SI8911973A - Process for the preparation of 7-substituted-hept-6-enoic and heptanoic acids and their derivatives and intermediates thereof - Google Patents

Abstract

A process for the preparation of 7-substituted hept-6-ene and heptanoic acids and their derivatives and intermediates. A new process for the preparation of compounds of formula I is described: 5 3 R - X - CH - CHj - CH - CHj - COORi OH OH wherein X is -CH 2 CH 2 - or -CH = CH-; Ri ester group, inert for reaction conditions; and R is an organic residue with groups which they are inert under reducing conditions; with stereoselective reduction the corresponding compounds of formula II: R - X - C - CBj - C - CHj - COORi I 'II 1 Zi Zj where R, Ri and X are as defined above and is one of Z1 and Z2 oxygen and other hydroxy and hydrogen,. The compounds of formula I are pharmacists, in particular anti-atherosclerotic, antihyperlipidemic and antihypercholesterolemic agents. The process can also used to prepare compounds of formula lu: in - OCHj - CHCHjCHCHj - C00Ru OH OH where u is triphenylmethyl (trityl) and Ru is allyl or an ester forming residue, inert under reaction conditions which are intermediates in the preparation some of the compounds of formula I. New processes are also described for preparing the above intermediates for use in the preparation among others compounds of formula I, namely process A comprising preparation of compounds of formula VII: (E) - OHC - CH = CH - N (Ri2) Ri3 wherein R12 is C1-3 alkyl, phenyl or phenyl substituted with 1 to 3 substituents, each of which is independently C1-3 alkyl, C1-3- alkoxy, fluoro, chloro, bromo or nitro with a maximum of two nitro groups; and R13 has the independent meaning indicated above for R12, from the corresponding compounds of formula Vlil: OHC - N (Ri2) Ri3 and method B, which comprises the preparation of compounds of formula Va: , wherein R 5 is hydrogen, C 1-3 alkyl, n-butyl, i-butyl, t-butyl, C 3 -cycloalkyl, C1-3alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; R 1 is hydrogen, C 1-3 alkyl, C 1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; with reservations, yes is not more than one of R5 and R6 trifluoromethyl, not more than one of R5 and R6 are phenolic and not more than one of R5 and R6 is benzyloxy; one of R7 and Re is phenyl trisubstituted by Rg, R10 and Ri1 and the other primary or secondary C 1-6 alkyl containing no asymmetric carbon atoms, C3-cycloalkyl or phenyl- (CH2) m-, where Rg is hydrogen, C1-3alkyl, n-butyl, i-butyl, t-butyl, Cisalkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; R10 is hydrogen, C1-3alkyl, C1-3alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; R11 is hydrogen, C1-2alkyl, Cisalkoxy, fluoro or chloro and m is 1, 2 or 3; with the reservation that it is not more than one of Rg and R10 trifluoromethyl, not more than one of Rg and R10 is phenolic and is not more than one of Rg and R10 benzyloxy; from subgroups of compounds of formula VII. Specific implementation of the above an inventive concept is shown by preparing the compound with the formula la: in racemic or optically pure form; in the form of free acid, salt, of ester or delta-lactone, i.e. of the internal ester.

Description

Process for the preparation of 7-substituted-hept-6-enoic and heptanoic acids and their derivatives and intermediates

The present invention relates to the preparation of 7-substituted hept-6-enoic and heptanoic acids and their derivatives and intermediates.

1. The subject

---- i

The invention relates to a process for the preparation of a compound of formula I

3

R - X - CH - CH ₂ - CH - CH ₂ - COORi (I)

OH OH where it is

X -Cri ₂ CH ₂ - or -CH = CH-;

R ₁ is an ester group inert to the reaction conditions; and

R is an organic residue with groups which are inert under reducing conditions.

It also refers to a dive for the preparation of the preceding intermediates (of formulas Va and VII, see below).

A common feature linking these different stages of the process is that they all lead to improvements at different stages in the preparation of the end products, 7-substituted hept-6-enoic and heptanoic acids and their derivatives, which are inhibitors of cholesterol biosynthesis. This link is shown below with a specific embodiment relating to the preparation of a specific cholesterol biosynthesis inhibitor, namely erythro- (E) -3,5-dihydroxy-7- / 3 '- (4-fluorophenyl) -1' - (1-methylethyl) indol-2'-yl / hept-6-enoic acid in racemic or optically pure form; v

-X.

in the form of free acid, salt, ester or O-lactone, i.e. of the internal ester.

The process of the invention for preparing a compound of formula I comprises stereoselective reduction of a racemic or optically pure compound of formula II

R - X - C - CH ₂ - c - CH ₂ - COORi Z _x Z ₂ where they are

R, R4 and X are as defined above and one of is oxygen and the other is hydroxy and hydrogen to give the corresponding compound of formula I.

- 3 As seen from Formula I, the compounds have sin, i.e. erythro configurations.

The symbol (E) - appearing at the beginning of the formula or in the name indicates that the double bond is in a trans configuration.

The invention also encompasses a compound of formula I as defined above, in a state of optical purity such that the erythro-to-threoisomer ratio is 99.1: 0.9 or more, preferably 99.5: 0.5 or more, especially 99, 7: Q3 or higher.

The compounds of formula I, which are esters, and the corresponding free acids, salts and cyclic esters (-lactones), are pharmaceuticals, in particular HMG-CoA reductase inhibitors, i.e. inhibitors of cholesterol biosynthesis, and are therefore indicated for use in the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.

2. Priority means

The ester group is preferably a physiologically acceptable ester group that can be hydrolyzed if the desired end product is an ester.

By the term physiologically acceptable hydrolysable ester group is meant a group which, together with the residue -C00- to which it is attached, forms an ester group which is physiologically acceptable and can be hydrolyzed under physiological conditions to give the corresponding carboxylic acid compounds of formula I (i.e., wherein R 1 is substituted by hydrogen) and an alcohol that is physiologically acceptable, i.e. non-toxic at the desired dosage level, in particular a group without centers of asymmetry.

is preferably R _g where R _{g is} C 1-6 -alkyl or benzyl, in particular R ₂ 'where R ₂ ' is -alkyl, n-butyl, i-butyl, t-butyl or benzyl, e.g. ethyl, preferably isopropyl or t-butyl, in particular t-butyl.

• X is preferably X ', where X' is -CH = CH-, preferably (E) -CH = CH-.

R is preferably selected from the group A, B, C, D, Ea, Eb, Ec, F, G, H, J, K, L, M or N as follows:

A is phenyl trisubstituted by R ^ _a , R _2a and R ^ where ^R 1a ' ^R 2a ^{and R} 3a are ^{independently} hydrogen; halo; C 1-6 alkyl;

C 1-4 haloalkyl; phenyl; halo substituted phenyl,

R 6 - alkoxy, C ₂ g-alkanoyloxy, N-alkyl or N-haloalkyl or -O ^{R 9} | _and wherein R _{2a is} hydrogen, C ₂ g-alkanoyl, benzoyl, phenyl, halophenyl, phenyl (C 1-6 -alkyl), _g- alkyl, cinnamyl,

C ^^ - haloalkyl, allyl, cycloalkyl (C ₁ alkyl), adamantyl (C ^ _ ₃ alkyl) or substituted phenyl (C ^ alkyl), where each substituent is selected from halo, alkoxy · C ^ - ₄ -alkyl and C ^^ - haloalkyl; wherein the halogen atoms are fluoro or chloro and cycloalkyl includes cyclohexyl;

7

a) - C = «C R, b = C i

R ₈ b or b)

CH ₂ -CH ₂ -CH ₂ -CH ₂ 5 where

R 6b is hydrogen, C 1-6 alkyl, C 1-4 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy;

R1b is hydrogen, N-alkyl, n-butyl, i-butyl, N-alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy;

R 6b is hydrogen, N -alkyl, N -alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy;

with the proviso that no more than one of R ^ b and R ^ b is trifluoromethyl, it is not more than one of R ^ b and R ^ b phenoxy and no more than one of R ^ b and R ^ b is benzyloxy;

Rgb hydrogen, 2 ^-a l ^k yl> ^C 1 2 * ^{all (ol (S} L fluoro or chloro;

R 6b is hydrogen, C 1-6 alkyl, n-butyl, i-butyl, N-alkoxy, n-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy;

R 6b is hydrogen, C 1-6 -alkyl, N-alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy;

with the proviso that it is not more than one of R? b and Rgb trifluoromethyl, it is not more than one of R? b and Rgb phenoxy and that it is not more than one of Ryb and Rgb benzyloxy;

with the further proviso that the free valences on the Ba and Bb rings are opposite each other;

wherein one of R ^ c and R ₂ c is phenyl substituted with R ^ -c, R ^ c and R ^ c, and the other is ^ -alkyl, n-butyl or i-butyl,

R 16 is hydrogen, N-alkyl, n-butyl, i-butyl, t-butyl, N-alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R c is hydrogen, C ₁ ^ alkyl, C ^ alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that no more than one of R c and R c is trifluoromethyl, not more than one of R ^ c and R ^ c are phenoxy and are not more than one of R ^ c and R ^ c are benzyloxy,

R ^ c is hydrogen, N-alkyl, n-butyl, i-butyl, t-butyl,

C_ ₃ alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R c is hydrogen, C ^ _ ₃ alkyl, C ^ _ ₃ alkoxy, trifluoromethyl, fluoro ,. chloro, phenoxy or benzyloxy, with the proviso that not more than one of R ^ c and R ^ c is trifluoromethyl, it is not more than one of R ^ c and R ^ c phenoxy and is not more than one of R ^ c and R ^ c benzyloxy and

RyC hydrogen, C ^ _2 ~ alkyl, ~ _ ₂ alkoxy, fluoro or chloro;

R id where it is

R η d is hydrogen or primary or secondary C ^^ alkyl which does not contain an asymmetric carbon atom, and

R ₂ d is a primary or secondary C 3-6 alkyl which does not contain an asymmetric carbon atom, or

R ^ d and R ₂ d together ^{or Z} ) -CH ₂ CH = CH-CH ₂ wherein m is 2, 3, 4, 5 or 6;

R ^ d is hydrogen, N-alkyl, n-butyl, i-butyl, t-butyl, N-alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

Rjjd is hydrogen, alkyl, C ₁ alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that no more than one of R ₂ d and R @ d is trifluoromethyl, not more than one of R ₂ d and R ^ d phenoxy and not more than one of R ₂ d and R ^ d benzyloxy,

R d is hydrogen, C ^ _ ₃ alkyl, n-butyl, i-butyl, T.-butyl, C ₁ ^ alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R d is hydrogen, alkyl, C ₁ alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that no more than one of R @ d and R @ d is trifluoromethyl, not more than one of R d and R ^ d are phenoxy and are not more than one of R ^ d and R ^ d are benzyloxy,

R _? d is hydrogen, 2 ^-a lkil, C_ ₂ ~ alkoxy, fluoro or chloro;

Ea

/

^R xe or

wherein each of R 4 is R 4 is and R 4 is independently fluoro, chloro, hydrogen or C 1-6 alkyl, wherein R 4 is preferably methyl;

* ₂ f where it is

R f C ₁ ~ 6 alkyl not containing an asymmetric carbon atom, and each one, and R f is independently hydrogen, C ^^ - alkyl, n-butyl, i-butyl, t-butyl, alkoxy, n- butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenyl, phenoxy or benzyloxy, each of Rf and Rf is independently hydrogen, R -alkyl, R -alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy and each of R f and R? f is independently hydrogen, C ₁ ~ ₂ alkyl,

C 1-6 -alkoxy, fluoro or chloro, with the proviso that not more than one of R ₂ f and R ^ f is trifluoromethyl, is not more than one of R ₂ f and R ^ f is phenoxy, is not more than one of R ₂ f and Rff are benzyloxy, not more than one of Rff and Rff are trifluoromethyl, not more than one of Rff and Rff are phenoxy and no more than one of Rff and Rff are benzyloxy;

with the proviso that (i) the free valence of the pyrazole ring is in position 4 or 5 and that (ii) the group R ^ f and the free valence ortho against each other

where it is

Rag a single bond to X Rbg is Rgg, Reg is R ^ g, Rdg is R ^ g and K is -N-; or

I

R-, Mr

Rag is R ^, Rbg is a single bond to X, Reg is R ₂ g, Rdg is R ^ g, k 0, S or -N-;

R ^ jg »R2S> R ^ S and R / g independently C 1-8 alkyl which does not contain an asymmetric carbon atom, γ-cycloalkyl or phenyl substituted with R g, R g g and Ryg, or in the case of R g and R ^ g is additionally hydrogen or for R ^ g when K is 0 or S and X X 'is additionally Ga, and is

Ga-C (R ₁₇ g) = C (R ₁ & g) R ₁ ^ g, where

R-, yg is hydrogen or C1-6-alkyl and are

Rggg and Rggg are independently hydrogen, N -alkyl or phenyl, each Rg-g is independently N-alkyl, n-butyl, i-butyl, t-butyl,

C1-6-alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, bromo, phenyl, phenoxy or benzyloxy;

each of Rgg is independently hydrogen, alkyl, C ₁ alkoxy, trifluoromethyl, fluoro, chloro, bromo, phenoxy or benzyloxy; and each R ^ g is independently hydrogen, C ^2-6 alkyl, C ₁ 2a ^{or colcy} , fluoro or chloro, with the proviso that only one of the trifluoromethyl, phenoxy and benzyloxy groups on each phenyl ring may be substituted with R ^ g. Rgg and Rg;

N-R2

t.

where it is

R ^ h is C 1-6 alkyl which does not contain an asymmetric carbon atom,

C1-8-cycloalkyl, adamantyl-1 or phenyl substituted with R4 h R4 h and Rgh,

1

R ^ h is C ₁ g-alkyl containing no asymmetric carbon atom, γ-cycloalkyl, adamantyl-1 or phenyl substituted with R ^ h,

Rgh and Rgh;

R ^ h is hydrogen, g-alkyl containing no asymmetric carbon atom, C ^ -cycloalkyl, adamantyl-1, styryl or phenyl substituted with R ^ h, R ^ h and R ^ h;

each of R ^ h, R? h and R ^ h independently is hydrogen, C 3-6 alkyl, n-butyl, i-butyl, t-butyl, N -alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, bromo, phenyl, phenoxy or benzyloxy, each of R ^ h, Rgh and R ^ h independently hydrogen,

C ₁ ^ alkyl, _g alkoxy, trifluoromethyl, fluoro, chloro, bromo, -COOR ^ h ^ h ^ -N, phenoxy or benzyloxy, wherein R- | yh hydrogen, R, or M gh, where

R gh C ^ _ ~ ₃ alkyl, n-butyl, i-butyl, t-butyl or benzyl and

M is defined as above, and each R ^ gh is independently g-alkyl containing no asymmetric carbon atom, and each of Rgh, Rgh and R ^ h is independently hydrogen, C1-6alkyl, C1-6 alkoxy, fluoro or chloro , with the proviso that more than one substituent on 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 phenyl ring is independently benzyloxy

each of Rp and Rp is independently g-alkyl containing no asymmetric carbon atom, N -cycloalkyl or phenyl- (CH ₂ ) _m -, wherein m is 0, 1, 2 or 3 and the phenyl group is unsubstituted or substituted by any of Rp, R ^ j and Rp, wherein R ^ j, Rp and Rp are defined as below; or is it

R _{2 is} -Y 1 -benzyl, -N (R ₂ ) ₂ or Ja, where Y 1 is -O- or -S-;

each R 8 is independently C 1-6 alkyl which does not contain an asymmetric carbon atom or may form part of a 5-, 6- or 7-membered ring Jb, wherein the ring Jb is substituted or unsubstituted and optionally contains one or more heteroatoms; and is

Yes Yes' or Yes where it is

Ja 'is a heterocyclic group which is unsubstituted or substituted by one or two C ₁ -C ₂ -alkyl or C ₁ -C ₂ -alkoxy groups, and is

Ja Jaa or Jab

where it is

R j is hydrogen, C ^ _ ~ ₃ alkyl, n-butyl, i-butyl, t-butyl, alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

Rjjj hydrogen, alkyl, C ₁ alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, and R j is hydrogen, C ₁ _2 ^a lkil, alkoxy, fluoro or chloro; with the proviso that it is not more than one of R ^ j and R ^ j trifluoromethyl, it is not more than one of R ^ j and R ^ l phenoxy and no more than one of R ^ j and R ^ j is benzyloxy;

wherein each of R ^ k and R ₂ k is independently (a) phenyl substituted with R ^ k, R ^ k and R ^ k, where

R 16 is hydrogen, C 1-6 alkyl, n-butyl, i-butyl, t-butyl, C 1-6 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy

R k is hydrogen, alkyl, C ₁ alkoxy, fluoro or chloro; and

Ryk is hydrogen, ^2-10alkyl , C1-6alkoxy, fluoro or chloro;

(b) hydrogen or primary or secondary θ-alkyl containing no asymmetric carbon atom;

(c) θ-cycloalkyl; or

where it is

Y1 -CH = CH-CH = N-, -CH = CH-N = CH-, -CH = N-CH = CH-, or -N = CH-CH = CH-, R ^ l primary C ^ _ ^ - alkyl containing no asymmetric carbon atom; or isopropyl;

R ₂ 1 is:

a) phenyl substituted with R 16, R 16 and R 18, wherein R 16 is t-butyl, C 1-6 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy;

R 16 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy;

with the proviso that it is not more than one of R ^ l and R ^ l trifluoromethyl, it is not more than one of R ^ l and R ^ l phenoxy and is not more than one of R ^ l and Ηθΐ benzyloxy,

R? 1 is hydrogen, C ^ _ 2 alkyl, C ₁ _2alkoksi, fluoro or chloro,

b) primary or secondary C ₁ -alkyl containing no asymmetric carbon atom,

c) Cg θ-cycloalkyl or

d) phenyl- (CH ₂ ) _m , wherein m is 1, 2 or 3;

where it is

R ^ m is C 1-6 alkyl which does not contain an asymmetric carbon atom,

C- - cycloalkyl, (C - - cycloalkyl) methyl, phenyl- (CH-) -,

5- / 5- (c. M pyridyl-2, pyridyl-3, pyridyl-4, thienyl-2, thienyl-3 or phenyl substituted with Rfm, Rfm and Rfm;

^R 2 ^{ra C} 1 does not contain an asymmetric carbon atom,

C _c -cycloalkyl, (C _c -cycloalkyl) methyl, phenyl- (CH-) -, pyridyl-2, pyridyl-3, pyridyl-4, thienyl-2, thienyl-3 or phenyl substituted with Rgm, R m and R m, with the proviso that not more than one of R ₂ and R ₂ m is a member of the group consisting of pyridyl-2, pyridyl-3, pyridyl-4, thienyl-2, thienyl-3, phenyl, substituted with Rfm, Rfm and Rfm, and phenyl substituted with Rgm, Rfm and _RlQm ;

H ₃ ffl C 1-10 -alkyl containing no asymmetric atoms carbon, C1-8-cycloalkyl or phenyl, substituted with R -j -j m , R. ^ ® ⁱⁿ R .j gin; R ₄ m C.j is g-alkyl which does not contain asymmetric atoms carbon, C1-8-cycloalkyl or phenyl, substituted with R ^ m , R ^ m and «16®;

wherein each of R ^ m, Rgm, ^R ii ^m - * - ^{n R} -, 4 ^{m is} independently hydrogen, ^ -alkyl, n-butyl, i-butyl, t-butyl, ^ -alkoxy, n-butoxy, i -butoxy, trifluoromethyl, fluoro, chloro, bromo, phenyl, phenoxy or benzyloxy, each of R ^ m, Rgq, R ^ ® and R ^ m independently hydrogen, C 1-6 alkyl, C 3-6 alkoxy, trifluoromethyl, fluoro, chloro , phenoxy or benzyloxy and each of R ^ m, Rθσι, R- ^ m and R ^ m independently hydrogen, 2 ^-a lkii> 2 ^a ik ° ksi, fluoro or chloro, with the proviso that there is no more than one substituent on each phenyl ring independently trifluoromethyl, no more than one substituent on each phenyl ring independently phenoxy and no more than one substituent on each phenyl ring independently benzyloxy

wherein each of R ^ n, R ^ n and R ^ n is independently alkyl of 1 to 4 carbon atoms; or phenyl which may be unsubstituted or substituted with either one or two alkyl or alkoxy groups of 1 to 3 carbon atoms or chloro; or with a single fluoro, bromo or trifluoromethyl substituent;

R ^ n is hydrogen or alkyl of 1 to 3 carbon atoms, e.g. methyl;

R4 is hydrogen, lower alkyl or alkoxy; halo, trifluoromethyl;

or phenyl, benzyl or benzyloxy, wherein the aromatic moiety may be unsubstituted or substituted by up to two groups, one of which may be fluoro, bromo or trifluoromethyl; or may be one or two lower alkyl or alkoxy or chloro;

R 6 is hydrogen, lower alkyl or alkoxy, halo or trifluoromethyl; and

R 6 is hydrogen, lower alkyl or alkoxy, halo or trifluoromethyl; and each of R ^ n + R ^ n, R ^ n + R ^ n or R ^ n + R? n can form either a residue -CH = CH-CH = CH- or - to form a ring which is substituted by Rgn , which is hydrogen; halo or lower alkyl or alkoxy;

provided that no more than one trifluoromethyl group and no more than two bromo substituents are present on the molecule.

The compounds of formula I can be divided into thirteen groups, i.e. groups IA to IN, according to the meaning of R, i.e.:

IA, when is R = A, IB, when is R = B, ic, when is R = c, ID, when is R = D, IE, when is R = Ea, IF, when is R = F, IG, when is R = G, IH, when is R = H, 1J, when is R = J,

IK when R = K,

IL, when is R = L, IM, when is R = M and IN, when is R = N.

3- Stereochemistry

When the hydroxy keto compound of formula II is reduced to the dihydroxy compound of formula I, an additional center of asymmetry is generally formed. Therefore, when a racemic compound of formula II is used, four stereoisomers (comprising two pairs of enantiomers, i.e. a pair of erythro and a pair of treo enantiomers) result in the formation of a compound of formula I. On the other hand, when using an optically pure compound of formula II, two diastereomers (i.e. one erythro and one tert isomer) of a compound of formula I, e.g. 3R, 5S and 3S, 5S diastereoisomers obtained from reduction of 5S hydroxy compounds. The diastereoisomers can be separated in the usual way, such as by fractionation crystallization, column chromatography preparative thin layer chromatography or HPLC. The erythro-to-treoisomer ratio obtained by these methods is usually variable and can be e.g. to about 98: 1.

In the stereoselective process of the present invention, almost exclusively, when a racemic compound of formula II is used, only two stereoisomers (comprising an erythro-pair of enantiomers) of the resulting compound of formula I. On the other hand, when an optically pure compound of formula II is used, almost only one enantiomer of a compound of Formula I is exclusive, and this enantiomer is the corresponding erythro enantiomer. E.g. The 3R, 5S enantiomer is obtained from the reduction of the 5S hydroxy compound, where X is -CH = CH-.

The erythro-to-treoisomer ratio obtained by the process of the present invention is about 99.1: 0.9 or greater, in particular about 99.5: 0.5 or greater, especially about 99.7: 0, 3 or more.

The term stereoselective as used herein means that the erythro-to-treo ratio is 99.1: 0.9 or greater.

The stereoisomers of the compounds of formula I wherein X is -CH = CH- according to the present invention are the 3R, 5S and 3S, 5R isomer and the racemate consisting of both, of which the 3R, 5S isomer and racemate are preferred.

The stereoisomers of the compounds of formula I, wherein X of the present invention are a 3R, 5R and 3S, 5S isomer and a racemate consisting of both, of which the 3R, 5R isomer and racemate are preferred.

4. State of the art

In conventional methods for reducing the keto group of a compound of formula II, soap reducing agents such as sodium boron hydride or t-butylamine and borane complex have been used in an inert organic solvent such as lower alkanol to obtain a mixture of diastereomeric forms from an optically pure starting compound, or, on the other hand, racemic diastereoisomers from the racemic starting material.

They used a three-step, partially stereoselective reduction process to obtain a predominantly erythro racemate from the racemic starting material. In a first step, a compound of formula II is contacted with either a trialkylborane compound or a compound of formula III r ₄ ob- (r ₃ ) ₂ (III) wherein R1 is allyl or lower alkyl having 1 to 4 carbon atoms, preferably non-ethereal, and R is _of a primary or secondary alkyl having 2 ib to 4 carbon atoms, preferably nejterciaren, in a reaction medium comprising an alcohol and tetrahydrofuran (THF). In the second step, such processes add sodium borohydride (NaBH4) to the reaction medium, and the reaction is carried out by reduction of the keto group and, on the other hand, to form a cyclic boronate or boron complex of the compound of formula I. In the third stage, a reaction mixture containing a boron complex and / or cyclic boronate ester, azeotroped with methanol or ethanol or, on the other hand, treated in an organic solvent with an aqueous peroxy compound such as peroxide, e.g. hydrogen peroxide or perborate, e.g. sodium peroxide to obtain the final compounds of formula I. The above procedure is said to provide an erythro ^ racemate with e.g. about 98% selectivity with respect to the treoisomers (Chen et al., Tetrahedron Letters 28, 155/1987 /) ·

5. Detailed description

The process of the present invention encompasses a method for stereoselective reduction of racemic and optically pure compounds of formula II to give almost exclusively erythro isomers of formula

I. The reduction of the keto group of the compound of Formula II is practically instantaneous. Compounds of formula I, i. erythro isomers are obtained in addition with increased chemical purity and can be further enriched to a chemical purity above 99% by simple recrystallization.

According to the first step of the process of the present invention / step (a) / a compound of formula III is mixed with NaBH 4 sodium borohydride in a reaction medium comprising alcohol and tetrahydrofuran.

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

V '

B / \

R - X - CHCH ₂ CH - CHjCOOI ^ and / or boron complex of formula IV (b) compound sr ₃ r ₃ '' b ⁷

T T

R - X - CHCH ₂ CH - CHjCOOR! [IV (b) J f

where R, R ^, R ^ and X are as defined above. The latter prevails over quenching. But quenching turns the boron complex into a boronate ester.

In the third step / step (c) / the product obtained in step (b), the vaccine is obtained to obtain the corresponding compound of formula I.

Step (a) is preferably carried out under substantially anhydrous conditions, preferably in an inert atmosphere, from about -100 ° to about + 30 ° C, preferably from about -80 ° to about -60 ° C, especially from about -78 ° to about - 70 ° C. The reaction medium used in step (a) j comprises a mixture of alcohol and tetrahydrofuran, wherein the alcohol has the formula AlkOH, wherein Alk is alkyl of 1 to 4 carbon atoms, e.g. methyl or ethyl, preferably non-ethereal.

One of the products of step (a) may be R ^ OH derived from the compound of formula III used. However, not all or part of Alk is required to be the same as R ^. Sodium borohydride should generally be present in at least an equimolar amount relative to the compound of formula II, more preferably in a slight excess, such as e.g. from about 1.1: 1 to about 1.5: 1 mol of NaBH ^ per mole of ketone. The molar ratio of the compound of formula III to the compound of formula II is at least about 0.5: 1, more preferably from about 0.7: 1 to about 1.5: 1 mol of borane compound per mole of ketone.

Step (b) is also preferably carried out at reduced temperatures, maintaining the internal temperature at about -100 ° C to about -40 ° C, especially from about -78 ° C to about -70 ° C. The compound of formula II is preferably in a solvent such as alcohol / THF or THF. Preferably, the reaction medium is selected for step (a) and the solvent for the compound of formula II, which is added to step (b), to obtain a combined medium wherein the ratio (v / v) of alcohol to tetrahydrofuran is from about 1: 3 to about 1: 6 alcohols against THF, especially from about 1: 3 to about 1: 4. The reduction of the keto group is exothermic and expires rapidly, i.e. it is desirable to add the keto compound in steps to maintain the internal temperature in the range of about -78 ° to about -70 ° C. The reduction is almost instantaneous, and the reaction mixture is then quenched by the addition of e.g. aqueous sodium bicarbonate, ammonium chloride or acetic acid to give a mixture of the desired cyclic boronate intermediate.

In step (c), the reaction product of step (b) can be azeotroped with methanol or ethanol, e.g. from about 60 ° to about 80 ° C under substantially anhydrous conditions. On the other hand, and especially where X is -CH = CH-, the product is neutralized by the addition of sodium bicarbonate (NaHCO3 dissolved in an organic solvent, eg ethyl acetate, and treated with aqueous (e.g. 30%) hydrogen peroxide or aqueous sodium perborate (NaBO ^ .4H ₂ O), initially at a reduced temperature, e.g., about + 10 ° C, and then allowed to warm to a moderate temperature, e.g., about 20 ° to about 30 ° C, to give the corresponding compound of formula I.

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

Because reducing conditions occur in the implementation of the invention, it is intended that any substituents or functions on the residue used as R are inert, i.e. that the residue is free of substituents or functions that would be reactive or sensitive to change under such conditions, e.g. using known methods of masking or protecting such features or introducing them at a later stage.

- 24.

Compounds of formula I corresponding to -lactone, free acids and salts, processes for converting a compound of formula I ^ wherein R. has one meaning, into a corresponding compound where it has another meaning,

Z and / or the corresponding u -lactone or free acid or salts are known.

The compounds of formula I can optionally be converted in the usual way to the corresponding free acid or salt forms, i.e. wherein R4 is replaced by hydrogen or cation, such as an alkali cation or ammonium, preferably sodium or potassium and especially sodium, in other ester forms, or in the corresponding < RTI ID = 0.0 > lactones, < / RTI > internal esters.

As mentioned above, the compounds of formula I obtained by the process of the invention are pharmaceuticals. In a further embodiment, the process of the invention may also be used to prepare chiral intermediates, e.g. with the formula Iu in - 0CH ₂ - CHCH ₂ CHCH ₂ - C00R _in (Iu)

OH OH where u is triphenylmethyl (trityl) and

R allyl or ester forming residue, inert under reaction conditions, preferably allyl or C 1-6 alkyl, n-butyl, i-butyl, t-butyl or benzyl, in particular t-butyl, by stereoselective reduction of the racemic or optically pure compound with formula IIu u - 0CH ₂ - C - CH ₂ --C - CH ₂ - COOR _U Zi Z ₂ (IIu) where u, R _u , Z ^ and Z ₂ are as defined above.

Such chiral intermediates are described e.g. in EP 244364. Indicated for use in the preparation of pharmacists.

6. Starting materials (Primary or secondary C 1-6 alkoxy or allyloxy) -di (primary C 1-6 -alkyl) borated by the formula III used as starting materials in the process of the present invention are known. / Koster et al, Ann. (1975), 352; Chen et al., Tetrahedron Letters 28, 155 (1987); and Chen et al., Chemistry Letters (1987), 1923-1926 /. However, they may be prepared in situ from the corresponding 3- (primary or secondary C 1-6 alkyl) boranes by reaction with primary or secondary C 1-6 alkanol or allyl alcohol, the concentration of the former being preferably from about 0.2 M to about 1 , 2 M, especially about 0.5 M.

The compounds of formula II are known or can be prepared analogously to known compounds of formula II, i.e. as described in USP 4 739 073 (e.g. for Z ₂ = oxygen) or in EP 216 785 (e.g. for Z ₁ = oxygen).

Thus, compounds of formula II, where Z _{2 is} oxygen, are usually prepared by metabolizing a compound of formula V

R - X - CHO (V) where R and X are defined as above, with the dianion of a compound of formula VI ch ₃ - CO - ch ₂ - COOR ₁ (VI) where R ₁ is defined as above.

- 26 7. Further embodiments relating to the foregoing intermediates

The compounds of formula V and VI are also known. In another embodiment, the present invention also provides a novel process for the preparation of a subset of compounds of formula V, namely compounds of formula Va

where it is

R 1 is hydrogen, C 1 -C 6 alkyl, n-butyl, i-butyl, t-butyl, _C 1 _-C cyclo5 1-3 3-b alkyl, N-alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy;

R 8 is hydrogen, C 1-6 alkyl, C 1-4 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy;

with the proviso that not more than one of R_ and R, trifluoromethyl, will be not more than one of R _c and R _c phenoxy and not more than one of 5 6

R _r and R _c benzyloxy;

o one of R? and Rg is phenyl, trisubstituted by Rg, and R4, and other primary or secondary alkyl, not containing an asymmetric carbon atom, gCycloalkyl or phenyl- (CH2) _ffl -, wherein

R 8 is hydrogen, C 1-6 alkyl, n-butyl, i-butyl, t-butyl, C 1-4 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phen-27 oxy or benzyloxy;

R _1q hydrogen, C ₁ alkyl, alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy;

R ^ is hydrogen, C _{1 2} alkyl, ₂ alkoxy, fluoro or chloro and m is 1,2 or 3;

with the proviso that it is not more than one of Rg and R4 trifluoromethyl, it is not more than one of Rg and R4 phenoxy and is not more than one 'of Rg and R4 benzyloxy;

from a subset of compounds of formula VII (E) - OHC - CH = CH - N (R ₁₂ ) R (VII) wherein ^ 12 ^C 1 3 ^{a is alkyl} , phenyl or phenyl substituted with 1 to 3 substituents each of which is independently alkyl, C1-6 alkoxy, fluoro, chloro, bromo or nitro with up to two nitro groups; and has

R ^ independently the meaning given above for R ^ as well as for the new process for the preparation of the compounds themselves of the formula

VII.

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

Compounds of formulas Va, VII and XVII (see 7.2) are known, inter alia, from US-PS 4 739 073, which describes compounds of formula VII wherein R _{2 is} C 1-6 alkyl and their use for synthesis of the compounds of formula Va, of the compounds of formula XVII in

- 28 use of compounds of formula Va for the synthesis of indole analogs of mevalonolactone and its derivatives, which are indicated for use as HMG-CoA reductase inhibitors. Because they inhibit cholesterol synthesis, they lower blood cholesterol levels and are therefore indicated for use in the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.

The compounds of formula VII and their synthesis are also described in GP-PS no. 945 536 and CS-PS no. 90 045. However, the procedures described there are different from process A in e.g. to the use of phosgene or phosphorus trichloride, pentachloride or oxychloride but not an oxalic acid derivative.

7.1. Method A (Preparation of Compounds of Formula VII)

Process for the Preparation of Compounds of Formula VII (Procedure

A) comprises (i) the reaction of a compound of formula VIII

OHC - N (R ₁₂ ) R (VIII) wherein R ₂ and R 4 are as defined above with a compound of formula IX

X - CO-CO - X (IX) a a where X is a monovalent leaving group, optionally in an inert anhydrous organic medium, to obtain the corresponding compound of formula X

X is _a - CM ⁺ (R ₁₂₎ R ₁₃ x _a - (X) wherein X _b, R ₂ and R are as defined above,

- 29 (ii) reaction of this compound of formula X with a compound of formula XI r _i4 o - ch = ch ₂ (XI) wherein R _{14 is a} monovalent group that does not deactivate the oxygen atom to which it is attached, optionally in an inert anhydrous organic medium to give the corresponding compound of formula XII (E) - R _{1i +} 0 - CH = CH - CH = N ⁺ (R ₁₂ ) R ₁₃ Χ _& (XII) where R ₁₂ , R 4, R ₁₄ and X _a defined as above, and (iii) hydrolysis of this compound of formula XII to give the corresponding compound of formula VII in the form of a free base or an acid addition salt and, if in the form of an acid addition salt, neutralization of the acid addition salt with the base.

In a variant of process A, it is possible to proceed without step (iii) and the compound of formula XII can be used directly in e.g. procedure B.

Steps (i) and (ii) can be performed simultaneously, or step (ii) may follow step (i); step (iii) follows step (ii) and step (iv) (see below), when used, follows step (iii).

^R 12 ^R 12a ^{'where R} 12a ^C I_ ₃ ^{alkyl; or R} i2b 'where ^z ^ ^z i ^emo Cj ₃ & lkila has the meaning given above to

R _{2 is} (i.e. phenyl or phenyl substituted with 1 to 3 substituents, each of which is independently ₃ alkyl, ₃ alkoxy, fluoro, chloro, bromo or nitro with up to two nitro groups).

R is preferably C.alkyl and most preferably & c. a and - £ methyl.

- 30 ^R 12b ^3e P ^{rednostno R} i2b '' ^to j ^{er de R} 12b ^{'is phenyl or} phenyl substituted with 1 or 2 substituents each of which is independently alkyl, ^ T ^ oxy or chloro, more preferably R "', wherein R _1OU 'is phenyl or phenyl substituted with

12b 12b or 2 methyl groups, and most preferably phenyl.

R 6 ^is preferably alkyl and most preferably methyl.

R 2 is preferably C 1-6 alkyl, preferably primary or secondary C 2-8 alkyl, more preferably n-C 2-4 alkyl, and most preferably ethyl or n-butyl.

Each X is preferably chloro or bromo, in particular chloro 3

Each X is preferably chloride or bromide, especially chloride.

The base used for hydrolysis or neutralization of step (iii) is preferably an inorganic base; such as sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide, more preferably sodium carbonate or potassium carbonate.

The preferred reaction conditions for process A are as follows:

Level (i) / when performed before stage (ii) /:

Temperature: -20 ° to + 50 ° C

Time: 1.5 to 5 hours

Reaction medium: Liquid halogenated lower alkane, e.g.

1,2-dichloroethane and methylene chloride; or acetonitrile; with methylene chloride and acetonitrile being the most preferred

Molar ratio of reactants: 1 to 1.5 moles IX per mol VIII

- 31 Level (ii) / when performed in step (i) /:

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

Time: 0.5 to 3 hours

Reaction medium: same as in step (i)

Molar Ratio of Reactants: 1 to 1.5 moles XI per mol VIII used in step (i)

Stages (i) and (ii) / when performed simultaneously /:

Temperature: -15 ° to + 35 ° C

Time: 2 to 6 hours

Reaction medium: same as in step (i) when performed before step (ii)

Molar ratio of reactants: 1 to 1.5 moles IX and 1 to 1.5 moles XI per mol VIII

Level (iii):

Temperature: 0 ° to 65 ° C

Time: 0.5 to 3 hours

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

Molar Ratio of Reactants: 2 to 4 equivalents of base per mole IX used in step (i)

Preferably, the hydrolysis of step (iii) is carried out with a base.

The reaction medium of steps (i) and (ii) may, on the other hand, and preferably consist of pure reagents,

i.e. reagents in the absence of any solvent, i.e. for step (i) of the compounds of formulas VIII and IX and for step (ii)

- 32 compounds of formulas X and XI. This is very convenient e.g. from an ecological point of view to avoid the presence of solvents such as acetonitrile in waste water or the emission of vapors, e.g. of methylene chloride into the atmosphere. Compounds of formulas VIII and IX respectively. X and XI can be reacted in the absence of solvent because they do not form a solid block when mixed but surprisingly form a suspension.

Process A may be divided into two sub-process depending on the meanings ^{and R} η ^3: (1) R ₁₂ and R are independently alkyl (one sub Aa) and (2) at least one of R ^ and R ^ j ^e is other than _C1 ^ alkyl, (Ab subprocess).

The product of step (iii) of sub-process Aa often contains a significant amount of a compound of formula XIII (E) - OHC - CH = CH - OR ₁₄ (XIII) wherein R1 is defined as above corresponding to the compound of formula VII obtained, wherein the mole the ratio of the compound of formula VII to the compound of formula XIII is typically about 2: 1. While it is, of course, possible to separate a compound of formula VII from a compound of formula XIII by conventional methods of separation, it is preferable to subject the product of step (iii), i.e., a crude compound of formula VII (mixture of a compound of formula VII with a corresponding compound of formula XIII) , stage (iv), t. j. :

(iv) treat the crude mixture containing the compound of formula Vila (E) - OHC - CH = CH - N (R. _O ) R._

12a 13 (Vila) where and are defined as above with the corresponding compound of formula XIV

H ' ^{N (R} 12a ^{) R} 13 ^(XIV) wherein R _12a ^R 13 are as defined above to convert any compound of formula XIII present therein to an additional compound of formula Vila.

Preferably, the reactants in sub-process Aa are those (a) wherein R _{12a is} C 1-6 alkyl, R is C 1-4 alkyl, R 4 is primary or secondary C 1-3 alkyl, each X is chloro and each X 2-4 'a ^d a is chloride;

(b) as (a) but where R ^ nC ₂ 4 ^{a is} -Lkyl;

(c) as (b), but where R _{2a is} ^R 3 is ^{methyl and} ethyl;

(d) - (f) as (a) - (c), but where the base used in step (iii) is sodium carbonate or potassium cabonate; and (g) - (i) as (d) - (f), but where the base used in step (iii) is potassium carbonate.

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

Level (s):

Temperature: 0 ° to 20 ° C, more preferably 0 ° to 15 ° C and even more preferably 5 ° to 15 ° C

Time 1.5 to 4 hours

- 34 Reaction medium: liquid halogenated lower alkane or acetonitrile or pure reagents; the most preferred being methyleneclorld or pure reagents

Molar ratio of reactants: 1 to 1.2 moles IX per mol VIII _Z , more preferably

1.1 to 1.2 moles IX per mol VIII;

Level (ii):

Temperature: 25 ° to 40 ° C

Time: 0.7 to 2.5 hours

Reaction medium: same as in step (i)

Molar ratio of reactants: 1 to 1.2 moles XI per mol VIII used in step (i), more preferably 1.1 to

1.2 mol IX ha mol VIII;

Level (iii):

Temperature: 20 ° to 65 ° C, more preferably 20 ° to 30 ° C

Time: 0.75 to 2 p.m.

Reaction medium: aqueous

Molar Ratio of Reactants: 2 to 4 equivalents of base per mole IX used in step (i);

Level (iv):

Temperature: 0 ° to 20 ° C, more preferably 10 ° to 20 ° C

Time: 0.3 to 1 hour

- 35 Reaction medium: C ₁ _ _{1 |} alkanol, with methanol being the most preferred

The reactant molar ratio: 0.15 to 1 mol XIV per mol VIII used in step (i), more preferably 0.15 to 0.4 moles XIV per mol VIII.

In sub-procedure Aa, step (ii) is performed preferably after step (i).

Preferably, sub-process Aa (i) is the reaction of pure reagents N, N-dimethylforraamide (compound of formula VIII where and R-methyl is) with oxalyl chloride (compound of formula IX where X is chlorine) or in methylene chloride at a temperature of 0 ° to 15 ° C to give the compound of formula Xa

Cl -CH = N ⁺ (CH ₃ ) ₂ Cl (Xa) (ii) the reaction of pure reagents of a compound of formula Xa. with ethylvinyl ether (a compound of formula XI wherein R is ethyl) or in methylene chloride at a temperature of 25 ° to 40 ° C to give a compound of formula XIIa (E) - C_H _c O - CH = CH-CH = N ⁺ (CH ) Cl “(XIIa) d Ό id (iii) hydrolysis of a compound of formula XIIa with potassium carbonate in aqueous medium at a temperature of 20 ° to 30 ° C to obtain a mixture of compounds of formula Vllaa (E) - OHC - CH = CH - N (CH ₃ ) ₂ (Vllaa) and of formula XIIIa (E) - OHC - CH = CH - OC-Hd b (XIIIa)

36 (iv) treating a mixture of compounds of formulas Vllaa and XIIIa with dimethylamine (a compound of formula XIV wherein ^R 13 is methyl) in methanol at a temperature of 10 ° to 20 ° C to convert a compound of formula XIIIa into an additional compound of formula

Vllaa.

More preferably, in sub-process Aa (1), the molar ratio of oxalyl chloride to N, N-dimethylformamide in step (i) is from 1: 1 to 1.2: 1, and step (i) is carried out by adding pure oxalyl chloride reagents to N, N-dimethylformamide or in methylene chloride solution for 1.5 to 4 hours at such a rate that the temperature is maintained at 5 ° to 15 ° C;

(2) in step (ii) the molar ratio of ethylvinyl ether to N, Ndimethylformamide used in step (i) from 1: 1 to 1.2: 1, and step (ii) is carried out by adding ethylvinyl ether to the reaction mixture 0.4 to 1 , For 5 hours at such a rate that the temperature does not exceed 30 ° C, and after the addition is complete, reflux the reaction mixture at 35 ° to 40 ° C for 0.3 to 1 hour and, if appropriate, recover as much methylene chloride as possible, at a temperature not exceeding 45 ° C;

(3) in step (iii) the molar ratio of potassium carbonate to oxalyl chloride used in step (i) from 1: 1 to 2: 1 and step (iii) is carried out by adding water to the product of step (ii) mixed at 20 ° to 30 ° C, allow the temperature to rise to 45 to 60 ° C, maintain this temperature during equilibration of the addition of water and 0.3 to 1 hour, cool the reaction mixture to 15 to 25 ° C, add 0.3 to 1.25 hours aqueous potassium carbonate solution at this temperature, extract the mixture with methylene chloride and distill as much methylene chloride as possible at a temperature not exceeding 45 ° C; and (4) in step (iv) the molar ratio of dimethylamine to N, Ndimethylformamide (used in step (i), from 0.15: 1 to 0.4: 1 and step (iv) is carried out by adding anhydrous dimethylamine to a solution of the product of step ( iii) in methanol mixed at 10 to 20 ° C at a rate not exceeding 20 ° C and distilling off the solvent and any excess dimethylamine at a temperature not exceeding 120 ° C.

Preferred reactants in sub-process Ab are those (a) wherein R _{12b is} ^R 12b ', ^R 13 ^c 1_ ₂ ^alkyl ' ^R 14 is primary or secondary C '' alkyl, each X chloro and each X ~ chloride:

2-4 'aa (b) as (a) but where R _{12b is} ^R 12b' and ^{nC is} 2-4 alkyl;

(c) as (b), but wherein ^R - _{2b is} phenyl, methyl and ethyl or n-butyl, in particular n-butyl;

(d) - (f) as (a) - (c), but where the base used in step (iii) is sodium carbonate or potassium carbonate, and (g) - (i) as (d) - (f ) but where the base used in step (iii) is sodium carbonate.

Preferred reaction conditions for subprocess Ab, especially when the reactants are those of subgroups (a), (d) and (g), more particularly when those of subgroups (b), (e) and (h) _; and in particular where those subgroups (c), (f) and (i) are:

- 38 Level (i) / when performed before stage (ii) /:

Temperature: -20 ° to + 45 ° C

Time: 1.5 to 5 hours

Reaction medium: Liquid halogenated lower alkane or acetonitrile, methylene chloride and acetonitrile being more preferred, acetonitrile being most preferred; or most preferably pure reagents;

The molar ratio of reactants: 1 to 1.2 moles IX per mol VIII, more preferably 1.1 to 1.2 moles IX per mol VIII;

Stage (ii) / when performed after step (i) /:

Temperature: 10 ° to 40 ° C

Time: 0.5 to 3 hours

Reaction medium: same as in step (i)

Molar ratio of reactants: 1 to 1.3 moles of XI per mol of VIII used in step (i), more preferably 1.1 to 1.25 moles of XI per mol of VIII;

Stages (i) and (ii) / when performed simultaneously /:

Temperature: -15 ° to + 35 ° C

Time: 2 to 6 hours

Reaction medium: same as in step (i) when step (ii) is performed

Molar ratio of reactants: 1 to 1.5 moles IX and 1 to 1.5 moles XI per mol VIII;

Level (iii):

Temperature: 0 ° to 35 ° C, more preferably 0 ° to 30 ° C

Time: 0 and 5 to 1.5 hours

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

Mole Ratio of Reactants: 2 to 4 equivalents of base per mole IX used in step (i).

There are three preferred variants of the Ab subprocess, namely, the Ab1, Ab2 and Ab3 variants- In the Ab1 variant, ethyl and reaction media are for steps (i) and (ii) methylene chloride or preferably pure reagents, and in Ab2 and Ab3 variants nbutyl and the reaction medium are for stages (i) and (ii) acetonitrile or preferably pure reagents. In Ab1 and Ab2 variants, step (ii) is performed after step (i) and in Ab3 variant, steps (i) and (ii) are performed simultaneously; in each variant, step (iii) is followed by steps (i) and (ii).

Variant Ab1 of sub-process Ab preferably comprises (i) the reaction of pure reagents of N-methylmethanilide (compound of formula VIII, wherein R _{12 is} phenyl and R methyl) with oxalyl chloride (compound of formula IX, where X

a.

chloro) or in methylene chloride at 15 ° to

45 ° C to give the compound of formula Xb ci - ch = n ⁺ (c ₆ h ₅ ) ch ₃ 'Cl (Xb) (ii) the reaction of pure reagents of the compound of formula Xb with ethylvinyl ether (compound of formula XI, where R ethyl) or in methylene chloride at a temperature of 15 to 40 ^{° C}

4Ό to give a compound of formula XIIb1 (E) - C ₂ H ₅ O - CH = CH-CH = N ⁺ (C ₆ H ₅ ) CH ₃ Cl '(XIIb1) (iii) hydrolysis of a compound of formula XIIb1 with sodium carbonate in mixtures of methylene chloride and water at a temperature of 20 to 30 ° C to give a compound of formula Vllb (E) - OHC - CH = CH-N (C, H _c ) CH_ (Vllb) b 5 3

More preferably, in variant Ab1, subprocess Ab, (1) the molar ratio of oxalyl chloride to N-methylformanilide in step (i) from 1: 1 to 1.2: 1, and step (i) is carried out by adding pure oxalyl chloride reagents to N-methylformanilide or in the solution in methylene chloride at 15 to 20 ° C for 1 to 2 hours and after completion of the addition gradually raise the temperature of the reaction mixture to 0.75 to 1.25 hours at 40 to 45 ° C and then reflux 0.75 to 1.25 hours;

(2) in step (ii) the molar ratio of ethylvinyl ether to N-methylformanilide used in step (i), 1 to 1.3-1, and step (ii) is carried out by cooling the product of step (i) to 15 to 20 ° C. by adding ethylvinyl ether for 0.5 to 1.5 hours at such a rate that the temperature does not exceed 30 ° C, and after the addition is complete, by refluxing the reaction mixture for 0.3 to 0.7 hours; and (3) in step (iii) the molar ratio of sodium carbonate to oxalyl chloride used in step (i) is from 1: 1 to 1.2: 1, and step (iii) is carried out by cooling the pro-product of step (ii) to 15 to 20 ° C by adding 0.5 to 1 hour to an aqueous solution of sodium carbonate at such a rate that the temperature of the reaction mixture is 20 to 30 ° C and after completion of the addition by stirring the mixture 0.2 to 0.5 hours at 20 to 30 ° C, allow the mixture to separate into two phases, separating the two phases and recovering the product from the organic phase.

Variant Ab2 of sub-procedure Ab preferably comprises (i) the reaction of pure N-methylformanilide reagents with oxalyl chloride or in acetonitrile at a temperature of -20 ° to + 20 ° C to give a compound of formula Xb (ii) the reaction of pure reagents of a compound of formula Xb with n -butylvinyl ether (a compound of formula XI wherein R is n-butyl) or in acetonitrile at a temperature of 10 to 40 ° C to give a compound of formula XIIb2 (E) - nC ^ HgO - CH = CH-CH = N ⁺ ( C ₆ H ₅ ) CH ₃ Cl '(XIIb2) and (iii) hydrolysis' of a compound of formula XIIb2 with sodium carbonate in a mixture of acetonitrile and water at a temperature up to 25 ° C to give a compound of formula Vllb.

More preferably, in variant Ab2, subprocess Ab, (1) the molar ratio of oxalyl chloride to N-methylformanilide in step (i) from 1: 1 to 1.2: 1, and step (i) is carried out by adding pure oxalyl chloride reagents to N-methylformanilide or in solution in acetonitrile at -18 ⁰ to +8 ° C for 1 to 2 hours and after the addition is complete by gradually raising the temperature of the reaction mixture to 12 ° to 20 ° C for 0.4 to 0.75 hours and then stirring for 0.2 to 0 , 4 hours at this temperature;

(2) in step (ii) the molar ratio of n-butyl vinyl ether to N-methylformanilide used in step (i) from 1: 1 to 1.2: 1, and step (ii) is carried out by adding N-butyl vinyl ether the product of step (i) stirred at 12 to 20 ° C for 0.5 to 1.5 hours at such a rate that the temperature does not exceed 30 ° C and after completion of the addition by stirring the reaction mixture for 0.3 to 0.7 hours at 25 to 35 ° C; and (3) in step (iii) the molar ratio of sodium carbonate to oxalyl chloride used in step (i) from 1: 1 to 1.3: 1, and step (ii) is carried out by cooling the product of step (ii) to 0 ° to 5 ° C, adding 0.5 to 1.2 hours of aqueous sodium carbonate solution at such a rate that the temperature of the reaction mixture is 5 ° to 12 ° C, and after completion of the addition with the addition of toluene, stirring the mixture at 15 ° to 25 ° C 0.2 to 0.5 hours, allow the mixture to separate into two phases, separating the two phases and recovering the product from the organic phase.

Variant Ab3 of sub-process Ab preferably comprises (i) and (ii) the reaction of pure N-methylformanilide reagents with oxalyl chloride or in acetonitrile at -10 ° to +30 ° C in the presence of n-butyl vinyl ether to give the compound of formula Xb, this compound and then reacted with n-butyl vinyl ether in the reaction mixture to form a compound of formula XIIb2, and (iii) hydrolysis of a compound of formula XIIb2 with sodium carbonate in a mixture of acetonitrile and water at a temperature of 0 ° to 25 ° C to give the compound with the formula Vllb.

More preferred is in the Ab3 variant, subprocess

Ab, (1) in steps (i) and (ii) the molar ratio of each of oxalyl chloride and n-butyl vinyl ether to N-methylformanilide from 1: 1 to 1.2: 1 and steps (i) and (ii) are carried out by adding a solution of pure Nmethylformanilide and N-butyl vinyl ether reagents or in acetonitrile to pure oxalyl chloride or in a solution in acetonitrile mixed at -10 ° to +10 ° C for 2 to 3 hours and after the addition is complete by gradually raising the temperature of the reaction mixture to 20 to 30 ° C for 0.4 to 1.5 hours and then stirring the reaction mixture at this temperature for 0.5 to 1.5 hours; and (2) in step (iii), the molar ratio of sodium carbonate to oxalyl chloride used in step (i) from 1: 1 to 1.3: 1 and step (iii) is carried out by cooling the product of step (ii) to 0 ° to 5 ° C, by adding 0.5 to 1.2 hours of aqueous sodium carbonate solution at such a rate that the temperature of the reaction mixture is 0 ° to 12 ° C, and after completion of the addition with the addition of toluene, stirring the mixture at 15 ° to 25 ° C 0.2 to 0.5 hours, allow the mixture to separate into two phases, separating the two phases and recovering the product from the organic phase.

The product of step (iii) of subprocess Ab can be subjected to step (iv) in analogy to step (iv) of subprocess Aa. However, there is usually no reason to do this because the product usually contains little or no formula XIII compound

7.2. Procedure B (Preparation of Compounds of Formula Va from Compounds of Formula Vile)

The process for the preparation of compounds of formula Va (process B) involves (i) the reaction of a compound of formula Vile (E) - OHC - CH = CH-N (R _12b ) R ₁₃ (Forks) where R 4b 13 is as defined above , with a compound of formula XV

PO (X _b ) ₃ (XV) wherein X _{b is} chloro or bromo, or with a compound selected from oxalyl chloride or -bromide; phosgene or carbonyromide; phosphorus trichloride or tribromide; phosphorus pentachloride or pent bromide; and alkyl or arylsulfonyl chloride or -bromide, such as p-toluenesulfonyl chloride or bromide or methanesulfonyl chloride or -bromide; to give the corresponding compound of formula XVI (E) - X _fe - CH = CH-CH = N ⁺ (R _12b ) R ₁₃ (XVI) and the corresponding anion, e.g. -P0 ₂ (D) _2, ^k j ^{er s0 X} b ^R 12b R1 ^ are as defined above, and (ii) reacting a compound of formula XVI with a compound of formula

XVII

(XVII) where Rg and Rg are defined as above,

(XVIII) and the corresponding anion, e.g. -PO ₂ (Xg) ₂ , wherein Rg, Rg, R ?, Rg, R- | 2 _b »Rj ^ and X _b are as defined above, and (iii) hydrolysis of this compound of formula XVIII to give the corresponding compound s formula Va.

As mentioned above for process A, in the variant in step (i), the compound of formula XII obtained by process A can be used directly instead of the compound of formula

Fairies.

The preferred meanings for R ^ b ^ 13 ^{are indicated} early, the preferred meanings for Rg, Rg, R? and Rg are those given for R _q , R, R _{2 and} . R4 in US-PS 4 739 073. Xg is preferably chloro.

The compound of formula Vile is preferably reacted with the compound of formula XV.

Steps (i) and (ii) are preferably carried out in an inert anhydrous organic medium.

The preferred reactants (and end products) are (a) - (d) those? Where R? _2b ^R 12b '' ^R 13 ^C 1_2 ^-alki1 ' ^each

Xb is chloro and Rg to Rg have the meanings of the respective variables of groups (i), (ii), (xxi) and (xxii) in US-PS 4 739 073;

(e) - (h) that of (a) - (d), where R? _2b ^R 12b * * * ^has i °

Rg to Rg mean the respective variables of groups (v), (vi), (xxv) and (xxvi) in US-PS 4 739 073;

(i) and (j) those of (e) and (f), where R? C? g-alkyl, Rg phenyl, methylphenyl, fluorophenyl, dimethylphenyl or methyl-fluorophenyl, Rg hydrogen, C? N-alkyl or 4 or 6-benzyloxy and R 8 is hydrogen or methyl;

(k) and (1) that of (g) and (h), where R _? phenyl, methylphenyl, fluorophenyl, dimethylphenyl or methyl-fluorophenyl, Rg is C1-6 alkyl, Rg is hydrogen, C1-6 alkyl or

4- or 6-benzyloxy and R8 is hydrogen or methyl;

(m) - (p) one of (i) - (l), wherein Rg is hydrogen and Rg is hydrogen;

(q) - (t) that of (m) - (p), wherein R _{12b is} phenyl and R _{13 is} methyl;

(u) that of (q), where R? 1-methylethyl and Rg 4fluorophenyl; and (v) that of (s) where R? 4-fluorophenyl and Rg 1-methylethyl.

Most preferably Rg and Rg are hydrogen, R? 1-methylethyl and Rg para-fluorophenyl.

The compounds of formula The forks used for step (i) may be in the form of a free base, or preferably in the form of an acid addition salt, e.g. in the form of the acid addition salt of the hydrochloride.

Preferred bases for step (iii) are inorganic hydroxides such as sodium hydroxide and potassium hydroxide, in particular the latter. However, as noted below, it is most preferable not to use any base in step (iii).

The preferred reaction conditions for process B are:

Level (s):

Temperature

Time: 0.1 to 0.5 to

-10 ° to + 25 ° C, more preferably -10 ° to +10 ° C.

1.2 hours, whichever is preferred.

- 49 Reaction medium: lower alkyl nitrile, acetonitrile being the most preferred

Molar ratio of reactants: 1 to 1.5 moles XV per mob of Fairies, more preferably 1.1 to 1.3 moles XV per mole of Fairies

Level (ii):

Temperature: 60 ° to 100 ° C, more preferably 65 ° C to 85 ° C.

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

Reaction medium: same as in step (i)

The molar ratio of reactants: 1 to 5 moles XVI per mol XVII, more preferably 2 to 3 moles XVI per mol. XVII (assuming 100% profit in step (i) in each measure)

Level (iii):

Temperature: 10 ° to 40 ° C when base is used and 35 ° to 60 ° C when not

Time: 0.1 to 1 hour when using the base and 2 to 4 hours when not

Solvent: mixture of water and reaction medium of step (ii) Molar ratio of reactants: when using a base, up to 8 equivalents of base, preferably sodium hydroxide or potassium hydroxide, per mole XV ^ used in step (i).

Even more preferred reaction conditions for process B, especially when the reactants and end products are those of subgroups (a) - (v), especially subgroups (i), (j), (m), (n), (q), (r ) and (u) are:

Level (s):

Temperature: -10 ° to +10 ° C

Time: 0.75 to 1 p.m.

Reaction medium: acetonitrile

Molar Ratio of Reactants: 1.1 to 1.3 moles of XV per mole of Will

Level (ii):

Temperature: 65 ° to 85 ° C, more preferably 80 ° to 83 ° C

Time: 3 to 16 hours, with 3 to 10 hours more preferred

Reaction medium: acetonitrile

Molar ratio of reactants: 2 to 3 moles XVI per mol VII, more preferably 2.1 to 2.5 moles

XVI per mole XVII (in each case we assume 100% one gain in step (i))

Level (iii):

Temperature: 20 ° to 55 ° C; preferably 25 ° to 35 ° C when using the base and 35 ° to 55 ° C when not in use

Time: 0.3 to 0.7 hours when using the base and 2 to 3 hours when not

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

Reactant Mole Ratio: When using a base, up to 6 equivalents of base, preferably sodium hydroxide per mole XV, used in step (i)

Most preferably, in step (iii) we do not use a base,

8. General conditions applicable to all procedures

Most of the molar quantities (ratios) listed here are for example only and can be varied, as is apparent to one skilled in the art.

Process steps A (i) and (ii) (including sub-steps Aa and Ab and variants thereof), process steps (i) and (ii), and preferred step (iv) sub-steps Aa are preferably carried out under anhydrous conditions and in an inert atmosphere, preferably in dry helium, argon or nitrogen, or in a mixture of them · usually in dry nitrogen. Stage (iii) from the process

A (including the subprocesses Aa and Ab and their variants) and process B are often, but not necessarily, performed in an inert atmosphere.

Similarly, most of the temperature ranges given above are for example only. All temperatures are internal temperatures unless otherwise stated. As used above, it covers the term reaction medium of a mixture of liquids and means that the reaction medium is a liquid at the desired reaction temperature. Therefore, it is intended that not all of the fluids indicated for a particular step should be used for the entire said temperature range. It is also intended that the reaction medium should be at least substantially inert to the reactants used, the intermediates formed and the final products under the reaction conditions used. It is intended that the reaction temperature may exceed the boiling point of the reactant or reaction medium if a condenser or closed system (reaction bomb) is used.

The above reaction times are also exemplary and subject to change.

It is also intended that conventional processing operations may be used. The term solvent, as used herein, encompasses solvent mixtures and means that the reaction medium is a liquid at the desired reaction temperature. Unless otherwise stated, all solvent mixtures are volumetric. 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 can optionally be purified by conventional techniques such as recrystallization, chromatography or fractionation distillation. All temperatures are in

Degrees Celsius and the room temperature is 20 ° to 30 ° C, usually 20 ° to 25 ° C, unless otherwise noted; evaporation was carried out under vacuum using minimal heating, the organic phases were dried over anhydrous magnesium sulfate and, unless otherwise stated, silica gel was used for all column chromatographies.

It should be appreciated that variants of the process described in the present invention are improvements in known similar processes; they can be used to obtain the desired end products, i.e. 7-substituted hept-6-enoic and heptanoic acids and their derivatives, e.g. in an easier way or e.g. in a state of greater chemical or optical purity than can be achieved by conventional methods.

The above process variants can be used either individually in conjunction with conventional processes or, if desired, or in combination, to obtain the desired end products.

9. Specific design

A specific illustration of the general inventive concept underlying the above process variants relates to the preparation of erythro- (E) -3,5-dihydroxy-7- / 3 '- (4' '- fluorophenyl) -1' - (1 '' -methylethyl) indol-2'-yl] -hept-6-enoic acid of formula Ia

in racemic or optically pure form; in the form of free acid, salt, ester or <^ - lactone, i.e. of the ester, in a multi-step process using all the above variants of the process, namely, processes A, B and stereoselective reduction of a compound of formula II, and comprises:

- by Procedure A:

a) reaction of a compound of formula Vlila

OHC - N (R _12b ) R _n (Vlila) wherein R ^ b ^R 13 is as defined above, with a compound of formula IX, optionally in an inert anhydrous organic medium, to obtain the corresponding compound of formula Xc x _a - CH = N (b, _L2B) R ₁₃ X is _a - (Xc) wherein X _a, R b ^R 13 are as defined above;

b) reacting this compound of formula Xc with a compound of formula XI, optionally in an inert anhydrous organic medium, to obtain the corresponding compound of formula XIIc

a (XIIc) (E) - R - CH = CH - CH = N ⁺ (R

c) hydrolysis of this compound of formula XIIc to give the corresponding compound of formula Vile in the form of a free base or an acid addition salt and, if in the form of an acid addition salt, the neutralization of an acid addition salt with a base;

- by procedure B:

d) reacting this compound of formula Vile with a compound of formula XV or with a compound selected from oxalyl chloride or -bromide;

phosgene or carbonyl bromide; phosphorus trichloride or tribromide; phosphorus pentachloride or pentabromide; and alkyl or arylsulfonyl chloride or -bromide, such as p-toluenesulfonyl chloride or -bromide or methanesulfonyl chloride or -bromide;

to give the corresponding compound of formula XVI and the corresponding anion, e.g. -PO ₂ (X _b ) ₂ ;

e) reacting this compound of formula XVI with 3- (4'-fluorophenyl) 1- (1'-methylethyl) -1H-indole (a compound of formula XVII, wherein R 1 and R 8 are hydrogen, R 1 is 1-methylethyl and Rg is p-fluorophenyl) to give the corresponding compound of formula XVIIIa

F

ch (cb ₃ ) ₂ (XVIIIa)

- 56 and the corresponding anion, e.g. ^{50 R} 12b ' ^R 13 ^and ^ a defined as above;

f) hydrolysis of this compound of formula XVIIIa to give (E) -3- / 3 '- (4' '- fluorophenyl) -1' - (1 '' -methylethyl) -1H-indol 2'-yl / -prop- 2-enal (a compound of formula Va, wherein R 1 and R 8 are hydrogen, R 1 -methylethyl and R 8 are p-fluorophenyl);

g) reacting that compound of formula Va with dianionom acetoacetic ester of the formula CH? COCl ^ COOR _1, where R ₁ is as defined above, to give a corresponding compound of formula Ila

wherein R 2 is as defined above; in racemic or optically pure form;

- by stereoselective reduction process:

h) stereoselective reduction of the racemic or optically pure compound of formula Ila in the first step / = step (a) under 5 above / by mixing the compound of formula III with sodium borohydride (NaBH ^) in a reaction medium comprising alcohol and tetrahydrofuran in the second - step (b) under 5 above /, by treating a compound of formula Iia in racemic or optically pure form with the resulting mixture under conditions suitable to give a mixture containing a cyclic boronate compound of formula IV (a) and / or a boron complex of formula IV (b) wherein

R / 3- (4'-fluorophenyl) -1- (1'-methylethyl) -1H-indol / -2-yl,

X -CH = CH- and sta

R ₁ and R 4 are as defined above; and in step 3 - step (c) below 5 above / by cleavage of the product obtained in step 2 to give the compound of formula Ia in ester. form; in racemic or optically pure form; and

i) optionally converting the compound of formula Ia into the ester form in a conventional manner into the free acid form, the salt form, the further ester form or the form of ^ -lactone ^ t. j. of the internal ester.

The compound of formula Ia may be in the form of a free acid, preferably in the form of a free acid or salt, preferably an alkali salt, in particular the sodium salt. Preferably, it is in racemic or alternatively optically pure (3R, 5S) enantiomeric form, especially in racemic form. As seen from formula Ia, this form is erythro form.

The specific embodiment shown under 9. is carried out either according to the methods described in the present invention or for some of the steps according to the prior art.

So

- steps a), b) and c) are carried out as described above

7.1. for the Ab subprocess, especially its degrees i), ii) and. iii) e.g. by Ab1, Ab2 and / or Ab3 variants of the Ab sub-procedure; stages a) and b) can thus e.g. is carried out at the same time as described above for process A:

- steps d), e) and f) are carried out as described above

7.2. for process B, in particular its stages i), ii) and. iii);

- step g) is carried out according to the procedures published e.g. in USPS 4 739 073, in particular in reaction scheme I in column 8 and in example 5, step 5, in column 47 of this file;

- step h) is carried out as described above under 5;

- step i) is carried out in the usual way, e.g. as described in US-PS 4 739 073, in particular in reaction schemes I (reactions C, D and E) in column 9; reaction scheme II (reaction L) in column 11; Reaction Scheme VIII (EE Reaction) in Column 16; and in cases 6 (a), 6 (b), 6 (c), 8 and 9 in columns 49 and 50 and 52 and 53 of this file, where THF can be advantageously substituted with ethanol.

In the second part of the above stereoselective reduction step h), a preferred compound of formula Ila is used, wherein R _{1 is} isopropyl, or in particular t-butyl, which facilitates the isolation of a relatively pure compound of formula I than with the group R 6 as methyl. Furthermore, surprisingly, the compound of formula I obtained is completely colorless, whereas in previous syntheses it has always been pale yellow.

As mentioned above, stereoselective reduction according to step h) can be carried out with a racemic or optically pure compound of formula Ha. An optically pure compound of formula Ha is obtained e.g. by chromatographic separation of the racemic compound of formula Ila obtained in step g), or preferably by asymmetric synthesis. On the other hand, the separation can be carried out in the next step or with the racemic end product.

The starting materials for this specific embodiment of the invention are also known or can be prepared according to known methods. Preparation of 3- (4'-fluorophenyl) -1- (1'-methylethyl) -1H-indole / compound of formula XVII, see step e) above / is described in US-PS 4 739 073 as an example of 5, steps 1 to 3, in columns 44 and 45 _? from fluorobenzene.

The invention also of course relates to the above processes A, B and the stereospecific reduction process individually when used to prepare a compound of formula Ia in combination with conventional methods not specifically described above.

- 60 10. EXAMPLES

The following examples illustrate the invention. All temperatures are in degrees Celsius. The optical purity is expressed as a percentage and so e.g. A 99.9% pure erythro isomer means that no more than 0.9% of the trio is present in the compound obtained.

10.1. Examples of stereoselective reduction of a compound of formula

11 to give the compound of formula I

Example 1: tert-butyl (+) -eritro- (E) -7- / 3 '- (4-fluorophenyl) -1' - ^{(1-ll-methylethyl) indol-2>} yl / 3,5-dihidroksihept6- enoic acids / Formula I: R = 3- (4'-fluorophenyl) -1- (1'-methylethyl) indol-2-yl;

X = (E) -CH = CH-; R t = t-butyl; in racemic form / (a) 47.67 g (1.26 mol) of sodium borohydride is added to a solvent comprising 1.32 l of dry tetrahydrofuran (THF) .and 356 ml of methanol under nitrogen at about -77 °. To the resulting solution was added 15 minutes 102 ml of 50% (4.09 M) diethylmethoxyborane in THF and the resulting mixture was stirred for another 10 minutes.

(b) 300.5 g (0.464 moles) 71.88% pure tert.butyl ester (-h) - (E) - 7- / 3 '- (4-fluorophenyl) -1' - (1 - methylethyl) indol-2 '-yl / -5-hydroxy-3-oxohept-6-enoic acid in 104 ml of THF and 26 ml of methanol at a temperature between about -74 ° to -77 ° C is added 1.5 hours dropwise to the mixture, formed in (a), and the resulting mixture was stirred for another 30 minutes. 720 ml of saturated sodium bicarbonate solution and 1.75 l of heptane are added to quench the reaction, then 500 ml of ethyl acetate are added and the resulting mixture is diluted with 3.5 l of water with stirring for 15 minutes, keeping the temperature of the mixture about 10 °. The upper organic layer was separated and washed several times with a total of 2.4 l of saturated sodium chloride solution, pH 7.5, and the organic layer was evaporated at 26.6 to 40 mbar at a maximum outdoor temperature of about 45 °. To the organic residue was added 375 ml of toluene and the solvent was distilled at 26.6 to 40 mbar at a maximum external temperature of about 45 °.

(c) 3.73 l of ethyl acetate are added to the resulting thick oil (mainly cyclic boronate). Then, 500 ml of a 30% hydrogen peroxide solution (4.41 mol) was added to the ethyl acetate solution while maintaining the internal temperature from 25 to 30 ° (with the addition initially exothermic) and the reaction mixture was stirred for about 2 hours at 20 to 25 ° until boronate was no longer present after thin layer chromatography. The upper organic layer was washed twice with a total of 2.22 l of saturated sodium chloride solution, pH 7.5. The upper organic layer was then separated, washed three times with a total of 2.61 1 10% sodium sulfite solution (until the organic layer was peroxide free) while maintaining an internal temperature of 25 °. The upper organic layer was then washed twice with a total of 1.72 l of saturated sodium chloride solution, pH 7.5, and the solvent was distilled off at 26.6 to 40 mbar and a maximum external temperature of about 45 °. The residue was dissolved in 1.17 l of refluxing ethyl acetate, the mixture filtered while still hot, and the filtrate was stirred at 20 to 25 ° for 18 hours. The solids were collected by filtration, dried under reduced pressure (about 26.6 to 40 mbar) at 25 ° C, washed with

550 ml of ethyl acetate / heptane (1: 4) was redissolved in 880 ml of ethyl acetate and stirred for 18 hours at room temperature. The solids were collected by filtration and washed with 480 ml of ethyl acetate / heptane (1: 2). The solids were dried under reduced pressure to give 114.5 g of product (mp 135 to 137 °).

A second yield is obtained from mother liquors, with a total yield of 149.5 g. The product has a chemical purity of 99.44% and is 99.67% pure erythro isomer. It can be separated into two optically active enantiomers, 3R, 5S and 3S, 5R, of which the former is preferred.

On the other hand, and preferably in step (a), half of said amount of sodium borohydride can be used.

On the other hand, in step (c), an aqueous solution of sodium perborate can be used instead of a 30% solution of hydrogen peroxide.

EXAMPLE 2 Methyl ether (t) -erythro- (E) -7- [3- ^, - (4-fluorophenyl-1 ^, - (1methylethyl) -indol-2 * -yl] -3,5-dihydroxyhept-6enoic acid / Formula I: R, X = as for Example 1; R ^ = methyl; in racemic form / (a) Sodium borohydride is treated in a manner analogous to example 1, step (a), but using 15% diethylmethoxyborane in

THF.

(b) 118.5 g (0.28 mol) of methyl ester (+) - (E) - / 7- (3 '- (4-fluorophenyl) -1' - (1-methylethyl) indol-2'-yl / -5-Hydroxy-3-oxohept-6enoic acid was treated analogously to Example 1, step (b), but diluted with 1.42 1 water and 1.185 1 heptane instead of only 3.5 1 water.

- 63 (c) To the organic residue (predominantly cyclic boronate) was added 2,375 l of ethyl acetate, the mixture was treated with 264 ml of 30% hydrogen peroxide solution (2,328 mol) and treated as described in Example 1, step (c). The residue was then dissolved in 130 ml of isopropanol. The mixture was heated to reflux temperature. Add 14 S of boric acid in hot water and reflux for 15 minutes. The mixture was then filtered and the filtrate was stirred for 18 hours at 20 to 25 °. The solids were collected by filtration, washed with 100 acres of isopropanol, dried under reduced pressure, to give 110 g of product (80% yield). The product was redissolved in methanol and recrystallized (mp 124 to 126 °). The product is 99.07% pure erythro racemate, which can be separated into two optical enantiomers, 3R>

5S and 3S, 5R, the former of which is preferred.

EXAMPLE 3'- Tert-Butyl ester (+) - erythro- (E) -3,5-dihydroxy-7- [1 (4-fluorophenyl) -4 * - (1-methylethyl) -2 * -phenyl-1Himidazole-5 * -yl / hept-6-enoic acid / Formula I: R = 1- (4'-fluorophenyl) -4- (1'-methylethyl) -2-phenyl-1H-ylrazazol-5-yl;

X = (E) -CH = CH-; R ₁ = tert.butyl; in (3R, 5S) -enantiomeric form / (a) 10.27 g (0.27 mol) of sodium borohydride is added to a solvent comprising 1.67 l of dry THF and 513 ml of methanol under nitrogen at about -76 °. To the resulting solution was added 30 minutes 387 ml of 15% diethylmethoxyborane in THF while maintaining the internal temperature below -77.5 ° and the resulting mixture was stirred for another 5 minutes.

(b) 110 g (0.223 mol) of tert-butyl ester (5S) - (E) -7- / 1 '- (4-fluorophenyl) -4', - (1-methylethyl) -2 (-phenyl-1H- imidazol-5 '- yl / -5-hydroxy- 64 3-oxoheptyl-6-enoic acid in 304 ml of THF and 76 ral of methanol at a temperature of about -74 ° to -77 ° was added 2 hours after dropwise to _Raes? incurred ( a) The resulting yellow solution was stirred for 6 hours at -76.5 ° Then 425 ml of saturated ammonium chloride were added to quench the reaction, maintaining the temperature at about -65 ° C. 950 ml of ethyl acetate, 950 ml of hexane and 1.13 were added. 1 of water, the temperature of the mixture being about 5 ° and the mixture stirring for 15 minutes, leaving the final temperature of the mixture about 5 ° The top organic layer was separated, washed successively with a total of 1.4 1 of saturated sodium chloride solution (pH 7.5) and the solvent was distilled at 26.6 to 40 rabe at a maximum outside temperature of about 45 °.

(c) 3.25 l of ethyl acetate are added to the resulting oil (mainly cyclic boronate). Then, 340 ml of a 30% hydrogen peroxide solution (3 moles) are slowly added to maintain an internal temperature of 20 ° to 25 ° and the reaction mixture is stirred for about 3 hours at 20 to 25 ° until boronate is present after thin layer chromatography. The upper organic layer was washed twice with a total of 1.6 l of saturated sodium chloride solution, pH 7.5. The upper organic layer was then separated, washed three times (each 10 minutes each) with a total of 1.5 1 10% sodium sulfite solution (until the organic layer was peroxide free) while maintaining an internal temperature of 25 °. The top organic layer was washed with 600 ml of saturated sodium chloride solution (pH 7.5). The solvent was distilled at 26.6 to 40 mbar at a maximum outside temperature of about 45 °. 106 g of crude material are obtained. 0.68 g of crude dihydroxy ester was purified by column chromatography using ethyl acetate / hexane

- 65 (1: 2) as eluant to give 490 mg (mp 143 to 145 °), which, by NMR analysis, shows that they contain an erythro isomer of 98.78% Purity (without thre isomers);

/ iU / _D ²⁰ = + 6.49 ° (c = 0.77, CH ₂ C1 ₂ ).

EXAMPLE 4 Tert.butyl ester (3R, 5S) -erythro-dihydroxy-6-trityloxyhexanoic acid / Formula lu: u = trityl; R _u = t-butyl; in (-) - enantiomeric form / (a) 5.61 g (148.4 mmol) of sodium borohydride is added to a solvent comprising 990 ml of dry THF and 280 ml of methanol under nitrogen at about -76 °. The temperature rises to about -74 °. To the resulting solution was added dropwise 129.7 ml of 15% diethylmethoxyborane in THF for 20 minutes, and the resulting mixture was stirred for a further 10 minutes at -77 ° to -76 °.

(b) 56 g (0.122 mmol) of (S) -5-hydroxy-6-trityloxy-3-oxohexanoic acid t-butyl ester in 165 ml of THF and 41 ml of methanol at a temperature of about -77 ° to -75 ° are added dropwise 40 minutes to the mixture formed in (a) and the resulting mixture was stirred for a further 2 hours at -77 ° to -75 °. 156 ml of saturated ammonium chloride solution are added to quench the reaction. Then add 500 ml of ethyl acetate, 500 ml of heptane and 600 ml of water. The upper organic layer was separated and washed successively with a total of 600 ml of saturated sodium chloride solution, pH 7.5, and the organic layer was evaporated at 26.6 to 40 mbar at a maximum outdoor temperature of about 45 °.

(c) To the resulting organic residue (containing predominantly cyclic boronate) was added 793 ml of ethyl acetate. Then 79 ml% hydrogen peroxide solution (0.7 mol) was slowly added and the reaction mixture was stirred for about 3 hours until boronate was no longer present after thin layer chromatography. The upper organic layer was washed twice with a total of 400 ml of saturated sodium chloride solution, pH 7.5. The upper organic layer was then separated, washed three times (each time for 10 minutes) with a total of 576 ml of 10% sodium sulfite solution (until the organic layer was free of peroxides) while maintaining an internal temperature of 25 °. The upper organic layer was then successively washed with a total of 200 ml of saturated sodium chloride solution, pH 7.5, and the solvent distilled at 26.6 to 40 mbar and a maximum external temperature of about 45 °. 54.3 g of the crude dihydroxy compound (mp 84 to 86 °) are obtained which contains 99.19% erythro isomer; / οΕ / ^ θ - -5.59 ° (c = 1.6, CH ^ C ^) ·

10.2.

Examples for the preparation of intermediates of formula VII according to method A

EXAMPLE 5: 3- (N, N-Dimethylamino) acrolein / = (E) -3- (N, N-dithylthiamine) prop-2-enal // Formula VII: R4, R-, β = methyl / / subprocess Aa / (Level (s): In a 12 1-round, 4-necked flask equipped with a mixer, a condenser filled with brine, a thermometer, a caustic washer, a feed hopper and a cooling bath, dosed under a nitrogen cushion 4, 0 1 methylene chloride, and 438 g (5.99 moles) of N, N-dimethylformamide The solution was cooled to 7 ° and 860 g (6.8 moles) of oxalyl chloride were added at 2.5 hours at such a rate that little or no solvent was present. and / or reagent

- 67 does not enter the condenser, maintaining the temperature of the reaction mixture at 5 ° to 10 °. A white solid is formed.

Step (ii): Add 483 g (6.7 mol) of ethylvinyl ether for 30 to 60 minutes while maintaining a maximum temperature of 25 ° to 28 °, with the addition being very exothermic. A brownish red solution is obtained. The reaction mixture was heated at 37 ° to 38 ° for 30 minutes, refluxing. Distillation at 40 to 53 mbar and 45 ° recovers as much methylene chloride as possible, and after completion of the distillation, the reaction mixture is maintained at 40 mbar and 45 ° for 30 minutes to give a dark, brown, mixable oil.

Step (iii): Cool the reaction mixture to 20 ° and add 450 ml of water for about 30 minutes; let the exotherm raise the temperature to 60 ° and maintain this temperature to balance the addition. The mixture was stirred for 30 minutes at 50 ° to 60 ° and cooled to 20 °. A solution of 1.71 kg (12.35 moles) of anhydrous potassium carbonate in 3.6 l of water was added for 30 to 45 minutes while maintaining the temperature at 20 to 22 °. The aqueous layer was extracted with 4 L of methylene chloride, the methylene chloride layer at the bottom was separated, and the upper aqueous layer was extracted four times with 1 L of methylene chloride.

The methylene chloride phases are combined, dried over 500 g of anhydrous sodium sulfate and filtered and the solid washed twice with 250 ml of methylene chloride. The washing liquids and the filtrate were combined and distilled as much as possible of methylene chloride as much as possible with distillation at 26.6 to 53 mbar and 45 ° to give a thick, miscible oil.

Step (iv): Cool the oil to 20 °, add 500 ml of methanol, cool the mixture to 10 ° and add 60 g (1.33 mol) of anhydrous dimethylamine while maintaining a maximum temperature of 20 °. Distill at 26.6 to 40 mbar and 70 ° to recover as much solvent as possible, reduce the pressure to 4 to 5.3 mbar and continue distillation while gradually raising the temperature until it reaches 120 ° and the steam temperature reaches 115 °, yielding 89.7% Pure product as an oil (412 g; Yield 62%; Pure product boiling 271 to 272.8 °).

EXAMPLE 6: 3- (N-Methyl-N-phenylamino) acrolein / = (E) -3- (N-methyl-N-phenylamino) prop-2-enal // Formula VII: R4 = phenyl; R ^ g = methyl // subprocess Ab, variant Ab1 /

Stage (I): In a 12 l round-bottomed four-necked flask fitted with a mixer, a brine-filled condenser, a thermometer, a caustic washer, a feed hopper and a cooling bath, dosed under a nitrogen cushion of 3.0 l of methylene chloride and 1.02 kg (7.4 mol) of N-methylformanilide. The solution was cooled to 15 ° and 1.10 kg (8.67 moles) of oxalyl chloride was added at a rate such that only little or no solvent and / or reagent reached the bottom of the brine-filled condenser, maintaining the temperature of 15 ° to 17 ° at mild reflux. The reaction mixture was slowly heated to 43 ° for 1 hour and refluxed for 1 hour at 43 ° to 45 ° to give a clear yellow solution and cooled to 15 °.

- 69 Step (ϋ): Add 648 g (8.99 moles) of ethylvinyl ether for 40 to 60 minutes while maintaining a maximum temperature of 28 ° to 29 °, with the reaction being very exothermic. The resulting brown red solution was heated at 38 ° to 39 ° for 30 minutes, refluxing and cooled to 15 °.

Step (s): A solution of 960 g (9.05 moles) of anhydrous sodium carbonate in 4.5 l of water is added for 45 to 60 minutes while maintaining the temperature of 22 ° to 30 °, with the addition being very exothermic. The mixture was stirred for 15 minutes at 22 ° to 25 ° and allowed to stand for two minutes. The organic phase was separated and the aqueous phase was extracted with 1.25 l of methylene chloride. The methylene chloride extract was combined with the previous organic phase and the combined solution was extracted with 1 L of water. The aqueous extract was back extracted with 250 ml of methylene chloride and this methylene chloride extract was combined with the previous organic phase. Distillation at 26.6 to 53 mbar and 60 ° recovers as much methylene chloride as possible, and the resulting oil is heated at 26.6 to 40 mbar and 60 ° to 65 ° 4 hours, yielding 83.5% pure product as oil (1,295 kg; 90.7% yield; pure product boiling point 244 ° (dec);

m.p. of pure product 46 to 47 ° from isopropanol / hexane 1: 1).

EXAMPLE 7 3i (N-methyl-N-phenylamino) acrolein / = (E) -3- (N-methyl-N-phenylamino) prop-2-enal // Formula VII: R4, ^ 3 ⁼ as for example 6 / / subprocess Ab, variant Ab2 /

Level (s): In 5 1-round, four-necked flask equipped with a mixer, a brine-filled condenser, a thermometer, a caustic washer, a feed hopper, and

- 70 cooling bath, place 350 ml of acetonitrile and 425 g (3) 8 moles of N-methylformanilide under a nitrogen pad. The solution was cooled to -15 ° and 440 hours (3.46 mol) of oxalyl chloride were added for 1.5 hours at such a rate that little or no solvent and / or reagent reached the bottom of the brine-filled condenser maintained at -25 ° to -20 °, maintaining a temperature of -15 ° to -10 ° with gentle reflux. The reaction mixture was slowly warmed to 15 ° for 30 minutes and stirred for 15 minutes at 15 ° to 18 °.

Step (ii): 339> 5 g (3.39 mol) of N-butylvinyl ether is added for 45 minutes while maintaining a maximum temperature of 28 ° to 30 °, with the reaction being very exothermic. The reaction mixture was stirred for 30 minutes at 30 ° to 35 ° to give a red-brown solution and cooled to

Step (iii): A solution of 395 g (3.73 mol) of anhydrous sodium carbonate in 1.75 l of water is added for 40 to 60 minutes while maintaining the temperature of 8 ° to 10 °, with the addition being very exothermic. 1.75 i toluene was added, the mixture was stirred for 15 minutes at 20 ° to 22 ° and allowed to stand for 15 minutes to separate into two phases. The organic phase was separated and washed twice with 150 ml portions of water. Distillation at 26.6 to 107 mbar and 60 ° to 90 ° recover as much toluene as possible and heat the remaining oil for 30 minutes at 26.6 to 40 mbar and 89 ° to 90 ° to give 86.6% - pure product as oil (492 g; yield 85.7%; pure product boiling point 244 ° (dec); melting point of pure product 46 to 47 ° from isopropanol / hexane 1: 1).

If the reaction mixture was stirred for 30 minutes at 28 ° to 30 ° instead of 30 ° to 35 °, a yield of 90.7% 92.3% pure product was obtained.

EXAMPLE 7a: 3- (N-methyl-N-phenylamino) acrolein / = (E) -3- (N-methyl-N-phenylamino) prop-2-enal // Formula VII: R4 and ^{R13 =} * ^{cot for} 6 // sub-procedure Ab, variant Ab2, pure reagents /

Step (i): In a 2.5 l four-necked flask, equipped as in Example 7, Step (i), was dosed in a nitrogen atmosphere with 223.2 ml (1.81 mol) of N-methylformanilide. The solution was cooled to 15 ° and 177.6 acre (2.07 mol) of oxalyl chloride was added for 20 minutes while maintaining the same temperature. The spontaneous evolution of gas occurs and an orange homogeneous solution is formed.

Step (ii): Add 278.4 ml (2.16 mol) of N-butylvinyl ether for 45 minutes while maintaining an internal temperature of 25 ° to 30 °, leaving the reaction exothermic. The orange suspension was stirred for 30 minutes at 40 ° to 45 ° and cooled to 0 °

Step (iii): Add a slow 4 N NaOH solution to the product of step (ii) for 90 minutes so that the temperature does not exceed 5 °. The mixture was warmed to room temperature and stirred for a further 60 minutes. The organic layer was separated in a 3 L funnel and the aqueous phase extracted with 100 ml of N-butanol. The combined organic layers were washed twice with 200 ml of brine and the solvent was distilled off at 80 ° / 20 mbar for 2 hours to give a thick brown black oil (295 g; yield 92%; chemical purity above 98%; pure product boiling point 244 ° (dec. .);

of pure product 46 to 47 ° from isopropanol / hexane 1: 1).

EXAMPLE 8: 3- (N-Methyl-N-phenylamino) acrolein / = (E) -3- (N-methyl-N-phenylamino) prop-2-enal // Formula Vil: R4, ^ 13 ~ ^{as for} P ^r i ^mer θ / / subprocess Ab, variant Ab3 /

Levels (i) and (ϋ): In a 12 1-round, four-necked flask equipped with a mixer, a condenser filled with brine, a thermometer, a caustic washer, an addition funnel and a cooling bath, put under a nitrogen bag of 1,056 kg ( 8.15 mol) of oxalyl chloride and 480 ml of acetonitrile. The solution was cooled to -10 ° and a mixture of 1.02 kg (7.395 mol) of N-methylformanilide, 816 g (7.98 mol) of N-butylvinyl ether and 360 ml of acetonitrile was added for 2.5 hours at such a rate that only little or no solvent was present. and / or the reagent reaches the bottom of the brine-filled condenser (maintained at -25 ° to -20 °) while maintaining the temperature at -10 ° to -5 ° with gentle reflux. The resulting homogeneous orange reaction mixture was slowly heated to 20 ° for 30 minutes; slight exotherm raises the temperature to 28 ° for 30 minutes. The reaction mixture was stirred for 1 hour at 28 ° to 30 ° to give a brown homogeneous mixture and cooled to 0 °.

Step (iii): A solution of 948 g (8.94 moles) of anhydrous sodium carbonate in 4.20 l of water is added for 45 to 60 minutes while maintaining the temperature of 8 ° to 10 °, the addition being very exothermic initially. 3.60 l of toluene was added, the mixture was stirred for 15 minutes at 20 ° to 22 ° and allowed to stand for 15 minutes to separate in two phases. The organic phase was separated and washed twice with 360 ml portions of water. Distillation at 26.6 to 106 mbar and 60 ° to 90 °

- 73 toluene is recovered as much as possible and the remaining oil is heated at 26.6 to 40 mbar and 89 ° to 90 ° for 30 minutes to give 89.1% pure product as oil (1.16 kg; yield 86.6%; boiling point of pure product 244 ° C (dec.); M.p. of pure product 46 to 47 ° from isopropanol / hexane 1: 1).

10.3. Examples for the preparation of intermediates of formula Va according to method B

EXAMPLE 9: (E) -3- / 3 '- (4-fluorophenyl) -1' - (1 '-methylethyl) -1H-indol 2'-yl / prop-2-enal / Formula Va: R 1, R 8 - H; R? = 1-methylethyl; Rg = 4-fluorophenyl / / process B / (i) In a 5 1-round, four-necked flask equipped with a mixer, a condenser, a thermometer, a pouring funnel and a cooling bath, dose 100 ml of dry acetonitrile under dry nitrogen cushion and 174.4 g (1.14 mol) of phosphorus oxychloride, the mixture was cooled to -5 ° and a solution was added for 45 minutes

184 g (0.96 mol) of 83.5% pure 3- (N-methyl-N-phenylamino) acrolein (product of Examples 6 to 8) in 156 acres of dry acetonitrile while maintaining a temperature of -5 ° to + 5 °. The reaction mixture was stirred at 0 ° to 5 ° for 10 minutes.

(ii) 115.2 g (0.45 mol) of 3- (4′-fluorophenyl) -1- (1′-methylethyl) 1H-indole (compound of Formula XVII) was added for 20 minutes while maintaining a temperature of about 5 °. The reaction mixture was refluxed at 83 ° for 9 hours and cooled to 10 °.

- 74 (iii) A solution of 228 g (5.7 mol) of sodium hydroxide in 2.0 l of water is slowly added over 30 minutes while maintaining the temperature of 25 ° to 30 °, with the addition being very exothermic. 1.6 l of toluene was added, the mixture was stirred for 30 minutes at 25 ° and filtered through a filter roll. The filter cake was washed with 100 ml of toluene and the wash liquid was combined with the previous filtrate. The organic layer was separated and a mixture of 93.4 g of conc. hydrochloric acid and 2 l of water followed by 400 ml of saturated sodium chloride solution. The mixture was stirred for 30 minutes at 25 ° and the resulting suspension was filtered through a filter roll. The resins were washed with 100 ml of toluene and the washing liquid was combined with the filtrate. The organic layer was separated, washed twice with 2 l portions of deionized water and filtered through a filter roll. Distillation at 40 to 77 mbar and an external temperature of 60 ° to 65 ° recovers as much toluene as possible to obtain a thick, miscible oil. Add 100 ml of 95% ethanol, distillate at 40 to 106 mbar and 60 ° to 65 ° to recover as much ethanol as possible and repeat this twice. 180 ml of 95% ethanol are added, the mixture is refluxed at 78 ° for 15 minutes and then cooled slowly to 20 ° for 2 hours, starting crystallization at about 55 °. The suspension was slowly cooled to 0 ° to 5 ° for 30 minutes, maintained at 0 ° to 2 ° for 1 hour and filtered. The filter cake is washed three times with 50 ml portions of cold (0 ° to 5 °) 95% ethanol and dried in vacuo at 60 ° to 65 ° for 16 hours to constant weight to give 98.7% pure product ( 101 g; yield 71.3%; mp 127 to 128 °).

Alternatively, isopropanol is used instead of 95% ethanol.

EXAMPLE 10: (E) -3- / 3 '- (4-fluorophenyl) -1 * - (1-methylethyl) -1H-indol2'-yl / prop-2-enal / Formula Va: R4, Rg, R ?, Rg = as for example 9 // procedure B, alternative process /

i) In a 5 l round-necked four-necked flask equipped with a mixer, condenser, thermometer, add funnel and cooling bath, 263 ml dry acetonitrile and 454 g (2.96 moles) of phosphorus oxychloride are added under a cushion of dry nitrogen. cooled to -5 ° and a solution of 471.6 g (2.49 mol) of 85.5% pure 3- (Nmethyl-N-phenylamino) acrolein in 406 ml of dry acetonitrile was added for 45 minutes while maintaining a temperature of 5 ° to 7 ° . The reaction mixture was stirred for 10 minutes at 5 ° to 7 °.

ii) 300 g (1.18 moles of 3- (4'-fluorophenyl) -1- (1'-methylethyl) -1H-indole (compound of formula XVII) are added over 10 minutes while maintaining the temperature at about 7 °. The reaction mixture is refluxed 3 hours at 83 ° and cooled to 22 °.

iii) 2.7 l of water is slowly added for 15 minutes while maintaining the temperature from 22 ° to 35 °, the addition being exothermic. The reaction mixture was stirred for 3θ minutes at 35 ° to 50 °, heated for 1.5 hours at 50 ° to 55 ° (longer complete warm-up time may be required for complete hydrolysis), cooled to 22 °, maintained for 15 minutes at 22 ° and filtered. The filter cake is evaporated three times with 600 ml portions of water and dried by suction at an aspirator pressure for 6 to 16 hours (N-methylaniline can be recovered from the aqueous layer and the washing liquids combined. Wet the filter cake to the original 5 ml pumpkin, 2.5 l of toluene and 180 g of pulverized (20 μm) cellulose are added, the mixture is heated at 50 ° to 55 ° for 1.5 hours, '

- 76 is cooled to 22 °, maintained at 22 ° for 15 minutes, and optionally filtered through a roll of 91 g of silica gel 70-230 mesh ASTM _; covered with filter cloth. The cellulose and silica gel rolls are washed three times with 200 ml portions of toluene. The toluene filtrate and the washing liquids were combined and distilled as much as possible through distillation at 40 to 77 mbar and 50 ° to 65 ° (external). Add 280 ml of 95% ethanol to the remaining dense oil, distill ethanol at 26.6 to 40 mbar and 60 ° to 65 °, add 280 ml of 95% ethanol and distillate at 40 to 106 mbar and 60 ° to 65 ° ethanol as much as possible. 700 ml of 95% ethanol are added, the mixture is refluxed at 78 ° for 15 minutes and cooled slowly to 20 ° for 1 hour, starting crystallization at about 55 °. The resulting suspension was cooled for 30 minutes at 0 ° to 5 ° and maintained for 30 minutes at 0 ° to 2 °, the solids collected by filtration, washed three times with 120 ml portions of cold (0 ° to 5 °) 95% ethanol and they were dried in vacuo for 16 hours at 60 ° to 65 ° to constant weight to give 99.4% pure product (276.6 g; 75.5% yield; mp 129 ° to 130 °).

Alternatively, isopropanol is used instead of 95% ethanol.

It is advantageous to omit the silica gel coil, i.e. the liquid containing the pulverized cellulose is subjected to simple filtration and the residue from this filtration is washed three times with 200 ml portions of toluene.

EXAMPLE 10a: (E) -3- / 3 * - (4 '-fluorophenyl) -1 * - (V'-methylethyl) -1H-indol2'-yl / prop-2-enal / Formula Va: R4, Rg , R ?, Rg = as in Example 9 // procedure B, alternative procedure /

i) In a 1.5 L flask equipped as described in Example 10 step (i), 170 ml of dry acetonitrile and 105.3 g of 3- (N-methyl-N- hydrochloride salt) are dosed under the cushion of dry nitrogen. phenylamino) acrolein at room temperature. To the mixture for 5 minutes was added 96.6 g of phosphorus oxychloride. A dark solution is obtained.

ii) 90 g of 3- (4′-fluorophenyl) -1- (1′-methylethyl) -1H-indole (compound of formula XVII) is added at 30 °. The mixture was heated to reflux for 4.5 hours at 75 ° to 83 °, then cooled to 22 °.

(iii) Add 250 ml of water at 5 ° and then 500 ml of water at room temperature for 15 minutes. The mixture was stirred for 30 minutes at 35 ° to 50 °, then heated to 50 ° to 55 ° for 1.5 hours. Dark suspension is obtained. The mixture was cooled to 30 °, maintained at 30 ° for 15 minutes and the brown suspension filtered. Wash the filter cake three times with a total of 540 ml of water. Dry the filter cake by suction under vacuum for about 4 hours. Transfer the solids to the original 1.5 L flask, add 750 ml of toluene and 54 g of pulverized (20 µm) cellulose and perform the following treatment as described in Example 10 step (iii) to give the product (89 g ; 81% yield; mp 123 to 129 °).

- 78 10.4. Specific Performance Examples

EXAMPLE 11: Sodium salt of (±) -erythro- (E) -3,5-dihydroxy-7- [3 ^, - (4 ^l, -fluorophenyl) 1 '- (1-methylethyl) indol-2'-yl / hept -6-enoic acids / Formula Ia: in racemic form; form of sodium salt /

Steps (a), (b) and (c): N-methylformanilide is reacted with oxalyl chloride and ethyl or n-butylvinyl ether according to process A, sub-process Ab, to give 3- (N-methyl-N-phenylamino) acrolein, such as described in Examples 6, 7, 7a or 8 / steps (i), (ii) and (iii) /.

Step (d): The above product, 3- (N-methyl-N-phenylamino) acrolein, is reacted with phosphorus oxychloride as described in the example

9,10 or 10a, step (i), to give the compound of formula XVI, wherein X is' chloro, R ₁₀ . phenyl and R. _o methyl but a 12b 13

Step (e): The above compound of formula XVI is reacted with 3- (4'fluorophenyl) -1- (1'-methylethyl) -1H-indole as described in Example 9, 10 or 10a, step (ii) to a compound of formula XVIIIa is obtained wherein X _{a is} chloro, R _12b is phenyl and R 1 is methyl.

Step (f): The above compound of formula XVIIIa is hydrolyzed as described in Example 9, 10 or 10a, step (iii) to give (E) -3- / 3 '~ (4-fluorophenyl) -1' - ( 1-methylethyl) -1H-indol-2'-yl / prop2-enal.

Step (g): 0.5 liters of tetrahydrofuran are dosed into the reactor under a nitrogen atmosphere, cooled to -10 ° and g of sodium hydride (60% mineral oil dispersion) carefully added.

Then, 237.3 g of t-butylacetoacetate are added carefully over 45 minutes

- 79 _ν ο. _ν

250 ml of THF while maintaining the temperature below 2. The resulting solution was stirred for 1 hour at -10 ° to 20 °. The mixture was cooled to -10 ° and 93θ acre of 1.6 M solution of n-butyllithium in hexane was added at such a rate that the temperature did not exceed 0 ° (above about 60 minutes). The mixture was stirred at this temperature for 10 minutes, then cooled to -10 ° and a solution of 230 g of the product of step (f) above in 650 ml of THF was added at such a rate that the temperature did not exceed 0 ° (above about 70 minutes). The reaction mixture was stirred for 15 minutes at 0 ° and poured onto a mixture of 248 ml of hydrochloric acid and 2.5 kg of ice with vigorous stirring for 5 to 10 minutes. The mixture was stirred vigorously for another 15 minutes, the organic phase separated, washed twice with 500 ml portions of saturated NaCl solution and evaporated under reduced pressure (about 33 mbar). 200 ml of toluene were added to the residue and the solution was evaporated again. The resulting crude t-butyl ester (+) - (E) -7- / 3 '- (4-fluorophenyl) -1' - (1-methylethyl) indol-2'-yl / -5-hydroxy-3-oxohept-6 -enoic acids (a compound of formula Ha, wherein R 1 is t-butyl, in racemic form) (503.6 g; 70.04% pure) was used in the next step without further purification.

Step (h): The crude product above is stereoselectively reduced as described in Example 1, step (a), (b) and (c) to give t-butyl ester (+) - erythro- (E) -7- / 3 ^, - (4-fluorophenyl) -1 '- (1-methylethyl) indol-2'-yl / -3,5-dihydroxy-hept-6-enoic acid.

Step (s): Add 42.5 g of the ester obtained in step (h) above to 275 ml of THF in 275 ml of THF over 5 minutes while maintaining the temperature below 10 °. The solution was stirred for 1 hour at room temperature, 275 ml of methanol was added, the mixture was evaporated at 33.3 mbar and 45 °, then 300 ml of deionized water was added, distillation was continued to a residual volume of 140 ml, then 380 ml of deionized water was added again and the solution was washed with a total of 640 ml of t-butyl methyl ether in 3 portions. The aqueous layer was evaporated at 33.3 mbar and 45 ° to a volume of about 300 acres, 220 ml of deionized water was added and the clear aqueous solution was lyophilized for 3 days. The title compound (35.9 g; yield 91%; chemical purity 98.9%; 99.9% pure erythro isomer; boron concentration below detection limit) is obtained.

Alternative process for step (i): To 35.0 g of the ester obtained in step (h) above are added in 175 ml of ethanol for 5 minutes while stirring 74 ml of 1 ^N sodium hydroxide solution while maintaining the temperature below 12 °. The solution was stirred for 1 hour, the mixture was evaporated at 33.3 mbar and 45 °, then 250 ml of deionized water was added, the distillation was continued to a residual volume of 115 ml, then 315 ml of deionized water was added and the solution was washed with a total of 525 ml of tert-butyl methyl ether. 3 shares. The aqueous layer was evaporated at 33.3 mbar and 45 ° to a volume of about 245 ml, 185 ml of deionized water was added and the clear aqueous solution was lyophilized for 3 days. The title compound (29.75 g; color pure white; yield 91%; mp 204 to 207 ° (dec.); Chemical purity 100%; 99.61% pure erythro isomer; boron concentration 3.96 ppm) is obtained .

Example 12: The sodium salt (j) -eritro- (E) -3,5-dihydroxy-7- / 3 '(4-fluorophenyl) -1' - (1 ¹¹ -Me tile til) ^indole-2; -yl / hept-6enoic acids / Formula la: in racemic form; form of sodium salt /

The title compound is obtained in a manner analogous to Example XI except that

- in step (g), methyl ester is obtained by reaction of dianion with methylacetoacetate instead of t-butylacetoacetate;

- step (h) is carried out as described in Example 2, steps (a), (b) and (c);

- step (i) is carried out by hydrolyzing the resulting methyl ester and step (h) as described in US-PS 4 739 073, example 6 (b) in column 50.

For

SANDOZ A "G.:

Claims (5)

PATENT APPLICATIONS A process for the preparation of a compound of formula I OH R - X - CH - CH ₂ - CH - CH ₂ - COORi OH OH (I) where X -CH ₂ CH ₂ - or -CH = CH-; R ₁ is an ester group inert to the reaction conditions; and R is an organic residue with groups which are inert under reducing conditions; by stereoselective reduction of the racemic or optically pure compound of formula II (II) wherein R, R ^ and X are as defined above and one of Z ₁ and Z _{2 is} oxygen and the other hydroxy and hydrogen, characterized in that after the first step / step (a) / compound of formula III r ₄ ob- (r ₃ ) ₂ (III) wherein R1 is allyl or lower alkyl of 1 to 4 carbon atoms and is R4 is primary or secondary alkyl of 2 to 4 carbon atoms - 83 is mixed with NaBH 4 sodium borohydride in a reaction medium comprising alcohol and tetrahydrofuran, in the second step / step (b) / compound of formula II, is treated with the mixture obtained in step (a) under conditions suitable to give a mixture containing a cyclic boronate compound of formula IV (a) f 'z \ oo I f R - X - CHCH ₂ CH - CH ₂ C00Ri (IV (a) 1 and / or boron complex of formula IV (b) R ₃ r _{3 y} B /. 0 OH τ τ R - X - CHCH ₂ CH - CHaCOORi (IV (b) J where R, 'R ^, R ^ and X are as defined above, and in step 3 / step (c) / cleave the product obtained in step (b) to give the corresponding compound of formula I. The process of claim 1 for the preparation of a compound of formula lu u - 0CH ₂ - CHCH ₂ CHCH ₂ - COOR _U OH OH (Iu) wherein u is three phenylmethyl (trityl) and is R _{u is} allyl or an ester forming residue, inert under reaction conditions, preferably allyl or g-alkyl, n-butyl, i-butyl, t-butyl or benzyl, in particular t-butyl, by stereoselective reduction of the racemic or optically pure compound with formula IIu u - 0CH ₂ - C-CHs-C - CH ₂ - COOR _U (IIu) l 1 fl Zi Z ₂ where u, R _u , and Z _{2 are} defined in this claim. 3- (4'-fluorophenyl) -1- (1'-methylethyl) -1H-indole (a compound of formula XVII wherein Rg and Rg are hydrogen, R1 is 1-methylethyl and Rg is pfluorophenyl) to give the corresponding compound with formula XVIIIa (XVIIIa) ch (ch ₃ ) ₂ and the corresponding anion, e.g. -ΡΟρίΧθ ^, where P ^ _{2 is} b ^de fi ⁿ i ^wound as in claim 13 and sta _O and X are as defined in claim 5; 13 a ' f) hydrolyze this compound of formula XVIIIa to give (E) -3- / 3 '- (4-fluorophenyl) -1' - (1-methylethyl) -1H-indol-2'-yl / prop-2-enal (a compound of formula Va, wherein R 1 and R 8 are hydrogen, Fi 1 is 1-methylethyl and R 8 is p-fluorophenyl); g) this compound of formula Va is reacted with the dianion of an acetocetester of formula CH2COd4COOR1, wherein R1 is defined as in claim 1 to give the corresponding compound of formula I1a where R1 is defined as in claim 1; in racemic or optically pure form; - by stereoselective reduction process: h) stereoselectively reducing the racemic or optically pure compound of formula Ila in the first step by mixing the compound of formula III as defined in claim 1 with sodium borohydride (NaBH 4) in a reaction medium comprising alcohol and tetrahydrofuran; in the second step by treating the compound of formula Ila in racemic or optically pure form with the resulting mixture under conditions suitable to give a mixture containing a cyclic boronate compound of formula IV (a) and / or a boron complex of formula IV (b), wherein R / 3- (4'-fluorophenyl) -1- (1'-methylethyl) -1H-indol / 2-yl, X -CH = CH- and sta R 2 and R 4 are as defined in claim 1; and in the third step by cleaving the product obtained in the second stage to give the compound of formula la in the form of an ester; in racemic or optically pure form; and i) optionally converting the compound of formula la in the ester form into the free acid form, the salt form, the further ester form or (> -lactone, i.e. the internal ester, in the usual way. The process of claim 15, wherein the compound of formula Ia is obtained in racemic form. Process according to claim 15, characterized in that the compound of formula Ia is obtained in (3R, 5S) enantiomeric form. 18. Procedure after request 15, characterized in that Yes the compound of formula Ia is obtained in the form of sodium salts. 19. Procedure after request 15, characterized in that Yes j® R ₁₀ , phenyl and R _{10 are} methyl. 12b 13 20. Procedure after request 15, characterized in that Yes is R.j t-butyl. For SANDOZ A.G .: PATtHINA LJUBLJANA 9 2Ο954-Χ-89 / KA - SUMMARY Process for the preparation of 7-substituted hept-6-enoic and heptanoic acids and their derivatives and intermediates A new process for the preparation of compounds of formula is described I 3-b 2 m where it is R 8 is hydrogen, C 1-6 alkyl, n-butyl, i-butyl, t-butyl, C 1-4 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phen88 oxy or benzyloxy; R _{w is} hydrogen, C 1-6 alkyl, C 1-4 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; R 1 is hydrogen, ₂ alkyl, _{1 2} alkoxy, fluoro or chloro and m is 1, 2 or 3; with the proviso that it is not more than one of Rg and R4g trifluoromethyl, it is not more than one of Rg and R4 phenoxy and no more than one 'of Rg and R6 is benzyloxy; characterized in that (i) a compound of formula Villa (E) - OHC - CH = CH-N (R _12b) R ₁₃ (Villa) wherein R ^ b ^ ^{of the} j ^era0 C ^^ - alkyl meaning indicated in claim 5 for R ₁₂ , and R ₁₃ is as defined in claim 5, reacted with a compound of formula XV PO (X _b ) ₃ (XV) wherein X _{b is} chloro or bromo, or with a compound selected from oxalyl chloride or bromide; phosgene or carbonyl bromide; phosphorus trichloride or tribromide; phosphorus pentachloride or pentabromide; and alkyl or arylsulfonyl chloride or -bromide, such as p-toluenesulfonyl chloride or -bromide or methanesulfonyl chloride or -bromide; to give the corresponding compound of formula XVI (E) - X _b - CH = CH-CH = N ⁺ (R _12b ) R ₁₃ (XVI) and the corresponding anion, e.g. -PO ₂ (X _b ) ₂ , wherein X _b and R ^ b are as defined in this claim and R ₁₃ is as defined in claim 5 89 (ii) a compound of formula XVI a substance with a compound of formula XVII (XVII) wherein Rg, Rg, R _? the corresponding compound s and Rg defined as in this claim to give formula XVIII and the corresponding anion, e.g. -PO ^^ g ^, wherein Rg, Rg, R ?, Rg, R ^ g ^ b are as defined in this claim and R ^ is defined as in claim 5, and (iii) hydrolyzed this compound of formula XVIII to the corresponding compound of formula Va is obtained. Process according to claim 13, characterized in that the compound of formula XVII is 3- (4'-fluorophenyl) -1- (1'-methylethyl) -1H-indole. A process according to claims 1, 5 and 13 for the preparation of erythro- (E) -3,5-dihydroxy-7- [3 '- (4-fluorophenyl) -1' - (1-methylethyl) indol-2'-yl N -hept-6-enoic acid of formula Ia in racemic or optically pure form; in the form of free acid, with salt, ester or (J-lactone, i.e. internal ester, characterized in that - by Procedure A: a) a compound of formula Vlila OHC - N (R _12b ) R ₁₃ (Vlila) wherein R _{2b is} defined as in claim 13 and is R ₃ defined as in claim 5 is reacted with a compound of formula IX, optionally in an inert anhydrous organic medium, to obtain the corresponding compound of formula Xc X _a - CH = N ⁺ (R _12b ) R ₁₃ X _a '(Xc) wherein X and R. _o are as defined in claim 5 and is R _12b as defined in claim 13; b) this compound of formula Xc is reacted with a compound of formula XI, optionally in an inert anhydrous organic medium, to give the corresponding compound of formula XIIc (E) - R ^ O - CH = CH-CH = N ⁺ (R _12b ) R ₁₃ X _a ~ (XIIc) wherein R ₁₃ is as defined in claim 13 and are Rj ₃ > R-, 2 | and X _a is as defined in claim 5; c) hydrolyze this compound of formula XIIc to give the corresponding compound of formula Vile in the form of a free base or an acid addition salt and, if in the form of an acid addition salt, neutralize the acid addition salt with a base; - by procedure B: d) treating this compound of formula Forks with a compound of formula XV or with a compound selected from oxalyl chloride or -bromide; phosgene or carbonyl bromide; phosphorus trichloride or 'tribromide; phosphorus pentachloride or pentabromide; and alkyls of arylsulfonyl chloride or -bromide, such as p-toluenesulfonyl chloride or -bromide or methanesulfonyl chloride or -bromide; to give the corresponding compound of formula XVI and the corresponding anion, e.g. -PO ₂ (X _b >₂; e) react this compound of formula XVI with The process of claim 1 for the preparation of a compound of formula Ia in racemic or optically pure form; in the form of free acid, salt, ester or cf-lactone, i.e. of the internal ester. A compound of formula I as defined in claim 1, in a state of optical purity such that the erythro-to-treo isomer ratio is 99.1: 0.9 or more. A process for the preparation of an intermediate of formula VII (E) - OHC - CH = CH - N (R ₁₂ ) R (VII) wherein - 85 ^R T2 C.j_ ₃ alkyl, phenyl or phenyl substituted with 1 to 3 substituents each of which is independently-alkyl, C ^ _ ~ ₃ alkoxy, fluoro, chloro, bromo or nitro with a maximum of two nitro groups ; and having the independent meaning given above for R1 'characterized in that (i) a compound of formula VIII OHC - N (R ₁₂ ) R ₁₃ (VIII) wherein R ₁₂ and R ₃ are as defined in this claim, reacted with a compound of formula IX X - CO-CO - X (IX) aa where X is a monovalent 'leaving group, optionally in an inert anhydrous organic medium, to obtain the corresponding compound of formula X • x _a - ch = n ⁺ (r ₁₂ ) r ₁₃ x _a (X) wherein X _b, R _12, and R @ ₃ are as defined in this claim, (ii) the compound of formula X is reacted with a compound of formula XI, R ₁₄ O - CH = CH ₂ (XI) wherein R _{4 is a} monovalent group which does not deactivate the oxygen atom to which it is attached, optionally in an inert anhydrous organic medium, to obtain the corresponding compound of formula XII (E) - R ₁₄ O - CH = CH - CH = N ⁺ (R ₁₂ ) R ₁₃ X _g ~ (XII) wherein R _2> ^R 13 ^R 14 and ^de ^ inirani as in this claim, and (iii) hydrolyzing that compound of formula XII to yield the corresponding compound of formula VII in the form of free base or acid addition salts and, if in the form of an acid addition salt, neutralize the acid addition salt with the base. Process according to claim 5, characterized in that step (iii) is omitted and the compound of formula XII is used directly instead of the compound of formula VII for further processing. 7. The method of claim 5, wherein (i) and (ii) are carried out simultaneously. A process according to claim 5, wherein R 1 is independently C 1-6 alkyl. Process according to claim 5, characterized in that one of R 6 and R 13 is other than R 4 -alkyl 10. The process according to claim 5, characterized in that steps (i) and / or (ii) use pure reagents. The process of claim 5, wherein Formula XII is in the form of an acid addition salt. 12. The process of claim 8, wherein the compound of formula VII is subjected to step (iv), i.e. (iv) a crude mixture containing a compound of formula Vila to the degree that Rη2 is at least, is a compound that is crude (E) - OHC - CH = CH where R _{12a is} C ^^ alkyl and is treated with the corresponding compound ^{N (R} 12a ^{) R} 13 (Vila) R. J3 as defined in claim 5, formula XIV H - K (R _12a ) R, ₃ (XIV) wherein R _12a is as defined in this claim and is R ₁₃ defined as in claim 5 to convert any compound of formula XIII present in it to an additional compound of formula Vila. 13. A process for the preparation of an intermediate of formula Va where it is R8 is hydrogen, N-alkyl, n-butyl, i-butyl, t-butyl, gcycloalkyl, N-alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; Rg hydrogen, C. | alkyl, C1-4 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; with the proviso that not more than one of R _r and R, trifluoromethyl, will be not more than one of R- and lb phenoxy and not more than one of 5 o Rg and Rg are benzyloxy; one of the R? and Rg is phenyl trisubstituted by R, and R, and the second primary or secondary C ^ _galkil containing no asymmetric carbon atom, C_, cycloalkyl or phenyl- (CH _O) 5 3 R - X - CH - CH ₂ - CH - CH ₂ - COORi I OH OH where it is X -CH ₂ CH ₂ - or -CH = CH ~; R.j is an ester group inert to the reaction conditions; and R is an organic residue with groups which are inert under reducing conditions; by stereoselective reduction of the corresponding compound of formula II R - X - C - CH ₂ - C - CH ₂ - COORi I 'H Zi Z ₂ II where they are R, Rj and X are defined as above and one of Z ^ and Z _{2 is} oxygen and the other hydroxy and hydrogen, The compounds of formula I are pharmaceuticals, in particular anti-atherosclerotic, antihyperlipidemic and antihypercholesterolemic agents. The process can also be used to prepare compounds of formula Iu u - 0CH ₂ - CHCH ₂ CHCH ₂ - COOR _U Iu OH OH -is ¹ where u is triphenylmethyl (trityl) and the allyl or ester-forming residue is inert under reaction conditions which are intermediates in the preparation of some of the compounds of formula I, New methods for the preparation of the above intermediates for use in the preparation are also described among other compounds of formula I, namely process A comprising the preparation of compounds of formula VII (E) - OHC - CH = CH - N (R ₁₂ ) R ₁₃ (VII) wherein ^R 12 is C _1-3 alkyl, phenyl or phenyl substituted with 1 to 3 substituent !, each of which is independently C ^ _ ~ ₃ alkyl, alkoxy, fluoro, chloro, bromo or nitro with a maximum of two nitro groups; and has R ₁₃ independently denotes the above meaning for R ₁₂ from the corresponding compounds of formula VIII OHC - N (R ₁₂ ) R (VIII) and process B comprising the preparation of compounds of formula Va (Va) - It's where it is R 8 is hydrogen, C 1-6 alkyl, n-butyl, i-butyl, t-butyl, C 1-6 cycloalkyl, C 1-4 alkyl. alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; R 8 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; with the proviso that not more than one of R _c and R _{c is} trifluoromethyl, not more than one of R _n and phenoxy and not more than one of 5 o Rg and Rg are benzyloxy; one of the R? and Rg is phenyl trisubstituted by Rg, R ^ g and R ^, and the other primary or secondary C? a alkyl containing no asymmetric carbon atom, gCycloalkyl or phenyl- (CH2) ^ -, where R 8 is hydrogen, C 1-6 alkyl, n-butyl, i-butyl, t-butyl, N-alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; R _J0 hydrogen, C ₁ _ ₃ alkyl, C ^ alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; R ^ is hydrogen, C ₁ _ ₂ alkyl, C. ^ Alkoxy, fluoro or chloro and m is 1,2 or 3; with the proviso that it is not more than one of R8 and R4 trifluoromethyl, it is not more than one of Rg and R4 phenoxy and is not more than one of R8 and R5 q benzyloxy; from a subset of compounds of formula VII. The specific embodiment of the above inventive shown by the preparation of a compound of formula la of the concept is (Ia) CH 2 CH 2 in racemic or optically pure form; in the form of free salt, ester or ci-lactone, i.e. of the internal ester. acids,