PT91980B - PROCESS FOR THE PREPARATION OF HEPT-6-ENOIC ACID AND HEPTANOIC ACIDS SUBSTITUTED IN POSITION 7 AND ITS DERIVATIVES AND INTERMEDIATE PRODUCTS - Google Patents

Description

2

the conditions of reduction, by means of the stereo-selective reduction of a racemic or optically pure compound of the formula II-CHO-COOR- (II)

R-X-C

In which R 1, R 2 and X have the abovementioned meanings, and one of Z 2 and Z 2 is oxygen and the other is hydroxy and hydrogen.

The compounds of formula I are pharmaceuticals, especially antisclerotic, antihyperlipidemic and antihypercholesterolemic agents. The process may also be applied in the preparation of compounds of formula Iu (Iu)

wherein u is triphenylmethyl (trityl) and (C 1 -C 4) alkyl;

Ru is allyl or a radical which forms an inert ester under the reaction conditions, which are intermediates for the preparation of some of the compounds of formula I. Further processes are also claimed for the preparation of

More preferred starting intermediates for the preparation of, inter alia, the compounds of formula I, are: Process A, which comprises the preparation of the compounds of formula VII (E) -OHC-CH = CH-N (R 12) R 13 (VII ) in which R1 is C1 -C4 alkyl, phenyl or phenyl substituted by 1 to 3 substituents, each of which is independently of the other C1 -C4 alkyl, C1 -C4 alkoxy, fluoro , chlorine, bromine or nitro with up to two nitro groups; and

R 2, R 3, R 4, R 5 and R 8 independently of one another are as defined above for R 2 'from the corresponding compounds of formula VIII and process B, which comprises the preparation of compounds of formula Va

(Va) 4 in which

R6 is hydrogen, C1 -C4 alkyl, n-butyl, i-butyl, tert-butyl, C3 -C6 cycloalkyl, C1-4 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro chloro, phenoxy or benzyloxy groups;

R8 is hydrogen, C1 -C4 alkoxy alkyl, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; with the provisos that not more than one of R6 and R6 is trifluoromethyl, not more than one of R1 and R2 is phenoxy and not more than one of R1 and R2 is benzyloxy; one of R1 and R2 is phenyl trisubstituted by R1, R2, R3 and R4; and the other is primary or secondary C1 -C6 alkyl and does not contain an asymmetric carbon, C3 -C6 cycloalkyl or phenyl- (CH2) m-, in which

R 2 is hydrogen, n-butyl, i-butyl, tert-butyl, C 1 -C 4 -alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; R q is hydrogen, C-to C alco alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy;

R11 is hydrogen, C1 -C4 alkyl, alkoxy in fluorine or chlorine, and m is 1, 2 or 3; with the provisos that not more than one of R6 and R10 is trifluoromethyl, not more than one of R1 and R10 is phenoxy and not more than one of R1 and R2 is benzyloxy; starting from a subgroup of compounds of formula VII.

A specific embodiment of the invention consists in the preparation of the compound of formula Ia

(Ia) a form in the racemic or optically pure form; in the form of free acid, salt, ester or delta lactone, i.e. under the ester of the inner ester. The invention relates to a process for the preparation of hept-6-endic and heptanoic acids substituted at the 7-position by their derivatives and intermediates. 61.

Goal

The invention relates to a process for the preparation of a compound of formula I in which X represents -CH 2 CH 2 - or -CH = CH 2 -CH 2 - R 2 is an inert ester group under reaction conditions; and R is an organic radical having groups which are inert under reducing conditions. The invention also comprises a process for the preparation of intermediates (of formula Va and VIII) (see below). The common feature connecting the various process steps is that they all lead to improvements in the various stages of preparation of 7-substituted hept-5-enoic acids and heptanoic acids, their derivatives and intermediates, which are cholesterol biosynthesis inhibitors. This linkage is hereinafter illustrated with a preferred embodiment, which relates to the preparation of an inhibitor of biosynthesis of the specific cholesterol, namely erythro- (E) -3,5-dihydroxy-7- [3- (4-fluorophenyl) -1- (1-methyl-ethyl) -indol-2'-ijb. ept-Î ± -enoic acid in the form of an optically pure form or a racemic mixture; in the form of a free acid, salt, oucophazol ester, i.e., as an internal ester.

The process of the invention formula I comprises pure or a

for the preparation of a selective reduction compound of a racemic optimate of the formula II

R-X

(II) in which R 1, R 2 and X are as defined above and one of the symbols and Z 1 is oxygen and the other is hydroxide and hydrogen, to prepare a compound of formula I.

As is apparent from formula I the compounds have sin, i.e. the erythro configuration. The symbol (E) - appearing at the beginning of a formula or a name indicates that the double bond is in the trans configuration. The invention also comprises a compound of formula I as defined above in an optical purity state wherein the ratio of the erythro isomer to the trans isomer is 99.1: 0.9 or greater, preferably 99.5: 0.5 or higher; especially 99.7: 0.3 or higher.

The compounds of formula I, which are esters, and the corresponding free salts and cyclic esters (< t-lactones) are pharmaceutically acceptable in particular HMG-CoA reductase inhibitors, i.e., cholesterol biosynthesis inhibitors and, accordingly, are indicated for use in the treatment of hypercholesterolemia, hyperlipoproteinemia and arteriosclerosis.

Preferred meanings 8

An ester group R3 is preferably a hydrolysable and physiologically acceptable ester group when an ester is desired as the end product. The phrase " hydrolysable and physiologically acceptable ester group " means a group which, together with the -COO- radical to which it is attached, forms an ester group which is physiologically acceptable and hydrolyzable under physiological conditions to give the carboxylic acid corresponding to the compound of formula I (i.e. wherein is substituted by hydrogen) and an alcohol which is itself physiologically acceptable, i.e., non-toxic at the desired dosage level, particularly a group which is free from asymmetry centers. R 2 is preferably R 2, wherein R 2 is C 1 -C 4 alkyl or benzyl, especially R 21 ', wherein R 2' is C 1 -C 6 alkyl, n-butyl, i-butyl, t-butyl or benzyl, for preferably ethyl, preferably isopropyl or t-butyl, preferably t-butyl. X is preferably X 'wherein X * is -CH = CH-, preferably (E) -CH = CH-. The group R is preferably selected from the group consisting of A, B, C, D, Ea, Eb, Ec, F, G, Η, I, J, K, L, M or N as follows: trisubstituted by R1a > R 2a and R 3a in which R 2a and R 3a are independently hydrogen; halogen; phenylalkyl; halogen substituted phenyl, C1 -C4 alkoxy, C1 -C4 alkanoyloxy, C1 -C4 alkyl or halogen -C1-4 alkyl; or -OR4a in which R4 & is hydrogen, C2-8 alkanoyl, benzoyl, phenyl, halogen,

phenyl, (C1 -C4 alkyl), C1 -C6 alkyl, cinnamoyl, C1 -C6 haloalkyl, cycloalkyl (C1 -C4 alkyl), adamantyl (C1 -C4 alkyl) or phenyl substituted C1-4 alkyl wherein each of the substituents thereof is selected from the group consisting of halogen, C1 -C4 alkoxy, C1 -C4 alkyl and halo-C1-4 alkyl; in which the halogen atoms are fluorine or chlorine; and cycloalkyl, which includes cyclohexyl.

B

in which

R 1 and R 2 together form a radical of the formula: 6 5

a) -C = C-C = C- or b) -CHO -OH-CHO-OH- in which R1 is hydrogen, alkyl in trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy alkoxy; R 2b is hydrogen, n-butyl, i-butyl, alkoxy in n-butoxy, i-butyl, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; R 2b is hydrogen, C 1-6 alkoxy alkyl, tri-fluoroethyl,

condition that only one of R1 and R2 is trifluoromethyl, not more than one of R1 and R2 is phenoxy, and only one of R1 and R2 is benzyloxy;

Rbb is hydrogen, C1-3 alkyl > fluoro or chloro;

Ryb is hydrogen, C1-4 alkyl, n-butyl, i-butyl, n-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy;

R 5b is hydrogen, C 1-4 alkyl, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; with the proviso that only one of Ryb and Rbb is trifluoromethyl, not more than one of Ryb and Rbb is phenoxy, and not more than one of Ryb and Rbb is benzyloxy; with another condition: that the free valence in rings Ba and Bb are orthogonal to each other;

in which one of R1 and R2 is phenyl substituted by R1, R2 and R3 and the other is C1 -C6 alkyl or n-butyl,

R1 is hydrogen, n-butyl, i-butyl, t-butyl, alkoxy in n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; R 4 is hydrogen, C 1-6 alkoxy alkyl, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; with the proviso that not more than one of R1 and R2 is trifluoromethyl, not more than one of R1 and R2 is either phenoxy and not more than one of R1 and R2 and are benzyloxy; R1 is hydrogen, C1-3 alkyl, n-butyl, i-butyl, t-butyl, C1-6 alkoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy, benzyloxy;

RgC is hydrogen, C1-4 alkoxy alkyl, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; with the proviso that not more than one of R1 and R2 is trifluoromethyl, not more than one of R1 and R2 is benzyloxy; and R4c is hydrogen, C1-3 alkyl, C1-2 alkoxy, fluoro or chloro;

in which R1 is hydrogen or C1-6 primary or secondary alkyl not having an asymmetric carbon atom and R2d is a primary or secondary alkyl which lacks an asymmetric carbon atom, or

R 1, R 2 and R 3 together are - (CH 2) 011 (2) -O-CH 2 - wherein Cl 2, 3, 4, 5 or 6; R1 is hydrogen, n-butyl, i-butyl, t-butyl, alkoxy in n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; R1 is hydrogen, alkyl in trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, alkoxy, with the proviso that not more than one of R2 and R3 is trifluoromethyl, not more than R2d and R 2 represents phenoxy and not more than one of R 2d and R 2d is benzyloxy; R1 is hydrogen, n-butyl, i-butyl, t-butyl, C1-4 alkoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy;

Rgd is hydrogen, alkyl in trifluoromethyl, fluoro, chloro, phenoxy, benzyloxy, alkoxy, with the proviso that not more than one of Rcd and Rgd is trifluoromethyl, not more than one of Rgd of Rgd is phenoxy and not more than one of R1 and R2 is benzyloxy;

R 4a is hydrogen, alkyl in fluoro or chloro alkoxy; 13

Ec

Sb in which each of R1, R2 and R3 are independently fluoro, chloro, hydrogen or alkyl in R1 and is preferably methyl;

14

in which R1 is C1 -C6 alkyl, which does not have an asymmetric carbon atom, each of R2, R3 and R4 is independently hydrogen, n-butyl, i-butyl, t-butyl, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenyl, phenoxy or benzyloxy; R1 and R2 are independently hydrogen, C1 -C4 alkyl, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy and each R1 and R2 are independently alkyl or C1 -C4 alkoxy; wherein R6 and R4 are trifluoromethyl, not more than one of R2 and R3 is phenoxy, not more than one of R2, R3, and f is benzyloxy, not more than one of R1 and R2 is trifluoromethyl, not more than one of the phenoxy and not more than one of R1 and R2 is benzyloxy; z > with the proviso that: (i) the free valency of the pyrazole ring is in the 4- or 5-position, and (ii) the group R4 is and the free valence is ortho to the other;

15 in which

Rag is a simple link to X; Rbg is R2g; Rcg is R4g;

Rdg is R4g and K is -N-; or: ilg

R9 is R6, R6 is a single bond to X, R8 is R2g, Rdg is R1, and K is O, S or -N-;

I

V R] _ > R 2g, R 2g and R 2g are independently C 1 -6 alkyl lacks an asymmetric carbon, cycloalkyl in η or phenyl substituted by R 2, R 3 and R 4, or in the case of R 2 and R 3 in addition to hydrogen, or for Râ,ƒ when Râ,, or X is Xâ € ²â € ²â € ‡ â € ‡ â € ‡ additionally Ga, and Râ, n-butyl, t-butyl, C1-4 alkoxy, i-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, bromo, i-butyl, phenyl, phenoxy or benzyloxy; each R g is independently hydrogen, trifluoromethyl, fluoro, chloro, bromo, phenoxy or benzyloxy; and each R1 is independently hydrogen, C1-12 alkyl, C1 -C2 alkoxy, fluoro or chloro, with the proviso that it may only be one of each of trifluoromethyl, phenoxy and benzyloxy, phenoxy and benzyloxy on each phenyl ring substituted by R5g, Rgg and R-yg; 16

R3h in which R1a is C1-6 alkyl having no asymmetric carbon, cycloalkyl in βg, β-adamantyl or phenyl substituted by R1, R2, R3 and R6; R4 is C1-6 alkyl which lacks an asymmetric carbon atom, adamantyl-1-cycloalkyl or phenyl substituted with R1, Rg and Rg; R4 is hydrogen, C1-6 alkyl having no asymmetric carbon atom, cycloalkyl, adamantyl-1, silyl or phenyl substituted by R1, R2 and R3 are each hydrogen, C1-4 alkyl, n-butyl, i-butyl, t-butyl, C ·-n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, bromo, phenyl, phenoxy or benzyloxy; each R4 is H, R8 and R4 is h. Independently, hydrogen, C1-4 alkyl; alkoxy in trifluoromethyl, fluoro, chloro, bromo, -COOR-, h, -NR1 R2, R3b, phenoxy or benzyloxy, wherein R4 is hydrogen, R4b or M, wherein R1 is n-butyl, t-butyl or benzyl, and M is as defined above, and each R4 is independently C1-6 alkyl which lacks an asymmetric carbon atom, and each symbol Rgh, Rg and R4 is independently hydrogen, C1 -C2 alkyl, alkoxy in fluorine or chlorine,

with the proviso that not more than one of the substituents of each phenyl ring is independently trifluoromethyl, no more than one substituent on each phenyl ring is independently phenoxy, and no more than one substituent on each ring phenyl is independently benzyloxy;

J

wherein each symbol and R1 is independently alkyl wherein it lacks an asymmetric carbon, cycloalkyl, or phenyl - (CH2) m- wherein m is 0, 1, 2, or 3 and the phenyl group is unsubstituted or substituted with any one of R 1, R 2 and R 2, in which R 1, R 2 and R 3 are as defined below; or R2d is -Yj-benzyl, -N (RQj) 2, or wherein Yj is -O- or -S-; each R 6 'is independently alkyl wherein it lacks an asymmetric carbon atom or may form part of a 5-i- or 7- unbranched ring J b, the ring J b being substituted or unsubstituted and optionally also contains one or more heteroatoms ; and Ja is Ja 'or Ja', where

Ja 'is a heterocyclic group which is unsubstituted or substituted by one or two C1-4 alkyl groups

(A) in which is hydrogen, C1-4 alkyl, n-butyl, i-butyl, t-butyl, C1-4 alkoxy, i-butoxy, i-butoxy, trifluoromethyl, fluoro chloro, phenoxy or benzyloxy and R 1a is hydrogen, C 1-2-alkyl, fluorine or chloro-alkoxy; R 2 is hydrogen, C 1 -6 -alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; with the proviso that not more than one of R1 and R4 is trifluoromethyl, not more than one of R1 and R3 is phenoxy and not more than one of R1 and R3 is benzyloxy ; 19 19

in which each R1-R2 and Rk is independently (a) phenyl substituted by R1, R2 and R3 in which R1 is hydrogen, n-butyl, i-butyl, t-butyl, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy;

Rk é is hydrogen, C alquilo alquilo ,alkyl, fluoroalkoxy, or chloro; and R y and R é are hydrogen, C_ alquilo »alkyl, C alco alco alcoalkoxy, and C_ »alcoalkoxy; fluorine or chlorine, (b) is hydrogen or a primary or secondary C1-6 alkyl group which does not contain an asymmetric carbon atom; (c) cycloalkyl in or (d) phenyl- (CH2) m-, wherein m is 1, 2, or 3;

In which Y 1 is -N = i V is Rpl is a)

R1 is t-butyl, alkoxy in n-butoxy, i-butyloxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy;

Rgl is hydrogen, alkyl in alkoxy in C1-4 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy, benzyloxy; with the proviso that not more than one of R1 and R2 is trifluoromethyl, not more than one of R1 and R1 is phenoxy, and not more than one of R1 and R2 is benzyloxy;

R1 is hydrogen, alkyl in alkoxy in

Cj_2 > fluorine or chlorine, b) primary or secondary C_ alquilo ,alkyl which lacks an asymmetric carbon atom, c) C ciclo ciclo ciclocycloalkyl or d) phenyl- (CH₂) j- wherein m is 1, 2 or 3;

R4m 21 21

in which R 1 is C 1 -6 alkyl, which lacks an asymmetric carbon atom, (C 1 -C 6) cycloalkyl, phenyl-, pyridyl-2, pyridyl-3, pyridyl-4, thienyl-2, thienyl R 2 and R 3 are independently selected from the group consisting of C 1 -C 4 cycloalkyl, C 1 -C 4 cycloalkyl, C 1 -C 4 cycloalkyl, C 1 -C 4 cycloalkyl, Pyridyl-2-pyridyl-3-pyridyl-4, thienyl-3 or phenyl substituted by R1, R2, R3, R9, R9, R9, R9 and R10 are as defined above, with the proviso that not more than one of R1 and R2 is a member of the group consisting of pyridyl-2, pyridyl-3, pyridyl-4, thienyl-2, thienyl-3, phenyl substituted by R 1 -m, R 2 and m is phenyl substituted by R 2m, R 2, m, and R1 is alkyl in g which does not have an asymmetric carbon atom, cycloalkyl or phenyl substituted by R1, R2, R3 and R4 is R4-alkyl which does not contain a carbon atom, cycloalkyl, or phenyl substituted by R1-m, R15m and R16m; and R4, R6, R4, R4 and R4 are each independently hydrogen, C1-4 alkyl, alkoxy in β, trifluoromethyl, n-butyl, i-butyl, t-tubyl, n-butoxy, i-butoxy, fluoro, chloro, bromo, phenyl, phenoxy or benzyloxy, each of R1, R2, independently, hydrogen, C ??? alkyl, C1-4 alkoxy > trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, and

R m, R m, R m and Rm are independently hydrogen, C alquilo alquilo alquilo alkyl, C ??? alkoxy > or chloro, with the proviso that not more than one of the substituents of each phenyl ring is independently trifluoromethyl, no more than substituent at each phenyl ring is independently phenoxy, and not more than one substituent in each phenyl ring is independently benzyloxy,

Rn

V wherein each of R1, R2 and R3 is independently alkyl of 1 to 4 carbon atoms; or phenyl, which may be substituted by either one or two alkyl or alkoxy groups of 1 to 3 carbon atoms, or chloro; or may be a fluoro, bromo or trifluoromethyl substituent; R4n is hydrogen or alkyl of 1 to 3 carbon atoms; for example methyl; R4n is hydrogen, lower alkyl or alkoxy; halogen, trifluoromethyl; or phenyl, benzyl, or benzyloxy, wherein the aromatic moiety may be unsubstituted or substituted by up to 2 groups, one of which may be

fluoro, bromo, or trifluoromethyl; or one or two of them may be lower alkyl or alkoxy, or chloro; R1 is hydrogen, lower alkyl or alkoxy, halogen or trifluoromethyl; and R4n is hydrogen, lower alkyl or alkoxy, halogen or trifluoromethyl; and any one of R3, R4, R4, R4, R4, R4, R4, R4, R4, R4, ) to form a ring which is substituted with Rgn which is hydrogen; halogen, or lower alkyl or alkoxy; provided that there is no more than one trifluoromethyl group and that there are no more than two bromo substituents in the molecule.

The compounds of formula I may be divided into thirteen groups ie IA to IN groups, depending on the meaning of the symbol R, i.e.: when R = A, IB when R = B, IC when R = c, ID when R When R = Ea, Eb or Ec, IF when R = F, IG when R = G, IH when R = H, IJ when R = J, IK when R = K, IL when R - 1, IM when R = M, and IN when R = N. 24 24

3. Stereochemistry

Generally, when a hydroxy keto compound of formula II is reduced to give a dihydroxy compound of formula I, an additional center of asymmetry is provided. Accordingly, when a racemic compound of formula II is used, four enantiomers of the resulting compound of formula I (comprising two pairs of enantiomers, i.e. a pair of erythro enantiomers and a pair of threo) are formed. Alternatively, when an optically pure compound of formula II is used, two diastereoisomers of the compound of formula I (i.e., an erythro isomer and another threo) are formed, for example the 3R, 5S and 3S, 5S diastereoisomers which result from the reduction of the hydroxyl compound 5S. The diastereoisomers can be separated by conventional methods, such as by fractional crystallization, column chromatography, preparative thin-layer chromatography or HPLC (High Pressure Light Chromatography). The ratio of the erythro isomers to threo by these methods is normally variable and can be, for example, greater than about 9S: 1.

With the stereoselective process of the present invention, when a racemic compound of formula II is used, only almost two stereoisomers of the resulting compound of formula I (comprising the erythro pair of the enantiomers) are formed. Alternatively, when an optically pure compound of formula II is used, only one enantiomer of the compound of formula I is almost exclusively formed, and this is the corresponding enantiomer erythro. For example, the 3R, 5S enantiomer results from the reduction of the 5S hydroxy compound, wherein X is -CH = CK-. The ratio of the erythro isomer to the threo obtained with the process of the present invention is about 99.1: 0.9, or even higher, especially about 99.7: 0.3 or more.

The term " stereoselective " as used herein means that the ratio of erythro enantiomers to threo is 99.1: 0.9 or higher.

The stereoisomers of the compound of formula I, wherein X is -CH.dbd.CH-- according to the invention are the 3R, 5S and 3S, 5S isomers and the racemic mixture consisting of both, the racemic mixture of the 3R isomer , 5S.

The stereoisomers of the compounds of the formula I, wherein X is -CH 2 CH 2 -, according to the present invention are the 3R, 5R and 3S, 5S isomers and the racemic mixture which comprises both, of which the 3R, 5R isomer and racemic mixture, 4. STATE OF THE ART

Conventional processes for the reduction of the keto group of a compound of formula II have used mild reducing agents such as sodium borohydride or a t-butylamine complex and borane in an inert organic solvent such as an α-canol to give a mixture of diastereoisomeric forms from optically pure initiation compounds, or alternatively, from the racemic diastereomers from the racemic initiation material.

A stereoselective three-phase reduction process has been used to obtain the erythro-racemic compound predominantly from the racemic initiation material. In the first step, a compound of formula II is reacted with a trialkylboron compound or a compound of formula III: in which is allyl or lower alkyl having one to four - 26

preferably a non-tertiary carbon, and is a primary or secondary alkyl having 2 to 4 carbon atoms, preferably non-tertiary, in a reaction medium comprising an alcohol and tetrahydrofuran (THF). In a second step of such a process, sodium borohydride (NaBH 4) is added to the reaction medium, and the reaction proceeds with the reduction of the keto group to form the cyclic boronate or a borane complex of the compound of formula I. In the third step, the reaction mixture containing the boron complex and / or the cyclic boronate ester is azeotroped with methanol and ethanol, or alternatively, treated in an organic solvent with an aqueous peroxy compound, such as a peroxide, for example hydrogen peroxide , or a perborate, for example sodium perborate, to give the resulting compounds of formula I. The above-mentioned process is said to provide an erythro racemate with, for example, about 98% relative selectivity for the threo isomers The method of the present invention comprises a method for stereoselective reduction of optical compounds pure derivatives of the formula II to obtain almost exclusively the erythro isomers of formula I. Advantageously, the reduction of the keto group of the compound of formula II occurs virtually instantaneously. The compounds of formula I, that is the erythro isomers, are further increasing the chemical purity and can be further enriched to about 99% by chemical purity by simple recrystallization.

According to a first step of the process of the present invention,

(a), a compound of formula III is mixed with sodium borohydride NaBH4 in a reaction medium, which comprises an alcohol and tetrahydrofuran.

In a second step / Step (b) 7 > The compound of formula II is treated with the mixture obtained in step (a) under suitable conditions to obtain a mixture containing a cyclic boronate compound of formula IV (a)

(A) and / or a boron complex of the formula IV (b) wherein R 1, R 2, R 3, R 4,

B /\

OH

Zlv (b27

Wherein R 1, R 2, R 3 and X are as indicated above. The last is the predominant, before temperament. However, tempering converts the boron complex into a boronate ester.

In a third step / step (c), the product obtained in step (b) is cleaved to give a corresponding compound of formula I. Step (a) is preferably carried out under essentially anhydrous conditions, preferably in an inert atmosphere, 28

in a temperature range of from about -100Â ° C to about -78Â ° C, preferably from about -20Â ° C to about -60Â ° C, especially from about -78Â ° C to about -70Â ° C. The reaction medium used in step (a) comprises a mixture of alcohol and tetrahydrofuran, wherein the alcohol is represented by the formula alkylOH, wherein the alkyl has 1 to 4 carbon atoms, for example methyl, or ethyl, preferably non-tertiary .

One of the products of step (a) may be R OHOH, derived from the compound of formula III used. However, it is not necessary that all or a portion of the alkyl be the same as R3. The sodium borohydride should generally be present at least in an equimolar amount with the compound of formula II, and preferably in a slight excess, such as for example about 1.1: about 1.5: 1 moles of NaBH4, per mole of cetone, and preferably 0.7: 1 to about 1.5: 1 moles of borane compound per mole of ketone. Step (b) is also preferably carried out at reduced temperatures, the internal temperature being maintained at about -100Â ° C to about -40Â ° C, especially in the range of about -78Â ° C to about -70Â ° C. Preferably the compound of formula II is preferably in a solvent with the alcohol THF or THF. The reaction medium of step (a) and the solvent of the compound of formula II, which is added in step (b), are selected to provide a combined medium, wherein the ratio (v / v) of alcohol to tetrahydrofuran is from about 1: 3 to about 1: 6, especially about 1: 3 to about 1: 4. The reduction of the ketone group is exothermic and occurs rapidly, and consequently the addition of the keto compound is in phases , desirably in order to maintain an internal temperature in the range of about -78 ° C to about -70 ° C. The reduction is almost instantaneous and the reaction mixture is then quenched by adding, e.g. of aqueous sodium bicarbonate, ammonium chloride or

acetic acid, whereby a mixture of the desired cyclic boronate is obtained.

In step (c) the reaction product of step (b) may be azeotroped with methanol or ethanol, for example a temperature range of about 60Â ° C to about 80Â ° C, under essentially anhydrous conditions. Alternatively and preferably, particularly when X is -CH = CH-, the product after being neutralized by the addition of sodium bicarbonate (NaCl) is dissolved in an organic solvent, for example ethyl acetate, and treated with hydrogen peroxide (for example 30%) or aqueous sodium perborate (NaB40), initially at reduced temperature, for example at about + 10 ° C, then being allowed to warm to a moderate temperature, for example in the temperature range of about 20Â ° C to about 30Â ° C, to provide the corresponding compound of formula I.

Alternatively, the cyclic boronate ester of step (b) may be extracted with an organic solvent such as ethyl acetate and then treated directly with an aqueous solution of a peroxy compound, such as 30% aqueous hydrogen peroxide or a solution of sodium perborate, to give the corresponding compound of formula I.

As far as practicable conditions of reduction occur in the practice of the invention, it is understood that any substituents or radical functions used as R3 will be inert, i.e., will be free of substituents or functions, which would be reactive or susceptible to change under such conditions, e.g. by known techniques to mask or protect such functions or to introduce them at a later stage. The compounds of formula I, the corresponding lactones, salts and free acids, processes for the conversion of

in which it has no meaning in the corresponding compound and in which they have the different meaning and / or in the corresponding < 5-lactone or exempt salts and acids.

The compounds of formula I may, if desired, be converted by conventional techniques into salts and corresponding free acids, i.e., wherein R4 is substituted by hydrogen or a cation, such as an alkali metal or ammonium cation, : sodium or potassium and especially sodium, in other forms esters, or other corresponding β-lactones, i.e. internal esters. As mentioned above, the compounds of formula I, obtained according to the process of the invention are pharmaceuticals. In another embodiment, however, the || The process of the invention may also be applied to the preparation of chiral intermediates of, for example, formula Iu - CH 2 CHCH 2 CHCH 2 --COORU (Iu)

Wherein u is triphenyl-methyl (trityl) and

Ru is allyl or a radical which forms an inert ester under reaction conditions, preferably allyl or alkyl in n-butyl, i-butyl, t-butyl, or benzyl, especially t-butyl, by stereoselective reduction, or a racemic derivative of the formula wherein R 1, R 2, R 2, R 2, R 2, R 2, 2 u in which

u, R 2, Z 2 and Z 2 are as defined above.

Such chiral intermediates are disclosed, for example, in European Patent Specification 244 364. These are indicated for use in the preparation of pharmaceuticals. 6. Materials to be started

The (alkoxy in primary or secondary or allyloxy) -di- (C2-C4) alkyl oranes of formula III used as starting materials in the process of the present invention are known. poster et al, Ann. (1975), 352; Chem. et al., Tetra-hedron Letters 28, 155 1987); and Chem. Chem., et al., Chemistry, (1987), 1923-192. However, these may be prepared in situ from the corresponding primary or secondary tri- (C1-4 alkyl) boranes by reacting them with an alkali metal in primary or secondary or an allyl alcohol, the concentration of the former in the latter being preferably from about 0.2M to about 1.2M, especially about 0.5M.

Compounds of formula II are known or may be prepared analogously to the known compounds of formula II, for example as described in U.S. Pat. 4 739 073 (for example, for Z 2 = oxygen) or in the European Patent ... 215 785 (for example, for Z 2 = oxygen).

Thus, compounds of formula II, wherein Z 2 is oxygen, are usually prepared by the reaction of a compound of formula V

R-X-CHO in which R and X are as defined above, (V)

with the dianion of a compound of formula VI in which R 1 is as defined above. 7. accomplishments that are referred to the first intermediaries

The compounds of formula V and VI are also known. In other embodiments, however, the present invention also comprises a novel process for the preparation of a subgroup of compounds of formula V, namely compounds of formula Va

in which R3 is hydrogen, C1-3 alkyl, n-butyl, i-butyl, t-butyl, C3-6 cycloalkyl, < / RTI > n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy, benzyloxy

R g is hydrogen, C1-3 alkyl, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; with the proviso that not more than one of R1 and R2 is trifluoromethyl, not more than one of R1 and R2 is benzyloxy; z > one of Ry and Rg is phenyl trisubstituted with Rg,

R 10

and R 11 and R 11 and R 11 and R 11 are independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkenyl,

R é is hydrogen, C alquilo alquilo ,alkyl, trifluoromethyl, trifluoromethyl, chloro, phenoxy or benzyloxy; R10 is hydrogen, C1-3 alkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy;

R3 is hydrogen, C1-3 alkyl, 2-fluoroalkoxy, chloro, and m is 1, 2 or 3; with the proviso that not more than one of R1 and R2 is trifluoromethyl, not more than one of R1 and R2 is phenoxy and not more than one of R1 and R2 is benzyloxy; starting the reaction from a subgroup of formula VII (E) -OHC-CH = CH-N (R 12) R 13 (VII) in which

R2 is C1-4 alkyl, phenyl or phenyl substituted by 1 to 3 substituents each of which is independently C1-3 alkyl, C1-3 alkoxy, fluoro, chloro, bromo or nitro with up to two nitro groups; and R3 independently has the abovementioned meaning for R12 'as well as a novel process for the preparation of the compounds of formula VII itself.

The process for the preparation of the compound of formula VII is hereinafter referred to as " process A " and the process for the preparation of the compounds of formula Va is hereinafter referred to as " process B ".

The compounds of formula Va, VII and XVII (see 7.2) are known from, inter alia, US Pat. No. 4,999,073, which discloses the compounds of formula VII, wherein is alkyl in and for use in the synthesis of compounds of formula Va, compounds of formula XXII, and their use of compounds of formula Va in the synthesis of indoles analogues to valonolactone and derivatives thereof, which are indicated for use as inhibitors of reductase HMG-CoA. Because they inhibit the synthesis of cholesterol, they lower the cholesterol level in the blood and are therefore indicated for use in the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.

The compounds of formula VII and their synthesis are also disclosed in British Patent Specification No. 945 536 and in the Czech-Slovak patent N5. 90 045. However, the process disclosed herein differs from process A with respect to, for example, the use of phosgene or phosphorus trichloride, phosphorus pentachloride or phosphorus oxychloride instead of an oxalic acid derivative. 7.1. Process A (Preparation of Compounds of Formula VII) The process for the preparation of compounds of Formula VII (Process A) which comprises

(i) reacting a compound of formula VIII

OHC-N (R 12) R 13 (VIII)

in which R1 and R2 are as defined above, with a compound of formula IX

Xa-CO-CO-Xa (IX)

in which Xa is a leaving group monovalent, optionally in an inert anhydride organic medium, to form the corresponding compound of formula X

Xa -CH = N + (R 12) Ri 3 (X) in which X 1, R 2 and R 3 are as defined above,

(ii) reacting the compound of formula X with a compound of formula XI

(XI) in which R4 is a monovalent group which does not deactivate the oxygen atom to which an inert anhydride organic medium is optionally attached to form a compound corresponding to formula XII (E) - (XII) (iii) by hydrolyzing this compound of formula XII there is obtained a corresponding compound of formula VII in the form of an acid addition salt or free base and, if the acid addition salt is obtained, said base salt is neutralized.

In a variant of process A, step (iii) can be dispensed by directly using a compound of formula XII in, for example, process B.

Steps (i) and (ii) may be carried out simultaneously or carrying out step (ii) after performing step (i); step (iii) follows step (ii) and step (iv) (see below), when applied, follows step (iii).  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒwherein R1a2a in independently C1-4 alkoxy were fluorine, chlorine, bromine or nitro with up to 2 nitro groups). R12a is preferably C1 to C12 alkyl, preferably methyl. R 12b is preferably phenyl or phenyl substituted by 1 or 2 substituents, each of which is independently C 1-12 alkyl or C 1-12 alkoxy, and R? > wherein R12b " Phenyl or phenyl substituted by 1 or 2 methyl groups, and preferably phenyl. is preferably C 12 alkyl, preferably methyl. R ^ is preferably alkyl in g, preferably primary or secondary C₂ alquilo, alkyl, more preferably n-C em em oualkyl or n -butyl.

Each Xa is preferably chlorine or bromine, especially chlorine. Each Xaa symbol represents chloride or bromide, especially chloride. The base used in the hydrolysis or neutralization of step (iii) is preferably an inorganic base

such as sodium carbonates, potassium carbonate, sodium hydroxide or potassium hydroxide, with sodium carbonate or potassium carbonate being preferred.

The preferred reaction conditions for process A are as follows:

Stage (i) / When carried out prior to step (i / 7) Temperature: -20 ° to + 50 ° C Time: 1.5 hours to 5 hours.

Reaction medium: liquid halogenated lower alkane, for example 1,2-dichloroethane and methylene chloride; or acetonitrile; with methylene chloride and acetonitrile being preferred.

Mole ratio of the reactants: 1 to 1.5 moles of the compound of formula IX per mole of the compound of formula VIII

Phase (ii) / When performed after step (i / 7:

Temperature: 10 ° to 60 ° C, preferably 10 ° to 40 ° C

Time: 0.5 to 3 hours

Reaction medium: the same as for step (i)

Mole ratio of the reactants: 1 to 1.5 moles of the compound of formula XI per mole of the compound of formula VIII, used in step (i)

Phase (i) and (ii) / When carried out simultaneously7: Temperature: -15 ° to + 35 ° C Time: 2 to 6 hours

Reaction medium: same as that of step (i) when carried out before step (ii)

I

Mole ratio of the reactants: 1 to 1.5 moles of the compound of formula IX and 1 to 1.5 moles of the compounds of formula XI per mole of the compound of formula VIII

Step (iii):

I

Temperature: 0 ° to 65 ° C

Time: 0.5 to 3 hours

Reaction medium: water or a mixture of water and the reaction medium used in step (ii)

Mole ratio of the reactants: 2 to 4 equivalents of the base per mole of the compound of formula IX used in step (i). It is preferred to carry out the hydrolysis of step (iii) with a base. The reaction medium for steps (i) and (ii) may, alternatively and preferably, be pure reagents, i.e., reactants with no solvent, i.e. for step (i) the compounds of formulas VIII and IX and for step (ii) the compounds of formulas X and XI. This is very advantageous from an ecological point of view since the presence of solvents such as acetonitrile in the waste water and the emission of steam eg methylene chloride into the atmosphere is avoided. The compounds of formulas VIII and IX may be reacted in the absence of solvent as they do not form a solid block when mixed but surprisingly form a suspension. Process A may be divided into two sub-processes depending on the meanings of R 1 and R 2 and R 1 and R 2 are independently C 1 -C 4 alkyl; (subprocess Aa) and -L- is other (2) At least one of R 1 and R 2 39

than a C1-3 alkyl

The product of step (iii) of subprocess Aa often comprises an appreciable amount of the compound of formula XIII (XIII)

Wherein R 1 is as defined above, which corresponds to the obtained compound of formula VII, the molar ratio of the compound of formula VII to the compound of formula XIII, typically being from about 2 : Obviously, while it is possible to separate the compound of formula VII from that of formula XIII by conventional separation techniques, it is preferred to subject the product of step (iii), ie the crude compound of formula VII (iv) treatment of a crude mixture comprising the compound of the formula (VII): (iv) treating the compound of formula VII with the compound corresponding to formula XIII) to step (iv), i.e. R 12a) R 13 (A)

in which R 2a and a are as defined above, with the corresponding compound of formula XIV in which R 1 and R 2 are defined above, to convert any compound present formula XIII in the additional compound of formula VIIa.

Preferred reagents for sub-process Aa are those in which: (a) R12a is alkyl at 0-21;

C2-6 alkyl is a primary or secondary alkyl; each Xa is chloro, and each symbol Xa - represents the chloride ion; (b) is equal to (a) but wherein R 14 is a C 1-6 alkyl; (c) equal to (b) but wherein * 14 is methyl, is methyl, and

R1 is ethyl; (d) - (f) equal to (a) - (c) but wherein the base used in step (iii) is sodium carbonate or potassium carbonate; (g) - (i) equal to (d) - (f) but wherein the base used in step (iii) is potassium carbonate.

Preferred reaction conditions for sub-process Aa, particularly where the reactants are those of subgroups (a), (d) and (g), and in particular when belonging to subgroups (b). (e) and (h) and especially when these are included in subgroups (c), (f) and (i), are:

Step (i):

Temperature: 0 ° to 20 ° C; 0 ° to 15 ° C, more preferred at 5 ° to 15 ° C.

Time: 1.5 to 4 hours

Reaction medium: liquid halogenated lower alkane or acetonitrile, or the pure reactants; with methylene chloride and pure reagents being preferred.

Mole ratio of the reactants: 1 to 1.2 moles of the compound of formula IX per mole of the compound of formula VIII, with 1.1 being preferred

1.2 moles of the compound of formula IX per mole of the compound of formula VIII;

Step (ii):

Temperature: 25 ° to 40 ° C

Time: 0.7 to 2.5 hours

Reaction medium: the same as step (i)

Mole ratio of the reactants: 1 to 1.2 moles of the compound of formula XI per mole of the compound of formula VIII used in step (i); 1.1 to 1.2 moles of the compound of formula IX being preferable per mole of the compound of formula VIII;

Step (iii):

Temperature; 20 ° to 65 ° C, preferably in the range of 20 ° to 30 °

Time: 0.75 to 2 hours

Reaction medium: aqueous

Mole ratio of the reactants: 2 to 4 equivalents base per mole of the compound of formula IX, used in step (i);

Step (iv):

Temperature: 0 ° to 20 ° C, preferably 10 ° to 20 ° C Time: 0,3 to 1 hour

Reaction medium: alkanol in 0 - 4% methanol (4% methanol)

Mole ratio of the reactants: 0.15 to 1 mole of the compound of formula XIV per mole of the compound of formula VIII used in step (i), preferably 0.15 to 0.4 mole of the compound of formula XIV per mole of the compound of formula VIII. In a subprocess Aa, step (ii) is preferably performed after step (i).

Preferably, the subprocess Aa comprises the steps of: (i) reacting Î ±, β-dimethylformamide (compound of formula VIII in which R1 and R2 are methyl) with oxalyl chloride (compound of formula IX wherein Xa is chloro) pure or in methylene chloride at a temperature in the range of 0 ° to 15 ° C to form a compound of formula Xa

(Ii) reacting the compound of formula Xa with ethyl vinyl ether (compound of formula XI in which R 2 is ethyl) pure or in chloride of methylene at a temperature of 25Â ° C to 40Â ° C to give the compound of formula Xlla (E) - C2H50 - CH = CH - CH = N + (CH3) 2Cl (XaI) (iii) hydrolysis of compound of formula XIIa with potassium carbonate in an aqueous medium at a temperature

(E) -OHC-CH = CH-N (CH 3) 2 (Vllaa) and of the formula X 1 -IIa ( (Iv) treating the compounds of the formulas Vllaa and Xaaa with dimethylamine (compound of formula XIV, in which R1a and a represent methyl) are treated in methanol at a temperature in the range of 10 to 20 ° C to convert the compound of formula XIIIa to an additional compound of formula Vlaa.

Preferably, in a subprocess Aa: (1) the molar ratio of oxalyl chloride to N, N-di-methylformamide in step (i) is in the range of 1: to 1.2: 1, and step (i) is carried out by adding oxalyl chloride to neat N, N-dimethylformamide or in a solution in methylene chloride over a period of 1.5 to 4 hours at a rate such that the temperature is maintained at a temperature in the range range between 5 ° and 15 ° C; (Ii) in step (ii) the molar ratio of ethyl vinyl ether to Ν, Ν-dimethylformamide used in step (i) is in the range of 1: 1 to 1.2: 1, and step (ii) is carried out by the addition of ethyl vinyl ether to the reaction mixture over a period of from 0.4 to 1.5 hours at a rate such that the temperature does not exceed 30 ° C and, after the addition has been completed, sub The reaction mixture is refluxed at a temperature in the range of 35 ° to 40 ° C for 0.3 to 1 hour, and if indicated by removing methylene chloride to a temperature not exceed 45 ° C; (3) in step (iii) the molar ratio of potassium carbonate to the oxalyl chloride used in step (i) is in the range of 1: 1 to 2: 1, and step (iii) is carried out by addition of water to the product obtained in step (ii) stirred at a temperature in the temperature range of 20Â ° to 30Â ° C, allowing the temperature to rise to about 45Â ° to 60Â ° C, equilibrium addition of water and for an additional period of 0.3 to 1.25 hours, the mixture is extracted with methylene chloride and any methylene chloride is distilled as possible at a temperature not exceeding (4) in step (iv) the molar ratio of dimethylamine to N, N-dimethylformamide used in step (i) is in the range of from 0.15: 1 to 0.4: 1, and phase (iv) is carried out by the addition of anhydride dimethylamine to a solution of the phase product (iii) in stirred methanol at a temperature range of 10Â ° to 20Â ° C at such that the temperature does not exceed 20 ° C and the solvent and excess dimethylamine is distilled at a temperature not exceeding 120 ° C.

Preferred reagents in the sub-process Ab are those (a) wherein R12b is a primary or secondary C1-4 alkyl, each Xa is chloro, and each Xa- is chloride; (b) is equal to (a) but wherein R 1 -

C,

(c) is equal to (b) but in which it is phenyl, is methyl, and is methyl or n-butyl, especially n-butyl; (d) is the same as (a) - (c) but wherein the base used in step (iii) is sodium carbonate or potassium carbonate, and (g) - (i) - (f) but wherein the base used in step (iii) is sodium carbonate.

The preferred reaction conditions for the subprocess Ab, particularly where the reactants are those belonging to the subgroups consisting of (a), (d) and (g), and more specifically when they are those comprised in subgroups (b), ) and (h) and especially when they belong to subgroups (c), (f) and (i), are:

Step (i) / when performed before step (iij_7:

Temperature: -20 ° C to + 45 ° 0 Time: 1.5 to 5 hours

Reaction medium: liquid halogenated lower alkane or acetonitrile; methylene chloride and acetonitrile being preferred; acetonitrile being preferred; or dropping preferences over pure reagents;

Molar ratio of the reactants: 1 to 1.2 moles of the compound of formula IX per mole of the compound of formula VIII, the range of 1.1 to 1.2 moles of the compound of formula IX per mole of the compound of formula VIII being preferred;

Step (ii) / when carried out after step (i / 7: 46

Temperature: 10 to 40 C Time: 0.5 to 3 hours

Reaction medium: identical to step (i)

Mole ratio of the reactants: 1 to 1.3 moles of the compound of formula XI per mole of the compound of formula VIII used in step (i); 1.1 to 1.25 moles of the compound of formula XI per mole of the compound of formula VIII being preferred;

Phases (i) and (ii) / when performed simultaneously: Temperature: -15 ° to + 35 ° C Time: 2 to δ hours

Reaction medium: equal to that of step (i) when carried out before step (ii)

Mole ratio of the reactants: 1 to 1.5 moles of the compound of formula IX and 1 to 1.5 moles of compound XI per mole of the compound of formula VIII;

Step (iii):

Temperature: 0 ° to 35 ° C, the range of 0 ° to 30 ° C being preferred

Time: 0.5 to 1.5 hours

Reaction medium: mixture of water and reaction medium from step (ii)

Reagent molar ratio: 2 to 4 equivalents base 47

t per mole of the compound of formula IX used in step (i).

There are three preferred variants of the Ab subprocess, namely the Abl, Ab2 and Ab3 variants. In the Abl variant, the symbol is ethyl and the reaction medium for steps (i) and (ii) is methylene chloride or, preferably, the pure reagents; and in the variants Ab 2 and Ab 3, the symbol is n-butyl and the reaction medium for steps (i) and (ii) is acetonitrile or preferably the pure reactants. In variants Abl and Ab2, step (ii) is carried out after step (i) and in variant Ab3 steps (i) and (ii) are performed simultaneously; in each variant, step (iii) follows steps (i) and (ii). The Abl variant of the sub-process Ab preferably comprises (i) reacting N-methylformanilide (compound of formula VIII in which R 1 is phenyl and R 4 is methyl) with oxalyl chloride (compound of formula IX, which Xa is chloro) pure or in methylene chloride at a temperature range of 15 ° to 45 ° C, to give the compound of formula Xb

Cl-CH = N + (C 1 -Hc) CH. Cl " (Xb) or (ii) reacting the compound of formula Xb with ethyl vinyl ether (compound of formula XI in which ethyl is pure) or in methylene chloride at a temperature in the range of 15 ° to 40 ° C to give the compound of formula Xlll (E) - C 2 H 50 - CH = CH-CH = N + (C 6 H 5) CH 3 Cl " (XIII) (iii) hydrolyzing the compound of formula Xllbl with 48

sodium carbonate in a mixture of methylene chloride and water at a temperature in the range of 20Â ° to 30Â ° C, to give the compound of formula Vllb (E) - CH = CH = IT (C 6 H 5) CH 3 (VIIb)

The molar ratio of oxalyl chloride to N-methyl-formanilide in step (i) is in the range of: 1 to 1.2: 1, and step (i) is carried out with the addition of oxalyl chloride to N-methylformanilide, pure or as a solution in methylene chloride, at a temperature in the range of 15 DEG-202 DEG C., for a time period of 1 to 2 hours and, after the addition has been completed, gradually raising the temperature to a temperature in the range of 40Â ° C to 45Â ° C, for a time interval of 0.75 to 1.25 hours and then refluxing it for 0.75 to 1.25 hours; (2) In step (ii) the molar ratio of ethyl vinyl ether to N-methylformanilide used in step (i) is from 1 to 1.3: 1, and step (ii) is carried out by cooling the product obtained in step (i) to a temperature in the range of 152 DEG to 202 DEG C., by adding ethyl vinyl ether, for a time period of 0.5 to 1.5 hours at a rate such that the temperature does not exceed 30 DEG C. , after the addition has been completed, the reaction is refluxed for 0.3 to 0.7 hours, and 1

In step (iii) the molar ratio of sodium carbonate

for the oxalyl chloride used in step (i) is in the range of 1: 1 to 1.2: 1, and step (iii) is carried out by cooling the product of step (ii) to a temperature in the range of 15 ° at 20 ° C by adding over 0.5 to 1 hour an aqueous solution of sodium carbonate at such a rate such that the temperature of the reaction mixture is in the range of 202 to 30 ° C , for a period of 0.2 to 0.5 hour, allowing the mixture to separate into two phases, separating the phases and recovering the product from the organic phase. The Ab2 variant of sub-process Ab preferably comprises (i) N-methylformimilylide is reacted with neat oxalyl chloride or in acetonitrile at a temperature in the range of -20 ° to + 202 ° C to give a compound of formula Xb ( ii) reacting the compound of formula Xb with pure n-butyl ester (compound of formula XI, wherein n is n-butyl) or acetonitrile at a temperature in the range of 102 DEG to 40 DEG C. (XIIb) and (iii) hydrolyzing the compound of formula XIIb2 with sodium carbonate in a compound of formula XIIB2 (E) mixing acetonitrile and water at a temperature in the range of O 2 at 25 ° C to give the compound of formula VIIb.

The molar ratio of oxalyl chloride to N-methyl-formanilide in step (i) is in the range of 1: 1 to 1.2: 1, and phase (1) is preferred. i) is carried out by adding oxalyl chloride to the pure N-methylformanilide or in solution in acetonitrile at a temperature in the range of-132Â ° C to 8Â ° C for a period of 1 to 2 hours, and after addition is complete, the temperature of the reaction mixture gradually increasing until it is in the range of 122 to 20Â ° C for a period of from 0.4 to 0.75 hours and stirring it for a period of time from 0.2 to 0.4 hour at this temperature ; (2) In step (ii) the molar ratio of vinyl n-butyl ether to N-methylformanilide used in step (i) is from 1: 1 to 1.2: 1, and step (ii) is brought to by adding n-butyl vinyl ether to the product of step (i) stirred at a temperature in the range of 122 to 20Â ° C for a period of 0.5 to 1.5 hours at a rate such that the temperature does not exceed 30Â ° C, and , after the addition was complete, stirring the additional mixture for 0.3 to 0.7 hours at a temperature in the range of 25 ° to 35 ° C; In step (iii), the molar ratio of the sodium carbonate to the oxalyl chloride used in step (i) is from 1: 1 to 1.3: 1, and step (iii) is carried cooling the product of step (ii) to a temperature in the range of 0 DEG to 5 DEG C., adding for 0.5 to 1.2 hours an aqueous solution of sodium carbonate at a rate such that the temperature of the reaction mixture is in the range of 52 to 122 ° C and, after the addition has been completed, adding toluene, the mixture being stirred at a temperature in the range of 152 to 25 ° C for 0.2 to 0.5 hours, allowing the mixture to separate into two phases and removing the product from the organic phase. The Ab3 variant of sub-process Ah preferably comprises: (i) and (ii) X-methylformanilide is reacted with pure oxalyl chloride or in acetonitrile at a temperature in the range of -102 to + 30 ° C in the presence of ether to give the compound of formula Xb, which compound then reacts with n-butyl vinyl ether in the reaction mixture to provide the compound of formula XIIb2, and (iii) hydrolyzing the compound of formula XIIb2 with sodium in a mixture of acetonitrile and water at a temperature of O 2 at 25 ° C to give the compound of formula VIIb.

More preferably, in an Ab3 variant of the subprocess Ab, (1) Xas phases (i) and (ii), the mole ratio of oxalyl chloride of n-butyl vinyl ether to N-methylformanilide is in the range of 1: 1 and steps (i) and (ii) are carried out by adding a solution of pure N-methylformanilide and butyl n-vinyl ether in acetonitrile to the pure oxalyl chloride or in solution in stirred acetonitrile a a temperature in the range of -102 ° C to + 102 ° C for a period of 2 to 3 hours and after the addition has been completed by gradually raising the reaction temperature to a temperature in the range of 202 to 30 ° C over a period of 0.4 for 1.5 hours and then stirring the reaction mixture at this temperature for 0.5 to 1.5 hours; and (52

(2) In step (iii), the molar ratio of the sodium carbonate to the oxalyl chloride used in step (i) is in the range of 1: 1 to 1.3: 1, and step (iii ) is carried out by cooling the product of step (ii) to a temperature in the range of from 00 to 590, adding, for a period of 0.5 to 1.2 hours, in an aqueous solution of sodium carbonate at such a rate that the temperature of the reaction mixture is in the range of 0Â ° to 12Â ° C and, after the addition has been completed, adding toluene, stirring the mixture to separate it in 2 phases, separating and removing the product from the organic phase . The product of step (iii) of the subprocess Ab may be subjected to a step (iv) analogous to step (iv) of subprocess Aa. However, there is usually no reason to do so, as the product generally comprises little or no compound of formula XIII. 7.2. Process B (preparation of the compounds of formula Va from the compounds of formula VIIc) The process for the preparation of the compounds of formula Va (process B) comprises (i) reacting a compound of formula VIIc (E) CH = CH-N (R 12b) R 13 (VIIc)

in which R 1 and R 3 are as defined above, with a compound of the formula wherein X 1 is chloro or bromo, or (XV)

with a compound selected from oxalyl chloride or oxalyl bromide; phosgene or carbonyl bromide; phosphorus trichloride or phosphorus tribromide; and an alkyl chloride or arylsulfonyl chloride, such as p-toluenesulfonyl chloride or bromide or methanesulfonyl bromide or chloride;

to give the corresponding compound of formula XVI

(XVI) and the corresponding anion, for example -PCâ, ..., Xâ,ƒâ g ¡in which Xâ, ..., Râ, ..., Râ, ... and Râ,, are the acâ, ,

(ii) reacting the compound of formula XVI with a compound of formula XVII

(XVII) wherein R5, IL2, and R6 are as defined above,

to give the corresponding compound of formula XVIII

(XVIII) and the corresponding anion, for example -PCI in which R3, R6, R6, R6, R6, R4 and R4 are as defined above, and (iii) hydrolyzing the compound of formula XVIII is converted to a corresponding compound of formula Va. As mentioned above for process A, in one variant, in step (i) a compound of formula XII obtained according to the invention; as process A can be used directly instead of a compound. of formula VIIc.

Preferred meanings for R1 and R2 are as defined above and references for R1, R2, R3 and R8 are those for RQ, R2, R3 and R4 respectively in U.S. Patent 4,739,073. X1 is preferably chloro. A compound of formula VIIc preferably reacts with a compound of formula XV. Steps (i) and (ii) are preferably carried out in an inorganic anhydride inert medium. Preferred reactants (and the final products) are:

(a) - (d) are those wherein R 1, R 2, R 2, R 3 and R 4 are each independently selected from the group consisting of (i), (ii), (xxi) and xxii) of U.S. Patent 4,739,073; (e) - (h) are those of (a) - (d) in which R1, R2 and R3 have the meanings corresponding to groups (v) , (vi), (xxv) and (xxvi) of the U.S. Application Deposition 4 739 C73; (i) and (j) are those of (e) and (f) wherein R4 is alkyl, phenyl, methylphenyl, fluorophenyl, dimethylphenyl, or methylfluorophenyl; Rc is hydrogen

J is alkyl or 4- or S-benzyloxy, and R8 is hydrogen or methyl; (k) and (1) are those of (g) and (h) wherein the symbol is phenyl, methylphenyl, fluorfenyl, dimethylphenyl or methylfurfenyl, R6 is benzyloxy or 6-benzyloxy, and R8 is hydrogen or methyl; R6 (m) - (p) are those of (i) - (1) wherein is hydrogen, and is hydrogen; (ΐ) - (ΐ) are those of (m) - (p) wherein R1 is phenyl, and R1 is methyl; (a) wherein R 2 is 1-methylethyl and R 6 is 4-fluorophenyl; and wherein R1 is 4-fluorophenyl, and R8 is 1-methyl-ethyl. (v) Preferably, the symbols and R representam are hydrogen, R é is 1-methyl-ethyl and R, is para-fluorophenyl.

The compounds of formula VIIc used in step (i) may be in free base form or preferably in the form of an acid addition salt, for example in the form of a hydrochloric acid addition salt. : Preferred bases for step (iii) are inorganic hydroxides, such as sodium hydroxide and potassium hydroxide, especially the former. However, such as abai-í; As it is stated, it is preferable not to use any basis in step (iii).

The preferred reaction conditions for process B are: Rase (i):

Temperature: -102 to 25-C, with -109 to + 102C being preferred

Time: 0.1 to 1.2 hours, preferably 0.5 to 1 hours

Reaction medium: lower alkyl nitrile, the preferred acetonitrile being.

Molecular ratio of the reactants: 1 to 1.5 moles of the compound of formula XV per mole of the compound of formula VIIc, preferably 1.1 to 1.3 moles of the compound of formula XV per mole of the compound of formula VIIc

Step (ii):

Temperature: 609 to 100 ° C, preferably 65 ° to 85 ° C

Time: 2 to 30 hours, preferably 3 to 24 hours. 57

Reaction medium: same as step (i): Mole ratio of the reactants: 1 to 5 moles of the compound of formula XVI per mol; of the compound of formula

XVII, preferably 2 to 3 moles of the compound of formula XVI

By weight of the compound of formula XVII (taken as a yield of step (i) in this case). ; Step (iii):

Temperature: 10 ° to 40 ° C when using a base, and 355 to 60 ° C when no base is used. Time: 0.1 to 1 hour when using a base and 2 to 4 hours when not in use. ii | Solvent: Mixture of water and reaction medium of phase j; (ii). The molar ratio of the reactants: 4 to 8 equivalents of the base, when a base is used, preferably sodium or potassium hydroxide, per mole of the compound of formula XV used in step (i). The preferred reaction conditions for process B, (q), (q), (q), (q), (q), (q), (q), (q), (q), (q), (n), I are:

I 58 58

Step (i):

Temperature: -10 ° to + 105 ° C

Time: 0.75 to 1 hour

Reaction medium: Acetonitrile

Mole ratio of the reactants: 1.1 to 1.3 moles of the compound of formula XV per mole of the compound of formula VII c

Step (ii):

Temperature: 65 to 85 ° C, with preference being 809 to 832C

Time: 3 to 16 hours, preferably 3 to 10 hours

Reaction medium: Acetonitrile

Mole ratio of the reactants: 2 to 3 moles of the compound of formula XVI per mole of the compound of formula XVII, preferably 2.1 to 2.5 moles of the compounds of formula XVI per mole of the compound of formula XVII (assuming, in each case, 100% yield for step (i)).

Step (iii):

Temperature: 202 to 552C, preferably 252 to 352C when using a hase and 352 to 552C when not used

Time: 0.3 to 0.7 hours when using a hase and 2 to 3 hours when not used. 59 I: I = i = i

Reaction medium

When using the base is 4 to 6 equivalents of the base, preferably sodium hydroxide, per mole of the compound of formula XV used in step (i) of step (i) . It is preferred not to use bases in step (iii). 3. General Conditions Applicable to All Processes Most molar amounts (ratios) set forth herein are exemplary only and can be varied, as is apparent to one skilled in the art.

Steps (i) and (ii) of process B and preferably phase (iv) of process Aa (including subprocesses Aa and Ab and their variants), steps (i) and (ii) of process B and preferably step (iv) of process Aa are, The process step (iii) of the process A (including the sub-processes Aa and Ab) and the reaction mixture is stirred at ambient temperature for a period of 1 hour, preferably under dry conditions under anhydrous conditions and preferably in an inert atmosphere, preferably dry helium, argon or nitrogen. and their variants) and process B are frequently, but need not be carried out in an inert atmosphere. In general, most of the temperature ranges given above are merely exemplary.All temperatures are internal temperatures, unless otherwise indicated. The term " reaction medium " as used above encompasses the term " reaction medium "

and mixtures of liquids and implying that the reaction medium is a liquid at the desired reaction temperature. It should therefore be understood that not all liquids listed for a particular phase can be used for the entire temperature range quoted above. It should also be known that the reaction medium should be at least substantially inert to the reagents used, intermediates generated and pro- under the reaction conditions used. It should still be; it is understood that the reaction temperature may exceed the boiling point of a reagent or reaction medium if a condenser or a closed system (reactive pump) is used. The reaction times given above are merely examples and I may vary. It will also be understood that conventional techniques of generation may be used. The term " solvent " as used herein encompasses mixtures of solvents and implies that the medium; is a liquid at the desired reaction temperature. Unless otherwise noted, all solvent mixtures are indicated by volume. The term " inert atmosphere " means an atmosphere which does not react with any of the reactants, intermediates or end products or otherwise interfere with the reaction. The product of each process may, if desired, be purified by conventional techniques, such as recrystallization, chromatography or fractional distillation.

All temperatures are given in (° C) degrees centigrade and the ambient temperature is in the temperature range of 202 to 302C, usually between 202 and 25 ° C, unless otherwise noted; the evaporations are carried out under vacuum under a minimum heating, the drying of the organic phases is carried out over magnesium sulfate anhydride.

and columns unless otherwise indicated, all silica gel is used in all chromatography.

It will be appreciated that the process variants disclosed with the present invention are improvements in known similar processes; they may be used to provide the desired end products, i.e. 7-substituted-hept-6-enoic and -heptanoic acids and their derivatives, for example more easily, or, for example, in a higher chemical purity state or optical, than can be achieved by conventional processes.

The above process variants may each be used either separately, together with conventional processes, or in combination, if so indicated or desired, to arrive at the desired end products. 9 · J_Espe £ Ifics

A specific illustration of the general inventive concept highlighting the variants of the foregoing processes relates to the preparation of erythro- (E) -3,5-dihydroxy-7- [1 '- (4' -fluorophenyl) -1 ' - (1-methyl-ethyl) indol-2'-yl] hept-6-enoic acid of formula Ia

F

C = C

H CH-NH2.

CH3 CH2 CH2 CH2 CH

CH-CH 2 -COOH

OH (Ia) 62

in an internal ester acid form. in the racemic or purely pure form: free, salt, ester or β-lactone, i.e.,

A multi-phase process using all the variants of the foregoing processes, namely processes A, B and the stereoselective re-production of a compound of formula II, and comprising: - process according to process A: a) reacting a (R 12b) R 13 wherein R 21-2 and R 13 are as defined, with a compound of formula IX, optionally in an inert anhydrous organic reaction medium, to give a corresponding compound to the formula Xc (Xc) xa - CH = r (K12b) S13 xa - in which Xa, Rb and b are as defined above; (b) reacting the compound of formula Xc with a compound of formula XI, In order to provide a corresponding inert organic solvent to give a corresponding compound of formula XIIc (E) - in which R 1, R 2, R 3, R 4, R 4, and X a the above-defined ones; C) hydrolyzing the compound of formula XIIc to give a corresponding compound of formula VIIc in the form of acid addition salt or free base, and if it is an acid addition salt, neutralization with a base;

according to process B d) reacting the compound of formula VIIc with a compound of formula XV or with a compound selected from oxalyl chloride or oxalyl bromide; phosgene bromide or carbonyl bromide; phosphorus trichloride or phosphorus tribromide; pentachloride or phosphorus pentabromide; and an alkyl or arylsulfonyl chloride or bromide, such as p-toluenesulfonyl chloride or p-toluenesulfonyl bromide; or methanesulfonyl chloride or bromide; to give the corresponding compound of formula XVI and the corresponding anion, for example -PO2 (X-b) 9; e) reacting the compound of formula XVI with 3- (4'-fluorophenyl) -1- (1'-methyl-ethyl) -1H-indole (the compound of formula XVII, wherein R6 and R6 are hydrogen, R is 1-methyl-ethyl and Ro is p-fluorophenyl) to give the corresponding compound of formula XVIIIa

(XVI) a) and the corresponding anion, for example -PCâ, ..., Xâ, "in which Râ," and Xa are as defined above;

1) hydrolyzing the compound of formula XVIIIa to give (E) -3- [1 - (4-fluorophenyl) -1- (1-methyl-ethyl) -1H- 2-enyl (the compound of formula Va wherein R6 is hydrogen and R3 is 1-methyl-ethyl and R8 is p-fluorophenyl); β-

the reaction of said compound of formula Va with the di-anion of an acetoacetic ester of the formula wherein R1 is as defined above, to give a corresponding compound of formula IIa:

wherein R3 is as defined above; in racemic or optically pure form; - in accordance with the stereoselective reduction process: h) the stereoselective reduction of the optically pure or racemic compound of formula IIa in a first step (a) of section 5 above, by mixing a compound of formula III with borohydride in a reaction medium comprising an alcohol and tetrahydrofuran; (b) of step 5 above, treatment of the compound of formula 1a in the form of a racemic or optically pure compound with the resulting mixture under the appropriate conditions to obtain a mixture containing a compound cyclic boronate of formula IV (a) and / or a boron complex of formula IV (b) in which R3 is: 3- (4'-fluorophenyl) -1- (1-methylethyl) -1H- indol-2-yl, X is -CH = CH- and R1 and R2 are as defined above; and in a third step / = step (c) of step 5 above > the product obtained in the second step being cleaved to give the compound of formula Ia as ester; in racemic to optically pure form; and i) if desired, converting the compound of formula Ia into the ester form by conventional methods, into the free acid, salt, and subsequently ester or S-lactone, i.e., inner ester forms. ; The compound of formula Ia may be in the form of free acid, salt, an ester of the lactone, i.e. an inner ester. Preferably it is in the form of a salt or free acid, preferably an alkali salt, especially a sodium salt. It is preferably in the racemic form or, alternatively, in the optically pure (3R, 5S) enantiomeric form, and preferably in the racemic form. As is apparent from formula Ia, this form is an erythro form.

It will be appreciated that the specific embodiment illustrated in 9. is carried out either according to the techniques disclosed by the present invention or, for some stages, according to the methods known in the art. . Thus: steps a), b) and c) are carried out as described above in item 7.1. for the subprocesses Ab,; especially phases i), ii) and, respectively, iii), j. ; according to the Abl, Ab2 and / or Ab3 variants of the subprocess Ab; steps a) and b) can therefore be carried out simultaneously as described above for process A:

Steps d), e) and f) are carried out as described in 7.2 above. for process B, especially phases i), ii) and phase iii) respectively; Step g) is carried out according to techniques published for example in U.S. Pat. 4,739,073, especially Reaction Scheme I at column 8 and Example 5, step 5 at column 47; - Step (h) is carried out as described above under 5.; Step i) is carried out in a conventional manner, for example as described in U.S. Pat. 4 739 073, especially in Reaction Scheme I (Reactions C, D and E) in column 9; Reaction Scheme II (Reaction L) in column 11; Reaction Scheme VIII (Reaction ΕΞ) 1 in column 16; and in Examples a (a), 6 (b), 6 (c), S and 9 in columns 49 and 50 and 52 and 53, whereby I can be substituted; advantageously. |

In a second part of step h) of the stereoselective reduction! described above, is preferably used from a compound of formula (II) in which R1 is isopropyl or especially t-butyl, which facilitates the isolation of a relatively pure compound of formula I, than with a group R 2, such as methyl. Subsequently, it is surprising! Thus the compound of formula I thus obtained is completely colorless, which by the foregoing synthetic procedures was obtained with a pale yellow color.

As mentioned previously, the stereoselective reduction according to step h), described above, with a compound of formula 11a, racemic or optically pure. An optically pure compound of formula IIa may be obtained, for example, by chromatographic resolution of a racemic compound of formula IIa obtained in step g) or, preferably, by an asymmetric synthesis. Alternatively, the resolution may be carried out at a subsequent stage, or in the final racemic product. : The initiation materials for this preferred embodiment of the invention are also known or may be prepared according to known techniques. The preparation of 3- (4'-fluoro-phenyl) -1- (1'-methyl-ethyl) -1H-indole / a compound of formula XVII, see step e) described above7 is disclosed in U.S. Pat. . 4,739,073 as Example 5, Steps 1 to 3 at columns 44 and 45, starting from fluoro-benzene. The invention also relates, of course, to the above described processes A, B and the stereoselective reduction process described above when applied to the preparation of the compound of formula Ia in combination with conventional techniques not specifically described above.

The examples which follow are illustrative of the invention.

All temperatures are given in degrees centigrade. | The optical purity is expressed in percentages and hence, for example " pure erythro-isomer 99.9% pure " means that there is at most 0.9 f? of the threo form in the obtained compound. 10.1. Examples for the stereoselective reduction of a compound. of formula II, to obtain a compound of formula I.

Example 1: (+) - Erythro- (E) -7- [1 '- (4'-fluorophenyl) -1' - (1-methyl-ethyl) indol-2 ' -3,5-dihydroxyhept-6-enoic acid R = 3- (4 " -fluorophenyl) -1- (1-methyl-ethyl) indol-2-yl; X = (E) -CH = CH-; R4 = t-butyl; in the racemic form (a) 47.67 g (1.26 moles) of sodium borohydride are added to a solvent comprising 1.32 l of dry tetrahydrofuran and 356 ml of methanol under nitrogen at about of -77 ° C. To the resulting solution was added 102 ml of 4.09 moles of 50% diethylmethoxyborane in THF over a period of 15 minutes, and the resulting mixture was stirred for another 10 minutes. (¾) 300.5 g (0.464 mole) of (+) - (E) -7 - [(4apos; -fluorophenyl)] - tert.- ? -Methyl-ethyl) -indol-2'-yl] -5-hydroxy-oxohept-6-enoic acid in 104 ml of THF? and 26 ml of methanol are added at a temperature in the range of from -78- to -11Â ° to the mixture obtained in (a) over a period of 1.5 hours, and the resulting mixture is stirred for an additional period of 30 minutes . 720 ml of a saturated sodium bicarbonate solution and 1.75 L of heptane is added to temper the reaction. 500 ml of ethyl acetate are then added and the resulting mixture is diluted with 3.5 l of water with stirring for 15 minutes, the mixing temperature being about 109 ° C. The upper organic layer is separated and washed several times with a total of 2.4 L of a saturated sodium chloride solution, pH 7.5, and the organic layer is concentrated at 20-30 mm Hg and at a maximum external temperature of about of 45 °. To the organic residue are added 375 ml of toluene, and the solvent is distilled at 20-30 mmHg, at a maximum external temperature of 45 ° C.

3.73 1 of ethyl acetate is added to the obtained thick oil (predominantly cyclic boronate). 50 ml of a hydrogen peroxide solution was then added at > (4.41 moles) was added to the ethyl acetate solution maintaining the internal temperature in the temperature range of about 20-25 ° C for about 2 hours until no boronatn was detected by thin layer chromatography. The organic layer The upper organic layer is then washed twice with a total of 2.2 l of a saturated sodium chloride solution of pH 7.5. The upper organic layer is then separated, washed three times with a total of 2.51 l of a solution of sodium to 10 (until the organic layer is peroxide free) while maintaining an internal temperature of 25 °. The upper organic layer is washed twice with a total of 1.72 l of a saturated sodium chloride solution, pH 7.5 and the solvent-

is distilled at 20-30 ng / Hg and at a maximum external temperature of about 45 ° C. The residue is dissolved in 1.17 L of refluxing ethyl acetate, the mixture is filtered while hot, and the filtrate is stirred at room temperature for 1 hour. in the range of 20-25 ° C for 1 hours. The solids are collected by filtration, dried under reduced pressure (about 20 to 30 mm Hg) at 25 ° C < washed with 550 ml of ethyl acetate / heptane (1: 4),

Redissolved in 880 ml of ethyl acetate and stirred. at room temperature for 18 hours. The solids are collected by filtration and washed with 480 ml of acetate: ethyl acetate / heptane (1: 2). The solids are dried under reduced pressure to give a product of 114.5 g (mp 135-137 ° C).

(A second collection is made from mother liquors to give a total yield of 149.5 g. The product was a pure erythrous isomer of 99.44% to 99.67% of chemical purity and can be analyzed as two optically active enantiomers, 3R, 5S and 3S, 5R, of which the first is preferred.

Preferably and as an alternative in step (a) one half of the indicated amount of sodium borohydride may be used.

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

I 71

. EXAMPLE 2 (+) - Ethyl- (S) -7- [1 - (4-fluorophenyl) -1 '- (1-methyl-ethyl) -indol-2'-yl] -: -3,5-dihydroxyhept-6-enoic acid, Formula I, R, X = as for Example 1; R1 = methyl; in the racemic form

(A) Sodium borohydride is treated in a manner analogous to Example 1, step (a), but dimethylmethoxybromane is used in THF. (b) 118.5 (0.28 mol) of (+) - (E) - [7 '- (4, L-fluorophenyl) -1' - (1-methyl-ethyl) indole-2-T-yl] -5-hydroxy-3-oxohept-6-enoic acid are treated analogously to Example 1, step (b), but the dilution is carried out with 1.42 L; of water and 1.135 l of heptane, instead of only 3.5 l of water. (c) To the organic residue (cyclic boronate predominantly) 2,375 1 of ethyl acetate is added and the mixture is treated with 264 ml of 30% strength hydrogen peroxide solution (2.328 moles) and worked up as described in Example 1, step (c). The residue is then dissolved in 130 ml of isopropanol. The mixture is heated to reflux temperature. While hot, 14 g of boric acid are added and the reflux is continuously for 15 minutes. The mixture is then filtered and the stirred filtrate at a temperature in the range of 20s to 25 ° C for 18 hours. The solids are removed by filtration, washed with 100 ml of isopropanol, and dried under reduced pressure to give a product of 110 g (80% yield). The product is re-dissolved in meta- | nol and recrystallized /Ϊ.Ε. 124-12β ° θ7. The product is a pure erythro-racemic mixture 99.07% which can be j *. optically acceptable, to be analyzed by observing 3R, 5S and 3S, 5R, of which is

two preferred enantiomers. EXAMPLE 3 (+) - 5R- (E) -3,5-Dihydroxy-7- [4- (4-fluorophenyl) - (1 "methylethyl) - 2 '-phenyl-1H-imidazol-5'-yl] -hept-6-enoic acid / Formula I: R = 1- (4'-Fluorophenyl) -4- (1,1-methyl-ethyl) -2- (3R, 5S) -enantiomeric form (a): 10.27 (1H, s), 3.66 (1H, s) (0.27 mol) of sodium borohydride was added to a solvent comprising 1.57 1 dry THF and 513 ml methanol under nitrogen at about -76 ° C. To the resulting solution was added 3 ml of dimethylmetoxyborane was added at 15 æM THF over a period of 30 minutes, while maintaining the internal temperature below -77.5 ° C, and the obtained mixture was stirred for an additional period of 5 minutes. (3R) -7- [1 (4R, 4S, 6R) -4- (1-methyl-ethyl) -2- 1-yl] -5-hydroxy-3-oxo-6-enoic acid in 304 ml of THF and 75 ml of methanol was added at a temperature in the range of about -72Â ° C to 77Â ° C, to the mixture obtained in (a) over a period of two hours. The resulting yellow solution is stirred at -76.5 ° C for 5 hours. 425 ml of saturated ammonium chloride are then added to quench the reaction, the temperature being maintained at about -65 DEG C. 950

ml of ethyl acetate, 950 ml of hexane and 1.13 l of water are added to the mixture, the temperature being about 5øC, and the mixture is stirred for 15 minutes, the resulting temperature of the mixture being about 5øC. The upper organic layer is separated and successively washed with a total of 1.4 l of a sodium chloride solution (pH 7.5), and the solvent is distilled at 20-30 mm Hg, at a maximum external temperature of about 45 ° C. (c) 3.25 1 of ethyl acetate was added to the obtained oil (the cyclic boronate was predominantly). 340 ml of hydrogen peroxide were then slowly added at 30 g. (3 moles) was added dropwise to maintain the temperature in the range of 202Â ° C to 25Â ° C for 3 hours until thin layer chromatography did not reveal boronate present. The upper organic layer is washed twice with a total of 1.5 L of a saturated sodium chloride solution, pH 7.5. The upper organic layer is then separated, washed three times (for 10 minutes at a time) with a total of 1.5 l of 10% sodium sulfide solution (until the organic layer is peroxide-free), while maintaining the internal temperature at 25 ° C. The upper organic layer is washed with 500 ml of saturated sodium chloride solution (pH 7.5). The solvent is distilled at 20-30 mm Hg at a maximum external temperature of about 45 ° C. 105 g of crude material is obtained. Purification of crude dihydroxy ester 0.58 g was carried out by column chromatography eluting with ethyl acetate / hexane (1: 2) in 490 mg (mp 143-145øC) yield, which by NMR analysis shows the erythrous isomer at 98.78% purity (the threo isomer not present); ] .delta. = + 6.49 ° (c = 0.77, CH 2 Cl 2). 74 '

EXAMPLE 4;

(3R, 5S) -5-Hydroxy-6-trityloxyhexanoic acid tert.-butyl ester; (A) 5.61 g (148.4 mmol) of sodium borohydride was added to a solvent which comprised 990 ml of THF. dried and 280 ml of methanol under nitrogen at about -76Â ° C. The temperature increased to about -78 ° C. The resulting solution was added 129.7 ml of 15% diethylmethoxyborane in THF, dropwise, carefully over a period of 20 minutes, and the obtained mixture was stirred for an additional period of 10 minutes at a temperature in the range of -77 ° C to -7 ° C. 56 g (0.122 mole) of (S) -5-hydroxy-5-trityl-4-oxo-3-oxo- hexanoic acid in 155 ml of TH 2 and 41 ml of methanol,

at a temperature in the range of -77Â ° C to -75Â ° C, to the mixture obtained in step (a) over a period of 40 minutes, and the resulting mixture was stirred for an additional period of 2 hours at a temperature in the range between -77 ° C and -75 ° C. 155 ml of a saturated solution of ammonium chloride were then added to quench the reaction mixture. Thereafter, 500 ml of ethyl acetate, 500 ml of heptane and 600 ml of water were added. The upper organic layer was separated and successively washed with a total of 500 ml of a saturated sodium chloride solution, pH 7.5, and the organic layer was concentrated at 20-30 mm Hg at a maximum external temperature of about 45 ° C. (c) To the obtained organic residue was added ethyl acetate (793 ml) (which contained predominantly cyclic boronate). 79 ml of a 30 (0.7 mol) hydrogen peroxide solution were then added slowly, and the reaction mixture was stirred for about 3 hours until thin layer chromatography turned out to be free of boronate. The upper organic layer was washed twice with a total of 400 ml of a saturated sodium chloride solution, pH 7.5. The layer was then separated, washed three times (for 10 minutes at a time) with a total of 575 ml of a 10% sodium sulfide solution. (until the organic layer was peroxide free) while maintaining the internal temperature at 25 DEG C. The upper organic layer was then successively washed with a total of 200 ml of a saturated sodium chloride solution, pH 7.5, and the solvent was distilled at 20-30 mm Hg and at the maximum external temperature of 45 ° C. 54.3 g of the crude dihydroxy compound (mp 84-85 ° C) were obtained, which showed the erythro isomer at 99.19 ± = -5.59 ° (c = 1.6, CH 2 Cl 2 ).

10.2. Examples for the preparation of intermediates of formula VII by Procedure A: EXAMPLE 5: 3- (Γ-Τ, Ν-Dimethylamino) acrolein = (E) -3- (N, N-dimethylamino) prop- Formula VII: R 2, = methyl 7 / Subprocess Aa 7

Step (i): A four-necked round bottom flask equipped with a stirrer, a condenser filled with saline solution, a thermometer, a caustic wipe,

an additional funnel and an ice bath is charged under nitrogen blanket with 4.0 l of methylene chloride and 438 g (5.99 moles) of ϊϊ, Ν-dimethylformamide. The solution is cooled to 7øC, and 860 g (5.8 moles) of oxalyl chloride are added over a period of 2.5 hours at such a low rate that no solvent and / or reagent is passed into the reaction vessel. condenser, while maintaining the temperature of the reaction mixture in the range of 50Â ° to 102Â ° C. A white solid forms.

Step (ii): 483 g (5.7 mol) of ethyl vinyl ether are added over a period of 30 to 50 minutes while maintaining the maximum temperature of 25 ° to 232 ° C, the addition being very exothermic. A red-brown solution is obtained. The reaction mixture is heated at a temperature in the range of 37Â ° C to 38Â ° C for 30 minutes under reflux. Recover as much as possible of methylene chloride by distillation at 30-40 mm Kg and at 45 ° C and, after distillation is complete, the reaction mixture is maintained at 30 mm Hg and 45 ° C for 30 minutes to give an oil agitated dark brown.

Step (iii): The reaction mixture is cooled to 20 ° C, and 450 ml of water are added over a period of about 30 minutes; the exothermic reaction is allowed to raise the temperature to 60 ° C, and this temperature is maintained for addition equilibrium. The mixture is stirred at a temperature in the range of 50Â ° C to 50Â ° C for 30 minutes and then cooled to 20Â ° C. A solution of 1.71 kg (12.35 moles) of potassium anhydride carbonate in 3.5 l of water is added over a period of 30 to 45 minutes while maintaining the temperature in the range of 20 ° C to 22 ° C. The aqueous layer is extracted with 4 L of methylene chloride, the

The methylene chloride layer is separated and the upper aqueous layer is extracted four times with 1 liter portions of methylene chloride. The five phases of methylene chloride are combined, dried over 500 g of anhydrous sodium sulfate and filtered, and the solid is washed twice with 250 ml portions of methylene chloride. The washings and the filtrate are combined, and as far as possible the methylene chloride is recovered by distillation at 20 mm Hg and 45ø to give a stirred viscous oil.

Step (iv): The oil is cooled to 20 ° C, 500 ml of methanol are added, the mixture is cooled to 10 ° C, and 60 g (1.33 mol) of dimethylamine are added while maintaining the maximum temperature at 202 ° C. As far as possible, the solvent is recovered by distillation at a pressure in the range of 20 to 30 mmHg and at 70Â ° C, the pressure is then lowered to 3 to 4 mmHg, and continued distillation, while gradually increasing the temperature to the reaction mixture is cooled to 120 ° C and the temperature of the vapor reaches 115 ° C to provide the pure product (9.7%) as an oil / 12 g; yield 62%; B.p. of pure product 2712-272Â ° C. EXAMPLE 6 3- (N-methyl-N-phenylamino) acrolein [(E) -3- (N -methyl- N -phenylamino) prop-2-enal] / formula VII: R1 = phenyl; = methyl7 / Sub-process Ab, Abl7 variant

Step (i): To a 4-well round bottom flask equipped with a stirrer, a condenser filled with a saline solution, a thermometer, a caustic wipe, an additional funnel and an ice bath, is charged t 78

under nitrogen blanket with 3.0 liters of methylene chloride and 1.02 kg (7.4 moles) of N-methylformamide. The solution is cooled to 15 DEG C., and 1.10 kg (8.67 moles) of oxalyl chloride is added over a period of 1.5 hours at such a low rate that no solvent and / or reagent passes into the bottom of the saline condenser, while the temperature is maintained in the range of 15 - 17 ° C under gentle reflux. The reaction mixture is slowly warmed to 43 ° C for 1 hour, refluxed for 1 hour at 43 ° -45 ° C to give a clear yellow solution and cooled to 152 ° C. (ii): 648 g (8.99 mol) of ethyl vinyl ether are added. during a period of 40 to 60 minutes while the

The maximum temperature is maintained in the range of 235 to 295C, I; ! the reaction being very exothermic. The resulting brownish red solution is heated to a temperature in the range of 385 ° to 39 ° C for 30 minutes, under reflux, and then cooled to 152 ° C. j1

Step (iii): A solution of 960 g (9.05 moles) of sodium carbonate hydrate in 4.5 l of water is added over 45 to 60 minutes while maintaining the temperature in the range of 22 to 30 ° C, very exothermic. The mixture is stirred at a temperature in the range of 225 to 25Â ° C for 15 minutes and allowed to stand for 15 minutes for two-phase separation to occur. The organic phase is separated, and the aqueous layer is extracted with 1.25 L of methylene chloride. The methylene chloride extract is with the previous organic phase, and the combined solution is extracted with water. The aqueous extract is extracted with 250 ml of methylene chloride and this extract is combined with the previous organic phase. The methylene chloride is recovered by distillation to a pressure in the range of 20 to 40 mmHg and 60Â ° C and the residual oil is heated to 60Â ° C at a pressure of 20-30 mmHg at 65Â ° C for 4 hours to afford 83.5 g of the pure product as an oil / 1.295 g; yield 90.7%; M.P. for pure product 2442C (dec.); P.P. of the pure product 4-472C from isopropanol / hexane 1: 7: 3- (N-methyl-N-phenylamino) acrolein E = (E) -3- (N-methyl-N-phenylamino ) prop-2-enal-7-yl] -benzoic acid as described for Example 67, Sub-process Ab, variant Ab27 i [Pass (i): To a four-inlet round bottom flask, , equipped with an agitator, condenser, saline solution, a thermometer, a caustic wipe, an additional funnel and in an ice bath under a blanket of 1 nitrogen were added 350 ml of acetonitrile and 425 g (3.5 mol) of N-methylformanilide. The solution is cooled to -15 °, and 440 g (3.46 moles) of oxalyl chloride are added over a period of 1.5 hours at such a small rate that it does not allow the passage of any solvent and / or reagent to the bottom of the condenser, which is maintained at a temperature in the range of -25Â ° to -20Â ° C, while maintaining the temperature in the range of -15Â ° to -10Â ° C under gentle reflux . The reaction mixture is slowly warmed to | 15 ° C over a period of 30 minutes and stirred for! 15 minutes at a temperature in the range; from 159 to 189C. 80 Phase

added over a period of 45 minutes while maintaining the maximum temperature in the range of 2830 to 303C, the reaction being highly exothermic. The reaction mixture is stirred at a temperature in the range of 303 to 352Â ° C for 30 minutes to give a red-brown solution and is cooled to 0Â ° C.

Step (iii): A solution of 395 g (3.73 moles) of sodium carbonate hydrate in 1.75 l of water is added over a period of 40 to 50 minutes while maintaining the temperature in the range of 83 to 1030 the reaction being very exothermic. 1.75 1 of toluene was added, and the mixture was stirred at a temperature in the range of 203 to 2230 for 15 minutes and was allowed to stand for 15 minutes to allow separation in 2 steps. The organic phase was separated twice with 150 ml portions of water. Toluene is recovered as much as possible by distillation at a pressure in the range of 20 to 80 mm Hg and at a temperature in the range of 503 to 90 ° C and the residual oil was heated to a pressure in the range of 20 to 30 mm Hg to 893 -) for 30 minutes to give 86.0% pure product as an oil. / 492 g; yield 85.77; Ρ.Ξ. of pure product 2449 (dec.); M.p. of pure compound 4 ° -47 ° C from 1: 7 isopropanol / hexane.

If the reaction mixture is stirred at a temperature in the range of 283 to 30 ° C for 30 minutes instead of 309-35 ° C, 92.3% of pure product is obtained in a yield of 90.7%. EXAMPLE 7a: 3- (N-methyl-N-phenylamino) acrolein / = (Ξ) -3- (N -methyl-N-phenylamin o) prop-2-nalj / Formula VII: = equal to Example oj / Subprocess Ab, variant Ab2, reagents puro_s7

Step (i): In a 4-inlet round bottom flask (2.5 L) as in Example 7, step (i) is charged under a nitrogen atmosphere with 223.2 ml (1.81 mol) of N-methylformanilide. The solution is cooled to 152 ° C and 177.6 ml (2.07 moles) of oxalyl chloride are added over a period of 20 minutes while maintaining the same temperature. The evolution of a spontaneous gas occurs and an homogeneous solution of orange forms.

Step (ii): 278.4 ml (2.16 mol) of n-butyl vinyl ether was added over 45 minutes while the internal temperature was maintained in the range of 25 ° C to 30 ° C, the reaction being very exothermic. The orange suspension is stirred at a temperature in the range of 402 DEG-45 DEG C. for 30 minutes and is cooled to 0øC.

Step (iii): To the product of step (ii) is added slowly, for about 90 minutes, a solution of 4N NaOH so that the temperature does not exceed 52C. The mixture is warmed to room temperature and stirred for an additional 60 minutes. The organic layer is separated into a funnel of 31 and the aqueous phase is extracted with 100 ml of n-butanol. The combined organic layers are washed 2 x 200 ml of saturated brine and the solvent is distilled off at 80øC / 15 Torr, 82

for 2 hours, yielding a thick, black oil, 295 g; chemical purity yield > 98 " M.P. of pure compound 244Â ° (dec.); P.P. of the pure compound 46-47 ° C from isopropanol / hexane 1: 7-BXSLIPLO 8: 3- (N-methyl-N-phenylamino) acrolein / = (E) -3- (N-methyl-N-phenylamino ) prop-2-enal-1

I / Formula VII. * 12 'R13 = as G0 Example 67 i / Subprocess Ab, variant Ab37: Phases (i) and (ii): In a 4-well round bottom flask | (12 1) equipped with a stirrer, a saline condenser, a thermometer, a caustic wipe, an additional funnel and an ice bath, were charged under nitrogen with 1.056 g (8.15 moles) of 1-oxalyl chloride and 480 ml of acetonitrile. The solution was to arre

and a mixture of 1.02 kg (7.395) of N-methylformamide, 0.1 g (7.98 mol) of n-butyl vinyl ether and 360 ml of acetonitrile is added over a period of 2.5 hours at such a small rate that no solvent and / or reagent passes to the bottom of the condenser filled with saturated saline solution (maintaining the temperature within the range of -25 DEG-202 DEG C.), while maintaining the temperature at -102 to -52Â ° C under gentle reflux. The resulting homogeneous orange reaction mixture is slowly warmed to 20 ° C over a period of 30 minutes; a slight exotherm increases the temperature to 28øC over a period of 30 minutes. The reaction mixture is stirred at a temperature in the range of 282 DEG-30 DEG C. for 1 hour to give a homogeneous brown mixture and is then cooled to 0øC.

Step (iii): A solution of 948 g (8.94 moles) of anhydrous sodium carbonate in 4.20 l of water is added over a period of 45 to 60 minutes, while maintaining the temperature in the range of 82 to 10 2C, the addition being very exothermic. 3.60 1 of toluene was added, and the mixture was stirred at a temperature in the range of 202 to 222C; for 15 minutes and allowed to stand for 15 minutes to allow separation in 2 steps. The organic phase was separated and washed twice with 360 ml portions of water. As much toluene was recovered as possible by distillation at a pressure in the range of 20 to 80 mm Hg and at a temperature range of 609 to 90 ° C, the residual oil being then heated to a pressure in the range of 20 to 30 mm Hg and at a temperature range of 892 to 90 ° C for 30 minutes to provide 89.1% of the pure product as an oil / 1.16 kg; yield 86.6 m.p. of pure product 244 ° C (dec.); B.p. of the pure product 45-47 ° C from 1: 17 isopropanol / hexane. 10.3. Examples for the preparation of intermediates of formula Va by the procedure of EXAMPLE 9; (E) -3- [11- (4 "-fluorophenyl) -1- (1,1-methyl-ethyl) -1H-indol-2-yl] propan-2-ol . R 1 = 1-methyl-ethyl; RQ = 4-fluorophenyl] Process B7 (i): A 4-neck round bottom flask was charged to

5 liters equipped with a stirrer, a thermometer, an addition funnel and ice bath, under nitrogen blanket, with 100 ml dry acetonitrile and 174.4 g (1.14 moles) phosphorus oxychloride, the mixture was cooled to -5-C, and a solution of 184 g (0.96 mol) of pure 3- (N-methyl-N-phenylamino) acrolein at 83.5 (product of Examples 6 to 8) in 156 ml of dry acetonitrile was stirred for 45 minutes while maintaining the temperature in the range of -5 ° C to + 50 ° C. The reaction mixture was stirred at a temperature in the range of O 2 at 5 ° C for 10 minutes. (ii) 115.2 g (0.45 mol) of 3- (4'-fluorophenyl) -1- (1'-methylethyl) -1H-indole (compound of formula XVII) is added over a period of 20 The reaction mixture is refluxed at 83 DEG C. for 9 hours and cooled to 10 DEG C. (iii) 228 g (5.7 mol) of sodium hydroxide in 2.0 1 of water is added over a period of 30 minutes while the temperature is maintained in the range of 25 ° to 30 ° C, the addition being very exothermic. Then 1.6 1 of toluene are added, the mixture is stirred the filtrate is washed with 100 ml of toluene, and the wash is combined with the previous filtrate The organic layer is separated, and a mixture of 93.4 g of concentrated hydrochloric acid and 21 l of water followed by 400 ml of a saturated sodium chloride solution. The mixture is stirred at 25 ° C for 30 minutes and the the resultant is filtered through a filter vat. The precipitate is washed with 100 85

ml toluene, and the wash is combined with the filtrate. The organic layer is separated, washed twice with 21 L portions of deionized water and filtered through a filter bath. As far as possible the toluene is distilled off at a pressure in the range of 30 to 50 mm Hg and at an external temperature in the range of 60-65Â ° C to give a fine, shaky oil. 100 ml of 95% ethanol is added, as much ethanol as possible is recovered by distillation at a pressure range of 30 to 80 mm Hg and 602 to 65 ° C, and the operation is repeated twice. 180 ml of 95% ethanol is added, and the mixture is refluxed at 78Â ° C for 15 minutes and cooled slowly to 20Â ° C over a period of 2 hours, crystallization initiating at about 55Â ° C. The slurry is slowly cooled to a temperature in the range of 0Â ° to 52Â ° C over a period of 30 minutes, maintaining the temperature in the O2 range at 22Â ° C for one hour and filtered. The filtrate is washed three times with 50 ml portions of cold 95% (o2 to 5%) ethanol and vacuum dried at 60-65 ° C for 16 hours to obtain constant weight giving 98.7% of pure product ( 101 g, yield 71.3%, mp 1272-1282).

In one embodiment isopropanol is used in place of 95% ethanol. EXAMPLE 10: -. (4-methyl-ethyl) -1H-indazol-4-yl] piperazin-2-one of formula Ya: R 2, R 3, R 4, R 5 = as for Example 97, Process B, alternative technique: (i) A 4-neck,

with a stirrer, a condenser, a thermometer, an additional funnel and in an ice bath, is charged, under a blanket of dry nitrogen, with 263 ml of dry acetonitrile and 454 g (2.96 moles) of phosphorus oxychloride, the mixture is cooled to -5 ° C, and a solution of 471.6 g (2.49 moles) of 3- (N-methyl-N-phenylamino) acrolein in 406 ml of dry acetonitrile is added over a period of 45 minutes while the temperature is maintained in the range of 5 to 79 ° C. The reaction mixture is stirred at this temperature for 10 minutes. (ii) 300 g (1.18 mol) of 3- (4'-fluorophenyl) -1- (1'-methylethyl) -1H-indole (compound of formula XVII) was added over a period of 10 minutes while was maintained at a temperature of about 72 ° C. The reaction mixture is refluxed at 83 ° C for 3 hours and cooled to 22 ° C. (iii) 2.7 l of water is added slowly over a period of 15 minutes, while the temperature is maintained in the range of 222 ° to 35 ° C, the addition being exothermic. The reaction mixture is stirred at a temperature in the range of 359 to 50Â ° C for 30 minutes, and is warmed to a temperature in the range of 502 to 55Â ° C for 1.5 hours (a longer heating period may be required for the complete hydrolysis), cooled to 22 ° C, and then maintained, for 15 minutes and filtered. The filtrate is washed three times with 600 ml portions of water and suction dried at the suction pressure for 6 to 16 hours (N-methylaniline can be recovered from the combined aqueous layer and washings). The wet filtrate is transferred to the original 5 L flask, and 2.5 l of toluene and 180 g of 20% of powdered cellulose are added, and the mixture is cooled to -78 ° C. is heated at 50Â ° -55Â ° C for 1.5 hours, cooled to 22Â ° C, held at 22Â ° C for 15 minutes and optionally filtered through the 70-230 mesh A.S.T.M. of silica gel covered filter. The cellulose tubulin and silica gel are washed three times with 200 ml portions of toluene. The filtrate and toluene washes are combined and as far as possible the toluene is recovered by distillation at 30-50 mm Hg and at an external temperature of 502 to 65 ° C. 280 ml of 95% ethanol was added. to the residual viscous oil, ethanol is distilled at a pressure in the range of 20-30 mm Hg and at a temperature of 602-65Â ° C. 700 ml of 95% ethanol are added and the mixture is refluxed at -78 ° C for 15 minutes and is slowly cooled to 20 ° C. period of 1 hour, with crystallization starting at about 55 ° C. The resulting slurry is cooled to a temperature in the range of 0Â ° to 52Â ° C over a period of 30 minutes and the temperature is maintained therein; O2 at 22C for 30 minutes, the solids are removed by filtration, washed three times with 120 ml portions of cold (95% O 2 at 52 ° C) and vacuum dried at a temperature in the range of 60 to 65 ° C for 16 hours to obtain constant weight giving 99.4 % of the pure product (276.6 g, 77.5% yield, mp 1292-138Â ° C). In one embodiment, isopropanol is used in place of ethanol; 95%. It is preferred to omit the silica gel tub, i.e., liquid j | comprising powdered cellulose and subjecting it to simple filtration; and it is its residue which is washed three times with of 200 ml of toluene. s 88/1. EXAMPLE 10a (E) -3- [3- (4-Fluorophenyl) -1- (1-methylethyl) -1H-indol-2'-yl] prop-2-en-y of formula Va: (I) A flask of 1.5 l, as described in Example 10, step (i) is charged, under nitrogen blanket, with 170 ml of dry acetonitrile and 105.3 g of 3- (N-methyl-N-phenylamino) acrolein hydrochloric salt at room temperature. 96.6 g of phosphorus oxychloride were added to the mixture over 5 minutes. A dark solution is obtained. (ii) 90 g of 3- (4'-fluorophenyl) -1- (1'-methyl-ethyl) -1H-indole (compound of formula XVII) was added at 30 ° C. The mixture is heated under reflux for 4.5 hours at a temperature in the range of 75-832C, and then cooled to 22C. (iii) 250 ml of water was added at 5Â ° C, then 500 ml of water was added at room temperature for 15 minutes. The mixture is stirred at 35-50Â ° C for 30 minutes, and then heated to a temperature in the range of 502-55Â ° C for 1.5 hours. A dark paste is obtained. The mixture is cooled to 30 ° C, held at 302 ° C for 15 minutes, and the brown slurry is filtered. The precipitate is washed three times with a total of 540 ml of water. The filtrate is vacuum dried by suctioning for 4 hours. The solids are transferred to the original flask described above, 750 ml of toluene and 54 g of cellulose

! in powder 20%, and subsequently the disclosed technique is used. in Example 10, step (iii) to give product I (89 g, yield 81%). 10.4. Examples for the specific embodiments EXAMPLE 11 (I) -Eritor- (E) -3,5-dihydroxy-7- [1 '- (4 "-fluorophenyl) -1- (1 " 2-yl] hept-6-enoic acid / Formula Ia: as racemic; sodium salt7

Step (a), (b) and (c): N-methylformanilide is reacted with oxalyl and ethyl chloride or n-butyl vinyl ester according to process A, subprocess Ab to afford 3- (N-methyl- phenylamino) -acetic acid, as described in Examples 6, 7, 7a or 8 Phases (i), (ii) and (iii27 ·

Step (d): The above product, 3- (N-methyl-N-phenylamino) acrolein, is reacted with phosphorus oxychloride as described in Example 9, 10 or 10a, step (i) to afford the title compound. formula XVI in which Xa is chloro, R_₂₂ is phenyl and R ^ é is methyl.

Step (e): The above compound of formula XVI is reacted with 3- (4'-fluorophenyl) -1- (1'-methyl-ethyl) -1H-indole as described in Examples 9 > 10 or 10a, step (ii) to produce the compound of formula XVIIIa, wherein the symbols: X & is chlorine, R ^ ® is phenyl and R ^ is methyl.

Step (f): The above compound of formula XVIIIa is hydrolyzed as described in Examples 9, 10, or 10a, step (iii) to yield (E) -3- [4- (4-fluoro-phenyl) ) -1 '- (1-methyl-ethyl) -1H-indol-2'-yl] -prop-2-enal.

Step (g): Under a nitrogen atmosphere is charged a reactor with 0.5 l of tetrahydrofuran (THE). The solution is cooled to -10 ° C, and 60 g of sodium hydride (60% dispersion in the mineral oil) are carefully added. Thereafter, 237.7 g of t-butyl acetoacetate are added in 250 ml of THF , carefully for 45 minutes while maintaining the temperature below 2 ° C. The resulting solution is stirred at -10Â ° to 20Â ° C for 1 hour. The mixture is cooled to -10 ° C and 938 ml of a 1.6 M solution of n-butyllithium in hexane are added at such a rate that the temperature does not exceed 0 ° C (for about 60 minutes). The mixture is stirred for 10 minutes at that temperature, and is then cooled to -10Â ° C, and a solution of 230 g of the product of step f) above in 650 ml of THF is added at such a rate that the temperature do not exceed 0 ° C (for about 70 minutes). The reaction mixture is stirred at 0-20 for 15 minutes and poured into a mixture of 248 ml of concentrated hydrochloric acid and 2.5 kg of ice under vigorous stirring for 5 to 10 minutes. The mixture is vigorously stirred for a further 15 minutes, the organic phase is separated, washed twice with 500 ml portions of a saturated NaCl solution and concentrated under reduced pressure (about 25 mm Hg). To the residue is added 200 ml of toluene and the solution is again concentrated. The crude product obtained, (+) - (E) -7- [3 - (4-fluorophenyl) -11- (1-methylethyl) indol-2'-yl] -5- 3-oxohept-6-enoic acid (compound of formula IIa wherein R4 is

! (503.6 g, 70.0% pure) is used in the next step without further purification. (a), (b) and (c) to give (+) - erythro-butyl ester, t-butyl ester, - (E) -7- [1 '- (4-Fluorophenyl) -1 (1-methyl-ethyl) indol-2-yl] -3,5-dihydroxyhept-6-enoic acid. li i ji j; Step (i) To 42.5 g of the ester obtained in step (h) above in 250 ml of THF was added 90 ml of 1N sodium hydroxide over 5 minutes while the temperature was kept below 101 ° C. The solution is stirred for 1 hour at room temperature, 275 ml of methanol is added, the mixture is concentrated at 25 mm Hg and at 45Â ° C. then deionized water (300 ml) is added, the distillation is continued to maintain a volume of 140 ml, after which 380 ml of fresh deionized water are added. and the solution is then washed with a total of 640 ml. of t-butyl methyl ether in 3 portions. The aqueous layer is concentrated at 25 mm Hg and 45 ° C to a volume of 300 ml, 220 ml of deionized water are added, and the clear aqueous solution is lyophilized for 3 days. The title compound is obtained (35.9 g, 91% yield, 98.9% chemical purity, 99.9% pure erythro isomer, boron concentration below the detection limit).

In an alternative technique for step (i): To 35.0 g of the ester obtained in step (h) in 175 ml of ethanol was added, 74 ml of a solution of sodium borohydride while maintaining the temperature 2 below 122 ° C. The solution is stirred for 1 hour, the mixture is concentrated at 25 mm Hg and at 45Â ° C, whereupon

250 ml of deionized water was added, the distillation was continued to give a volume of 115 ml, after which 315 ml of deionized water were added thereto and the solution was washed with a total of 525 ml of tert-butyl methyl in 3 portions. The aqueous layer was concentrated to 25 mm Hg and at 45 DEG to a volume of 245 ml, 185 ml of deionized water were added, and the clear aqueous solution was lyophilized for 3 days. The title compound (291) was obtained. 75 g, pure white, 91% yield, mp 204 DEG-20 DEG C., chemical purity: 100 DEG-61 DEG of the pure erythro isomer, boron concentration 3.96 ppm). EXAMPLE 12 (+) - erythro- (E) -3,5-dihydroxy-7- [3- (4 "-fluorophenyl) -1 '- (1 H, -methyl-ethyl) indol-2 -yl] hept-6-enoic acid. I-h / Formula Ia: racemic form; The title compound is obtained in a manner analogous to Example 11, except that: in step (g) the methyl ester is produced by the reaction with the dianion of methyl acetoacetate instead of with t-butyl acetoacetate; step (h) is carried out in a manner analogous to Example 2, steps (a), (b) and (c); step (i) is carried out by hydrolysis of the methyl ester: obtained in step (h), as described in U.S. Pat. 4 739 073, Example 5 (6), in column 50.

Claims (2)

93 iis. A process for the preparation of 7-substituted hept-6-enoic and hepenoic acids of the formula I in which X is -CH 2 CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 - or -CH = CH-; ;; R 2 is an inert ester group under the reaction conditions; and R 2 is an organic radical having groups which are inert under? the reduction conditions, by stereoselective reduction of a racemic or optically pure compound of formula (II) (II) C - CHO - COOR II 2 Zo | R 2, R 2 and X have the abovementioned meanings, eg one of the symbols Z 2 and Z 2 is oxygen and the other is hydroxy and hydrogen, which comprises; The operation of mixing a compound of formula (III): wherein R1, R2, R3, in which is allyl or a lower alkyl radical having 1 to 4; and is a primary or secondary alkyl radical having from 1 to 4 carbon atoms, with sodium borohydride NaBH4 in a reaction medium which comprises an alcohol and tetrahydrofuran; (a) treating a compound of formula II with the mixture obtained in step (a) under suitable conditions to provide a mixture containing a cyclic boronate compound of formula IV (a) :  € ƒâ € ƒâ € ƒand / or a boron complex of formula IV (b) R 1, R 2, R 3, R 4, in which R 1, R 2, R 3 and X have the abovementioned meanings, and in a third step / step (c) 7> the cleavage of the product obtained in step (b) , in order to obtain a corresponding compound of the formula I. 95 2 ^. A process according to claim 1, wherein for the preparation of a compound of formula I wherein triphenyl is methyl (trityl) and R @ 3 is allyl or a radical which forms an inert ester under the reaction conditions, preferably allyl or an alkyl radical in n -methyl, i-butyl, t-butyl or benzyl, especially t-butyl, if the isotonic selective reduction of a racemic or optically pure compound of formula II in which u, R11 and Z2 have the abovementioned meanings. j | 3â. 2. A process according to claim 1, characterized in that a compound of formula Ia is obtained. in the form of the free acid, salt, ester or delta lactone, i.e., an inert ester. i4 & A process according to claim 1, wherein a compound of formula (I) is obtained in a state of optical purity such that the ratio of the erythro isomer to the threo isomer is 99.1: 0.9 or more. ; 5-. A process for the preparation of an intermediate product of the formula (VII) in which R 1 is hydrogen; R 2, R 2, R 2, R 3, R 4, R 7, 3 substituents, each of which is, independently of the others, C1 -C4 alkyl, C1 -C4 alkoxy, fluoro, chloro, bromo or nitro with up to two nitro groups; (VIII) in which R 2 and R 3 are independently selected from the group consisting of (i) reacting a compound of formula Are as defined above, with a compound of formula (IX) in which X is a monovalent leaving group, optionally in an inert anhydrous organic medium, to form the corresponding (X) wherein X, R12 and R13 are as defined above (ii) reacting said compound of formula X with a compound of formula XI wherein R1, -CH = CH 2 (XI) in which R1 is a monovalent group which does not deactivate the oxygen atom to which it is attached, optionally in an anhydrous inert organic medium, to form a corresponding compound of formula (XII) in which R1, R2 and X have the following formula (XII): wherein R1, R2, R3, the above-mentioned meanings and (iii) hydrolyzing said compound of formula XII to give a corresponding compound of formula VII in the form of the free base or acid addition salt and, if it is in the acid addition salt form , neutralizing the acid addition salt with a base. 6s. A process according to claim 5, wherein phase (iii) is omitted and the compound of formula XII is used directly, instead of a compound of formula VII, for further processing. 7â. 5. A process according to claim 5, wherein steps (i) and (ii) are carried out simultaneously. 83. A process as claimed in claim 5, wherein: R 1 and R 2 are independently from each other C 1 -C 4 -alkyl. 9a. A process as claimed in claim 1 wherein at least one of the C1 -C4 alkyl ring symbols. 5, characterized in that R 'is different. 10 & 5. A process according to claim 5, wherein in steps (i) and / or (ii) the reactants are pure employed. . 5. A process according to claim 5, wherein: The compound of formula XII is in the form of the acid addition salt. i | A process according to claim 8, characterized in that the compound of formula VII is subjected to step (iv) ie (iv) treating the crude mixture containing the compound of formula ) In which R1 R2a is C1-4 alkyl and R4 is as defined in claim 5, with a corresponding compound of formula XIV H-N (E12a) ) R13 (xiv) in which R12a is as defined above, and R13 is defined as in claim 5; to form any compound of formula XIII present therein in the additional compound of formula VIIa. I 100! « 13a. A process of formula Va for the preparation of an intermediate product I in which R3 is hydrogen, C1 -C4 alkyl, n-butyl, i-butyl, tert. C »-C»-alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; R8 is hydrogen, C1 -C4 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; with the provisos that no more than one of the symbols and | R6 is trifluoromethyl, not more than one of R5 and R6 is phenoxy and not more than one of R1 and R2 is benzyloxy; one of R1 and R2 is phenyl trisubstituted by R1, R2 and R3 and the other is primary or secondary C1 -C6 alkyl and does not contain an asymmetric carbon, C3 -C6 cycloalkyl or phenyl-CH2) wherein R1 is hydrogen, C1 -C4 alkyl, n-butyl, i-butyl, tert-butyl, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; R1 is hydrogen, C1 -C4 alkyl, C1 -C4 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; fluorine R11 is hydrogen, C1 -C4 alkyl, C1-4 alkoxy, or chlorine, and m is 1, 2 or 3; With the provisos that not more than one of R6 and R4 is trifluoromethyl, not more than one of R6 and R4 is phenoxy and not more than one of R1 and R2 is benzyloxy, (i) reacting a compound of formula VIIc (E) -OHC-CH = CH-N (R 12b) R 13 (VIIc) in which R 12b has the meanings given in claim 5; for R 2, other than C 1 -C 4 alkyl, and R 13 is as defined in claim 5, with a compound of formula XV wherein X 1 is chloro or bromo, or a a compound selected from oxalyl chloride or bromide; phosgene or carbonyl bromide; phosphorus trichloride or tribromide; pentachloride or phosphorus pentabromide; and an alkylsulfonyl or arylsulfonyl chloride or bromide, such as p-toluenesulfonyl chloride or bromide, or methanesulfonyl chloride or bromide; to give the corresponding compound of the formula XVI + (E) -Xb -CH = CH-CHN (R 12b) R 13 (XVI) and the corresponding anion, for example -P02 (Xb) 2, 102 in which R1 and R2 are the abovementioned meanings, and R1 is as defined in claim 5, (ii) reacting said compound of formula XVI with a compound of formula XVII (XVII) in which R,, R,, R e and R têm have the abovementioned meanings, to give a corresponding compound of formula XVIII. and the corresponding anion, for example, in which R,, R,, R,, R,, R_ and R₂ are as hereinbefore defined, and R ^ is as defined in claim 5, and iii) hydrolyzing said compound of formula XVIII to give a corresponding compound of formula Va. ! 14§. 11. A method according to claim 13, The compound of formula XVII is 3- (4-amino-2-phenylphenyl) -1- (1-methyl-ethyl) -1H-indole. j'15â. A process according to claims 1, 5 and 13 for the preparation of erythro- (E) -3,5-dihydroxy-7- [1 '- (4'-fluorophenyl) (1-methylethyl) -indol-2'-yl] hept-6-enoic acid of formula Ia (Ia) in racemic or optically pure form, or in the form of the free acid, salt, ester or delta lactone, i.e. internal ester, which comprises according to the invention with the process A: I a) reacting a compound of formula VIa wherein R 12b is as defined in claim 13, and R1 is as defined in claim 5, with a compound of formula IX, optionally in an inert anhydrous organic medium, to form a compound of formula Xc Xa -CH = S + (R 12b) R 13 X- (Xo) in which X &; and R^ são are as defined in claim 5 and 12¾ as defined in claim 13, reacting said compound of formula Xc with a compound of formula XI, optionally in an inert anhydrous organic medium, to form a corresponding (XIII) in which R1 is as defined in claim 13, and R13, R1 and Xa are as defined in claim 13 wherein R13 is as defined above. the meanings indicated in claim 5, the hydrolysis of said compound of formula XIIc to provide a corresponding compound of formula VIIc in the form of the free base or acid addition salt and, if it is in the acid addition salt form, the neutralization of the acid addition salt with a base according to process B: reacting said compound of formula VIIc with a compound of formula XV or with a compound selected from oxalyl chloride or bromide; phosgene or carbonyl bromide ; phosphorus trichloride or tribromide; penta-chlor phosphorous acid or pentobromide, and an alkylsulfonyl or arylsulfonyl chloride or bromide, such as " methanesulfonyl bromide; to form a corresponding compound of formula XVI and the corresponding anion, for example, e) reacting said compound of formula XVI with 3- (4'-fluorophenyl) -1- (1,1- methylethyl) -1H-indole (compound of formula XVII, wherein R6 is hydrogen, R1 is 1-methylethyl and R8 is p-fluorophenyl) to form a corresponding compound of formula XVIIIa and the corresponding anion, for example, â € ƒâ € ƒâ € ƒwherein R1R5; R13 and Xa are as defined in claim 13, and have the meanings indicated in claim f) hydrolyzing said compound of formula XVIIIa to give (E) -3- [1- (4-fluorophenyl) -1- (the compound of formula Va, in which R 1 and R 2 are hydrogen, R 2 is 1-methylethyl and R 2 is p-fluorophenyl); g) reacting said compound of formula Va with dianion 106 of an acetoacetic acid ester of the formula CH 2 COCl 2 -COOR 4, in which R 1 is as defined in claim 1, to give a corresponding compound of formula in which R1 has the meanings recited in claim 1; in racemic or optically pure form; according to the stereoselective reduction process; the stereoselective reduction of the racemic or optically pure compound of formula IIa via the first step of the step of mixing a compound of formula III as defined in claim 1 with sodium borohydride (NaBH in a reaction medium comprising an alcohol and tetrahydrofuran; in a second step, treatment of a compound of formula 11a in racemic or optically pure form with the resulting mixture under conditions suitable for the preparation of the compound of formula IIa. (a) and / or a boron complex of formula IV (b) in which R is 1 - (4-fluorophenyl) -1- (1 ' tetramethyl) -1H-indol-2-yl; X is -CH = CH- and e have the meanings given in claim 1; and in a third step, the cleavage of the product obtained in the second step, to obtain the compound of formula Ia in ester form, or in the racemic or optionally pure form; and i) if desired, converting the compound of formula Ia into ester by conventional means in the form of a free acid, a salt, another ester form or delta lactone, i.e. , of the internal ester. 16.4. 2. A compound according to claim 15, wherein the compound of formula Ia is obtained in the racemic form. 17δ. 2. A process according to claim 15, wherein the compound of formula Ia is obtained in the enantiomeric form (3R, 5S). 18ã. 5. A process according to claim 15, The compound of the formula Ia is prepared as described above. form of sodium salt. !! 19®. 5. A process as claimed in claim 15, wherein said phenyl is methyl. 20®. 7. A process according to claim 15, wherein R1 is tert-butyl. Lisbon, October 13, 1989. The Official Agent of Industrial Property A i k L-Americo of Cliva Carvalho Agasta Ofisial ia Prepri.daí. Industrial R. Cutiiho, 201-3. E.-1000 US80A Telefe. 651339-6546 13