PL163118B1 - Method of obtaining 7-substituted hept-6-enic acid and 7-substituted heptanic acid and their derivatives - Google Patents

Abstract

A method for producing a 7-substituted acid hept-6-ene of formula 1, wherein X is CH = CH-, the group COORi forms an ester group, in which Ri is Ci4alkyl or benzyl and R is an organic radical containing the groups that are inert under reducing conditions, possibly in free acid, salt or 6-lactone forms by the way stereoselective reduction, racematic or optically pure compound of formula II, wherein R, R 1, and X m are meaning as defined above, and One of the symbols Zi and Zn is oxygen and the other is hydroxyl 1 hydrogen, optionally in the form of a salt or a lactone, characterized by but in the first step (step / a / j is mixing is a compound of formula 3. wherein Rl is a group allyl or lower alkyl containing οα 1 to 4 carbon atoms and R3 is semi-order or a secondary alkyl group having 2 to 4 atoms carbon, with sodium tetrahydroborate NaBH3 in reaction medium containing alcohol and tetrahydrofuran, in the second step [step / o / [compound o is subjected to formula 2 by treatment of the mixture obtained in step / a / under conditions suitable for obtaining a mixture containing the cyclic boronate compound of formula 4a l / or b boron complex of formula IVb in which formulas are R. R and R 3 1X are as defined above, and in in the third stage [step / c / 1 the product obtained is cleaved off in step / b / to the corresponding compound of formula 1, then. If desired, the compound of Formula 1 in the ester form is transformed into free acid, salt or δ-lactone.

Description

R ^ mud in ad / r ^^ lazku jast way ^ ⁽ⁱ ^ in the present ^STY 7-podstawionθgt acid (NAP-O-t enowago.

The invention relates to a process for the production of the compound 1, in which X is -CH »CH-, the group COORr forms an aster group, where Rj is a group CR-R4 or a peptide, and R is an organic radical of the group which is indifferent under raducing conditions, aoθntualthia in the form of free acid, salt or β-lactone, is the intrinsic astru

The process of the invention for the production of compound 1 includes the old salted raduction in the form of rrjajt or optically pure compound of formula 2, wherein R, Rj, and X have the meanings as defined above, and Jadan with the symbol Ζγ 1 Zg means

Oxygen and the other is hydroxy and hydrogen to give the corresponding compound of formula 1.

As can be seen from formula 1, the compounds have a syn configuration, i.e. the erythro configuration.

The symbol / E / appearing at the beginning of the pattern or in the name indicates that the double trapping occurs in the trans configuration.

The invention encompasses a process for the preparation of a compound of formula I as defined above, which has an optical purity state such that the ratio of the erythro isomer to the threo isomer is 99.1: 0.9, or greater, preferably 99.5: 0.5, or is greater than or equal to 99.5: 0.5. higher, especially 99.7 and 0.3 or higher.

Compounds with ^^ (^ r 1, constituting esters and corresponding free acids, salts and cyclic esters / O-lactones / are pharmaceuticals, in particular reductase inhibitors / HMG-CoA, they are inhibitors of cholesterol biosynthesis, and therefore it is advisable to use them for treatment of hypercholesteroleemia, hyperlipoprotelnemil and atherosclerosis.

When the desired end product is an ester, preferably an ester group with the symbol COJRj is an ester group which is allowed to be physiologically acceptable and hydrooisolised.

The term ester group allowed physJotogicznia 1 hydrooisable * is understood to mean a group that is allowed f ^^ Joot ^ g and ^^ lower ^ e 1 undergoes hydroysis under f ^^ J ^^^ common conditions, with the formation of the corresponding carboxylic acid from with a compound of the formula 1 / R i.e. it is zestępione hydrogen / alcohol which itself is physiologically permitted, it is non-toxic at levels pożędanym dαwkowiatβ _t a particular group not containing the centers asyrnetrri.

R ₄ represents a Cg_ -alkioowę or benzyl and in particular is R? <Wherein R is a group Cg_g-alkioowę, n-butyl, isobutyl, tart-bulytowę or benzyl, eg. Ethyl, preferably lzopropy.towę or tert-butyoowę. especially tert-shoe.

X is preferably X ', where X * is -CH-CH-, preferably / E / -CH-CH-, R preferably is selected from the groups designated A, B, C, O, Ea, Eb, Ec, F, G , H, 0, K, L, M or N As follows:

A: a phenyl group with three substitutions with the symbols Rj ^ Rga and Rga 'where Rga <

Rg _e 1 R 3a are independently hydrogen, halo, C 1-4 alkyl, C ₈ -4 halogeno-alkyl, phenyl, phenyl substituted halo, C 8 -s-alkoxy, C 8 -g-aHanoyloxy, C 8 -4 -alkyl or C 8 -4 alkyl-ORlog group, Where R 2 is hydrogen, C 8 -alkenoyl, benzoyl, phenyl, hαloganophenyl, phenyl (Cg- ₃ -alkyl), _Cg-g -alkyl, cinnamyl, Cs- ₄ -haltgenoyl, aH-, cycloalkyl / Cg-slkyl /, adeomntylo / Cj_3-al ^ k Lo ^ ^ hose or substitutions phenyl / Cg_g-alkylation /, wherein each substituent is selected from the group halogenowia, C ^ -alkoxy, CL_ ₄ -alkitiwθJ 1 Cg_ -hnloganoβlkitoweJ _4, wherein the carbon The halogen atoms are fluoro or chloro and cycloalkyl includes cyclohexyl

B and formula B, where Rgb and R 'b together form a radical of formula a / 19 or o -CHg-CHg-CHj-CHg-, in which formulas Rgb is hydrogen, Cg-g-aHyl, C8-g-alkoxy, trifltmmαtyl · fluoro, chloro, phenocell or benzyloxy, R _4b is hydrogen, Cg_3-alky, n-butyl, isobutyl, C8_. _3- alkoxy n-butoxy, isobutoxy, t-tethemyl, fluoro, chloro, phanoxyl or benzyloxy, Rgb means C1-6alkyl, CJ_3-alkoxy, trffltotematite, fluoro, chloro, phatoxyl or benzoyloxy more mz One of the symbols ^ Rgb and R _ą D means the trl group. rlootMet> oię · not more than one of the symmoo ^ Rgb and R $ b means fantksllowa and me more than one zs ^ oU Rgb and Rgb means the benzylokeyl group Rgb means hydrogen , C1-8-alkyl, C1-8-elkoline, fluoro or chloro. Pisces means hydrogen, Cg_g-αlkitic, n-butyl, isobutyl, Cg-alkoxy, n-butoxy, triflooromethyl, fluorine, chlorine, phantlell or Oenzyloxy group Rgb is hydrogen, Cg_3-alkylyl> Cg ^ -tralkoxy locomyl, fluoro, chloro, fanolsyl or benzyltxyl with the proviso that no more than One of the symbols of Pisces and Rgb means a group of ^ Πυο ™ methyl, no more than One of the symbols of Pisces and R ₀ b means a phenolsyl group and no more

163 118 syndoli than one of R b and R _g D represents a benzyloxy group and continue with the free valencies of the rings Ba and Bb are forced into a position ortho to each other;

C and formula C, where One of the symbbH R ^ c and R 'c is a phenyl group substituted with RgC, Rgc and RyC groups, and the other is a Cj - ^ - alkyl, n-outyo or isobutyl group,

RgC stands for hydrogen, C 1-8 alkyl, n-outyl, isobutyric, tert-butyl, C 1-8 alkoxy, ^^ outoxyl ^^, inbu toxic, trifloo-ohmetic, fluoro, chloro, tenoxyl or benzylxyl, R ^ c is hydrogen, Cj'3-alkyla, Cy_J-alkoxylloy, thifllolmπletyl, fluoro, chloro, phyllkayl or benzyloxy, but no more than one of the symbols R ^ c and R ^ c is a trifΙκ ^ ο ^! yl group , not more than One of the symbols R ^ ci R ^ c is a femkayl group and not more than one of the symbols R ^ c and R ^ c is a benzyloxy group, Rgc is a hydrogen, C2_g '* θaklll ° e, n-butyl, isobutyl group , tert-butyl, C 1-4 alkoxy. n-butoxy, isobutoxy, trfflolonethyl, fluoro, chloro, phenocayl or benzyloxy, Rgc is hydrogen, ^ -3 ^ 1 ^ (^, C ^ 3- ^ Clxyl, trffllolomatyl, fluoro, chloro, phenokyl or O ^ -nzyl-thymyl) group that no more than One of the ο / ιΟοΗ Rgc and Rgc is a trffllolomatyl group, me more than One of the symbbH RgO and Rgc is a phancyl group and no more than One of the eymbols Rgc and Rgc is a benzyloxy group, and R? c is hydrogen, a C ^^^ - eeli ^ t ^ l ^ these, C _2 ^- ^ alkoxy lion, fluorinated or chlorinated;

O: formula O, where R ^ d is hydrogen or a primary or secondary g-alkU group, not containing an asymmetric carbon atom, and R ^ is a primary or secondary C ^ g-aJ ^ kH ^ group not containing an asymmetric carbon atom or R &lt; d &lt;&gt; and Rgd together will be the group "/ ^CH 2 ^ _m " ^or / Z / -CH 2 -CH "CH-CH2-. where is 2, 3, 4, 5 or 6, R 8d is hydrogen, C 1-7cellkyl, n-butyl, isobutyric, tertiary hydrogen, C | , n-Outoxyl, isobutoxy, trifluorine back, fluoro, chloro, phenltyl or Oenzylkayl, Rcd means hydrogen, C ^ cC- ^e ^^ ^k H ° ^w E C j-3-alkoxy, trffluormnetyl, fluoro, chloro, phenoxy or benzyloxy, with the proviso that not more than One of syi ^ bH R? d and Rcd means the group tΓi-fluornmatyl ° a, not more than One of the symbbH Rjd and Rgd means the phenoxy group 1 not more than One of the symbbH Rjd 1 RgP is benzyloxy, Rgd is hydrogen, C1-6alkyl, n-butyl, inbutyl, tert-butyl, C1-6-alkyl, n-outoxy, isobutyll ° e, tit11lnmethyl, fluoro, chloro, farlxyl degrees or benzyloxy, RGD is hydrogen, Cj-g-alkyl radical '' ^t rfffl ^of l ^om ethyl degrees, fluoro, chloro, phenoxy or Oenzyllksylową, with the proviso that no more than one of symibUi _Rc di RGD is the group trifllolmmaty, not more than One of the synonyms Rgd and Rgd means a phanoxy group and not more than One of the symbols Rgd and Rgd means the Oenzyllk group Shiloh ° E, R? d is hydrogen, C ^ _. ^ - (^ ^ l.klJ these C * _j c_2 ^and CCokeylową, fluorinated or chlorinated;

Es: Ee pattern, pattern Eb or Ec formula in which formulas R a, R e and Rce independently represent fluoro, chloro, or a wodir Ci_c- ^and lkHowę, wherein Rce preferably represents a mf / Lowe;

F: formula F where R ^ f is the Cj group; g-elk11 does not contain an asymmetric carbon atom, each symbol Rjf 1 Rgf is independently flooded by hydrogen, Cj-3ealkyl ° a, n-butyl group , irooutyl, tert-butyl, al / oxy, n-ophthylxyl, isobutoxy, trifluoromathyl, fluoro, chloro, phenyl, phanoxy or benzylxyl, each of syiAboH Rgf and Rgf are independently hydrogen, Ci -2-alkyl, Cc-3-alkoxy, trifluoromethane, fluoro, chloro, phanocoyl or Oanzylxyl and each of the symbols Rf 1 Rf independently represents hydrogen, Cc-2-alkyl group ° a, Cc-2-alkyl, fluorine or chlorine, except that not more than One of the symbols Rjf and Rgf is a trithHonmethyl group, not more than One of the symbols R5f and Rgf is a faroxyl group, not more than One of the symbon Rgf 1 R ^ f ornacra the Oenzyllxyl group, not more than One of the synUi Rgf 1 Rgf group is the tifllOlmmatyl group, not more than One of the synUl Rgf and Rgf group is the phanoxyl group and not more than One of the symbbH Rgf and Rgf is a benzyllxyl group, with the / 1 / free valence on the pyrazo ring being 4- or 5-position, and / 11 / the R-f group and the free valence being ortho to each other;

163 118

G: formula G wherein Rag is a pojedyócze bond to X, Rbg is R ₂ g, Reg is R g, Rdg is R ₄ g and K is a group of the formula 20, or Rag is R g, Rbg is pojecfyrtcze towers of X Reg is R ₂ g, Rdg is RGG and K is O, S, or R 21, R g, R ₂ 9, R 39 * R ₄ 9 independently represent a group Gj ^ g-alkyl radical not zawierejęcę asymmetric carbon atom, a group G 8, cycloalkyl or phenyl substituted with groups of the symbol R _g g, R g and R g, or in the case of R g and R ₄ g additionally hydrogen, or in relation to R g, when K is 0 or 5 and X is X ' additionally Ga, and Ga -G / ^^ ZG / Rieg / ^ gg, wherein R _7g represents hydrogen or a 4-Gj alkHowę and R4g9 1 R gg each independently represent hydrogen, C ^ _j-N clone or phenyl, each Rgg symbol independently represents hydrogen, a ^ -accloyl, n-butyl, lbbutyl, tertbuut yOw, Cl4 ₃ -elkoeβyl, π-I ^ u ^^ I ^ ibj-low, lzlbutylxyll, triph ^ οkaline , chlorine, bromine, phenyl, phenoc, etc., or b enzyloxy each of symbbH R4g is independently hydrogen, a Gj_g-alkHo group,

Gj g-alkoxy-alkoxy, t1-lonoBiethyl, fluoro, chloro, bromo, ierkyl or benzyloxy, and each of the symbols Rg is independently hydrogen, G ^ j-alkU, G | _ ₂ -xylo, fludic or chloro with the proviso that on each ring substituted with the symool groups R _g g, R g and R g, only one of the groups such as trifluoromethyl 8, phanoxy and benzyllkβyllwa} can be present.

H: Formula H, wherein R 4h is a Gj_g-alkH group not containing an asymmetric carbon atom, Gg_. ₇ -cykllalkllooę, 1-adamantyl or phenyl groups, monovalent hydrocarbon bases ^ symbol R _4h, R _h and RGH, R 4h represents a C4_g-alkllowę zawierejęcę no asymmetric carbon atom, G ₃ _t-cykllβlkilooę, 1-adamantyl or phenyl groups podstawlonę with the symbol Ryh, Rog and Rgh, R4h is hydrogen, the group G ^ _galkHowy not containing an asymmetric carbon atom, G ₃ - t-cycllβlkyloo, 1-aoamantyl, styryl or phenyl substituted with groups with the symbol Righ, R ^ n and R12 ⁿ · ke2dy 2 synDoh l ^ h, R? h and R 4p _h independently represents a G4_g-slkl ^ hose, n-outyJ ^ these, isobutyl tyiowę, ter t-DUT yOwę, g ^ g alkoxy, n-bu toksylowę, izoburlksylooę, trfflor ^ Methyl, fluoro, chloro, bromo, phenyl, ienoxyl or benzyloxy, each of Si ^ b ^ Rgh, Rgh and R ^ h is independently hydrogen, G ^ galkyl, g-alkoxy, Off, phenyl, fluoro, chloro, bromo , a group of the formula -GOOR ^ h, a group of the formula -N / RjggA, faroxyloy or benzyllxyloy, in which R 1 'h is hydrogen, a group of R ^ h or M, where Rjgh denotes a Gj_g-alkyl, n-butyl, isoDutyl, raοtbbutyl or benzyl group, and N has the meaning defined above and each symbol Rj.gh independently denotes a G ^^ e ^ Howa group that does not contain an asymmetric carbon atom, and each βυο0οΗ Rgh, Rgh, and R42n are hydrogen, a group

2-a4klloy, O2-alkyxyoyl, fluoro or chloro, provided that no more than One of the substituents of each phenyl ring independently is a trfflllmmethyl group, no more than One of the substituents of each phenyl ring independently is an ienxyla group and no more than One of the substituents of each phenyl ring independently is a benzyloxy group) □: formula 3, where each of the symbbH Rj_j and R-> J independently represents a G ^ g-alkyl group not containing an asymmetric carbon atom, a Cg_gcytloelkyl group or a group of the formula phenyl-ZCH ^ / ^ - where m is 0, 1, 2 or 3, and the phenyl group is unsubstituted or substituted ^ dr ^^ iek of the groups Rgj, R4J and Rgj, where Rg, R4J and Rgj have the meaning taken down below, or R2J is a -YJ-oanzyl group, a group of the formula -N / RgJ / ₂ or 3a, in which YJ is -O- or -S-, each Rgj independently represents a C1-4alkyl group not containing an asymmetric carbon atom or maybe t to form a 5-, 6- or 7-membered oagl part of ring 3b, wherein ring 3b is substituted or unsubstituted and eo-nrually also contains one or more heteroatoms and 3a is 3a * or I, where Oa 'is heterocyclic, unsubstituted or substituted by one or two C _1-2 -alkyl or C 1-2 -alkoxyoyl groups, and 3a is a group of formula 3a a or I '* b, in which R 4J is hydrogen, G 1 g-alk Howe, n- outyl, isobutyloooo, rertbbutylooo, C4_g-elkoxylooa, ιr-Ourlxyl,

163 118 isoDutoxy, trifluoronethyl, fluoro, chloro, phenokeyl or benzyloxy,

R 4J is hydrogen, C 1-8 alkH, C 1-6 alkoxy, trifluolomethyl, fluoro, chloro, phenoxy or benzyloxy group and R 8J is hydrogen, C 1-2 -alkyloxy, C 1-8 -alkokeyl, or chloro, except that One of the symbols RgJ 1 RjJ is a trffluoroaethyl group not more than One of the symbols RgJ 1 RjJ is a phttuxyl group of 1 not more than One of the symbols RgJ 1 RjJ is a benzyloxy group;

K 1 is a K group, in which each of the symbols Rjk and Rjk independently represents / a / a phenyl group substituted with groups of eym ^ t ^^ u Rgk, Rgk and Ryk, where the symbol Rgk represents hydrogen, the group Cj 3-elkll, n- butyl, isobutyl, tert-butyl, C1-6-elkoxy, n-Outuxyl, isoOutokeyl, tritluoromatyl, fluoro, chloro, phenoxy or Oenzylokeyl, Rgk is hydrogen, C1- elkyl, C1-6-elkoxy and, R? k is hydrogen, C ^ g-BlkHową, C, _. ^ a _a Luoka ^^ rc ^ group, Huooową or chloro, / b / hydrogen or Getting szorządową or secondary a C ^ g-elkHową not containing an asymmetric carbon atom, (c) a C8-8-cycloalquiU group or / d) a group of the formula phenyl-ZCH4-6 in which m is 1, 2 or 3;

L and the secondary L. where Y1 is -CH-CH-CH-N-, -CH-CH-N-CH-, -CH-N-CH-CH- or -N »CH-CH» CH-, Rj represents a primary C 1-6 elk group not containing an asymmetric carbon atom or an isopropyl group, R '1 represents / a / a phenyl group substituted with groups of the symbol Rgl, Rg ·' 1 R71, where Rgl represents: a / a phenyl group substituted with groups with the symbol Rgl, Rgl and R? 1, where Rgl denotes a tert-butyl group, CJ_g-elkoxy, n-butoxy, isobutoxy, trifluoromethyl, fluoro, chloro, phthnoxyl or benzyloxy group, Rgl is hydrogen, and the C1 group is elk. oe, Cy_g-alkoxyl, thifluormmethyl, fluoro, chloro, phthoxyl or otnzyloxy, except that no more than One of the symbols Rgl 1 Rgl means a trifluoroβ ttyr group, not more than One of sii ^ bH Rgl 1 Rgl means a phenyl group and not blow than one of the syi ^ bH RGL RGL is benzyloxy, R? 1 oznecza hydrogen, a C | _2-alkίlooę, C_ _β Luola ^ t ^ ^^ YRC hose, fluoro or chloro-words, o / pierwszonzędową or druguΓ there is a group of a C1-8-10 group containing no asymmetric carbon atom, a group of a C1-8 group cycloalkyl group or a group of C1-8-8 gCycloalkyl, in which formula m is 1, 2 or 3;

I-1 Formula M, where R 8 m is a C 1-8 alkyl group not containing an asymmetric carbon atom _{, C 8 7} -kyl, / C _1-7 -cycloαlkyl / mttyl, fedyl-ZCH2-, 2-pyridyl, 3 - pyridyl, 4-pyridyl, 2-ttenyl, 3-tnenyl or phenyl substituted with groups sym ^ c ^ ^ in Rgm, Rgb and R ^ m, R ^ m is a group that does not contain an asymmetric carbon atom.

₇ ^ Cg -cyklrαlk ditch, / ₇ Cg_ -cykloαlkilo / methyl fanylo- / CH ^ _m - 2-pi rydlową, 3-pyridyl, 4-pyridyl, 2-ttenylową, 3-ttenyrową or phenyl substituted by the radical R _g m, R ^ mi Rn ** · ^{2 t} ^ ⁱⁿ * and ^{e η1β} more than One of the symbols R ^ m and R? m is a member of the group consisting of the group consisting of 2-pyridylJ, 3-pyridyl- 4-pyridyl -J- 2-th eons ^ wee, 3-teenylowej, phenyl substituted by the radical R-πι, RGM, and R ₇ m and a phenyl substituted by the radical RGM, RGM and R ^ m, RGM is a group Cj_g-alkllowę containing no asymmetric carbon atom, Cg_7-cykloalkHową or phenyl substituted with groups with sym ^ t ^^ u R ^^ m, Rj2 ¹ Ri3 ^m

RJM group is Cj_g-aikHową not containing an asymmetric węcla, Ci-7-cyklualkilową or substituted phenyl groups of R &lt; m, Rjgin.i Rjg®, wherein each of R _c m, rime, RJJ and RJJ independently hydrogen, C1-6alkyl, n-butyl, isobutyl, tertiary, C1-8-alkoxy, n-butokeyl, iso-butoxy, tri-butyl, t, fluoro, fluoro, chloro, bromo, phenyl, ltn-alkoxy or Otnzylukeyluoe, each of eymbori RGM, Rgq, RJ2 ^m 1 Ri5 ^m independently is hydrogen, Cl_ggalkilooę, C _. ^ - ί ^ lkukeyluoą, trifluuronetylroe, fluoro, chloro, ftnukeylooe or Oeπzyloksylooę and each of the symbols R7m, R10m, ^R 13 ^m 1 ^R 16 ^{m n and} dependent t is hydrogen, CJ_2-elkylely, CJ_2-elkokeyl, fluoro or chloro, with no more than one substituent of each phtnyl ring independently being a trif ^ 0 ^ 0 ^ rear group, no more than One substituent of each phenyl ring independently is itoxyl and no more than one substituent each phenyl ring independently is a benzyluxyl group;

163 118

Ν: formula Ν, wherein each of the symbols R ^ n, R ^ n and R ^ n independently represents an alkyl group containing 1-4 carbon atoms, or a phenyl group which may be unsubstituted or substituted with one or two alkUic or Blkoxy groups with 1-3 carbon atoms, or with chlorine groups, or with one fluoro, bromo or trifluoromethite substituent, R ^ n is hydrogen or an alkali group containing 1-3 carbon atoms, e.g. alky or alkoxy, halogen, triflate or phenyl, benzyl or bansyloxy, the aromatic part of which may be unsubstituted or substituted with no more than two groups, one of which may be fluoro, bromo or thi ^ and t ^ uLK rmethyl or one / or both of which may be lower alky or alkoxy or chloro, R n is hydrogen, lower alky or alkoxy or alpha cyclxyl, halo or triflol, R n is hydrogen, lower group alcohol or alcohol a halogen, halogen or triflooryl grouping, and Any □ grouping R ^ n + ^R 5n, R ^ n ★ R ^ n or R ^ n * R? n may be either the radical -CH "CH-CH" CH "or a radical - / CH _2/4 ~ to form a ring, which is substituted with a substituent symbol R ^ n, which is hydrogen, halo or lower alkyl ^ drive axle the or alkoxy group, wherein in the molecule the present SE no more than one group trifytows 1 is not more than two bromine feeders.

Compounds of formula 1 can be divided into thirteen groups, i.e. groups IA to IN, depending on the meaning of the symbol R, i.e.IA if RA, 16 when RB, IC when RC, 10 when R »O, 1E when R * Ea , Eb or Ec, IF when R - F, IG when R - G, IH when R · H, 10 when R «3. IK when R = K, IL when RL, IM when RM and IN when R» N.

In general, when the hydroxy ketone compound of Formula II is reduced to the dihydroxyhydroxy compound of Formula I, an additional asymitric center is formed. In kmsequinnji, when the acetic compound of formula 2 is used, four steroisomers are formed (consisting of two pairs of nnnnJJooeo), that is, a pair of erythrocyte enantiomers and a pair of nnanJJlonr. the compound of formula II, two diαtt "tθollomeoy" are formed (this is the erythro isomer and the threo isomer) of the compound of formula 1, e.g. diester 3R, 5S and 35.5S, which results from the reduction of the 5S-hydolxyl compound. Diestereoisoers can be separated by conventional means, such as fractional crystallizations, column chromatography, non-active (thin film fluid chromatography) or HPLC (highly spiffy liquid chromatography). The ratio of the proportion of erythro isomer to threo isomer obtained by the methods, is usually variable and may be, for example, up to about 98: 1.

In the case of the process s terms el eto wnew / dzlntgl with the method according to the invention, when using a compound of formula 2, almost ^^ lag ^ nm I add only two steroisomers / ot: nJoujaJe a pair of en / nJjomeo erythr! /. Alternatively, when an optically active compound of formula 2 is used, only one nantiomer of the compound of formula 1 is formed, and this nnanjomer is the first nnβnc erythnomer. For example, the reduction of the 5S-hydooctyl compound in which X is -CH.CH- gives the 3R.5S enencJooer.

The ratio of the erythro isomer to the threo isomer obtained by the process of the invention is about 99.1: 0.9 or higher, in particular about 99.5 and 0.5. or is greater, especially about 99.7: 0.3, or greater.

Terom tnΓθlttlnktywny: used in the description, I mean that the ratio of the mytn isomer to the isoonou trao share is 99.1: 0.9 or is higher.

The common isomers of the compounds of formula I are the 3R, ES and 3S.5R isomers and composed of both, the 3R, 5S and oaJnmat isomers being preferred.

Conventional methods for reducing the oxo group in a compound of formula II assume the use of mild reducing agents such as tettahydroOoo / n sodium or a tert-butyl borane complex in an inert organic solvent such as a lower alkanol to give a mixture of optically pure the compound of the starting form diattθreoylOonychnycn or, alternatively, from oaJoic οθ / θγι / ^ ^^ yćc ^ owago, raJemic diastereoisomers.

The use of a three-step, part of the process of reduction was adopted in order to obtain mainly eryins from the racemic material. In the first stage.

Compound of formula II is contacted either with a tri-alkylborate compound or with a compound of formula III in which R is an alliOn or a lower alkyl group of 1 to 4 carbon atoms, preferably a non-tertiary group, and Rg is a primary or secondary group an alkyl group having 2-4 carbon atoms, preferably a non-tertiary group, in a reaction medium containing alcohol and tetrahydrofuran (THF).

In the second stage of processes of this type, sodium tetrahydroborate (NeSH) is added to the reaction medium and the reaction proceeds with the reduction of the oxo group and, in turn, from the utoerranae cyclic compound of the ooronlenic compound of the lorine complex with the compounds of the formula 1, In the third stage, the reaction mixture containing the hydrogen complex and / iuD cyclic loromenic ester is motropically distilled with mtano ^^ mL ethanol, alternatively, subjected to an aqueous solution of a peroxygen compound, such as n ^ t ^ oxide, e.g. hydrogen peroxide, in an organic solvent environment, or perborate, e.g., sodium perchlorate, to give compounds of formula 1. The above-poneate method is said to provide an erythro racemate with a selectivity of e.g. about 98% relative to the threo / Chen isomers et al., Tetrahedron Letters, 28, 155 (1987) /.

The process of the present invention comprises the method of steeply reducing optically pure race 1 compounds of formula 2, whereby almost exclusively the erythro isomers of formula 1 are obtained. Preferably, the reduction of the oxo group in the compound of formula 2 is indeed instantaneous. The compounds of formula I, i.e. erythro isomers, are additionally obtained in a state of increased chemical purity and can be made to a chemical purity above 99% by means of conventional recrystallization.

Accordingly, in the first step of the process according to the invention (step (a)), the compound of formula 3 is mixed with the nitrile of the formula 3 with sodium and sodium chloride (NaBH) in an alcohol-containing reaction medium. and tetrahydrofuran.

In the second step / step / 0 / / the compound of formula 2 obtained in step / a / is treated under conditions suitable to obtain a mixture containing the cyclic compound lerenieneww of formula 4a 1 / or the Pore complex of formula 4l, wherein R formulas,

Rg, Rg and X are as defined above. This latter relationship prevails before the task of a reaction maneuver. However, such a difficult task leads to the conversion of the yorium complex into a Perenian ester.

and; in stage three (stage / c) / the product obtained in stage / l / is cleaved to obtain the corresponding compound of formula 1.

Step / a / is preferably carried out under conditions essentially ^^ preferably in the area of obooętnej at a temperature from about -1.00 eye ^{L C} e ^k e ^wit about 30 ° C Iton ^ rnie ottoło from -80 ° C to about - δΛ and more preferably from about O ^L O ^k -78 ° C to Ole e ^k -70 ° C. As used in the step ^{of p} e / a /, the reaction mixture contains a mixture of alcohol and tatrahwdrefurrnu, wherein the alcohol has the formula AikOH, wherein Alk is rlkieowę having 1-4 carbon atoms, a portfolio groan group mitylewα lul ethyl, preferably not tertiary group Ledeč.

One of the products produced in step / a / may be μογίι RgOH derived from the compound of formula III used herein. However, it is not an electronic thing, but the whole part of the group with the symbol Alk ly is the same as R ^. The sodium tetrahydrate should, in general, be present in an amount at least equilibrium to the compound of Formula II, and more preferably in a slight excess, such as, for example, from about 1.1: 1 to about 1.5: 1 mole of NeBHg. per mole of ketone. The molar ratio of Formula 3 to Formula 2 is at least about 0.5: 1, and more preferably about 0.7: 1 to about 1.5: 1 mole of equilibrium compound per mole of ketone.

Also etep / l / is preferably carried out at lowered, the tempe ^r t ^u r ^{e o} eft ^ trrn ^ę persist ^E porlemla otcoło - ¹⁰ ° ^C to a yellow-^ - ⁴⁰ ° C and in particular on ^or about - 78 ° ^C to about -70 ° C. Preferably, the compound of formula 2 is present in a solvent such as alcohol such as THP alcohol. Preferably, the reaction medium in step / a / 1, the solvent of the compound of formula 2, which is added in step / 1 /, is selected so as to prepare a medium in which the ratio of alcohol to tetrahydrofuran is from about 1: 3 to the preparation of a mixture of alcohol to tetrahydrofuran. about 1: 6, and more preferably from about 1: 3 to about 1: 4. Reduction of the oxo group

163 118

S exothermic reaction proceeds rapidly, and therefore it is desirable to add a keto compound gradually ^to maintain the internal temperature in the range ^{± d} of about -78 ° to -70 ° C olcoło. Reduction takes place almost immediately, e yieszanin ^± realkcyjną then s ^Yb co treated, for example. Aqueous sodium bicarbonate, ammonium chloride or acetic acid to give a mixture of the desired SIA cykliznnyrn związkeem boron · oitano¼yry As związkeem intermediate.

In step / c / the reaction product of step / 0 / can be subjected azeotropic distillation with methanol iut) ethane ^ m at a temperature, for example. Of ^K O ^L O 60 ^d of oldło ⁸ °° ^C, under the conditions of ^a s ^and anhydrous dniczo . Alternatively, and preferably, if X is -CH-CH-, the product neutralized by adding sodium bicarbonate / NaHCO-g is dissolved in an organic solvent such as ethyl acetate and treated with an aqueous, e.g. 30%, solution m ^ aqueous hydrogen peroxide or ΓϋΠΜ ^ βιι sodium perborate /NaBOg.A HgO / initially at obnijnej ^{ns such} as eye ^L of ^{łlTC, p} being allowed to warm to temperatuy dies ^k o ^ r ^ ^ee, the ^k nd I ^k of about 2 ^d °° C ^ about 3 ° ^C to give the corresponding mięzek of formula 1.

Alternatively, the cyclic boronate ester from step (0) may be extracted with an organic solvent such as ethyl acetate followed by direct addition of an aqueous peroxide such as 30% aqueous hydrogen peroxide Iud aqueous sodium perborate, resulting in the corresponding compound of formula I is obtained

Since reducing conditions exist in the practice of the invention, it is understood that any substituents or functional groups on the radical used in the symbol R will be inert, i.e. the radical will not contain substituents or functional groups that would be reactive or susceptible to such changes. conditions, which can be achieved, for example, by known methods of masking or protecting such functional groups by introducing them at a later stage in the process.

The compounds of formula ^1, corresponding ⁶ -laktony, free Itwasy sol and ^ ^p are transformed into ^a person ^s łcania compound of formula 1 wherein R has a specific meaning to the corresponding compound which in the accompaniment symbol has a different significance and / or into the corresponding Lactone ^{l £} as a free acid, or salts thereof, are mane.

If desired, the compounds of formula I can be converted by conventional means into the corresponding free acid or salt forms, that is to say into compounds in which Rg is replaced by hydrogen or a cation, such as an alkali metal or ammonium cation, preferably a cation. sodium or potassium, and especially sodium, in other esters or in the corresponding ony-lactones, this is internal asters.

• As mentioned above, the compounds of formula 1 according to the invention are pharmaceuticals.

As materials wyjścoowe used in the process according to the invention / or secondary prΓnwszorzędowy ^ Cg alkoxy or alllloksy / -dl / pieswlzorzęlowy Cg_ ₄ alkyl / 0oeany are known / "Koster et al., Ann., 352/1975 / j Chen et al ., Tetrahedron Letters, 28, 155 (1987) and

Chen et al., Chemistry Letters, 1923-1926 (1987). However, they can be prepared in situ from the corresponding _{C8 -4-} alkyl / boron tri / endo-alkyl / boron by reaction with a primary or long-chain Cy g-alkanol a) or allyl alcohol, the concentration of the former in the latter being of the compound is from about 0.2 T1 to about 1.2 L, most preferably about 0.5 M.

Compounds of formula 2 are known, and can be prepared by a method analogous to the preparation of known compounds of formula 2, e.g. as described in U.S. Patent No. 4,773a,073 / e.g. in case 2g is oxygen / or in EP 216 785 / e.g. where Zg is oxygen /. Thus, compounds of formula 2 wherein Z? is oxygen, normally prepared by reacting a compound of formula 5, wherein R and Z are as defined above, with a deacon of a compound of formula 6, wherein R g is as defined above

A specific illustration of the process according to the invention relates to the preparation of erythro- (E) -3,5-dihydrokey-7- (3 * - (4-fluoro-phenyl) -1 '- ([mu] mmethylethyl) n-indol-Z 1 -ylOh / hapt-e acid. -enowe

As the free acid, salt, ester or 6-lactone, i.e. internal ester, of formula Ie is present in a process comprising: atereoselactive reduction of a racemic or optically pure compound of formula IIa, wherein Rj has the above-mentioned meaning, in the first step of combining the compound of formula 3 with sodium tetrahddrbbornnne (NaBH 3) in a reaction medium containing alcohol and tetreadrofur, in the second step of treating the compound of formula 2a in racemic or optically pure form with btΓzmmannJ mesmin under appropriate conditions, to give a mixture containing a cyclic boronate compound of formula 4a and / or a boron complex of formula 4b, wherein R is the group (-3- (4f) uoro phenyl) -1- (1 * -methylethyl) Z-1H- ifido ^ ZZ-low, X stands for -Cl'CH-, and R ^ and R ^ are detonated above, but in the second stage of cleavage of the second product in the second stage of cleavage, X is obtained, as a result of which a compound of the formula I is obtained ester in the form of rajemljrnnj or optically clear, and if desired, converting a compound of wzorm Ia in ester using typo ^O cn śrbdków ⁱⁿ zwózek in the form of a) lne ^g of ^acid, salt, other ^G ester or octocoon, that is, internal ester.

The compound of formula Ia may exist in the form of the free acid, salt, or 6-lactone ester, i.e., internal ester. Preferably, it is in the form of a free acid or salt, preferably an alkali salt, especially a sodium salt. Preferably it is in the α-mimic form or, alternatively, the optically pure enantiomer (3R, 5S), in particular in the form Γ8 "ιηκζη6]. 3As it turns out from the formula le, this form is the erythro form.

ΊΙ the second part of the reduction stage above ^! For stereoselective reaction, it is preferable to use a compound of formula IIa, in which Rj is an isopropyl group, or, especially, a tert-butyl group, which facilitates the isolation of a relatively purer compound of formula 1 than when R | stands for a group like a metal group. Unexpectedly, the compound of value 1 obtained in this way is completely colorless, whereas in the previous syntheses it was always obtained as a pale yellow product.

Other reductions can be made with the use of a compound of formula 2a rαcnmnn or optically pure as previously supported. An optically pure compound of formula 2a is obtained, for example, by chromatographic separation of a racemic compound of formula 2e or, preferably, by assyrneeric synthesis. Alternatively, the separation can be performed in the next step or at the level of the final tomic product.

The starting materials for this specific embodiment of the invention are also known or can be prepared according to known methods. Process for the Preparation of 3- (4'-Fluorophenyl) -1- / 1'-methyloylZ-1H-Indole is disclosed in U.S. Patent No. 4 73S 073 as Example 5, steps 1 to 3 in columns 44 and 45, with fluorbenzene as an exit relationship.

The following examples illustrate Wynnlazek. All temperatures are given in degrees Celsius. The optical purity is expressed as a percentage, so for example an erythro isomer with a purity of 99.9%, means that there is at most 0% and% of the threo form in the ester.

The following examples illustrate the sterosal active reduction of a compound of formula 2 to obtain a compound of formula 1.

Example 1. Acid tert-butyl ester / ♦ / -erztro- / E / -7- / 3 '- / 4 · -flbobonθnzlo / -1' - / 1 • mne t yloe t ylo / indo o-2 '- 1 lo / - 3, S-dihydroxyhep r-6-enoyngb. / i. "Formula 1: R" 3- (4 "-fluorotenyl) -1- (1'-methylethyl) -1ndo1-2-1l group, X = (E) -CH = CH, Rj" tertburbower group; in the form r ^ emic ^ ej /.

/ a / 47.67 g / 1.26 mole / of sodium rntrahydroDoranu added to a solvent comprising 1.32 rope sucnego tetaahydrofutonu / THF / ml and 356 neeanolu under an atmosphere ^of nitrogen and ^{at a} temperature of about ⁷ -7 ° C. To the reaction solution, 102 ml of a 5C% dithymethoxyboane solution (4.09 M) in THF ^{are added over 15 minutes, and the resulting mixture is stirred for an additional 10 minutes.}

/ b / to the mixture formed in p. / a / is added dropwise to 1.5 within the first n temperature of from about -74 ° to -77 ° C ³⁰⁰ 5 ^g / 0.464 mol / rertb0utylywego acid ester / ^ / - / 6 / - 7- / ³ '- / 4 *' - tl.uoro163 118 f eny lc ^ / l '- / 1''- ^ tt ^ loe tt ^ l <^ / mdc ^ l-2' -Ho / -5- hydroxy-3-okeohept-6-ene, pure

71.8% in 104 mL of THF and 26 mL, and the mixture was kept dry for an additional 30 minutes. 720 ml of saturated sodium bicarbonate solution and 1.75 liters of heptene are then quickly added to stop the reaction, then 500 ml of ethyl acetate are added and the resulting mixture is diluted with 3.5 liters of water with stirring for 15 minutes, the temperature of the mixture being stirred for 15 minutes. is around 10 ° C. The upper organic layer is separated and washed several times with a saturated solution of sodium chloride in a total volume of 2.4 liters, pH 7.5, then the organic layer is concentrated at a pressure of 26.6 - 39.6 hPa, with a maximum external temperature of about 45 ° C. Oo the organic residue is added 375 ml of toluene and the solvent was distilled off under ciśnieneem 26.6 - 39.9 hPa and the temperature of the outer makaymmanej ottoJ ⁴ 5 ° C.

(c) (o) the thick oil thus obtained (in the course of the cyclic boronate compound), 3.73 liters of ethyl acetate are added. Oo created ethyl acetate solution was added ^p y ^y ^ maintaining the temperature inside rznej of 25 ° ^d 30 ° C / adding ^p sys ^ę tkowo is egzotarmicznaa, 500 mL 3C% hydrogen peroxide / 4.41 mcoa and / otrzymaeę medzaninę reaction iesza t ^o a temperature ^{of 20} ° ^d 25 ° C for about 2 hours with about mommeeu ^{d, k} Errors chrommtonΓ8tlθ Jίθnkonar8nwona have not demonstrated the absence of the compound bornylaennego. The upper organic layer is washed twice with saturated sodium chloride solution, pH 7.5, in a total volume of 2.22 liters. The upper organic layer is then separated, washed three times with 10% sodium sulfite solution in a total volume of 2.61 liters (until the peroxide is removed from the organic layer), while maintaining an internal temperature of 25 ° C.

Then the upper organic layer is washed two times with a saturated sodium chloride solution, pH 7.5, in a total volume of 1.72 liters, and then the solvent is distilled off at a pressure of 26.6 - 39.9 hPa and at the mmximeter of the outer pad at about 45 °. C. The residue obtained is dissolved in 1.17 liters of refluxed ethyl acetate, the mixture is filtered hot and the mesh is filtered at 20 to 25 ° C for 16 h. The resulting solids are collected by filtration, dried under reduced pressure. changed with reduced pressure (about 26.6 - 39.9 nPa) at 25 ° C, washed with 550 ml of a mixture of ethyl acetate and heptane 1: 4, eneonally dissolved in 880 ml of ethyl acetate and the mash at ambient temperature for 18 h. the resulting solids were collected by odsęczenia and washed with 480 ml of ethyl acetate and haetaeu 1: 2, then dried under pressure to give 114.5 g product / eθyperatkra m.p. 135 137 C ^O /.

The second crop is obtained from matte lyes, thus achieving a total yield of 149.5 g. The purity of the compound is 99.44% and the erythro isomer is 99.67% pure. It can be separated into two optically active aeancs, JnneΓy, 3R.5S and 3S, 5R, with the former being the preferred one.

Alternatively and preferably, half of the indicated amount of sodium tetrahydroborate may be used in step (a).

Alternatively, in step / c), an aqueous sodium perborate solution may be used instead of a 30% solution of peroxide in sodium peroxide.

Example II. Acid methyl ester / + / - ery t m- / E / -7- / 3 '' - / 4 fluoro phenyl /

-1 '- / l' '- methyl / endol-2'-yl] -3,5-dihydroxyhae t-6-ene.

Formula 1; R, X are as in Example I, R R »methyl group; in the form of raJamlce.

(a) Sodium tetrehydroborate is used in a manner analogous to epnsnbk in Example 1, step (a), but with 15% diethymatoxybnbk in THF.

/ b / 118.5 g / 0.28 mytylonegn acid ester / + / - / E / - £ 7- / 3 '- / 4''- fluorophenyl / -1 * ^ / 1. '* - ^^ 1 · ^^ ^ο θtylo ^ i ^ ndol ^ ² * -i ^o <^ 7 -S> -by ^d rn ^k ey - 3noksoha ^p t-6annowe ^g n ^ can be prepared in a manner analogous to of the method of Example 1, step / b / - / ₍ but the dilution is made using 1.42 liters of water and 1.185 liters of heptane, instead of just 3.5 liters of water.

/ c / o o organic eosolvent, ethanizing mostly as a cyclic bornnene compound, 2.375 liters of ethyl acetate are added and the mixture obtained is mixed with

163 118

264 ml of a 30% hydrogen peroxide solution (2.328 mlf), followed by further work-up as described in Example 1, step (c). The resulting residue is then dissolved in 130 ml of isopropanol. The resulting mixture was heated to reflux temperature. While hot, 14 g of boric acid are added and heating under reflux is continued for another 15 minutes. The mixture is filtered and stirred in przesłcz tem ^ t ^ ^^^ Urze and ²⁰ ° to 5 ° C in ² you ^g in ^{18 g} odzin. The solids were collected by ^SIU drainage aid ^and washed with 100 ml of isopropanol and dried under iejszt d ^ ^^ ^ m and pressure to give 110 g of product / 80% yield. This product is redissolved in methanol and recrystallized. Melting point 124-126 ° C.

The resulting compound is an erythro racemate with a purity of 93.07% and can be separated into two optical eMncjMers, 3R, 5S and 3S.5R, the former being preferred.

Example III. Tert-butyric acid ester / t (eerythro / E) -3,5-dihydroxy-7Λ. * - / ⁴ '' -f norofen ^ o / - ⁴ '' - / 1 * '-mee yHe e yH / - ² ' -f en ^r l / -lH- ^a billionalol // 5 * -Ho> / J hapt-6-enowago.

Formula 1: R o 1- (4-fluorofβnyro) -4- (l * mmeaylethyl) -2-rtnyl-lH-amidazol-5Howa group, X e (E/-CH.CH-, R &lt; 2 &gt; tertiarybutyl group; as the 3R, 5S enantiomer.

/ a / U, 27 □ / 0.27 ml / sodium tetaahydrotnran is added to a solvent containing 1.67 liters of dry THF and S13 ml of methanol, in nitrogen aam ^^^ and at temperature Ho -76 ° C. Dr. ^ Manego solution (jodaje ^SIU over ³⁰ ° C ^{lnut, p} y ^y Hold Ann ^ ^ tem perature wewnntrznej below -77.5 ° C, 387 ml of 15% dimetyJ ^ t ^ o ^ ^ meth ks ^ ^ boron and nu in THF. The salty mixture was stirred for an additional 5 minutes.

/ b / 110 g / 0.223 acid tetbburyl ester / 5S / - / E / -7- £ / is added dropwise, at a temperature of about -74 ° C to -77 ° C, in the course of 2 hours, to the meshes formed in wp / a / 1 '- / 4 * * -fluorophyco-J * - / 1''-methylethyl / -2 * -fanyl-1H-imidazol-5 * -yl / J -5-hydroxy-3-oxohept-e-anone in 304 ml of THF and 76 ml of methylene chloride. The resulting yellow solution Bert stirred at aam ^ e ^ r ^^ tuι · Zr -76.5 ° C for 6 h. Then added quickly to quench the reaction, 425 ml cone ^ ^ ammonium chloride solution erz ^y ^ ma ^ m and ^ ^y waniu the ^m ^ ee ^ ^y turns about -65 ° to 0. Followed by addition of 950 ml of ethyl acetate and 950 ml of hexane and 1.13 liter of water, the temperature is oltoH partitioned between ⁵ ° C and stirred mietzanla ^{t SIU} within ¹⁵ minutes, e ^r with ^r ^ white part in the ^y-component The temperature of the mixing process is about ⁵ ° C. The upper ^and the organic layer was separated ^SIU and washed successively with saturated sodium chloride / pH 7.6 / in a total amount of 1.4 liters, and the solvent was distilled off under ^ m of difference of 2.66 to 3.99 hPa, with a maximum external temperature of about 45 ° C.

/ c / 3.25 liters of ethyl acetate was added to the resulting oil / slanowięcegl predominantly cyclic compound boronilaow ^y r · POMH then added 340 ml of 30% hydrogen peroxide / 3 so as ^to from ^a rzyaίa ^C ^ rnewn fac 20 ° to 25 ° 0.

Irzyma alaszlaia ^ ^{E being} mixed ^SIU at 2 ° ° to 25 ° C in pregnancy ^g of ^L eye for three hours ^and, to mommetu when ia cienkowlΓsnwowl not demonstrate the absence of the boron compound / nilnowego. The upper organic layer is washed with a two-column wash with a saturated β / dl chloride solution, pH 7.5, with a total volume of 1.6 liters. Then the upper organic layer is treated, washed three times (each time for 10 minutes) with a 10% solution of sodium sulphite for a total volume of 1.5 liters / until. to remove the organic layer peroxide / and the utrzy mywaniu tempe £ ^ ^y wemjrznej turns ²⁵ ° C. Mrnę or wars ^ ^g ^ ent aniczn ^{± SIU} and 600 ml nls ^r conrgl tldlnrgl chloride solution / pH 7.5 /. The dissolver is distilled at 2.66 to 3.99 mbar at the mmximeter of the external temperature of about 45 ° C. 106 g of crude aallarial are obtained. After purification of 9.68 g of crude dlhridyl ester by column chromatography, eluting with ethyl acetate: hexane 1: 2, 490 mg of a compound with a flux temperature of 1.43-1.4 ° C are obtained. Anali.za ^NMR indicates that this is the ^desired isomer erjro a purity of 98.7% and there is a me isomer tm.

'* ^{6' 49} ° Κ = 0.77. CH ₂ C1 ² /.

Example IV. Sodium salt of acid / ^ '/ EErytl0- / E / -3,5-hihydloxr-7- / ^_ 3 · - / 4 · ^, -fluorophy ^ / l * - / l “-meendl- ² ' -yl / hept6 / enloneq /.

/ Formula la: in the form rlcrmiczner, as sodium salt /

163 11Θ

Stage / a /: Crude acid tert-butyl aster / + / - / E / -0- / 3 '- / 4-fluoroephenyl / -l * - / l · retyltrtyl / indol-2'-1I0_7-Syhylrot- The 3-O-ssonppt-6-ene (compound of the formula 2a, in which Rj is a tert-butyl group, in racemic form) is subjected to stereoselective reduction as described in Example I above, steps / a /, / b / and / c /, with the formation of teΓ / -butyl acid / ^ / - erythro- / E / -7- / 3 * - / 4 * -fluorophenyl / -1 * - / 1 "minethylethyl / iedol-2'-chloro / -3,5ddihdr rksy yhβρΝδ-aowvego.

Step / b /: To 42.5 g of otzzimanego in step / a / above in 205 l of THF are added you ^g in 5 minutes, with using ^s ^ utrzyi Ann temperature ^yp oniżej Lo ^C, SD il ¹ N sodium hydroxide. The resulting solution is stirred for 1 hour at room temperature, then 205 ml of mtant are added and the resulting mass is concentrated under 33.26 IPa at 45 ° C. Then add ^j e a 3DD ml wo ^{dy d} of ^deionized and ^d estylację! <Ont ^y eluje until a volume pozoasałości 14D ml and again added 38D ml of deionized water and the resulting solution was washed 6ię three portions of ether teΓtbUutylooOimetylowθgo in total volume of 64D ml. The aqueous layer was concentrated under ciśneenemm 33.25 IPA at 45 ° C ^{D E} is the ^COG volume of about 3DD ^ml of ^p e ^j being added to ²² ml of water D onJoel2owaeej ^y ^ c bran many clear aqueous solution is in within 3 days of freeze-drying, which gives 35, S g (S1% yield) of the title compound, chemical purity S8.9%, being the erythro isomer with purity SS, S%. Boron concentration below detection limit.

Alternative procedure for step / fa /. To 35 g of D otryimanego in Step C / a / above in 105 ml of ethanol are added within the first five minutes while stirring and maintaining the temperature * ^1, below 12 ° ^ 74 ml of ¹ N sodium hydroxide. Otrzymy solution of the mass within the first one and then otrtimaeę mixture was concentrated under ciśnienńem 33.25 YPA ^at 45 ° followed ^ ^A DD 250 ml wotty ^(j de.jonizowane AIE and distillation continued until a volume of 115 pozossałości Then 315 ml of deionized water are added and the resulting solution is washed with three portions of tert-butyl methyl ether in a total volume of 525 ml. The aqueous layer is concentrated at the average temperature of 33.25 IPa at 45 ° C. ^ ^d vol ^ę toast olkoło 245 and of the ^ ^{p (SIU} added ¹⁸⁵ ml water ^yd ejonizowanej and transparent aqueous solution is within the first three days lioflCzzacJc, to give 29.05 g of the SCE /% yield S1 / compound tytutawego the color of pure white, /. melting point D ^{2 4 0} -20 ° C / ^ order ro /. Czystoś ^C eiicma about ^10%. Związel <isomer of the erythro SS purity, 61%. boron concentration of 3 ppm S6 .

Examples ^ e ^ ^v · Acid sodium salt / + / - eΓytro- / E / 33,5-diyZydrocoy-7- / ~ 3 * - / 4-fluOΓphenyto-1 * - / 1 -methylethyl / indol-2'- Clo-7-hept-6-ene-ene-1a: in the crude form, as the sodium salt of J.

The title compound is prepared in a manner analogous to that of Example IV, except that: in step / a /, the mmtyl ester is used and the reaction is carried out as described in Example II, steps / a /, / b / and / c /. and step / b / is performed by hydrolysis of the methyl ester obtained in step / a / as described in Ammeyka's US Pat. No. 4,739,073, Example 6 (b) in column 50.

Claims (2)

Patent claims 1. The method for the preparation of 7-substituted-hept-6-ethowagt acid t in the formula 1, where X is -CH — CHh, the COORr group forms an aster group, where Rr is a C1-4 alkylene or banzyl group, and R is an organic radical containing the group providers who are inert under the conditions of radukuj ^{o t} o ^s c ^h awantualnia ^g in the form of the free acid of the salt lu ^b έ -laktonu to ^d ro ^d a · staraoselekt> wnej radukcji racamicznago or optically pure compound of formula 2 wherein R Rr 1 X has the meaning defined above, and Jadan with the symbols Zr and Zg means oxygen, and the second means a hydroxyl group and hydrogen, possibly in the form of a salt or lactone, characterized by the fact that in the first therapy / 'atap / a / _7 m. is the compound of formula 3 in which R r is a H 2 or lower alkyl group containing 1 to 4 carbon atoms, and R g is a semi-primary or secondary alkyl group containing 2 to 4 carbon atoms, with tai: rhl ^ '^ d ^ ^ t ^ oren sodium NjBHr in a raak ^ ci environment containing alcohol and tatrahydrofuran, in the second therapy / atap / b / J, the compound of the formula 2 is subjected to the action of a mixture, obtained in atapy / a / under conditions of exclusion ^^^ by ^^ cn to obtaining a mixture containing a cyclic boronate compound of the formula 4a 1 / or boron complex 4b, in which the formulas r, Rr, Rg and X have a significantly higher score, and in the third therapy (step / c) / _7 the product obtained in atapia is split up / b / into the corresponding compound of formula 1, then, if desired, the compound of formula 1, if desired, orza 1 in the form of astru is converted by known methods into free acid, salt or 6-lactone. 2. The method according to p. According to claim 1, characterized by the following. For in the case of preparation of compound of formula Ia in raJemiJznej or optically pure wolnago in the form of an acid salt of ^l Astrue ^b S -laktonu ^is jast Astrue wθwo exterior ^g of ^n, is subjected t ^{o y} stereoselekt football ra ^{d u} cj and the racamous or optically pure compound 2a, wherein Rr is as defined in claim 1 by means of, in a first step, mixing the compound of formula 3 as defined in claim 1, 1 with sodium tatrhydtoborane / NaBR / in a reaction environment containing alcohol and tatrahydrofuran, in the second, treatment with the compound of formula 2a in manual or optically pure action, obtain mechanine under appropriate conditions to obtain a mixture containing / cyclic compound and 4 boron of the formula 4b, in which R is the group (-3- (4'-flutophenyl) -1- (1'-methylethyl) -lH-indoJ) - 10o, X is -CH = CH- as well as Rj and Rg have a connection as defined in claim 1 and, in atapy, rtzsz acid, salt, other aster or "end", this is the "intrinsic" aster.