RU2051907C1 - Method for production of 7-substituted heptene-6-oic acid - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: desired product having formula

is prepared as racemic form or as optically pure form, as free acid, salt, ester or δ lactone. R₂O-B(R₃)₂ where R₂ represents alkyl or C₁-C₄ alkyl, R₃ represents primary or secondary C₁-C₄ alkyl is used as reagent 1, NaBH₄ being used as reagent 2. Their interaction is carried out in the medium which contains alcohol and tetrahydrofuran.

where R₄-3-(4′- fluorophenyl-1′-methyl)1H-indole] -2-yl, X represents -CH=CH- group is used as reagent 3. Reaction is carried out to isolate desired product. EFFECT: improves efficiency of method. 9 cl

Description

 The invention relates to organic synthesis and relates to a method for producing 7-substituted hepten-6-hydroxy acid, its derivatives and intermediates for its preparation.

CH= CH-

-CH₂-

-CH₂-COOH его рацематные или оптически чистые формы; целевые соединения могут представлять собой чистую кислоту, соли, эфиры или δ-лактамы, т.е. внутренние эфиры.According to the invention receive a compound of formula Ia

CH = CH-

-CH ₂ -

—CH ₂ —COOH its racemic or optically pure forms; the target compounds may be pure acid, salts, esters or δ-lactams, i.e. internal esters.

CH= CH-

-CH₂-

-CH₂-COOR₁ где R₁ эфирная группа, инертная в условиях реакции.A process for the preparation of a compound of formula Ia according to the invention involves the stereo selective reduction of a racemic or optically pure compound of formula IIa

CH = CH-

-CH ₂ -

—CH ₂ —COOR ₁ where R _{1 is an} ether group inert under the reaction conditions.

 In general, if the hydroxy compound of formula II is reduced to the dioxo compound of formula I, an additional center of asymmetry is formed. Therefore, if a racemic compound of formula II is used, then four stereoisomers are formed (containing two pairs of enantiomers, i.e. a pair of erythro and a pair of threo enantiomers) of the obtained compound of formula I.

 Alternatively, if an optically pure compound of formula II is used, two diastereoisomers (i.e., one erythro and one threo isomer) of a compound of formula I are formed, i.e. 3R, 5S and 3S, 5S-distereisomers, which are obtained by reduction of the 5S-hydroxy compound. Diastereoisomers may be resolved by conventional means such as fractional crystallization, column chromatography, preparative thin layer chromatography or high performance liquid chromatography. The ratio of the erythro-isomer to the threo-isomer obtained by these methods usually varies and can be, for example, up to 98: 1.

 By the stereo-selective method according to the invention, if a racemic compound of formula II is used, only two stereoisomers (containing an erythro-pair of enantiomers) of the obtained compound of formula I are almost exclusively obtained

 Alternatively, if an optically pure compound of formula II is used, then only one enantiomer of the compound of formula I is formed almost exclusively, and this enantiomer is the corresponding erythro-enantiomer. For example, a 3R, 5S-enantiomer is formed upon reduction of the 5S-hydroxy compound.

 The ratio of erythro to threo isomer.

 Obtained by the method according to the invention is about 99.1: 0.9 or higher, in particular about 99.5: 0.5 or higher, in particular about 99.7: 0.3 or higher.

 The term “stereo selective” as used herein means that the ratio of erythro to threo form reaches 99.1: 0.9 or higher.

 The stereoisomers of the compounds of formula Ia according to the invention are the 3R, 5S and 3S, the 5R isomer and the racemate containing both of them, with the 3R, 5S isomer and racemate being preferred.

 Conventional keto reduction methods for the compounds of formula IIa employ mild reducing agents such as sodium borohydride or a complex with tert-butylemin and borane in an inert organic solvent such as a lower saturated alcohol to prepare a mixture of diastereomeric forms from an optically pure starting compound or alternatively racemic diastereoisomers from racemic starting material.

A three-stage, partially stereo-selective reduction method was used to obtain predominantly erythroracetate from racemic starting material. In a first step, a compound of formula II is reacted with either a trialkylborane compound or a compound of formula III:
R ₄ OB (R ₃ ) ₂ in which R ₄ is allyl or lower alkyl having 1 to 4 carbon atoms, preferably non-tertiary, and R ₃ is primary or secondary alkyl having 2-4 carbon atoms, preferably not tertiary in a reaction medium containing alcohol and tetrahydrofuran. In the second stage of such processes, sodium borohydride is added to the reaction medium and the reaction proceeds with the restoration of the keto group and, in turn, leads to the formation of a cyclic boronate or borane complex of the compound of formula Ia. In a third step, a reaction mixture containing a boron complex and / or cyclic boronate ester is converted to an azeotropic mixture with methanol or ethanol, or alternatively, treated in an organic solvent with an aqueous peroxide compound such as peroxide, i.e. hydrogen peroxide or perborate, for example, sodium perborate to obtain the target compound of formula Ia. Said method provides the production of erythro racemate with approximately 98% selectivity for the threo isomers (Chen et al. Tetrahedron Letters, 28, 155 (1987)).

 The process according to the invention includes a method for stereoselectively reducing a racemic and optically pure compound of formula (IIa) to produce almost exclusively the erythro isomers of formula I. Preferably, the keto group of the compound of formula IIa is restored almost rapidly. The compound of formula Ia, i.e. the erythroisomer is obtained additionally of high chemical purity and can further achieve approximately 99% chemical purity by simple recrystallization.

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

и/или комплекс бора формулы IV(b)

где R [3-(4-'фторфенил)-1-(1'-метилэтил)- 1Н-индол] -2-ил; Х-группа -СН=СН- и с небольшим избытком, таким как, например, от 1,1: 1,0 до 1,5:1,0 моля боргидрида натрия на 1 моль кетона. Молярное соотношение соединения формулы III и соединения формулы II по меньшей мере около 0,5:1,0 и более предпочтительно от 0,7:1,0 до 1,5:1,0 моль боранового соединения на моль кетона.From the second stage of the process / step (b), the compound of formula IIa is treated with the mixture obtained in step (a) under conditions suitable for preparing a mixture containing the cyclic boron compound of formula IV (a):

and / or a boron complex of formula IV (b)

where R [3- (4-'fluorophenyl) -1- (1'-methylethyl) -1H-indole] -2-yl; The X-group —CH = CH— and with a slight excess, such as, for example, from 1.1: 1.0 to 1.5: 1.0 mol of sodium borohydride per 1 mol of ketone. The molar ratio of the compound of formula III to the compound of formula II is at least about 0.5: 1.0, and more preferably from 0.7: 1.0 to 1.5: 1.0 mol of the borane compound per mole of ketone.

Step (b) is also preferably carried out at low temperatures, keeping the internal temperature between -100 and ^-40 ° C, especially from -78 to -70 ^C. The compound of formula II is preferably in a solvent such as a mixture of alcohol and tetrahydrofuran or tetrahydrofuran . Preferably, the reaction medium in step (a) and the solvent of the compound of formula II that are added in step (b) are selected so as to obtain a combined medium in which the volume ratio of alcohol to tetrahydrofuran is from 1: 3 to 1: 6, in particular from 1: 3 to 1: 4. Keto regeneration occurs rapidly and exothermically and therefore addition of keto compounds it is desirable to carry out gradually so as to maintain the internal reaction temperature at -78 to -70 ° ^C. The regeneration is almost instantaneous and the reaction mixture was then quenched by adding, e.g., aqueous sodium bicarbonate sodium, ammonium chloride or acetic acid and get the mixture of the desired intermediate cyclic boronate compounds.

In step (c) the reaction product of step (b) can be converted to an azeotrope with methanol or ethanol, for example at 60-80 ^{° C} while maintaining a largely anhydrous conditions. Alternatively and preferably, the product neutralized by the addition of sodium bicarbonate (NaHCO ₃ ) is dissolved in an organic solvent, i.e. ethyl acetate, and treated with aqueous (i.e. 30%) hydrogen peroxide or an aqueous solution of sodium perborate (NaBO ₃ · 4H ₂ O) initially at low temperature, i.e. about 10 ^{° C} and then heated to a moderate temperature, i.e. from 20 to 30 ^about With to obtain the corresponding compounds of formula Ia.

 Alternatively, the cyclic boron-containing fats obtained in step (b) can be extracted with an organic solvent, such as ethyl acetate, and then treated directly with an aqueous solution of a peroxide compound, for example a 30% aqueous solution of hydrogen peroxide or an aqueous solution of sodium perborate to obtain the corresponding compound of formula Ia.

 Compounds of formula I in the form of a δ-lactone, free acid and salt, as well as methods for converting a compound of formula Ia in an ester form into the corresponding δ-lactone or free acid or salts, are known.

The compound of formula Ia in the form of an ester can be converted by conventional methods into the forms of the corresponding free acids or salts, i.e. forms in which R _{1 is} substituted with hydrogen or a cation, such as an alkali metal or ammonium cation, preferably sodium or potassium, in particular sodium, into other ester forms or into the corresponding δ-lactones, i.e. internal esters.

 The compound of formula Ia obtained by the method according to the invention is a drug.

(primary or secondary C ₁ -C ₄ alkoxy or allyloxy) di- (primary C ₁ -C ₄ alkyl) -borane of formula III, used as starting materials in the method according to the invention, are known [Chem. et al. Tetrahedron Letters, 28, 155 (1987); Koster et al. Ann. (1975), 352 and Chen et al. Chemistry Letters, (1987), 1923-1926]
However, they can be obtained in situ from the corresponding tri- (primary or secondary C ₂ -C ₄ -alkyl) borane by reaction with a primary or secondary C ₁ -C ₄ -alkanol or allyl alcohol, the concentration of the former in the latter being preferably equal to 0.2 M, in particular 0.5 M.

 Compounds of formula IIa are known or can be prepared analogously to known compounds of formula II, i.e. as described in US patent N 4739073.

Thus, a compound of formula II in which Zr is oxygen is usually prepared by reaction of a compound of formula V
RX CHO in which R and X have previously defined meanings, with the dianion of a compound of formula VI
CH ₃ CO CH ₂ COOR ₁
in which R ₁ has previously defined meanings.

Compounds of formula V and VI are also known. A compound of formula V can be prepared from a subgroup of a compound of formula VIIc:
(E) OHC CH CH N (R _12b ) R ₁₃ wherein R _12b is phenyl, R ₁₃ is methyl.

 A method for producing a compound of formula VII is hereinafter referred to as “process A”, and a method for producing a compound of formula VI is hereinafter referred to as “process B”.

 Compounds of formula I, VIIc and 3- (4'-fluorophenyl) -1- (1'-methylphenyl) -1H-indole are known from US Pat. No. 4,739,073, which describes compounds of formula VIIc that are used to synthesize indole analogues of mevalonolactone and their derivatives which are indicated for use as inhibitors of HMG-CoA reductase.

 Since they inhibit cholesterol synthesis, they lower blood cholesterol and are therefore indicated for use in the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.

 The compound of formula VII and its synthesis are also disclosed in the description of UK patent N 945536 and Czechoslovak patent N 90045. However, the methods described therein are characterized in that they use phosgene or phosphorus trichloride phosphorus pentachloride or chloroxide instead of an oxalic acid derivative.

= C

(Ia) в рацемической или оптически чистой форме, в форме свободной кислоты, соли, или сложного эфира или δ-лактона, т.е. внутреннего сложного эфира, можно получить в многостадийном способе, используя все варианты процесса стереоизбирательного восстановления соединения формулы IIa, и включающего:
а) взаимодействие соединения формулы VIIa:
OHC N(R_12b)R₁₃ где R_12b фенил и R₁₃ метил с соединением формулы IX
Xa CO CO Xa где Ха одновалентная отщепляемая группа, необязательно в инертной безводной органической среде с образованием соответствующего соединения формулы Xc:
Xa CH N⁺(R_12b)R₁₃ Xa
в которой Ха, R_12b и R₁₃ имеют ранее определенные значения;
b) взаимодействие этого соединения формулы Хс с соединением формулы Хс с соединением формулы XI
R₁₄O CH CH₂
где R₁₄ моновалентная группа, которая не влияет дезактивирующим образом на атом кислорода, с которым она связана, необязательно в инертной безводной органической среде с образованием соответствующего соединения формулы XIIc
(E) R₁₄O CH CH-CH N⁺(R_12b)R₁₃Xa
в которой R_12b, R₁₃, R₁₄ и Ха определены выше;
с) гидролиз этого соединения формулы XIIc для получения соответствующего соединения формулы VIIc
(E) OHC CH CH N(R_12b)R₁₃ где R_12b и R₁₃ имеет приведенные значения в форме свободного основания или кислотно-аддитивной соли, нейтрализацию кислотно-аддитивной соли основанием;
d) взаимодействие этого соединения формулы VIIc с соединением формулы XV
PO(Xb)₃ где Xb имеет значение хлор- или бром, или с соединением, выбранным из группы: хлористого оксалина или бромистого оксалина, фосгена или бромистого карбонила, треххлористого фосфора или трехбромистого фосфора, пятихлористого фосфора или пятибромистого фосфора и хлористого алкил- или арилсульфонила или бромистого алкил или арилсульфонила, такого как хлористый пара-толуолсульфонил или бромистый пара-толуолсульфонил или хлористый или бромистый метонсульфонил, с образованием соответствующего соединения формулы XVI
(E) Xb CH CH CH N⁺ (R_12b)R₁₃
где R_12b, R₁₃ и Xb имеет значения, указанные выше, и соответствующего аниона, т.е. PO₂(Xb)₂;
e) взаимодействие этого соединения формулы XVIс 3-(4'-фторфенил)- 1-(1'-метилэтил)-1Н-индолом с образованием соответствующего соединения формулы XVIIIa

и соответствующего аниона, т.е. PO₂(Xb)₂, в которых R_12b, R₁₃ и Xb имеют значения, определенные ранее:
f) гидролиз этого соединения формулы XVIIIa для получения (E)-3-[3'-(4"-фторфенил)-1'-(1"-метилэтил)-1Н-индол-2'-ил] проп- 2-енала;
g) взаимодействие этого соединения с дианионом сложного эфира ацетуксусной кислоты формулы CH₃COCH₂COOR₁, в которой R₁ имеет значения, определенные ранее, с получением соответствующего соединения формулы IIa:

= C

в которой R₁ имеет значения, определенные выше, в рацемической или оптически чистой форме;
h) стереоизбирательное восстановление рацемического или оптически чистого соединения формулы IIa путем:
на первой стадии смешение соединения формулы III с боргидридом натрия (NaBH₄) в реакционной среде, содержащей спирт и тетрагидрофуран;
на второй стадии обработка соединения формулы IIa в рацемической или оптически чистой форме полученной смесью в условиях, подходящих для получения смеси, содержащей циклическое боронатное соединение формулы IV(a) и/или комплекс бора формулы IV(b), в которой R представляет собой [3-(4'-фторфенил)-1-(1'-метилэтил)-1Н-индол] 2-ил, Х является -СН=СН- и R₁ и R₂ имеют значения, определенные выше, и
на третьей стадии разложение продукта, полученного на второй стадии, с получением соединения формулы Ia в форме сложного эфира, в рацемической или оптически чистой форме, и
i) если желают, то превращение соединения формулы Ia в форме сложного эфира традиционными средствами в форму свободной кислоты, в форму соли, в другую форму сложного эфира, или α-лактона, т.е. циклического сложного эфира.Erythro- (E) -3,5-dihydroxy-7- [3 '- (4 "- fluorophenyl) -1' - (1" -methylethyl) -indol-2'-yl] -hepten-6-oic acid of the formula Ia

= C

(Ia) in racemic or optically pure form, in the form of a free acid, salt, or ester or δ-lactone, i.e. the internal ester can be obtained in a multi-stage method using all variants of the process of stereo-selective recovery of the compounds of formula IIa, and including:
a) the interaction of the compounds of formula VIIa:
OHC N (R _12b ) R ₁₃ where R _{12b is} phenyl and R _{13 is} methyl with a compound of formula IX
Xa CO CO Xa where Xa is a monovalent leaving group, optionally in an inert anhydrous organic medium to form the corresponding compound of formula Xc:
Xa CH N ⁺ (R _12b ) R ₁₃ Xa
in which Xa, R _12b and R ₁₃ have previously defined meanings;
b) the interaction of this compound of formula Xc with a compound of formula Xc with a compound of formula XI
R ₁₄ O CH CH ₂
where R _{14 is a} monovalent group that does not deactivate the oxygen atom to which it is bonded, optionally in an inert anhydrous organic medium to form the corresponding compound of formula XIIc
(E) R ₁₄ O CH CH-CH N ⁺ (R _12b ) R ₁₃ Xa
in which R _12b , R ₁₃ , R ₁₄ and Xa are as defined above;
c) hydrolysis of this compound of formula XIIc to obtain the corresponding compound of formula VIIc
(E) OHC CH CH N (R _12b ) R ₁₃ wherein R _12b and R ₁₃ are as provided in the form of a free base or an acid addition salt, neutralization of the acid addition salt with a base;
d) the interaction of this compound of formula VIIc with a compound of formula XV
PO (Xb) ₃ where Xb is chloro or bromo, or with a compound selected from the group: oxaline chloride or oxaline bromide, phosgene or carbonyl bromide, phosphorus trichloride or phosphorus trichloride, phosphorus pentachloride or phosphorus pentachloride and alkyl chloride or arylsulfonyl chloride or alkyl bromide or arylsulfonyl, such as para-toluenesulfonyl chloride or para-toluenesulfonyl bromide or methanesulfonyl chloride or bromide, to form the corresponding compound of formula XVI
(E) Xb CH CH CH N ⁺ (R _12b ) R ₁₃
where R _12b , R ₁₃ and Xb have the meanings indicated above and the corresponding anion, i.e. PO ₂ (Xb) ₂ ;
e) reacting this compound of formula XVI with 3- (4'-fluorophenyl) -1- (1'-methylethyl) -1H-indole to form the corresponding compound of formula XVIIIa

and the corresponding anion, i.e. PO ₂ (Xb) ₂ , in which R _12b , R ₁₃ and Xb are as previously defined:
f) hydrolysis of this compound of formula XVIIIa to obtain (E) -3- [3 '- (4 "fluorophenyl) -1' - (1" methylethyl) -1H-indol-2'-yl] prop-2-enal ;
g) reacting this compound with an acetic acid ester dianion of the formula CH ₃ COCH ₂ COOR ₁ , in which R ₁ has the same meaning as previously defined, to give the corresponding compound of formula IIa:

= C

in which R ₁ has the meanings given above, in racemic or optically pure form;
h) stereo selective reduction of the racemic or optically pure compound of formula IIa by:
in a first step, mixing a compound of formula III with sodium borohydride (NaBH ₄ ) in a reaction medium containing alcohol and tetrahydrofuran;
in a second step, treating the compound of formula IIa in racemic or optically pure form with the resulting mixture under conditions suitable for preparing a mixture containing a cyclic boronate compound of formula IV (a) and / or a boron complex of formula IV (b) in which R is [3 - (4'-fluorophenyl) -1- (1'-methylethyl) -1H-indole] 2-yl, X is —CH = CH— and R ₁ and R ₂ are as defined above, and
in a third step, decomposing the product obtained in the second step to obtain a compound of formula Ia in an ester form, in racemic or optically pure form, and
i) if desired, the conversion of the compound of formula Ia in the form of an ester by conventional means into the free acid form, into the salt form, into another form of the ester, or α-lactone, i.e. cyclic ester.

 The compound of formula Ia may be in the form of a free acid, salt, ester or δ-lactone, i.e. in the form of a cyclic ether. Preferably in the form of a free acid or salt, preferably an alkaline salt, especially in the form of a sodium salt. Preferably in racemic or alternatively optically pure (3R, 5S) -enantiomeric form, especially in racemic form. As can be seen from formula Ia, the form is an erythro form.

 Keeping in mind that this particular embodiment, illustrated in section 9, is carried out either according to the processes described in this invention, or in some operations according to methods known in the art.

In the second part of the stereo selective reduction step (h), a compound of formula IIa is preferably used in which R ₁ is isopropyl or in particular tert-butyl, which facilitates the isolation of a relatively larger amount of pure compound of formula I than with an R ₁ group such as methyl. Further, unexpectedly, the compound obtained in this case is completely colorless, while in the known earlier syntheses it was always obtained a pale yellow color.

 As previously mentioned, the stereo selective reduction according to step h) above can be carried out with a racemic or optically pure compound of formula IIa. An 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 preferably by asymmetric synthesis. Alternatively, the separation can be carried out in a subsequent step or on a racemic final product.

 The starting materials for this particular embodiment of the invention are also known or can be obtained by known methods. The preparation of 3- (4'-fluorophenyl) -1- (1'-methylethyl) -1H-indole is disclosed in US Pat. No. 4,739,073 as Example 5, Steps 1-3, Columns 44 and 45, from fluorobenzene as starting material.

 The following examples illustrate the invention. All temperatures are given in degrees Celsius. Optical purity is expressed as a percentage measurement and thus, for example, “99.9% pure erythro-isomer” means that the compound obtained contains the highest 0.9% of the threo form.

 PRI me R 1. tert-Butyl ether (+) - erythro- (E) -7- [3 '- (4 "-fluorophenyl) -1- (1" -methylethyl) -indole-2' - yl] -3,5-dioxihept-6-enoic acid.

(a) 47.67 g (2.26 mol) of sodium borohydride was added to a solvent comprising 1.32 liter of dry tetrahydrofuran and 356 ml of methanol under nitrogen at -77 ^o C. To this solution was added 102 ml of 50% (4, 09 M) diethylmethoxytorane in tetrahydrofuran for 15 minutes and the resulting mixture was stirred for an additional 10 minutes.

(b) 300.5 g (0.464 mol) of 71.88% pure tert-butyl ether (± - (E) -7- [3 '- (4 "fluorophenyl) -1' - (1" methylethyl) indole -2-yl] 5-hydroxy-3-heptyl-6-enoic acid in 104 ml of tetrahydrofuran and 26 ml of methanol at a temperature of from -74 to -77 ^{° C} was added dropwise to the mixture obtained in step (a) for an hour and a half and the resulting mixture was stirred for an additional 30 minutes, 720 ml of a saturated solution of sodium bicarbonate and 1.75 L of heptane were added to stop the reaction, then 500 ml of ethyl acetate was added and the resulting mixture was diluted with 3.5 L of water with stirring for 15 minutes, maintaining the temperature was 10 ^C. The upper organic layer was separated and washed several times with a total of 2.4 l of saturated sodium chloride solution at pH 7.5 and the organic layer was concentrated at 20-30 mm Hg and a maximum external temperature of about 45 ° ^C.

(c) 3.73 L of ethyl acetate was added to the viscous oil obtained in the previous step (mainly cyclic boronate). To the ethyl acetate solution was added 500 ml of a 30% solution of hydrogen peroxide (4.41 mole), maintaining an internal temperature 25-30 ^{° C} (at the beginning of the addition reaction is exothermic) and the reaction mixture was stirred at 20-25 ^{° C} for about 2 hours until thin layer chromatography did not show the presence of boronate. The upper organic layer was washed twice with a total of 2.22 L of saturated sodium chloride solution at pH 7.5. The top organic layer was separated, washed three times with a total of 2.61 liters of 10% sodium sulfite (until until no peroxide in the organic layer), while maintaining the internal temperature is ^about 25 C. The upper organic layer washed twice with a total of 1.72 l of saturated sodium chloride solution at pH 7.5 and the solvent was distilled at 20-30 mm Hg and a maximum external temperature of about 45 ° ^C. The residue was dissolved in 1.17 l of refluxing ethyl acetate, the mixture was filtered hot and the filtrate was stirred at 20-25 ^{° C} for 18 . The solid was collected by filtration, dried under reduced pressure (20-30 mm Hg) at ²⁵ ° C, washed with 550 ml of ethyl acetate-heptane 1: 4, re-dissolved in 880 ml of ethyl acetate and stirred at room temperature for 18 h. Solids were collected by filtration and washed with ethyl acetate-heptane 1: 2 (480 ml). The solid phase was dried under reduced pressure and the desired product was obtained in an amount of 114.5 g (point pl. 135-137 ^about C).

 The second yield was obtained from the mother liquors and the total yield was 149.5 g. The product had 99.44% chemical purity and 99.67% pure erythro-isomer. It can be split into two optically active enantiomers, 3R, 5S and 3S, 5R, of which the first isomer is preferred.

 Alternatively and preferably, in step (a), half of the indicated amount of sodium borohydride can be used.

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

 PRI me R 2. Methyl ether (±) -erythro- (E) -7- [3 '- (4 "-fluorophenyl) -1' - (1" -methyl-ethyl) -indole-2'- yl] -3,5-dioxihept-6-enoic acid.

 (a) Sodium borohydride was treated in a similar manner to that described in Example 1, step (a), but using 15% diethylmethoxyborane in tetrahydrofuran.

 (b) 118.5 g (0.28 mol) of methyl ester (±) - (E) -7- [3 '- (4 "- fluorophenyl) -1' - (1" -methylethyl) -indole-2 ' -yl] -5-hydroxy-3-oxohept-6-enoic acid was treated analogously to Example 1 (step (), but 1.42 L of water and 1.185 L of heptane were diluted instead of only 3.5 L of water.

(c) To the organic residue (cyclic boronate predominates), 2.375 L of ethyl acetate was added and the mixture was treated with 264 ml and 30% hydrogen peroxide solution (2.328 mol) and treated as described in Example 1, step (c). The residue was then dissolved in 130 ml of isopropanol. The mixture was heated at reflux temperature. 14 g of boric acid was added to the hot mixture and heating under reflux was continued for 15 minutes. The mixture was then filtered and the filtrate was stirred at 20-25 ^{° C} for 18 hours. The solids were collected by filtration, washed with 100 ml of isopropanol and dried under reduced pressure to give 110 g of product (80% yield). The product was redissolved in methanol and recrystallized (melting point 124-126 ^about C). The product is 99.07% pure erythroracetate, which can be resolved into two optical enantiomers, 3R, 5S and 3S, 5R, of which the former is preferred.

 PRI me R 3. tert-Butyl ether (±) -erythro- (E) -3,5-dioxi-7- [1 '- (4 "-fluorophenyl) -4' - (1" - methylethyl) - 2'-phenyl-1H-imidazol-5'-yl] -hept-6-enoic acid).

(a) 10.27 g (0.27 mol) of sodium borohydride was added to a solvent comprising 1.67 liter of dry tetrahydrofuran and 513 ml of methanol, under nitrogen at -76 ^o C. To this solution was added 387 ml of 15% diethylmethoxyborane in THF over a 30 minute period, keeping the internal temperature below -77.5 ^{° C,} and the resultant mixture was stirred for an additional 5 min.

(b) 110 g (0.223 mol) of (5S) tert-butyl ether - (E) 7- [1 '- (4 "fluorophenyl) -4' - (1" methylethyl) -2'-phenyl-1H- imidazol-5-yl] -5-si -tuples-3-heptyl-6-enoic acid in 304 ml of tetrahydrofuran and 76 ml of methanol at a temperature of about -74 to -77 ^{° C} was added dropwise to the mixture formed in step ( a) for 2 hours. The resulting yellow solution is stirred at -76.7 ^{° C} for 6 hours. Then was added 425 ml of saturated ammonium chloride for fast quench the reaction, maintaining the temperature at about -65 ° ^C. was added 950 ml of ethyl acetate. 950 ml geksisana and 1.13 liters of water at a temperature of 5 ^{° C} the mixture and the mixture was stirred for 15 minutes, causing the temperature of the mixture to about 5 ° ^C. The upper organic layer was separated and washed successively with a total of 1.4 l of saturated sodium chloride solution (pH 7 , 5) and the solvent was distilled off at 20-30 ml Hg at a maximum external temperature of about 45 ° ^C.

(c) 3.25 L of ethyl acetate was added to the resulting oil (mainly cyclic boron). Then slowly added 340 ml of 30% hydrogen peroxide solution (3 moles) to maintain an internal temperature of 20-25 ^{° C} and the reaction mixture was stirred at 20-25 ^{° C} for about 3 hours, until thin layer chromatography showed no boronate present. The upper organic layer was washed twice with a total of 1.6 L of a saturated solution of sodium chloride with a pH of 7.5. The organic layer was separated, three times (for ten minutes each time) was washed in total 1.5 L of 10% sodium sulfite solution (until the organic layer until it contained a peroxide) while maintaining an internal temperature of 25 ^C. The upper organic layer washed with 600 ml of a saturated solution of sodium chloride (at pH 7.5). The solvent is distilled at 20-30 mm Hg and a maximum external temperature of about 45 ° ^C. The obtained 106 g of crude material. Purification of 0.68 g crude dioksiefira was performed by column chromatography using ethyl acetate-hexane 1: 2 as eluent to give 490 mg of product (mp 143-145 ^{° C)} which is shown in the analysis of the NMR spectrum of the erythro-isomer content with 98.78% purity (no threo-isomer was present at all): (α) $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ + 6.49 ^o (s 0.77, CH ₂ Cl ₂ ).

PRI me R 4. 3- (N-Methyl-N-phenylamino) -acrolein [- (E) -3- (N-methyl-N-phenylamino) -prop-2-enal]
Operation (i). In a 12 L four-necked round-bottomed flask equipped with a stirrer filled with a refrigerant condenser, a thermometer, an alkaline scrubber, an additional funnel and a cooling bath, 3.0 L of methylene chloride and 1.02 kg (7.4 mol) of N-methylform were charged under nitrogen atmosphere. anilide. The solution was cooled ^to 15 ° C and 1.10 kg (8.67 mol) of oxalyl chloride for 1.5 hours at a rate such that little or no solvent and / or reagent is not supplied to the bottom of the filled refrigerant of the condenser, while maintaining the temperature 15-17 ^about With a slight formation of phlegm. The reaction mixture was slowly heated to 43 ^about C for 1 h, heated under reflux for 1 h at 43-45 ^about C and received a clear yellow solution, which was cooled to 15 ^about C.

Stage (ii). Was added 648 g (8.99 mol) of ethyl vinyl ether was added over 40-60 minutes while maintaining a maximum temperature of 28-29 ^{° C} the reaction was very exothermic. The resulting brown-red solution was heated at 38-39 ^{° C} for 30 min, and there has been a formation reflux and cooled to 15 min.

Stage (iii). A solution of 960 g (9.05 mol) of anhydrous sodium carbonate in 4.5 l of water was added over 40-60 min, keeping the temperature 22-30 ^{° C,} adding a very exothermic reaction occurred. The mixture was stirred at 22-25 ^{° C} for 15 min and kept for 15 minutes to separate into two phases. The organic phase was separated, the aqueous phase was extracted with 1.25 L of methylene chloride. The methylene chloride extract was combined with the previously obtained organic phase and the combined solution was extracted with 1.0 L of water. The aqueous extract was again extracted with 250 ml of methylene chloride and this methylene chloride extract was combined with the previous organic phase. Distillation at 20-40 mm Hg and 60 ° ^C removed the greatest possible amount of methylene chloride, the residual oil is heated at 60 65 ^o C and a pressure of 20-30 mm Hg for 4 hours to give 83.5% pure product as an oil (1.295 kg yield 90.7% boiling point of pure product 244 ^о С (decomp.): melting point of pure product 46-47 ^о С from isopropanol-hexane mixture in the ratio 1: 1).

Example 5. 3- (N-methyl-N-phenylamino) acrolein [= (E) -3- (N-methyl-N-phenylamino) - prop-2-enal]
Stage (i). In a 5 L four-necked round-bottom flask equipped with a stirrer, a condenser filled with a refrigerant, a thermometer, an alkaline scrubber, an additional funnel and a cooling bath in a nitrogen atmosphere, 350 ml of acetonitrile and 425 g (3.8 mol) of N-methylformanilide were charged. The solution was cooled to -15 ^{° C} and for 1.5 hours was added 440 g (3.46 mol) of oxalyl chloride at a rate such that little or no solvent and / or reagent has been received on the bottom filled refrigerant condenser while maintaining the temperature of -25 to ^-20 ° C in a refrigerator at a reaction temperature of -15 to ^-10 ° C under slight reflux for. The reaction mixture was slowly warmed ^to 15 ° C for 30 min and stirred for 15 min at 15-18 ° ^C.

Stage (ii). 339.5 g (3.39 mol) of n-butyl vinyl ether was added over 45 minutes while maintaining a maximum temperature of 28-30 ^{° C,} the reaction proceeds with violent heat generation. The reaction mixture was stirred at 30-35 ^about C for 30 minutes and received a reddish-brown solution, which was cooled to 0 ^about C.

Stage (iii). A solution of 395 g (3.73 mol) of anhydrous sodium carbonate in 1.75 l of water was added over 40-60 min while maintaining the temperature 8-10 ^{° C,} the addition was accompanied by vigorous evolution of heat. 1.75 liters of toluene was added, and the mixture was stirred at 20-22 ° ^for 15 min and kept for 15 minutes to separate into two phases. As much as possible toluene was removed by distillation at 20-80 mm Hg and a temperature of 60-90 ^о С, residual oil was heated at 20-30 mm Hg and 89-90 ^о С for 30 min, and a product with a purity of 86.6% was obtained as an oil (492 g yield was 85.7% pure product boiling point 244 ^C (with decomposition), the melting point of pure product 46-47 ^{° C} from a mixture of isopropanol: hexane 1: 1).

If the reaction mixture was stirred at 28-30 ^{° C} for 30 min, the yield was 90.7% product purity of 92.3%
PRI me R 5A. 3- (N-Methyl-N-phenylamino) -acrolein [= (E) -3- (N-methyl-N-phenylamino) -prop-2-enal]
Stage (i). In a 2.5 L four-neck flask equipped as in Example 7 with the necessary devices in step (i), 223.2 ml (1.81 mol) of N-methylformanilide were charged under nitrogen atmosphere. The solution was cooled ^to 15 ° C and 177.6 ml (2.07 mol) oksalina chloride within 20 minutes while maintaining the same temperature. Spontaneous gas evolution and the formation of an orange homogeneous solution were observed.

Stage (ii). Was added 278.4 mL (2.16 mol) of n-butyl vinyl ether was added over 45 minutes while maintaining an internal temperature 25-30 ^{° C} while the reaction proceeded exothermically. The orange slurry was stirred at 40-45 ^{° C} for 30 minutes and cooled to 0 ° ^C.

Stage (iii). To the product obtained in step (ii), was added slowly over 90 min 4 n.rastvor sodium hydroxide so that the temperature did not exceed 5 ^o C. The mixture was warmed to room temperature and stirred for another 60 min. The organic layer was separated into a 3 L funnel and the aqueous phase was extracted with 100 ml of n-butenol. The combined organic layers were washed twice with 200 mL of brine and the solvent was distilled off at ⁸⁰ ° C and a pressure of 15 mm Hg for two hours. Obtained viscous brown-black oil (295 g, yield 92% chemical purity greater than 98% boiling point of pure product 244 ^{° C} (decomposes): mp of pure product 46-47 ^{° C} from isopropanol-hexene in a ratio of 1: 1).

PRI me R 6. 3- (N-Methyl-N-phenylamino) -acrolein [= (E) -3- (N-methyl-N-phenylamino) -prop-2-enal]
Operations (i) and (ii). In a 12 L four-necked round-bottom flask equipped with a stirrer, a condenser filled with a refrigerant, a thermometer, an alkaline scrubber, an additional funnel and a cooling bath, 1,056 kg (8.15 mol) of oxaline chloride and 480 ml of acetonatrile were charged in a nitrogen atmosphere. The solution was cooled to ^-10 ° C and a mixture of 1.02 kg (7.395 mol) N-methylformanilide, 816 g (7.98 mol) of n-butyl vinyl ether and 360 ml of acetonitrile for 2.5 hours at a rate at which bit or no solvent and / or reactant did not fall to the bottom of the filled refrigerant of the condenser (the temperature of which was maintained in the range of -25 to ^-20 ° C) at a reaction temperature of -10 to ^-5 ° C with gentle reflux for. The resulting homogeneous orange reaction mixture was slowly heated to 20 ^° C for 30 minutes, the weak heat generation accompanying the reaction heated the reaction mixture to 28 ^° C for 30 minutes. The reaction mixture was stirred at 28-30 ^about 1 hour and received a brown homogeneous mixture, which was cooled to 0 ^about C.

Stage (iii). A solution of 948 g (8.94 mol) of anhydrous sodium carbonate in 4.20 l of water for 45-60 min, maintaining the temperature at 8-10 ^{° C,} the addition initially accompanied by active heat release. 3.60 liters of toluene was added and the mixture was stirred at 20-22 ^{° C} for 15 minutes and allowed to stand for 15 minutes for separation into two phases. The organic phase was separated and washed twice with 360 ml portions of water. Was removed by distillation perhaps more toluene at 20-80 mm Hg and 60-90 ^{° C,} the residual oil is heated at 20-80 mm Hg and 89-90 ^{° C} for 30 minutes to give a product with a purity of 89.1% as an oil ( 1.16 kg: 86.6% yield of pure product boiling point of 244 ^{° C} (decomposes) of pure product mp 46-47 ^{° C} from ethyl izopropanolgeksan 1: 1).

 PRI me R 7. (E) -3- [3 '- (4 "fluorophenyl) -1' - (1" methylethyl) -1H-indol-2'-yl] -prop-2-enal .

(i) In a 5 L four-necked round-bottom flask equipped with a stirrer, condenser, thermometer, additional funnel and cooling bath, 400 ml of dry acetonitrile and 174.4 g (1.14 mol) of chloroxy phosphorus were charged under a nitrogen layer, the mixture was cooled to -5 ^o C and a solution of 184 g (0.96 mol) 3- (N- methyl-N-phenylamino) -akroleina 83.5% purity (prepared according to examples 6-8) 156 ml of dry acetonitrile for 45 min, maintaining a temperature of -5 to 5 ^C. The reaction mixture was stirred in the temperature range of from 0 ^to 5 ° C for 10 min.

(ii) 115,2 g (0.45 mol) of 3- (4'-fluorophenyl) -1- (1'-methylethyl) - 1H-indole was added over 20 minutes while maintaining the temperature at about 5 ° ^C. The reaction mixture was heated refluxed at 83 ^C. 9 hours and cooled to 10 ° ^C.

(iii) A solution of 229 g (5.7 mol) of sodium hydroxide in 2.0 L of water was added slowly over 30 minutes keeping the temperature 25-30 ^{° C,} adding a strong exothermic reaction was. 1.6 L of toluene was added, and the mixture was stirred at ²⁵ ° C for 30 minutes and filtered through a pad filtered. The filter residue was washed with 100 ml of toluene and the washing liquid was combined with the previous filtrate. The organic layer was separated and a mixture of 93.4 g of concentrated hydrochloric acid and 2 L of water was added, followed by the addition of a saturated solution of sodium chloride. The mixture was stirred at 25 ° C. ^for 30 minutes and the resulting suspension was filtered through a filter layer. The products on the filter were washed with 100 ml of toluene and the washing liquid was combined with the filtrate. The organic layer was separated, washed twice with 2 L portions of deionized water and filtered through a filter pad. Was removed by distillation perhaps more toluene at 30-50 ml Hg and an external temperature of 60-65 ^{° C} to give a thick, amenable to mixing oil. Was added 100 ml of ethanol (95%) by distillation at 30-80 mm Hg and a temperature of 60-65 ^{° C} was removed perhaps more ethanol and the process repeated twice. Was added 180 mL of 95% ethanol and the mixture was refluxed at 78 ° ^for 15 min and slowly cooled to 20 min for 2 hours. The crystallization starts at about 55 ^C. The slurry was slowly cooled to 0-5 ^{° C} for 30 minutes, maintained at 0-2 ^{° C} for 1 hour and filtered. The residue on the filter was washed three times with 50 mL portions of chilled (0-5 ° ^C) 95% ethanol and dried in vacuo at 60-65 ^{° C} for 16 hours until constant weight to yield product purity of 98.7% (101 g, yield 71.3% boiling point 127-128 ^about C).

 In an embodiment, isopropanol was used instead of 95% ethanol.

 PRI me R 8. (E) -3- [3 '- (4 "-fluorophenyl) -1' - (1" -methylethyl) - 1H-indol-2'-yl] -prop-2-enal .

i) In a 5 L four-necked round-bottom flask equipped with a stirrer, condenser, thermometer, additional funnel and cooling bath, 263 ml of dry acetonitrile and 454 g (2.96 mol) of phosphorus oxychloride were charged under a dry nitrogen layer, the mixture was cooled to -5 ^о С and a solution of 471.6 g (2.49 mol) of 85.5% purity of 3- (N-methyl-N-phenylamino) -acrolein in 406 ml of dry acetonitrile was added over 45 minutes, maintaining the temperature at 5-7 ^о С . The reaction mixture was stirred at 5-7 ^C for 10 min.

ii) 300 g (1.18 mol) of 3- (4'-fluorophenyl) -1- (1'-methylethyl) -1H-indole was added over 10 minutes while maintaining a temperature of about 7 ° ^C. The reaction mixture was refluxed at 83 ^about 3 hours and cooled to 22 ^about C.

iii) 2.7 L of water was slowly added over 15 minutes, maintaining the temperature at 22-35 ^о С, the reaction upon the introduction of the additive is exothermic. The reaction mixture was stirred at 35-50 ° ^for 30 min, heated at 50-55 ^{° C} for 1.5 hours (a longer period of time may be required for complete hydrolysis), cooled to 22 ^{° C} and maintained at 22 ^{° C} for 15 min and filtered. The filter residue was washed three times with 600 ml portions of water and dried by suction under a vacuum pressure of 6 to 16 hours (N-methylaniline can be isolated from the combined aqueous layer and washing liquid). The wet cake was transferred to the original 5 l flask, 2.5 l of toluene was added and 180 g cellulose powder with a particle size of 20 microns and the mixture was heated at 50-55 ^{° C} for 1.5 hours, cooled to 22 ^{° C,} kept at 22 ^about C for 15 minutes and optionally filtered through salts of 91 g of silica gel with a particle size of 70-230 mesh, covered with filter cloth. Cellulose and a layer of silica gel were washed three times with 200 ml portions of toluene. Toluene filtrate and washing liquids were combined and as much as possible toluene was removed by distillation at 30-50 mm Hg and 50-65 ^о С (external temperature). 280 ml of 95% ethanol were added to the residual dense oil, ethanol was distilled off at 20-30 mm Hg and 60-65 ^о С, 280 ml of 95% ethanol were added and as much ethanol was distilled off at 30-80 mm Hg and 60-65 ^о С was added 700 mL of 95% ethanol and the mixture was refluxed at 78 ^C for 15 min and slowly cooled ^to 20 ° C for 1 h, crystallization started at 55 ^C. The resulting suspension was cooled to ^0-5 C for 30 minutes and held at 0-2 ° ^for 30 min, the solids were collected by filtration, washed three times with 120 ml portions of cold (0-5 ° ^C) 95% ethanol and Su sewed in vacuo at 60-65 ^{° C} for 16 hours to constant weight to give 99.4% pure product (276.6 g, yield 75.5% Boiling point 129-130 ° ^C).

 In an embodiment, isopropanol was used instead of 95% ethanol. It is preferable not to use a silica gel pad, i.e. the liquid containing powdered cellulose is subjected to simple filtration and the residue after it is washed with 200 ml portions of toluene.

 PRI me R 8a. (E) -3- [3 '- (4 "fluorophenyl) -1' (1" methylethyl) -1H-indol-2'-yl) prop-2-enal.

 (i) In a 1.5 L flask equipped as described in Example 8, steps (i) were charged under a layer of dry nitrogen with 170 ml of dry acetonitrile and 105.3 g of 3- (N-methyl-N-phenylamino) - hydrochloride acrolein at room temperature. 96.6 g of phosphorus oxychloride was added to the mixture over 15 minutes. Received a dark solution.

(ii) was added 90 g of 3- (4'-fluorophenyl) -1- (1'-methylethyl) -1H-indole at 30 ^C. The mixture was refluxed for 4.5 hours at 75-83 ^{° C,} then cooled up to 22 ^about C.

(iii) 250 ml water was added at ⁵ ° C followed by addition of 500 ml of water at room temperature for 15 min. The mixture was stirred at 35-50 ^{° C} for 30 min, then heated to 50-55 ^for 1.5 hours. The dark suspension was obtained. The mixture was cooled ^to 30 ° C, maintained at 30 ^{° C} for 15 min and the brown suspension is filtered. The filter cake was dried by suction under vacuum for about 4 hours. The solid was transferred to an initial 1.5 L flask, 750 ml of toluene and 54 g of pulp powder with a particle size of 20 μm were added, and subsequent processing was carried out as described in Example 8, step (iii ) and received the product (89 g, yield 81% boiling point 123-129 ^about C).

 Example 9. Sodium salt of (+) - erythro (E) -3,5-dioxo-7- [3'- (4 "fluorophenyl) -1 '- (1" methylethyl) indole -2'-yl] -hept-6-enoic acid.

 (Formula: racemic form, sodium salt form).

 Steps (a), (b) and (c): N-methylformanilide is reacted with oxalyl chloride and ethyl or n-butyl vinyl ether to form 3- (N-methyl-N-phenylamino) acrolein as described in Examples 4, 5 5a or 6 of step (i), (ii) and (iii).

Step (d): The obtained product, 3- (N-methyl-N-phenylamino) acrolein is reacted with phosphorus oxychloride as described in examples 7, 8 or 8a, step (i) to form a compound of formula XVI, in which X _a is a chlorine atom, R _12b is phenyl and R _{13 is} methyl.

Step (e): the obtained compound of formula XVI is reacted with 3- (4'-fluorophenyl) -1- (1'-methylethyl) -1H-indole as described in examples 7, 8 or 8a, step (ii) to form a compound formula XVIIIa, in which Xb represents a chlorine atom, R _12b is phenyl and R ₁₃ methyl.

 Stage (f): the obtained compound of formula XVIIIa is hydrolyzed as described in examples 7, 8 or 8a, stage (iii) to form (E) -3- [3 '- (4 "-chlorophenyl) -1' - (1" -methylethyl) -1H-indol-2'-yl] prop-2-enal.

Stage (g). Under a nitrogen atmosphere the reactor was charged with 0.5 l of tetrahydrofuran, the solution was cooled to ^-10 ° C and carefully added to 60 g of sodium hydride (60% dispersion in mineral oil). Then carefully added 237.3 g of tert-butyl ester atsetuksusnoy acid in 250 ml of tetrahydrofuran over 45 minutes while maintaining the temperature below 2 ° ^C. The resulting solution was stirred at -10-20 ^{° C} for 1 h. The mixture was cooled to ^-10 C. and 938 ml of a 1.6 M solution of n-butyllithium in hexane at a rate such that the temperature did not exceed ⁰ ° C, for about 60 minutes. The mixture was stirred for 10 minutes at this temperature, then cooled to ^-10 ° C and a solution of 230 g of the product from step (f) above in 650 ml of tetrahydrofuran at a rate such that the temperature did not exceed ⁰ ° (over about 70 min). The reaction mixture was stirred at ⁰ ° C for 15 min and poured into a mixture of 248 ml of concentrated hydrochloric acid and 2.5 kg of ice while stirring vigorously for 5-10 min. The mixture was continued to vigorously stir for another 15 minutes, the organic phase was separated, washed twice with 500 ml portions of a saturated solution of sodium chloride and concentrated under reduced pressure (about 25 mm Hg). 200 ml of toluene was added to the residue, and the solution was concentrated again. The resulting crude product, tert-butyl ether (±) - (E) -7- [3 '- (4 "fluorophenyl) -1' - (1" methylethyl) indol-2'-yl] 5-hydroxy- 3-oxohept-6-enoic acid (a compound of formula IIa in which R ₁ is tert-butyl in racemic form) (503.6 g; 70.04% purity) was used in the next step without further purification.

 Stage (h). The resulting crude product was stereo-selectively reduced as described in Example 1, steps (a), (b) and (c) to give (±) -erythro (E) -7- [3 '- (4 "- tert-butyl ester fluorophenyl) -1 '- (1 "- methylethyl) indol-2'-yl] -3,5-dioxo-hept-6-enoic acid.

Stage (i). To 42.5 g of the ester obtained in step (h) in 275 ml of tetrahydrofuran was added over 5 minutes 30 ml of 1 N. sodium hydroxide, maintaining the temperature below 10 ° ^C. The solution was stirred 1 h at room temperature, 275 ml of methanol was added, the mixture is concentrated at 25 mm Hg and 45 ^{° C,} then 300 ml of deionized water, distillation was continued until a residual volume of 140 ml, then 380 ml of deionized water were again added and the solution washed with a total of 640 ml of tert-butylethyl ether in three portions. The aqueous layer is concentrated at 25 mm Hg and 45 ^C to a volume of about 300 ml were added 220 ml of deionized water and a clear aqueous) was lyophilized during three days. The target compound was obtained (35.9 g: 91% yield: chemical purity 98.9% 99.9% purity and erythro isomer; boron concentration below the sensitivity limit of the method).

 An alternative process in step (i).

To 35.0 g of the ester obtained in step (h) above: in 175 ml of ethanol was added over 5 minutes while stirring 74 ml of 1N. sodium hydroxide solution, keeping the temperature below 12 ° ^C. The solution was stirred for one hour, the mixture is concentrated at 25 mm Hg and 45 ^{° C,} then 250 ml of deionized water, distillation is continued to a residual volume of 115 ml, was added 315 ml of deionized water and the solution washed a total of 525 ml of tert-butyl methyl ether in three portions. The aqueous layer is concentrated at 25 mm Hg and 45 ^C to a volume of 245 ml, was added 185 ml of deionized water and a clear aqueous solution is lyophilized over three days. Obtained compound of the title (29.75 g; color pure white; 91.01% yield, boiling point 204-207 ^C, with decomposition; chemical purity 100% 99.61% pure erythro isomer; boron concentration 3 96 ppm).

 PRI me R 10. Sodium salt of (±) -erythro- (E) -3,5-dioxo-7- [3 '- (4 "fluorophenyl) -1' = (1" -methylethyl) -indole -2'-yl] hept-6-enoic acid.

(Formula Ia: in racemic form; sodium salt form)
The target compound was obtained by a method similar to that described in example 9, except that:
in step (g), methyl ester was prepared by reacting with the dianion of acetic acid methyl ester instead of tert-butyl acetic acid ester;
stage (h) was carried out as described in example 2, stage (a), (b) and (c);
step (i) was carried out by hydrolysis of the methyl ester obtained in step (h) as described in US Pat. No. 4,739,073, Example 6 (b) in column 50.

Claims (8)

1. METHOD FOR PRODUCING 7-SUBSTITUTED HEPTEN-6-ACID ACID of General Formula I

in racemic or optically pure form, in the form of a free acid, salt, ester or δ-lactone, i.e. cyclic ester comprising stereospecific reduction of a racemic or optically pure compound of general formula II

where R ₁ is an ether group inert under the reaction conditions,
characterized in that in the first stage the compound of the general formula III is mixed

where R ₂ is allyl or lower C ₁ - C ₄ alkyl;
R ₃ - primary or secondary C ₂ - C ₄ -alkyl,
with sodium borohydride (NaBH ₄ ) in a reaction medium containing alcohol or tetrahydrofuran, in a second step, a compound of formula II is treated with the mixture obtained in the first step under conditions suitable for preparing a mixture containing a cyclic compound of general formula IV

and / or a boron complex of the general formula IV a

where R ₄ - [3- (4′-fluorophenyl) -1- (1′-methylethyl) -1H-indole] -2-yl;
X is a group —CH = CH—;
R ₃ has the indicated meanings
in the third step, the product obtained in the second step is cleaved to obtain a compound of formula I in the form of an ester in racemic or optical pure form and, if desired, the compound of formula I in the form of an ester is converted into a free acid form, into a salt form, into another form of ester or δ-lactone, i.e. in the form of a cyclic ester by conventional means.  2. The method according to claim 1, characterized in that the compound of formula I is obtained in racemic form.  3. The method according to claim 1, characterized in that the compound of formula I is obtained in the [3R, 5S] enantiomeric form.  4. The method according to claim 1, characterized in that the compound of formula I is obtained in the form of a sodium salt.  5. The method according to claim 1, characterized in that the compound of formula I is obtained in a state of optical purity, in which the ratio of erythro and threisomers is 99.1: 0.1 or higher. 6. 7-Substituted hepten-6-oic acid of General formula I

in the form of a free acid, salt, ester or δ-lactone, in a state of optical purity in which the ratio of erythroisomer and threisomer is 99.1: 0.9 or higher.  7. The compound according to claim 6, characterized in that the ratio of the erythro- and threoisomer is 99.5: 0.5.  8. The compound according to claim 6, characterized in that the ratio of the erythro- and threoisomers is 99.7: 0.3.