¶Aï_125) sqf + ¿$ 20 ml 2N nuffiumhyaroxid oçh o fi was stirred at 25 ° C below 36 fimmqr. The solution was given according to pH Hvqrefier it lugrudes at -10 ° C (freezer) over the notfen. The 10 15 ” 20 255 30 0448 576555 - ¿se imaged the crystals uphsc fi lcdes through »filf: erí fi g, washed: ¶I kdllf vuttehloc fi tbrkuäes mëd 720 mg ïricholomsyro. The original 5sprunglíQq1fiï1rutef lyophilíserudes and that resulted in poly- »Reï was taken up in * 4, ml-water, filtered and% vüffddés with two _ 4.ml poriíónår kblït vuften'oCh torknï fi gen go¶ another 160 mg frícholomšyruyffof fi lf üfßyté 80%). " ~ Körnš5i fi рresonunš (D = 0) ¿_5,65-5,35 (1H, M, ïing CH), 4,27 5 - @ ^ V¿§1H1 dl Jf = ¶3,5 H3, ¶q-H), 3.69 (2H, a, 0 5 J: 9, s.Hs, 5cH¿); Tünnékåktskrg fi atogrofíz Rfåvörde = 0.31 (nínhydrin), (solution- K 5 * agents: 60% methyl ethyl ketone, 20% ocetone, 15% vattep; 5% öftíksyrc).

VC-k§rnšpÅnnresoncns_ (D20): 154.6 (CONH); 79.4 (CHO), 56.8 (u-C), 36.8 (CH 2). J 5 '5 Eïggåiëllníng 30 _Ffolyltíícholomšyru-métylésfår Iïå. H ', I "' ',. Fia W. - 5 2.5 400 mg (255 mmbl) tçibholomsyrc, 720 mg nufrium korbonut, 6 ml of water and 1.2 g of Nfkcrbetoxiffulimide bluhdodes with it later pch was appointed in t; e po; tí§her uñåer 2 hours. Effèr acidification tillf5Hévördef 3 with 3N sulïšyrq two fi des reukfíons- w 'â fi J? 10 15 zoí 30 448 376 87 the mixture with 2 x 25 ml of ethyl acetate. De sommunslcgnd orgcnískc¶ phases two were mixed with common salt, precoded over sodium sulphate and concentrated in yokuum. Ktomotogrofi (QC-4, 50% “å75% E / H gradient) gave fidlyl-freecholic acid, 1Corn spinneretone (methanol 845: 7.86 (4H, s, ø), 5.65-5.0 δ '(zH, m, cHo, a-H), 2.92 (2H, d, rïg fi gåkißäåkšgmgïggšgfíi 7 (AIX) _Rf-Value å 0,15 (UV, yellow color .med vuníllín / H3P0, šproy, [>).

The product was taken up in 10 ml for: tetrohydrofuran and treated des with en-eferlöspíng of diozomethane, Kromofogrufi (silica gel 75% E / H) gave 160 mg Cod Spin Calculation (QDCl 3): 5.65-5.3 (1H, m, CHO), 5.3-5.1 '(1H, m, of H), 3.06 (2H, d, CH 2, P fi TH > unchanged. §Ggg§5¿g¿¿g¿9 @ g¿9Q; g¿¿ = (AIX) Rf-varae = 0.33 ¶ ¶ ¶ -. (502 E / H) Rf_varde = 0.15; (AT-125- derivof) Rf = 0.42, I ënolvsí fl Kßeröknaf for C, 55.26; H, 3.98; N, 9.21. 77 'Found: C, 55.20; H, 4.60; N, 8.43.

Moss Spec fi efriz M + m / e 304- (ß fl j, 272 (H + ~ CH2OH), 244 i (M + _co2cH3), 219.

Exemgel T_ (aS, 5S) ¿chloro-Å, 5-dihydrp-α-pholimido-5-isoxu2ol- Oxygen-benzhydryl ester '_ 10 15 20 30 448 3760? ° - se _ co2çH (c H ¶co2cH¶c6H5) 2 A 655 hrs O IN IN ! in \ ¿, "ISLAND hrs _O Ildí> V 0 0- f 'I IC1 Ti11 192 / U1 (2 mmol) carbon effluent colloid 1 25 ml: crf feffahydro- .efuren in nitrogen utemeför at rumsfempemufur was set 310 / ul _ (1.9 mmol) hexamethylphosphorus ~ fricmid dropwise for one minute.

Inem minferfer fillsoffes 590 mg (1.3 mmol) (aS; 5S) -oxo-a- Fclimide-5-isbozozolidine fatty acid, benzhydryl ester acid in opproxímofívt 5 ml dry tefrahydfofuron snmbbïß The heferogenc The solution was stirred at 45 ° C for 48 hours. Alternatively suffers 590 mg (1; 3 mmCl) (αS, 5Sy-oxo-α-phenylimido-5-isoOXo2) ~ din in 20 ml dry fetichydrophufon in a nitrogen atmosphere at room temperature e ppfur 610 mg (2.6 mmol) hegumefylf ° s {@ rffiqm1d_d1k1 ° r1a (frem- filter with hexecloxetane in ucephonifril with hexemephylphosphorusfriomide in accordance with Appel and Schölef, Chem. Ber. , 110, 2382, (1977)). The reflux coconut solution for 48 hours. Reckfíonsblond-7 The mixture was dissolved in 50 ml of ethyl acetate and fed with 50 ml of water 10.1 N sulfuric acid followed with mercury and precipitated over sodium sulfof.

After concentrefíon in vacuum chromufogruferodes åfersfoden på 50 g of silica gel with 30% ethyl oxide in hexone (200 ml of elution) I with efi yield dv 200 mg crude product (33% ufbyte), 245 mg starting material (42%). The preno product gave (a5.5S) ~ 3- chloro-Å, 5-dihydrofaéf {ulimído45-ísoxuzol-ütfíksyrc som nålar, hl ' 31o'2 152 ' w 20 «25 448 376 .393 í “ Melting point at 78 ~ 179§C at ambient temperature.

Tunnskikfskr0motogrpfí: Rf ~ vörde_ (§rodukien) = 0.70 to 35% étylbcefot / he3un; Initial motor_ = 0.11- [α] 20 D (CHCl 3) j +, 799 (540 μm) _: 232 ° (573) ¶ + _9493 (547) + 1§3 ° (436) 2 +2569 (365) 1¶ _ _ 3 Kargspi fi nfesgga fi s' (c0c1¿) =, '7,8of (4H,' m, PHTH), 7,32 Den 7,22 '' 'i 2 (10H, s, ø), e, 9s (1H,;. øc5), Δ ¶¶5.6 (1H, m, 050), 5.26 (1H, 3, 3-H), 3.32 (2H, 3, cH).

ClN 2 O 5: C, 65.75; 1H, 4.03; N, 5.90.- ¶C, 65.45; ^ 2, ¶H, 4.03; N, 5.95- _Unulys: "Beföknnf för C26H19 erha11ef = ï Use of the procedure described above but using (aS, SS) -3¿cXo ~ 4,5-dihydro ~ 4É '~ ffQlímídb-50-isoxo2ol-efiksyro- Benzhyarflestef (Vlib) gave (aS, 5S) (respectively) 3-chloro-4,5- -Kdí fi yäro-4B ~ ftølimidö ~ 5u ~ ísbxozol-acetic acid ~ benzhydryl ester (v111c, x, = 01); ExemÉ0lÅå_7 (as, 5S) ~ klofo ~ 4,5-dihydro ~ c «fto1ímído-5 ~ isoXazol- Våffiksyru V 30, ¶ 1_o ¿ 15 zo- 30 * -An @ 1ys = seí-akngf for cwHàclmzoy c, 4Til, 1.5 mg (0.4 mmol) 3-chloro-Å, Edidihydro-α-ffulimido-5-isoXc , z§lÅëffiksyrcfbeñ2hyd; ylesfe: i 3 ml fór; nífïdmefun on one Put in the nitrogen solution with Ubbludes tórf¶vötèchloride for 5 minutes.

Bo fl et uvlögsnoäes ßch lögníngen omrördeà en fímme. After the ïtration cv the solution in Vacuum chromiumfogrqfeïcdes the residue on CC-4 kíšelg§1 (30 Å) mèd 30% -éfylocefut / hexun, Vurvíd Qrhölls 1Ü5 mg GV eit Qítfzsku fi. This foam was crystallized from 4: 1 hexone} phenol, pyridyl acetate (uS, 5S) - 3-chloro-4,5-dihydro-phthuli- míd fl-5 ~ ísoxczoiàötfíksyrc me fi en smëlfpunkt ßå 176-177 ° C I (bíldadç etf hyÉr§t vid utsäifønde för fuktíghef).

Tqnnskíkiškromutogrçfi: Rf-vörde: ¥ Ö, 45 (AIX§ V Körnspínn§escnuhs: (Åcefëdó) 7.95 (4H, s; PHTH), - 5.6 (1H, m, 'ego), _5, _2_7 (JH, d_, «-H), =" a, 57 (2H, »a, m2). W 50.58; , 2.94; , 9.08; so, 57; 3¿0É; ' _9,4e-, ¶ Honorable: ', \ Z 'IJSÜ Z I' 21) (f ma Q 448 376 91 Using the sum procedure described above but í 'šföllef (fl5,55) -3+ kl0r0-4; 5 ¥ díhydrgf4ß ~ ffgIímído ~ 5q-isoxozol- 1og 15 YOU C). öftíkšyrc ~ benzhydry1esfer (VIIIc, X = chlorine) gave ¶aS, 5S) resp. 3-Chloro-4,5-dihydro-4-fulimide-5α-isoxo-olefinic acid (VIIIb, _ I X = chlorine). ', ~ ExemEeIU3_ (αSβ5S) bromo-4,5-dihydro-α-phthulimido-5-isbozol- öffiksyæo, To 185 mg (0.4 mmol) of (5S5S) -chloro-4,5-dihydro-α-fiolimido- 5-Iso2-ozol-β-Acetic acid-benzhydrylesfer in 3 ml of dry nifromium on e %% isbød i kvävebtmosfür bubblodes for: vätènrømíd under 5 The solution was stirred and the solution was stirred for a while. NJ u! 30 Concentration of the solution in a vacuum chromatographic method sfoden på CC ~ 4fkíselgel (30 g) med 30% efylocefut í hexun fill no? yield of 115 mg as ef? white foam. Deftc foam omkristclli- serodes.ur 4: 1 (hexunzefonol) to give 3-bromo-4,5-di- hvdro-a-fiolimido ~ 5-i $ øxczol ~ öffíksyrc. Q 9§rN2Q5: n C, 44.21; H, d 2.57; N, 7.93.

Analysis: Berdknof for CT3H 10 15 30 44s * s76 'Efha11ef = ¿K' d d “I d .. c, j44,49; H, ZQÖ4; ¶ ¶ d N,?, Aa. [«] 20 (meon) + 67 ° (589 mm) d 709 'i_ (s7s) _ d 79 ° dI (s47) 131 ° 1 (436) d ïs79: d (365) id Using the sumüd procedure as in Example 3 but with The resulting hydrobromide or iodine hydrogen was obtained from 3-iodo-4,5-dihydro- a-ffalímido-5ÅisoXazole ~ öitíksyrq. Again, the same procedure as in Example 3 was used but with Replacement cv hydrogen bromide with hydrogen fluoride was obtained 3 ~ fluoro ~ 4,5- dihydio-α-ffulimido-5-isoxynzole-acetic acid. E§g @ 9Élwí ~; Ftdlyl ~ (aS; 55) -a ~ ømínof3-klord-4,5 ~ díHydfo ~ 5FísoXa ~ ~ zol-fatty acid-methyl ester U; ftclylfrichlomsyra- A .mefylesfer d @ d ddddd fdd d 0 ._>} \\ 1} ¶ d t J H% ,, »l \ T /” Nš_ 'C) ¶ L d .ß 7 d., cozc fi aïd Y. co2cH¿ : Ia d id d d I dïc 2 ¶ _ d. _ 2 f (iv n! - 10 f-o 'LH ao ~ _mefylesfer; 44sls7s I 93 'Till óQ mg. (0.2 mmel) richolemsyrcåesfer ~ ftelimide in 1 ml dry teiruhydrefurun at room pemperotur in nitrogen atmosphere suf- tes 25jU1 kolietruk1oridlföljf_ev 30 / ul hexqmefylphosphor triamide.

After 16 hours fillsuffêsgytierligore 10 / ul carbonaceous chloride and , 10 / pljfoefin. Löšníngeníueparbetudes efter en iotcl reukfions- time of 36 hours with ethyl acetate / dike. Produkfernc cremato- -groferudes on 5 g silica gel (50% Y / H) for extraction of ftulyl ~ ~ (aS, 55) ~ aamine-3-chloro ~ 4¿É4dinydro # 5-isoxozole ~ acetic acid ~ Körnsgíngšesonunsz K (CDCl3) identical to AT-125 e PHTH-methyl- d ter derived from natural (+) dATQ125 according to Fromstöllning 30. gIL§: Ideniisklmed “AT-125¿PHTH-methyl ester (UV and dyeing iden ~ fish); .§ŠÉm9el; â (uS; §S) ¥ q ~ ømino-3-chloro-4,54-dihydro-5-isoxozole-7 i “in affiksyrc or AT-125. ci i ni n n l _ i il .'l _ 4 To 7lÛ mg (2.3 mmpl) 3åklQro ~ 4,5 ~ dihydro- @ ~ ffolimído-5- isoxazole-hydrochloric acid_15 ml ml of water was added 260 .mu.l of hydruzine hydride. * and the solution was stirred at 50 ° C for 7 hours. After cooling , jusierudes the pH of the solution fill 5.5 with acetic acid (80 / ul), The precipitate was filtered and diluted with 13 ml of liquid. Filfru- ref was diluted with 200 ml of 2-butanol and allowed to crystallize in a refrigerator under 18 microns. The filfrufet gave 240 mg (cs, 5S) ~ 10 15 25 30 1 Iunnskißiškšggpíógšofíz, Rf-vëråe 0,40 (60: 20: 15: 5; MEK: Acéføn: .1-'¶ 216 “ 1 ^ ï 44s, z7s 94 α-amino-3-chloro [4,5]; dihydro-5-isodoxy-acetic acid; mother liquor concentfefudés¿upprokihb% ívf 15%, varvid erhöllš 50 mg av en , andra $ kÉrd av (aS; 5S) ¿aÄumíno-3-klopo-4§5 ~ díh¶dro ~ 5 ~ ísoxczol- _ 3 ätfíksyyc (71%). ': _fvutfen: üftíksyrà1. ßëàgšBànnàešoncn§¿_ (ÜZO) 5.2 (1H, m, CEO-); 4.17 (1H, d; a-H), _. 3'6- |, (f2. | _ |, D, QH2): _ V 7- V; _ Mèd añqö fi dning av Qommd förforuhde som óvon beskííves men med onvänåníng çv DL- ellef D-3 ~ klqroè4,5-díhydro ~ 4ß-ftulímído ~ 5a4i $ oxozolic acid (VIIIb, X = klqf) gave DLQ or D- f (respectively) -3 ~ chloro-4,54dihydroQ ~ 4ߧamino-5a ~ isoxuzo1 ~ öffík% : acid (VIIIG). En likpunde "sUbstífufi§n uy IIb i siüllef för Ib 'gave fiicholomic acid.

Analysis; Calculate: fs¿ CšH9c1N2o3 = c, 33.63; H, 3, §5; _ ¶ N, 15.69; al, 19.86, C N co- Q m ° * - 13,300 ¶ -Efha11ef = 1, 33,60; H, 4.11; , 16.15; Cl, 19.63.

, .§§§ @ Egl_§_ (aS; 55) -afqmí fi o-3-byomo-4,5-dí fi ydrd-5-ísoxuzolé affíksyraí Z 1 (y »___ n .. -._.__....__.____, ......«, 1.1 dm 10 _20 N * u: 448 376 95 IG5 Till 710 mg (2.3 mmol) 3 ~ bromide ~ 4.5 ~ dihydro »a ~ fflimimido ~ 5-isox- dzol-dïïiksyrc í 15 nl vdtten sd§Ées, 260 / ul hydrazínhydrøf och the solution was stirred at 5006 for 7 days. Effer cooling jusfe- The pH of the solution is 5.5 with acetic acid (80 .mu.l), filtered. rerodes and the precipitate tvüïïudçs with 13 ml vat% en¿ Fíltrotei Dilute with 200 ml of 2-buiønol and fíllüfà kfísfqlliserd í reff refrigerator during T8_Hours, Filtration gave 240 mg (aS, 5S) -H , a-umino ~ 3 ~ bromo ~ 4,5 ~ dihydrq ~ 5-ísoxczdl-öttíksyic; koncenfroïíon of mother air to uproxímdtívt 15% gcV and other harvest cv (αS, 5S) 4: -omino-3-b: omo-4,5-dihydro-5-isoxazoleic acid (71%).

The layered chromophogrophy and the core spin characteristics could not be separated ï : ån chloronulogen., UV spectrum showed total extinction, but at 214 nm. “_ cs; Q gis, = 11,250 3 = d §, 26.92; H, 3.16; N, 12.56; Br, 15.73.

C, 26.63; H, 3.33; N, 12.60; Br, 15.58.

(BÉ was determined from Cl kuüloñetrískf nrøv) x Analysis: Visit for_C5H7BrN20 Obtained: f. 10 ?O K) (31 448 57.6 l9e ' Moss spectrum at the diesel association indicates M + -15 at 352 'øch 354 m / e. 7 IQ.

Exdmgel 77 Díre fi t conversion of frícholomsyrd fill AT-125 Gb IId i I IQ To 140 mg of tricholomic acid in 3 ml of POCl3 in a nitrogen atmosphere at room temperature ïempercïur suffgs 160 ul renod díefylumilin. The blond place- frodes i ef? bid on TOOGC under 5 minafer._P0Cl3 nølögsnodes i vpkuum, The resultfexandezfusfa material was treated with 2 ml of H 2 O and stirred for 10 minutes under neutralization with concentrated NH4QH, Efier lyophilization cv mcteriolef on-- Transfer 10 g of silica gel column and elute with 85% EfOAc / 5% H20 / 1O% ~ acetic acid..E {f -marker band at thin-layer chromoiogrufi 7 med_scmmu tube holder sóm AT-125 received. Moteríulef was biological pyovof v Buctílí subTílís. (sy fi.) and proved to have a mini- mum víd 2% ufbyie (cnfugo fi de off ufgångs-frícholomsyrcn var to 100% pure and with knowledge of the biological oktívíteien in frlcholomic acid). §§EmEel 8 (aS, 5S) -3-methoxyl-4,5-dihydro-α-fiulimido-5-isoxa2ol- ötfíksyrq-benzhydrylesfer _ ï _ - 7 'm 1 ,; ... _ Lu m * 1ol '15 20 25 ' '3O 448 376 97Ä t t t 'rtïïq f t _t fl * ft t t1¿tt (x = GCH3) , Till 90 mg (0,2 m fi§ l) »3« oxo ¥ ç ~ ftølímído = 5; isuxàzolídín-öttíksyru ~ Benzyl dydyl ether (IIO) in 5 ml of methyl chloride, 50% molar solution was added. , škott av en sténdor fl išerud dí fi zometcneterlösníng. A variety of '5 / ul cv 6F3.Et2O tíllsqttes_och-efter 30 minut kqncentrercdes reuktíonsblondníngén, och.återstoden kromdtogiuferodes vid prepa- : ctiv thin-layer chromotogrophy Üéd AIX as eluent, wherein There was obtained (45 mg) 3α-ethoxy-4,5-dihydro-α-phtholimido-5-isoxoZol- acetic acid pho-benghydryl ester Run fi sptnnresonons (CDCl3): '7, $ Ö (m, 4H) ¿7% 32 oçh 7QZ2 T '(S, 1QH, PH), 6; 96_ (s, Phåc fi), 5.1_5, sj (m, ZH), 3.75 (S, CHBQ), 3.07 (d, J = 7.5 HZ 2H) ' Tunnskíktåkromotogrcfi (AïX) = ~ Rf; vÖfd§: 9,60.

* A wonder product was formed (35 mg) with the structure , 44s§76¶ 1 98 - ä * 'in g TO »Iïd Nuclear spin resonance, (CDCl 3): 7.82 (m, 4H), 7.32 and 7.22 15, ¶_ j f. = ¶ (s, 1014) -, 6.97 (s, m), 5.1-5.9 7 '(m, _2H), 3.1Q (S, NCHa>, 2.81 f 7 _¿ (m, 2H) I ' _ Tpnnskíkiskromdiogrqfí (AIX): Rfïvöyde = 0,40-

Claims (1)

un. ._ V.. n »QUAUU / e 20 25 30 35 ïbromine, chlorine or methoxy, -where R14 and R15 represent hydrogen, -COOR 44s? 376e BAT e where R 1 represents hydrogen, alkyl having 1 to 8 carbon atoms or halogenated alkyl having 1 to 5 carbon atoms and 1 to 3 halogen atoms, where X represents 6; -COR7, where R6 represents alkyl of 1-8 carbon atoms or halogenated alkyl of 1-5 carbon atoms and 1-3 halogen atoms, where R7 represents alkyl of 1-12 kelet atoms or where R represents the group n Q where R8 represents a group consisting of 14 and R15 having the nitrogen atom a) 'I; R 11, R 11 and R 12, where R 9, R 10, R 11 and R 12 represent hydrogen or alkyl having 1-5 carbon atoms, 'b> e _ CH 2 - \ / \ CH ï fl z CH CH _ / \ f? cells '' 1 cCH2 c) orthointerphenylene, characterized in that a compound of formula 710 eloo ¶ 44s, 376 COORL I NR14R15 where RL R14 ooh R15, previously defined; is chlorinated using hexamethylphosphoric triamide dichloride in the presence of a solvent at a temperature of 254 DEG C. and when X represents Br diazomethane in an ether solvent with a catalytic amount of boron trifluoride etherate. IN