HRP940993A2 - Process for the preparation of 7-substituted hept-6-enoic and -heptanoic acids and derivatives and intermediates thereof - Google Patents

Description

The proposed invention relates to the preparation of 7-substituted hept-6-enonic and heptanonic acids and their derivatives and intermediates.

Case

The invention relates to the process of preparing the compound of formula I

[image]

where is:

X -CH2CH2- or -CH=CH-;

R1 is an ester group, internal to the reaction conditions; and

R is an organic residue with groups that are internal under reducing conditions.

The invention also relates to the preparation process of auxiliary intermediates (with formulas Va and VII, see below).

The common feature that connects these different stages of the process is that they all lead to the improvement of different stages in the preparation of the final products, 7-substituted hept-6-enonic and heptanoic acids and their derivatives, which are cholesterol biosynthesis inhibitors. This connection is shown below with specific embodiments, which relate to the preparation of a specific inhibitor of cholesterol biosynthesis, in particular erythro-(E)-3,5-dihydroxy-7-[3'-(4''-fluorophenyl)-1'- (1''-methylethyl)indol-2'-yl]hept-6-enonic acid in racemic or optically pure form; in the form of a simple acid, salt, ester or δ-lactone, i.e. of the internal ester.

The process according to the invention for the preparation of the compound of formula I comprises the stereoselective reduction of the racemic or optically pure compound of formula II

[image]

where are they:

R, R1 and X are the same as previously mentioned, and one of Z1 and Z2 is oxygen, and the other is hydroxy and hydrogen, to obtain the corresponding compound of formula I.

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

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

The invention also includes a compound of formula I, as defined above, in a state of optical purity, such that the ratio of erythro to threo isomer is 99.1:0.9 or more, preferably 99.5:0.5 or more, especially 99.7 :0, 3 or more.

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

Important notes

The ester group R1 is advantageously a physiologically acceptable ester group, which can be hydrolyzed, and whose desired end product is an ester.

The term "physiologically acceptable ester group, which can be hydrolyzed" refers to a group which, together with the -COO- residue to which it is attached, forms an ester group, which is physiologically acceptable and can be hydrolyzed under physiological conditions, whereby we obtain the corresponding the carboxylic acid of the compound of formula I (that is, where R1 is replaced by hydrogen) and the alcohol, which itself is physiologically acceptable, that is, non-toxic at the desired dosage level, especially the group, which is without centers of asymmetry.

R1 is preferably R2 where R2 is C1-4alkyl or benzene, especially R2' where R2' is C1-3alkyl, n-butyl, i-butyl or benzyl, eg ethyl, preferably isopropyl or t-butyl, especially 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, M or N, as follows:

A phenyl, trisubstituted with R1a, R2a and R3a, where R1a, R2a and R3a are independently hydrogen; halogen; C1-4 alkyl; C1-4haloalkyl; phenyl; phenyl substituted with halogen, C 1-4 alkoxy, C 2-8 alkanoyloxy, C 1-4 alkyl or C 1-4 haloalkyl; or -OR4a where R4a is hydrogen, C2-8alkanoyl, benzoyl, phenyl, halophenyl, phenyl(C1-3alkyl), C1-9alkyl, cinnamyl, C1-4haloalkyl, allyl, cycloalkyl (C1-3alkyl), adamantyl (C1-3alkyl) or substituted phenyl(C1-3alkyl), in which each substituent is chosen from halogen, C1-4alkyl, C1-4alkyl and C1-4haloalkyl; wherein the halogen atoms are fluorine or chlorine cycloalkyl includes cyclohexyl;

B

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where R1b and R2b together form the rest of the formula:

[image]

where is:

R 3b is hydrogen, C 1-3 alkyl, C 1-3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy;

R 4b is hydrogen, C 1-3 alkyl, n-butyl, i-butyl, C 1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluorine, chlorine, phenoxy, or benzyloxy;

R5b is hydrogen, C1-3alkyl, C1-3alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy;

provided that not more than one of R4b and R5b is trifluoromethyl, not more than one of R4b and R5b phenoxy and not more than one of R4b and R5b benzyloxy;

R 6b is hydrogen, C 1-2 alkyl, C 1-2 alkoxy, fluorine or chlorine;

R7b is hydrogen, C1-3alkyl, n-butyl, i-butyl, C1-3alkoxy, n-butoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy;

R8b is hydrogen, C1-3alkyl, C1-3alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy;

provided that not more than R7b and R8b is trifluoromethyl, not more than one of R7b and R8b phenoxy and not more than one of R7b and R8b benzyloxy;

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

C

[image]

where is:

one of R1c and R2c is phenyl, substituted with R5c, R6c and R7c, and the other is C1-3alkyl, n-butyl or i-butyl,

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

R 4c is hydrogen, C 1-3 alkyl, C 1-3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,

provided that not more than one of R3c and R4c is trifluoromethyl, not more than one of R3c and R4c is phenoxy and not more than one of R3c and R4c is benzyloxy;

R 5c is hydrogen, C 1-3 alkyl, n-butyl, i-butyl, t-butyl, C 1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,

R 6c is hydrogen, C 1-3 alkyl, C 1-3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,

provided that not more than one of R5c and R6c is trifluoromethyl, not more than one of R5c and R6c phenoxy and not more than one of R5c and R6c benzyloxy and,

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

D

[image]

where is:

R1d is hydrogen or primary or secondary C1-6alkyl, which does not contain an asymmetric carbon atom, and

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

R1d and R2d together are -(CH2)m- or (Z)-CH2CH=CH-CH2-

where m is 2, 3, 4, 5 or 6;

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

R 4d is hydrogen, C 1-3 alkyl, C 1-3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,

provided that not more than one of R2d and R3d is trifluoromethyl, not more than one of R2d and R3d phenoxy and not more than one of R2d and R3d benzyloxy,

R 5d is hydrogen, C 1-3 alkyl, n-butyl, i-butyl, t-butyl, C 1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,

R 6d is hydrogen, C 1-3 alkyl, C 1-3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,

provided that not more than one of R5d and R6d is trifluoromethyl, not more than one of R5d and R6d phenoxy and not more than one of R5d and R6d benzyloxy,

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

[image]

where is:

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

F

[image]

where is:

R1f C1-6alkyl, which does not contain an asymmetric carbon atom, each of R2f and R3f is independently hydrogen, C1-3alkyl, n-butyl, i-butyl, t-butyl, C1-3alkoxy, n-butoxy, i-butoxy, trifluoromethyl , fluoro, chloro, phenyl, phenoxy or benzyloxy, each of R 3f and R 6f is independently hydrogen, C 1-3 alkyl, C 1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, and

each of R 4f and R 7f is independently hydrogen, C 1-3 alkyl, C 1-3 alkoxy, fluorine or chlorine,

provided that it is not more than one of R2f and R3f trifluoromethyl, not more than one of R2f and R3f phenoxy, not more than one of R2f and R3f benzyloxy, not more than one of R5f and R6f trifluoromethyl, not more than one of R5f and R6f phenoxy and not more one of R5f and R6f is benzyloxy, provided that

(i) is the free valence of the pyrazole ring in position 4 or 5 and that they are

(ii) group R1f and free valency ortho opposite each other;

MR

[image]

where is:

Rag single bond to X Rbg is R2g, Rcg is R3g, Rdg is R4g or

[image]

Rag is R1g, Rbg is a single bond of X, Rcg is R2g, Rdg is R3g, k o, s or

[image]

R1g, R2g, R3g and R4g are independently C1-6alkyl, which does not contain an asymmetric carbon atom, C3-7cycloalkyl or phenyl, substituted by R5g, R6g and R7g, or in the example of R3g and R4g additionally hydrogen or for R3g, when k o or s i X is X' additionally Ga, i

Ga is -C(R17g)=C(R18g) R19g, where:

R17g is hydrogen or C1-3alkyl and

R18g and R19g are independently hydrogen, C1-3alkyl or phenyl,

each R 5g is independently C 1-3 alkyl, n-butyl, i-butyl, t-butyl, C 1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluorine, chlorine, bromine, phenyl or benzyloxy,

each R 6g is independently C 1-3 alkyl, C 1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, phenyl or benzyloxy; and

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

provided that it can be one of the trifluoromethyl, phenoxy and benzyloxy groups on each phenyl ring substituted with R5g, R6g and R7g;

H

[image]

where is:

R1h C1-6alkyl, which does not contain an asymmetric carbon atom, C3-7cycloalkyl, adamantyl-1 or phenyl, substituted with R4h, R5h and R6h,

R2h C1-6alkyl, which does not contain an asymmetric carbon atom, C3-7cycloalkyl, adamantyl-1 or phenyl, substituted with R7h, R8h and R9h,

R3h is hydrogen, C1-6alkyl, not containing an asymmetric carbon atom, C3-7cycloalkyl, adamantyl-1, styryl or phenyl, substituted with R10h, R11h and R12h;

each of R4h, R7h and R10h is independently hydrogen, C1-3alkyl, n-butyl, i-butyl, t-butyl, C1-3alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluorine, chlorine, bromine, phenyl, phenoxy or benzyloxy,

each of R5h, R8h and R11h is independently hydrogen, C1-3alkyl, C1-3alkoxy, trifluoromethyl, fluorine, chlorine, bromine, -COOR17h-N(R19h)2, where R17h is hydrogen or M where R18h is C1-3alkyl, n- butyl, i-butyl, t-butyl or benzyl and M is the same as above, and each R 19 h is C 1-6 alkyl, which does not contain an asymmetric carbon atom, and is

each of R6h, R9h and R12h is independently hydrogen, C1-2alkyl, C1-2alkoxy, fluorine or chlorine,

provided that not more than one substituent on each phenyl ring is independently trifluoromethyl, not more than one substituent on each phenyl ring is independently phenoxy, and not more than one substituent on each phenyl ring is independently benzyloxy;

J

[image]

where is:

each of R1j and R2j is independently C1-6alkyl, which does not contain an asymmetric carbon atom, C3-6cycloalkyl or phenyl-(CH2)m-, where m is 0, 1, 2 or 3 and the phenyl group is unsubstituted or substituted with any of R3j, R4j and R5j, where R3j, R4j and R5j are the same as listed below; or

R 2j is -Yj -benzyl, -N(R 8j ) 2 or I, where Yj is -o- or -s-;

each R8j is independently C1-4alkyl, which does not contain an asymmetric carbon atom or can form part of a 5-, 6- or 7-membered ring Jb, wherein ring Jb is substituted or unsubstituted and in a given example also contains one or more heteroatoms; you

I is I' or I'', where:

I' heterocyclic group, which is unsubstituted or substituted with one or two C1-2alkyl or

C1-2 alkoxy groups, and

Ja'' is Ja''a or Ja''b

[image]

where is:

R3j is hydrogen, C1-3alkyl, n-butyl, i-butyl, t-butyl, C1-3alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,

R4j is hydrogen, C1-3alkyl, C1-3alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy, and

R 5 is hydrogen, C 1-3 alkyl, C 1-3 alkoxy, fluorine or chlorine;

provided that no more than one of R3j and R4j is trifluoromethyl, no more than one of R3j and R4j phenoxy and no more

one of R3j and R4j benzyloxy;

K

[image]

where is:

each of R1k and R2k independently

(a) phenyl, substituted with R5k, R6k and R7k, where

R 5k is hydrogen, C 1-3 alkyl, n-butyl, i-butyl, t-butyl, C 1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy;

R 6k is hydrogen, C 1-3 alkyl, C 1-3 alkoxy, fluorine or chlorine; and

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

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

(c) C3-6cycloalkyl; or

(d) phenyl -(CH2)m-, where m is 1, 2 or 3;

L

[image]

where is:

Y1 -CH=CH-CH=N-, -CH=CH-N=CH-, -CH=N-CH=CH- or -N=CH-CH=CH-

R 11 is primary C 1-6 alkyl, which does not contain an asymmetric carbon atom;

or isopropyl;

R2l is:

a) phenyl, substituted with R 51 , R 61 and R 71 , where

R51 t-butyl, C1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy;

R 61 is hydrogen, C 1-3 alkyl, C 1-3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy;

provided that not more than one of R5l and R6l is trifluoromethyl, not more than one of R5l and R6l phenoxy and not more

one of R5l and R6l benzyloxy,

R7l is hydrogen, C1-2alkyl, C1-2alkoxy, trifluoromethyl, fluorine or chlorine,

b) primary or secondary C1-6 alkyl, which does not contain an asymmetric carbon atom,

c) C3-6cycloalkyl or

d) phenyl -(CH2)m-, where m is 1, 2 or 3;

M

[image]

where is:

R1m C1-6alkyl, which does not contain an asymmetric carbon atom, C5-7cycloalkyl, (C5-7cycloalkyl) methyl, phenyl -(CH2)m-, pyridyl-2, pyridyl-3, pyridyl-4, thienyl-2, thienyl-3 or phenyl, substituted with R5m, R6m and R7m;

R2m C1-6alkyl, not containing an asymmetric carbon atom, C5-7cycloalkyl, (C5-7cycloalkyl) methyl, phenyl -(CH2)m-, pyridyl-2, pyridyl-3, pyridyl-4, thienyl-2, thienyl-3 or phenyl, substituted with R8m, R9m and R10m,

provided that one of R1m and R2m is no longer a member of the group, in which pyridyl-2, pyridyl-3, pyridyl-4, thienyl-2, thienyl-3, phenyl, substituted with R5m, R6m and R7m, and phenyl, replaced by R8m, R9m and R10m;

R3m C1-6alkyl, which does not contain an asymmetric carbon atom, C5-7cycloalkyl or phenyl, substituted with R11m, R12m and R13m;

R4m C1-6alkyl, which does not contain an asymmetric carbon atom, C5-7cycloalkyl or phenyl, substituted with R14m, R15m and R16m;

where is:

each of R5m, R8m, R11m and R14m is independently hydrogen, C1-3alkyl, n-butyl, i-butyl, t-butyl, C1-3alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluorine, chlorine, bromine, phenyl, phenoxy or benzyloxy,

each of R6m, R9m, R12m and R15m is independently hydrogen, C1-3alkyl, C1-3alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy, and

each of R7m, R10m, R13m and R16m is independently hydrogen, C1-2alkyl, C1-2alkoxy, fluorine or chlorine,

provided that not more than one substituent on each ring is independently trifluoromethyl, not more than one substituent on each phenyl ring is independently phenoxy, and not more than one substituent on each phenyl ring is independently benzyloxy;

N

[image]

where is:

each of R1n, R2n and R3n 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 with 1 to 3 carbon or chlorine atoms; or with one fluoro, bromo or trifluoromethyl substituent;

R4n is hydrogen or alkyl of 1 to 3 carbon atoms, for example methyl;

R5n is hydrogen, lower alkyl or alkoxy; halogen, trifluoromethyl; or phenyl, benzyl or benzyloxy, whose aromatic part may be unsubstituted or substituted with up to two groups, one of which may be fluorine, bromine or trifluoromethyl; or one or two are lower alkyl or alkoxy or chloro;

R6n, hydrogen, lower alkyl or alkoxy, halogen or trifluoromethyl; and

R7n, hydrogen, lower alkyl or alkoxy, halogen or trifluoromethyl; and each of R4n + R5n, R5n + R6n or R6n + R7n can form either a residue -CH=CH-CH=CH- or -(CH2)4-, to form a ring, which is substituted by R8n, which is hydrogen; halogen 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.

Compounds of formula I can be divided into thirteen groups, i.e. groups IA to IN, considering the indication of R, that is:

IA, when R=A,

IB, when R=B,

IC, when R=C,

ID, when R=D,

IE, when R=Ea, Eb or Ec,

IF, when R=F,

IG, when R=G,

IH, when R=H,

IJ, when R=J,

IK, when R=K,

IL, when R=L,

IM, when R=M i

IN, when R=N.

Stereochemistry

When a hydroxy-keto compound of formula II is reduced to a dihydroxy compound of formula I, an additional center of asymmetry is generally formed. That is why, when we use the racemic compound of formula II, four stereoisomers (which include enantiomers, i.e. a pair of erythro and a pair of threo enantiomers) of the obtained compound of formula I disappear. On the other hand, when we use an optically pure compound of formula II, two diastereoisomers (i.e. one erythro and one threo isomer) of the compound of formula I, for example 3R,5S and 3S,5S diastereoisomers, which we obtain from the reduction of the 5S hydroxy compound. Diastereoisomers can be separated in the usual way, such as with fractional crystallization, column chromatography, preparative thin-layer chromatography or HPLC. The ratio of erythro to threo isomer obtained by these procedures is usually acceptable and may be, for example, about 98:1.

In the stereoactive process in terms of the proposed invention, when we use the racemic compound of formula II, two stereoisomers (which include the erythro pair of enantiomers) of the obtained compound of formula I are formed almost exclusively. On the other hand, when we use the optically pure compound of formula II, almost exclusively one enantiomer of the compound is formed of formula I and that enantiomer corresponds to the erythro enantiomer. For example, the 3R, 5S enantiomer is obtained by reducing the 5S hydroxy compound, where X is -CH=CH-.

The ratio of erythro to threo isomer, obtained according to the process according to the invention, is about 99, 1:0, 9 or more, especially about 99, 5:0, 5 or more, especially about 99, 7:0, 3 or more.

The term "stereoselective", as used herein, means that the ratio of the erythro to threo form is 99, 1:0, 9 or more.

The stereoisomers of the compound of formula I, where X is -CH=CH-, in the sense of the proposed invention are the 3R, 5S and 3S, 5R isomer and the racemate, which is formed from both, of which the 3R, 5S isomer and the racemate are more favorable.

The stereoisomers of the compound of formula I, where X is -CH2CH2-, in the sense of the proposed invention are the 3R, 5R and 3S, 5S isomer and the racemate, which is formed from both, of which the 3R, 5R isomer and the racemate are more favorable.

State of the art

In ordinary procedures for the reduction of the keto group of the compound of formula II, mild reducing agents, such as sodium borohydride or a complex of t-butylamine and borane, are used in an inert organic solvent, such as a lower alcohol, to obtain a mixture of diastereomeric forms from the optically pure starting compound, or with the other side of the racemic diastereoisomer from the racemic starting substance.

A three-stage, partially stereoselective reduction procedure was used to obtain predominantly the erythro racemate from the racemic starting substance. In the first step, the compound of formula II comes into contact with either a trialkylborane compound or a compound of formula III

R4O-B-(R3)2 (III)

where R4 is allyl or lower alkyl with 1 to 4 carbon atoms, preferably not tertiary, and R3 is primary or secondary alkyl with 2 to 4 carbon atoms, preferably not tertiary, in a reaction medium comprising alcohol and tetrahydrofuran (THF). In the second stage of such a process, we add sodium borohydride (NaBH4) to the reaction medium and the reaction originates from the reduction of the keto group and on the other side of formula I. In the third stage, the reaction mixture, which contains boron complex and/or cyclic boronate ester, is azeotroped with methanol or ethanol or with the other side is treated in an organic solvent with a water peroxide compound, as a peroxide, e.g. hydrogen peroxide or perborate, e.g. sodium perborate, to obtain the final compounds of formula I. For the above procedure, they say that it gives erythroracemate with e.g. about 98% selectivity in relation to threo isomers (Chen et al., Tetrahedron Letters 28, 155 /1987/).

Detailed description

The process in terms of the proposed invention includes a process for the stereoselective reduction of racemic and optically pure compounds of formula II, to obtain almost exclusively the erythro isomers of formula I. In this case, the reduction of the keto group of the compound of formula II occurs practically instantaneously. Compounds of formula I, i.e. erythro isomers, are obtained, among other things, with increased chemical purity and can be further enriched to a chemical purity above 99% by means of simple recrystallization.

In the first stage of the process in terms of the proposed invention /stage (a)/ we mix the compound of formula III with sodium borohydride NaBH4 in a reaction medium, which removes alcohol and tetrahydrofuran.

In the second stage /stage (b)/ we process the compound of formula II with the mixture obtained in stage (a), with a favorable condition, to obtain a mixture containing the cyclic boronate compound of formula IV(a)

[image]

and/or boron complex of formula IV(b)

[image]

where R, R1, R3 and X are the same as previously stated. The latter prevails before shutdown. Quenching converts the boron complex into boronate ester. In the third stage / stage (c) / the product obtained in stage (b) is grafted to obtain the corresponding compound of formula I.

Step (a) is preferably carried out in the presence of anhydrous conditions, preferably in an inert atmosphere from about -100 to about +30ºC, preferably from about -80 to about -60ºC, especially from about -78 to about -70ºC. The reaction medium used in step (a) comprises a mixture of alcohol and tetrahydrofuran, where the alcohol has the formula AlkOH, where Alk is alkyl with 1 to 4 carbon atoms, for example methyl or ethyl, preferably not tertiary.

One of the products of step (a) can be R4OH, derived from the compound of formula III used. In particular, it is not necessary that all portions of Alk are equal to R4. The sodium borohydride must generally be present in an equimolar amount relative to the compound of formula II, preferably in a slight excess, such as about 1.1:1 to 1.5:1 moles of NaBH4 per mole of ketone. The molar ratio of the compound of formula III to the compound of formula II is always about 0.5:1, preferably from about 0.7:1 to about 1.5:1 mole of borane compound per mole of ketone.

Stage (b) is also advantageously performed at reduced temperatures, where the internal temperature is maintained at around -100 to around -40ºC, especially from around -78 to around -70ºC. The compound of formula II is preferably in a solvent such as alcohol/THF or THF. We favorably choose the reaction medium for step (a) and the solvent for the compound of formula II that we add in step (b), so that we get a combined medium, where the ratio (v/v) of alcohol to tetrahydrofuran is from about 1:3 to about 1:6 of alcohol to THF, especially from about 1:3 to about 1:4. The reduction of the keto group is exothermic and proceeds quickly, that is, we preferably add the keto group step by step, maintaining the internal temperature in the range from about -78ºC to about -70ºC. The reduction is almost instantaneous, the reaction mixture is then quenched by the addition of, for example, aqueous sodium bicarbonate, ammonium chloride or acetic acid, and a mixture of the desired cyclic boronate intermediate is obtained.

In step (c), the reaction product of step (b) is azeotroped with methanol or ethanol, for example at about 60°C to about 80°C in the presence of anhydrous conditions. On the other hand, it is advantageous to dissolve the product, especially where X -CH=CH-, which has been neutralized by adding sodium bicarbonate (NaHCO3), in an organic solvent, for example ethyl acetate, and treat it with aqueous (for example 30%) hydrogen peroxide or aqueous sodium perborate (NaBO3.4H2O), initially at reduced temperatures, for example around +10ºC, and then let it heat up to the desired temperature, for example around 20ºC to around 30ºC, whereupon we obtain the corresponding compound of formula I.

On the other hand, the cyclic boronate ester from step (b) is extracted with an organic solvent, such as ethyl acetate, and then treated directly with an aqueous solution of the peroxy compound, such as 30% aqueous hydrogen peroxide, or aqueous sodium peroxide, to obtain the corresponding compound of the formula AND.

When reducing conditions occur during the execution of the invention, it is assumed that any substituents or functions on the residue used as R are inert, that is, the residue is without substituents or functions that would be reactive or sensitive to change under such conditions. for example with known procedures for masking or protecting such functions or introducing them at a later stage.

Compounds of formula I, corresponding δ-lactones, simple acids and salts, procedures for converting a compound of formula I, where R1 has one meaning, into the corresponding compound, which has another meaning, and/or the corresponding δ-lactone or simple acid or salt, are known .

Compounds of formula I can be converted, if desired, in the usual way into the appropriate form of a simple acid or salt, that is, where R1 is replaced with hydrogen or a cation, such as an alkali cation or ammonia, preferably sodium or potassium and especially sodium, into another ester form, or into the corresponding δ-lactones, i.e. internal esters.

As stated above, the compounds of formula I are pharmaceutically obtained according to the process of the invention. In a further embodiment, the process according to the invention is also used for the preparation of chiral intermediates, for example formula Iu.

[image]

where is:

in triphenylmethyl (trityl) and

Ru allyl or ester-forming residue, inert under the reaction conditions, preferably allyl or C1-3alkyl, n-butyl, i-butyl, t-butyl or benzyl especially t-butyl, with stereoselective reduction of the racemic or optically pure compound of formula IIu

[image]

where u, Ru, Z1 and Z2 are the same as above.

Such chiral intermediates are described for example in EP 244364. They are indicated for use in the preparation of pharmaceuticals.

Starting substances

(Primary or secondary C1-4 alkoxy or allyloxy)-di-(primary-C2-4 alkyl)boranes of formula III, used as starting materials in the process in terms of the proposed invention, are known. / Koster et al., Ann. (1975), 352; Chen et al., Chemistry Letters (1987), 1923-1926/. They can be prepared in situ from the corresponding 3-(primary or secondary C2-4alkyl)boranes with primary or secondary C1-4alkanol or allylalcohol, wherein the concentration of the former in the latter is advantageously about 0.2 M to about 1.2 M, especially about 0.5 M.

Compounds of formula II are known or can be prepared analogously to known compounds of formula II, i.e. as described in US-PS patent 4,739,073 (for example for Z2 is oxygen) or in EP 216,785 (for example for Z1 is oxygen).

Thus, compounds of the formula II, where Z2 is oxygen, are usually prepared by partitioning the compound of the formula V

R – X – CHO (V)

wherein R and X are the same as above, with the dianion of the compound of formula VI

CH3 - CO – CH2 - COOR1 (VI)

where R1 is the same as stated earlier.

The following performances refer to earlier intermediates

Compounds of formula V and VI are also known. In the following embodiments, with the proposed invention, we also go for a new process for the preparation of a subgroup of compounds of formula V, especially compounds of formula Va

[image]

where is:

R 5 is hydrogen, C 1-3 alkyl, n-butyl, i-butyl, t-butyl, C 3-6 cycloalkyl, C 1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy;

R 6 is hydrogen, C 1-3 alkyl, C 1-3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy;

provided that not more than one of R5 and R6 is trifluoromethyl, not more than one of R5 and R6 is phenoxy and not more than one of R5 and R6 is benzyloxy;

one of R7 and R8 phenyl, trisubstituted by R9, R10 and R11, and the other primary or secondary C1-6alkyl, which does not contain an asymmetric carbon atom, C3-6cycloalkyl or phenyl-(CH2)m-, where

R 9 is hydrogen, C 1-3 alkyl, n-butyl, i-butyl, t-butyl, C 1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy;

R 10 is hydrogen, C 1-3 alkyl, C 1-3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy;

R 11 is hydrogen, C 1-2 alkyl, C 1-2 alkoxy, fluorine or chlorine and m is 1, 2 or 3;

provided that not more than one of R9 and R10 is trifluoromethyl, not more than one of R9 and R10 is phenoxy and not more than one of R9 and R10 is benzyloxy;

from the subgroup of compounds of formula VII

(E) – OHC – CH=CH – N(R12)R13 (VII)

where is:

R 12 C 1-3 alkyl, phenyl or phenyl substituted with 1 to 3 substituents, each of which is independently C 1-3 alkyl, C 1-3 alkoxy, fluorine, chlorine, bromine or nitro with at most two nitro groups; and there is

R13 independent meaning previously stated above for R12, as a new process for the preparation of the compounds of formula VII themselves.

The procedure for the preparation of compounds of formula VII is referred to below as "procedure A", and the procedure for the preparation of compounds of formula Va is referred to below as "procedure B".

Compounds of formula Va, VII and XVII (see under 7.2.) are known, among other things, from US-PS 4,739,073, where compounds of formula VII, where R12 is C1-3alkyl, and their use for the synthesis of compounds of formula Va are described , compounds of formula XVII and the 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. As they inhibit cholesterol synthesis, they lower the level of blood cholesterol and are therefore indicated for use in the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.

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 differ from procedure A in relation to, for example, the use of phosgene or phosphorus trichloride, pentachloride or oxychloride, rather than oxalic acid derivatives.

Process A (preparation of compounds of formula VII)

The process for the preparation of compounds of formula VII (process A) includes

(i) reaction of compounds of formula VIII

OHC – N(R12)R13 (VIII)

where R 12 and R 13 are the same as those mentioned above, with the compound of formula IX

Xa – CO-CO – Xa (IX)

where Xa is a monovalent leaving group, in the given example in an inert anhydrous organic medium, to obtain the corresponding compound of formula X

X – CH=N+(R12)R13 Xa- (X)

where Xa, R12 and R13 are the same as previously,

(ii) reaction of said compound of formula X with compound of formula XI

R14O – CH=CH2 (XI)

where R14 is a monovalent group, which does not deactivate the oxygen atom to which it is attached, in the given example in an inert anhydrous organic medium, to obtain the corresponding compound of formula XII

(E) - R14O - CH=CH - CH=N+(R12)R13 Xa- (X)

where X12, R13, R14 and Xa are the same as mentioned above, and

(iii) hydrolysis of said compound of formula XII to obtain the corresponding compound of formula VII in the form of a simple base or acid addition salt and, if in the form of an acid addition salt, neutralization of the acid addition salt with a base.

The variant of process A can be carried out without step (iii) and the compound of formula XII can be used directly in, for example, process B.

Compounds (i) and (ii) can be carried out simultaneously or step (ii) can follow step (i); stage (iii) follows stage (ii) and stage (iv) (see below), when we use it, and stage (iii) follows.

R 12 is R 12a , when R 12a is C 1-3 alkyl; or R12b, where R12b is C1-3alkyl, specified earlier for R (that is, phenyl or phenyl substituted with 1 to 3 substituents, each of which is independently C1-3alkyl, C1-3alkoxy, fluoro, chloro, bromo or nitro with up to two nitro groups).

R12a is preferably C1-2alkyl and most preferably methyl.

R12b is preferably R12b', where R12b' is phenyl or phenyl substituted with 1 or 2 substituents, each of which is independently C1-3alkyl, C1-3alkoxy or chlorine, even more preferably R12b'', where R12b'' is phenyl or phenyl substituted with 1 or 2 methyl groups, and preferably phenyl.

R13 is preferably C1-2alkyl and most preferably methyl.

R14 is preferably C1-6alkyl, preferably primary or secondary C2-4alkyl, even more preferably n-C2-4alkyl and most preferably ethyl or n-butyl.

Each Xa is preferably chlorine or bromine, especially chlorine. Each Xa- is preferably chloride or bromide, especially chloride. The base used in the 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.

Favorable reaction conditions for process A are as follows:

Stage (i) /when we perform it before stage (ii)/:

Temperature: -20ºC to +50ºC

Duration: 1.5 to 5 hours

Reaction medium: liquid halogenated lower alkane, for example 1,2-dichloroethane and methylene chloride; or acetonitrile; where the most favorable are methylene chloride and acetonitrile

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

Stage (ii) /when we perform it after stage (i)/:

Temperature: 10ºC to 60ºC, where 10ºC to 40ºC is favorable

Duration: 0.5 to 3 hours

Reaction medium: liquid halogenated lower alkane, for example 1,2-dichloroethane and methylene chloride; or acetonitrile; where the most favorable are methylene chloride and acetonitrile

Molar ratio of reactants: 1 to 1.5 moles of IX per mole of VIII, used in step (i)

Stages (i) and (ii) /when we perform them simultaneously/:

Temperature: -15ºC to +35ºC

Duration: 2 to 6 hours

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

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

Degree (iii)

Temperature: 0ºC to 65ºC

Duration: 0.5 to 3 hours

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

Molar ratio of reactants: 2 to 4 equivalents of base per mole of IX used in step (i). It is advantageous to carry out the hydrolysis of step (iii) with a base.

The reaction medium for steps (i) and (ii) on the other hand advantageously consists of pure reagents, i.e. reagents in the absence of any solvent, i.e. for step (i) compounds of formulas VIII and IX and for step (ii) compounds of formulas X and XI. This is very favorable, for example, from an ecological point of view, because it avoids the presence of solvents, such as acetonitrile in the waste water, or the emission of steam, for example methylene chloride, in the atmosphere.

Compounds with formulas VII and IX, respectively X and XI, are prepared until the reaction in the absence of a solvent, because they do not form a solid block, and when we mix them, they still surprisingly form a suspension.

Procedure A can be divided into two sub-procedures in relation to marks R12 and R13:

(1) R 12 and R 13 are independently C 1-3 alkyl (sub-process Aa) and

(2) At least one of R12 and R13 is different from C1-3alkyl (sub-process Ab).

The product of step (iii) of pre-process Aa contains a substantial amount of the compound of formula XIII

(E) – OHC – CH=CH – OR14 (XIII)

where R14 is the same as before,

which corresponds to the resulting compound of formula VII, where the molar ratio of compounds of formula VII to compound of formula XIII is typically about 2:1. However, as it is of course possible to separate the compound of formula VII from the compound of formula XIII using conventional separation procedures, it is advantageous to subject the product of step (iii), i.e. the crude compound of formula VII (a mixture of the compound of formula VII with the corresponding compound of formula XIII), to step (iv ), that is:

(iv) process the crude mixture, which contains the compound of formula VIIa

(E) – OHC – CH=CH – N(R12a)R13 (VIIa)

wherein R 12a and R 13 are the same as previously, with the corresponding compound of formula XIV

H-N(R12a)R13 (XIX)

where R12a and R13 are the same as listed earlier,

to convert any compound of formula XIII, which is present therein, into an additional compound of formula VIIa.

Favorable reactants in sub-process Aa are those,

(a) where R 12a is C 1-2 alkyl, R 13 is C 1-2 alkyl, R 14 is primary or secondary C 2-4 alkyl, each Xa is chlorine and each Ka is chloride;

(b) as (a), especially where R 14 is n-C 2-4 alkyl;

(c) as (b), especially where R 12a is methyl, R 13 is methyl and R 14 is ethyl;

(d) – (f) as (a) – (c) especially where the base used in step (iii) is sodium carbonate or potassium carbonate; you

(g) – (i) as (d) – (f), especially where the base used in step (iii) is potassium carbonate.

Favorable reaction conditions for sub-process Aa, especially when the reactants are those from subgroups (b), (e) and (h), and especially when they are from subgroups (c), (f) and (i), are:

Degree(s):

Temperature: 0ºC to 20ºC, where 0ºC to 15ºC is more favorable and 5ºC to 15ºC is the most favorable

Duration: 1.5 to 4 hours

Reaction medium: liquid halogenated lower alkane or acetonitrile or pure reagents; where the most favorable are methylene chloride and pure reagents

The molar ratio of reactants: 1 to 1.2 moles of IX per mole of VIII, with the most favorable being 1.1 to 1.2 moles of IX per mole of VIII;

Level (ii):

Temperature: 25ºC to 40ºC

Duration: 0.7 to 2.5 hours

Reaction medium: liquid halogenated lower alkane or acetonitrile or pure reagents; where the most favorable are methylene chloride and pure reagents

Molar ratio of reactants: 1 to 1.2 moles of IX per mole of VIII, used in step (i), where the most favorable is 1.1 to 1.2 moles of IX per mole of VIII;

Degree (iii)

Temperature: 20ºC to 65ºC, where 20ºC to 30ºC is more favorable

Duration: 0.7 to 2.5 hours

Reaction medium: aqueous

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

Degree (iv):

Temperature: 0ºC to 20ºC, where 10ºC to 20ºC is more favorable

Duration: 0.3 to 1 hour

Reaction medium: C1-4alkanol, with methanol being the most preferred

Molar ratio of reactants: 0.15 to 1 mole of XIV per mole of VIII, used in step (i), where 0.15 to 0.4 mole of XIV per mole of VIII is most favorable.

In sub-procedure Aa, we perform step (ii) advantageously according to step (i).

Advantageously, sub-process Aa comprises

(i) reaction of pure reagents N,N-dimethylformamide (a compound of formula VIII, where R12 and R13 are methyl) with oxalichloride (a compound of formula IX, where Xa is chlorine) or in methylene chloride at a temperature of 0ºC to 15ºC, to obtain a compound of formula Xa

C1 – CH=N+(CH3)2 C1- (Xa)

(ii) reaction of pure reagents of formula Xa with ethyl vinyl ether (compound of formula XI, where R14 is ethyl) or in methylene chloride at a temperature of 25ºC to 40ºC, to obtain a compound of formula XIIa

(E)-C2H5O-CH=CH – CH=N+(CH3)2 C1- (XIIa)

(iii) hydrolysis of the compound of formula XIIa with potassium carbonate in an aqueous medium at a temperature of 20ºC to 30ºC, to obtain a mixture of compounds of formula VIIaa

(E) – OHC – CH=CH – N(CH3)2 (VIIaa)

and formulas XIIIa

(E) – OHC – CH=CH – OC2H5 (XIIIa)

(iv) treat the mixture of compounds of formula VIIaa and XIIIa with dimethylamine (compound of formula XIV, where R12a and R13 are methyl) in methanol at a temperature of 10ºC to 20ºC, to convert the compound of formula XIIIa into an additional compound of formula VIIaa.

It is more favorable in procedure 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 reagents to N,N-dimethylformamide or in a solution in methylene chloride 1.5 up to 4 hours at such a speed that we maintain the temperature from 5ºC to 15ºC;

(2) in step (ii) the molar ratio of ethyl vinyl ether to N,N-dimethylformamide, used in step (i) from 1:1 to 1.2:1, and step (ii) is carried out by adding ethyl vinyl ether to the reaction mixture 0, 4 to 1.5 hours at such a rate that the temperature does not exceed 30ºC, and at the end of the addition, we reflux the reaction mixture at 35ºC to 40ºC for 0.3 to 1 hour and, if necessary, recover as much methylene chloride as possible at a temperature that is not below 45ºC;

(3) in step (iii) the molar ratio of potassium carbonate to oxalyl chloride, used in step (i), is from 1:1 to 2:1 and step (iii) is carried out with the addition of water to the product of step (ii), mixed at 20ºC to 30ºC , let the temperature rise to 45ºC to 60ºC, maintain the temperature in that area by adding water for another 0.3 to 1 hour, cool the reaction mixture to 15ºC to 25ºC, add the aqueous potassium carbonate solution at that temperature for 0.3 to 1.25 hours, extract the mixture with methylene chloride and distill as much methylene chloride as possible at a temperature not above 45ºC; you

(4) in step (iv) the molar ratio of dimethylamine to N,N-dimethylformamide (used in step (i), from 0.15:1 to 0.4:1 and step (iv) is carried out with the addition of anhydrous dimethylamine to the solution of the product of step (iii) in methanol, stirring at 10ºC to 20ºC, at such a rate that the temperature does not exceed 20ºC, and distill the solvent and excess dimethylamine at a temperature not exceeding 120ºC.

Favorable reactants in sub-process Aa are those,

(a) where R12b, R12b', R13 is C1-2alkyl, R14 is primary or secondary C2-4alkyl, each Xa- is chloride;

(b) as (a), especially where R12b, R12b'' and R14 are n-C2-4alkyl;

(c) as (b), especially where R12a is phenyl, R13 is methyl and R14 is ethyl or n-butyl, especially n-butyl;

(d) – (f) as (a) – (c) especially where the base used in step (iii) is sodium carbonate or potassium carbonate; you

(e) – (i) as (d) – (f), especially where the base used in step (iii) is potassium carbonate.

Favorable reaction conditions for sub-procedure Ab, especially, when the reactants are those from subgroups (a), (d) and (g), more favorable, when they are from subgroups (b), (e) and (h), and especially, when are those from subgroups (c), (f) and (i), are:

Stage (i) /when we perform it before stage (ii)/:

Temperature: -20ºC to +45ºC

Duration: 1.5 to 5 hours

Reaction medium: liquid halogenated lower alkane or acetonitrile, in which methylene chloride and acetonitrile are more favorable, in which acetonitrile is the most favorable; or are the most favorable pure reagents;

The molar ratio of reactants: 1 to 1.2 moles of IX per mole of VIII, with the most favorable being 1.1 to 1.2 moles of IX per mole of VIII;

Stage (ii) /when we perform it after stage (i)/:

Temperature: 10ºC to 40ºC

Duration: 0.5 to 3 hours

Reaction medium: liquid halogenated lower alkane or acetonitrile, in which methylene chloride and acetonitrile are more favorable, in which acetonitrile is the most favorable; or are the most favorable pure reagents;

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

Stages (i) and (ii) /when we perform it simultaneously/:

Temperature: -15ºC to +35ºC

Duration: 2 to 6 hours

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

The molar ratio of the reactants: 1 to 1.5 moles of IX and 1 to 1.5 per mole of XI per mole of VIII;

Degree (iii)

Temperature: 0ºC to 35ºC, where 0ºC to 30ºC is more favorable

Duration: 0.5 to 1.5 hours

Reaction medium: mixture of water and reaction medium of stage (ii);

Molar ratio of reactants: 2 to 4 equivalents of base per mole of IX used in step (i).

Variants of sub-procedure Ab, especially variants Ab1, Ab2 and Ab3, are more favorable. In variant Ab1 R14 is ethyl and the reaction medium for stages (i) and (ii) is methylene chloride or preferably pure reagents and in variants Ab2 and Ab3 R14 is n-butyl and the reaction medium for stages (i) and (ii) is acetonitrile or preferably pure reagents. In variants Ab1 Ab2 we perform stage (ii) after stage (i) and in variant Ab3 we perform stages (i) and (ii) simultaneously; in all variants, stage (iii) follows stages (i) and (ii).

Variant Ab1 sub-process Ab advantageously comprises

(i) reaction of pure reagents N-methylformanilide (compound of formula VIII, where R12 is phenyl and R13 methyl) with oxalyl chloride (compound of formula IX, where Xa is chlorine) or in methylene chloride at a temperature of 15ºC to 45ºC, to obtain a compound of formula Xb

C1 – CH=N+(C6H5 )CH3 C1- (Xb)

(ii) reaction of pure reagents of formula Xb with ethyl vinyl ether (compound of formula XI, where R14 is ethyl) or in methylene chloride at a temperature of 15ºC to 40ºC, to obtain a compound of formula XIIb1

(E) – C2H5O – CH=CH – CH= N+(C6H5 )CH3 C1- (XIIb1)

(iii) hydrolysis of the compound of formula XIIb1 with sodium carbonate in a mixture of methylene chloride and water at a temperature of 20ºC to 30ºC, to obtain the compound of formula VIIb

(E) – OHC – CH=CH – N(C6H5 )CH3 (VIIb)

It is more favorable in the Ab1 variant of the sub-procedure Ab,

(1) the molar ratio of oxalyl chloride to N-methylformanilide 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-methylformanilide or in solution in methylene chloride at a temperature of 15ºC to 20ºC 1 up to 2 hours, and after complete addition, raise the temperature of the reaction mixture to 40ºC to 45ºC for 0.75 to 1.25 hours and then reflux for 0.75 to 1.25 hours;

(2) in step (ii) the molar ratio of ethyl vinyl ether to N-methylformanilide, used in step (i), from 1:1 to 1.3:1, and step (ii) is carried out by cooling the product of step (i) to 15ºC to 20ºC, by adding ethylvinyl ether for 0.5 to 1.5 hours at such a rate that the temperature does not exceed 30ºC, and at the end of the addition, we reflux the reaction mixture for 0.3 to 0.7 hours; you

(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 product of step (ii) to 15ºC to 20ºC, by adding 0.5 to 1 hour of aqueous sodium carbonate solution at such a rate that the temperature of the reaction mixture is 20ºC to 30ºC, let the mixture settle into two phases, separate both phases and recover the product from the organic phase.

Variant Ab2 sub-process Ab advantageously comprises

(i) reaction of pure reagents of N-methylformanilide with oxalyl chloride or in acetonitrile at a temperature of -20ºC to +20ºC, to obtain the compound of formula Xb

(ii) reaction of the pure reagents of the compound of formula Xb with n-butyl vinyl ether (compound of formula XI, where R14 is n-butyl) or acetonitrile at a temperature of 10ºC to 40ºC, to obtain the compound of formula XIIb2

(E) – n-C4H9O – CH=CH–CH=N+(C6H5 )CH3 C1- (XIIb1)

(iii) hydrolysis of the compound of formula XIIb2 with sodium carbonate in a mixture of acetonitrile and water at a temperature of 0ºC to 25ºC, to obtain the compound of formula VIIb.

It is more favorable in variant Ab2 sub-procedure 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 performed by adding pure reagents of oxalyl chloride to N-methylformanilide or in solution in acetonitrile at -18ºC to +8ºC 1 up to 2 hours and after complete addition by gradually raising the temperature of the reaction mixture to 12ºC to 20ºC for 0.4 to 0.75 hours and then stirring for 0.2 to 0.4 hours at that temperature;

(2) in step (ii) the molar ratio of n-butyl vinyl ether to N-methylformanilide, used in step (i), is from 1:1 to 1.2:1 and step (ii) is performed by adding N-butyl vinyl ether to the product of step ( i), by stirring at 12ºC to 20ºC, for 0.5 to 1.5 hours, at such a speed, that the temperature does not exceed 30ºC, and after complete addition by stirring the reaction mixture for 0.3 to 0.7 hours at 25ºC to 35ºC; you

(3) in step (iii) the molar ratio of sodium carbonate to oxalyl chloride, used in step (i), is from 1:1 to 1.3:1 and step (ii) is carried out by cooling the product of step (ii) to 0ºC to 5ºC, adding 0.5 to 1.2 hours of an aqueous solution of sodium carbonate, at such a rate that the temperature of the reaction mixture is 5ºC to 12ºC, and after complete addition with the addition of toluene, stirring the mixture at 15ºC to 25ºC for 0.2 to 0.5 hours, let it the mixture is precipitated in two phases, after the precipitation of both phases we recover the product from the organic phase.

Variant Ab3 sub-process Ab advantageously comprises

(i) and (ii) reaction of pure reagents N-methylformanilide with oxalyl chloride or in acetonitrile at -10ºC to +30ºC in the presence of n-butylvinyl ether, to obtain the compound of formula Xb, then this compound reacts with n-butylvinyl ether in the reaction mixture, to obtain the compound of formula XIIb2, and

(iii) hydrolysis of the compound of formula XIIb2 with sodium carbonate in a mixture of acetonitrile and water at a temperature of 0ºC to 25ºC, to obtain the compound of formula VIIb.

It is more favorable in variant Ab3 sub-procedure Ab,

(1) in steps (i) and (ii) the molar ratio of each between oxalyl chloride and n-butyl vinyl ether to N-methylformanilide from 1:1 to 1.2:1 and steps (i) and (ii) are performed by adding a solution of pure reagents N-methylformanilide and n-butylvinyl ether or in acetonitrile pure oxalyl chloride or in solutions in acetonitrile by stirring at -10ºC to +10ºC, 2 to 3 hours and after complete addition by gradually raising the temperature to the reaction mixture to 20ºC to 30ºC 0.4 to 1.5 hours and then by stirring the reaction mixture at that temperature for 0.5 to 1.5 hours; you

(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 obtained by cooling the product of step (ii) to 0ºC to 5ºC, adding 0, 5 to 1.2 hours of aqueous sodium carbonate solution at such a rate that the temperature of the reaction mixture is 0ºC to 12ºC, and after complete addition with the addition of toluene, stirring the mixture at 15ºC to 25ºC for 0.2 to 0.5 hours, let the mixture settle in two phases, by excreting both phases we recover the product from the organic phase.

The product of stage (iii) of sub-procedure Ab can be subjected to stage (iv) analogously to stage (iv) of sub-procedure Aa. Of course, there is no reason for such work, since the product usually contains little or almost no compound of formula XIII.

Process B (preparation of compound of formula Va from compound of formula VIIc)

The procedure for the preparation of the compound of formula Va (procedure B) includes

(i) reaction of a compound of formula VIIc

(E) – OHC – CH=CH – N(R12b)R13 (VIIc)

where R 12b and R 13 are the same as mentioned above, with a compound of formula XV

(Xb)3 (XV)

where Xb is chlorine or bromine, or with a compound selected from oxalyl chloride or -bromide; phosgene or carbonyl bromide; phosphorus trichloride or tribromide; phosphorus pentachloride or penta bromide; and alkyl- or arylsulfonyl chloride or -bromide, such as p-toluenesulfonyl chloride or -bromide or methanesulfonyl chloride or -bromide; to obtain the corresponding compound of formula XVI

(E)- Xb – CH=CH – CH=N+(R12b)R13 (XVI)

and the corresponding anion, eg –PO2(Xb)2, where Xb , R12b and R13 are the same as above.

(ii) Reaction of compound of formula XVI with compound of formula XVII

[image]

where R5, R6, R7 and R8 are the same as mentioned earlier, to obtain the corresponding compound of formula XVIII

[image]

and the corresponding anion, eg –PO2(Xb)2, where R5, R6, R7, R8, R12b, R13 and Xb are the same as above, and

(iii) Hydrolysis of that compound of formula XVIII, to obtain the corresponding compound of formula Va. As previously mentioned procedure A, we can, in a variant in step (i), use the compound of formula XII, obtained according to procedure A, directly instead of the compound of formula VIIc.

More favorable indications for R12b and R13 are listed earlier, favorable indications for R5, R6, R7 and R8 are the same as for R0, R, R2, respectively. R3 in US-PS 4,739,073. Xb is the favorable chlorine.

The compound of formula VIIc is advantageously partitioned with the compound of formula XV.

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

Favorable reactants (and end product) are

(a) - (d) those where R12b, R12b', R13 is C1-2alkyl, each Xb is chlorine and R5 to R8 feature corresponding changes of groups (i), (ii), (xxi) and (xxii) in US- PS 4,739,073;

(e) - (h) those of (a) - (d), where R12b, R12b'', and R5 to R8 feature corresponding changes of groups (v), (vi), (xxv) and (xxvi) in US-PS 4,739,073;

(i) and (j) those of (e) and (f), wherein R7 is C1-3alkyl, R8 is phenyl, methylphenyl, fluorophenyl, dimethylphenyl or methylfluorophenyl, R5 is hydrogen, C1-3alkyl or 4- or 6-benzyloxy and R6 is hydrogen or methyl;

(k) and (1) those of (g) and (h), where R7 is phenyl, methylphenyl, fluorophenyl, dimethylphenyl or methylfluorophenyl, R8 is C1-3alkyl, R5 is hydrogen, C1-3alkyl or 4- or 6-benzyloxy and R6 hydrogen or methyl;

(m) - (p) those of (i) - (1), where R5 is hydrogen and R6 is hydrogen;

(q) - (t) those of (m) - (p), wherein R12b is phenyl and R13 is methyl;

(u) those of (q), wherein R7 is 1-methylethyl and R8 is 4-fluorophenyl; you

(v) those of (s), wherein R7 is 4-fluorophenyl and R8 is 1-methylethyl.

The most favorable are R5 and R6 hydrogen, R7 1-methylethyl and R8 parafluorophenyl.

The compounds of formula VIIc, used for step (i), can be in the form of a single base or preferably in the form of an acid addition salt, for example in the form of an acid addition salt of the hydrochloride.

Favorable bases for step (iii) are inorganic hydroxides, such as sodium hydroxide or potassium hydroxide, especially the latter. Of course, as stated earlier, it is most advantageous not to use any bases in step (iii).

Favorable reaction conditions for procedure B are:

Degree(s):

Temperature: -10ºC to +25ºC, where -10ºC to +10ºC is favorable.

Duration: 0.1 to 1.2 hours, where 0.5 to 1 hour is favorable.

Reaction medium: lower alkane nitrile, in which acetonitrile is favorable;

Molar ratio of reactants: 1 to 1.5 moles of XV per mole of VIIc, with 1.1 to 1.3 moles of XV per mole of VIIc being advantageous.

Level (ii):

Temperature: 60ºC to 100ºC, where 65ºC to 85ºC is favorable.

Duration: 2 to 30 hours, where 3 to 24 hours is advantageous.

Reaction medium: same as in step (i)

Molar ratio of reactants: 1 to 1.5 mol of IX per mol of XVII, in which case 2 to 3 mol of XVI per mol of XVII is advantageous (in which case a 100% addition to step (i) is implied in each example).

Degree (iii):

Temperature: 10ºC to 40ºC, when we use the base, and 35ºC to 60ºC, when we do not use the base.

Duration: 0.1 to 1 hour, when we use the base, and 2 to 4 hours, when we don't use the base.

Solvent: mixture of water and reaction medium of stage (ii)

Molar ratio of reactants: when we use a base, 4 to 8 equivalents of base, preferably sodium hydroxide or potassium hydroxide, per mole of XV used in step (i).

More favorable reaction conditions for procedure B, especially when the reactants and the end product are those of subgroups (a) - (v), especially subgroups (i), (j), (m), (n), (g), (r) and (in), are:

Degree(s):

Temperature: -10ºC to +10ºC

Duration: 0.75 to 1 hour

Reaction medium: acetonitrile

Molar ratio of reactants: 1.1 to 1.3 mol XV to mol VIIc

Level (ii):

Temperature: 65ºC to 85ºC, where 80ºC to 83ºC is more favorable.

Duration: 3 to 4 p.m., with 3 to 10 a.m. being more favorable.

Reaction medium: acetonitrile

Molar ratio of reactants: 2 to 3 moles of XVI per mole of XVII, with 2.1 to 2.5 moles of XVI per mole of XVII being more favorable (in which case 100% addition in step (i) is implied in each example).

Degree (iii):

Temperature: 20ºC to 55ºC, where 25ºC to 35ºC is more favorable, when we use the base, and 35ºC to 55ºC when we do not use the base

Duration: 0.3 to 0.7 hours, when we use the base, and 2 to 3 hours when we don't use the base.

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

Molar ratio of reactants: when we use a base, 4 to 6 equivalents of base, preferably sodium hydroxide per mole of XV, used in step (i).

It is best not to use a base in step (iii).

General conditions, suitable for all procedures

Most of the molar amounts (ratios) listed here are general and may vary, as will be apparent to one skilled in the art.

Stages (i) and (ii) of procedure A (including sub-procedures Aa and Ab and their variants), stages (i) and (ii) of procedure B and preferably stage (iv) of sub-procedure Aa are conveniently carried out under anhydrous conditions and in an inert atmosphere, preferably in dry helium, argon or nitrogen or in their mixture, usually in dry nitrogen. Step (iii) from sub-procedure A (including sub-procedures Aa and Ab and their variants) and procedure B are often, although not necessarily, carried out in an inert atmosphere.

Most of the above temperature ranges are given for informational purposes only. All temperatures are internal temperatures, unless otherwise stated. As used above, the term "reaction medium" includes a mixture of liquids and indicates that the reaction medium is a liquid at the desired reaction temperature. For this reason, we believe that we should not use all the liquids specified for the appropriate grade, for the entire specified temperature range. The opinion is also that the reaction medium must always be essentially inert for the reactants used, the resulting intermediates and the final products using the reaction conditions. The opinion is that the reaction temperature can exceed the boiling point of the reactants or the reaction medium, if we use a condenser or a closed system (reaction flask).

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

He is also of the opinion that we can use the usual processing procedures. The term "solvent", as used herein, includes a mixture of solvents and indicates that the reaction medium is a liquid at the desired reaction temperature. Unless otherwise stated, all solvent mixtures are by volume. The term "inert atmosphere" means an atmosphere which does not react with any of the reactants, intermediates or final products or interferes with the reaction in any way.

If desired, the product of each procedure can be purified using the usual techniques, such as recrystallization, chromatography or fractional distillation. All temperatures are in degrees Celsius, room temperature is 20ºC to 30ºC, usually 20ºC to 25ºC, unless otherwise stated; the evaporation is carried out in a vacuum using minimal heating, the organic phases are dried over anhydrous magnesium sulfate and, unless otherwise specified, silica gel is used for all chromatography on the column.

It should be emphasized that the variants of the procedure described in the proposed invention are improvements of known suitable procedures; we can use them to obtain the desired end products, i.e. 7-substituted hept-6-enanonic and heptanonic acids and their derivatives, for example in an easier way or, for example, in a state of greater chemical or optical purity, as we can obtain them by usual procedures.

The above variants of the procedures can be used either separately with the usual procedures or as desired or necessary in combination, to reach the desired final products.

Specific performance

A specific illustration of the general inventive concept, which is the basis of the above process variants, refers to the preparation of erythro-(E)-3,5-dihydroxy-7-[3'-(4''-fluorophenyl)-1'-(1'' -methylethyl)indol-2'-yl]-hept-6-enonic acids of formula Ia

[image]

in racemic or optically pure form; in the form of a simple acid, salt, ester or δ-lactone, i.e. an internal ester, in a multi-step process with the use of all the above process variants, especially process A, B and stereoselective reduction of the compound of formula II, and includes:

- according to procedure A:

a) reaction of the compound of formula VIIIa

OHC – N(R12b)R13 (VIIIa)

where R12b and R13 are the same as previously mentioned, with the compound of formula IX, in the given example in an inert anhydrous organic medium, to obtain the corresponding compound of formula Xc

Xa – CH=N+(R12b)R13 Xa- (Xc)

where Xa , R 12b and R 13 are the same as previously mentioned;

b) the reaction of that compound of the formula Xc with the compound of the formula XI, in the given example in an inert anhydrous organic medium, to obtain the corresponding compound of the formula XIIc

(E) - R14O – CH=CH – CH=N+(R12b)R13Xa-(XIIc)

where R 12b , R 13 , R 14 and Xa are the same as above;

c) hydrolysis of that compound of formula XIIc, to obtain the corresponding compound of formula VIIc in the form of a base or an acid addition salt and, if it is in the form of an acid addition salt, neutralization of the acid addition salt with a base;

- according to procedure B

d) the reaction of that compound of formula VIIc with the compound of formula XV or with the compound between 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-toluenesulfonitride or -bromide or methanesulfonyl chloride or -bromide; to obtain the corresponding compound of formula XVI and the corresponding anion, for example –PO2(Xb)2;

e) reaction of that compound of formula XVI with 3-(4'-fluorophenyl)-1-(1'-methylethyl)-1H-indole (compound of formula XVII, where R5 and R6 are hydrogen, R7 is 1-methylethyl and R8 p- fluorophenyl), to obtain the corresponding compound of formula XVIIIa

[image]

and the corresponding anion, eg -PO2(Xb)2, where R12b, R13 and Xa are the same as above;

f) hydrolysis of that compound of formula XVIIIa, to obtain (E)-3-[3'-(4''-fluorophenyl)-1'-(1''-methylethyl)-1H-indol-2'-yl]-prop -2-enal (compound of formula Va, where R5 and R6 are hydrogen, R7 1-methylethyl and R8 p-fluorophenyl);

g) the reaction of that compound of formula Va with the dianion of the acetoacetate ester of the formula CH3COOH2COOR1, where R1 is the same as mentioned earlier, to obtain the corresponding compound of formula IIa

[image]

where R1 is the same as previously mentioned; into racemic or optically pure form;

- according to the stereoselective reduction procedure:

h) stereoselective reduction of the racemic or optically pure compound of formula IIa

in the first stage /is stage (a) under 5. above/ with mixing of the compound of formula III with sodium borohydride (NaBH4) in the reaction medium, which includes alcohol and tetrahydrofuran;

in the second stage /is stage (b) under 5. above/, by processing the compound of formula IIa in racemic or optically pure form with the resulting mixture under acceptable conditions to obtain a mixture containing a cyclic boron compound of formula IV(a) and/or boron complex of formula IV(b), where R is [3-(4'-fluorophenyl)-1-(1'-methylethyl)-1H-indol]-2-yl, X is –CH=CH- and R1 and R3 same as above; and

in the third stage /is stage (c) under 5. above/ with cleavage of the product obtained in the second stage, to reject the compound of formula Ia in the form of an ester; in racemic or optically pure form; and

i) if desired, conversion of the compound of formula Ia in the form of an ester in the usual way in the form of a simple acid, the form of a salt, the form of the following ester or the form of δ-lactone, i.e. the internal ester.

The compound of formula Ia can be in the form of a simple acid, salt, ester or δ-lactone, i.e. of the internal ester. A simple acid or salt form is preferred, preferably an alkaline salt, especially a sodium salt. It is advantageous in racemic or optically pure (3R, 5S) enantiomeric form, especially in racemic form. As can be seen from formula Ia, this form is the erythro form.

The specific performance, shown under 9, is carried out either in accordance with the procedure described in the proposed invention, or for some of the stages in accordance with the procedure from the state of the art.

So

- stages a), b), and c) are carried out, as previously described under 7.1. for sub-procedure Ab, especially its stages i), ii) or Iii), for example according to variants Ab1, Ab2 and/or Ab3 of the sub-procedure Ab; steps a) and b) can be carried out simultaneously, for example, as described above for procedure A;

- stages d), e) and f) are carried out, as previously described under 7.2. for procedure B, especially for its stages i), ii) or iii);

- step g) is carried out according to the procedures published, for example, in US-PS 4,739,073, especially in reaction scheme I in column 8 and in example 5 of step 5, in column 47 of that description;

- stage h) performed as described earlier under 5.;

- step i) is carried out in the usual way, for example as described in US-PS 4,739,073, especially in reaction scheme I (reactions C, D and E) in column 9; reaction scheme II (reaction L) in column 11; reaction scheme VIII (reaction EE) in column 16; and in examples 6(a), 6(b), 6(c), 8 and 9 in columns 49 and 50 and 52 and 53 of that file, where we can replace THF with ethanol.

In the second part of the above stereoselective reduction step h), we preferably use the compound of formula IIa, where R1 is isopropyl or especially t-butyl, which facilitates the isolation of a relatively purer compound of formula I than the group in which R1 is methyl. Furthermore, it is common that the obtained compound of formula I is completely colorless, while in earlier syntheses we often obtained pale yellow.

As stated earlier, we can perform the stereoselective reduction according to step h) in a racemic or optically pure compound of formula IIa. The optically pure compound of formula IIa is obtained, for example, by chromatographic separation of the racemic compound of formula IIa, obtained in step g), or advantageously by asymmetric synthesis. On the other hand, we can perform the separation in the next step or with the racemic end product.

The starting materials for that specific embodiment of the invention are also known or can be prepared according to known procedures. The 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 Example 5, steps 1 to 3, in columns 44 and 45, from fluorobenzene.

The invention naturally refers to the above processes A, B and the stereospecific reduction process, especially when we use them for the preparation of the compound of formula Ia in combination with the usual processes that are not specifically described above.

Examples

The following examples illustrate the invention. All temperatures are in degrees Celsius. Optical purity is expressed in percentages, so for example "99.9% pure erythro isomer" indicates that the maximum 0.9% threo form is in the obtained compound.

Examples for the stereoselective reduction of a compound of formula II to obtain a compound of formula I

Example 1

Tert-butyl ester (+)-erythro-(E)-7-[3'-(4''-fluorophenyl)-1'-(1''-methylethyl)indol-2'-yl]-3,5-dihydroxyhept -6-enonic acids

/formula I: R is 3-(4'-fluorophenyl)-1-(1'-methylethyl)indol-2-yl; X is (E)-CH=CH-; R 1 is t-butyl; in racemic form/

a) 47.67g (1.26 mol) of sodium borohydride are added to a solvent comprising 1.32 1 of dry tetrahydrofuran (THF) and 356 ml of methanol under nitrogen at about -77ºC. 102 ml of 50% (4.09 mol) diethylmethoxyborane in THF is added to the resulting solution for 15 minutes and the resulting mixture is stirred for another 10 minutes.

b) 300.5g (0.464 mol) 71.88% pure tert.butyl ester (+)-(E)-7-[3'-(4''-fluorophenyl)-1'-(1''-methylethyl) )indol-2'-yl]-5-hydroxy-3-oxohept-6-enonic acid in 104 ml of THF and 26 ml of methanol at a temperature between about -74ºC to -77ºC is added dropwise over 1.5 hours to the mixture, formed in ( a) and mix the resulting mixture for another 30 minutes. Add 720 ml of saturated sodium bicarbonate solution and 1.75 l of heptane to quench the reaction. Then add 500 ml of ethyl acetate and dilute the obtained mixture with 3.5 l of water while stirring for 15 minutes, at which time the temperature of the mixture is about 10ºC. Separate the upper organic layer and wash it several times together with 2.4 1 of saturated sodium chloride solution, pH 7.5 and evaporate the organic layer at 26.6 to 40 mbar at the highest external temperature of about 45ºC. Add 375 ml of toluene to the organic residue and distill the solvent at 26.6 to 40 mbar at the highest external temperature of around 45ºC.

c) Add 3.73 1 of ethyl acetate to the obtained thick oil (mainly cyclic boronate). Then, we add 500 ml of a 30% solution of hydrogen peroxide (4.41 mol) to the ethyl acetate solution while maintaining the internal temperature from 25ºC to 30ºC (where the addition is initially exothermic) and the reaction mixture is stirred for about 2 hours at 20ºC to 25ºC, while at by thin-layer chromatography, boronate is no longer present. The upper organic layer is washed twice together with 2.22 l of saturated sodium chloride solution, pH 7.5. The upper organic layer is then separated, washed three times together with 2.61 L of a 10% sodium sulfite solution (until the organic layer remains free of peroxide) while maintaining an internal temperature of 25ºC. The upper organic layer is then washed twice together with 1.72 1 of saturated sodium chloride solution, pH 7.5, and the solvent is distilled at 26.6 to 40 mbar and the highest external temperature is around 45ºC. The rest of the solution in 1.17 1 of refluxing ethyl acetate, the mixture is filtered while it is still hot and the filtrate is stirred for 18 hours at 20ºC to 25ºC. The solids are collected by filtration, dried under reduced pressure (about 26.6 to 40 mbar) at 25ºC, washed with 55 ml of ethyl acetate/heptane (1:4), redissolved in 880 ml of ethyl acetate and stirred for 18 hours at room temperature. The solids are collected by filtration and washed with 480 ml of ethyl acetate/heptane (1:2). We dry the solids under reduced pressure, where we get 114.5 g of product (melting point 135ºC to 137ºC).

The second yield is obtained from the mother liquor, where the total yield is 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 first is favorable.

On the other hand, we can advantageously use half of the specified amount of sodium borohydride in step (a).

On the other hand, in step (c), we can use an aqueous sodium perbonate solution instead of a 30% hydrogen peroxide solution.

Example 2

(+)-erythro-(E)-7-[3'-(4''-fluorophenyl)-1'-(1''-methylethyl)indol-2'-yl]-3,5-dihydroxyhept-6 -enonic acids

/formula I: R, X is as in example 1; R 1 is methyl; in racemic form/

(a) Sodium borohydride is processed in a manner analogous to example 1, step (a), of course with the use of 15% diethylmethoxyborane in THF.

(b) 118.5 g (0.28 mol) methyl ester (+)-(E)-7-[3'-(4''-fluorophenyl)-1'-(1''-methylethyl)indole-2' -yl]-5-hydroxy-3-oxohept-6-enonic acid is treated analogously to example 1, step (b) of course is diluted with 1.42 1 of water and 1.185 1 of heptane instead of only with 3.5 1 of water.

(c) Add 2.375 1 of ethyl acetate to the organic residue (mainly cyclic boronate), treat the mixture with 264 ml of 30% hydrogen peroxide solution (2.328 mol) and treat as described in example 1 of stage (c). The residue is then dissolved in 130 ml of isopropanol. The mixture is heated to the reflux temperature. Add 14 g of boric acid to the hot mixture and reflux for another 15 minutes. The mixture is then filtered and the filtrate is stirred for 18 hours at 20ºC to 25ºC. The solids are collected by filtration, washed with 100 ml of isopropanol, dried under reduced pressure, and 110 g of product are obtained (80% yield). The product is re-dissolved in methanol and recrystallized (melting point 124ºC to 126ºC). the product is a 99.07% pure erythro racemate, which can be separated into two optical enantiomers, 3R, 5S and 3S, 5R, of which the first is favorable.

Example 3

Tert-butyl ester (+)-erythro-(E)-3,5-dihydroxy-7-[1'-(4''-fluorophenyl)-4'-(1''-methylethyl)-2'-phenyl-1H -imidazol-5'-yl]hept-6

-enonic acids

/Formula I: R is 1-(4'-fluorophenyl)-4-(1'-methylethyl)-2-phenyl-1H-imidazol-5-yl; X is (E) -CH=CH-; R 1 is 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 -76ºC. Add 387 ml of 15% diethylmethoxyborane in THF for 30 minutes to the resulting solution while maintaining the internal temperature below –77.5ºC and stir the resulting mixture for another 5 minutes.

(b) 110 g (0.223 mol) tert.butyl ester (5S)-(E)-7-[1'-(4''-fluorophenyl)-4'-(1''-methylethyl) indole-2'-phenyl -1h-imidazol-5'-yl]-5-hydroxy-3-oxohept-6-enonic acid in 304 ml of THF and 76 ml of methanol at a temperature of about -74ºC to -77ºC is added dropwise for 2 hours to the mixture formed in (a ). The obtained yellow solution is stirred for 6 hours at -76.5ºC. Then, to quench the reaction, we add 425 ml of saturated ammonium chloride, while maintaining the temperature at around -65ºC. We add 950 ml of ethyl acetate, 950 ml of hexane and 1.13 1 of water, at which the temperature of the mixture is about 5ºC, and the mixture is stirred for 15 minutes, at which the final temperature of the mixture is about 5ºC. The upper organic layer is separated, washed sequentially together with 1.4 1 of saturated sodium chloride solution (pH 7.5) and the solvent is distilled at 26.6 to 40 mbar at the highest external temperature of around 45ºC.

(c) 3.25 1 ethyl acetate is added to the resulting oil (mainly cyclic boronate). Then we slowly add 340 ml of a 30% solution of hydrogen peroxide (3 moles, so that we maintain the internal temperature of 20ºC to 25ºC and stir the mixture reaction for about 3 hours at 20ºC to 25ºC, while in the case of thin-layer chromatography of the boronate present in us..The upper organic layer twice washed together with 1.6 1 of a saturated sodium chloride solution, pH 7.5. The upper organic layer is then separated, washed three times (each time for 10 minutes) together with 1.5 1 of a 10% sodium sulfate solution (while the organic layer does not remain without peroxide) while maintaining an internal temperature of 25ºC. The upper organic layer is washed with 600 ml of saturated sodium chloride solution (pH 7.5). The solvent is distilled at 26.6 to 40 mbar with a maximum internal temperature of about 45ºC. We obtain 106 g of crude material 0.68 g of crude dihydroxy ester is purified by column chromatography using ethyl acetate/hexane (1:2) as eluent, in which we obtain 490 mg (m.p. 143ºC to 145ºC), which is shown by NMR analysis to contain the erythro isomer with 98, 76% purity (there is no threo isomer present); [α]D 2 O = +6.49º (c=0.77, CH 2 Cl 2 ).

Example 4

Tert-butyl ester (3R, 5S)-erythro-dihydroxy-6-trityloxyhexanoic acid

[Formula Iu; u is trityl; Ru is 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 -76ºC. The temperature rises to around -74ºC. 129.7 ml of 15% diethylmethoxyborane in THF is added to the resulting solution in drops for 20 minutes and the resulting mixture is stirred for another 10 minutes at -77ºC to -76ºC.

(b) 56 g (0.122 mmol) of t-butyl ester (S)-5-hydroxy-6-trityloxy-3-oxo-hexanoic acid are added to 165 ml of THF and 41 ml of methanol at a temperature of about -77ºC to -75ºC for 40 minutes in drops to the mixture formed in (a), and then the mixture is stirred for another 2 hours at -77ºC to -75ºC. To quench the reaction mixture, add 156 ml of saturated ammonium chloride solution. Then add 500 ml of ethyl acetate, 500 ml of heptane and 600 ml of water. The upper organic layer is separated and sequentially washed together with 600 ml of saturated sodium chloride solution, pH 7.5 and the organic layer is evaporated at 26.6 to 40 mbar at the highest external temperature of about 45ºC.

(c) Add 793 ml of ethyl acetate to the obtained organic residue (containing predominantly cyclic boronate). Then we slowly add 79 ml of a 30% solution of hydrogen peroxide (0.7 mol) and stir the reaction mixture for about 3 hours, until in thin-layer chromatography no more boronate is present. The upper organic layer is washed twice together with 400 ml of saturated sodium chloride solution, pH 7.5. The upper organic layer is then separated, washed three times (each time for 10 minutes) together with 576 ml of 10% sodium sulfite solution (until the organic layer remains free of peroxide) while maintaining an internal temperature of 25ºC. The upper organic layer is then sequentially washed together with 200 ml of saturated sodium chloride solution, pH 7.5, and the solvent is distilled at 26.6 to 40 mbar and the highest external temperature is around 45ºC. We obtain 54.3 g of the crude dihydroxy compound (m.p. 84ºC to 86ºC), which contains 99.19% of the erythro isomer; [α]D 2 O = +5.59º (c=1.6, CH 2 Cl 2 ).

Examples of preparation of intermediates of formula VII according to procedure A

Example 5

3-(N,N-dimethylamino) acrolein

[Chemical designation (E)-3-(N,N-dimethylamino) prop-2-enal]

[Formula VII: R12, R13 is methyl]

/sub-procedure Aa/

Step (i): Into a 12 liter round-bottomed 4-necked flask equipped with a stirrer, brine-filled condenser, thermometer, caustic scrubber, addition funnel, and cooling bath, dispense under nitrogen blanket 4.0 and methylene chloride and 438 g (5.99 moles) of N,N-dimethylformamide. We cool the solution to 7ºC and for 2.5 hours add 860 g (6.8 moles) of oxalyl chloride at such a rate that little or almost no solvent and/or reagent goes into the condenser, where we maintain the temperature of the reaction mixture at 5ºC to 10ºC. A white solid is formed.

Step (ii): 483 g (6.7 moles) of ethyl vinyl ether are added over 30 to 60 minutes while maintaining the highest temperature of 25ºC to 28ºC, where the addition is very exothermic. We get a brownish red solution. The reaction mixture is heated for 30 minutes at 37ºC to 38ºC, at which point it refluxes. By distillation at 40 to 53 mbar and 45ºC we recover as much methylene chloride as possible, and at the end of the distillation we combine the reaction mixture for 30 minutes at 40 mbar and 45ºC to obtain a dark brown oil, which can be mixed.

Stage (iii): Cool the reaction mixture to 20ºC and add 450 ml of water for about 30 minutes; let the temperature rise exothermically to 60ºC and maintain that temperature by balanced addition. The mixture is stirred for 30 minutes at 50ºC to 60ºC and cooled to 20ºC. For 30 to 45 minutes we add a solution of 1.71 kg (12.35 mol) of anhydrous potassium carbonate in 3.6 L of water while maintaining the temperature at 20ºC to 22ºC. The aqueous layer is extracted with 4 l of methylene chloride, the methylene chloride layer at the bottom is separated and the upper aqueous layer is extracted four times with equal parts of methylene chloride. We combine the 5 methylene chloride phases, dry over 500 g of anhydrous sodium sulfate and filter the solid substance and wash it twice with a 250 ml portion of methylene chloride. We combine the washing liquids and the filtrate, and by distillation at 26.6 to 53 mbar and 45ºC, we recover as much methylene chloride as possible, which gives a thick oil that can be mixed.

Step (iv): Cool the oil to 20ºC, add 500 ml of methanol, cool the mixture to 10ºC and add 60 g (1.33 mol) of anhydrous dimethylamine while maintaining the highest temperature of 20ºC. By distilling at 26.6 to 40 mbar and 70ºC, we recover as much solvent as possible, reduce the pressure to 3 to 5.3 mbar and continue the distillation with a complete rise in temperature, until we reach 120ºC and the steam temperature reaches 115ºC, at which point we get 89, 7% pure product as oil (412 g; yield 62%; boiling point of pure product 271ºC to 272.8ºC).

Example 6

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

[chemical designation (E)-3-(N-methyl-N-phenylamino) prop-2-enal]

[Formula VII: R12 is phenyl, R13 is methyl]

/sub-procedure Ab, variant Ab1/

Step (i): Into a 12 liter round-bottomed 4-neck flask equipped with stirrer, brine-filled condenser, thermometer, caustic, addition funnel, and cooling bath, dispense under nitrogen blanket 3.0 1 methylene chloride and 1.02 kg (7.4 moles) of N-methylformanilide. Cool the solution to 15ºC and for 1.5 hours add 1.10 kg (8.67 moles) of oxalyl chloride at such a rate that little or almost no solvent or reagent is added to the bottom of the condenser filled with salt water, where we maintain the temperature at 15ºC to 17ºC with slight reflux. The reaction mixture is slowly heated to 43ºC for 1 hour and refluxed for 1 hour at 43ºC to 45ºC, whereupon a clear red solution is obtained, which is cooled to 15ºC.

Step (ii): 648 g (8.99 moles) of ethyl vinyl ether are added over 40 to 60 minutes while maintaining the highest temperature of 28ºC to 29ºC, where the reaction is very exothermic. The resulting brown-red solution is heated for 30 minutes at 38ºC to 39ºC, at which point it refluxes, and cooled to 15ºC.

Step (iii): A solution of 960 g (9.05 mol) of anhydrous sodium carbonate in 4.5 1 of water is added for 45 to 60 minutes while maintaining a temperature of 22ºC to 30ºC, where the addition is very exothermic. Mix the mixture for 15 minutes at 22ºC to 25ºC and let it stand for 15 minutes to separate the two phases. The organic phase is separated and the aqueous phase is extracted with 1.25 l of methylene chloride. The methylene chloride extract is combined with the previous organic phase and the combined solution is extracted with 1 1 of water. The aqueous extract is re-extracted with 250 ml of methylene chloride and this methylene chloride extract is combined with the previous organic phase. By distillation at 26.6 to 53 mbar and 60ºC, we recover as much methylene chloride as possible, and heat the resulting oil for four hours at 26.6 to 40 mbar and 60ºC to 65ºC, whereupon we obtain an 83.5% pure product as oil (1.295 kg; yield 90.7%; boiling point of pure product 244ºC in decomposition); melting point of pure product 46ºC to 47ºC from isopropanol/hexane 1:1).

Example 7

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

[chemical designation (E)-3-(N-methyl-N-phenylamino) prop-2-enal]

[Formula VII: R12, R13 are as in Example 6]

/sub-procedure Ab, variant Ab2/

Step (i): Into a 5 liter round-bottomed 4-necked flask equipped with a stirrer, condenser filled with salt water, thermometer, caustic scrubber, addition funnel and cooling bath, dose under nitrogen blanket 350 ml of acetonitrile and 425 g (3 .8 moles) of N-methylformanilide. Cool the solution to -15ºC and add for 1.5 hours 44 g (3.46 moles) of oxalyl chloride at such a rate that little or no solvent and/or reagents pass to the bottom of the condenser filled with salt water, which is maintained at -25ºC to 20ºC, while maintaining temperatures -15ºC to -10ºC with slight reflux. The reaction mixture is slowly heated to 15ºC for 30 minutes and stirred for 15 minutes at 15ºC to 18ºC.

Step (ii): 339.5 g (3.39 moles) of N-butylvinylether are added for 45 minutes while maintaining the highest temperature of 28ºC to 30ºC, where the reaction is very exothermic. The reaction mixture is stirred for 30 minutes at 30ºC to 35ºC to obtain a red-brown solution which is cooled to 0ºC.

Step (iii): A solution of 395 g (3.73 mol) of anhydrous sodium carbonate in 1.75 1 of water is added for 40 to 60 minutes while maintaining a temperature of 8ºC to 10ºC, where the addition is very exothermic. Add 1.75 1 of toluene, stir the mixture for 15 minutes at 20ºC to 22ºC and let it stand for 15 minutes, so that it separates into two phases. The organic phase is separated and washed twice with a 150 ml portion of water.

By distillation at 26.6 to 107 mbar and 60ºC to 90ºC, we recover as much toluene as possible, and heat the remaining oil for 30 minutes at 26.6 to 40 mbar and 89ºC to 90ºC, to obtain an 86.6% pure product as an oil (492 g ; yield 85.7%; boiling point of pure product 244ºC with decomposition; melting point of pure product 46ºC to 47ºC from isopropanol/hexane 1:1).

If we stir the reaction mixture for 30 minutes at 28ºC to 30ºC instead of 30ºC to 35ºC, we achieve a yield of 90.7%, 92.3% purity of the product.

Example 7a

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

[chemical designation (E)-3-(N-methyl-N-phenylamino) prop-2-enal]

[Formula VII: R12, R13 are as in Example 6]

/sub-procedure Ab, variant Ab2, pure reagents/

Step (i): 223.2 ml (1.81 mol) of N-methylformanilide are metered into a 2.5 L four-necked flask, equipped as in Example 7, step (i), under a nitrogen atmosphere. Cool the solution to 15ºC and add 177.6 ml (2.07 moles) of oxalyl chloride for 20 minutes while maintaining the same temperature. Spontaneous evolution of gas occurs and an orange homogeneous solution is formed.

Step (ii): 278.4 ml (2.16 moles) of N-butyl vinyl ether are added for 45 minutes while maintaining the internal temperature of 25ºC to 30ºC, where the reaction is exothermic. Stir the orange suspension for 30 minutes at 40ºC to 45ºC and cool it to 0ºC.

Stage (iii): The product of stage (ii) is treated slowly for 90 minutes with a 4 N NaOH solution, so that the temperature does not exceed 5ºC. Heat the mixture to room temperature and stir for another 60 minutes. Separate the organic layer in a 3-liter funnel and extract the aqueous phase with 100 ml of N-butanol. The combined organic layers are washed twice with 200 ml of salt water and the solvent is separated by distillation in 2 hours at 80ºC and 20 mbar to obtain a thick brown black oil (295 g; yield 92%; chemical purity above 98%; boiling point of the pure product 244ºC with decomposition ; melting point of pure product 46ºC to 47ºC from isopropanol/hexane 1:1).

Example 8

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

[chemical designation (E)-3-(N-methyl-N-phenylamino) prop-2-enal]

[Formula VII: R12, R13 are as in Example 6]

/sub-procedure Ab, variant Ab3/

Steps (i) and (ii): Into a 12 1 round-bottomed, four-necked flask, equipped with a stirrer, brine-filled condenser, thermometer, caustic scrubber, addition funnel, and cooling bath, dispense under nitrogen blanket 1.056 kg (8 .15 mol) of oxalyl chloride and 480 ml of acetonitrile. Cool the solution to -10ºC, and for 2.5 hours add a mixture of 1.02 kg (7.395 mol) of N-methylformanilide, 816 g (7.98 mol) of N-butyl vinyl ether and 360 ml of acetonitrile at such a rate that little or no solvent and/or reagents passes to the bottom of the condenser filled with salt water (which is maintained at -25ºC to -20ºC) while maintaining a temperature of -10ºC to 5ºC with slight reflux.

The obtained homogeneous orange reaction mixture is slowly heated for 30 minutes at 20ºC; a light exotherm raises the temperature to 28ºC in a time of 20ºC; a light exotherm raises the temperature to 28ºC in 30 minutes. The reaction mixture is stirred for 1 hour at 28ºC to 30ºC to obtain a brown homogeneous mixture which is cooled to 0ºC.

Step (iii): Dissolve 948 g (8.94 mol) of anhydrous sodium carbonate in 4.29 1 of water and add for 45 to 60 minutes while maintaining a temperature of 8ºC to 10ºC, where the addition is initially very exothermic.

Add 3.60 1 of toluene, stir the mixture for 15 minutes at 20ºC to 22ºC and let it stand for 15 minutes to separate the two phases. The organic phase is separated and washed twice with a 360 ml portion of water. By distillation at 26.6 to 106 mbar and 60ºC to 90ºC, we recover as much toluene as possible and heat the remaining oil for 30 minutes at 26.6 to 40 mbar and 89ºC to 90ºC, to reject the 89.1% pure product as oil (1.16 kg ; 86.6%; boiling point of pure product 244ºC in decomposition; melting point of pure product 46ºC to 47ºC from isopropanol/hexane 1:1).

Examples of preparation of intermediates of formula Va according to procedure B

Example 9

(E)-3-[3'-(4''-fluorophenyl)-1H-indol-2'-yl]prop-2-enal

/Formula Va: R5, R6 are hydrogen; R7 is 1-methylethyl; R8 is 4-fluorophenyl/

/sub-procedure B/

(i) Into a 5-liter round-bottomed, 4-necked flask, equipped with a stirrer, condenser, thermometer, addition funnel, and cooling bath, dose 100 ml of dry acetonitrile and 174.4 g (1.14 mol) of phosphorus oxychloride, cool the mixture to -5ºC and add a solution of 184 g (0.96 mol) of 83.5% pure 3-(N-methyl-N-phenylamino)-acrolein (product of examples 6 to 8) in 156 ml for 45 minutes of dry acetonitrile while maintaining the temperature -5ºC to +5ºC. The reaction mixture is stirred for 10 minutes at 0ºC to 5ºC.

(ii) 115.2 g (0.45 mol) of 3-(4'-fluorophenyl)-1-(1'-methylethyl)-1H-indole (compound of formula XVII) is added for 20 minutes while maintaining the temperature around 5ºC. The reaction mixture is refluxed for 9 hours at 83ºC and cooled to 10ºC.

(iii) A solution of 228 g (5.7 mol) of sodium hydroxide in 2.0 1 of water is slowly added for 30 minutes while maintaining a temperature of 25ºC to 30ºC, where the addition is very exothermic. Add 1.6 1 toluene, stir the mixture for 30 minutes at 25ºC and filter through a filter roll. The filter cake (probably you mean the sediment?) is washed with 100 ml of toluene and the washing liquid is connected to the previous filter. Separate the organic layer and add a mixture of 93.4 g of concentrated hydrochloric acid and 2 1 of water, then another 400 ml of saturated sodium chloride solution. The mixture is stirred for 30 minutes at 25ºC and the obtained suspension is filtered through a filter roll. The resins are washed with 100 ml of toluene and the washing liquid is combined with the filtrate. The organic layer is separated, washed twice with 2 1 parts of deionized water and filtered through a filter roll. By distillation at 40 to 77 mbar and an external temperature of 60ºC to 65ºC, we recover as much toluene as possible, which gives us a thick oil that can be mixed. We add 100 ml of 95% ethanol, by distillation at 40 to 106 mbar and 60ºC to 65ºC we recover as much ethanol as possible and repeat this twice. Add 180 ml of 95% ethanol, reflux the mixture for 15 minutes at 78ºC and then slowly cool it to 20ºC for 2 hours, at which point crystallization begins at around 55ºC. Cool the suspension slowly over 30 minutes to 0ºC to 5ºC, keep for 1 hour at 0ºC to 2ºC and filter. The filter cake is washed three times with a 50 ml portion of cold (0ºC to 5ºC) 95% ethanol and dried in a vacuum at 60°C to 65ºC for 16 hours until constant weight, to obtain a 98.7% pure product (101 g; yield 71.3%; melting point 127ºC to 128ºC).

In the variant, let's use isopropanol instead of 95% ethanol.

Example 10

(E)-3-[3'-(4''-fluorophenyl)-1'-(1''-methylethyl)-1H-indol-2'-yl]prop-2-enal

/Formula Va: R5, R6, R7 and R8 are as in picture 9/

/procedure B, alternative procedure/

(i) Add 263 ml of dry acetonitrile and 454 g (2.96 mol) of phosphorus oxychloride under a layer of nitrogen to a liter flask with a round bottom and 4 doors, equipped with a stirrer, a condenser, an addition funnel and a cooling bath, and cool the mixture to -5ºC and for 45 minutes we add a solution of 471.6 g (2.49 moles) of 85.5% pure 3-(N-methyl-N-phenylamino) acrolein in 406 ml of dry acetonitrile while maintaining the temperature at 5ºC to 7ºC. The reaction mixture is stirred for 10 minutes at 5ºC to 7ºC.

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

(iii) 2.7 1 of water are slowly added over 15 minutes while maintaining a temperature of 22ºC to 35ºC, where the addition is exothermic. The reaction mixture is stirred for 30 minutes at 35ºC to 50ºC, heated for 1.5 hours at 50ºC to 55ºC (longer heating time may be required for complete hydrolysis), cooled to 22ºC, maintained for 15 minutes at 22ºC and filtered. The filter cake is washed three times with a 600-ml portion of water and dried with suction at aspirator pressure for 6 to 16 hours (N-methylaniline can be recovered from the aqueous layer and the washing liquids, which we have combined). Transfer the wet filter cake to the original 5-liter flask, add 2.5 liters of toluene and 180 g of cellulose powder (20 μm), heat the mixture for 1.5 hours at 50ºC to 55ºC, cool it to 22ºC, maintain it for 15 minutes at 22ºC and, in the given example, filter through a roll of 92 g silica gel 70 to 230 mesh A.S.T.M., covered with filter cloth. Cellulose and silica gel rolls are washed three times with a 200 ml portion of toluene. We combine the toluene filtrate and washing liquids and with distillation at 40 to 77 mbar and 50ºC to 65ºC (external) recover as much toluene as possible. Add 280 ml of 95% ethanol to the remaining thick oil, distill the ethanol at 26.6 to 40 mbar and 60 ºC to 65 ºC, add 280 ml of 95% ethanol and distill at 40 to 106 mbar and 60 ºC to 65 ºC as much ethanol as possible. Add 700 ml of 95% ethanol, reflux the mixture for 15 minutes at 78ºC and slowly cool it to 20ºC for 1 hour, whereupon crystallization begins at around 55ºC. The resulting suspension is cooled for 30 minutes at 0ºC to 5ºC and maintained for 30 minutes at 0ºC to 2ºC, the solids are collected by filtration, washed three times with a 120 ml portion of cold (0ºC to 5ºC) 95% ethanol and dried in a vacuum for 16 hours at 60ºC to 65ºC to constant weight, to obtain a 99.4% pure product (276.6 g; yield 75.5%; melting point 129ºC to 130ºC).

In the variant, let's use isopropanol instead of 95% ethanol.

It is advantageous to take a roll of silica gel, i.e. a liquid containing the appropriate cellulose, subject it to a simple filtration and wash the residue from that filtration three times with a 200 ml portion of toluene.

Example 10a

(E)-3-[3'-(4''-fluorophenyl)-1'-(1''-methylethyl)-1H-indol-2'-yl] prop-2-enal

/Formula Va: R5, R6, R7, and R8 are as in example 9/

/procedure B, alternative procedure/

(i) 170 ml of dry acetonitrile and 105.3 g of the hydrochloride salt of 3-(N-methyl-N-phenylamino) are dosed under a layer of dry nitrogen into a 1.5 liter flask, equipped as described in example 10, entry (i). of acrolein at room temperature. Add 96.6 g of phosphorus oxychloride to the mixture in 5 minutes. We get a dark solution.

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

(iii) Add 250 ml of water at 5ºC, then 500 ml of water at room temperature for 15 minutes. The mixture is stirred for 30 minutes at 35ºC to 50ºC, then heated for 1.5 hours at 50ºC to 55ºC. We get a dark suspension. Cool the mixture to 30ºC, hold for 15 minutes at 30ºC and filter the brown suspension. The filter cake is washed three times together with 540 ml of water. Dry the filter cake by suction under vacuum for about 4 hours. We transfer the solids to the original 1.5 liter flask, add 750 ml of toluene and 54 g of cellulose dust (20 μm) and carry out the following processing, as described in example 10, step (iii), to obtain the product (89 g; yield 81 %; melting point 123ºC to 129ºC).

Examples for specific performance

Example 11

Sodium salt (+)-erythro-(E)-3,5-dihydroxy-7-[3'-(4''-fluorophenyl)-1'-(1''-methylethyl)indol-2'-yl]- hept-6-enonic acid

/Formula Ia: in racemic form; sodium salt form/

Steps (a), (b) and (c): N-methylformanilide is partitioned with oxalyl chloride and ethyl- or n-butyl vinyl ether according to procedure A, sub-procedure Ab, to obtain 3-(N-methyl-N-phenylamino)acrolein, as described in example 6, 7, 7a or 8 /steps (i), (ii) and (iii)/.

Step (d): The bottom product, 3-(N-methyl-N-phenylamino)-acrolein, is partitioned with phosphorus oxychloride, as described in Example 9, 10 or 10a, step (i), to obtain a compound of formula XVI, where Xa is chlorine, R12b is phenyl and R13 is methyl.

Step (e): The above compound of formula XVI is partitioned with 3-(4'-fluorophenyl)-1-(1'-methylethyl)-1H-indole, as described in example 9, 10 or 10a, step (ii), with we obtain the compound of formula XVIIIa, where Xa is chlorine, R12b is phenyl and R13 is methyl.

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

Stage (g): Under a nitrogen atmosphere, dose 0.5 1 of tetrahydrofuran into the reactor, cool the solution to -10ºC and carefully add 60 g of sodium hydride (60% dispersion in mineral oil). Then carefully add 237.3 g of t-butylacetoacetate in 250 ml of THF for 45 minutes while maintaining the temperature below 2ºC. The resulting solution is stirred for 1 hour at -10 to 20ºC. Cool the mixture to -10ºC and add 938 ml (1.6 moles) of n-butyllithium solution in hexane at such a rate that the temperature does not exceed 0ºC (in about 60 minutes). The mixture is stirred for 10 minutes at that temperature, then cooled to -10ºC and a solution of 230 g of the product of step (f) in 650 ml of THF is added at such a rate that the temperature does not exceed 0ºC (for about 70 minutes). Stir the reaction mixture for 15 minutes at 0ºC and pour into the mixture 248 ml of concentrated hydrochloric acid and 2.5 kg of ice with vigorous stirring for 5 to 10 minutes. The mixture is vigorously stirred for another 15 minutes, the organic phase is separated, washed twice with a 500 ml portion of saturated sodium chloride solution and evaporated under reduced pressure (about 33 mbar). Add 200 ml of toluene to the residue and evaporate the solution again. Obtained crude t-butyl ester (+)-(E)-7-[3'-(4''-fluorophenyl)-1'-(1''-methylethyl) indol-2'-yl]-5-hydroxy-3 -oxohept-6-enonic acid (compound of formula IIa, where R1 is t-butyl, in racemic form) (503.8 g; 70.04% pure) was used in the next step without further purification.

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

Step (i): To 42.5 g of the ester, obtained in step (h) above, in 275 ml of THF, 90 ml of 1 N sodium hydroxide are added for 5 minutes while maintaining the temperature below 10ºC. Stir the solution for 1 hour at room temperature, add 275 ml of methanol, evaporate the mixture at 33.3 mbar and 45ºC, then add 300 ml of deionized water, continue with distillation until the remaining volume is 140 ml, then add 380 ml of deionized water again and wash the solution together with 640 ml of t-butylmethylether in 3 parts. Evaporate the aqueous layer at 33.3 mbar and 45ºC to a volume of about 300 ml, add 220 ml of deionized water and lyophilize the clear aqueous solution for 3 days. The title compound is obtained (35.9 g, yield 91%; chemical purity 98.9%, 99.9% pure erythro isomer; boron concentration below detection limit).

Alternative procedure for step (i): To 35.0 g of the ester obtained in step (h), add 74 ml of 1 N sodium hydroxide solution to 175 ml of ethanol for 5 minutes while maintaining the temperature below 12ºC. We stir the solution for 1 hour, evaporate the mixture at 33.3 mbar and 45ºC, then add 250 ml of deionized water, continue distilling until the final volume is 115 ml, then add 315 ml of deionized water and wash the solution together with 525 ml of tert.butylmethylether in 3 parts .

Evaporate the aqueous layer at 33.3 mbar and 45ºC to a volume of about 245 ml, add 185 ml of deionized water and lyophilize the clear aqueous solution for 3 days. The title compound is obtained (29.75 g; color pure white; yield 91%; melting point 204ºC to 207ºC in decomposition; chemical purity 100%; 99.61% pure erythro isomer; boron concentration 3.96 ppm).

Example 12

Sodium salt (+)-erythro-(E)-3,5-dihydroxy-7-[3'-(4''-fluorophenyl)-1'-(1''-methylethyl)indol-2'-yl]- hept-6-enonic acid

/Formula Ia: in racemic form; sodium salt form/

We obtain the title compound in a manner analogous to Example XI, except that

- in step /g) we obtain methyl ester with the reaction of methylacetoacetate dianion instead of t-butylacetoacetate;

- perform step (h) as described in example 2, steps (a), (b) and (c);

- step (i) is performed by hydrolyzing the obtained methyl ester and step (H), as described in 4,739,073, example 6(b) in column 50

Claims (14)

1. Procedure for preparing the compound of formula I [image] where is X -CH2CH2- or -CH=CH-; R1 ester group, inert for reaction conditions; and R is an organic residue with groups inert under reducing conditions, provided that when R is triphenylmethyl, then R1 additionally includes allyl and X is -OCH2-, with stereoselective reduction of a racemic or optically pure compound of formula II [image] where are they R, R1 and X are the same as above, and one of Z1 to Z2 is oxygen, and the other is hydroxy and hydrogen, characterized by the fact that in the first stage /stage (a)/, the compound of formula III R4O-B-(R3)2 (III) where is R4 allyl or lower alkyl with 1 to 4 carbon atoms and R3 primary or secondary alkyl with 2 to 4 carbon atoms, mixed with sodium borohydride NaBH4 in a reaction medium comprising alcohol and tetrahydrofuran; in the second stage /stage (b)/, the compound of formula II is treated with the mixture obtained in stage (a) under conditions favorable for obtaining the mixture, which contains the cyclic boronate compound of formula IV(a) [image] and/or boron complex of formula IV(b) [image] where R, R1, R3 and X are the same as above; and in the third stage /stage (c)/, we inoculate the product obtained in step (b), to obtain the corresponding compound of formula I, and if necessary, we convert the obtained compound of formula I by known means into the form of an unbound acid, salt, further form of ester or δ-lactone, i.e. into the internal ester form. 2. The process according to claim 1, characterized in that it is used to prepare the compound of formula Iu [image] where is in triphenylmethyl (trityl) and Ru allyl or an ester-forming radical, inert under reaction conditions, preferably allyl or C1-3alkyl, n-butyl, i-butyl, t-butyl or benzyl, especially t-butyl, with stereoselective reduction of the racemic or optically pure compound of formula IIu, [image] where u, Ru, Z1 and Z2 are the same as specified in this claim. 3. The method according to claim 1, characterized in that it is used for the preparation of the compound of formula Ia [image] in racemic or optically pure form; in the form of an unbound acid, salt, ester or 5-lactone, i.e. in the form of an internal ester, and including, if necessary, converting the obtained compound of formula Ia in the form of an ester by known means into the form of an unbound acid, salt, further form of an ester or 5-lactone, i.e. into the internal ester form. 4. The process according to claim 1, in which the compound of formula Va precedes [image] where is R 5 is hydrogen, C 1-3 alkyl, n-butyl, i-butyl, t-butyl, C 3-6 cycloalkyl, C 1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy; R 6 is hydrogen, C 1-3 alkyl, C 1-3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy; provided that no more than one R 5 and R 6 is trifluoromethyl, no more than one R 5 and R 6 is phenoxy, and no more than one R 5 and R 6 is benzyloxy; one of R7 and R8 are phenyl three times substituted with R9, R10 and R11, and the second is primary or secondary C1-6 alkyl, which does not contain an asymmetric carbon atom, C3-6cycloalkyl or phenyl-(CH2)m-, where R 9 is hydrogen, C 1-3 alkyl, n-butyl, i-butyl, t-butyl, C 1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy; R 10 is hydrogen, C 1-3 alkyl, C 1-3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy; R 11 is hydrogen, C 1-2 alkyl, C 1-2 alkoxy, fluorine or chlorine, and m is 1, 2 or 3; provided that no more than one R 9 and R 10 is trifluoromethyl, no more than one R 9 and R 10 is phenoxy, and no more than one R 9 and R 10 is benzyloxy; characterized in that the preparation of the starting substance in formula II is carried out as follows: (i) by reacting a compound of formula VIIIa OHC - N(R12b)R13 (VIIIa) where is R12b is phenyl or substituted phenyl with 1 to 3 substituents, each of which is independently C1-3alkyl, C1-3alkoxy, fluorine, chlorine, bromine or nitro with at most two nitro groups; and R 13 has the independent meaning previously given above for R 12b or is C 1-3 alkyl, with a compound of formula IX Xa - CO-CO - Xa (IX) where Xa is a monovalent leaving group, optionally in an inert anhydrous organic medium, to give the corresponding compound of formula Xc Xa - CH=N+(R12b)R13 Xa- (Xc) where Xa, R12b and R13 are as defined in this claim, (ii) by reacting the compound of formula X with the compound of formula XI R14O - CH=CH2 (XI) where R14 is a monovalent group, which does not deactivate the oxygen atom to which it is attached, arbitrarily in an inert anhydrous organic medium, to obtain the corresponding compound of formula XIIc (E) - R14O - CH=CH-CH=N+(R12b) R13 Xa- (XIIc) where R 12b , R 13 , R 14 and Xa are as defined in this claim, i (iii) hydrolyzing the compound of formula XIIc to give the corresponding compound of formula VIIc (E) - OHC - CH=CH - N(R12b)R13 (VIIc) where R12b and R13 as stated in this claim, are in the form of a free base or in the form of an acid addition salt, and if they are in the form of an acid addition salt, by neutralizing the acid addition salt with a base, (iv) by reacting the compound of formula VIIc with the compound of formula XV PO (Xb)3 (XV) wherein Xb is chlorine or bromine, 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 chlorides or bromides, such as p-toluenesulfonyl chloride or bromide or methanesulfonyl chloride or bromide; in order to obtain the corresponding compound of formula XVI (E) -Xb -CH=CH - CH=N+(R12b) R13 (XVI) as well as the corresponding anion, eg -PO2(Xb)2, where Xb, R12b and R13 are as specified in this claim, (v) by reacting the compound of formula XVI with the compound of formula XVII [image] wherein R 5 , R 6 , R 7 and R 8 are as defined in this claim, to give the corresponding compound of formula XVIII [image] as well as the corresponding anion, eg -PO2(Xb)2, where R5, R6, R7, R8, R12b and Xb are as defined in this claim and (vi) hydrolyzing a compound of formula XVIII to give the corresponding compound of formula 5. Process according to claim 4, characterized in that step (iii) is omitted and the compound of formula XII is used directly instead of the compound of formula VIIc in the further process. 6. The method according to claim 4, characterized in that steps (i) and (ii) are performed simultaneously. 7. The method according to claim 4, characterized in that in step (i) and/or (ii) we use pure reagents. 8. The process according to claim 4, characterized in that the compound of formula XII is in the form of an acid addition salt. 9. The process according to claim 3, in which the starting substance in formula II is the same as in formula IIa [image] where R 1 is as set forth in claim 1; in racemic form or optically pure form; indicated by the fact that its preparation is carried out as follows: a) by reacting the compound of formula VIIIa as set forth in claim 4 with the compound of formula IX as set forth in claim 4, optionally in an inert anhydrous organic medium, to obtain the corresponding compound of formula Xc as set forth in claim 4, b) by reacting the compound of formula Xc with the compound of formula XI as specified in claim 4, optionally in an inert anhydrous organic medium, to obtain the corresponding compound of formula XIIc as specified in claim 4, c) by hydrolyzing the compound of formula XIIc to obtain the corresponding compound of formula VIIc as specified in claim 4 in the free base or in the form of an acid addition salt, and if it is in the form of an acid addition salt, by neutralizing the acid addition salt with a base; d) by reacting the compound of formula VIIc with the compound of formula XV as specified in claim 4 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 chlorides or bromides, such as p-toluenesulfonyl chloride or bromide or methanesulfonyl chloride or bromide; to give the corresponding compound of formula XVI as set forth in claim 4, as well as the corresponding anion, eg -PO2(Xb)2; e) by reacting the compound of formula XVI with 3-(4'-fluorophenyl)-1-(1'-methylethyl)-1H-indole (compound of formula XVII where R5 and R6 are hydrogen, R7 is 1-methylethyl and R8 is p-fluorophenyl ) in order to obtain the corresponding compound of formula XVIIIa [image] as well as the corresponding anion, eg -PO2(Xb)2, wherein R 12b , R 13 and X 6 are as defined in claim 4; f) hydrolyzing the compound of formula XVIIIa to obtain (E)-3-[3'-(4''-fluorophenyl)-1'-(1''-methylethyl)-1H-indol-2'-yl]-prop- 2-enal (compound of formula Va where R5 and R6 are hydrogen, R7 is 1-methylethyl and R8 is p-fluorophenyl); and g) by reacting the compound of the formula Va with the dianion of the ester of acetic acid of the formula CH3COCH2COOR1 where R1 is as specified in claim 1. 10. The process according to claim 3, characterized in that the compound of formula Ia is obtained in racemic form. 11. The method according to claim 3, characterized in that the compound of formula Ia is obtained in the (3R, 5S) enantiomeric form. 12. The method according to claim 3, characterized in that the compound of formula Ia is obtained in the form of a sodium salt. 13. The method according to claim 4, characterized in that R12b is phenyl and R13 is methyl. 14. The method according to claim 3, characterized in that R1 is t-butyl.