DD296908A5 - PROCESS FOR THE PREPARATION OF SUBSTITUTED HEPT-6-ENCARBONESAEURES AND HEPTANCARBONSAEURES AND DERIVATIVES HEREVOEN IN STAGE 7 - Google Patents

Abstract

The invention relates to a process for the preparation of substituted in position 7 Hept-6-encarbonsaeuren and heptanecarboxylic acids and derivatives thereof. The above compounds have the formula {method; manufacture; Position 7; substituted hept-6-encarboxylic acids; Heptancarbonsaeuren; derivatives; pharmaceuticals; antiatherosclerotic; antihyperlipidaemisch; antihypercholesterolemic}

Description

CH ₂ -C-CH ₂ -COOH 0

wherein

R ₁ WIeJnAnSPmCh 1 is reacted in racemic or optically pure form; - that after the stereoselective reduction process: (h) the racemic or optically pure compound of formula (Ha) of a stereoselective

Reduction is subjected to by

in a first step, mixing a compound of formula (III) as defined in claim 1 with sodium borohydride (NaBH ₄ ) in a reaction medium containing an alcohol and tetrahydrofuran;

in a second step, treating a compound of formula (Ha) in racemic or optically pure form with the resulting mixture under conditions which yield a mixture comprising a cyclic boranate compound of formula (IVa) and / or a boron complex

of formula (IVb) wherein

R is [3- (4'-fluorophenyl) -1- (1'-methylethyl) -1H-indol] -2-yl,

X is (E) -CH = CH- and

R ₁ and R _{3 are} as defined in claim 1; and

in a third stage the product obtained in the second stage by cleavage into the compound of formula (I a) in the form of an ester and in racemic or optically pure form

is transferred; and (i) if desired, converting the compound of formula (Ia) in the form of an ester using conventional methods into a free acid, a salt, another ester or the δ-lactone, namely an internal ester.

5. Process according to claims 1 to 4, characterized in that the compound of formula (I), (Iu) or (la) is obtained in racemic form.

6. Process according to claims 1 to 4, characterized in that the compound of formula (I), (I u) or (I a) is obtained in the form of the 3R, 5S enantiomer.

7. Process according to claims 1 to 4, characterized in that the compound of formula (I), (I u) or (I a) is obtained in the form of the sodium salt.

8. The method according to claim 4, characterized in that R ₁₂ b is phenyl and R _{13 is} methyl.

9. Process according to claims 1 to 4, characterized in that R ₁ or R _{u is} t-butyl. A compound of formula I as claimed in claim 1 in the state of such optical purity that the ratio of erythro isomers to threo isomers is 99.1: 0.9 or higher.

Field of application of the invention

The invention relates to a process for the preparation of substituted in position 7 hept-6-enecarboxylic acids and heptanecarboxylic acids and derivatives thereof.

More particularly, the invention relates to a process for the preparation of a compound of formula (I)

RX-CH- CH ₂ - CH - CH ₂ - COOR ₁ ÖH ÖH

X is -CH ₂ CH ₂ -or-CH = CH-,

R _{1 represents} an ester group which is inert to the reaction conditions, and R represents an organic radical having groups which are inert under reducing conditions.

Characteristic of the known state of the art

The compounds of formula (I), the corresponding δ-lactones, free acids and salts, the processes for the conversion of a compound of formula (I) wherein R _{1 has} a particular meaning into the corresponding compound wherein R ₁ has another meaning has, and / or in the corresponding δ-lactone or the free acid or salts thereof, are known. The compounds of formula (I) are pharmaceuticals. According to the known prior art (Tetrahydron Letters 28, pages 155 ff. [1987]), they are prepared in a three-stage and partially stereoselective reduction process from the keto group of a compound of the formula (II)

RXC-CH ₂ -C-CH ₂ -COOR ₁ (II)

Ζ, Z ₂

wherein R, Ri and X are as defined in the formula (I) above, won. However, this process is quite expensive.

Object of the invention

The aim of the invention is to provide a more economical process for the preparation of compounds of formula (I). The process according to the invention for preparing a compound of the formula (I) comprises reacting a racemic or optically pure compound of the formula (II)

RXC-CH ₂ -C-CH ₂ -COOR ₁ (II)

Z ₁ Z ₂

wherein R, R ₁ and X are as defined above and one of the substituents Z ₁ and Z _{2 is} oxygen and the other is hydroxy or hydrogen,

is converted by stereoselective reduction in a corresponding compound of formula (I) in racemic or optically pure form and the product thus obtained, if desired, in orom the free acid, a salt, an ester or the δ-lactone, namely an internal ester won becomes.

From the formula (I), it is apparent that these compounds have the syn configuration, namely, the erythro configuration. If the symbol (E) occurs at the beginning of a formula or in the name of a compound, it means that there is a double bond in trans configuration.

The invention also includes a compound of formula (I) as defined above having an optical purity such that the ratio of erythro-isomer to threo-isomer is 99.1: 0.9 or higher, preferably 99.5: 0.5 or higher, and in particular 99.7: 0.3 or higher.

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

Preferred meanings

An ester group R ₁ is preferably a physiologically acceptable and hydrolyzable ester group when the desired end product is an ester.

By a physiologically acceptable and hydrolyzable ester group is meant a group which, together with the residual COO to which it is attached, forms an ester group which is physiologically acceptable and hydrolyzable under physiological conditions and the corresponding carboxylic acid of the compound of formula (I ), namely a compound in which R _{1 is} replaced by hydrogen, and an alcohol which itself is physiologically acceptable, namely is nontoxic at the desired dosage level, so as to give above all a group which is free of asymmetric centers.

The substituent R ₁ is preferably R ₂ , where R _{2 is} C ₁ -C ₄ -alkyl or benzyl, where R _{1 is} in particular R ₂ ', where R ₂ ' is C ₁ -C ₃ -alkyl, η- Butyl, isobutyl, t-butyl or benzyl, and examples of such radicals are ethyl and preferably isopropyl or t-butyl, with t-butyl being particularly preferred.

The group X is preferably the group X ', wherein X' is -CH = CH- and preferably (E) -CH = CH-.

The substituent R is preferably selected from one of the following groups A, B, C, D, E a, E b, E c, F, G, H, J, K, L, M or N:

Phenyl which is tri-substituted by R, a, R ₂ a and R ₃ a wherein R, a, R ₂ a and R ₃ a are independently hydrogen, halogen, C, -C ₄ alkyl, C ₁ -C ₄ -haloalkyl , Phenyl, phenyl which is halogen, C ₁ -C ₄ -alkoxy, C ₁ -C 5 -alkanoyloxy, C ₁ -C ₄ -alkyl or C ₁ -C ₄ -haloalkyl, or a radical of the formula -OR ₄ a, in which R ₄ a is hydrogen, C ₂ -C ₈ -alkyl, benzoyl, phenyl, halophenyl, phenylC 1-4 -alkyl), C 1 -C ₉ -alkyl, cinnamyl, C 1 -C ₄ -haloalkyl, allyl, cycloalkyKCi-Cs-alkyl ), Adamantyl (C 1 -C ₃ -alkyl) or substituted phenyUCi-Qä-alkyl), wherein each substituent is selected from halogen, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkyl and C, -C ₄ - Haloalkyl is selected, wherein the halogen atoms are fluorine or chlorine and cycloalkyl also includes cyclohexyl;

wherein R ^ and R ₂ b together form a group of the formulas

8 7 6 5 a) -C = CC = CR ₇ b

or

b) -CH ₂ -CH ₂ -CH ₂ -CH ₂ -

R ₈ b

form, in which

R ₃ b is hydrogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, R ₄ b is hydrogen, C ₁ -C ₃ -alkyl, η-butyl, isobutyl , C ₁ -C ₃ -alkoxy, n-butoxy, isobutoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,

With the provisos that not more than one of the substituents R ₄ b R ₅ b is hydrogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, and R ₅ b is trifluoromethyl, not more than one of the substituents R ₄ b and R ₅ b is phenoxy and not more than one of the substituents R ₄ b and R ₅ b is benzyloxy, R ₆ b is hydrogen, C ₁ -C ₂ alkyl, C C ₁ -C ₂ -alkoxy, fluorine or chlorine, R ₇ b is hydrogen, C ₁ -C ₃ -alkyl, n-butyl, isobutyl, C ₁ -C ₃ -alkoxy, n-butoxy, trifluoromethyl, fluorine, chlorine, phenoxy or

Benzyloxy, R ₈ b represents hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that not more than one of the substituents R ₇ b and R ₈ b is trifluoromethyl, not more than one of the substituents R ₇ b and R ₈ b is phenoxy and not more than one of the substituents R ₇ b and R ₈ b is benzyloxy, and with the further proviso that the free valences at the rings Ba and Bb are ortho to each other;

wherein one of the substituents R ₁ C and R ₂ C is phenyl which is substituted by R ₆ C, R ₆ C and R ₇ C, and the other of

C ₁ -C ₃ -A ^ yl, η-butyl or isobutyl, R ₃ C is hydrogen, C ₁ -C ₃ -alkyl, η-butyl, isobutyl, t-butyl, C ₁ -C ₃ -alkoxy, n- Butoxy, isobutoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R ₄ C is hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the proviso that not more than one of the substituents R ₃ C and R ₄ C is trifluoromethyl, not more than one of the substituents R ₃ C and R ₄ C is phenoxy and not more than one of the substituents R ₃ C and R ₄ C is benzyloxy, R ₅ C is hydrogen, C ₁ -C ₃ -alkyl, η Is butyl, isobutyl, t-butyl, C ₁ -C ₃ -alkoxy, n-butoxy, isobutoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,

R ₆ C is hydrogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy, with the proviso that not more than one of the substituents R ₅ C and R ₆ C is not more than one of the substituents R ₆ C and R ₆ C is phenoxy and not more than one of the substituents R ₅ C and R ₆ C is benzyloxy, and

Is R ₇ C is hydrogen, C, -C ₂ alkyl, C ₁ -C ₂ -alkoxy fluorine or chlorine;

R, d is hydrogen or primary or secondary C, -C ₆ alkyl which does not contain an asymmetric carbon atom and R ₂ d is C ₁ -C ₆ primary or secondary alkyl which does not contain an asymmetric carbon atom, or R, d and R ₂ d

together are - (CH ₂ ) _m - or (Z) -CH ₂ -CH = CH-CH ₂ -, wherein m is 2,3,4,5 or 6, R ₃ d is hydrogen, C, -C ₃ - Alkyl, η-butyl, isobutyl, t-butyl, C ₁ -C ₃ -alkoxy, n-butoxy, isobutoxy, trifluoromethyl, fluorine, chlorine,

Phenoxy or benzyloxy means

R ₄ d is hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that not more than one of the substituents R ₂ d and R ₃ d is trifluoromethyl, not more than one of the substituents R ₂ d and R ₃ d is phenoxy and not more than one of the substituents R ₂ d and R ₃ d is benzyloxy, R ₅ d is hydrogen, C ₁ -C ₃ alkyl, η Butyl, isobutyl, t-butyl, C ₁ -C ₃ -alkoxy, n-butoxy, isobutoxy, trifluoromethyl, fluorine, chlorine,

Phenoxy or benzyloxy means

R ₆ d is hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the proviso that not more than one of the substituents R ₆ d and R ₆ d is trifluoromethyl, not more than one of the substituents R ₅ d and R ₆ d is phenoxy and not more than one of the substituents R ₆ d and R ₆ d is benzyloxy, R ₇ d is hydrogen, C ₁ -C ₂ alkyl, C C ₁ -C ₂ -alkoxy, fluorine or chlorine;

or

Eb

bc

wherein each of the substituents R 1 e, R ₂ e and R ₃ e is independently fluorine, chlorine, hydrogen or C ₁ -C ₄ -alkyl, preferably methyl;

Rif is C 1-6 alkyl which does not contain an asymmetric carbon atom, each of the substituents R ₂ f and R ₅ f is independently hydrogen, C ₁ -C ₃ alkyl, η-butyl, isobutyl, t-butyl, C ₁ -C ₃ -alkoxy, n-butoxy, isobutoxy, trifluoromethyl, fluorine, chlorine, phenyl, phenoxy or benzyloxy, each of the substituents R ₃ f and R ₆ f is independently hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ -alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, and each of the substituents R ₄ f and R f _7, independently, hydrogen, C ₁ -C ₂ -alkyl ₁ C ₁ -C ₂ -alkoxy, fluorine or chlorine is, with the provisos that not more than one of the substituents R ₂ f and R ₃ f is trifluoromethyl, not more than one of the substituents R ₂ f and R ₃ f is phenoxy, not more than one of the substituents R ₂ f and R ₃ f is benzyloxy, not more than one of the substituents R ₅ f and R ₆ f is trifluoromethyl, not more than one of the substituents R ₅ f and R ₆ f is phenoxy and not m More than one of the substituents R ₆ f and R ₆ f is benzyloxy, and with the further provisos that (i) the free valency of the pyrazole ring is in the position 4 or 5, and (ii) the group R ^ and the free valence are arranged in ortho position to each other; G

rbg

Rag is a single bond to the group X, Rbg is R ₂ g, Reg is R ₃ g, Rdg is R ₄ g and K is a group of the formula -N-, or Rag is Rig, Rbg is a single bond to the group X is, Reg is R ₂ g, Rdg is R ₃ g and

Rig is O, S or a group of the formula -N-, R ^, R ₂ g, R ₃ g and R ₄ g are independently C ₁ -C ₆ alkyl which is not asymmetric

Contains carbon atom, C ₃ -C ₇ -cycloalkyl or by R ₅ g, R ₆ g or R ₇ g substituted phenyl or in the case of R ₃ g and R ₄ g additionally hydrogen or in the case of R ₃ g, if Kfür O or S is X and X is the group X ', additionally Ga represents, and Ga is -CC (Ri7g) = C (Ri ₈ g) R! 9g, in which R ₁₇ g is hydrogen or C ₁ -C ₃ -alkyl, and Ri ₈ g and ₁₉ g of R is independently hydrogen, Ci-C ₃ alkyl or phenyl, R ₅ g each independently hydrogen, C ₁ -C ₃ -alkyl, η-butyl, isobutyl, t-butyl, C ₁ -C _3- alkoxy, n-butoxy, isobutoxy,

Trifluoromethyl, fluorine, chlorine, bromine, phenyl, phenoxy or benzyloxy, R _g g are each independently hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ -alkoxy, trifluoromethyl, fluorine, chlorine, bromine, phenoxy or benzyloxy , and

Each R ₇ g is independently hydrogen, C ₁ -C ₂ -alkyl, C ₁ -C ₂ -alkoxy, fluorine or chlorine,

with the proviso that on each phenyl ring which is substituted by R ₅ g, R ₆ g and R ₇ g, only one of the groups trifluoromethyl, phenoxy and benzyloxy may be present; H

R ₁ h is C, -C ₆ alkyl not containing an asymmetric carbon atom, C ₃ -C ₇ cycloalkyl, adamantyl-1 or phenyl, which

is substituted by R ₄ h, R ₆ h and R ₆ h, R ₂ h is C ₁ -C ₆ alkyl which does not contain an asymmetric carbon atom, C ₃ -C ₇ cycloalkyl, adamantyl-1 or phenyl;

is substituted by R ₇ h, R ₈ h and R ₉ h, R ₃ h is hydrogen, C ₁ -C ₆ alkyl which contains no asymmetric carbon atom, C ₃ -C ₇ -CyClOaIkYl, adamantyl-1, styryl or phenyl which is substituted by Ri _O h, R ₁₁ Ii and R ₁₂ h,

R ₄ h, R ₇ h and R ₁₀ h are each independently hydrogen, C ₁ -C ₃ -alkyl, η-butyl, isobutyl, t-butyl, C ₁ -C ₃ -alkoxy, n-butoxy, isobutoxy, trifluoromethyl, fluorine , Chloro, bromo, phenyl, phenoxy or benzyloxy, R ₆ h, R ₈ h and Ruh are each independently hydrogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, trifluoromethyl, fluorine, chlorine, bromine, - COOR ₁₇ h, -N (R ₁₉ h) ₂ , phenoxy or benzyloxy, in which R ₁₇ h is hydrogen, R ₁₈ h or M, where R ₁₈ h is C ₁ -C ₃ -alkyl, η-butyl, isobutyl, t-butyl or benzyl and M is as defined above, and

R ₁₉ h is, in each case, independently C ₁ -C ₆ -alkyl which contains no asymmetric carbon atom, and R ₆ h, Rgh and R ₁₂ h are each independently hydrogen, C ₁ -C ₂ -alkyl, C ₁ -C ₂ -alkoxy, Fluorine or chlorine, with the provisos that not more than one substituent on each phenyl ring is independently trifluoromethyl, is not more than one substituent on each phenyl ring, independently is phenoxy, and no more than one substituent on each phenyl ring is independently benzyloxy;

R ₁ J and R ₂ J are each independently C ₁ -C ₆ alkyl, which does not contain an asymmetric carbon atom, C ₃ -C ₆ -CyClOalkVl or phenyl- (CH ₂ ) _m - wherein m is O, 1, 2 or 3 and the phenyl group is unsubstituted or substituted by one of the radicals R ₃ J, R ₄ J and R ₆ J, where R ₃ ], R ₄ J and R ₅ J are as defined above, or R _{2 is} J for -Yj-benzyl, -N (R ₈ J) ₂ or Yes, where Yj is -O- or -S- and

Each R ₈ J is independently C ₁ -C ₄ -A ^ yI, which does not contain an asymmetric carbon atom, or can form part of a 5-membered, 6-membered or 7-membered ring Jb, said ring Jb being substituted or unsubstituted, and

optionally also containing one or more heteroatoms, and Y represents Ya 'or Y.sup

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

Yes "for the following formulas yes" aoder yes "stands

R ₅ J

J * "b

wherein

R ₃ J is hydrogen, C ₁ -C ₃ -alkyl, n-butyl, isobutyl, t-butyl, C ₁ -C ₃ -alkoxy, n-butoxy, isobutoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,

R ₄ J is hydrogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy and R _{6 is} hydrogen, C ₁ -C ₂ -alkyl, C ₁ - C ₃ -alkoxy, fluorine or chlorine, with the provisos that not more than one of the substituents R ₃ J and R ₄ J is trifluoromethyl, not more than one of the substituents R ₃ J and R ₄ J is phenoxy and not more than one of the substituents R _{3 is} J and R _{4 is} benzyloxy;

and R ₂ k each independently have the following meanings

(a) phenyl which is ksubstituiert by R ₅ k, k R ₆ and R _7, wherein

R ₆ k is hydrogen, C ₁ -C ₃ -A ^ yI, η-butyl, isobutyl, t-butyl, C, -C ₃ alkoxy, n-butoxy, isobutoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

Represents R ₆ k is hydrogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, fluorine or chlorine, and R ₇ k is hydrogen, C, -C ₂ alkyl, C ₁ -C ₂ -alkoxy, fluorine, or Chlorine is,

(b) hydrogen or a primary or secondary C ₁ -C ₆ alkyl which does not contain an asymmetric carbon atom,

(c) C ₃ -C ₆ cycloalkyl or

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

Y 1 is -CH = CH-CH = N -, - CH = CH-N = CH -, - CH = N-CH = CH- or -N = CH-CH = CH-, R _{1 is} primary C ₁ - C ₆ -AlkYl containing no asymmetric carbon atom, or isopropyl, R ₂ I has the following meaning

(a) phenyl substituted by R ₆ I, R ₆ I and R ₇ I, wherein

R 51 is tert-butyl, C ₁ -C ₃ -alkoxy, n-butoxy, isobutoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy, R ₆ I is hydrogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy , trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that not more R5I and R ₆ I trifluoromethyl than one of the substituents, one of the substituents is not more R ₅ I and R ₆ I phenoxy and not more than one of the substituents R ₅ I and R ₆ I is benzyloxy, R ₇ I is hydrogen, C ₁ -C ₂ -alkyl, C ₁ -C ₂ -alkoxy, fluorine or chlorine,

(b) a primary or secondary C ₁ -C ₆ alkyl which does not contain an asymmetric carbon atom,

(c) C ₃ -C ₆ -cycloalkyl or

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

R ₁ Oi is C ₁ -C ₆ alkyl which does not contain an asymmetric carbon atom, C ₆ -C ₇ cycloalkyl, (C ₅ -C ₇ cycloalkyl) methyl, phenyl (CH ₂ L-, pyridyl-2, pyridyl 3, pyridyl-4, thienyl-2, thienyl-3 or phenyl which is substituted by R _B m, R ₆ m and R ₇ m

R ₂ m is C ₁ -C ₆ alkyl which does not contain an asymmetric carbon, Cs-C ₇ cycloalkyl, (C 5 -C ₇ cycloalkyl) methyl, phenyl (CH ₂ ) _m -, pyridyl-2 , Pyridyl-3, pyridyl-4, thienyl-2, thienyl-3 or phenyl which is substituted by R ₈ m, R ₉ m and R _lo m

with the proviso that not more than one of the substituents R ₁ ^ i and R ₂ m is a member of the group consisting of pyridyl-2, pyridyl-3, pyridyl-4, thienyl-2, thienyl-3, phenyl, which is substituted by R _s m, R ₆ m and R ₇ m, and phenyl which is substituted by R ₈ m, R ₉ m and R ₁₀ , R ₃ m is C ₁ -C ₆ alkyl which is not contains asymmetric carbon atom, Cs-Cj-cycloalkyl or phenyl which is replaced by rum,

R ₁₂ m and R ₁₃ m is substituted, R ₄ m is C ₁ -C ₆ -alkyl which does not contain an asymmetric carbon atom, Cs-Cj-cycloalkyl or phenyl which is replaced by rum,

R ₁₅ m and Ri ₆ m is substituted, in which

R ₅ m, R ₈ m, R _n and R m _and m each independently hydrogen, C ₁ -C ₃ -alkyl, η-butyl, isobutyl, t-butyl, Ci-C ₃ alkoxy, n-butoxy, isobutoxy, Trifluoromethyl, fluorine, chlorine, bromine, phenyl, phenoxy or benzyloxy, R ₆ m, R m, R ₁₂ m and R ₁₅ m are each independently hydrogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, trifluoromethyl, Fluorine, chlorine, phenoxy or benzyloxy, and

R ₇ m, R ₁₀ m, R ₁₃ m and R ₁₆ m each independently represent hydrogen, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, fluorine or chlorine, with the provisos that no more than one substituent independently of each phenyl ring is trifluoromethyl, not more than one substituent on each phenyl ring independently represents phenoxy and not more than one substituent on each phenyl ring independently represents benzyloxy;

R, η

R, n, R ₂ n and R ₃ n are each independently alkyl of 1 to 4 carbon atoms or phenyl which is unsubstituted or substituted by one or two alkyl groups or alkoxy groups each having 1 to 3 carbon atoms or by chlorine or by a fluoro, bromo or trifluoromethyl substituents, R ₄ n is hydrogen or alkyl having 1 to 3 carbon atoms, such as methyl,

R ₅ n is hydrogen, lower alkyl, lower alkoxy, halogen, 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 one or two lower alkyls may be lower alkoxy or chloro, R ₆ is n is hydrogen, lower alkyl, lower alkoxy, halogen or Trifluormethyi, and R ₇ n is hydrogen, lower alkyl, lower alkoxy, halogen or Trifluormethyi and R4n + R ₅ s, R ₅ s + R ₆ noderR ₆ n + R ₇ n may be either a group -CH = CH-CH = CH- or a group- (CH ₂ J ₄ - and may thus form a ring which is substituted by a radical R ₈ n, which is hydrogen, halogen , Lower alkyl or lower alkoxy,

with the proviso that on the molecule not more than one trifluoromethyl group and not more than two bromine substituents are present.

The compounds of the formula (I) can be subdivided into thirteen groups, namely into the groups IA to IN, depending on the meaning of the substituent R, so that the following individual groups result:

IA with R = A,

IB with R = B,

IC with R = C,

ID with R = D,

IE with R = Ea, Eb or Ec,

IF with R = F,

IG with R = G,

IH with R = H,

IJ with R = J,

IK with R = K,

IL with R = L,

IM with R = mouth

IN with R = N.

stereochemistry

When a hydroxyketo compound of the formula (II) is reduced to a dihydroxy compound of the formula (I), a further center of asymmetry is generally formed. Thus, when using a racemic compound of formula (II), the resulting compound of formula (I) thus forms four steroidomers (consisting of two pairs of enantiomers, namely a pair of erythro enantiomers and a pair of threo enantiomers). When an optically pure compound of formula (II) is used, optionally two diastereoisomers of formula (II) are formed (namely an erythro-isomer and a threo-isomer), for example the 3R, 5S diastereoisomers and 3S, 5S diastereoisomers, which result in the reduction of the 5S-hydroxy compound. The diastereoisomers may be resolved in a conventional manner, such as by fractional crystallisation, column chromatography, praperative thin layer chromatography or high pressure liquid chromatography (HPLC). The ratio of erythro-isomeric to threo-isomeric that results from these methods is usually different, and may, for example, be up to about 98: 1.

In the stereoselective process of the present invention using a racemic compound of the formula (II), only two stereoisomers (which constitute the erythro pair of enantiomers) are almost exclusively formed from the obtained compound of the formula (I). On the other hand, when an optically pure compound of the formula (II) is used, only one enantiomer of the compound of the formula (I) is almost exclusively formed, and this enantiomer is the corresponding erythro-enantiomer. The 3R, 5S enantiomer is obtained, for example, by reduction of the 5S-hydroxy compound wherein X is -CH = CH-.

The ratio of erythro-isomeric to threo-isomerem, which results in the process according to the invention, is about 99.1: 0.9 or even higher, in particular about 99.5: 0.5 or even higher, and especially at about 99.7: 0.3 or even higher. By "stereoselective" it is thus understood herein that the proportion of the erythro-form to the threo-form is 99.1: 0.9 or even more.

The stereoisomers of the compound of formula (I) wherein X is -CH = CH- are thus according to the invention the 3 R, 5 S isomers and the 3S, 5R isomers and the racemate consisting of these two isomers, of which the 3R, 5S isomers and the racemate thereof are preferred.

The stereoisomers of the compound of formula (I) wherein X is Wr-CH ₂ CH ₂ - are thus according to the invention, the 3R, 5R isomers and the 3S, 5S isomers as well as consisting of these two isomers racemate, of which 3R, 5R isomers and the racemate thereof are preferred.

State of the art

The conventional methods for reducing the keto group of a compound of formula (II) are carried out using mild reducing agents such as sodium borohydride or a complex of t-butylamine and borane in an inert organic solvent such as a lower alkanol to give a mixture of diastereomers Forms from the optically pure starting compound or optionally the racemic diastereoisomers from the racemic starting material. By using a three-stage and partially stereoselective reduction, the erythro-racemate is predominantly obtained from the racemic starting material. The first step consists of treating a compound of formula (II) with either a trialkyl borane compound or a compound of formula (III)

R ₄ OB- (R ₃ I ₂ (III),

wherein R _{4 is} allyl or lower alkyl of 1 to 4 carbon atoms, which is preferably non-tertiary, and R _{3 is} a primary or secondary alkyl of 2 to 4 carbon atoms, preferably also non-tertiary, in a reaction medium of an alcohol and tetrahydrofuran (THF). In the second step of these methods, sodium borohydride (NaBH ₄ ) is added to the reaction medium, and this reaction proceeds to reduce the keto group to form the cyclic boranate or a borane complex of the compound of the formula (I). In the third step, the reaction mixture containing the boron complex and / or the cyclic borane ester is azeotroped with methanol or ethanol or optionally treated in an organic solvent with an aqueous peroxygen compound, for example a peroxide such as hydrogen peroxide, or a perborate such as sodium perborate to give the corresponding compound of formula (I). This process should give the erythro racemate in a selectivity of, for example, about 98% to the threo isomer, for example, see Tetrahedron Letters 28, page 155 (1987) (Chen et al.).

Detailed description of the invention

The process of the invention consists in a stereoselective reduction of racemic and optically pure compounds of the formula (II), resulting in almost exclusively the erythro-isomers of the formula (I). The reduction of the keto group of formula (II) is conveniently carried out almost immediately. The compounds of formula (I), namely the erythro isomers, are additionally formed in an increased chemical purity and can be further enriched by simple recrystallization to a chemical purity of greater than 99%.

In a first step of the process of the invention, namely step (a), a compound of formula (III) is mixed with sodium borohydride NaBH ₄ in a reaction medium containing an alcohol and tetrahydrofuran.

In a second step, namely step (b), a compound of formula (II) is treated with the mixture obtained according to step (a) under conditions which give a mixture comprising a cyclic boranate compound of formula (IVa)

r / ^X o ^(IVa)

for

RX-CHCH ₂ CH - CH ₂ COOR ₁ and / or a boron complex of the formula (IVb)

/ \ <^lvb>

0 OH

RX-GHCH ₂ Ch-CH ₂ COOR ^

wherein R, R ₁ , R ₃ and X are as defined above. The latter compound prevails over deterrence. However, deterring converts the boron complex into a borane ester.

In the third step, namely step (c), the product obtained according to step (b) is converted by cleavage into the corresponding compound of formula (I).

Step (a) is preferably carried out under anhydrous conditions, preferably in an inert atmosphere, at temperatures of about -100 ° C to about +30 ⁰ C, preferably about -80X to about -60 ° C, and especially about -78 ° C to about -70 ° C,

carried out. The reaction medium used in step (a) is a mixture of an alcohol and tetrahydrofuran, the alcohol having the formula AlkOH, wherein Alk is alkyl of 1 to 4 carbon atoms, such as methyl or ethyl, which is preferably non-tertiary.

One of the products obtained in step (a) may be a compound of the formula R ₄ OH which results from the compound of the formula (III) used. However, it is not necessary that all or part of the alk is the same as the radical R ₄ . The sodium borohydride is generally to be present in an amount at least equimolar to the compound of formula (II) and is preferably present in a slight excess, for example in an amount of from about 1.1: 1 to about 1.5: 1 mole of NaBH ₄ 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, and preferably constitutes about 0.7: 1 to about 1.5: 1 mole of borane compound per mole of ketone.

Step (b) is preferably also carried out at reduced temperatures, so that the internal temperature to about - is kept 100 ° C to about ⁰ -4o C, and especially about -78 ° C to about -70 ° C. The compound of formula (II) is preferably dissolved in a solvent such as alcohol / THF or THF. The reaction medium of step (a) and the solvent for the compound of formula (II) which is added in step (b) is preferably designed to give a combined reaction medium in which the ratio (volume: volume) from about 1: 3 to about 1: 6 alcohol to tetrahydrofuran to THF, and more preferably from about 1: 3 to about 1: 4. The reduction of the keto group is exothermic and occurs rapidly, and the keto compound is therefore advantageously such gradually added so that an internal temperature in the range of about -78 ° C is maintained to about -70 ⁰ C. The reduction occurs almost immediately and the reaction mixture is then quenched, for example, by the addition of aqueous sodium bicarbonate, ammonium chloride or acetic acid to give a mixture of the desired cyclic borane intermediate. In step (c), the reaction mixture of step (b) may be azeotroped with methanol or ethanol, for example at a temperature from about 60 ^° C. to about 80 ^° C., under substantially anhydrous conditions. Optionally, and preferably, especially when X is -CH = CH-, the product neutralized by the addition of sodium bicarbonate (NaHCOa) is dissolved in an organic solvent such as ethyl acetate and the solution is treated with aqueous (e.g. 30%) hydrogen peroxide or aqueous sodium perborate (NaBO ₃ · 4H ₂ O) is first at a reduced temperature, for example about +10 ⁰ C and then allowed to warm to a medium temperature, for example about 20 ⁰ C to about 30 ° C treated to give the corresponding compound of formula (I ).

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

The process of the invention is carried out under reducing conditions, so that substituents or functions on the radical R used should be inert. Therefore, this group is not intended to include substituents or functions which are reactive or capable of being modified under the conditions employed, such that such functions must be either masked or protected using known methods, or introduced at a later stage.

The compounds of formula (I), the corresponding δ-lactones, free acids and salts, the processes for the conversion of a compound of formula (I) wherein R _{1 has} a particular meaning into the corresponding compound wherein R ₁ has another meaning has, and / or in the corresponding δ-lactone or the free acid or salts thereof, are known. The compounds of formula (I) can, if desired, be converted by conventional methods into the corresponding free acids or salts, namely in compounds in which R _{1 is} replaced by hydrogen or a cation, for example by an alkali metal cation or by ammonium, preferably by sodium or Potassium and in particular by sodium, or they can be converted into other esters or into the corresponding δ-lactones, ie the inner esters. The compounds of the formula (I) obtained by the process according to the invention are, as already mentioned, pharmaceuticals. In a further embodiment, however, the process according to the invention can also be applied to the preparation of chiral intermediates, and such a process consists, for example, in the preparation of a compound of the formula (Iu) ₍

u - OCH ₂ - CHCH ₂ CHCH ₂ - COOR ₁₁ (Iu)

OH OH wherein

u is triphenylmethyl (trityl), and R _{u is} allyl or a radical which forms an ester which is inert under the reaction conditions, where R _{u is} allyl or

C ₁ -C ₃ -A ^ yl, η-butyl, isobutyl, t-butyl or benzyl are preferred and t-butyl is particularly preferred, by stereoselective reduction of a racemic or optically pure compound of the formula (II u) _f

U-OCH ₂ -C-CH ₂ -C-CH ₂ -COORu (Hu)

Z ₁ Z ₂

wherein u, R _u , Z ₁ and Z _{2 are} as defined above.

Such chiral intermediates are described for example in EP-A0244364. They can be used for the production of pharmaceuticals.

raw materials

The (primary or secondary C ₁ -C ₄ -alkoxy or allyloxy) -di- (primary C ₂ -C ₄ -alkyl) boranes of the formula (III) which are used as starting materials in the process according to the invention are known compounds, for example Ann., page 352 (1975) (Koster et al.), Tetrahedron Letters 28, page 155 (1987) (Chen et al.) and Chemistry Letters, pp. 1923-1926 (1987) (Chen et al.) , However, they can be prepared in situ from the corresponding Tn- (primary or secondary C ₂ -C ₄ -alkyl) boranes by reaction with a primary or secondary C 1 -C ₄ -alkanol or with allyl alcohol, the concentration of the former in the latter preferably about 0.2 molar to about 1.2 molar and in particular about 0.5 molar.

The compounds of formula (II) are either known or can be prepared analogously to known compounds of formula (II), and thereto is for example made to US-A4739073 (compounds of formula II, wherein Z ₂ is, for example, oxygen) or EP -AO 216785 (compounds of formula II wherein Z is, for example, oxygen). The compounds of the formula (II) in which Z _{2 is} oxygen are therefore usually prepared, for example, by reacting a compound of the formula (V)

R-X-CHO (V),

wherein R and X are as defined above, with the dianion of a compound of formula (Vl)

CH ₃ -CO-CH ₂ -COOR ₁ (VI),

wherein R _{1 is} as defined above, is reacted.

Earlier intermediates

The compounds of formulas (V) and (VI) are also known. Compounds of the formula (Va)

J ^ (Va)

R _{5 is} hydrogen, C ₁ -C ₃ -alkyl, η-butyl, isobutyl, tert-butyl, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₃ -alkoxy, n-butoxy, isobutoxy, trifluoromethyl, fluorine, Chlorine, phenoxy or benzyloxy,

R _{6 is} hydrogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy, with the provisos that not more than one of the substituents R ₅ and R _{6 is} trifluoromethyl, not more than one of the substituents R ₅ and R _{6 is} phenoxy and not more than one of the substituents R ₅ and R _{6 is} benzyloxy, one of the substituents R ₇ and Rs is phenyl which is trisubstituted by R ₉ , R ₁₀ and R ₁₁ and the other of these substituents for primary or secondary C ₁ -C ₆ -alkyl which does not contain an asymmetric carbon atom, is C ₃ -C ₆ -cycloalkyl or phenyl- (CH ₂ ) _m -,

R _{9 is} hydrogen, C ₁ -C ₃ -alkyl, η-butyl, isobutyl, t-butyl, C ₁ -C ₃ -alkoxy, n-butoxy, isobutoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,

R _{10 is} hydrogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy, R _{11 is} hydrogen, C ₁ -C ₂ -alkyl, C ₁ -C ₂ -alkoxy , Fluorine or chlorine, and

m is 1,2 or 3,

with the provisos that not more than one of the substituents R ₉ and R _{10 is} trifluoromethyl, not more than one of the substituents R ₉ and R ₁₀ phenoxy and not more than one of the substituents R ₉ and R _{10 is} benzyloxy, for example starting from a subgroup of compounds of the formula (VII)

(E) -OHC-CH = CH-N (R ₁₂ ) R ₁₃ (VII)

R _{12 is} C ₁ -C ₃ -alkyl, phenyl or monosubstituted to trisubstituted phenyl, where these substituents are each independently C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, fluorine, chlorine, bromine or nitro, however, a maximum of two nitro groups are present, and R _{13 is} independently as defined above for R ₁₂ .

The process for the preparation of the compounds of the formula (VII) is hereinafter referred to as "Process A", while the process for the preparation of compounds of the formula (Va) is hereinafter referred to as "Process B". The compounds of formulas (Va), (VII) and (XVII) (see later section 7.2) are known, for example, from US-A-4739073 wherein the compounds of formula (VII) wherein R _{12 is} C ₁ -C ₃ alkyl , and their use for the synthesis of

Compounds of the formula (Va), the compounds of the formula (XVII) and the use of the compounds of the formula (Va) for the synthesis of indole analogues of mevalonolactone and derivatives thereof which can be used as HMG-CoA reductase inhibitors. These compounds inhibit the synthesis of cholesterol and therefore lower the level of cholesterol in the blood so that they are useful in the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.

Compounds of formula (VII) and methods for their preparation are also described in GB-B945536 and in CS-A90045. However, the methods described therein are different from the method A, for example, in that here phosgene or phosphorus trichloride, phosphorus pentachloride or phosphorus oxychloride is used and no oxalic acid derivative.

Method A (preparation of the compounds of formula VII)

The process for the preparation of the compounds of the formula (VII) (process A) consists in that (i) a compound of the formula (VIII) ₍

OHC-N (R ₁₂ ) R ₁₃ (VIII)

wherein R ₁₂ and R, _{3 are} as defined above, with a compound of formula (IX)

X ₃ -CO-CO-X ₈ , (IX)

wherein X _{8 is} a monovalent leaving group, optionally in an inert anhydrous organic medium, to give the corresponding compound of formula (X)

X ₃ -CH = N ⁺ (R ₁₂ ) R ₁₃ X ₃ "(X)

wherein X ₃ , R ₁₂ and R _{13 are} as defined above, (ii) a compound of the above formula (X) is reacted with a compound of the formula (XI) ₍

R ₁₄ O-CH = CH ₂ (XI)

wherein R _{14 is} a monovalent group which 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 ₁₄ O-CH = CH-CH = N ⁺ (R ₁₂ ) R ₁₃ X ₃ "(XII)

wherein R ₁₂ , R ₁₃ , R ₁₄ and X _{3 are} as defined above, and (iii) a compound of the above formula (XII) is converted by hydrolysis to the corresponding compound of the formula (VII) in the form of the free base or an acid addition salt is, and, if it is an acid addition salt, the obtained acid addition salt is neutralized with a base.

In a variant of process A, step (iii) may be omitted and a compound of formula (XII) used directly, for example, for process B.

Steps (i) and (ii) may be carried out simultaneously or step (ii) may follow step (i), and step (iii) may be followed by step (ii), step (iv) ( see later description), if any is used following step (iii).

The substituent R ₁₂ corresponds to the substituent R ₁₂₃ , in which R _{123 is} C ₁ -C ₃ -alkyl or the substituent R _12b , where R _12b, with the exception of C ₁ -C ₃ -alkyl, is the one given above for R ₁₂ Meaning has (namely phenyl or monosubstituted to trisubstituted phenyl, whose substituents are each independently C ₁ -C ₃ -AlkYl, C ₁ -C ₃ -alkoxy, fluorine, chlorine, bromine or nitro, with a maximum of only two nitro groups may be present )

The substituent R ₁₂₃ is preferably C ₁ -C ₂ -A ^ yI and especially methyl.

The substituent R _12b preferably corresponds to the substituent R _12b · wherein R _12b · is phenyl or mono- or di-substituted phenyl whose substituents are each independently C ₁ -C ₃ alkyl, C ₁ -C ₂ alkoxy or chloro, wherein the substituent R _12b more preferably corresponds to the substituent R _12b -, wherein R _12b - is phenyl or phenyl substituted by one or two methyl groups and in particular is phenyl

The substituent R ₁₃ is preferably C ₁ -C ₂ -A ^ yI and especially methyl.

The substituent R ₁₄ is preferably C ₁ -C ₆ alkyl, preferably primary or secondary C ₂ -C ₄ alkyl, more preferably n-Cr-C-alkyl and especially ethyl or n-butyl.

Each of the substituents X _a is preferably chlorine or bromine and especially chlorine. Each X _a ~ is preferably chloride or bromide and especially chloride. The base used for the hydrolysis or neutralization in the step (iii) is preferably an inorganic base such as sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide, and especially sodium carbonate or potassium carbonate.

Process B (Preparation of the compounds of the formula Va from the compounds of the formula VIIc) The process for the preparation of the compounds of the formula (Va) (process B) consists in that

(i) a compound of the formula (VIIc).

(E) -OHC-CH =CH-N (R _12b ) R, 3 in which Ri 2 b and R _{13 are} as defined above, with a compound of the formula (XV)

(VIIc)

(XV)

wherein X _{b is} chlorine or bromine, or with a compound selected from oxalyl chloride or oxalyl bromide, phosgene or carbonyl bromide, phosphorus trichloride or phosphorus tribromide, phosphorus pentachloride or phosphorus pentabromide and an alkylsulfonyl chloride or arylsulfonyl chloride or an alkylsulfonyl bromide or arylsulfonyl bromide such as p-toluenesulfonyl chloride or p- Toluenesulfonyl bromide or methanesulfonyl chloride or methanesulfonyl bromide to give the corresponding compound of formula (XVI)

(E) -X _b -CH = CH-CH = N ⁺ (Ri2b) Ri ₃

(XVI)

and the corresponding anion, such as the anion PO ₂ (Xb) 2, in which X _b , R _12b and R _{13 are} as defined above, (ii) reacting a compound of the formula (XVI) with a compound of the formula (XVII)

(XVIl)

wherein R ₅ , R ₆ , R ₇ and R _{8 are} as defined above, to give a corresponding compound of formula (XVIII)

(XVIII)

and the corresponding anion, such as the anion "PO ₂ (Xb) ₂ , wherein R ₅ , R ₆ , R ₇ , R ₈ , R _12b , R ₁₃ and X _{b are} as defined above, and

(iii) hydrolyzing the compound of formula (XVIII) to form a corresponding compound of formula (Va). As mentioned above for process A, in a variant of step (i) a compound of formula (XII) obtained according to process A can be used directly in place of a compound of formula (VIIc). A compound of the formula (VIIc) is preferably reacted with a compound of the formula (XV). The steps (i) and (ii) are preferably carried out in an inert anhydrous organic medium.

General conditions applicable to all procedures

The majority of the molar amounts (ratios) mentioned herein are merely exemplary and can be varied as would be understood by those skilled in the art.

Steps (i) and (ii) of process A and steps (i) and (ii) of process B are preferably carried out under anhydrous conditions and in an inert atmosphere, preferably under dry helium, argon or nitrogen, or a mixture thereof under dry nitrogen. Stage (iii) of Process A and Process B are also often conducted under an inert atmosphere, but need not.

Similarly, the majority of the specified temperature ranges is merely exemplary. All temperatures are internal temperatures, unless otherwise stated. The term reaction medium includes mixtures of liquids and implies that the reaction medium is a liquid at the desired reaction temperature. Not all fluids listed for a given level can therefore be applied over a full specified temperature range. It should also be mentioned that the reaction medium must be at least virtually inert to the reactants used as well as the intermediates and final products formed under the reaction conditions. The reaction temperature may exceed the boiling point of a reactant or the reaction mixture if a condenser or a closed system (reaction bomb) is used.

The above-mentioned reaction times are merely exemplary and can be changed.

The term solvent includes mixtures of solvents and implies that the reaction medium is a liquid at the desired reaction temperature. All solvent mixtures are by volume, unless otherwise stated. Under an inert atmosphere, an atmosphere is formed understood that does not react with the reactants, intermediates and end products or that does not interfere with the reaction otherwise

If desired, the product of each process can be purified by conventional methods such as recrystallization, chromatography or fractional distillation

AlleTemperaturen are in degrees Celsius, and under room temperature eineTemperaturvon20 ° C to 30 ⁰ C, usually from 20 ⁰ C to 25 ° C, it is understood, unless otherwise stated the required evaporations are performed under reduced pressure and application of a minimal heating, and Drying of organic phases is carried out over anhydrous magnesium sulfate unless otherwise stated and silica gel is used for all column chromatographic procedures

The process variants described in connection with the invention are, of course, improvements over known similar processes, and with these processes, the desired end products, namely the hept-6-enecarboxylic and heptanecarboxylic acids substituted in position 7 and the derivatives thereof, for example, more easily or for example in higher chemical or optical purity as obtained using the conventional methods

Each of the above process variants may be used either separately together with conventional processes or, if desired, also in combination to produce the desired end products

Special embodiment

A specific example of the general inventive concept relates to a process for preparing erythro (E) -3,5-dihydroxy-7- [3 '- (4 "-fluorophenyl) -1' - (1" -methylethyl) mdol-2'-yl] -hept-6-encarbonsaureder formula (la)

(La)

CH-CH - CH-CHj-COO OH OH

in racemic or optically pure form, in the form of a free acid, a salt, an ester or a δ-lactone, namely an internal ester, according to a multistage process, namely process A, covenant of the stereoselective reduction of a compound of formula (II) that consists in

- that according to the method A

(a) a compound of the formula (VIII a) ₍

OHC-N (R _12b ) R _l3 (Villa)

wherein R) 2b and R _{13 are} as defined above, with a compound of formula (IX), optionally in an inert anhydrous organic medium, to the corresponding compound of formula (Xc).

X _a -CH = N ⁺ (R _12b ) R ₁₃ X _a - (X c)

wherein X ₃ , R ₁₂ b and R _{13 are} as defined above, is reacted,

(b) the particular compound of the formula (Xc) with a compound of the formula (XI), if appropriate in an inert anhydrous organic medium, to give a corresponding compound of the formula (XIIc)

(EhR ₁₄ O-CH = CH-CH = N- (R _12b ) R, 3 X _a ~ (XIIc)

wherein R _12b , R ₁₃ , R ₁₄ and X _{a are} as defined above, and

(C) the respective compound of formula (XIIc) is hydrolyzed by hydrolysis to the corresponding compound of formula (VIIc) in the form of the free base or an acid addition salt, and, if it is an acid addition salt, this acid addition salt is neutralized with a base .

- that according to method B

(d) the obtained compound of the formula (VIIc) with a compound of the formula (XV) or with a compound selected from oxalyl chloride or oxalyl bromide, phosgene or carbonyl bromide, phosphorus trichloride or phosphorus tribromide, phosphorus pentachloride or phosphorus pentabromide and an alkylsulfonyl chloride or arylsulfonyl chloride or a Alkylsulfonyl bromide or arylsulfonyl bromide, such as p-toluenesulfonyl chloride or p-toluenesulfonyl bromide or methanesulfonyl chloride or methanesulfonyl bromide, to give the corresponding compound of the formula (XVI) and the corresponding anion, such as the anion "PO ₂ (X _b ) _2"

(e) a compound of formula (XVI) with 3- (4'-fluorophenyl) -1- (1'-methylethyl) -1H-indole (a compound of formula (XVII) wherein R ₅ and R _{6 are} each hydrogen , R7 is 1-methylethyl and R ₈ is p-fluorophenyl) to the corresponding compound of formula (XVIIIa)

(XVIlIa)

and the corresponding anion, such as the anion ~PO ₂ (X _b ) ₂ , in which R ₁₂ b, R 13 and X _{a are} as defined above,

(f) hydrolysis of a compound of formula (XVIIIa) to give (E) -3- [3 '- (4 "-fluorophenyl) -1'-CI" -methylethyl) -1H-indol-2'-yl] -prop-2-enal (namely the compound of formula (Va) wherein R ₅ and R _{6 are} each hydrogen, R _{7 is} 1-methylethyl and R _{8 is} p-fluorophenyl),

(g) a compound of the formula (Va) with the dianion of an acetoacetic acid ester of the formula CH ₃ COCH ₂ COOR ₁ , in which R _{1 is} as defined above, to give the corresponding compound of the formula (IIa)

(Ua)

CH-CH ₂ -C-CH ₂ -CCX) R.

I Il

OH O

wherein R _{1 is} as defined above, is reacted in racemic or optically pure form, - that after the stereoselective reduction process:

(h) subjecting the racemic or optically pure compound of formula (Ma) to stereoselective reduction by reacting, in a first step (= step (a) in Section 5 above), a compound of formula (III) with sodium borohydride (NaBH ₄ ) in a reaction medium of an alcohol and tetrahydrofuran; in a second step (= step (b) according to Section 5 above) a compound of formula (IIa) in racemic or optically pure form is treated with the resulting mixture under conditions which give a mixture comprising a cyclic boronate compound of the formula ( IVa) and / or a boron complex of the formula (IVb) in which R is [3- (4'-fluorophenyl) -1- (1'-methylethyl) -1H-indol] -2-yl, X is (E ) -CH = CH- and R ₁ and R _{3 are} as defined above, and

in a third stage (= stage (c) according to section 5 above) the product obtained in the second stage is converted by cleavage into the compound of formula (Ia) in the form of an ester and in racemic or optically pure form, and ( i) if desired, the compound of formula (Ia) in the form of an ester using conventional methods

a free acid, a salt, another ester or the δ-lactone, namely an internal ester. The compound of the formula (Ia) may be in the form of a free acid, a salt, an ester or a δ-lactone, namely an internal ester. It is preferably in the form of the free acid or a salt, preferably an alkali metal salt and in particular a sodium salt. Preferably, this compound is a racemic or optionally optically pure 3R, 5S enantiomer, and especially a racemic form. The compound of formula (Ia) has the erythro-form.

embodiments

The invention will be further illustrated by the following examples. All temperatures are given in degrees Celsius. The optical purity is expressed in%, so that, for example, the statement 99.9% of pure erythro-lsomeres means that in the resulting compound the threo form highest is present in a proportion of 0.1%.

Example 1 (± J-erythro- (E) -7- [3 '- (4 "-fluorophenyl) -1' - (1" -methylthyl) -indol-2'-yl] -3,5-dihydroxy-hept-6-one T-butyl encarboxylate (Formula (I): R = 3- (4'-fluorophenyl) -1- (1'-methylethyl) indol-2-yl; X = (E) -CH = CH-; R ₁ = t-butyl, in racemic form)

(a) 47,67g (1.26 MoI) Natriumborhydridzu It is a solvent of 1.321 dry tetrahydrofuran (THF) and 356 ml methanol at about -77 ⁰ C under a nitrogen atmosphere The solution obtained is during a period of 15 minutes 102 ml a 50% (4.09 molar) solution of diethylmethoxyborane in THF, and the resulting mixture is stirred for a further 10 minutes

(b) 300.5 g (0.464 mol) of (±) - (E) -7- [3 '- (4 "-fluorophenyl) -1' - (1" -methylethyl) -mole-2'-yl] are added. T-butyl 5-hydroxy-3-oxohept-6-enecarboxylate having a purity of 71.88% in 104 ml of THF and 26 ml of methanol at a temperature of about -74 ° C to -77 ° C dropwise over a period of time 1.5 hours to the mixture formed in step (a) above, and the resulting mixture is stirred for a further 30 minutes. The reaction is stopped by adding 720 ml of a saturated sodium bicarbonate solution and 1.751 heptane. 500 ml of ethyl acetate are added and the resulting mixture is diluted with stirring during 15 minutes 3.51 water, the temperature of the mixture is maintained at about 10 ⁰ C. the upper organic layer is separated and washed several times with a total of 2.41 of a saturated sodium chloride solution of pH 7.5, and the organic layer is concentrated under a vacuum of 27 to 40 mbar at a maximum external temperature of about 45 ° C. The resulting organic residue is treated with 375 ml of toluene, and the solvent is distilled off under a vacuum of 27 to 40 mbar at a maximum external temperature of about 45 ° C

(c) The thick oil obtained (which mainly consists of a cyclic boronate) is reacted with 3.731 of ethyl acetate The Ethylacetatlosung is then treated with 500ml of a 30% hydrogen peroxide solution (4.41 mol), wherein the outer temperature to 25 ⁰ C to 30 ⁰ C is kept (the addition is initially exothermic), and the reaction mixture is about

The mixture is stirred for 2 hours at 20 ⁰ C to 25 ° C until the Dunnschichtchromatogramm find no boronate Let the upper organic layer is washed twice with a total of 2,221 of a saturated sodium chloride solution of pH 7.5 The upper organic layer is then separated, washed three times with washed a total of 2.611 of a 10% Sodium sulfite solution (until the organic solution is peroxide-free), while maintaining an internal temperature of 25 ° C. The upper organic layer is then washed twice with a total of 1.721 a saturated sodium chloride solution of pH 7.5, after which the solvent Distillation is removed under a vacuum of 27 to 40 mbar and at a maximum external temperature of about 45 ° C. The residue is dissolved in 1.171 refluxing ethyl acetate, the mixture is filtered while hot, and the filtrate is 18 hours at 20 ⁰ C to 25 ° C stirred The solids are collected by filtration, under reduced pressure (e about 27 to 40 mbar) at 25 ° C, washed with 550ml of a 1 4 mixture of ethyl acetate and heptane, dissolved in 880 ml of ethyl acetate and stirred at ambient temperature for 18 hours. The solids are collected by filtration and with 480 ml of a 1 2 mixture washed from ethyl acetate and heptane The solids are dried under reduced pressure to give 114.5 g of a product having a melting point of 135 ° C to 137 ° C. From the mother liquors, a second crop is obtained giving a total yield of 149.5 g The product has a chemical purity of 99.44% and consists of 99.67% pure erythro isomer. It can be split into two optically active enantiomers, namely the enantiomers 3R, 5S and 3S, 5R, of which the former is preferred is optional, and preferably only one half of the stated amount of sodium borohydride can be used in step (a)

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

Salt formation (stage 1) of the special embodiment)

42.5 g of the ester obtained as described above in 275 ml of THF during 5 minutes with 90 ml of normal sodium hydroxide, while the temperature is kept below 10 ⁰ C The solution is stirred for 1 hour at room temperature, with 275 ml of methanol, whereupon The mixture is concentrated at 33 mbar and 45 ⁰ C, then treated with 300 ml of deionized water and then brought by further distillation to a volume of 140ml, after which one adds again 380 ml of deionized water and then the solution three times with a total of 640 ml t Washing the aqueous layer at 33 mbar and 45 ^° C. to a volume of about 300 ml and adding 220 ml of deionized water, and the clear aqueous solution is lyophilized for 3 days to give the sodium salt of the title compound (35). 9g, yield = 91%, chemical purity = 98.9%, purity of the erythro isomer = 99.9%, boron concentration = below the detection limit)

Other requirement for salt formation

Add 35.0 g of the ester obtained as described above in 175 ml of ethanol while stirring for 5 minutes with 74 ml of 1 normal sodium hydroxide solution while keeping the temperature below 12 ° C. The solution is stirred for 1 hour and then the mixture is allowed to stand Concentrated 33 mbar and 45 ⁰ C, whereupon the whole with 250 ml of deionized water and the distillation is continued to a volume of 115 ml, followed by 315 ml of deionized water and the solution washes three times with a total of 525 ml of t-butyl methyl ether The aqueous layer is concentrated at 33 mbar and 45 ° C to a volume of about 245 ml and treated with 185 ml of deionized water, whereupon the clear aqueous solution while

3 days is lyophilized to give the title compound (29,75g, Color = pure white, yield = 91%, mp = 204 ° C to 207 ⁰ C with decomposition, chemical purity = 100%, erythro-lsomeres = 99.61 % pure, boron concentration = 3.96 ppm)

The starting material used in step b) is obtained as follows

3- (N-methyl-N-phenylamino) acrolein

(= (E) -3- (N -methyl-N-phenylamino) prop-2-enal) (Formula (VII) R ₁₂ = phenyl, R, ₃ = methyl

Stage (i)

A 12 l four-necked flask equipped with a stirrer, a brine-filled condenser, a thermometer, a soda-filled scrubber, a dropping funnel and a cooling bath is pressurized under nitrogen with 3, 1 l methylene chloride and 1.02 kg ( 7.4 moles) of N-methylformanilide. The solution is cooled to 15 ° C and treated with 1.0 kg (8.67 moles) of oxalyl chloride over a period of 1.5 hours such that little or no solvent and / or reagent is added to the bottom of the saline solution Cooler is entrained, the temperature is maintained under mild reflux to 15 ° C to 17 ⁰ C. The reaction mixture is slowly warmed to 43 ° C over a period of 1 hour and refluxed for 1 hour at 43 ° C to 45 ° C to give a clear yellow solution, which is then cooled to 15 ° C.

Stage (ii)

During a period of 40 to 60 minutes, 648 g (8.99 mol) of ethyl vinyl ether are added while maintaining the temperature at a maximum of 28 ° C to 29 ° C, since the reaction is very exothermic. The brown-red solution is heated for 30 minutes at 38 ⁰ C to 39 ° C, resulting in a refluxing, and the solution is then cooled to 15 ° C.

Stage (iii)

A solution of 960 grams (9.05 moles) of anhydrous sodium carbonate in 4.5 liters of water and added over a period of 45 to 60 minutes while maintaining the temperature at 22 ° C to 30 ° C, since this addition is very exothermic. The mixture is stirred for 15 minutes at 22 ° C to 25 ⁰ C, whereupon it is allowed to stand for 15 minutes in two layers to separate. The organic layer is separated and the aqueous layer is extracted with 1,251 methylene chloride. The methylene chloride extract is combined with the previous organic layer and the combined solution is extracted with 11% water. The aqueous extract is back-extracted with 250 ml of methylene chloride and the resulting methylene chloride extract is combined with the previous organic layer. By vacuum distillation at 27 to 53 mbar and 60 ⁰ C as much methylene chloride is recovered, and the remaining oil is heated for 4 hours under vacuum at 27 to 40 mbar and 6O ⁰ C to 65 ° C, whereby the product is an oil with a purity of 83.5% (1.295 kg, yield = 90.7%, boiling point of the pure product = 244 ⁰ C with decomposition, melting point of the pure product after recrystallization from a 1: 1 mixture of isopropanol and hexane = 46 ° C bis47 ° C).

Second regulation stage (i)

A 5-liter four-necked flask equipped with a stirrer, a brine-filled condenser, a thermometer, a soda-type scrubber, a dropping funnel and a cooling bath is treated under nitrogen with 350 ml of acetonitrile and 425 g (3.8 Mol) of N-methylformanilide. The solution is cooled to -15 ° C and 440 g (3.46 mol) of oxalyl chloride are added over a period of 1.5 hours, with little or no solvent and / or reagent in the bottom of the saline solution and on -25 ° C to -20 ⁰ C entrained while a temperature of -15 ° C to -10 ⁰ C is maintained under slight reflux. The reaction mixture is heated for a period of 30 minutes slowly to 15 ⁰ C and then stirred for 15 minutes at 15 ° C to 18 ° C.

Stage (ii)

One gives 339.5 g (3.39 mol) of n-butyl vinyl ether over a period of 45 minutes, slowly, with a maximum temperature of 28 ° C to 3O ⁰ C is maintained, since the reaction is very exothermic. The reaction mixture is stirred for 30 minutes at 30 ⁰ C to 35 ° C, resulting in a red-brown solution, which is then cooled to 0 ⁰ C.

Stage (iii)

A solution of 395 g (3.73 mol) of anhydrous sodium carbonate in 1.751 of water is added over a period of 40 to 60 minutes while maintaining a temperature of 8 ° C to 10 ⁰ C, since the addition is very exothermic. Then you are added to 1.755 toluene and the mixture is stirred for 15 minutes at 20 ⁰ C to 22 ° C, whereupon it is allowed to stand for 15 minutes in two layers to separate. The organic layer is separated and washed twice with 150 ml of water each time. By vacuum distillation at 27 to 106mbar and 60 ⁰ C to 9O ⁰ C as much toluene is recovered, and the remaining oil is heated for 30 minutes at 27 to 40 mbar and 89 ° C to 90 ⁰ C, whereby the product is an oil with a Purity of 86.6% (492g, yield = 85.7%, boiling point of the pure product = 244 ⁰ C with decomposition, melting point of the pure product after recrystallization from a 1: 1 mixture of isopropanol and hexane = 46 ° C bis47 ^c C).

The reaction mixture is instead stirred at 28 ° C to 3O ⁰ C for 30 minutes at 30 ⁰ C to 35 ° C, then a product is obtained having a purity of 92.3% in a yield of 90.7%.

Third regulation stage (i)

A 2.5 liter four neck flask equipped as described in the second protocol is charged with 223.2 ml (1.81 mol) of N-methylformanilide under a nitrogen atmosphere. The solution is cooled to 15 ° C and 177.6 ml (2.07 mol) of oxalyl chloride are added over a period of 20 minutes while maintaining the same temperature. There is a spontaneous evolution of gas and the formation of an orange homogeneous solution.

Stage (ii)

During a period of 45 minutes, add 278,4ml (2.16 mol) n-butyl vinyl ether, an inner temperature of 25 ° C to 3O ⁰ C is maintained, because the reaction is exothermic. The orange suspension is stirred for 30 minutes at 40 ° C to 45 ⁰ C and then cooled to 0 ° C.

Stage (iii)

The product of step (ii) is slowly added to a 4-normal sodium hydroxide solution over about 90 minutes such that the temperature does not rise above 5 ° C. The mixture is warmed to room temperature and stirred for an additional 60 minutes. The organic layer is separated in a 3-L separatory funnel and the aqueous layer is extracted with 100 ml of n-butanol. The combined organic layers are washed twice with 200 ml of brine each time, and the solvent is then distilled for 2 hours at 80 ° C and 20 mbar to give a thick brown-black oil (295 g, yield = 92%, chemical purity = over 98 %, Boiling point of the pure product = 244 ° C with decomposition, melting point of the pure product after recrystallization from a 1: 1 mixture of isopropanol and hexane = 46 ° C to 47 ° C).

Third provision stages (i) and (ii)

A 12-liter four-necked flask equipped with a stirrer, saline-filled condenser, thermometer, soda-type scrubber, dropping funnel, and cooling bath is treated under nitrogen with 1.056 kg (8.15 moles) of oxalyl chloride and 480 ml of acetonitrile. The solution is cooled to -10 ° C and treated with 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 over a period of 2.5 hours such that only little or no solvent and / or reagent into the bottom of the filled with brine cooler (maintained at -25 ° C to -20 ⁰ C) is introduced while maintaining a temperature of -10 ⁰ C to -5 ° C with gentle Rückflußsieden is maintained. The resulting homogeneous orange reaction mixture is slowly heated to 20 ° C over a period of 30 minutes, after which the temperature rises to 28 ° C over a period of 30 minutes due to a mild exotherm. The reaction mixture is stirred for 1 hour at 28 ° C to 30 ° C, whereby a brown homogeneous mixture is obtained, which is then cooled to 0 ⁰ C.

Stage (iii)

Over a period of 45 to 60 minutes, a solution of 948 g (8.94 mol) of anhydrous sodium carbonate in 4.2 oil of water is added, maintaining a temperature of 8 ° C to 10 ° C, since the addition is very exothermic at the beginning , Priority 3,601 of toluene and the mixture is stirred for 15 minutes at 20 ⁰ C to 22 "C, after which it is allowed to stand to separate into two layers 15 minutes. The organic layer is separated and washed twice with 360 ml of water. By vacuum distillation at 27 to 106 mbar and 60 ⁰ C to 90 ⁰ C as much toluene is recovered, and the remaining oil is heated for 30 minutes at 27 to 40 mbar and 89 ⁰ C to 90 ⁰ C, whereby the product is an oil with a purity of 89.1% (1.16 kg, yield = 86.6%, boiling point of the pure product = 244 ° C with decomposition, melting point of the pure product after recrystallization from a 1: 1 mixture of isopropanol and hexane = 46 ° C. up to 47 ° C).

2) (E) -t 3 '- (4 "-fluorophenyl) -1' - (1" -methylethyl) -1H-indol-2'-yl] prop-2-enal Step (i)

A 5-liter four-necked flask equipped with a stirrer, a condenser, a thermometer, a dropping funnel and a cooling bath is mixed under dry nitrogen as a protective gas with 100 ml of dry acetonitrile and with 174.4 g (1.14 mol) of phosphorus oxychloride and the mixture is cooled to -5 ° C and then over a period of 45 minutes with a solution of 184 g (0.96 mol) of 3- (N-methyl-N-phenylamino) acrolein with a purity of 83.5%. (Product of Examples 6 to 8) in 156 ml of dry acetonitrile, wherein the temperature is maintained at -5 to +5 ⁰ C. The reaction mixture is stirred at 0 ° C to 5 ° C for 10 minutes.

Stage (ii)

Over a period of 20 minutes, 115.2 g (0.45 mole) of 3- (4'-fluorophenyl) -1- (1'-methylethyl) -1H-indole (a compound of the formula [XVIIJ) are added, the Temperature is maintained at about 5 ° C. The reaction mixture is refluxed for 9 hours at 83 ° C and then cooled to 10 ⁰ C.

Stage (iii)

During a period of 30 minutes a solution of 228g (5.8 moles) of sodium hydroxide is added in 2.01 of water slowly, maintaining the temperature at 25 to 30 ⁰ C is maintained, since the addition is very exothermic. Add 1.61 toluene, stir the mixture at 25 ° C for 30 minutes and then filter through a filter plug. The filter cake is washed with 100 ml of toluene and the wash is combined with the previous filtrate.

The organic layer is separated and treated first with a mixture of 93.4 g of concentrated hydrochloric acid and 21 of water and then with 400 ml of a saturated sodium chloride solution. The mixture is stirred for 30 minutes at 25 ° C, after which the resulting slurry is filtered through a filter pad. The tarry material is washed with 100 ml of toluene and the wash is combined with the filtrate. The organic layer is separated, washed twice with 21% each deionized water and filtered through a filter pad. By vacuum distillation at 40 to 67 mbar and an external temperature of 60 to 65 ⁰ C as much toluene is recovered, resulting in a thick stirrable oil. The oil is mixed with 100 ml of 95% ethanol, whereupon as much ethanol as possible is recovered by vacuum distillation at 40 to 106 mbar and 60 to 65 ° C., and this procedure is repeated twice. The mixture obtained after the addition of 180 ml of 95% ethanol is kept at reflux temperature at 78 ° C for 15 minutes and then slowly cooled to 20 ° C over a period of 2 hours, at about 55 ° C crystallization begins. The slurry is slowly cooled over a period of 30 minutes at 0 ⁰ C to 5 ° C, then 1 hour at 0 ⁰ C 2 ⁰ C to held and finally filtered. The filter cake is washed three times with 50 ml of cold (0 ⁰ C to 5 ° C) 95% ethanol and dried under vacuum at 60 to 65 ° C for 16 hours to constant weight, giving a product having a purity of 98.7 % (101g, yield = 71.3%, melting point = 127 to 128 ⁰ C)

 In one variant, isopropanol is used instead of 95% ethanol.

Second regulation stage (i)

A 5-liter four-necked flask equipped with a stirrer, condenser, thermometer, dropping funnel and cooling bath is added under dry nitrogen as a protective gas with 263 ml of dry acetonitrile and 454 g (2.96 mol) of phosphorus oxychloride, whereupon the reaction mixture to 5 Cooled and added over a period of 45 minutes with a solution of 471.6 g (2.49 mol) of 3- (N-methyl-N-phenylamino) acrolein with a purity of 85.5% in 406 ml of dry acetonitrile, while keeping the temperature at 5 to 7 ° C. The reaction mixture is stirred for 10 minutes at 5-7 ° C.

Stage (ii)

Over a period of 10 minutes, 300 g (1.18 mol) of 3- (4'-fluorophenyl) -1- (1'-methylethyl) -1H-indole (compound of the formula [XVII]) are added, the temperature is kept at about 7 ° C. The reaction mixture is held at 83 ° C for 3 hours at reflux temperature and then cooled to 22 ° C.

Stage (iii)

During a period of 15 minutes, 2.71 ml of water are slowly added, keeping the temperature at 22 to 35 ° C, as the addition is exothermic. The reaction mixture is stirred for 30 minutes at 35 to 50 ° C, then heated for 1.5 hours at 50 to 55 ⁰ C (for complete hydrolysis, a prolonged heating may be necessary), then cooled to 22 ° C, 15 minutes at 22 ° C. kept and finally filtered. The filter cake is washed three times with 600 ml of water each time and then dried under suction at aspirator pressure for 6 to 16 hours (whereby N-methylaniline can be obtained from the combined aqueous layers and the washing liquids). The wet cake is transferred to the original 5-L four-necked flask, added with 2.51 toluene and 180 g cellulose powder with a grain size of 20pm, and the mixture was heated 1.5 hours to 50 to 55 ⁰ C, cooled to 22 ⁰ C, Held for 15 minutes at 22 ° C and optionally by a pad of 91 g silica gel with a particle size of 0.06 to 0.20 mm, which is covered with a filter cloth, is filtered. The cellulose and the silica gel are washed three times with 200 ml of toluene each time. The toluene filtrate and the washings are combined, and from the combined solution as much toluene is recovered by vacuum distillation at 40 to 67 mbar and 50 to 65 ⁰ C (outside). The remaining thick oil is mixed with 280 ml of 95% ethanol, the ethanol is distilled off at 27 to 40 mbar and 60 to 65 ° C, whereupon 280 ml of 95% ethanol are added and if possible by vacuum distillation at 40 to 106mbar and 60 to 65 ° C much ethanol is distilled off. One 700 ml of 95% ethanol added and the mixture was heated for 15 minutes under refluxing to 78 ° C, after which the whole is slowly cooled to 20 ⁰ C over a period of 1 hour, utilizing the crystallization at about 55 ° C. The resulting slurry is cooled over a period of 30 minutes at 0 ⁰ C to 5 ° C and held for 30 minutes at 0 ° C to 2 ° C, after which the solids were collected by filtration, washed three times with 120 ml of cold (0 ⁰ C to 5 ° C) 95% ethanol and dried for 16 hours under vacuum at 60 to 65 ° C to constant weight to give the desired product with a purity of 99.4% (276.6g, yield = 75.5 %, Melting point = 129 to 130 ° C). In a variant of the above method, isopropanol is used instead of 95% ethanol.

Preferably, the bulking on silica gel is omitted, so that the liquid containing the powdery cellulose is subjected to simple filtration, the residue thus obtained being washed three times with 200 ml of toluene each time.

Third regulation stage (i)

A 1.5 liter flask equipped as described in Example 10, step (i), is mixed under dry nitrogen as a protective gas with 170 ml of dry acetonitrile and 105.3 g of S-dM-methyl-N-phenylaminolacrolein hydrochloride salt at room temperature , The reaction mixture is treated for 5 minutes with 96.6 g of phosphorus oxychloride. It creates a dark solution.

Stage (ii)

90g 3- (4'-fluorophenyl) -1 Priority - (1 "methylethyl) to -1 H-indole (compound of formula [XVII]) at 30 ⁰ C. The mixture is held at 75 to 83 ° C for 4.5 hours at reflux temperature and then cooled to 22 "C.

Stage (iii)

Add first 250 ml of water at 5 ° C and then 500 ml of water at room temperature for 15 minutes. The mixture is stirred for 30 minutes at 35 to 50 ° C and then heated at 50 to 55 ° C for 1.5 hours. This results in a dark slurry. The mixture is cooled to 30 ⁰ C and held for 15 minutes at 30 ⁰ C, after which the brown slurry is filtered. The filter cake is washed three times with a total of 540 ml of water. The filter cake is dried by suction under vacuum for about 4 hours. The solids are transferred to the original 1.5 liter flask and treated with 750 ml of toluene and 54 g of powdered cellulose with a particle size of 20μηι, whereupon the whole in the second method, step (iii), worked up, which is the desired product gives (89g, yield = 81%, melting point = 123 to 129 ⁰ C).

3) (±) - (E) -7- [3 '- (4 "-fluorophenyl) -1' - (1" -methylethvl) indol-2'-yl] -5-hydroxy-3-oxohept-6- ene carboxylic acid t-butyl ester under a nitrogen atmosphere a reactor is charged with 0.51 tetrahydrofuran (Figure 2), step iii), and the solution is carefully to -10 ⁰ C (under cooling with 60 g of sodium hydride added in the form of a 60% dispersion in Mineral oil added.

Then, over a period of 45 minutes, gently add 237.3 g of t-butyl acetoacetate in 250 ml of THF, keeping the temperature below 2 ° C. The resulting solution is then stirred for 1 hour at -10 to 20 ⁰ C.

The reaction mixture is cooled to -10 ⁰ C and 938 ml of a 1.6 molar solution of n-butyllithium in hexane added so that the temperature does not rise above 0 ° C (for about 60 minutes). The mixture is stirred for 10 minutes at this temperature, whereupon it is cooled to -10 ° C and so with a solution of 230g of the product of the above step iii)

according to 2) in 650 ml of THF, that the temperature does not rise above 0 ⁰ C (during about 70 minutes) The reaction mixture is stirred for 15 minutes at 0 ⁰ C and then with vigorous stirring for 5 to 10 minutes, my mixture of 248 The mixture is stirred vigorously for a further 15 minutes, whereupon the organic layer is separated, washed twice with 500 ml of saturated sodium chloride solution and concentrated under reduced pressure (about 33 mbar). The residue is washed with 200 ml of toluene The crude toluene solution is concentrated again to give the crude (±) - (E) -7- [3 '- (4 "-fluorophenyl) -1' - (1" -methylethyl) -mdol-2'-yl] -5 obtained -hydroxy-S-oxohept-e-encarboxylic acid t-butyl ester (compound of formula [Ha] in which R ₁ is but-butyl, in racemic form) (503.6 g, purity = 70.04%) is obtained without further purification used at the next stage

Example 2 (±) -erythro- (E) -7-t3 '- (4 "-fluorophenyl) -1' - (1" -methylethyl) -indol-2'-yl] -3,5-dihydroxyhept-6- methyl encarboxylate (formula [I] R, X = as in example 1, R ₁ = methyl, in racemic form)

(a) Sodium borohydride is treated analogously to Example 1, step (a), but using 15% diethylmethoxyborane in THF

(b) 118.5 g (0.28 mol) of (±) - (E) -7- [3 '- (4 "-fluorophenyl) -1' - (1'-methylethyl) indole-2'-yl] are treated. 5-hydroxy-3-oxohept-6-enecarboxylic acid methyl ester analogously to Example 1, step (b), but diluted with 1.421 water and 1.1851 heptane and not with 3.5I water alone

(c) The organic residue (consisting mainly of cyclic boronate) is added with 2.375 L of ethyl acetate and the mixture is treated with 264 mL of a 30% hydrogen peroxide solution (2.328 mol) and worked up as described in Example 1, step (c) the residue is then dissolved in 130ml isopropanol the mixture is heated at reflux temperature the mixture is treated in the hot state with 14g boric acid and an additional 15 minutes kept at reflux temperature the mixture is filtered, and the filtrate for 18 hours at 2O ⁰ C to 25 ° C The solids are collected by filtration, washed with 100 ml of isopropanol and dried under reduced pressure to give 110 g (yield = 80%) of a product. After dissolution in methanol and recrystallization, a product with a melting point of 124-126 ° C is obtained for this product it is the desired erythro-Razemat with a purity of 99.07%, which is divided into two optical E nantiomers, namely the enantiomers 3 R, 5 S and 3 S, 5 R, of which the former is preferred

Example 3

(+ (- erythro-fEJ-S.S-dihydroxy-y-tl''-fluorophenyl-A'-ti-methyl-ethyl) -phenyl-IH-imidazol-B'-y-hept-e-encarboxylic acid-t-butyl ester

Formula (I) R = 1- (4'-fluorophenyl) -4- (1'-methylethyl) -2-phenyl-1H-imidazol-5-yl, X = (Ey-CH = CH-, R ₁ = t Butyl, in the form of the (3R, 5S) enantiomer)

(a) Add 10.27 g (0.27 mol) of sodium borohydride to a solvent of 1.671% dry THF and 513 ml of methanol under a nitrogen atmosphere at about -76 ° C. The resulting solution is treated with 387 ml of a 15% over a period of 30 minutes. solution of diethylmethoxyborane in THF, the internal temperature being kept below -77.5 ° C, and the resulting mixture is stirred for a further 5 minutes

(b) Add 110 g (0.223 mol) of (5S) - (E) -7- [1 '- (4 "-fluorophenyl) -4' - (1" -methylethyl) -2'-phenyl-1H-imidazole-5 '-yl] -5-hydroxy-3-oxohept-6-enecarboxylic acid t-butyl ester in 304 ml of THF and 76 ml of methanol at a temperature of about -74 ⁰ C to -77 ⁰ C dropwise over a period of 2 hours to the The resulting yellow solution is stirred at -76.5 ° C for 6 hours. The reaction is stopped by addition of 425 ml of saturated ammonium chloride keeping the temperature at about -65 ° C. 950 ml are added Ethyl acetate, 950 ml of hexane and 1.113 of water, the temperature of the mixture to about 5 ° C and the mixture is stirred for 15 minutes, the resulting temperature of the mixture is about 5 ° C. The upper organic layer is separated and in turn with total 1.41 of a saturated sodium chloride solution (pH = 7.5), and the solvent is then removed under a vacuum of 27 to 40 mbar at a maximum outside temperature distilled off temperature of about 45 ° C.

(c) Place 3.251 ethyl acetate to the obtained oil (which mainly is cyclic boronate) Then are added 340 ml of a 30% hydrogen peroxide solution (3 moles) to so slow that an internal temperature of 20 ⁰ C to 25 ° C is maintained, and the reaction mixture is then stirred at 20 ⁰ C to 25 ° C for about 3 hours, and let to notice in Dunnschichtchromatogramm no boronate the upper organic layer is washed twice with a total of 1.61 of a saturated sodium chloride solution of pH 7.5 The upper organic layer is then separated and then washed three times (10 minutes each) with a total of 1.51 of a 10% sodium sulfite solution (until the organic layer is peroxide-free), maintaining an internal temperature of 25 ° C washed with 600 ml of a saturated sodium chloride solution of pH 7.5 The solvent is, by distillation under vacuum at 27 to 40 m bar and a maximum external temperature of about 45 ⁰ C removed to give 106 g of a crude material obtained by saulenchromatographische purification of 0.68g of this crude dihydroxy ester using a 1 2 mixture of ethyl acetate and hexane as the eluant one obtains 490 mg of a product having a melting point from 143 to 154 ° C, which by NMR analysis is a product containing the erythro-isomer in a purity of 98.78% (no threo-isomer present) This product has a [a] g ° value of +6.49 ⁰ C (c = 0.77, CH ₂ Cl ₂ )

Example 4

(3R, 6Sl-erythro-dihydroxy-e-trityloxyhexanecarboxylic acid t-butyl ester

(Formula [Iu] u = trityl, R _u = t-butyl, in the form of the (-) - enantiomer)

(a) Place 5,61g (148,4mMol) of sodium borohydride under a nitrogen atmosphere at about -76 ⁰ C to a solvent of 990 ml of dry THF and 280 ml of methanol, the temperature increases to about -74 ° C The solution obtained is while a period of 20 minutes is added dropwise with a 15% solution of diethylmethoxyborane in THF, and the resulting mixture is stirred for an additional 10 minutes at -77 ° C to -76 ° C

(b) Mangibt56g (0,122mMol) (S) -5-hydroxy-6-trityloxy-3-oxohexancarbonsäure-t-butylesterin165mlTHFund41 ml of methanol at a temperature of about -77 ⁰ C to -75 ⁰ C during a period of 40 minutes dropwise to the mixture formed in the above step (a), and the resulting mixture is then stirred for a further 2 hours at -77 ° C to -75 ° C. Then the reaction is stopped by adding 156 ml of a saturated ammonium chloride solution. Then 500 ml of ethyl acetate, 500 ml of heptane and 600 ml of water are added. The upper organic layer is separated and washed in succession with a total of 600 ml of a saturated sodium chloride solution of pH 7.5, whereupon the organic layer is concentrated under a vacuum of 27 to 40 mbar at a maximum external temperature of about 45 ° C.

(c) Add 793 ml of ethyl acetate to the resulting organic residue (containing predominantly the cyclic boronate). 79 ml of a 30% strength hydrogen peroxide solution (0.7 mol) are then added slowly, and the reaction mixture is stirred for a further 3 hours until no more boronate can be detected in the thin-layer chromatogram. The upper organic layer is washed twice with a total of 400 ml of a saturated sodium chloride solution of pH 7.5. The upper organic layer is then separated and washed three times (for 10 minutes each) with a total of 576 ml of a 10% sodium sulfite solution until the organic layer is peroxide-free, maintaining an internal temperature of 25 ° C. Then, the upper organic layer is washed successively with a total of 200 ml of a saturated sodium chloride solution of pH 7.5, and the solvent is then removed by distillation under vacuum at 27 to 40 mbar and a maximum external temperature of about 45 ⁰ C, whereby 54.3 g the crude dihydroxy compound having a melting point of 84 to 86 ° C containing 99.19% erythro-lsomeres. This compound has a [a] D ⁰ value of -5.59 ° C (c = 1.6, CH ₂ Cl ₂ ).

Example 5

(±) -erythro- (E) -3,5-dihydroxy-7- [3 '- (4 "-fluorophenyl) -1' - (1" -methylethyl) indol-2'-yl] hept-6-one encarboxylic acid atrium salt (formula [Ia]: in racemic form and in the form of the sodium salt)

The title compound is prepared analogously to Example 1 except that in step 3) the methyl ester is formed by reaction with the dianion of methyl acetoacetate instead of t-butyl acetoacetate, the stereoselective reduction as in Example 2, steps (a), (b) and (c), and in step (i) (salification) hydrolysis of the resulting methyl ester is carried out as described in US-A-4739073, Example 6 (b), in column 50.

Claims (3)

1. Process for the preparation of a compound of the formula (I) 5 3 RX-CH-CH ₂ -CH-CH ₂ -COOR ₁ (I) OH OH X is -CH 2 -CH 2 -or-CH = CH-, R _{1 represents} an ester group which is inert to the reaction conditions, and R represents an organic radical having groups which are inert under reducing conditions, by stereoselective reduction of a racemic or optically pure compound of the formula (ΙΙ) _; RXC-CH ₂ -C-CH ₂ -COOR ₁ (II) Z ₁ Z ₂ wherein R, R ₁ and X are as defined above and one of the substituents Z ₁ and Z _{2 is} oxygen and the other is hydroxy or hydrogen, characterized in that according to a first step (step [a]) a compound of the formula (III ) R ₄ OB- (R ₃ I ₂ (III) R _{4 is} allyl or lower alkyl of 1 to 4 carbon atoms and R _{3 is} a primary or secondary alkyl of 2 to 4 carbon atoms, mixed with sodium borohydride NaBH ₄ in a reaction medium containing an alcohol and tetrahydrofuran in a second step (step Ib)) a compound of formula (II) is treated with the mixture obtained according to step (a) under conditions which give a mixture comprising a cyclic boranate compound of formula (IVa) ^R 3 B
/ (IVIa]) ο o R- X- CHCH ₂ CH-CH ₂ COOR ,,
and / or a boron complex of the formula (IVb) R ₃ R ₃ / \ (IVIb]) 0 OH
RX-CHGH ₂ YEAR-GW ₂ COOR ,, wherein R, R ₁ , R ₃ and X are as defined above, and in a third step (step [c]) the product obtained according to step (b) is converted into racemic or optically pure form by cleavage into the corresponding compound of formula (I), and the compound of formula I thus obtained, if desired, using conventional Methods to a free acid, a salt, an ester or the δ-lactone, namely an inner ester, is converted. 2. The method according to claim 1 for the preparation of a compound of formula (I u) 'j - OCH ₀ - CHCH CHCH _O "- CGCR
2 2 2 α UH GH (Iu) wherein u represents triphenylmethyl (trityl) and R _{u is} allyl or a radical which forms an ester which is inert under the reaction conditions, wherein as radicals R _u allyl or C ₁ -C ₃ -alkyl, η-butyl, isobutyl, t-butyl or benzyl are preferred and t Butyl is particularly preferred, characterized in that a racemic or optically pure compound of the formula (Hu) U-OCH ₂ -C-CH ₂ -C-CH ₂ -COORu (Hu) Z ₁ Z ₂ wherein u, R ₁₁ , Z ₁ and Z _{2 are} as defined in this claim, subjected to a stereoselective reduction.
3. The method according to claim 1 for the preparation of the compound of formula (I a) "GH-CM ₂ -CH-CH-COOH
OH OH (La) in racemic or optically pure form and in the form of the free acid, a salt, an ester or the δ-lactone, namely an internal ester, characterized in that according to a first stage (stage [a]) a compound of formula III, as in claim 1, mixed with sodium borohydride (NaBH ₄ ) in a reaction medium containing an alcohol and tetrahydrofuran, in a second stage (step [b]) a compound of formula II in racemic or optically pure form, in the R is [3- (4'-fluorophenyl) -1- (1'-methylethyl) -1H-indol] -2-yl, X is - (E) -CH = CH- and R ₁ , Z ₁ and Z _{2 have} the meaning given in claim 1, treated with the mixture obtained according to step (a) under conditions which yield a mixture comprising a cyclic boranate compound of the formula (IVa) and / or a boron complex of the formula (IVb) wherein R and X are as defined in this claim and R ₁ and R ₃ are as defined in claim 1, and in a third step (step [c]) the product obtained in step (b) is cleaved into the compound of the formula (Ia) in the form of an ester and in racemic or optically pure form, and the compound of the formula (Ia) thus obtained in the form of an ester, if desired using conventional methods, to give a free acid, a salt another ester or the δ-lactone, namely an inner ester, is converted. 4. The method according to claim 1 and 3 for the preparation of erythro (E) -3,5-dihydroxy-7- [3 '- (4 "-fluorophenyl) -1' - (1" -methylethyl) indole-2'- yl] hept-6-encarboxylic acid of the formula (Ia) (La) CH-CW ₂ -CH-CH-COOH
OU ÖH in racemic or optically pure form and in the form of the free acid, a salt, an ester or the δ-lactone, namely an internal ester, characterized - that according to method A: (a) a compound of the formula (Villa) OHC-N (R _12b ) R ₁₃ (Villa) in which R _{12b is} phenyl or monosubstituted to trisubstituted phenyl, the substituents of which are each independently C ₁ -C 4 -alkyl, C ₁ -C ₃ -BOXoxy, fluorine, chlorine, bromine or nitro, where only a maximum of two nitro groups may be present, and R _{13 is} independently C 1 -C ₈ -alkyl or has the meaning given for R _12b , with a compound of the formula (IX) ₁ X ₃ -CO-CO-X ₃ (IX) wherein X _{a is} a monovalent leaving group, optionally in an inert anhydrous organic medium, to the corresponding compound of the formula (Xc), X _a -CH = N ⁺ (R _12b ) R ₁₃ Χ, "(X c) wherein X ₃ R ₁₂ b and R _{13 are} as defined in this claim; (b) the particular compound of the formula (Xc) with a compound of the formula (XI) _/ R ₁₄ O-CH = CH ₂ (XI) wherein R _{14 is} a monovalent group which does not deactivate the oxygen atom to which it is attached, optionally in an inert anhydrous medium to give a corresponding compound of the formula (XIIc) ₍ (E) -R ₁₄ O-CH = CH-CH = N ⁺ (R ₁₂₁₃ ) R ₁₃ X _a "(XIIc) wherein R _12b , X _a , R 13 and R _{14 are} as defined in this claim; (c) reacting the respective compound of formula (XIIc) by hydrolysis to the corresponding compound of formula (VIIc) in the form of the free base or an acid addition salt, and in the case of an acid addition salt, neutralizing this acid addition salt with a base; - that according to method B: (d) the resulting compound of formula (VIIc) ₍ (E) -OHC-CH = CH-N (R _12b ) R ₁₃ (VIIc) in which R ₁₂ b and R _{13 have} the meaning given in this claim with a compound of the formula (XV) PO (Xb) ₃ (XV) X _{b is} chlorine or bromine or with a compound selected from oxalyl chloride or oxalyl bromide, phosgene or carbonyl bromide, phosphorus trichloride or phosphorus tribromide, phosphorus pentachloride or phosphorus pentabromide and an alkylsulfonyl chloride or arylsulfonyl chloride or an alkylsulfonylbromide or arylsulfonylbromide such as p-toluenesulfonyl chloride or p-toluenesulfonylbromide or Methanesulfonyl chloride or methanesulfonyl bromide, to the corresponding compound of the formula (XVI) (E) -Xb-CH = CH-CH = N ⁺ (R ₁₂₆ ) R ₁₃ (XVI) and the corresponding anion, such as the anion PO ₂ (XJ ₂ , wherein X _b , R ₁₂ b and R _{13 have} the meaning given in this claim. (e) a compound of formula (XVI) with 3- (4'-fluorophenyl) -1- (1'-methylethyl) -1H-indole (a compound of formula (XVII), (XVII) R ₅ and R _{6 are} each hydrogen, R _{7 is} 1-methylethyl and R _{8 is} p-fluorophenyl) to the corresponding compound of formula (XVIII a) (XVIIIa) CH (CH ₃ ) and the corresponding anion such as the anion PO ₂ (Xb> 2 / in which R _12b , R ₁₃ and X _{6 are} as defined in this claim;
(f) a compound of formula (XVIIIa) by hydrolysis to give compound (E) -3- [3 '- (4 "fluorophenyl) -1' - (1" -methylethyl) -1H-indol-2'-yl [prop -2-enal (namely, the compound of formula (Va) wherein R ₅ and R _{6 are} each hydrogen, R _{7 is} 1-methylethyl and R _{8 is} p-fluorophenyl); (g) a compound of formula (Va) with the dianion of an acetoacetic acid ester of formula CH ₃ COCH ₂ COORvWOrIn R ₁ as defined in claim 1, to the corresponding compound of formula (Ha),  = G \ CH- OU (Ha)