DE1190450B - Process for the production of hydroxyaldehydes or their cyclohemiacetals, their esters and ethers - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

Int. Cl .:

C 07 c

GERMAN

PATENT OFFICE

EDITORIAL

German KL: 12 ο - 7/03

Number: 1190 450

File number: C 26596 IV b / 12 ο

Filing date: March 27, 1962

Opening day: April 8, 1965

A simple access route to γ- and o-hydroxyaldehydes or their cyclohemiacetals consists in the reduction of the corresponding lactones. The reaction has become particularly important for the synthesis of natural substances. For example, an important step in the industrial production of the physiologically highly effective mineralocorticoid aldosterone is the partial hydrogenation of a γ-lactone group to the cyclohemiacetal stage.

For the reduction of lactones to the corresponding cyclohemiacetals are so far only complex metal hydrides such as lithium aluminum hydride or lithium borohydride are used been. It has been shown that the success of the implementation occasionally depends on structural factors is dependent. Reasonably satisfactory results will only be obtained if there is a neighboring one functional group achieved to enter into an additional bond with the metal hydride anion able. In addition, the reducing agent must be used carefully to prevent further reduction be dosed. The adjacent functional group can e.g. B. from a hydroxy group or a simultaneously reacting acyloxy group or oxo group. The possibility is missing the intramolecular formation of a bifunctional hydride complex, the reaction remains not at the level of the hydroxyaldehyde cyclohemiacetal stand, but leads to the corresponding diol. So z. B. the transfer of I into II and the conversion of III to IV important in the production of aldosterone, however, resulted in the reduction of V, in which no adjacent, for the formation of the above-mentioned intramolecular metal process for the production of hydroxyaldehydes or their cyclohemiacetals, their esters and ethers

Applicant:

CIBA Aktiengesellschaft, Basel (Switzerland)

Representative:

Dipl.-Chem. Dr. rer. nat. B. Redies, Dr.-Ing. Dr. jur. F. Redies and Dr. D. Turk, Patent Attorneys, Opladen, Rennbaumstr. 27

Named as inventor:

Dr. Albert Wettstein, Riehen; Dr. Julius Schmidlin, Basel (Switzerland)

Claimed priority:

Switzerland of March 30, 1961 (3799)

complex capable functional group is present, practically only the 11 / 3,18-diol VI.

OH

CH ₃
C = O

LiAlH ₄ .

CH ₃ CHOH

II

509 538/448

O CH ₂ - OH

OH CH ₂ - OH

LiAlH ₄ .

OH CH ₃

_J

LiAlH _4th

According to the invention, however, saturated or unsaturated lactones can be partially reduced to the corresponding hydroxyaldehydes or their cyclohemiacetals, irrespective of the presence of sterically favorable substituents, without careful dosing of the reducing agent being necessary ; Rather, the reducing agent can be used in excess.

The invention relates to a process for the preparation of hydroxyaldehydes or their cyclo hemiacetals, their esters and ethers by reducing the lactones of the corresponding hydroxycarboxylic acids and optionally esterifying or etherifying the reaction product. The method is characterized in that aluminum hydrides with dialkyl or these equivalent AIu- miniumtrialkylen at temperatures of - 70 to + 20 ⁰ C is reduced, the resulting aluminum salt with water, alcohols or acids solvolysis, or with an acylating agent or an alkylating medium converts and isolates the cyclohemiacetals obtained, their esters or ethers in a manner known per se.

The selective, partial reduction with the hydrides mentioned is surprising since, for example, the dialkyl aluminum hydrides have hitherto been regarded as reducing agents equivalent to the alkali aluminum hydrides. Another unexpected fact is that γ-lactones, which are split directly into the metal salts of the corresponding diols with sodium borohydride, ie with a hydride which is inferior to lithium aluminum hydride in terms of reducing power, but only with dialkylaluminum hydrides or these equivalent aluminum trialkyls can be reduced to the hemiacetal level. The method is therefore a significant enrichment of the technology, in that many reductions can now be carried out that could not or only poorly be achieved according to the old method. But even in cases in which the complex hydrides had previously been used and in which reduction to hydroxyaldehyde was possible, the more selective mode of action of the reducing agents according to the invention is expressed in a marked increase in the yields.

The solvents used for carrying out the process of the invention are primarily aromatic, aliphatic or araliphatic hydrocarbons into consideration. Otherwise are generally suitable liquid substances that have a solvent capacity for the respective reducing agent with the same but do not react like open or cyclic ethers, e.g. B. diethyl ether, tetrahydrofuran or Dioxane, and amines such as tripropylamine or pyridine. The cleavage of the addition products that are primarily formed leads to depending on the nature of the selected By means of either the free hydroxyaldehydes or their cyclohemiacetals, their esters and Ethers.

In general, saturated and unsaturated lactones, in particular, are used as starting materials for the purposes of the invention Five-ring and six-ring lactones, use e.g. B. those of the aliphatic, cycloaliphatic, aromatic, araliphatic and heterocyclic series, especially the steroid series. The specific starting materials of the steroid series are lactones from saturated or unsaturated hydroxycarboxylic acids the pregnane and androstane series, e.g. B. 18, ll /? - Lactones of llß-hydroxy-pregnan- or -androstane-18-acids, 19,6 / 3-lactones of 6/3-hydroxypregnan- or -androstane-19-acids, 19, ll /? - lactones of 11/3 hydroxy-pregnanoic or -androstanoic acids and 18.20a- and 18.20 / i-lactones of 20a- or β-hydroxy-pregnane-18-acids; also the 20,18-lactones of saturated and unsaturated 18-hydroxyethic acids and the saturated or unsaturated Cardanolide or bufanolide. Carbon-carbon double bonds, also conjugated, become generally not attacked during the reduction.

Any ketone and aldehyde groups present can, if desired, before the reduction after per se known methods, for example by acetalization, are protected.

As starting materials from the above-mentioned classes of non-steroidal lactones, z. B. called: butyrolactone, valerolactone, angelicalactone, O-hydroxymethyl-benzoic acid lactone (phthalide), O-coumaric acid lactone (coumarin), reserp acid lactone. Deserpidic acid lactone, meconin, pilocarpine and other alkaloid lactones.

The products of the process are compounds with valuable biological properties or intermediate products for their production. Various new substances can also be produced by using the process. What is new, for example, is the 18,11 / i-cyclohemiacetal of 3,20-bisäthylenedioxy, which is easily accessible from the 18,11 / i-lactone of 3,20-bisäthylenedioxy-II /? - hydroxy-J ^{5 -pregnen-18-acid} -1 l / J-hydroxy-18-oxo-J ⁵ -pregnens; after cleavage of the ketal groups in the 3- and 20-positions, it can be obtained by biochemical hydroxylation, for. B. by means of fungi of the genus Wojnowicia graminis can be converted into the genuine mineral metabolism hormone aldosterone in a single process step. This reduction of the lactone mentioned produces a mixture of the stereoisomeric cyclohemiacetals at the newly formed asymmetric center C-18, which can easily be separated due to their different physical properties. The cyclohemiacetal diketal, which has the configuration of aldosterone at C-18, does not undergo any rearrangement during acid hydrolysis of the ketal groups, while the 18-iso compound is simultaneously epimerized in the 18-position during this treatment. As a result, both 18-epimeric cyclohemiacetal diketals can be converted into aldosterone in the same way. The separation of the mixture of epimers obtained during the reduction is therefore unnecessary for the stated purpose.

The present method differs significantly from similar ones already in the literature known methods for the reduction of lactones and points to these also completely significant advantages. As already mentioned, the reduction with complex light metal hydrides, in particular lithium aluminum hydride is well known (see Journal of the American Chemical Society, 75, 1953, pp. 2413-2415; British patent specification 701 220). however, one could use the reduction only up to the hydroxyaldehyde or cyclohemiacetal stage only with precisely dosed amounts of complex Perform aluminum hydride, which makes the technical handling of the method considerably more difficult and you mostly mixtures of hydroxyaldehyde and the corresponding dialcohol is obtained. With the dialkyl aluminum hydrides the present invention is also effective when working with an excess of reducing agent only the hydroxyaldehyde or its hemiacetal obtained. Although from the Journal of the American Chemical Society, 83, p. 486 (1961), known that one can reduce lactones to the corresponding hydroxyaldehydes can use boranes, but assign these compared to here using aluminum hydrides have certain disadvantages, especially when working up the reduction mixture, in which there is hydrogen peroxide must be used, while here a mild solvolysis is sufficient and the fact that borane -C = C double bonds with formation of addition products attack, which does not happen with the dialkyl aluminum hydrides. The dialkyl aluminum hydrides of the present invention are already used for the reduction of lactones (see British patent specification 803 178), however the specific form claimed here is the Reduction at lower temperatures, with the with it

ίο associated unexpected and technically significant result of their completely uniform course with formation of the hydroxyaldehydes not yet realized there.
The invention is illustrated by the following examples. The analogous transfer to other cases is evident from this. The temperatures are given in degrees Celsius.

example 1

215.2 mg of 18.1IjS-LaCtOn of 3.3: 20.20-bisäthylendioxy-II / i-hydroxy-J ⁵ -pregnen-18-acid are poured over 15 ml of dry toluene in a pure nitrogen atmosphere and the suspension is poured over with strict exclusion of moisture and stirring at 20 ° 10 ml of a 0.1 molar solution of diisobutylaluminum hydride in toluene were added dropwise over the course of 15 minutes. After the addition is complete, the resulting clear solution is stirred for a further 45 minutes at 20 °, the organoaluminum compound is then broken down while cooling in an ice-water mixture by shaking with 0.2 ml of water and 0.5 g of kieselguhr for 15 minutes and the toluene solution is filtered after drying with 2 g of sodium sulfate through a sintered glass funnel. The bare filtrate is evaporated on a high vacuum pump, the amorphous residue is taken up in tetrahydrofuran and ether and the solution is again evaporated in vacuo to remove the remaining toluene. The crude product crystallizes from ether. Is obtained as a top fraction 105.2 mg of pure lS.ll ^ -Cyclohemiacetal of 3.3; 20,20-Bisäthylendioxy ^{LJS-1-hydroxy-18-oxo-5} J -pregnens from

170 to 172.5 degrees.

The mother liquor residue (100.9 mg) is dissolved in 4.0 ml of tetrahydrofuran and applied to forty sheets of Whatman No. 1 paper (format: 18.5 x 45 cm; washed with chloroform and methanol). The two zones with Rf values 0.16 to 0.28 and 0.30 to 0.44 are eluted from the chromatogram running down to 38 ° in solvent system A according to B ush, each separately, with 20% and 50% aqueous and 100% tetrahydrofuran and evaporated the extracts in vacuo. The dry residue of the lower zone, which is distributed over a large surface, is extracted with a total of 25 ml of benzene, the collected extract is strongly concentrated in vacuo, filtered through 25 mg of activated charcoal and the filtrate is evaporated. The residue from tetrahydrofuran ether gives 16.45 mg of the IS-cyclohemiacetal obtained as the main product of sJ ^ O ^ O-bisäthylenedioxy-lljS-hydroxy-IS-oxo-J ⁵ -pregnens with a temperature of 170.0 to 172.5 °. 24.30 mg of the 18-epimeric 18, 11 ^ -Cyclohemiacetals des

3.3; 20.20 - Bisäthylenedioxy - 11/3 - hydroxy - 18 - oxo-J ⁵ -pregnens from the F. 124.5 to 129.0 ° / 154.5 to 162.0 °.

The raw material used is produced in a manner that is not claimed, for example as follows:

1.933 g of 18.11 / S-lactone der3,20-dioxo-l 1/3-hydroxypregnene-18-acid are dissolved in 365 ml of a 0.002 molar solution of p-toluenesulfonic acid monohydrate in ethylene glycol by heating to 85 to 90 ° and about 300 ml of ethylene glycol was distilled off on the high vacuum pump in the course of 3 hours. After cooling, the suspension obtained is poured into a mixture of 20 ml of 0.5N sodium hydrogen carbonate, 100 g of ice and 80 ml of water, rinsing with 40 ml of 0.2 N sodium hydrogen carbonate and 100 ml of methylene chloride, and immediately shaken well. The lower layer is then separated off and the aqueous phase is extracted a further six times with 50 ml of methylene chloride each time. All the extracts are washed in sequence with water and then dried with sodium sulfate. The solution filtered off from the desiccant is first evaporated to a residual volume of about 10 ml and the remaining methylene chloride is then displaced by distilling off the ether added in portions. 1.900 g of 18.11 / S-lactone of 3,3; 20,20-bisäthylenedioxyl / 9-hydroxy-zl ⁵ -pregnen-18-acid with a melting point of 235 to 240 ° crystallize from a final volume of about 20 ml within one hour the end.

Example 2

A solution of 186.2 mg of 18.11 / S-lactone of 3,3-ÄthyIendioxy-20 / S-hydroxy- / I ⁵ -pregnen-18-acid in 45 ml of anhydrous toluene is cooled to -70 ° with exclusion of moisture and 5.0 ml of a 0.5 molar solution of diisobutylaluminum hydride in toluene were added dropwise within 15 minutes with stirring. After the reaction mixture has been stirred for a further 20 minutes at -70 °, the excess reducing agent is destroyed at -70 ° by slowly adding 10 ml of an isopropanol 1 molar mixture of anhydrous isopropanol and toluene and then shaking at 0 ° for 5 minutes 0.25 ml of water. 0.5 g of kieselguhr is then added, the mixture is dried with sodium sulfate and the inorganic components are filtered off from the toluene solution. The pure filtrate is evaporated in vacuo and the solid residue, which has been completely freed from toluene in a high vacuum, is recrystallized from ether using tetrahydrofuran as a solubilizer. A total of 150.0 mg of pure 18.20 / 3-cyclohemiacetal of 3,3-ethylenedioxy-18-oxo-20 / S-hydroxy- Δ ⁵ - pregnens with a melting point of 188.0 ° to 192.0 ° is obtained.

The starting material used can, for example, according to the method of the Belgian patent 587 496 dated August 11, 1960.

Example 3

A solution of 135 mg of o-hydroxymethylbenzoic acid lactone in 25 ml of anhydrous toluene is added, after cooling to -70 °, within 30 minutes with 2.5 ml of a 1 molar solution of diisobutylaluminum hydride in toluene. After completion of the addition, the reaction mixture is first stirred for a further 3 ¹ Iz hours at -70 °, the excess hydride then at -70 ° by dropwise addition of 0.60 mL of isopropanol in 6.9 ml of toluene and then destroyed at 0 ° by persistent shaking with 0.25 ml of water hydrolyzed. The resulting suspension is stirred with 0.25 g of kieselguhr, dried with 1.5 g of sodium sulfate and filtered.

The pure solution is evaporated and the residue, dissolved in benzene, is chromatographed on 5 g of silica gel. The fractions detached with benzene / ethyl acetate (1: 1) and ethyl acetate are obtained pure hydroxyphthalane (phthalanol) as a colorless oil by distillation in a high vacuum, yield 80%.

Example 4

To a suspension prepared in a dry nitrogen atmosphere of 1.076 g of the 18,11 / S-lactone of 3,3; 20,20-bisäthylenedioxy-II / 3-hydroxy-ZJ ⁵ -pregnen-18-acid in 112, 5 ml of anhydrous toluene are added at -20 to ^{-25 ° C.} in the course of 15 minutes, 12.5 ml of a 1 molar solution of diisobutylaluminum hydride in toluene, and the batch is then stirred for a further 1% hour at -20 °. 25 ml of a 2 molar solution of isopropanol in toluene are then added dropwise over the course of 15 minutes, the reaction mixture is then shaken with 2.5 ml of water at 0 to 3 ° for 15 minutes, then with 1.25 g of kieselguhr while thawing to room temperature, and the mixture is filtered resulting suspension after drying with 5 g of sodium sulfate through a sintered glass funnel. The filtrate is evaporated in vacuo and the residue is recrystallized from ether using tetrahydrofuran as a solubilizer. The first fraction obtained is 870 mg of 18.1 lβ - cyclohemiacetal des 3,3; 20.20 - bisäthylendioxy- 1 l / 3-hydroxy-18-oxo-zl ⁵ -pregnens with a temperature of 183 ° to 187 ° and as the second fraction another 41 mg of the same compound with a melting point of 179 ° to 186 °, corresponding to 84% of theory.

Example 5

21.25 mg 18.1 l / S-lactone of the 3,3; 20,20-bisäthylenedioxy - 1 Iß - hydroxy - A ⁵ - 17 - isopregnene - 18 - acid are poured over with 2.5 ml of anhydrous toluene and in a nitrogen atmosphere adds 0.50 ml of a 0.5 molar solution of diisobutylaluminum hydride in toluene at -20 to -25 ° within 6 minutes.

After the batch has been stirred for a further 20 minutes, the excess hydride is destroyed at -20 ° with 0.50 ml of a 2 molar solution of isopropanol in anhydrous toluene, the reaction mixture then after dilution with 1.5 ml of toluene at 0 to 3 ° Shaken for 15 minutes with 0.050 ml of water, then 1 ml of ethyl acetate and 50 mg of kieselguhr were added and the suspension was thawed to room temperature with 100 mg of sodium sulfate. The solid components are then filtered off while rinsing with a total of 8 ml of ethyl acetate-toluene (4: 1) mixture and the pure filtrate is evaporated in vacuo. The residue that remains is a viscous oil (21.5 mg) and, as the content determination by paper chromatography in the formamide / cyclohexane and Bush A systems shows, at least 90% of theory contains the 18.1 l / S-cyclohemiacetal des 3.3; 20 , 20-Bisäthylendioxy-11/3-hydroxy-18-oxo-zl ⁵ -17-isopregnens.

The raw material used can be produced in a manner not claimed as follows:

A solution of 967.5 mg 18, ll (8-lactone of 3,3-ethylenedioxy-1β-hydroxy-20-oxo / l ⁵ -pregnen-18-acid with a melting point of 239 ° to 241 ° in 1250 ml , 01 molar

Solution of p-toluoisulfonic acid dihydrate in benzene is, after adding 1.25 ml of water, heated in a bath at 80 to 85 ° for 48 hours with stirring. The reaction solution is then cooled to 25 °, shaken out with 0.5N sodium hydrogen carbonate and water, the organic phase is dried with sodium sulfate and evaporated in vacuo. The amorphous crude product (914 mg) is dissolved in 30 ml of tetrahydrofuran and chromatographed in descending order on three hundred sheets of Whatman paper No. 1 [format: 18.5-45 cm] in the formamide / cyclohexane-benzene (1: 2) system. From the bottom up spilled, and then dried in air chromatogram is deposited, the UV-absorbing zone of the Rf value from 0.60 to 0.75, the paper eluted with 1800 ml of 20 ° / ₀ sodium and 600 ml of 40% aqueous Tetrahydrofuran, evaporates the extract in vacuo to a volume of about 20 ml and shakes the resulting aqueous residue exhaustively with benzene. The collected benzene extract, washed with a little water, is dried with sodium sulfate, concentrated in vacuo to a volume of about 25 ml and the solution is completely evaporated after being decolorized on 250 mg of activated charcoal. By recrystallizing the eluate from ether, using tetrahydrofuran as a solubilizer, 406.3 mg of pure 18.110-lactone of 3.20-dioxo-11 /? - hydroxy-J ⁴ -17-isopregnen-18-acid with a melting point of 174 to 176 °.

342.4 mg of the 17-iso-compound described above are dissolved with exclusion of moisture and stirring at 80 ° bath temperature in 50 ml of 0.002 molar solution of p-toluenesulfonic acid dihydrate in ethylene glycol and a total of 40 ml of glycol is then distilled off in the vacuum of the ulrotation pump over the course of 2 hours. The cooled reaction mixture is made alkaline with 5 ml of 0.5 N sodium hydrogen carbonate and, after pouring onto 20 g of crushed ice, the diketal is shaken out with methylene chloride while rinsing with 15 ml of 0.1 N sodium hydrogen carbonate. The extracts washed with water are combined, dried with sodium sulfate and evaporated. From the residue is obtained by crystallization from tetrahydrofuran ether as a top fraction 351 mg 18.11 ^ -lactone of 3.3; 20.20 - bisäthylenedioxy-1 Iß - hydroxy ^{- I 5} -17 - isopregnene-18-acid from F. 190.5 to 196 ° and from the concentrated mother liquor completely freed from tetrahydrofuran a further 41.5 mg of the same compound with a melting point of 189.5 to 196 °.

5 °

Example 6

A solution of 3.70 mg reserp acid lactone in 2.25 ml, prepared in a dry nitrogen atmosphere anhydrous tetrahydrofuran is "cooled to -65 to -70 ° with strict exclusion of moisture and after adding 0.25 ml of a molar solution of diisobutylaluminum hydride in toluene Stirred for 4 hours at this temperature. The excess hydride is then destroyed at -65 to -70 ° with 0.50 ml of a 2 molar solution of isopropanol in tetrahydrofuran, stir more 15 minutes and then add 0.50 ml of a reaction mixture, which has then been thawed to -20 to -15 ° 2.5 molar solution of water in tetrahydrofuran too. After adding 25 mg of purified kieselguhr The reaction mixture is then up to 0 to 3 ° 45 minutes Shaken vigorously, the suspension then rinsing with a total of 2.5 ml of toluene-tetrahydrofuran mixture (1: 9) filtered through a sintered glass suction filter and the filtrate evaporated in vacuo. The residue (4.0 mg) is a yellowish oil, which after moistening with ether on standing gradually crystallized. Like the analysis in the thin-layer chromatogram in the systems n-propanol, ethyl acetate, water (7: 1: 2) and t-amyl alcohol - Isopropanol - water (10: 4: 1) shows, the yield of reserpaldehyde cyclohemiacetal is at least 80% of theory.

Example 7

A solution of 16 g of diisobutylaluminum hydride presented with exclusion of moisture in a pure nitrogen atmosphere in 100 ml of ether is left at -70 ° with stirring for 15 minutes an anhydrous solution of 5.00 g of y-valerolactone in 25 ml of ether flow in. After a further 15 minutes, the excess hydride is slowly removed Inlet of 125 ml of water-saturated ether at -70 ° destroyed and the reaction mixture then using nitrogen in the course of 30 minutes, rinsing with a total of 50 ml of ether, to 125 ml ice-cold 2 molar potassium sodium tartrate solution, being cooled from the outside with ice and is stirred quickly. This creates a gelatinous paste that can just be stirred, which at 0 to 3 ° with Transfer 75 ml of 2 molar potassium sodium tartrate, 50 ml of water and 125 ml of ether into a separatory funnel will. After brief shaking at 0 to 3 °, the contents separate into two layers. The lower one, Aqueous phase is exhaustively extracted ice-cold with ether and the extracts, as before, the separated upper phase in a further separating funnel washed with 25 ml of 2 molar potassium sodium tartrate solution. The combined ethereal solution delivers after drying with sodium sulfate and distilling off the ether on a Vigreux column of 25 cm rise in an initially still ethereal concentrate of practically pure γ-hydroxy-valeraldehyde, This, as the gas chromatographic analysis shows, is less based on the γ-valerolactone used contains less than 0.1% unchanged starting material and less than 3% pentane-1,4-diol. From the The crude product is obtained by distillation in a water jet vacuum, with good cooling of the Templates, 4.41 g of pure γ-hydroxy-valeraldehyde (86% of theory), which boils between 65 and 66 ° at 12 mm.

Example 8

To one in a dry nitrogen atmosphere

- 70 ° cooled solution of 3.75 mg digitoxigenin 0.125 ml of about 1 molar is added to 1.125 ml of anhydrous tetrahydrofuran over the course of 10 minutes Diisobutylaluminum hydride in toluene. After stirring for 8 hours at -70 °, the excess hydride becomes by carefully adding 0.25 ml of a 2.5 molar mixture of water and tetrahydrofuran destroyed, the whole thing then for another 45 minutes

- Stirred 70 °, then with 7.5 ml of ice-cold 0.2 molar Potassium sodium tartrate is added and extracted at 0 to 3 ° with methylene chloride-ether (1: 2). The extracts washed with 2 molar potassium sodium tartrate and water are combined with sodium sulfate dried, filtered and evaporated in vacuo. From the residue one obtains by conversion

S09 538/448

crystallize from ether — isopropyl ether 3.0 mg des the cyclohemiacetal corresponding to the lactone used, having a melting point of 77 to 88.5 °.

Example 9

One cooled to -70 ° in a dry nitrogen atmosphere presented solution of 7.65 mg digitoxin in 2.25 ml tetrahydrofuran is set within 15 minutes 0.25 ml about 1 molar Diisobutylaluminum hydride in toluene. After constant stirring at -70 °, it is decomposed Reaction mixture at -70 ° by carefully adding 0.50 ml of a 7.5 molar solution of Water in tetrahydrofuran, first stirred for another 45 minutes at -70 °, then added 6.25 ml ice-cold water is added and the organic solvents are removed at 0 ° in a water-jet vacuum. On that the aqueous suspension to which 705 mg of potassium sodium tartrate is added is shaken at 0 ° Methylene chloride. The methylene chloride extracts are washed twice with 0.5 molar potassium sodium tartrate washed, dried with sodium sulfate and evaporated. The residue represents the starting material corresponding cyclohemiacetal; shows a sample of the substance dissolved in methylene chloride no more lactone CO absorption. By recrystallizing the crude product from ether, under Using tetrahydrofuran as a solubilizer, 5.55 mg of colorless, small ones are obtained Druze from 203 to 212.5 °.

Example 10

7.67 mg of 20,22-dihydro-digitoxin with a temperature of 248 to 252 ° in 2.25 ml of anhydrous tetrahydrofuran are reduced in a dry nitrogen atmosphere at -70 ° with 0.25 ml of about 1 molar diisobutylaluminum hydride in toluene. After ^{stirring for 5 3/4} hours, the reaction mixture is hydrolyzed and worked up by extraction, as detailed in the preceding Example 10. From the solid crude product is obtained by recrystallization from ether, using tetrahydrofuran as a solubilizer, 5.75 mg of small, colorless drusen of the cyclohemiacetal corresponding to the starting material

F. 209 to 210 °. A sample of the reduction product thus obtained, dissolved in methylene chloride, has no carbonyl absorption in the region of 5.5 to 6.0 μ.

Claims (3)

Patent claims: 1. A process for the preparation of hydroxyaldehydes or their cyclohemiacetals, their esters and ethers by reducing the lactones of the corresponding hydroxycarboxylic acids and optionally esterifying or etherifying the reaction product, characterized in that one with dialkylaluminum hydrides or these equivalent aluminum trialkyls at temperatures from -70 to +20 ⁰ C, the resulting aluminum salt is solvolyzed with water, alcohols or acids or reacted with an acylating agent or an alkylating agent and the resulting cyclohemiacetals, their esters or ethers are isolated in a manner known per se. 2. The method according to claim 1, characterized in that with diisobutylaluminum hydride reduced. 3. Process according to claims 1 and 2, characterized in that y-valerolactone, the 18.11 /? - lactone of the 3,3; 20,20-bisäthylendioxy -1 Iß - hydroxy - J ⁵ - pregnen -18 - acid or the 18.20 / 3 - lactone of 3,3 - ethylenedioxy-20 | S - hydroxy - Δ ⁵ - pregnen -18 - acid, ο - hydroxymethyl-benzoic acid lactone and reserp acid lactone. Considered publications: British Patent Nos. 701 220, 803 178; Angewandte Chemie, 67, 1955, p. 424; Journal of Organic Chemistry, 24, 1959, pp. 627 to 630; Journal of the American Chemical Society, 75, 1953, pp. 2413-2415, and 83, 1961, p. 486; Helvetica Chimica Acta, 38, 1955, pp. 1423 to 1437; H. Zeiss, Organometallic Chemistry, 1960, pp. 215-231. 509 538M48 3.65 Bundesdruckerei Berlin