SA90100111B1 - Method for preparing 7-substituted-HPT-6-anoic acid and heptanoic acid and derivatives thereof - Google Patents

Abstract

Abstract: This invention relates to the preparation of 7-substituted-hept-6-enoic acid and heptanoic acid and their derivatives and intermediates thereof. So it relates to a method for preparing compounds of formula I: where: X is -CH2CH2- or -CH=CH-; R1 is an ester group that is inert towards reaction conditions, R is an organic radical containing groups that are inert towards reduction conditions. The method of the invention for preparing a compound of formula I involves the stereoselective reduction of a racemic compound or a pure photoactive compound of formula II in which R1, R and X are as defined above and one of Z1 and Z2 is oxygen and the other is hydroxy or hydrogen, to yield an identical compound of Formula I. These compounds of formula I have therapeutic properties, especially as anti-atherosclerotic agents and to reduce blood lipids and blood cholesterol. The method can be used to prepare compounds of formula Iu, where u is triphenylmethyl (trityl), and Ru is The allyl or radical forms an inert ester under reducing conditions, which is an intermediate in the preparation of some compounds of formula I. It reveals new methods for the preparation of early intermediates for use in the preparation, for example, of compounds of formula I called method A and includes the preparation of compounds of formula VII(VII) E)- OHC- CH = CH-N(R12)R13)Where R12 is an alkyl with 1 to 3 carbon atoms (C1-3), a phenyl or a phenyl substituted with one to three groups which are independent of the alkyl (C1-3) ), 3-alkoxy, fluoro, chloro, bromo, or nitro with at most two nitro groups; and R13 separately have a significance shown above for the R12 moiety, starting with the corresponding compounds of formula VIII (OHC-N(R12)R13 (VIII) method B, comprising the preparation of compounds of formula Va wherein r5 is a hydrogen, or an alkyl containing 1 3 carbons (C1-3), n-butyl, i-butyl, t-butyl, 3 to 6 carbon alkyl (C3-6 cycloalkyl), 1 alkoxy 3- C1 carbon atoms (3alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; provided that there are not more than R5 and R6 is trifluoromethyl, there is no more than R5 and R6 is phenoxy and there is no

Description

¥ How to prepare 1-substituted -hept acid -? Substituted-hept-6-enoic-7 and heptanoic acid and derivatives thereof Full description Background of the invention: This invention relates to the preparation of 1-substituted-hept-enoic acid 7-substituted-hept -6-enoic and heptanoic acid and their intermediate compounds. The invention is concerned with the preparation of a method for the preparation of compounds of formula 1Z: 3 5 R- %-CH- CH - CH- CH - COOR, (I) ] 08 08 where: X | is -CH,CH,- R ~CH=CH- Ry º The ester group is inert towards the reaction conditions; And: : SSR Ve Lo is an organic radical root that contains inert groups towards the 'reduction' conditions. It is required that; When it is 14 triphenylmethyl J-fia then it includes an extra Ry allyl and X is ~OCHp- Different stages in the preparation of 7-substituted-hept-6-enoic acid and ga es heptanoic acid, which is considered as a final product, as well as its derivatives that are used for construction Bio: Cholesterol. This connection between the different steps can be understood here with a particular embodiment z if we consider the preparation of an inhibitor of cholesterol biosynthesis; called Earthru yay |

Y

ethyl)indole-?-lithium-"1(-1-)lenv gE) PTY hydroxy lio oF (B) yl]-7-heptanoic acid

Erythro(E)-3,5-dihydroxy-7-[3'-(4"-fluorophenyl)-1'-(1" -methylethyl) indol-2"-y1] hept-6-enoic acid in the racemic form Or the pure optical form, in the form of a free acid ° in the form of a cyclic ester (8-lactone) 5-lactone of ester or in the form of a salt; or an ester The method used in this invention is to prepare a compound of the formula 1 includes a pure photoactive procedure or compound having a racemic stereoselective reduction process for a racemic compound Lo

IT Formula 8-3 - 6 - 08. - © - CH - COR, | (II)

A! 2; . Vo has been defined above. X and 18: R where while the other is hydroxyl oxygen or 72 whichever is oxygen 1 .7 or hydrogen 07070860 to produce an identical compound with the formula hydroxyl i.e. esyn el Fi As it is clear from formula 1, the compound has a stereotactic form Ll a stereotactic erythro form. ve - which appeared at the beginning of the formula or in the name of the compound indicates that (B) the symbol rans the double bond They are in the keto group position. The usual methods are used to reduce the keto group. The chemical formula [1] is an ordinary reducing agent such as sodium borohydride: tributylamine with borane complex or sodium borohydride 01 in the presence of Inert organic solvent such as alcohols t-butylamine and borane low diastereomeric isomers to give a mixture of diastereomeric forms

Yay | z

¢ Stereoisomeric from a pure, photoactive starting compound; or alternatively; Distereomeric forms of racemic starting material. Three steps were used to complete this steric-selective reduction reaction to obtain a dominant erythro-racemic form from the racemic starting material. © In the first step; A compound of formula IT comes into contact with a tricyclic derivative of trialkylboron or with a compound of formula TIT: R40-B-(Rs) (Im 1 where Ry is an allyl group or a low alkyl group lower alkyl (£7) carbon atoms; Preferably the dE group and Rs 0 be not a primary or secondary alkyl group containing EY carbon atoms; preferably not a third group; In a reaction medium containing an alcohol and tetrahydrofuran in the second step of the operations sodium borohydride - (NaBHy) is added to the reaction medium; Thus the reaction proceeds by reducing the do sane of the ketone and thus leads to the formation of cycloborons or a boran complex with the compound of formula 1. In the 0 third step; The reaction mixture containing the boron complex and/or the ester of cyclic boronate 1! for an azeotrope 21 is treated with methanol or ethanol 0 Co or any other organic solvent with a peroxyl compound such as Jie peroxide hydrogen peroxide hydrogen peroxide or Jie perborate | sodium perborate; In order to obtain the compounds resulting from the formula TX, this aforementioned method is known as erythro-racemic with a ratio of about 9698, selective for the threo isomers, see (Chen et al.

Tetrahedron Letters,28 155[1987]) This invention includes the preparation of a compound of formula 1 as defined above in optical purity such that the ratio between erythro isomers to threo is 1,4:44,1 Yo or More, preferably 99.0 v0 more, especially 139 1,” or more. Yay

These are compounds of formula J that are esters; or the corresponding free acids; Cyclic esters and salts (5-lactones) have therapeutic activity; Especially as HMG-CoA reductase inhibitors, meaning inhibitors of the biosynthesis of cholesterol, and therefore can be used to treat cases of increased cholesterol, increased protein in the blood, and angina pectoris. © GENERAL DESCRIPTION OF THE INVENTION: The Ry ester group preferably has an acceptable physiological function and is hydrolyzable when the desired end product is an ester. The term 'do sand' ester with acceptable physiological function and hydrolyzable" means that the group which attaches to the 000 moiety)-forms an ester group with acceptable physiological function 0- for hydrolysis under physiological conditions yielding to the corresponding carboxylic acid of the compound with Formula ]; (meaning that Ry replaces a hydrogen atom) and an alcohol that : by itself has an acceptable physiological function; that is, it does not have toxicity within the desired dose limits; especially a group that is devoid of any symmetric centres. Ry is preferably Ry where Ry is an alkyl group containing 1-6 Ve carbon atoms “Crgalkyl or cbenzyl benzyl” and especially Ry where Ry is an alkyl group containing 1-? carbon atom “Crs alkyl butyl n-butyl gale isopropyl dsopropyl tert-butyl or benzyl, for example” ethyl, and preferably isopropyl or tert-butyl, especially tert-butyl. allyl when +1 is triphenyltriphenylmethyl Jie and X is —OCH,- a X would rather be X' where X' would be CH=CH- " and preferably (E)-CH=CH- R | Preferably choose from “G F Ec Eb Ea D “C B (A ic sand 11 MLK J 17 as follows: A) Tri-substituted phenyl Roa “Rya and Ria where Roa (Ryd and Rja separately form hydrogen); halogen an alkyl group containing a cap a Yo carbon atom; a halo alkyl containing 0,0 carbon atoms; Phenyl is a substituted phenyl

halogen The alkoxide group contains a Ca carbon atom; The alkanoyl oxy group contains Coa carbon atom; an alkyl group containing .04 carbon atoms or a halo alkyl group containing from © a carbon atom; or ORga where 1848 is hydrogen; Alkanoyl contains and a carbon atom; benzoyl; vinyl; halophenyl; Alkylphenyl© contains 1 carbon atom; An alkyl has 0,0 carbon atoms; cinnamoyl halo Justi contains 1 carbon atom the allyl of the cyclic alkyl has a Ca carbon atom; adamantyl (an alkyl containing from .6 atom

{carbon) or a substituted phenyl (an alkyl containing a carbon atom cap) where each of the halogen substituents is selected; An alkoxy contains a -b© carbon atom; an alkyl of 0 has a carbon atom; an alkyl halide containing 0,0 carbon atoms; Cus that the halogen atoms are either fluoro or chloro and the cycloalkyl Jai cycloalkyl on cyclohexyl 1 R.b 27K 2 . R,b Pp 3 Rib ' Rb 3D R, b { 0 4 where Rib and Ryb together form a radical of the formula: 6 7 8 -C=C-CxC- or b) = CH,~CH,~CH;~CHz- Rb Rgb m \ . Where Yav v is a carbon atom; alkoxy containing Ca forms hydrogen; Alkyl contains Rib.” Fluoro; chloro; trifluoromethyl phenoxy on .1 carbon atom; trifluoromethyl .oxobenzyl or phenoxy oxybenzyl hydrogen formation; An alkyl contains f a carbon atom; NORDINARY BUTYL; RUD isobutylalkoxy containing: f carbon atom; Regular Biotoxy © Isobutoxy 08001107 Trifluoromethyl; fluoro; chloro; Phenoxy n-butoxy or oxybenzyl.

Cg is a carbon atom; alkoxy Ca containing JST forming hydrogen; Rsh on each carbon atom; trifluoromethyl; fluoro; chloro; phenoxy or oxybenzyl or trifluoromethyl tame; And it should not be Rab, provided that it is not more than one out of 1

Rub is phenoxy and may also not be more than one of Rsb or Rub more than one of oxybenzyl. Rsb with hydrogen formation; An alkyl contains: © a carbon atom; An alkoxy contains ½ carbon atom; fluoro; chloro.Co on cde is not hydrogen; An alkyl has 0,0 carbon atoms; butyl Rolf Isobutyl; an alkoxy has a -9l) carbon atom; ordinary biotoxin; tri-oxybenzyl. methyl benzyloxy; fluoro; chloro; phenoxy or 3 carbon atoms; alkoxy cap forming hydrogen; an alkyl containing Rsb on .l) a carbon atom; trifluoromethyl; fluoro; chloro; phenoxy or oxybenzyl or trifluoromethyl tame; And not to be Rob, provided that it is not from one of the 0

Rsb from either Tptha or SST phenoxy; And the Reb must not be more than one of 1670 or . Oxybenzyl benzyloxy in the Bb position of the ring (Ba) and also provided that the free valences on the rings are ortho with respect to each other;

Yay | | 0

A | Roc ej \ 1 7 0 m 0 since one of 18:6 and Roe is substituted in the phenyl group by 6, 8, Rec and Law © and the other is an alkyl containing . and 0 carbon atoms ; ordinary butyl; or © isobutyl. with the formation of hydrogen; An alkyl contains a Ca carbon atom; ordinary butyl; isobutyl; tert-butyl An alkoxy contains: .l) a carbon atom; ordinary biotoxin; isobutoxy; trifluoromethyl; fluoro; chloro; phenoxy; or to oxybenzyl; be hydrogen; An alkyl has 0,0 carbon atoms; The alkoxy contains 0 states of a carbon atom; trifluoromethyl; fluoro; chloro; benzyloxy sl us sis Provided that not more than one of R3C 1846 is trifluoro edie and not more than one of Rye Ric is phenoxy and also not more than one of Ru R30 is oxybenzyl; RsVo is hydrogen; The alkyl sing has: and 0 carbon atoms; ordinary butyl; isobutyl; tert-butyl An alkoxy contains: a carbon atom; ordinary biotoxin; isobutoxy; trifluoromethyl; fluoro; chloro; phenoxy; or to oxybenzyl; Ree is hydrogen; an alkyl with 9 carbon atoms; An alkoxy contains: © a carbon atom; trifluoromethyl; fluoro; chlorine Phenoxybenzyloxy sf 00 oxybenzyl.

Provided that no more than one of 0 and 5 Ree is trifluoromethyl; and not more than one Ree RsC to be phenoxy. and not more than one of the Rec (Rs) oxybenzyl. Rye forms hydrogen. Alkyl contains: © carbon atom; alkoxy © contains f. carbon atom; fluorine; or chloro; Red. Moi 854 Rad 1 D Road Rad where Rud is hydrogen or a primary or secondary alkyl group sind on an M6 carbon atom; does not contain a carbon atom other than Alle : Rod Ve is a primary or secondary alkyl group It contains M© carbon atom and non-0 contains an asymmetric carbon atom of Ryd and Ryd together they form -(2)-CH,-CH=CH-CHy- where 10 be k k k * or . Ryd is hydrogen; An alkyl contains: f0 carbon atoms; ordinary butyl; Vo isobutyl; tert-butyl An alkoxy contains a Ca carbon atom; butoxy (ile) isobutoxy; Phenoxy or Oxybenzyl Yay

No, provided that not more than one Rad Rod is trifluoromethyl; And not more than one of Rad Rad Phenoxy and not more than one Rid 5 Rod Oxybenzyl. Rad is hydrogen; An alkyl contains: f) a carbon atom; ordinary butyl; © isobutyl; Butyl (AG) alkoxy contains .1 carbon atom; butoxy (gale) isobutoxy. trifluoromethyl; On: © carbon atom; trifluoromethyl; fluoro; chloro; phenoxy or oxybenzyl, provided that it is not more than one of 450 Red trifluoromethyl and that 0 is not more than one of Red Rd phenoxy and that it is not More than one of Rod Rsd Oxybenzyl Rad Hydrogen formation Alkyl contains 2 carbon alkoxy Z © contains a carbon atom Fluoro or chloro : Re Rye N = A Co Re RR x) * Spray 2 : O R 3 \o Where each of Rae Roe (Rie is a fluorochloro; hydrogen; or an alkyl containing © carbon atom; Rye is preferable be an instance. Yav |

yyyy Raf — 6 Fs yyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyy R,§ . between us each 86 Ref 8 apart form hydrogen; An alkyl group © contains and a carbon atom; ordinary butyl; isobutyl; tert-butyl An alkoxy contains: a carbon atom; ordinary biotoxin; isobutoxy; methyl trifluoride; chlorofluoride; vinyl; phenoxy or oxybenzyl; Also, both Raf and Ref individually form hydroenes; An alkyl group contains 0,0 carbon atoms; an alkoxy group containing Ca 8 carbons; methyl trifluoride; fluoro; chloro; vinyl; Phenoxy or Ssh sedi 01 Ruf and Rof separately form hydrogen; an alkyl group containing and a carbon atom; an alkoxy contains 0 carbon atoms; fluoro or chloro; provided that it is not more than one of 1424 and Raf is methyl trifluoride; Nor can more than one of Raf Rof be a phenoxy group; ve also not to have more than one of the Raf 18 oxybenzyl group; and not more than one of Rsf and Ref to be methyl trifluoride; And that more than one of Rsf and Ref should not be a phenoxy group, and that more than one of Rf and Ref should not be an oxybenzyl group. The following is required: Yav

VY

In the £ or (pyrazole) position, the free valency of the pyrazole ring (3) should be 540 z with respect to (ortho), and the free valence in the ortho position should be Rif, both (iD) of the other .Reg Rb 3 / a

Rdg yt Rag 0 Whereas

Rug R3g be Reg Rog be Rpg ¢X be single bond with Rpg or ¢N- be K be 1848 and . Ri g is Rag Rag Reg eX is single bond with Rog (Rug is Rog Ve or =N- or 5 (past represents K and Rag

Rig \ Crp atoms are separately alkyl containing Rug and Rag Rog Rug carbons that do not have an asymmetric carbon; Cycloalkyl with no carbon or phenyl atom substituted

Rig plus hydrogen; or Rug and Rg or Rog or Reg Rog by Vo represents oxygen or 5 and kz is 36 plus 08; and K when

EN ~C(R178)=C(R15g)R1og 0158 Ga Carbon. 30Ca form hydrogen; or an alkyl containing 8 each to form hydrogens; An alkyl containing 0.0 Ryog atom or a carbon or phenyl group; 0

Yay z

VY

A carbon atom; Ca is separated from a hydrogen atom; an alkyl containing 8-N-butyl; isobutyl; tert-butyl an alkoxy containing .9 carbon atoms ordinary butoxy; isobutoxy; methyl trifluoride; fluoro; chloro; promo; phenoxy or oxybenzyl. Reg ° be hydrogen-sparing; An alkyl has 0,0 carbon atoms; An alkoxy contains a Ca carbon atom; methyl trifluoride; fluoro; chloro; promo; phenoxy or oxybenzyl. Rog 0 is hydrogen-independent; An alkyl contains 0.02 carbon atoms; An alkoxy contains: © a carbon atom; fluoro; or chloro; Provided that only one of three 0 Jil fluorides may be phenoxy; Or oxybenzyl in each phenyl ring substituted by Rsg Reg and Rag for “Rih N ~~ N==R2 ph h 3 2 z as alkyl formation contains: ml A carbon atom that does not have a carbon atom other than La 5 alkyl congenital containing 7:© carbon atom; Adamantelle -; or A substituted by tamkel {Reh sRsh Roh be an alkyl containing a © carbon that does not have an asymmetric carbon atom; A cycloalkyl containing a ©7 carbon atom; Adamantyl-11; or Jib substituted 'Roh (Rgh (R7h) by fav

1 An alkyl hydrogen is formed containing an M carbon atom that does not have an asymmetric Rsh carbon atom; a cycloalkyl with 0,7 carbons; adamantyl-0; or substituted vinyl

Rph terbatil Roh ial separately forms hydrogen; Alkyl contains Ryoh and each of Tabgul Tabqul

Cai is a carbon atom; ordinary butyl; isobutyl; tert-butyl an alkoxy contains 5 carbon atoms; ordinary biotoxin; isobutoxy; methyl trifluoride; chlorofluoride; phenoxy or oxybenzyl; alkyl containing .0 a Reh (Rsh { carbon) atom; alkoxy containing .0 carbon atom; methyl trifluoride; fluoro; chloro; phenoxy or oxybenzyl; N(Rish)y 0007 bromo; 0

M or Righ is hydrogen; Rizh is an alkyl form containing 0.0 carbon atoms; ordinary butyl; Rgh wherein isobutyl; tert-butyl or benzyl; 1/1 is as defined above; Separately, an alkyl is formed that contains a carbon atom that does not have a Roch carbon atom.

Allie is Vo

Cot and Dba each separately form hydrogen; An alkyl containing a Roh (Reh) carbon atom; an alkoxy containing 0 CFC or CFC; 3

DE provided that not more than one substituent in each phenyl ring is methyl fluoride; and that no more than one substituent in each phenoxy-ring is phenoxy; And not to have more than one substitute in each phenyl oxybenzyl ring separately. 0

TadNA5

Roy

Yay

Vo where z

Lesh Each separately forms an alkyl containing a carbon atom; Ryj and Ryj (011)-J are not an asymmetric carbon atom; Cycloalkyl contains only one carbon atom or or ¥ and the phenyl group is not substituted or substituted by any of (Yo) Gia = M where the lid and M 1 as they were known as Rg Rj where Ry and Ry Ry is an alkyl unit containing a © carbon atom; It does not have a carbon atom, Ry, which is five, six, and seven; Jp is asymmetric; or form part of a ring that is either substituted or unsubstituted and may contain one or more atoms J, ring or L where Ta is heterocyclic; Unsubstituted Dla J group, 01 carbon atoms or Cop groups by one or two alkyl groups containing

Ta" ol is a carbon atom" and "wa is," and the alkoxy Cop contains

Raq wl fi SRT 53 z Ja"a Jah: Whereas, your time forms hydrogen. An alkyl contains 0.0 carbon atom; ordinary butyl Vo

Sl Isobutyl” tert-butyl; methyl trifluoride; fluoro; chloro; phenoxy; or benzyl; a carbon atom; alkoxy containing Ca forms hydrogen; an alkyl containing (RY) a carbon atom; methyl trifluoride; fluoro; chloro; phenoxy; or oxy Cay on benzene; Ye a Yay

Ry] forms hydrogen; an alkyl contains a 30Ch carbon; An alkoxy contains 1 carbon atom; fluoro; chloro; : Provided that not more than one of Raj and ERY) edie fluoride and not more than one of Raj and Ryj phenoxy and not more than one of Raj and Ryj oxybenzyl ; Rak of which R 1 k where JKRok Rik separately is (2) a phenyl group substituted by (Rsk) in each Rk where Rsk 01 is hydrogen; an alkyl containing a Ca atom carbon;normal butyl;isobutyl;tert-butyl;alkoxy containing Ca carbon atom;normal butoxy;0a isobutoxy;methyl trifluoride;fluoro;chloro;phenoxy or oxybenzyl.Rek forms hydrogen;alkyl contains On ..and 0 carbon atoms; an alkoxy contains a carbon atom © fluoro; or chloro; and Rk Vo forms hydrogen; an alkyl contains a ...© carbon atom; an alkoxy contains a carbon atom ©.; fluoro; or chloro; (b) hydrogen or a mono- or secondary alkyl containing Cor carbon with no asymmetric carbon. (©) cycloalkyl containing Cos carbon atom; or (d) 2-phenyl- ..(012)- where 20 is zero or 1 or ?or ?; m” Yay

VY

RoE

Sum

N

Le

Co where “-CH=CH-N=CH- “ CH=CH-CH=N- go 1 . “—N=CH-CH=CH- R -CH=N-CH=CH- A carbon atom without a carbon atom Cp To form a monoalkyl containing Ryl ° heterocyclic or azopropyl .. To form : Rol where: Ral and Rel (Rl phenyl substituted by (a) carbon atom; butoxy Cap form tert-butyl; alkoxy containing Rl isobutoxy; methyl trifluoride; fluoro; chloro phenoxy or oxybenzyl 0 carbon alkoxy contains Ca forming hydrogen alkyl contains Rel! carbon atom methyl trifluoride fluorochloro phytoxy or oxybenzyl Ca b on methyl trifluoride; and Rl Ral shall not be from one of SST provided that it is not phenoxy; and Rl Rl shall not be more than one of 491 lm152 oxy (iy 0) carbon atoms; alkoxyp contains Cop is hydrogen; an alkyl containing RA fluoro; or chloro; 08350 Cog on a carbon without a carbon Coup mono or secondary alkyl containing asymmetric; carbon atom » or z Cos a) a cycloalkyl containing

FY or 1 where 00 is zero or (CH) phenyl (d

Yay a

Ya

Rim

R jw b TX i.

Ra via where: A carbon atom does not have a carbon atom other than Cop Tdka forming an alkyl containing

Crs is a carbon atom; methyl (cycloalkyl containing identical Crs; cycloalkyl containing =X “-pipridyl 0711071-2” 7-pipridyl; “-pipridyl”; ACH) carbon atom.); phenyl © and Rem Rsm or phenyl substituted by 3-thienyl tinyl —¥ 2-thienyl Jud 'R-m carbon atom with no carbon other than Cop being an alkyl containing Rom

Crs (Cycloalkyl die carbon; Crs symmetric; Cycloalkyl die 1-Copyridyl; 4 Bow pyridyl-2"-pyridyl ACH carbon atom) Phenyl 0: and Rom Rem daly or fuse substituent 3-thienyl Judi = v 2-thienyl Jud { Rom - a member (part) of the Rom group (Rim provided that not more than one of the substituent Ji consisting of 7-pibridyl; be an alkyl containing Rem

Rpm is a carbon atom; or vinyl replaced by identical Crs; Cycloalkyl containing 'Rism' and Rpm being an alkyl containing 6 carbons with no carbon atom other than Rym carbon atom; or vinyl replaced by a cyclic Crs tickle containing identical J; yo tired and wb

Yay

Where Rpm (Rgm “Rsm | and SRyym) separately form hydrogen; an alkyl containing a Cag carbon atom; ordinary butyl; isobutyl; tertiary butyl; alkoxy containing two carbons; ordinary butoxy; isobutoxy; trifluoride methyl; fluoro; chloro; phenyl bromoide; phenoxy; or oxybenzyl; and Z Rim Rpym Rom (Rem) each separately forms hydrogen; an alkyl contains an F carbon atom; an alkoxy contains a Ca carbon atom; a tertiary Methyl fluoride; fluoro; chloro; phenoxy; or oxybenzyl; JSRigm's Tobthyl modal will separately register the formation of hydrogen; an alkyl containing 0 and a carbon atom; an alkoxy containing a Co carbon atom; a fluoro; or a chloro; provided Not more than one of the substituents in each phenyl ring shall be “Db methyl fluoride” and not more than one of the substituents in each phenyl ring shall be phenoxy; and SST shall not be of one of the substituents in each phenyl ring Oxy RL" R7n Ah Romy Rn 0 Free 0 Ryn Regn Rn 11 Where Z Ran Ryn Ryn | Each separately forms an alkyl containing Cap a carbon atom an unsubstituted or substituted phenyl with one or more alkyl groups, or an alkoxy containing a Coy carbon atom; or chloro; or a fluoro-seed; promo; or Yo-methyl trifluoride. Yay

Yo a carbon atom" on Ca forms hydrogen; or an alkyl group containing Ryn, for example, a methyl group; low alkyl; or Low Alkoxy;Ren Methyl Fluoride; or vinyl; benzyl or oxybenzyl as the aromatic portion may be unsubstituted or substituted in two groups; One of them could be fluoro; promo; or © methyl trifluoride” and either or both can be low alkyl or low alkoxy; or chloro; form hydrogen; low alkyl; or low alkoxy; Hello; or three fluoromethyl ren; and form hydrogen; low alkyl; or low alkoxy; Hello; or three Ron 01 : | Methyl Fluoride; can be RyntRsn, RsntRen, or RegntRon of ls in order to be a ring substituted by «(CHy)4- or the radical ~CH=CH -CH-CH- can be hydrogen; halogen or low alkyl; or a low alkoxy. Ren Z, noting that the substituents in the molecule do not exceed one group of methyl Vo trifluoride; and there are not more than two bromine atoms. Compounds of formula 1 can be divided into thirteen groups; meaning; 3 meaning: (Ral) on the basis of the significance or nature of IN to TA that groups of

A =R Laie TA each =R when IB 6 for “C =R when IC DL =R when ID

Ec or Eb Ea = R Laie IE

F = R when IF 0-8 when 16 Yo

H = R Lac TH

Yay

1

J = R when IJ each = R Laie TK

JL = R Laie IL and M = R when IM

N =R Laie IN 0 Stereochemistry -#” has the formula hydroxy-keto When a hydroxy-keto dale compound is reduced as a base of formula 1, it generates a non-dihydroxy concentrate to a dihydroxyl compound TT 0 An additional congener. It forms four isomers (JT) and therefore when using a racemic compound with the formula Va i.e. “stereoenantiomers 00 - (includes two pairs of enantiomers, a pair of which is in the etherthro form and the pair is in the trio form) - of the resulting compound having (OE) formula 1. Alternatively; When a pure photosynthetic compound having formula [1] is formed (meaning one is in the form of erythro and the other in diastereomers 55 3R diastereomers as the triisomer) the resulting compound of formula 1 for example Vo is formed from diastereomers Which results from the reduction of the hydroxy compound 55.55 (3S and B) can separate the stereoisomers (diastereomers) by suitable methods, such as molar crystallization; separation by column chromatography; thin layer chromatography or HPLC chromatography high pressure of the liquid that the ratio of the erythro isomer to the threo isomer obtained by using this Yo

AAA Methods are always variable, for example, by applying the vacuum selection method in this invention; When a compound is used, only two stereoisomers of racemic dT of formula (containing a pair of erythro enantiomers) can be obtained from the resulting compound of formula 1 without being formed on one enantiomer JI except for it. as an alternative; By using a photosynthetic compound that has the formula Yo, and this enantiomer is identical to the erythro. of only the resulting compound that has the formula

Yay

YY

Reduction of the hydroxyl compound 55 3S, for example, results in the enantiomer ~CH=CH- be X since 5 The ratio of the erythro-isomer to the threo-isomer that can be obtained is 19.0 preferably “JST Or “.5-44.1” using the method in this invention is 1.7: 55.7 or more, especially the “stereoselective ratio” used here #0. Stereoisomers SE that the term etherthro form to threo form is 199 9 or more. The stereoisomers according to this invention are ~CEHLCHy- be X where the IT is of the compound of formula and 35;55 and the racemic form consists of both, where SR is the form of isomer 318; and the racemic form is preferred. To obtain almost exclusively the racemic and optically pure IT isomers of the formula One of the advantages is the reduction of the keto group of the compound with J erythro of the formula Jie oI isomers Compounds of the formula Glee of formula [1] are instantaneous Beneficially No 9644 erythro; in addition to having an increased chemical purity which may reach more than 0 chemical potency by intermediate repolymerization. A compound of (a) is mixed according to a first step of the process of the present invention [Step in reaction media including alcohol NABH formula 111] with sodium borohydride tetrahydrofuran and tetrahydrofuran 0 with the resulting mixture of JT a compound of formula (f(D)) is treated in a second step [step Under appropriate conditions to obtain a mixture containing boronate compound (a) step IV (a) cyclic with the formula boronate a

YY

Z' B 1 R - X - CHCH,CH - CH,COOR, [1V(a)]

IV(b) boron of the formula complex and/or superimposed

Ry and 8 \ " 0 Ne

R - X - CHCH,CH - CH,COOR, - (IV(b)] above. The last compound before the quenching cde LEX Rs Ry Rf dua o reaction however quenches the reaction converts the boron complex to an ester borons. (b) The product obtained from step d(C) splits in a third step [step N

J To obtain an identical compound of formula 01 it is best to carry out step (a) under basic non-aqueous conditions; preferably in an inert atmosphere; at about -100" C to about OF oF preferably at about OA to -0 C and especially at about -/m to about -0 to 7 O*C; the reaction medium used in method (A) includes a mixture of alcohols and a tetrahydrofuran since the alcohol is of the formula AIKOH in which the alkyl is cup-containing a carbon atom such as methyl or ethyl V0 and not preferably tertiary One of the products of the step R4OH (a) may be a derivative of a compound of formula II used, however, it is not necessary that all or part of a mixture be the same as Yay |

Y¢ aforementioned; In general, sodium borohydride should be present at least in the amount of Ry and preferably in a slight increase; As an example of this from about JT is isoquant to a compound of formula per gram molecular weight NaBH gram molecular weight of 1 ho to about 1:1 on IT to the compound of formula TIT for a ketone; The molecular ratio of a compound with formula weight 1 he to about 1 iY preferably more than about vo is less than about © per gram molecular weight of a ketone. borane Molecular borane at low temperatures . (b) It is better to make a special Lad step from about (281m) internal temperature at about -100"C to about . to about -<07"C. It is preferable that the compound of formula [ 1 dissolved in 2OVA- it is better to choose (THE) alcohol tetrahydrofuran or tetrahydrofuran die solvent 0 b which is added in step IT (reaction medium for step 8 and solvent for compound 53 (formula) to make A common medium where the ratio of alcohol to tetrahydrofuran (vol/v) is from 4:1 to approx. The reduction of the keto group is exothermic and the reaction occurs rapidly, so the addition of the keto compound temporarily is desirable in order to stabilize the internal temperature within the range of VO instantaneously, and therefore the mixture of Tu quenches the reduction ae is about </ La'm to about sodium bicarbonate chloride b Reacting abruptly by adding sodium bicarbonate .. obtaining Ole acetic acid or ammonium chloride acetic acid a mixture of the desired intermediate cyclic boronate. In step (0) the reaction product from step 5 may take azeotropic forms

PA from about 10 m to about Oli with methanol or ethanol; At 0 the X Late is under essentially anhydrous conditions. Instead, it is especially preferable to dissolve the neutralized product by adding sodium bicarbonate [10<011-] ethyl acetate and treat with hydrogen peroxide (Ja) in an organic solvent; (001100 ( psp small) or perborate ) 96 0 Ni) aqueous hydrogen peroxide Yo oo Jie starting at low temperature (NaBO3.4H,0) aqueous sodium perborate

Yay

Yo is about +100*C; then it is left to warm to a moderate temperature Die about 1*C to about OF to obtain a compound corresponding to the formula [Yas] from that; The cycloborate ester may be extracted from step 0 with an organic solvent such as ethyl acetate and then directly treated with an aqueous solution of Methylated Peroxide 96760 Aqueous Hydrogen Peroxide

J or an aqueous sodium perborate solution to obtain the compound conforming to the formula © 0 Ly that the circumstances of the invention occur when applying the invention; It is understood that any of the substitutions or functional groups on the Gall used R die tend to be inactive m; Sia that it will be one of the substituents or functional groups that interact or LE to be replaced under those conditions, for example, by the known methods of blocking or protection of these | functional groups or their introduction at a later stage. 0 Compounds of formula <I and matching § lactones; free acids and their salts, and methods for converting a compound of formula 1 where Ry is of the same denominator to an identical compound where it has a different denominator and/or to an identical lactone 6, a free acid, or known salts of their own. Yo and at will the compounds of formula 1 may be converted by the usual methods into the form of similar free acids or the form of salts; Meaning where: Ry is replaced by a hydrogen or a ketone and Jia is a strong metal cation or ammonium; Sodium or potassium, and in particular sodium, is preferred to the form of other esters or to 5-lactones corresponding in the sense to the internal esters. 7 as mentioned above; Compounds of formula (han T) thereon according to the method of the invention are pharmaceutical preparations. In a further embodiment of the invention, however, the method of the invention may also be used in the preparation of cchiral intermediates such as the formula Ju u - OCH, - CHCH;CHCE; - COOR, (Iu)

O.E.8

Yay

Cade “forms triphenylmethyl (e(trityl) and Ru) forms an allyl or radical forming an inactive ester under reaction conditions; preferably an allyl; or an alkyl containing a Cay carbon atom; normal butyl; isobutyl; butyl tertiary or benzyl© and especially tertiary butyl by a stereoselective reduction process of a racemic compound or a pure optically active compound of formula [0] CH - COOR, | (Iu) ; - A - OCH; - L 1 where Ru au : 7 and 72 as defined above. Such chiral media are disclosed for example in EP 5477140-00 ? and are indicated for use in the preparation of pharmaceutical preparations. Raw Materials Boranes (alkoxy containing Cp atom or primary or secondary (di-(alkyl) oxy-allyls containing carbon atoms of Can primary) of formula 111 as starting materials in the method of the present invention [see [Koster et al, Ann. (1975), 532 Chen et al., Tetrahedron Letters Yo and Chen et al, Chemistry Letters (1987), 1923- 12926 [155(1987, 28, 12926) However, it can be prepared in situ from corresponding boranes (mono- or di-alkyl (containing © carbon atom) in reaction with canol containing © carbon atom or ll das © primary or secondary” the concentration of the first component in the last component is from about ods oY mole to about 011 gram weight of Gude diay favourite; Especially about 6,5 gram molecular weight. Yav |

JT compounds are not known; or they may be prepared in an analogous form to known compounds of Formula IT eg as described in US Patent No. EVAL VY (Example 72- Oxygen) or EP No. 1170 (Example oxygen =Z; Oxygen). o Thus, compounds of formula [1 Gus Zp are usually prepared as oxygen oxygen by reacting a compound of formula V R -<- CHO 07 { where SILEX R is above. with the dianion of the compound of formula VI CH; - CO - CH, - COOR, (VD) Vo where Ry is as I mentioned earlier. Other Embodiments Related to Intermediate Compounds For which compounds of formula V and VI are also known and in additional embodiments; However it also includes the preparation of the compounds of the present invention by means of a modern process for the preparation of 10 subsets of the compounds of Formula 7; Named compounds with the formula Va: bb u "Rg Dim N Neg | 8 Ry 0 : where Rs is hydrogen; JST contains Cag a carbon atom; Butyl; Yay

' YA carbon atom; Alkyl oxy Cap forms hydrogen; alkyl containing Rs perfluoromethyl; fluoro; chloro; phenoxy or benzyl (DE) containing 1 carbon atom; One of the Rg Rs is more than one of 0 benzyl oxy; Rbc Rip Rg is a phenyl tri-substituted by Rg (Ry) one carbon atom and does not contain a Co atom and the other is an alkyl primary or secondary containing db carbon atom; Coz asymmetric carbon; or cycloalkyl containing —~(CHp)p- 0 carbon atom; butyl Ca where: f15 is a hydrogen “containing alkyl On a carbon atom; butoxy Cap isobutyl; tert-butyl; alkoxy containing normal cole; isobutoxy; trifluoromethyl; fluoro; chloro; phenoxy or benzyloxy; carbon atom; alkoxy containing Cap forming hydrogen An alkyl containing Ryg chloro, phenoxy or benzyl oxy; gst. contains two carbon atoms; OR Provided that it is not 1:1 carbon atom fluorochloro and 120 Cog is over

Rio Ro is a trifluoromethylation and not more than one of the Ry Ry of one of the benzyl oxyformation; Starting at 18:0 Ro be Fenoxy and not more than one of

VII is a subgroup of compounds with the formula Yo (E) - OHC — CH=CH - MoI (VID) wherein, a carbon atom; phenyl or phenyl substituted with one Cap and which is an alkyl containing a carbon atom; The alkoxy Cap is divided into three substituents, each of which separately forms an alkyl containing a carbon atom; fluoro; chloro; Promo or nitro with two nitro groups Ca containing Yo at most.

v4 | |Ry each separately has a significance shown above for the root Rpp in addition to a new method for preparing compounds of the same VIT formula. The method of preparation for compounds with the formula Le VIT is denoted by “method. “A” denotes the method of preparation lS pall of formula LedVa followed by “Method UB 0 defines compounds of formulas VII Va and XVID (see under paragraph (Y=V) of For example, the American patent No. EVAL YY, which reveals compounds with formula 1, where Ry is an alkyl containing a carbon atom, and its use for the construction of compounds with formula (Va, compounds with formula XVIT, and the use of compounds with formula Va For the synthesis of indole analogues of mevalonolactone and its 0-derivatives, which have been indicated for use as inhibitors of HMG-CoA reductase activity for lipid deposition.As they inhibit cholesterol synthesis, they lower blood cholesterol levels and were until then indicated for use in the treatment of hypercholesterolemia. compounds of formula 1711 and their syntheses were also disclosed in UK Patent No. 145870 and Czechoslovak Patent No. 90045 However, the methods disclosed in these patents differ from Method A with regard to the use of - phosgene or DE chloride or phosphorus penta or oxychloride; As well as iia oxalic acid. Method A (preparation of compounds of formula (VII | º ous 7) Method of preparation of compounds of formula 1711 (method H (A) (i) Reactor of compound of formula 17111 1) 0110-11 Whereas, with all Ry3 as previously mentioned with a compound of formula IX X, — CO-CO - X, (IX) Yo where X is a monovalent leaving group; optionally in an inert SLY organic medium; to form the conforming compound of formula 76 s | Yay

Xe- (X) and we will see that Rip X, Bh [ as I knew above. Aelia (if that compound of formula X with a compound of formula XT CH=CH, (XI) — mm where Ry is a monovalent group that does not inhibit the attached oxygen atom cle and optionally in an inert anhydrous organic medium to form the corresponding compound of formula XII X,- (XID): and Baqar 6) 10-11-0724 — (E) - R140 where X is Rpg Riz Rp as defined above ; They mentioned previously. (iid Ya) The compound of formula XT is hydrolyzed to obtain a compound conforming to the formula [171] in a free base medium; or in the form of an acidic salt; and if it is intended to be obtained in the form of an acidic salt; the acidic salt is equivalent to a base. In Heterogeneous step of method (A) may dispense with step (11); and directly use 0. A compound of formula XII in method, for example. Steps (1) and (i) may take place at a time cantly or 6 that step (i) can be likened to step (i), step (iii) following step oii) and step “(iv) (see later); when used following step (011). Rip is Ripa, where Rigg is an alkyl containing a de carbon atom; or Rppb 11 where, with the exception of the Ca alkyl, bears a carbon atom that has the above denotation of the Rip radical (meaning to be phenyl; OR phenyl substituted by 1 to + separately substituents Ca-containing alkyl; C-an alkoxy-fluoro-chloro-bromo or nitro-states with a maximum of two nitro groups). Rppa is preferably an alkyl Containing Co carbon atom and the most preferred Yo such as methyl : Yay

Rigb is preferably Rigb where "8:20 is phenyl; or phenyl substituted by one or more substituents; each separately alkyl with a cap carbon; an alkoxy with one to two carbons; or a chloro ; and the best "18:20 Gun "continued to be Ji or Phenyl substituted with one or two methyl groups; and more preferably to be Phenyl. Ry is preferably an alkyl containing a Co carbon atom; and it is most preferred to be Ryg ! is preferably a Car-containing alkyl and most preferably a primary 'primary' or a 'cap-secondary' alkyl; It is also more preferred ethyl or ordinary butyl All Xa is preferred to be chloro or bromo especially chloro Both Xa is preferable to be chloride or bromide especially chloride All Xa is preferred to be used in hydrolysis or neutralization Step (iii) has an inorganic base such as sodium carbonate, potassium carbonate, sodium hydroxide, or potassium hydroxide; It is most preferred that 1 be “sodium carbonate as sa” or potassium carbonate. The preferred reaction conditions for method A are as follows: 0 Step 1 [when carried out before step [(ii) temperature : = pain to +6 50m Time: 0# to five hours. Reaction medium: alkane is a low halogenated liquid; Y Jie OLY 1,2-dichloroethane and methylene chloride 0097106 or cacetonitrile +5 and more preferably methylene chloride and acetonitrile. Yay

YY

To 1.0 gram molecular weight of 1 the molecular ratio of the substances involved in the reaction:

VII per gram weight of compound IX compound [(i) [when carried out before step ii step 1m temperature: 10°C to 56"C 01" most preferred ° hours. VJ 6.0 : time (1) Reaction medium: the same as in the gram-molecular step from ids 1.0 to 1 Molecular ratio of the substances involved in the reaction: {

VIL per gram molecular weight of compound XT compound [when they run simultaneously] (i)ol) step 0

OF + temperature: -15 then to: time: ? to a hours. (if) Reaction medium: the same as in step (1) when it is carried out before the step Its gram molecular weight is from Vo to 1 Molecular ratio of the substances involved in the reaction: .711] gram molecular weight one of compound JS IX compound _ (iif) step 2°10 temperature: zero to da - to ¥ 1.5 hours : time | (ii) reaction medium: Water or a mixture of water and reaction medium used in the step; base equivalents per weight JAY Molecular ratio of substances involved in the reaction: 4 (i) used in step TX Molecular of compound with base. (iff alternatively and preferably, the hydrolysis of the step is carried out; with (if)efi reagents the reaction medium for the steps may be pure; That is, reagents in the absence of any solvent, meaning that for step (1) 3 compounds of two formulas (if) are used, and for step IX compounds with formulas 17111; Yo are used, and these are very useful, for example, from an environmental point of view, due to the presence of solvents such as acetonitrile XT

Yav | .

YY

in waste water or to avoid the emission of vapors such as methylene chloride to the atmosphere. They are, respectively, in the absence of the solvent because they are XTX or IX VIIT reactants. Compounds with formulas are not a solid mass when mixed together but form; to an astonishing degree; hanging.

Riz Rip into two sub-methods on the basis of the semantics of A. The method may divide a carbon atom, Cap, DbCl, and Bca, each of them separately, to form an alkyl containing (1) 8 and (Aa) (a sub-method). Cap is other than an alkyl containing Riz Rig at least one (1) 0 (Ab) other carbon (sub-method 0) a significant amount of Aa compound of sub-method (fii) step product contains

XIII The formula 8 0 - OHC - CH=CH - Its denomination (XID) is as defined above; And in conformity with the compound obtained Rig, where the molecular ratio of the compound of formula 1711 to the compound (VII) of it having the formula of formula [1211] is typically about ?: ) while it is of course; It is possible to separate (Smal) from that compound of formula 12111 by the usual means VII of the compound of formula Vo (a mixture of VII), it is preferable to expose the product of step (1 to 1); i.e. the crude compound of formula Viz: (iv ) of step XII the compound of formula 1711 with the corresponding compound of formula

VIIa Processing of the crude mixture containing the compound of formula (iv) (E) - OHC — CH=CH - 11) striped (VIIa)

XIV as defined above. With an identical compound of formula Ry3 Ripa where Ye

H-N(Rj;2)R 13 (XIV) is as defined above; To convert any compound of formula Ry3 Riga, where: : Vila present there, to an additional compound of formula 1, as follows: Aa The preferred reaction materials in the sub-method are alkyl Z Ras a carbon atom » Y to 1 is an alkyl group containing Ripa where (a) Yo is a primary alkyl group or Rug containing 1 to 2 carbons; ? 1 | z

Ye is Xa' is chloro; Both Xa are carbon atoms; Both Cop are secondary containing chloride; Cap atoms, but where Bra is a normal alkyl containing (a) as (b) carbon. hip be methyl; Riga but where (b) Jie (©) © ethyl; it is (if) but the rule used in step (0)-(a) is like (H- (d) is sodium carbonate; or potassium carbonate; and it is z (i) same as (0)-0) but the base used in step (D-(2) is potassium carbonate. Ye especially when Substances Aa die jill 3 shall under favorable reaction conditions belong to Laie (0); B) and (€) “(b) subsets and (0) are as follows: (0”)©( :)) step 0 220 Shpall zero to 2000 be more (oY Temperature: Saphram to 05852200 is also more preferable.‎ Up to − hours.© 1, Time: Reaction medium: Preferably low halogenated liquid acetonitrile or pure reagents; methylene chloride or pure reagents be more favourable. 0 aS yall to ¥, \mw of 1 Molecular ratio of the reactants: molecular weight of VY to 011 k per gram-molecular weight of the compound [1711; For each gram molecular weight of the compound [1711] is more preferable. TX Compound (ii) Step Temperature: ° C to 2 C Yo h. Yo to 0.7 Time: YAV

Yo (i) reaction medium: Like the step per XT “, the molecular gram of the compound: 1 reactant: of gall molecular ratio aa weight VY to 011 used from step ( ); VIIT is the molecular weight of the compound

VII grams of the compound Fada and for each weight IX grams per gram mole of the compound

Ola is more © (iif) The step is more preferred. 1 Temperature: 10*C to 210 10**C to 2 hours 1,785 Z Time: Reaction medium: aqueous to; basic equivalents per molecular weight Ale Endl Molecular ratio of materials 01 (i) used in step XT grams of compound (iv) step Temperature: zero to 10 * m; and from 10 pm to 010 * pm is more preferable.‎ to 1 hour," Time: | Carbon atom; the most preferred alcohol Cap Reaction medium: Cannol contains methanol. Weight Molecular 10117 per 1 to 106 Molecular Ratio of Reactants: \ wt. 0.4 to 116 (i) molecular weight of compound [1711 used in step 7017 per gram molecular weight of compound [1711] is more preferred. Jase after step (). Preferably (if) it is preferred to perform step Aa in the following Yo sub-method: Aa sub 3 shall include (compound N,N-dimethylformamide N,N dimethylformamide reactant (7) methyl) with oxalyl clozide (compound having Rus with the formula [1711] in which it is pure chloroformation; or in methylene chloride At the degree of Xa, where IX of the formula Xa is zero temperature” to 10 °C to form a compound with the formula Yo

Cl-CH=N+(CHs), CI (Xa)

Yay

(11) Reacting the compound of formula Xa with ethyl vinyl ether (a compound of the formula XT where Rg is ethyl) purely or in methylene chloride at a temperature of 75*C to 60C to form the compound with Formula Xa (E) —-C,Hs0 - CH=CH-CH=N'(CH;), CI (XIla) e (fi) The compound of formula XTTa hydrolyzed with potassium carbonate in aqueous medium at a temperature of 10°C to OF to form a mixture of compounds of formula VIlaa (E) — OHC — CH=CH — N(CH), (Vila) 0 and of formula 71118 (E) — OHC - CH=CH - OC,H;s (XIIa) Ya (i) | Treatment of the mixture of compounds with formulas VIIa 101118 with a dimethyl amine (compound with formula XIV where Ry3 Riga They form methyl) in methanol at a temperature of 10*C to 0 22% to convert the compound of formula 121118 into an additional compound of formula 71188. The most preferred Vo in the Aa sub-method is: (1) The ratio sal of oxalyl chloride to b-NN-dimethylformamide (dimethylformamide) from step (1) from 1:1 to 1:1" and to carry out step (); by adding oxalic acid chloride to ( Lalla dimethylformamide or in a solution of methylene chloride over a period of 0.9 to ; Vo hours at a rate at which the temperature remains constant at (p01 5-0 (Y) in step (1) the molecular ratio of ethyl phenyl ether to dimethylformamide in step (1) is 1:1 to 1 IVY and step (11) is carried out by adding ylphenyl ether to the reaction mixture during a period of time from 1.4 to 1.8 hours at a rate not exceeding the temperature (oF) and upon completion of the addition; and rad condensation of the reaction mixture At Fo .. an hour and as indicated; recover the largest possible amount of chloride 0-1,” to 06 for a period of 2 ° 80 Yo methylene at a temperature not exceeding:

Yay m."

Ba (YY) in step (ii) the molecular ratio of potassium carbonate to oxalic acid chloride used in step (1) is from 1:1 to VY and step (iif) is carried out by adding water to the product of the step (01; stirred at 10°C to Fe allowing the temperature to rise from 080 to 221°C) and this temperature is maintained during the equilibrium of adding water and for a period of CY© to an additional hour; and cooling the reaction mixture to M or Yo Adding an aqueous solution of potassium carbonate over a period of time from 1, “to dela), Yo at the same temperature and extracting the mixture with methylene chloride and distilling the largest possible amount of it at a temperature not exceeding 56”C; db” (8) ( in step (iv) the molecular ratio of dimethylamine to dimethylformamide 0 used in step (4) is from 1 0 ih) to 1,8 1; step (iv) is carried out by adding dimethylformamide methylation of the anhydrous amine to a solution produced from step (iif) in methanol; The mixture is stirred at 10*C to 10*C at a rate such that the temperature does not rise above 0C; the aly solvent is dripped with an excess of dimethylamine at a temperature not exceeding SONY Vo of the preferred reactants In step AD the following can be stated: (a | where Rb is Rus (Rigb') is an alkyl containing one carbon atom to two carbons; Ryy is a primary or secondary alkyl containing Cag A carbon atom; each of the Xa is a chloro; both of the Xa is a chloride. (a Jia (b) but since Rigb is a Robb you can form a 0-atom-containing normal alkyl Carbon; (b Jie )© | but since Rob is phenyl Ry5 sphenyl is sphenylated; it is likely to form ethyl or normal butyl; especially butyl. Jie (D- (d) (e)-( ©) but where the base used in step (iii) is sodium carbonate; or potassium carbonate; and (D)-(g) Yo is the same as (F)-(d) but where the base used in Step (iii) is sodium carbonate.” 0 a

YA | The preferred reaction conditions for the (AD) substep are especially when the reactants are from subgroups (8)” (8); (g) and especially when they belong to subgroups (0)-(0) such as (2(-)0) but where the base is used in step (iif) it is sodium carbonate; or potassium carbonate; and 8 (8)-(0) is the same as (0-60) but where the base is used in step (iii) They are potassium carbonate The preferred reaction conditions for the sub-step Ad especially Lad ic The 1 substances involved in the reaction are from subgroups (a) (4); (b) )€(« 0 Step 1 [when performed prior to step [(ii) Temperature: = for then to +46 then time V0 to five hours. Reaction medium: a low-halogenated liquid alkane such as or acetonitrile; methylene chloride; and acetonitrile is more preferable and acetonitrile is the most preferred; as well as reagents pure Vo: molecular ratio of reactants: 1 to VY gram molecular weight of 3 compound TX per weight mole of compound [1711 11 to 017 tin gram weight of compound IX per mole weight of compound] 711 being the most detailed; 0 Step 11 [when it takes place after step ()] Temperature: 10 C to 56 C: Time: 1.5 to ? hours Reaction medium: same as step (1) Molecular ratio of substances involved in the reaction: Preferred 0 to 11” YO molecular weight of compound [Cr per gram molecular weight of compound 111 used in (0); Yay |

1 to 0.7© gram molecular weight of compound 251 per weight (is gram of compound 1711) being most preferred. The two steps (); (i) [run together at the same time] ds a Temperature: dave + 70 °C © 0 o Time: ?to caleba 1 Reaction medium: such as step (i) when it takes place before step (if) the molecular ratio of pall involved in the reaction : 1 to 1.0 molar weight of Compound IX and 1 : 0.9 molar weight of Compound XT for every | one molecular weight of compound 7111?; : 0 step (iii) Temperature: 0 to oF preferably 0 to 1" C. Time: 0.5 to t,o h. Reaction medium: mixture of water and reaction medium for step (i) ) Molecular ratio of the reactants: ?to ;base molecular equivalent per VO gram molecular weight of compound IX used in step (1).There are three preferred variants of the method Ab Variable: Ruy is ethyl; the reaction medium for steps (1) and (i) is methylene chloride or, better, pure reagents; and in the two variables, Any, it is = Ryg, butyl is normal; and the reaction medium for the two steps is ( (11) acetonitrile; The best are pure 0 detectors, and in the two variables (Ap App), step (if) takes place after step (1), and in variable Av, the two steps (); (i) take place at the same time; and in each variable, step (i). Follow the two steps (il) (i) It is preferable that the variable App of the sub-method Ab include the following: () reactivity N-methylformanilide (methylformanilide) (compound of formula Yo 17111 where Ryp is phenyl; Ry is methyl) with oxalic acid chloride (compound Yay oo 0

q has formula IX where Xa is pure chloro) or in methylene chloride at 1 °C to 220 to form a compound of formula Xb Cr (Xb) purely — Cl (ii) Reaction of the compound of formula XD with ethyl vinyl ether of the compound of formula XT 0 where Ry is pure ethyl) or in methylene chloride at a temperature of 9010 to 0 C to form a compound of formula 70151 CH =CH-CH=N"(C¢Hs)CH; CI' (XIIb1) — robustness — (BE) Z A (ii) The compound with formula (01101) was hydrolyzed with sodium carbonate in a mixture of chloride methylene and water at a temperature of 10" to 10 *C to obtain 0 compound of formula (VIIb) (E) - OHC — CH=CH-N(C¢Hs)CH; (VIIb) iS) in preference in the variable App for sub-method Ap to be: (1) The molecular ratio of oxalic acid chloride to ON formanylide from step (1) is from 1:1 to 1 , 7: 1 and that step 1) be carried out by adding 1-oxalic acid chloride to pure JAN formalanilide or in a solution of methylene chloride at 1°C > 05 to 10°C over a period of time from elu Yo) and when the addition is complete; The temperature of the reaction mixture is raised gradually to 49-966*C over a period of 76 to Yo elu, then condensation takes place in rads that takes 75 to 075 hours. (7) In step (i) the molecular ratio of ethyl phenyl ether to ©_methylformylide used in step () is of (I), “1:1a” and step (i) is carried out by cooling the product of step (1) (to 10"C-70"C" add ethyl vinyl ether over a period of time from to 0.5 hour at a rate so that the temperature does not rise above ade 52°F the completion of the addition; CES, reaction mixture under condenser 0.7 rad to 1.7 hr (©) in step (1) The molecular ratio of sodium carbonate to chloride of Yo oxalic acid used in step (0) is from 1:1 to 1 LY The step (nNZ) is carried out by cooling the product of step (i) to 10 * m or Ye is added during a period of time of 1.0 Yay

to 1 hour; An aqueous solution of sodium carbonate at a rate such that the temperature of the reaction mixture does not exceed OF to OF and when the addition is complete; The mixture is stirred at 010°C to 0°C sad 7 to dela 1.0 leaving the mixture to separate into two layers; They were separated and the product recovered in the organic state; The variant (Ab of the © submethod Ab) preferably includes the following: Jie N Aelia (3) formanilide with pure oxalic acid chloride or in the presence of acetonitrile at 0°F to +0?” M Lequin Compound of formula Xb (i) 0 Reaction of compound of formula Xb with ordinary butyl phenyl ether (compound of formula XT where Rig is ordinary butyl) pure or in acetonitrile at 0 °C 901 to 80 to form a compound of formula 251102 (XIIb2) purely L-ptomata. of acetonitrile and water at a temperature of 0 to 5?*C to obtain 2 compound with formula 171110 it is better in the variable Ay of the sub-method Ap to be: (1) Vo the molecular ratio of oxalic acid chloride to Jam N Formanilide from step (0) from 1:1 to 1,7:1 and that step (i) is carried out by adding 3-oxalic acid chloride to pure Jie N formalanilide or in a solution of acetonitrile at PV A = to +8 "C over a period of 1-1 hour; upon completion of the addition, the temperature of the reaction mixture is raised to 11" to 10 *C gradually over a period of 4 to 1.76 hours 0 Then the mixture is stirred for 1.1 to 0.4 hours at this temperature. (Y) in step (1) the molecular ratio of n-butyl vinyl ether to 17-methylformanilide used in step ( ) is 1:1 to VY 1; step (0) by adding normal butyl dad ether to the product of step (1) and the mixture is stirred at SONY to 10*C over a period of time from 1.5 to 1.69 hours at a rate not exceeding YO The temperature is 1 OF and when the addition is completed, the reaction mixture is stirred from “,; to A; at oYo to 8 * C; and Yay |

(©) in step (i) the molecular ratio of sodium carbonate to oxalic acid chloride used in step () is from 1:1 to DY (©) and step (ii) is carried out by cooling the product of step (i) to ©ina to £70 by adding an aqueous solution of sodium carbonate over a period of time from 0.0 to 0.7 hours at a rate at which the temperature of the reaction mixture is 0°C to OVY and when the addition is complete; Toluene is added; the mixture is stirred at 00°C to 5°C for a period of 6 to 6 vo hours; the mixture is left to separate into two layers; the two layers are separated and the product is recovered from the organic phase. The variable cAgy of the Ay sub-method is better to include the two steps ( 6)” (i) wherein N-methylformanilide is reacted with pure oxalic acid chloride or in 0-acetonitrile at -10 *m to pF in the presence of normal butylphenyl ether to form Sal of the formula o(Xb) which thus reacts with normal butylphenyl ether in the reaction mixture to form the compound of formula 75110 and (iif) the compound of formula (2102) Le (2102) decomposes using sodium carbonate in a mixture of acetonitrile and water at a temperature from zero*m to 2Y0 to obtain a compound of formula (17110). The most favorable Vo in the variable w of the sub-method and is z (1) In the two steps (1( i) the molecular ratio of each of oxalic acid chloride and butyl-Nphenyl ether to 17-methylformanilide is from 1:1 to 0:17 The two steps (“Gi”) are carried out by adding a solution of 17-methylformanilide and pure normal butylphenyl ether; or in acetonitrile; Flip at -10*m to +100*m over a period of time ge Yo ? to ¥ hours and when the addition is complete; The temperature of the reaction mixture is gradually raised to OV Ye over a period of time from 1.4 to 0.5 hours; Then reaction mixture 1 at that temperature is stirred 1.6 sad to 1.0 h; and ¥ (in step oii) the molecular ratio of sodium carbonate to oxalic acid chloride used in step (a) is from 1:1 to 1 DF; step (iH) Ye is carried out by cooling the product of step ( i) to zero 020 and adding an aqueous solution of sodium carbonate at a rate that keeps the temperature of the reaction mixture at zero to 11°C during a period of z Yay

Time from © to 0.7 hours. when the addition is completed; toluene is added; The mixture is stirred at 220°C for a period of 19 to 1.5 hours; the mixture is allowed to separate into two layers. The two layers separate and the product from the organic phase is recovered. The product of step (i) of sub-method Ab may be presented to step AB) (iv) © for step (iv) in method 8. However, there is no reason to do this as long as the output always contains some amount of ALB or none of a compound of the formula KIT method B Preparation of compounds of formula Va from compounds of formula Vic z The method for preparing compounds of formula Va (method (B) (i) includes the reactance of a compound of formula 17116 º (E) - or With a compound of choice of acidic chloride or bromide phosgene “LILY” phosgene or carbonylbromide; No phosphorus trichloride; or phosphorus tribromide; phosphorus pentachloride or phosphorus pentabromide and alkyl chloride or bromide or arylsulfonyl Jie chloride or para bromide p-toluene sulphony] - or methanesulfonyl chloride or bromide to form the compound of formula XVI (E) - Xp — CH=CH-CH=N+(R2)R1 (XVI) | Yo and the corresponding anion (eg POLK) where Rs Rizo Xp is as defined above. (ii | reactance of that compound of formula XVI with a compound of formula ]22171 Rg and 8 Rg | (XVII) d Yay |

Whereas, Rg Ry (Rg Rs) is as defined above to form a conformational compound of formula XVI Rs (XVIII) 8 8 "s | Ss RoR

Ry 7 m ab) 13 and the corresponding anion eg PO (Xp) wherein Riz Rs Ry Rg Rs © and pristine are as defined above. (ii) hydrolyse that compound 53 of formula [747711] to yield an identical compound of formula Va as above for method A in a variable; in step (1) a compound of formula XIT obtained may be used According to method A directly instead of a compound with the formula Vile 0 L. The preferred indications for the root of Ry Rupp are shown above, and the preference for roots (cracks) is Rg (Ry (Rg) as mentioned, bearing the same connotations as Ry (Ry) (Rp respectively in US Patent No. 47,796,977. Thanks to the fact that Xb is chloro. Reacting compound of formula 7118 with compound of formula XV preferably VO performs steps (1) (11) in an anhydrous organic medium Inert. Preferred reactants (and end products) are as follows: (8)-1) where I and Ka are Ris Rig being an alkyl containing a 1-?0 carbon atom; and both Xp being chloro.” and Rs to Rg have significances for variables corresponding to groups (XXII) (XX) (ii) oi) US Pat. Zgm 4774/1. Yay

¢ has Rg to Rs that corresponds to (8)-(0) where it turns out to be “taubal (h)-(e) for patent (xxvi) and (XXV) (Vi) (V) Indications for the variables corresponding to the groups. Phenyl; Dimethylphenyl; or Methyl-Fluorin; Rg carbon; © dirt carbon atom; or ?- or Cop hydrogen; alkyl containing SIRs that form hydrogen or methyl; Re oxy; form phenyl; methylphenylfluorophenyl; binary Ry where (hg is corresponding to 0-0”

Rs (carbon atom; Ca) being an alkyl containing Ry methylphenyl; or methyl-fluorophenyl;

Rs -benzyl oxy; of carbon atom; or - Cap is hydrogen; An alkyl contains 0 die forming hydrogen. or

CSRs are hydrogens; Rs where I(T) that corresponds to (p-(m) hydrogen is phenyl; and B is methyl; Rygp where it has (p-(m) that corresponds L(q-(t) con4-fluoro Rg is 1-methyl ethyl; Ry where the q (corresponding to dlls (u Ve) is phenyl; and Lithium-1 is Ry phenyl; lit be Ry where in (x is that corresponding to)”

LJ

Rg is 1-methyl ethyl; and Ry is hydrogen; Re Rs is the most preferred; To be P-F.0 used in step (1) in the form (VIC) Compounds of the formula may be free base, or better, in the form of the acidic salt in the form of the acidic salt Hydrochloric are inorganic hydroxides such as hydroxide (iD) The preferred bases for the step are sodium and potassium hydroxide, especially sodium hydroxide. However, as _8 (iif) below it is preferable not to use any base in the step

Yay

£1 The preferred reaction conditions for method 5 are as follows: Step 1 Temperature: OY em to +757*C; Preferably Vt (Np vm : Time: 1.1 to 0.7 hours; v0 to 1 hour preferred 8 Reaction medium: Low alkyl benzyl; acetonitrile preferred. Molecular ratio of reactants: 1 to 0.6 mole weight of compound 7 per molecular weight of compound VTE and more preferably 11 to 1” weight of > 1 gram of compound XV per molecular weight of compound 17116. Step 11 01 Temperature: 20 to 100 * C, best 915 to AOA Time: ? to dela 1 and most preferably ? to YE hours Reaction medium: as step () Molecular ratio of the reactants: 1 to © molecular weight of compound XVI per molecular weight of compound XVID more preferable Y to * 1 gram molecular weight _ of compound XVI per molecular weight of compound [16171 96000] Outcome in step (1) is assumed in each case. 0 Step ii Temperature: 10*C to Hf when using base 1005C when no base is used. Yo Time: 1.1 to 1 hour when using the “? to ; hours when no solvent base is used: mixture of water and reaction medium for step (i) molecular ratio af gall reactant: when a base is used; ; to dL SoA base; The best sodium hydroxide or potassium hydroxide per molecular weight of > XV all Yo used in step (i) | | to

Also, the best reaction conditions are for the o(B) method, especially when the reactants. The final products belong to subgroups 8)-)”; Especially the sub-groups (1), ((m), ,)( ,)@(, (0) and (uw) are as follows Step i o Temperature: -901 to 22V ot Time: V0 ,+ to hr Reaction medium: acetonthiryl.1 Molecular ratio of sell reactant: 111 to 10 “molecular weight of compound XV per molecular weight of compound Ve 0 Step fi Temperature: 20 to PAO and preferably 80 C to SAY Time: ? to dela 11 preferably to 10 hours Reaction medium: acetonitrile Molecular ratio of the reactants: ? To * MG of compound Ne 61d per GM of compound XVID preferably 7.1 to Yoo MG of compound XVI per GM of compound XVI (+ + % b outcome (yield) in Step 1 is suggested for each case). Step iii Temperature: OF to ©**C; °Yo is preferred to 70" when using the Xo 50 rule?" to 905 when not in use. Time: 1 to 0.7 hours when using a rule; 7 to ¥ hours in Alla no galas Reaction medium: mixture of water and reaction medium for step (ii) ° Molecular ratio of the reactants: when using a base use ; to 6 equivalents of Yo base; the best is hydroxysodium; per gram molecular weight of compound XV used in step 1. 0 | appeared

It is preferable not to use a rule in step (11): the general conditions used in all methods are that most of the molecular amounts (percentages) that are given are just Aad and may vary as it becomes clear to the average person who is not experienced in this technique. (0) It is preferable to perform steps (ol) 1) for the method (Ala Sd) A on the two sub-methods Ab Aa and their variants and the two steps (); (if) for method (03); and the best step (iv) for the sub-method Aa under anhydrous conditions and a dry atmosphere preferably in an atmosphere of helium, argon, or nitrogen, or a mixture of them. Dry nitrogen is used mostly. Mostly but not necessarily step (ji) of method A (including sub-methods Ab Aa 0 and their variants) and method 13 under inert atmosphere. Similarly, many of the degree limits given above are examples. All temperatures are internal degrees; Unless otherwise indicated. As used above.” The term “reaction medium” includes mixtures of liquids and Gara requires that the reaction medium be a liquid at the desired temperature. (lI) It should be understood that not all liquids listed V0 A particular step may be used to cover the whole range of temperatures.It must also be understood that the reaction medium at least must be inert labial to the reactants used.~ and the resulting intermediates and final products under the reaction conditions used; therefore it must be understood that the temperature of the reaction The boiling point of the reactants or reaction medium may not exceed 1) Use a condenser or closed system (Jolin flask or reactor). 7 The above reaction times are also examples only; It may vary. Lind should understand that traditional processing processes may be used. The term “solvent” as used here includes mixtures of solvents and Gan requires that the reaction medium be liquid at the desired reaction temperature; Unless otherwise mentioned; All solvent mixtures will be by volume. Yo The term "inert atmosphere" means an atmosphere that does not react with any of the reactants; or intermediates or final products or not disturb the reaction. Yay

If desired, the product of each method may be purified by conventional methods such as re-Ohl, chromatographic purification, or fractional distillation. All temperatures are Asie degrees and room temperature from Yo C to 0 to dale 1?* to Yo unless otherwise indicated. Evaporation is carried out under vacuum using minimum heating; The organic phases were dried over anhydrous magnesium sulfate and unless indicated otherwise a Lu gel per aan was chromatographically on Al columns for chromatography. 0 jal shall state that the method variants disclosed by Lal are improvements to known similar methods; It may be used to obtain the final products “Jie ise galt 0 7-substituted-hept-7-enoic acid” and heptanoic acid and their derivatives in a more accessible way; or in a state of greater chemical or optical purity than obtained by conventional methods. | A qualitative embodiment AS in all of the above method variants relates to a sample depiction of the general inventive concept 1 with the preparation of erythro-acid ()-; 0-dihydroxy-71-[?-( >fluorophenyl)- — Jie) ethyl)indole-?-yl]-hept-<7”-enoic acid of formula Ja Erythro-(E )-3, 5-dihydroxy-7-[3'-(4"-fluorophenyl)-1'-(1"- : methylethyl)indol-2-yI)]-hept-6-enoic acid 1 4 ec' (Ia) oi a 4 tn 38 oH ch Nery Ye. in the pure racemic or photoactive form or in the form of free acid ester ¢ or salt 5-lactone ¢ meaning internal ester in multi-step method; Using all the variables of the coded method called AB methods and the stereoselective reduction of a compound of formula [1] and including: . Yay ou

A according to method 171118 is a compound with the formula Aelia (a

OHC - N(Ri2)R13 (VIIa) are as defined above. With a compound of the Raz Rug formula

Xe optionally in an inert anhydrous organic medium to form a compound of formula IX©

X, - purely rum and alkalosis followed by the above convention. Rig whereby, optionally, XI with a compound of formula XC is the reaction of that compound of formula (b z XT) in an organic medium Anhydrous inert for the formation of an identical compound of formula (E) R140 — CH=CH-CH=N"(Rizu)R1i3 Xi (XIIc) 1 defined above. An identical compound (XTC) The decomposition of that compound with the formula (©) in a free base or the salt form of the acid addition and the formula of the addition salt (VIC) of the formula acid to base if it is desired to obtain the salt form of the acid addition.

B - According to method Vo or with XV reacting such compound of formula 17118 with a compound of formula d or phosgene a selected compound of oxalic acid bromide chloride or phosphorus trichloride carbonyl bromide; or phosphorous trichloride or phosphorus pentachloride; or 010801070189 pentachloride phosphorus bromide pentachloride of phosphorus; chloride or alkyl bromide-or arylsulfonylchloride” 010801070189 chloride or p-toluene carbonyl bromide or chloride or methanesulfonyl bromide, to form a compound —POy(Xp)y Jia and the corresponding anion XVI is identical of formula XVI with the reactance of that compound 53 (formula)© “-(?-fluorophenyl)- 1-(1-methylethyl)-111-indole (compound with formula with two hydrogen formation; Rs where XVII Yo

Yav o) form (para-fluorophenyl) to form an identical compound Rg form 1-methylethyl; Ry 0 122171118 for formula . F (XVIIIa) 7 Neda IR and ton B: ca(cs,), as done X, and Riz Rupp where PO(XKp)y and the corresponding anion are as defined above; Hydrolyze that compound with the formula 1771118 to obtain (£ ° -purb-[li-"-lodna-111-)litha_litham-1(-7-)lenff_rolf->(-©1-+-2) "-enal (E)-3-[3'-(4"-fluorophenyl)-1-(1"-methylethyl)-1H-indol-2'"-yl)|prop- 2-enal . 1- Ry forms two hydrogens;

(g) Reacting that compound of formula Va with the di-ion of an acetoacetic ester of formula: [0]1:00011:00016 where Ry is as above, to obtain an identical compound of formula 1: Ia

(11a) | B, R, : Vo cyan Ny” cama A oH 0 Yay | ov was previously known in a racemic or optically pure form Ry, since - according to the stereo selective reduction method:

Ha optically of formula JN selectively and stereoisically reduces the racemic compound or (h) by:

IIT mixed a compound of formula dled© under (a) in a preliminary step [<step ©] with sodium borohydride (b[148311]) in a reaction medium including alcohol and tetrahydrofuran (tetrahydrofuran) under para © above]; Treating a compound with formula (b) in a second step [step of racemic or optically pure form with the resulting mixture under appropriate conditions to obtain i [a] to obtain a mixture containing a compound of cyclic borons having formula (17)8 and/or superimposed 0 where: TV(b) boron of the formula ethyl)-111-indole] complex-?-yl; Jie J = (Jed) is [7-(4-fluoro R 3-(4) '-fluorophenyl)-1-(1'methylethyl)-1H-indol]-2-yl s—CH=CH- be X godel and O as above Ry Vo the part of the obtained product fle 0 tgt Paragraph (0) 3 sha] GE in step b in the second step to obtain the compound of formula 18 in the form of an ester; A compound of conventional formula (i-8) has either a free acid form or a salt form; also an ester form or a YL lactone form; i.e. an internal ester form. -56 A compound of formula 18 may be a free acid form; a salt; An ester or lactone, meaning an internal ester; it is preferable to be a free acid or a salt, and the best is an alkali salt, especially in the form of a sodium salt. It is preferable to be in a racemic form or rather than, especially when in the form of (BR, 55) that; photopure or in a racemic Yo enantiomeric form; As shown by formula 18, that form is the form erythro: z

Yay oy it is estimated that the vascular embodiment described under Paragraph 9 is carried out according to the processes disclosed by this invention or by following some steps according to methods known in the art to be in fact as described above under Paragraph cba (Technology). And so on. Steps run

Lid as is (iin) and therefore (i)oi) especially the two steps Ay of the sub-method 1-1: in (b) «(a) the two steps Ap of the sub-method Ags may take place or [5 Ap App for variable © ®), (e), (d) Steps A run the same time as described above for method

Sally (i) “i) for method 3 especially the two-step Y-V as described above under (ii) z | Step 0 is carried out according to the methods published eg in US Patent No. and in Example 0 Step © in column A in column 1 especially in Reaction Plan 77407 0 y of Example. EY “0 as described above Under Paragraph (h) the step is carried out Step (1) is carried out in the traditional manner; such as as described in the patent (l) in column D, © US No. 4779077 especially in reaction schemes (reactions in EE (Reaction A and Reaction Plan 01 in Column DL and Reaction Diagram? (Reaction Y4 Vo)

OF (oY gov in columns 54 t 1 A (z) and in the following examples (b) OT is a column for the examples in which it is preferable to substitute tetrahydrofuran with ethanol. It is preferable to use o (h) in the part The second step of the previous SSR is isopropyl alcohol or especially tert-butyl, which is Ry, since Ta is a compound with formula like Ry. Yo To a surprising degree, the compound represented by Formula 1 obtained is completely colorless, while it obtains a pale yellow color in early construction processes. By using a racemic or optically pure compound with formula 118, a pure compound is obtained by chromatographic analysis of a racemic compound having photoactive Oia 11 from the sample Yo

Yay of formula 118 obtained in step (p)”; or preferably by non-metastatic synthesis. Alternatively; The analysis process may be constructed in a next step; or on the racemic final product. The raw materials for this specific embodiment of the invention are also known or may be prepared according to known methods. Reveals the preparation of 7-(;?-fluorophenyl)-1-(1-methylethyl)-111-[his-3-(4'-fluorophenyl)-1-(1'methylethyl)-1H-indol [-2-yl edol © 4774 YY see step (©) above] in US Patent No. XVII the formula to * in columns 4 and £0 starting with 1-fluorobenzene steps co as an example Z .fluorobenzene examples

Ay gil The following example illustrates the invention; All temperatures are expressed in 01 964.5 degrees. The term Ball means, for example, dy shall, and expresses the optical purity for a pure erythro-isomer, that there are at most 960.4 of the trio form in the obtained compound. To obtain a compound of TT Examples of stereoisomer selective reduction of a compound of formula

I formula 10 º | 1 Example: tert-butyl ester of (+)-erythro-(-7-[3“-(4-fluorophenyl)-7-(7-methyl0ethyl)indole-7-yl]-” *-dihydroxyhept-+-enoic (£)-Erythro-(E)-7-[3'-(4"-fluorophenyl)-1-(1"-methylethyl)indol-2'- y1)]3 ,5-dihydroxyhept-6-enoic acid tert-butyl ester Ye (Jr Yds 7-(?-fluorophenyl)-1-(07-methylethyl) =R:1 [Formula: 3-(4) '-fluorophenyl)-1-(1'methylethyl)-indol]-2-yl tert-butyl; in racemic form] Ry «(E)-CH=CH- =X z mol) from sodium borohydride to solvent VY) add 57.17 g (2) ml methanol in a nitrogen atmosphere at YOU liter tetrahydrofuran and 0.7" of g S Yo diethyl (Use 5.05) 9680 10 ml of about -777 * m. is added to the resulting solution

Yay

oo 01 in tetrahydrofuran over diethylmethoxyborane over a minute; The resulting mixture was stirred for an additional 10 minutes. Purity of ester %YY AA mol (from + ETE) 700.6 g (b) tert-butyl acid of ()-7-02(7-[©-[©]) was added dropwise. -(©-fluorophenyl-7-(7-methylethyl)indole-

0 ?-yl]-*-hydroxy-”-oxo Juss cua (+)-Erythro-(E)-7-[3'-(4"-fluorophenyl)-1-(1"-methylethyl)indol -2'- yl]5-dihydroxyhept-6-enoic acid tert-butyl ester 1 vol" in 016 mL tetrahydrofuran; 776 mL methanol at a temperature of about Vim

to -Al7A*Mn over the mixture formed in step (a) over a period of 1.0 hours and A0 stirred the resulting mixture for another Fe min. 780 ml of a saturated solution of 1.70 ml sodium bicarbonate heptane was added to quench the reaction. Then 0 | ml was added through ethyl acetate Ji and the resulting mixture was dried by 0.0 liter water with stirring for 11 minutes; The temperature of the mixture is about 10 * C. The top organic layer is separated and washed several times with a saturated solution of sodium chloride in the amount of ‎EYE Jay! No pH 7.5; The organic layer is concentrated at 17"-#0 mm Hg and at an outside temperature not exceeding about 5*C. To the organic stagnant A is added 75 mL toluene; the solvent is distilled at dey (35 pf r = Ye) an outside temperature not exceeding Approximately oto (0) “2.7 L ethyl acetate is added to the slurry oil obtained (ratio .ANY to cycloboronates). Then 0000 mL of 9678 hydrogen peroxide solution (£61 mol) is added to Ethyl acetate solution keeping the internal temperature in the range from Yo to "C (in the beginning the addition is exothermic) and the reaction mixture is stirred at UY 10 8 C for about two hours until it becomes clear that there are no borons when performing the YO chromatographic process of Thin layer type. The top organic layer was washed twice with a total volume of 7.77 liters of a saturated solution of sodium chloride Yay |

pH LY,0 The upper organic layer is then separated and washed three times with a total amount of 7.61 liters of 96100 sodium sulfur solution (until the organic layer is free of superoxide) and during that the internal temperature is kept at 5? then. The top organic layer is then etched with a total volume of 1.77 liters of a saturated solution of © _NaCl,; pH 5,; The solvent is distilled at 17"-8" mm (Gti) and an external temperature does not exceed about 0°C. The remaining substance is dissolved in 1,117 Cr through condensed ethyl by evaporation. The mixture is filtered while it is hot and the filtrate is stirred at 10 to 20°C for a period VA h. Solids were collected by filtration, dried under reduced pressure (approx. oY | mmHg) at 2°¥0, washed with +00 mL of ethyl acetate/heptane: (1) (2) and re-dissolved in AA ml ethyl acetate and stirred at room temperature for VA 1 hour - the solids were collected by filtration and washed by 580 ml of ethyl acetate/heptane (1:1). The solids were dried under low pressure to give a product of 05 Ahi g) melting 7-170 1ml) The second product is obtained from the original liquid to give a total yield of 155.9 959 g.The chemical purity of the product reaches 9694.454 and AY is a pure erythro isomer - and can Decomposition of the product into active enantiomers 38;58 and 38 58 oo, the first being considered the best. As a better alternative, half the amount of sodium borohydride referred to in step (A) 7 can be used, and as an alternative, an aqueous solution of sodium perborate can be used in step (0) in place of 96,700 hydrogen peroxide solution. Example ?: © methyl ester of (©)-earthro-()-71-7-(+-fluorophenyl)-7-(71-methylethyl) 0 Fd Yd -dihydroxyhept-1 -enoic (+)-Erythro-(E)-7-[3'<(4"-fluorophenyl)-1-(1"-methylethyl)indol-2'- Yo ‎y1]3,5-dihydroxyhept-6-enoic acid methyl ester in racemic form. hydrofuran .yt (2 mol) of a methyl ester (TA) g 114.5 treats (B)ethyl)indole-?-yl]-0— hydroxy-?- JEN J (da (8)-1-7[?-(;-fluoro) but by making a dilution by (b) sshd) oxo-Hbt-7-indicates in a similar way to example heptane; instead of using ©,© l water Only ALY VAG 7 L water 1.75 is added to the organic residue (mostly cycloboronate) (©) 960 ml of TAF peroxide solution 1.75 L ethyl acetate; the mixture is treated with (0). (Step 1 mol) The work is carried out as described in the example TVA) Hydrogen 0 mL isopropanol. The mixture is heated to 11 degrees, after which the residue is dissolved in g boric acid VE 00006 rad heat of condensation. Add to the hot mixture for a minute. The mixture was then filtered 11 and heated at rad condensation temperature for an hour. solids collection by filtration; The VA?” was washed for 71-5, the filtrate was stirred and dried under reduced pressure to give dsopropanol 01 ml isopropanol by Veo

Lai] Gm (96/80 score). The product is re-dissolved in methanol and recrystallized 011 product weight The photoconference of the product is 9694.07 pure erythro-racem; [AVIV fusion EE 1st is best. SR 3S and 55 BR can be hydrolyzed to photoenantiomers iY eg -7[-7-e-dihydroxy Fm butyl ester tert-(+)-erythro-(10)0ethyl)-"-phenyl-111-imidazole-*-yl]-hept-?-ia) == (dd (*-fluoro | | imidazol-5"-yl] hept-6-enoic t-butyl ester phenyl)-;-(1-methylethyl)-7-phenyl-11- and Rolf-?(-1 mR:1 [Formula] Yo «dro—ds lua z Yay oA 1-(4'-fluorophenyl)-4-(1'-methylethyl)-2-phenyl]1H-imidazol-5'yl1 -photo (58, 3R) butyl 3 in =R, «(E)-CH=CH-=X enantiomerine] mol) of sodium borohydride to solvent YY) 0777 g add (a) mL methanol in an atmosphere of 519 cla L tetrahydrofuran YY contains

SE 9615 mL of VAY lll nitrogen at about -77°C. Added to the solution, Lady ABS ?0 reservation over the range of THE ethyl methoxyborane in tetrahydrofuran; The internal temperature is under -77.0 * C. The resulting mixture is stirred for an additional 0 minutes. From SG acid (mol) of butyl ester (YY) 0011 gm (b) -2- ethyl) is added dropwise -?-phenyl-111-imidazole-lithium-1 (Jd and Rolfe-(-1 (55)-rq-bhz a yl]-*-hydroxy-7-oxo-HPT-7-inoyl (58) )-(E)-7-[1'-(4"-fluorophenyl)-4'-(1"-methylethyl)-2-phenyl} 111- imidazol-5' —yl-hydroxy-3-oxohet-6- enoic acid ml methanol at a temperature of about 176 ml tetrahydrofuran “Vo tJ” to -77 to the mixture formed in step (3) over two hours and stir VES 10 to the resulting yellow solution at 71 °C for > hours Then add 70 ml of ammonium chilride to quench the reaction. A liter of water; the temperature of the mixture is reached to about 00 and the mixture is stirred for a period of time to separate the upper organic layer p20 minutes; the temperature of the resulting mixture is about To for a reading of 0.6 and it is washed several times with a saturated solution of sodium chloride total amount : Hg and at a temperature ae to 01 and the solvent is distilled at V0 (pH external about 2980 z ethyl acetate to the oil obtained (the predominant ratio is 3.71 z (©) A ml of Viv okay 96980 superoxide solution (cycloboronate) is added. After that, Yo "m is added and the mixture of © - Yoo hydrogen (* mol) is stirred, bringing the internal temperature to A?

The reaction was carried out at 7-015 C for about 2 hours until the absence of borons was determined using the thin-layer chromatographic method. The top organic layer was washed twice with a total volume of 1.7 L of a saturated solution of NaCl; pH 5, Then the top organic layer is separated and washed three times (for 2 10 minutes each time) with a total amount of 0.000 liter of sodium sulfite solution (until the organic layer is free of superoxide). ) While the internal temperature is kept at L200, the top organic layer is washed with Tee ml of a solution: saturated with sodium chloride (pH (V,0). The solvent is distilled at mY “mm Hg. And an external temperature is not challenged About £0 M. Yoo g is obtained from the raw material Vo purifies ty 1A g of the crude dihydroxy ester through column chromatography using ethyl acetate/hexane (Y:1) as the eluting solvent eluant to give .£9 mm (melting point 10-7 M) shown by NMR analysis; containing 909/8 erythro isomer (no trio isomerism); photorefractive index [op] at (CHCl, cr, VY =(< 3:5 59) °4,¢4+ =a°Y 0 Vo Ex: the butyl ester (AU) of (58,318)-erythro-dihydroxy-6-triethyl acid oxy-ana-hexanoic acid (3R,58)-Erythro-dihydroxy-6-trityloxyhexanoic acid t-butyl ester [formula =u Ju trityl; =Ru butyl thiazide in (-)-enantiomeric form] (a) Yo 5.111 g (VEAL mol) sodium borohydride is added to a solvent containing 198 mL tetrahydrofuran YAY Gla mL methanol in atmosphere of nitrogen at about -6 qt. The temperature is raised to about —£ 22Y and the solution is added dropwise Output 1? 1 ml of 9611 diethyl methoxyborane in tetrahydrofuran over a period of "m" Addy and stirred the mixture formed for another 101 minutes at -lala to 1 2 º (b) Yo added dropwise oY g (1 0 YY mmol) of an aged tert-butyl ester of acid gua gh ¥= iS of Ji Si 1= mS 5 pa 0—(S)-hexanoic acid Yay

(S)-5-hydroxy-6-trityloxy-3-oxo-hexanoic acid t-butyl ester in 166 mL trihydrofuran; 1 mL of methanol at a temperature of about -la to −V to the mixture formed in step (a) over a period of 500 minutes; The resulting mixture was stirred for another 1 hour at -7 °C to L220, after which 155 ml of a saturated © solution of ammonium chloride was added to quench the reaction. Then add Jeo ethyl acetate and 5060 ml clin 001 ml water. The top organic layer is separated and washed through with a load of 0.010 mL of a saturated solution of sodium chloride; pH 5, − 8, organic layer at ae - 01 (34) and at an external temperature of about 0 d mm A: vs (©) VAY ml ethyl acetate is added to the obtained organic residue ( Containing Aa boronates at an expensive rate). Then slowly add 79 ml of 0 hydrogen peroxide solution (7:0 1 se) and stir the reaction mixture (sad) about lel wt until no borons are found when performing the thin-layer chromatographic test. The organic layer is washed. The upper organic layer was then separated twice with a total volume of 5086 ml of saturated NO NaCl solution; pH V,0 The top organic layer was then separated and washed three times (for 10 minutes each time) with a total volume of 571 ml of solution 9600 sodium sulfur (so that the organic layer is extracted free from superoxide) Ley The internal temperature is kept at 76 "C. The top organic layer is washed with 100 ml of a saturated solution of sodium chloride (pH (V, 0 is distilled 0. The solvent at a¥ mY Hg and an external temperature not exceeding about 200 g OFT is obtained from a crude dihydroxy compound (melting point 4 748 μm); which denotes Li gal as 9694.19 isomer Aerothro; refractive index [op] at 08 -1D,H (concentrations)- {CHLCly 117 Examples of preparing intermediate compounds of formula VIT by the method A Yo Example 0e: : AE-N,N )-Y : methylamino)acrolein 3-(N,N-dimethylamino)acrolein | ?

[-(-)-7-(14,10-Dimethylamino)prop-7-enal] [Formula [die =Ry3 Ry VII] [Sub-method [Aa] (Step (i) is completed under cover of Nitrogen 11 liter round-bottomed flask with © four necks, equipped with stirrer, brine sles condenser (a mixture of ice and table salt), thermometer, caustic gas scrubber, cooling ales addition funnel; 0.5 liter methyl chloride and EVA is 4 mol (A) g of SENN methylformamide. the solution is cooled up to sleeve; 450 g (TA mol) of oxalyl chloride is added over a period of 0.¥ hour at a rate of less or no scavenging of the solvent and/or reactant to cial and as desired. The temperature of the reaction mixture is kept at −10”C. .sale is a white solid. (Step (if) “18 g (Use TY) of ethyl vinyl ether is added over a period of 0*- 000 minutes while keeping the maximum temperature at YO to OYA, and this addition is exothermic at Ale degree Very much A red-brown solution is produced The reaction mixture is heated at -*# 17 °C for a period of Fo min, thus the reverse condensation process takes place The largest amount of Aes 0 of methylene chloride is recovered by distillation at a pressure of pat Te Hg After stopping the distillation, the reaction mixture is kept at 10 mm Hg and at 5 * C for a period of Vr min and at 46 C for chickpeas on a thick stirred oil door that can be stirred. 590 ml of water is added over a period of Ye iss min; the expellant heat brings the temperature to 10*C; and gli 0 is maintained at this temperature from the addition. The mixture is stirred at 0 90C-10 then Posed minutes and cooled to 10 * m. A solution of 1.71 kg 17.75 (mol) of anhydrous potassium carbonate © 7 liter of water is added over a period of “+1 to £0 min Lay The temperature is kept at OYTO, the layer (Ala) is extracted from methylene chloride, the bottom methylene chloride layer is separated, and the top organic layer is extracted; times by one ° Yo liter of methyl chloride in parts. The five methylene chloride layers combine; It is dried on 000 grams of ASLO a gp gall sulfate, and the steel is washed twice with You ml chloride > Yay 0"

7+0 two instances in parts. The washers collect and filter and recover as much methylene chloride as possible by distillation at 01 to 56 mm Bh) and A060 obtaining thick oil (step iv) the oil is cooled to a temperature of 1*C; 5000 is added ml methanol; 0 and the mixture is cooled to 901 and Te (g (VY mol) dimethylamine) is added and the temperature is maintained during this so that it does not exceed LOY The largest possible amount of solvent is recovered by distillation at a pressure of 17”-1 *mmhg The distillation continues while the temperature is gradually raised until it reaches pV Yr and the steam temperature reaches 1110”C, thus obtaining a pure product with a ratio of BAY as an oily substance [£1 g; Yield 9667 Boiling Point Product 0 Meet TYVY,A-YYY Example +: º (N)-¥ -methyl-17-phenylamino) acrolein 3-(N,N-methyl-N-phenylamino) acrolein : [-(i)-7-(11-methyl-17-phenylamino)prop-?-en]Vo [formula “dsb =Ryp VII pAro]- [de [method] Sub-paralyzing heterodimer ‎Ab z

(b) step (i 505) under a nitrogen cap an 11 liter four-necked bottle equipped with a stirrer, a brine gles condenser (a mixture of ice and table salt), a thermometer, a caustic gas scrubber, an addition funnel, and a cooling bath; by ©,0 liters of methylene chloride

Yo Wala, 0 g (5, nMol) of A-Jie Formatelide. The solution is cooled to 210 (0 g ATTY) mol) oxalyl chloride is added over the course of 1.5 hours at a rate with little or no scavenging of the solvent and/or reactant to the bottom of the brine-filled condenser; Meanwhile, the temperature is kept between 11 to PY under conditions of softening rad condensation. The reaction mixture was slowly warmed up to LEY over an hour and the rad condensation process took place for an hour at ??-Yo 40°C to obtain a clear yellow solution and then cooled to 11 then.

(Step (if) TEA gm (8,595 mol) of Jd ethyl ether is added over a period of 1-6 minutes while the temperature is maintained so that it does not exceed 1-74 7”C; the reaction is highly exothermic The resulting red-brown solution is heated at –¥A 4°C for yo min, reverse condensation is carried out and then cooled to 2210° (Step 171) added over a period of ¥4 to 10 min while keeping the temperature The temperature is between YY to °F A solution of 960 g (9.05 mol) of anhydrous sodium carbonate in 0.0 L water; this addition is accompanied by the release of a large amount of heat. The 0 mixture is stirred at 70-77"C for 10 min and then left still for 11 min to allow two separate layers to form Organic phase separated; aqueous phase (layer) extracted with 0.59 0 L of methylene chloride Combined methylene chloride extract to previous organic phase; combined solution extracted by liters of water.The aqueous extract is re-extracted with You ml methylene chloride and this methylene chloride extract is combined to the previous organic phase.The largest amount of methylene chloride is recovered by distillation at a pressure of 2-701 mmHg and a temperature of 10”C; and heated residual oil at par = e Hg and V0 1 to 210 for £ hours to obtain AY,0% pure product as oily substance [, 795 kg; Yield OY Boiling point of pure product 44 7"C (decomposition); Melting point of pure product 476 REV of isopropanol/hexane [1:1]. Example: N)-¥-methyl-17- 3-(N-methyl-N-phenylamino) acrolein 00 [-(-)-7-(11-methyl-17-phenylamino)prop-7-enal] [Formula =Ry3 Rip VII As in Example 6] [Ap sub-method hetero [Ay] (Step (i) Fill under a cap of nitrogen a 0 liter bottle having four necks Yo and equipped with a stirrer and a flee condenser with brine (a mixture of ice and salt food), thermometer, caustic gas scrubber, addition funnel, and cooling bath; Wor ml acetonitrile; Yay |

+ g (7.8 mol) of [1-methylformanilide]. The solution is cooled to -51*m; 65 g (WoT) mol) of oxalyl chloride is added over 1.0 h at a rate with little or no scavenging of the solvent and/or reagent (reagent) to the bottom of the brine condenser at a temperature of Yom to oY er while the temperature is kept between Vom to 10*C under conditions of © softening rad condensation. The reaction mixture Jia 220 was slowly warmed over the course of 70 minutes and stirred for 10 minutes at 10 h. step (il) is added at intervals of £0 min while the temperature is kept at ~YA 00°C 4.58 7 g (7.79 mol) of butyl (gale) fatyl n-butyl vinyl cether | and it is accompanied by the release of a large amount of heat. The reaction mixture is stirred at 1767 °C 0 for 0© minutes, a red-brown solution is obtained, then cooling is carried out until zero "m.z" (step () iid is added over a period of 50 to 10 minutes while the temperature is kept between 4 to 10”C; a solution of 985 g (77, mol) of anhydrous sodium carbonate in 1,705 liters cele and this addition is accompanied by the release of a large amount From the heat, add 0.7©* liter of toluene” and stir the mixture at 7-177*C for 10 minutes and then leave it still for 15 minutes to allow separation into two layers. The organic phase (layer) is separated and washed twice with You mL at a time Recover the largest possible amount of toluene by distillation at mmHg and a temperature of 01 to 0V - and the remaining oil is heated at mY mmHg and a temperature of 485 to 00C for a period of 0V Jan min on 96/7.7 pure product as oily substance [97; kg; yield 9686.7; pure 01 product boiling point LOVEE (disintegration); Melting point of the pure product p28 VE of isopropanol/hexane JY on If the reaction mixture was stirred at VA 227 for 1 min instead of at 1?-m obtaining a yield of 9698.7 percent of a pure product of 9617, 7. Example iv: N)-¥ Yo-methyl-17-phenylamino) acrolein 3-(N-methyl-N-phenylamino)acrolein Yay

+ [-(-)-7-(11-methyl-17-phenylamino)prop-7-enyl] [formula =Ry3 «Rp VII as in Example 7] [Ap submethod heterodimer App reagents [Lalla Step (7) fill under a cap of nitrogen a bottle of 0.0 liter capacity with four necks and equipped as in example 7a (step oi by 777.7 VAY mol) Ns Jie Formatelide. The solution is cooled to 00*C; 177.6 mL (7.07 mol) oxalyl chloride is added over a period of 10 minutes while the temperature is kept at the same temperature. Spontaneous outgassing occurs and an orange homogeneous solution is formed. Step (11) Over a period of 0 lbs min while the temperature is kept at –Yo 0 F, an amount of YYAE g (15,? mol)_ of (Normal) butyl ether oJ is added and this reaction is exothermic. The orange suspension was stirred at 45-680 then for Yh minutes and cooled to zero degrees. Step (11) A solution of AN of sodium hydroxide is slowly added over the course of 90 minutes to the product of step (II) so that the temperature does not exceed #”C. The mixture is heated to room temperature and stirred for 10 minutes. [ A torr over 2 hours yields a thick brown-black oil [745 g; PAY yield Chemical purity AA Product boiling point EY. 44 7*m (disintegration) Melting point of pure product 47 -7?*m from isopropanol/yn-hexane Example: (N)-¥-methyl-17-phenylamino)acrolein 3-(N-methyl-N-phenylamino)acrolein Yo [- ()-7-(11-methyl-17-phenylamino)prop-?-en] [formula = Ry3 Ryp VII as they are in Example 1] b

[Ap sub-method heterotrophic [Abs] Steps (if) (i) Fill under a nitrogen cap a 0-litre round-bottom flask with four necks, equipped with stirrer, sles condenser, thermometer, gas scrubber, and funnel Add and cool bath 1,067 kg (AYO) mol) 0-oxalyl chloride” and 4,850 mL acetonitrile. The solution is cooled to Vo and a mixture of 0.11 kg (v.10 mol) of 17-Jie-formanilide is added; and MT g (7,548 mol) of butyl ether (normal) 01 Jt ml nitrile acetic acid over a period of 7.5 hours at a rate of less or no 0 scavenging the solvent and/or sale reaction reagent to bottom Agaba condenser (kept at Yom to 0°C); while the temperature is kept at -01 to -#*°C under conditions of softening rad condensation. The resultant reaction mixture is slowly warmed to 10"C over a period of GEE*0 and the heat released rises negligibly to OYA over a period of Ye min. The reaction mixture is stirred at 7817C for 1 hour to obtain a brown homogeneous mixture; Then it is cooled to 0 °C (Step 111) added over a period of 0 lb to 1 min while the temperature is kept at 0 °C between + to 10 * C; a solution of 5548 g (84 mol) of sodium carbonate Z Anhydrous in 5.71 liters of water; at first the addition is accompanied by the release of a large amount of heat Lo. ©, 1 liter of toluene is added; the mixture is stirred at 4 (OY Y-Y) for 11 minutes and then left still for 11 minutes to allow separation into two layers, the organic phase is separated and washed twice by 60 ml at a time. residual at <7” mm Hg and a temperature of 44 to 090 for yo min. a pure product with a ratio of 9644.1 as oleoresin [1.11 kg; yield OAT, boiling point of pure product 4 4 “m) is obtained dissociation); the melting point of the product (El) 46 -47 then of isopropanol/hexane [1 : 1 Yo]. Examples of preparation of intermediates according to formula Va using method B Yay |

In Example 9: gust -V]-Y—(E) phenyl)-7-(7-methylethyl)-111-indole- “-yl]prop- ? (E)-3-[3'-(4"-fluorophenyl)-1'-(1"-methylethyl)1 H-indol-2"-yl |prop-2- enal o [Formula: Va and all =Rg «Jit Litham-1 =R7 dH =R¢ ;-fluorophenyl] [Method [B (1) Fill a bottle of © liter with four necks and equipped with a nitrogen cap. with a stirrer, a condenser filled with brine (a mixture of ice and table salt), a thermometer, a caustic gas scrubber, an addition funnel, and a cooling bath; in the amount of 100 ml acetonitrile” 175.4 g (Je)VE)0 phosphorus oxychloride; the mixture was cooled to a%0— and a solution of AS g (187+ mol) of NF methyl-17-phenylamino) acrolein of SATO purity (Examples product 1 to /) in 106 mL is added of dry acetonitrile over £0 min while maintaining the temperature to be om + 00. The reaction mixture was stirred at a temperature of 0 to 220 for 10 min. (i) Vo added 115.7 g) 080 mol) of '-(;-fluoro Gf VV (did-ethyl)-111-etdol 3-(4"-fluorophenyl)-1-(1"-methylethyl)1 H-indol A (compound with formula (XVIT) over a period of yo min while maintaining the temperature at about #©"C. Adee radcondensates the reaction mixture at LAY for 9 h and then cools to 10"C. Ye | (101) added slowly over Yr min while maintaining the temperature to be between Yo to 17"C; a solution of 174 g (0.9 mol) NaOH in 7.0 L water; The addition is accompanied by the release of a large amount of heat. 0.6 liters of toluene is added; The mixture was stirred at OVO for 1 min and then filtered through a filter pad. The filter cake was washed with 100 ml toluene; The washing solution is incorporated into the pre-filtration. class Z 8 _ separates membership; A mixture of 97.4 g of concentrated hydrochloric acid and * liter of water is added, followed by the addition of 5050 ml of saturated sodium chloride solution. The mixture is stirred at °Yo Yay |

TA

The output through a felt filter. The bituminous materials were washed with STUITY for +7 minutes, the suspension was filtered with 1 ml of toluene, and the washing was added to the filtrate. The organic layer is separated and washed by 1 twice with 1 liter of deionized water each time and filtered through filter felt. The largest possible amount of toluene is recovered by distillation at 0 mm Hg and at a temperature of 001 ml to 51 °C to obtain Thick stirred oil. 01 external heat is added from © ethanol at a concentration of 965 and the largest possible amount of ethanol is recovered by distillation at +?*-. How much YAY is added to 2 ° “and this treatment is repeated twice, adding Te Hg and a temperature of

Yo for 2 YA, and the rad condensation process is carried out on the mixture at Jodo ethanol at a concentration of: °C over a period of two hours; Crystallization begins at about 270 °C, cools 0 to eda minutes, cools down to 1 minute while maintaining the temperature Yo a, the suspension slowly to between zero 0 5 m over a range of #0 at zero to 200 for an hour, then filtered. The filter cake was washed three times using 1 ml each time of cold 40% ethanol (zero blood) and vacuum dried at

PANY 1 hour until weight stability to obtain a pure product by 1 for 2270-10 (2° 11 H) 1 g yield 96977 Melting point 011 Isopropanol is used as a dispersant to replace L-9645 ethanol. phenyl)-7-(7-methylheavy)-111-indole-7-yl] gst ~V]-Y—(E) 01: Example: a prop-?-enal (E)-3- [3'-(4"-fluorophenyl)-1-(1"-methlethyl)-1H-indol-2-yl]prop-2- enal [4 as in eg =Rg Jggl Rg Rs :Va [Formula Yo [Method <B < alternative procedure] 0) Fill under a nitrogen cap a 0 liter four-necked bottle equipped with stirrer, condenser, thermometer, adding funnel and cooling bath; in the amount of YAY mL nitrile free tof “alo g (uh mol) phosphorus oxychloride Yeo The mixture is cooled to *-*”C and added over £0 min keeping the temperature at © to 7”C A solution of 971.1;5g (Use YE) from ?*- ach

(17-methyl-17-phenylamino) acrolein with a purity of 0.0% A in 5076 ml of dry acetonitrile. The reaction mixture was stirred at -7"C for 10 minutes.

(i) Add over 10 minutes while maintaining the temperature at approx

Latham Foo g (1.18 mol) of 7-(?-fluorophenyl)-1-(1-methylethyl)-111-indole

© (compound of formula XVIT) Reflective condensation of the reaction mixture takes place at 87/*m

for three hours and then cooled to OY

(i) VY liter water is slowly added over the course of Vo min while maintaining a temperature of

0 temperature is between YY to 5”C; the addition is exothermic; the reaction mixture is stirred at 20Yo for 0 min; heated at 5-0200C for 1.0 h (may be Ala) a period

0 heating is necessary to complete the hydrolysis process); Then it is cooled to YY and maintained at

heat at OY for 10 minutes; And then filter. The filter cake is washed three times

601 ml of water at a time and dried by vacuum under the pressure of an aspirator.

for > to VT hours (JEN can recover aniline from the co-aqueous layer

And the babysitter). Transfer the wet filter cake to the original 0-litre vial and add

-5 0 μm; The mixture is heated to 10 g of VAG cellulose powder*, ? liter of toluene” Vo

then for 0.5 hours and cool down to 77 °C; And maintains the temperature at 2200 for

10 minutes and optionally filtered through a felt layer of 91 g ga silica gel 8.5.1.14 (70-17? mesh aperture) covered with a filter cloth. Wash off the cellulose and silica gel felts

Three times at 100 ml toluene each time. Collect the toluene filtrate and wash

0 and recover the largest possible amount of toluene by distillation at mV mmHg and a temperature of

ben on 2210 (outside) add 780ml of ethanol 96905 to the remaining thick oil;

Ethanol was distilled at par = Yr Hg and a temperature of 15-78*C; 80 ml of

ethanol 9695; The largest possible amount of ethanol is distilled at 220m (Bi)ah eT

7001 ml of ethanol 9695 is added; The process of reflective condensation of the mixture takes place at

Yo is then left for 10 minutes and slowly cooled to 10*C over an hour interval; The je tall process begins at about ¨m. The resulting suspension is cooled from 0 to #**C over a period of 10 minutes; And saves

Yay

nor at zero to “m for Fo minutes; solids are collected by filtration; It was washed three times with 101 ml ethanol 9646 cold (0 to 0 m) and dried in a vacuum at 16-70 then for 10 hours until constant weight to obtain a pure product with a ratio of 9694.4 (YVT, T): g ; score 9675.5; Melting point 179 -: 217 C). In the opposite method, isopropanol is used instead of sii 30. It is preferable to omit the felted silica gel; This means exposing the liquid containing cellulose powder to a simple filtration process. In this case, the residue is washed three times with 100 ml toluene in parts. Example 10a: (©)-7*-1+--fluorophenyl)-7-(7-methylethyl)-111-isindole-7-yl] Ys prop-?-enyl (E)-3 -[3'-(4"-fluorophenyl)-1-(1"-methlethyl)-1H-indol-2'-ylJprop-2- enal [Formula: Va mcgl ggl = Rg As in Example 4 [Method (B Alternative Procedure) Ve (7) Fill under a nitrogen cap a 1.5 liter bottle prepared as described in Example 10; step (); by 171 mL dry acetonitrile; 70.015 g salt of “NY methyl-1-phenylamino)acrolene hydrochloride at room temperature. 97.76 g of phosphorus oxychloride is added to the mixture over a period of minutes. A dark colored solution is obtained. Te 00 is added at about eT g of ET (phenyl)-1-(1-methylethyl)-111-indole (compound with formula (XVI) The mixture is heated to the point of inverting condensation for 0.£ an hour at Vo to AY after which it is cooled to OXY (iid) Yoo mL of water at “C” is added followed by 0610 mL of water at room temperature over a period of Vo min. The reaction mixture is stirred at Vo at 0 °C for Ve min; Yo is heated at 2006 °C for 0.5 h a dark colored suspension is obtained; the mixture is cooled to (OF) and kept there for 11 min; the brown suspension is filtered. Washed filter paste

Vy three times with a total amount of water + 08 ml. The filter cake is dried by emptying the original liter; 0.5 of the solid is added to the vial with a capacity of pall of air for four hours. micron); The work steps take place in (Vr) ml toluene; 5 g cellulose powder Vou g; A) to obtain the product (ii) next step 01 as described in example (Mt17 1-177). Melting point PAY Yield ©: Examples of qualitative embodiment

PY Example “VV-Dihydroxyethylene 0 is the sodium salt of (-)-erythro-(15)- ;

Gir ethyl)indole-?"-yl] de) (gh fluoro(+)-Erythro-(E)-3,5-dihydroxy-7-[3'-(4"-fluorophenyl)-1 '-(1"- 1 methylethyl)-indol-2"-yl]hept-6-enoic acid sodium salt as racemic tla [formula] 17-methylformanilide reacts with oxalyl chloride and ether :)©(, (b), (a) Steps to produce 7-(11-methyl-Ay) ethyl (or butyl) phenyl according to method A sub-method [Steps A, 7, or 7a; or 1 amino) acrolein as described in Proverbs JN Yo ,(3n)]. (@w), )(amino) acrolein with NFR NYY lle product reacts (d) step 0 “oo step(); “DBC1 is Xp where XVI is to produce the compound with the formula

Jia 0 -1-)lenf with 7-(?-fluoro XVI step (©) reaction of the high compound of formula 1 step Ve or 01 ethyl)-111-indole as described in Example 9 or Jie?) to be vinyl; rugp to be chloro” X, (); To produce the compound with the formula 12171118, as Ry3

Yay

For step (10) the hydrolysis of the compound of formula XVIa as described in Example 9, 01, or 01 (fH) is carried out to produce (5)-7-[3-(-fluorophenyl J)-Jie)-ethyl)-111-indole-?-yl]-prop-?-enal. Step (p) Fill a reaction vessel under nitrogen atmosphere with 1.6 L of © tetrahydrofuran; The solution is cooled to -0*C; 10 g of sodium hydride (as a suspension in 96750 mineral oil) is cautiously added. Thereafter, cautiously and over a period of £0 min keeping the temperature below 0°C, add 717 g of JIE acetobutyl acetate in You ml tetrahydrofuran. The resulting solution is stirred at a temperature of -01 to OY for an hour. The mixture is cooled to -10"C; Ce ATA 0.0 is added from a solution of 0.6 mol butyl (normal) lithium in hexane at a rate that does not allow the temperature to increase at 0"C. le) orbit about 1 min) the mixture was stirred for 10 minutes at the same temperature; then cooled down to vm (2%) and added at a rate not exceeding 0 °C (over a period of about 71 minutes ) Aged solution of 71 g of step (1) product Ale in 1560 mL tetrahydrofuran The reaction mixture was stirred at 0°C for 9#1 min and poured with vigorous stirring over a mixture of YEA mL concentrated hydrochloric acid ; 1.5 kg of ice over a period of 1 to 10 minutes. The mixture was stirred vigorously for another 0 minutes. separates the organic phase; It was washed twice with 500 ml each time of a saturated solution of NaCl and concentrated under reduced pressure (approximately 1 yo mm Hg). To the remaining substance 100 ml of toluene is added and the solution is concentrated again. 0 In the next step, the crude obtained without additive purification is used, which is the tertiary butyl ester of (2)-7-[3-(+-fluorophenyl)-1-(17-methylethyl)indole-?-yl]- E-Hydroxy-7-oxo-Hbt-"-enoic (compound with formula RyCusTa tert-butyl formation; in racemic form) can 00 FT (4 9676.0 purity). Step (h) Selectively reduce the crude product high as described in ob Ji Yo steps (0), (0), (8), (0), to yield the JB butyl ester of ()-erythro-(05)-7 acid. - Yay vy indole-?-yl]-7;©-dihydroxy-hept- (JS JAY) [-(?-fluorophenyl)-

REP

(1) To 7.0 lb of the ester obtained from step (i) step 908 mL hydroxide 908 mL tetrahydrofuran is added over © minutes a high amount of YYo at the temperature is maintained under 10 m. The solution was stirred for 1 hour at IN sodium © sulfur; pa¥ © methanol; The mixture is concentrated at room temperature Ja¥VO pressure; At a temperature of 20°62 and then add 00 ml of deionized water; It continues, and then the distillation process is added again da 161 until the remaining volume reaches Po

TE ml deionized water and wash the solution three times with a total volume of FAY mmHg; 55" up to YO volume at LAL) tert-methyl butyl ether. Concentrate the layer ge de 0 ml deionized water; make the clear aqueous solution 771 ml; then add 000 about 9641 over an hour Three days; the compound entitled (58.5 g cyl boron concentration minus i iso-erythro 9644.9 HAA yield; chemical viability of detection) was obtained. g of ester obtained from 5 0, Alternative process for step (7) Add to Vo ml VE ml ethanol and over a period of 175 minutes with stirring the amount of step ((high) in

VY of NaOH with temperature kept below IN of a solution of 0 The solution is stirred for 1 hour; The mixture was concentrated at (? mm Hg” 10°80) and then 11 ml of deionized water was added, and the distillation continued until the remaining volume reached YOu ml of deionized water, and the solution was washed three times with the amount of WYO, then added Xo at a total Lala pressure of 00 ml of tert-methyl butyl ether. Concentrate slew ml YAO volume of about 48 µl; add Jin 2220 mm Hg; deionized YO temperature; The clear aqueous solution was made alkaline over three days Melting point (dl as 9691) was obtained for the titled compound 79.70 g; pure white color; pure erythro-isomer” concentration BAY 96000 (dissociation); purity Chemical OV V-YaE 5 Boron © 97,ppm).

Yav

Y¢

NY eg e-Dihydroxy-7-[3-(1- FY (B)- gsi ( ) sodium salt of Tad-enyl acid [d= fluorophenyl)-7-(17- methyl(ethyl)indole [Formula 18: in racemic form; pic sodium salt] except that: 11 the titled compound was obtained in a manner similar to the example ° the methyl ester was produced by the reaction with methyl acetoacetate (g) in the step instead of with tert-butyl aceto; meth acetoacetate (0), (b), (a) » is described in the LS example Step (h) takes place Step (7) is carried out by the metholysis of the methyl ester obtained from step (n ); as described in US Patent #4,774077 Example 1b in column 0

On

Yay

Claims (1)

Yeo Claims 1:) A method for preparing a compound of formula 1 - 1 3 R-X-CH- CH - CH - CB - 08 (I) Y 08 0 where 1 ~CH=CH- R ~CH,CH,- represents the x ¢ ' inactive element with respect to the conditions of the ester group Represents the ester group Ry ° “Organic with groups that are inactive under radical Has a root R Unmethyl Jd Reducing conditions provided that when +[ my triodes A includes additionally an alkyl Ry then driphenylmethyl ; by steric selective reduction “—QOCH,- X “alkyl \ or optically pure that Racemic racemic oS all Stereoselective 11 L has the formula (L): 1 7 8-1-6 - 08: - GC - Y (11) Z h : VY has the same definition as above; XR;R where \¢ hydroxy and one of the 2:22 is oxygen and the other is hydroxy Yo and hydrogen and includes according to the first step [Step (1) the Vi 0 Yay compound is mixed 7 has the formula II (Rs), (III) A 3 -0-y1 1 where Ry is the allyl or lower alkyl 1-4 lower alkyl Ye ; 71 carbon atoms: 8 : Ry is a primary or secondary alkyl with EY carbon atoms in it; YY with sodium borohydride (NaBH) in a reaction medium comprising yy alcohol and tetrahydrofuran and in a second step [ve step (b)]; The compound of formula [1] is treated with the resulting mixture in stage (1) under appropriate conditions to obtain a mixture containing a compound vy cyclic boronate of formula IV (a) 1 YA 2 { R - X - CHCH,CH - CH,COOR, [IV(a)] ºC 'a with/or a boron complex of formula TV(b) Ry Rs y v. \ { R ~ X - CHCH,CH - CH,COOR [IV(b)] 1 where 1:4 Ry and X have the same definitions as above; and m in a third step [step (c) ]; cleavage of the product in step (b) to obtain rv to obtain an identical compound of formula 1 Yav yy by appropriate methods into T form converting the resulting compound of formula eng Jf and if ve 5- from 6-lactone sal ester free acid; salt form; ester form internal vo. ester any ester form dJactone 9 Ju For the preparation of a compound of formula 1 method according to the element -Y \ 10 01: - CHCH,CHCE, - COOR, mw z 0 !0 and o(trityl) triphenylmethyl formation 0 Cua y inactive ester inducing a radical ester component or allyl radical forming the Ru allyl ¢ or alkyl cally the best callyl allyl reaction conditions preferably allyl 0 isobutyl n-butyl carbon atom “normal butyl” Cole contains 1 especially benzyl butyl or t-butyl butyl Tert-dsobutyl 7 Adee stereoselective reduction by t-butyl tertiary A: or a pure, optically active racemie Sl stereoselective q JT compound of formula 1 NO - OCH, - Cf - (8; - COOR, (Iu) 1 Lh rbd and tam as defined above. Ru where VY Yay ’ YA : (Ia) for the preparation of a compound of formula 1 by a method according to element 1 1 =C=C, NH Chem Ctij=CHuCHy=C00 H {Ia) CH 0 OH bid OH CH, CH, or optically pure; In racemic acid form, in racemic form. - internal; ester i.e. 8-lactone ester or 5-lactone ester salt; Ester on Ia and it includes - if desired - the conversion of the resulting compound of the formula ° by known methods into a free acid form » salt form; ester form 1 ester i.e. ester form S-lactone or 5 - LAT lactone is an internal ester form 7. A with precursor in which the starting compound 1 of element Wk method is —¢ 1: (Va) Formula Y Ry : Rg 1 0 1 And for c=c” {Va) a Rs H CHO R, that Cua ¢ the measure of it is from -1? chydrogen carbon atoms form hydrogen Rs 8 butyl “i-butyl isobutyl” (Ci alkyl) 1 yay va z z 7 tert-t-butyl cycloalkyl “(C3 cycloalkyl) alkoxy A ([-160l0,,28); Ordinary butoxy n-butoxy iso-butoxy d-butoxy q trifluoromethyl fluoro 01 chloro phenoxy or tbenzyloxy Rg 11 be alkyl toadieryl hydrogen; Alkoxy “Cpialkoxy VY” trifluoromethyl drifluoromethyl fluoro fluoro VY chloro “chloro phenoxy” or oxybenzyloxy “Z 0” provided that it is not more than one of the Rg Rs Trifluoromethyl is trifluoromethyl Yo and more than one of the Rg Rs is phenoxy 1 and no more than one Rg Rs is benzyloxy VY and one of the Rg Ry is phenyl Tertiary substituted by (Rg ha Ryn Rug) and the other is a primary or binary non-symmetric 8 carbon alkyl Crs; a cycloalkyl yl or (CHy)ge phenyl 0 where Rg 91 Formation of alkyl hydrogen Craalkyl n-butyl YY Isobutyl d-butyl tert-butyl Cpzalkoxy YY Butoxy n-butyl 0-manna; iso ci-butoxy Y¢ trifluoromethyl fluoro yo chloro phenoxy or oxybenzyloxy 1 Ry hydrogen alkyl (Cry alkoxy) (Cra trifluoromethyl fluoro; vy chloro phenoxy or oxybenzyl. Ry YA forms alkyl hydrogen “Cy; alkoxy Yq is a fluoro “fluoro or chloro” provided that it is not: in more than one of Rig Ry trifluoromethyl drifluoromethyl or else Yay A and more than phenoxy Rig Ry is more than one of 1 benzyloxy oxybenzyl Rip Rg and one of the starting material of formula [1] prepared as follows: ry 171118 a complex reaction of which Formula (i) ve OHC-N(R12) Ris Yo d Whereas substituted with one substituent to phenyl or phenyl phenyl there are three phenyl Rye vy alkoxy Crzalkyl three and each is independent representing the alkyl YA Or nitro bromo “chloro fluoro” Cjjalkoxy v9 (NItro) with a maximum of two groups of 0 lb 3 for an independent bA that has the aforementioned definition for ,18:2 or is (170:) With a compound of the formula “Cyzalkyl alkyl 3 X,-CO-CO-X, (IX) 5 a monovalent leaving group Xp where to ! £1 and optionally in an inert anhydrous organic medium; To form the corresponding compound of formula Xe (Xe) EA (CH=N' Rip) Riz Mar £9 where Riz Rygy Xp has the same definition as given in this item (if) 5, react that Compound of formula (X) 2 with compound of formula (XI) Ry, O-CH=CH, (XI) oY z Cua oy 14:4 monovalent group does not reactivate an atom of oxygen, which is attached to Baha and optionally in an organic medium, no Yay} AY is an inert aqueous; 00 (Xe) to form an identical compound of formula 0 (E)- Ris O-CH=CH - CH=N"R2,)R13 X, (Xe) ov and has the same definitions mentioned In this Ry Riz Rpgy of where oA : element; and 99 hydrolyze that compound of compound 7216 to yield (ii) 1 Vc congruent compound of formula 0 } E- OH C- CH=CH -N (Ris) Ris (VIIc) +7 11 Whereas, DBC and Yaa have the same definitions mentioned in this element; in the form of a free base or salt in addition to an acid if it is in the form of a salt 18 in addition to an acid, then the salt in addition to the acid is neutralized with the base. For (iv) the reaction of that compound of formula (171116) with a compound of formula (XV) A PO (Xp) (XV) 14 Va where Xj is chloro or bromo or with a compound B A selected from chloride or foxalyl bromide phosgene of carbonyl bromide phosphorus trichloride vy or phosphorus tribromide ; phosphorus pentachloride Yo or phosphorus pentabromide a alkyl — or arylsulfonyl chloride or bromide; Jie chloride or bromide YA p-toluenesulfonyl choride or bromide v4 methanesulfonyl choride or Yav 1 AY (XVI) to form the corresponding compound with formula bromide As (E) X, -CH=CH - CH = N'(Rj25)Ris (XVI) AN “PO; (Xp)y Jia 'and the corresponding anion' AY have the same definition as given in this element. Rys and Rpg 'Xp Sua AY' with a compound of formula (XVI) The reaction of that compound of formula (V) At XVII Ao 8 A Rg 007 (XVII) "9b has the same identification as that given in this element Rg (Ry (Rg (Rs Cus AY (XVIII)) to form an identical compound of formula AA Ry Rs AS A A {(XVII1) H R | >= + 6 rH C=N (Rp2 b) mr 7 and H ,. -PO, (Xp and the corresponding anion 3 such as 89 have the same definition as mentioned. Xp alkyl, dobaka, and bl Ry mcl Rs, where 51 in this element ay aqueously to obtain (XVID) the hydrolysis of that The compound of formula (vi) qy Yav ' AY .Va is a compound of formula q¢ and used (ii) in a way according to the element. ; and in which step 1 VIC directly substitutes the compound of formula (XT) for the compound of formula Y for further processing. 1 at a time (ii) “(1) method according to element € and in which step =A \ . . aslY 1-1 is the element's ils method; Whereas, in step (0) and/or (i) Y the reagents used are pure. —A 1 method by element; in which the compound of element 1811 at oC Y is salt plus acid form. 1/4- A method according to the element “in which the starting material of formula TT has Y formula Ila F ¥ A N muo speed uCH,=C00 tm A but CH, CH, . 0 racemic form de); > Since it has the definition mentioned in the element, or it is optically pure, and it is prepared as follows: racemic ° Yay Ag as defined in the element; With compound Villa a) Reaction of a compound of formula 1 and optionally in an organic medium cf as defined in the element TX of formula v as defined in an inert anhydrous Xe; To form an identical compound of formula A ot element q as XT with a compound of formula Xo b) react that compound 53 (of formula y. (Jala) defined in element 6; optionally in an anhydrous organic medium 11 to form an aqueous identical compound of formula ©7711 as defined in element 4; \Y c) decompose that compound of formula 70116 to obtain an identical compound 1 defined in element; in the form of a free base or WS Ve of the formula ‎ ) ¢ a salt plus an acid” and if it is in the form of a salt plus an acid; yo The addition salt of an acid is neutralized by a base. defined in the element; or with a selected compound of VA chloride or bromide or phosgene oxalyl chloride or bromide oxalyl 1 ccarbonyl bromide ¢ phosphorus trichloride or tribromide B 71 phosphorus chloride or phosphorus pentabromide A - and ¢ pentachloride or pentabromide YY “alkyl-or arylsulfonyl chloride or bromide or arylsulfonyl Y ¢ as Yo chloride or p-toluenesulfonyl bromide p-toluenesulfonyl chloride or bromide 4 “methanesulfonyl chloride or bromide” is methanesulfonyl chloride, as defined in element XVI, in order to form an identical compound with the formula YA PO, (Xp), and the corresponding anion such as 1 baht Ao 55 = 8) =F with XVI m e) the reaction of that compound 53 (element methylethyl)-111-indole —1) -1-)linf 1 (compound 3-(4') -fluorophenyl)-1-(1'-methylethyl)-1H-indole vy R; hydrogen hydrogen Rg Rs wherein XVII of formula vy para--fluorophenyl Rg «I-methylethyl methylethyl 1- It is v4 .(p-fluorophenyl Yo XVIa) to form an identical compound of formula 1 JF ry Ai | 1071138 Nom Rab Ri p "CH (CH,) , P.O.(Xp); Jie and the corresponding anion” YA v4 Lo where Xs “Ry Rip has the same definitions as given in £ element ¢ ¢ (£ f) hydrolyzes that compound 53 of formula 72171118 to obtain (B) 7 # - [©*- ¢— (E)-3-[3'-(4"-fluorophenyl)[3'-(4"-fluorophenyl) -1'-(1"-methylethyl)-1H- §¢ indole-2'-yl]-prop-2-enal go (compound with the formula (Va) in which the Re Rs are hydrogen < hydrogen a can be 1-Ry; Yay AT “p-fluorophenyl parachlorophenyl £A ... from a dianion with a di-anion Va g) The reaction of that compound of formula 4 having formula acetoacetic ester 84 is as defined in Ry where “CH3COCH, COOR; 21 A element oY -0 1 | method according to element? Whereas, the compound of formula 18 is 7 Obtaining it in racemic form: 1-1 method according to the element * where the compound with Y formula 18 is obtained in the form (55; (BR enantiomeric). 1-1 A method according to the element? Where the compound with formula 18 Y is obtained in the form of sodium salt. VY 1: A method according to the element, where Rygp is phenyl" Riz 7 methyl 1 = method according to the element ?Rul Com be tert-butyl Yav