DE2325806A1 - METHOD OF MANUFACTURING DELTA HIGH 16 -STEROID-14BETA, 18, 20-TRIOLS AND -14BETA, 20-DIOL-18-ALEN OF THE PREGNAN SERIES - Google Patents

Description

CIBA-GEIGY AG BASEL (SWITZERLAND)

Case64-82O5 '. -

Germany

Process for the production of Δ -Steroid-14ßjl8,20-

triplets and 14β, 20-diol-18-alene of the pregnane series

The present invention relates to a process for the "production of Δ -steroid-14β ₃ 18; 20-triplets and Δ-steroid-14βj20-diol-18-alene of the pregnane series and their esters and ethers, the 17-pregnane side chain of which is one of the two has the following partial formulas:

- ι

II

20 S configuration 20 E configuration

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wherein R is a free, esterified or etherified hydroxyl group represents, from Δ -Steroid-l ^ ß ^ lS-diol-aO-ones of the Pregraan series, in which the 1 ^, 18-diol group is ketalized with a ketone.

The method can be used for the synthesis of pregnane derivatives serve, which the above-mentioned side chain in 17rPosition and which have pharmacologically interesting effects, including in particular the alkaloids of the batrachotoxin and batrachotoxin A group.

Among the mentioned pregnan derivatives according to the present Invention are both compounds of the 5a as well as the 5ß-pregnane series to be understood like their descendants, which have a double bond starting from the 5-position.

Particularly noteworthy are the process products of the following formula

III

in which P one of the above partial formulas I or IT is assigned, R is a free or protected oxo group or a free, esterified or etherified hydroxyl group together with a

Hydrogen atom, R two hydrogen atoms or one hydrogen atom in addition to a 7,8 double bond, a protected oxo group or a

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Hydrogen atom together with a free esterified or etherified hydroxyl group, R ^ two hydrogen atoms or a hydrogen atom next to a 9,11 double bond or a free or protected oxo group or a free, esterified or etherified hydroxyl group together with a hydrogen atom, R ^ a Hydrogen atom or a free, esterified or etherified hydroxy group and R ₁ together with R ^ a 3-hydroxy-3,9 ~ oxido group or such a group with an etherified or esterified 3-hydroxy group

and Z and Z_ each represent a free, esterified or etherified hydroxyl group and Z, and Z "together represent a ketalized 14,18-diol group and Z-. but also represent an oxo group, and in which in.einer of the 4,5- or 5,6-positions and / or optionally in the case that Ep or R ^ is a hydrogen atom, also in one of the 7,8- and / or S ₃ 11-position double bonds may be present.

The esterified hydroxy groups mentioned are preferably derived from organic carboxylic acids of the aliphatic, alieyclisehen ₃ aromatic or heterocyclic series, in particular on those with 1-18 carbon atoms, for example from lower aliphatic carboxylic acids having 1-6 C atoms, for example formic acid, acetic acid, propionic acid, of butyric acids, valeric acids, such as n-valeric acid, or trimethyl acetic acid., trifluoroacetic acid, of caproic acids, such as β-trimethyl propionic acid or diethylene acetic acid or of enanthic, caprylic, ₃ feiargonic, capric, undecylic acids, for example undecylenic acid, lauric acid -3 myristic, palmitic or stearic acids, for example oleic acid, cyclopropane, butane, pentane and hexane carboxylic acid, cyclopropyl methane carboxylic acid, cyclobutyl methane carboxylic acid, cyelopentyl ethane carboxylic acid, cyclohexyl ethane carboxylic acid, cyclohexyl ethane carboxylic acid, or cyclohexyl ethane carboxylic acid, cyclohexyl ethane carboxylic acid or cyclohexyl ethane carboxylic acid, cyclohexyl ethane carboxylic acid, or cyclohexyl _{ethane carboxylic acid 2} of benzoic acid,

Phenoxyalkanoic acids, such as phenoxyacetic acid, dicarboxylic acids, such as Succinic acids, phthalic acid, quinolinic acid, furan-2-carboxylic acid, 6-tert. -Butyl-furan-2-carboxylic acid, '5-B ^ oni-furan-2-carboxylic acid, of nicotinic acid or isonicotinic acid, or of pyrrole carboxylic acids and alkyl-substituted pyrrole carboxylic acids, such as 2,4,5-trimethyl-pyrrole-3-carboxylic acid, 2,4-dimethyl-pyrrole-3-carboxylic acid or 2-ethyl-4-methyl-pyrrole-3-carboxylic acid, or of sulfonic acids, such as benzenesulfonic acids or inorganic acids such as phosphoric or sulfuric acids.

Etherified hydroxyl groups are especially those which are derived from alcohols with 1-8 carbon atoms, such as lower aliphatic alkanols with 1-5 carbon atoms, such as ethyl alcohol, methyl alcohol, propyl alcohol, isopropyl alcohol, butyl or amyl alcohols or from araliphatic alcohols Alcohols, in particular of monoeyelic aryl-lower aliphatic alcohols, such as benzyl alcohol, or of heterocyclic alcohols, such as α-tetrahydropyranol or -furanol.

The ether groups, and in particular an etherified hydroxyl group in the 14-position, can preferably also be derived from sulfur-containing alcohols, for example those of the formulas • -VV , V

. J ² (3 B) _j2

A) V-, - C - S - C - V ,. or V ₁ -C - S - 0

¹ Il ^{4 1} I.

OH V _K 'OH

5 ■ ·

derive where V, - V are hydrogen or alkyl or aryl groups, in particular lower alkyl groups, and 0 is an aryl group, in particular an unsubstituted or substituted phenyl nucleus, ie

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of optionally in 1 and / or 3-position by further alkyl or Aryl groups substituted 2-thiapropanols or 2-thia-arylethanols., primarily from 2-thiapropanol. Form such ether groups E.g. in the treatment of the Hydroxy -St er ο ids with dialkyl or aralkyl sulfoxides of the formulas

'Ti. ' J ₁

C) O = S- _D)

C-V or: 0 = S '

/ V ⁵ 0

VV.

■ ^V 3 ^V 4

in the presence of a carboxylic acid anhydride, preferably a lower aliphatic one Carboxylic anhydride.

Protected oxo radicals are, for example, ketal groups, preferably those which see lower alkanediols or alkanols, e.g. derive from ethylene glycol, methanol or ethanol.

A protected oxo group in the 3 "position can in particular also in the form of the 3-hydroxy-3, 9-oxiolo-hemiketal group, or in

In the form of the 3-ethers or 3-esters of a single hemiketal group, the ethers and esters are derived, for example, from the abovementioned alcohols or acids, preferably from non-aliphatic alcohols or acids. In particular, this hemiketal group represents a 3a _J 9a-epoxy-3ß-hydroxy group or its 3-ethers or 3-esters.

I> The compounds of the above formula III are valuable Intermediate products in the production of e.g. in the German Disclosure Papers 2029169, 2052166, 2136635 described Pregnan compounds represents. Within the group encompassed by the formula III

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of compounds therefore claim the compounds of the following Formula, as-important intermediates for the production of batrachotoxinin A, Epibatrachotoxini'n A and their 7,8-dihydro derivativesj as well as esters, or ethers thereof., in particular the 20-pyrroleic acid esters, which also includes the well-known, highly effective alkaloid batrachotoxin, of great importance

IV

wherein P has the meaning given for formula III, A a Hydroxy group together with a hydrogen atom or an oxo group, X an etherified or esterified hydroxy group and Y and Z each one

mean esterified hydroxyl group, as well as their esters and ethers and Ketals of the 14, 18-Diols. The ester groups, especially especially an esterified group Jk in the string P is to be understood, are in turn those of the above-mentioned carboxylic acids or inorganic acids or sulfonic acids, in particular the lower aliphatic acids Carboxylic acids, especially acetic acid. The etherified hydroxyl groups are preferably derived from lower aliphatic groups Alcohols with I-5 carbon atoms or one of the above-mentioned heterocyclic Alcohols, in particular also from the sulfur-containing alcohols mentioned, preferably from a 2-thiapropenol of formula C) with up to 8 carbon atoms, such as 2-thiapropanol. the 14, 18-ketals of 14,18-diols are mainly those that differ from

* ■ - ■ - ■ * ^: «..VivJ

a ketone of the formula.

(V) O = C

deduce whatir. W ₁ and W "are two unsubstituted or substituted hydrocarbon radicals or together rat the carbon atom, on d,.; they are bound, mean an unsubstituted or substituted ring-closed hydrocarbon radical. These groups W and W are above all aliphatic or araliphatic hydrocarbon radicals, but can also be alicyclic or aromatic; they can optionally also be substituted, for example, by hydroxy, lower alkoxy, lower aeyloxy, thiol or amino groups or halogen atoms, the term lower alkyl groups having 1-6 carbon atoms. W and ¥ _p can also together with the carbon atom to which they are attached form a ring-closed hydrocarbon radical. Such a hydrocarbon radical is preferably an alicyclic hydrocarbon radical with a total of 1-12 carbon atoms and 5-7 ring carbon atoms, especially a CyeXopentylidene or cyclohexylidene radical. The groups W and Wp single hydrocarbon radicals of aliphatic nature, they preferably each 1-6 carbon atoms and are especially methyl, ethyl, propyl, butyl, pentyl or hexyl but _s they can also be alicyclic nature, such as Cyclopentyl or, in particular, cyclohexyl radicals. Aromatic radicals W and W are in particular phenyl groups or through lower alkyl radicals or halogen

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BATH ORIGINAL

atoms substituted phenyl groups. First and foremost, W and Wp each represent a methyl group, i.e. that according to the present process 14, 18-diols that can be prepared are in the form of acetonides.

Among the compounds according to the above formula IV, the compounds of the formulas occupy an outstanding position

AcO-.

(VI)

Alc

Alk 0

'OAc

in which Alk stands for a lower alkyl group with 1-6 carbon atoms, Ac for a lower aliphatic acyl radical with 1-6 carbon atoms and P ^f for one of the two partial formulas. · '

(VIII)

H.

1?

CH

20 S configuration

IX

OR » Jl

1?

H_

20 E. Configuration

are, in which R ^f 'is hydrogen or a lower aliphatic acyl group with 1-6 C atoms and the derivatives and 14 ethers of the compounds of the formula VI formed by ketalization of the 14,18-diol grouping of the formula VI with the above-mentioned preferred ketones of the formula V Formula VII, in particular derived from one of the above

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mentioned alcohols, e.g. with one of the mentioned 2-thiapropanols with 2-8 carbon atoms, especially 2-thiapropanpl. These connections are particularly valuable for the synthesis of batrachotoxin A and epi-batrachotoxinin A and their 20-esters, such as batrachotoxin. Specific Compounds of this group are, for example, those of the formulas VI and VII, wherein Alk is methyl and Ac is acetyl and R ″ in the formulas (Viii) or IX

Denotes hydrogen or acetyl, the 14, 18 ~ acetoniae in the case of the compounds of the formula VI, and the I ² I - (2 '-thiapropyleather of the compounds of the formula VII.

The method of the present application for making

the. A ¹⁶ -steroid-14β, 18,20-triplets and. A ^16- steroid-14β, 20-diol-18-alene of the pregnane series and its esters and ethers is characterized in that a -Diol group is ketalized with a ketone, with a complex light metal hydride, which has an oxo group

reduced to hydroxyl group, but esterified hydroxyl groups intact

lets, treated, and, if desired, in any order and optionally simultaneously from the mixture of the 20 S and 20 R hydroxy compounds formed or their functional derivatives in another at least one of the two epimers is known to be isolated, and / or sets free any protected functional groups that may be present and / or functionally modifies functional groups and / or the 18-hydroxy group is selectively dehydrated to the 18-oxo group.

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- IQ -

The procedural reduction of the labeled starting materials is made with complex hydrides, which are pre-esterified Leave the hydroxyl groups intact. Alkali borohydrides, in particular sodium borohydride and complex alkali aluminum hydrides, are primarily used as such of type

(X)

OX

wherein X ₁ , Xg and X are each a tertiary lower alkyl group and Me is an alkali metal, such as tri-tert. butoxy lithium alrininium hydride or tri-tert. amyloxy-lithium-aluminum hydride. The reduction with these complex hydrides is carried out in a manner known per se. The solvent used is, for example, in the case of the complex alkali aluminum hydrides mentioned, an ether such as diethyl ether, diisopropyl ether, dioxane or. Tetrahydrofuran, in the case of an alkali borohydride, preferably an aliphatic or cycloaliphatic alcohol, such as, for example, methanol, ethanol, propyl alcohol, isopropyl alcohol, butanols or amyl alcohols.

The temperature for carrying out the reduction according to the process can vary within wide limits, depending on the selected temperature, the ratio of the two 20-epimeric alcohols formed varies in the reduction mixture. You can,

3 0 9 8 5 0/1209

especially in the case of the use of alkali borohydrides, at lower levels Temperature, e.g. O to -50, but also below, work or especially in the case of using Tri-ter. alkoxy-lithium-aluminum hydrides, above 0 °, e.g. between 0 ° and 100 °. The reaction time to be selected depends on the starting product used, depending on the reducing agent and the reaction temperature, it is generally several hours.

The separation of at least one of the epimeric 20-hydroxy compounds from the reduction mixture before or after the release of functional groups, in particular the 14,18-ketal grouping present in the reduction product, and before or after functional groups Conversion of other groups, such as in particular the 20-alcohol group, take place. The separation can be carried out in a manner known per se by crystallization, chromatography or other physical means or chemical methods can be achieved.

If desired, protected functional groups in any order, such as ketal, ether or ester groups in the corresponding free functional groups are transferred, what can be done in a manner known per se. For example, ketalized oxo groups or the ketalized 14,18-diol group and Ether groups preferably through the action of acidic agents such as mineral acids e.g. hydrochloric acid, sulfuric acid or perchloric acid, or organic carboxylic acids and sulfonic acids, such as lower aliphatic acids Carboxylic acids, e.g. acetic acid, split, ester groups through the action of basic agents. For example, the 14, 18-ketal grouping becomes preferably by exposure to a strong acid such as p-toluenesulfonic acid, saponified to the 14,18-diol grouping.

3,098 50 / 120.9

The functional modification of hydroxyl or oxo groups can also 'be carried out in a manner known per se. the Esterification of free hydroxyl groups can e.g. by treatment with an acylating derivative of an acid, such as a carboxylic acid, preferably the anhydride or a halide, e.g. in the presence a tertiary base such as pyridine or köllidine can be obtained.

The etherification of free hydroxyl groups takes place, for example, by treatment with a reactive functional derivative of alcohol concerned, such as an alkyl halide or alkyl sulfate, e.g. a dialkyl sulfate, in the presence of an organic or ^ inorganic Base such as sodium or potassium hydroxide or pyridine.

Isolation of the 20 R and 20 S hydroxy compounds will preferably carried out in the mixture of the free alcohols obtained directly by the reduction with the complex light metal hydride. If desired, however, the separation can take place at a later stage, for example after esterification of free hydroxyl groups, in particular the 20-hydroxy group itself, i.e. the epimeric 20-hydroxy compounds can also be isolated in the form of one of their functional derivatives.

If compounds with the free 14, 18-diol group or are prepared with the 18-aldehyde group, then any Step the 14,18-ketal group in a manner known per se, e.g.

described above, removed. This is preferably done after separation of the epimeric mixture of 20-alcohols and, in particular if the 18-hydroxy group is then to be dehydrogenated to an oxo group, after esterification of oxidizable free hydroxy groups, e.g.

3.0 9850/1209.

the 20-hydroxy group.

The selective dehydrogenation of the 18-hydroxy group to the oxo group., which can optionally be carried out according to the present method, is preferably after prior protection oxidizable free hydroxyl groups made in other positions., e.g. after acylation of a 20-hydroxy group. As an oxidizing agent become those for the dehydrogenation of a primary alcohol to an aldehyde group used known from the literature, such as compounds of hexavalent chromium, e.g. chromium trioxide, in particular Chromium trioxide in pyridine, optionally with the addition of other solvents such as chlorinated hydrocarbons, e.g. methylene chloride or Chromium trioxide in acetone and sulfuric acid (Jones reagent) or chromium trioxide and pyridine-sulfur trioxide complex. A particularly cheap one The method which gives good yields is oxidation with dimethyl sulfoxide acetic anhydride according to the method of Albright and Goldmann (Journal of the American Chemical Society 89, 2416 (1967) ' Similar mixtures of a homologue of Dimethylsulfoxyds can also be used like those of formulas C) and D) mentioned above, and of acetic anhydride use, such as diethyl sulfoxide and propionic anhydride. Using this method is used at the same time as the 18-hydroxy group Aldehyde group dehydrated and the 14-hydroxy group with sdem the relevant Dialkyl sulfoxide corresponding thiapropanol of the above general formulas A) or B) etherified. When using dimethyl sulfoxide changes the 14-hydroxyl group into the 2-thiapropyloxy group (or methyl-thio-methoxy group) -0 - CH- -S- CH converted. the

3Q9850 / 12Q9

so etherified l4-hydroxy group can easily by acid treatment or hydrolyzed to alcohol by treatment with chloramine in dioxane water. If the acidic treatment is e.g. with hydrochloric acid If carried out in an alcohol, the corresponding acetal of the 18-aldehyde group is formed at the same time.

. The 14-ethers mentioned represent the 18-aldehydes formed particularly valuable starting products or intermediates for Preparation of the batrachotoxinin A and epibatrachotoxinin A compounds and their analogs and conversion products, as follows will be shown. . ·

The 14, 18-ketals of Δ -20-oxo-steroid-14ßjl8-diols of the pregnane series to be used as starting materials can be used in an known catfish by reaction of the corresponding 14β, 18-diols with a desired ketone or, even more advantageously, with a ketal of such a ketone with the addition of an acidic agent, preferably in catalytic amounts. One uses preferably as ketals lower aliphatic ketals of the ketone, especially the dimethyl ketals, e.g. in the case of acetone, the 2,2-dimethoxypropane, and sets preferably at room temperature, in the presence of traces of an acid, e.g. -p-toluenesulphonic acid.

The mentioned Δ -20-oxo-steroid-14ß, 18-diols of the pregnane series are known or can be produced according to published methods. In particular, such starting materials are

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2326806

.Applies that have the substituents specified above or which correspond to the formulas III - VII listed above for the products of the process. The production of such starting materials is e.g. the German Offenlegungsschrift 2 I36 635 described.

A preferred combination of the process steps described consists in that after the reduction of the 14, 18-ketals of the Δ -20-oxosteroids-14β, 18-diols with the complex light metal hydrides mentioned, the corresponding Δ -20-hydroxy Compounds acylated the 20-hydroxy group in the manner described above, in the compounds obtained by the action of an acid, under mild conditions, as shown above, cleaves the 14, 18-ketal group and the 18-hydroxyl group.according to the above-mentioned method of Albright and Goldmann, dehydrated using a lower aliphatic alkyl sulfide in the presence of a lower aliphatic carboxylic acid anhydride, the Δ -20-aeyloxy-14β- (2 ^! R-OH or -O-Ac and 20 S-OH or -OAc compounds are isolated Preferably, the compounds which are epimeric in the 20-position are isolated immediately after the reduction nsstufe, made with the free alcohols. This combination is illustrated by the following reaction scheme in the case of a starting compound corresponding to the compounds of the above formula VI

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AcO.

-: .it ¹ Na B E ^ (-30 °)

Alk 0

XII

- Py

. HO,

AIk ο

XIV-

CH

'CH-

Ac Ac

: O p-Tosyl-OH

αι ·;

XIII

AcO,

, OAc

QCHp-S-CH

XV copy

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In this scheme, Alk denotes a lower alkyl group, especially methyl, Ac denotes a lower aliphatic acyl radical, primarily acetyl, while W and Wp have the meanings given for the formula V above. The cleavage of the ketal group is carried out under mild conditions, e.g. by means of catalytic amounts of an acid at room temperature and with a short reaction time under these conditions an etherified hemiketal group, such as the etherified 3 ^a, 9 ^a ~ hemiketal group, remains unaffected.

In the above scheme, the reduction is carried out with NaBH u at low temperature in methanol, the 20 S-OH epimer being formed in the predominant amount, which can be isolated from the reduction product without difficulty, for example by simple crystallization. According to the special combination of process steps described above, mixtures of the two epimeric 20-pregnane alcohols with varying proportions can be obtained by varying the reaction conditions and the reducing agent, and the pure epimers are optionally isolated at any stage. If, for example, the abovementioned hydrides of the formula X are used at elevated temperature, for example at 70 °, the predominant amount obtained is the 20 R alcohol, which can likewise be easily separated off from the reduction product.

The conversion of the products of the process into the pharmaceutically active compounds mentioned at the outset can be based on the following Reaction schemes are illustrated showing the conversion of a compound of Formula XV above to batrachotoxinin "A:

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AcO

OAc

--OJ OCH ₂ SCH ₃ OAc

NH ₂ AcO,

CH ₃ O

LO T OCH ₂ SCH

OAc

AcO,

OAc

ClCH ₂ -CO-Cl CH ₃ O

I OCH ₂ SCH Via.- *>

OA

HCl +

CH OH

AcO

H .

OAc AcO

CH ₃ O

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OH

OAc

COPY

OH

Py +

SOCl,

AcO

CH ₃ O

, OAc

19 -

Acylation , room temp.

Li AlH,

CH ₃ O

CH.,

CII,

H "Batrachotoxin A

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-ZO-

In an analogous manner, 20-S and 20 R epimers of e.g. in the above-mentioned German Offenlegungsschrift 2052166 Compounds can be prepared from corresponding process products of the present invention. The transfer such process products according to the formula scheme shown above is described in the Swiss application application no. 4-8206 and claimed.

The invention is described in the following examples. The temperatures are given in degrees Celsius, the rotations are measured in chloroform (temperature 22), the IR spectra data figure as wave numbers (cm) where the. Measurement is also carried out in chloroform, and the UV-spetral data relating to the measurement in ethanol, in each case the figures given words, the maximum absorption wavelength corresponding to the / \> in nanometers and reflect the absorbance C.

Unless expressly stated otherwise, “working up” a reaction mixture obtained means uptake of the reaction mixture in ethyl acetate, washing with water or saturated sodium chloride solution until neutral, drying over magnesium sulfate and evaporation in a rotary evaporator. Unless otherwise noted,

For chromatography the use of silica gel is pure 0.05-0.2 mm Merck and for "crystallization" or "crystallize" Circulation from acetone-hexane, ge'-ex- ^ t.

3. 09850/1209

-2A-

example 1

-ν

2 g 3ß-methoxy-3a, 9a-oxido-lla-acetoxy-l4ß, l8-dihydroxy-

l6
20-οχο-Δ "-5ß-pregnen..are stirred with 6G mg p-toluenesulfonic acid in 80 ml 2,2-dimethoxypropane for 20 minutes. Then it is neutralized with aqueous sodium bicarbonate solution and worked up The resulting mother liquor in benzene / ethyl acetate (1: 1) solution gives a total of 1.9 g of the (14β, - £ 18) -acetonide of 3β-methoxy, ~ 3a, 9a-oxido-Ila-acet.oxy-14β , 18-dihydroxy-20-oxo-A -5β-pregnens, m.p. 183-184 °. [aJ _D = -4γ ° (0.38) IR: 1730, 1665, 1615, 1370 (strong), 1240. UV 239 (83ΟΟ)

Example 2

316 mg of the (14 '-> 18) -acetonide of 3ß-methoxy ~ 3a, 9a-oxido-Ua-acetoxy-14ß, 18-dihydroxy-20-oxo-A -5ß-pregnen in 15 ml of abs. Dioxane reduced with 700 mg of tri-tert-butoxy-lithium aluminum hydride for 15 minutes at 70. Customary work-up and chromatography in a methylene chloride-methanol (20: 1) mixture first give 142 mg of crystalline (14- > 18) -acetonide of (20R) -3β-methoxy-3a, 9a-oxido-11a-acetoxy-14ß, 18 , 20-trihydroxy-A ¹ -5β-pregnen. After three crystallizations 14-143 °. IRs 35ΟΟ (broad), 283Ο, 1740, 1250.

Later fractions yield 64 mg of amorphous (14-18) -acetonide of (20S) ~ 3ß-methoxy-3a, 9a-oxido-lla-acetoxy-14ß, 18,20-tri-

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hydroxy-Δ -5β-pregnen. IR: 3600, 3500 (broad) 2830, 1738, 1240.

Example 3

400 mg of the (l4 > l8) -acetonide of 3ß-methoxy-3a, 9a-oxido-

lla-acetoxy-l4ß _J) l8-dihydroxy-20-oxo-A ~ 5ß-pregnene be in 3 ^m ° l abs. Dioxane with 1, 2 g of tri-tert.amyloxy lithium aluminum hydride for 20 minutes at 80th Work-up and chromatography in methylene chloride-methanol (50: l) solution give 213 ^m S of the (14-> 18) -acetonide of (20R) -3ß-methoxy-3a _J 9a-oxido-11a-acetoxy-14ß _i 18,20-trihydroxy-Δ -5ß-pregnene, and 77 mg of (l4 - * l8) -Acetonids of (20S) -3ß-methoxy-3a _J, 9a-oxido-lla-acetoxy-l4ß, 183 20-trihydroxy -A ° - 5ß-pregnen.

Example 4

700 mg of the (Ϊ4 ^ l8) -acetonide of ^ ß

11a-acetoxy-14ß _J 18-dihydroxy-20-oxo-A -5ß-pregnen is cooled, dissolved in 50 ml of abs. Methanol to -30 and adds 500 mg of solid sodium borohydride. Then the mixture is stirred for 19 hours at -30 _, worked up and chromatographed in methylene chloride-methanol (50: l) solution. First 121 mg of the (14 · - »18) -acetonide are eluted from (20R) ~ 3ß-methoxy-3a _, 9a-oxido-Ila-acetoxy-14ß ^ 18,20-trihydroxy-A -5ß-pregnen. Later fractions give 462 mg of the corresponding (2OS) epimer.

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Example 5

331 mg of the (14 £ 18) -acetonide of (20R) -3ß-methoxy-

, 9a-oxido-11a-acetoxy-14ß., 18, 20-trihydroxy-A -5ß-pregnen are aeetylated overnight at room temperature in 40 ml of acetic anhydride-pyridine (1: 1) mixture. Then it is evaporated in vacuo und.filtriert the crude product in methylene chloride on neutral aluminum oxide (Akt-III). This results in 320 mg of amorphous (14-18) -acetonide of (20R) -3ß-methoxy-3a, 9a-oxido-11a, 20-diacetoxy-14ß, 18-dihydroxy-Δ -5ß-pregnen. IR: 1730, 1240.

Example 6

495 mg of the (14—J-18) -acetonide of 20S) -3β-methoxy-3a _J 9aoxido-lla-acetoxy-14β _J 18,20-trihydroxy-A -5β-pregnen are aeetylated as in the previous example. This results in 50I mg

amorphous (l4 ^ l8) -acetonide of (20S) -3ß-methoxy-3a _J> 9a-oxido-

IIß _J 20-diacetoxy-14ß _J 18-dihydroxy-A ¹⁶ -5ß-pregnen. IR 1730, 1240.

Example 7

330 mg of the (14 ^ 18) -acetonide "of (20R) -3ß-methoxy-

3a, 9a-oxido-11a ₃ 20-diacetoxy-14ß _J 18-dihydroxy-A -5ß-pregnen is dissolved in 40 ml of methanol and treated with a solution of 40 mg of p-toluenesulfonic acid in a mixture of 20 ml of methanol and 4. ml

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23258Q8

Water. Then it is left to stand for 1 3/4 hours at room temperature and then worked up. This results in 280 mg of ('20R) -3ß-methoxy-3a, 9a-oxido-11a, 20-diacetoxy-14ß, 18-dihydroxy-A -5ßpregnen, which are not purified. IR: 3550 (broad), J-3 ¹ OO (broad), I73O, I25O.

Example 8

53 ° mg of the (14> 18) -acetonide of (20S) ~ 3ß-methoxy-

3a, 9a-oxido-11a, 20-diacetoxy-14ß, 18-dihydroxy-A -5ß-pregnen in 35 ml. abs. Methanol with 15 mg p-toluenesulfonic acid for 15 minutes left to stand at room temperature. Work-up and one-time crystallization of the crude product from methylene chloride-hexane yield 398 mg crystals of (20S) -3ß-methoxy-3a, 9a-oxido-11a, 20-diacetoxy-14ß, 18-dihydroxy-A - ~ 5ß-pregnen from m.p. 175-176 -1 ° (0.65). IR: 3520, 34OO, 1725, 1250.

Example 9

26O mg (20R) -3ß-methoxy ~ 3a, 9a-oxido-lla, 20-diacetoxy-l4ß, 18-dihydroxy-A -5β-pregnen are in 6 ml of abs. "Dimethylsülfoxyd dissolved, with 6 ml abs. Acetic anhydride added and 17 hours at Left to stand at room temperature. Then you work up and chromatograph the resulting crude product in benzene-ethyl acetate ("4: 1) mixture. This gives 220 mg (20R) -3ß-methoxy-3a, 9a-oxido-lla, 20-

309850/1209. 'OfliQSNAk iNSPECTED

diacetoxy-14ß-raethyl-th: i _f Qmethoxy ~ 18-oxo-A -5ß-pregnen in amorphous form. IR: ■ '2750, 1735, 1245.

Example 10

298 mg (20S) -3ß-MethQxy-3a, 9a-axido-lla, 20-diacetQxy-l4ß, 18-dihydroxy-A -5ß-pregnen are in 9 ml dimethylsulfoxide-acetic anhydride (l: l) mixture as above Example implemented, then worked up and chromatographed in benzene-ethyl acetate (2: l) solution. This results in 255 mg of crystals of (20S) -3ß-methaxy ~ 3a, 9a-oxidollff _J 20-diacetoxy-l ⁱ l-ß- methyl-thiomethoxy-18-oxo-A -5β-pregnen of melting point 114-115 °. Ea] _n = + 24 (0.75), IR: 2830, 2740, 1735, 1245-

Example 11

120 mg of 3ß-methoxy- ^ a _J 9a-oxido-7a _JI lla-diacetoxy-l4ß _i l8-dihydroxy-20-οχο-Δ -5ß-pregnen with 3 ^m S .p-toluenesulfonic acid for 10 min. At room temperature in stirred for 3 ml of 2, 2-Dimethaxypropan, are then added to aqueous NaHCO -Losung, .extrahiert with Essigester and washed with saturated aqueous NaCl solution until neutral. The crude product obtained after drying and evaporation of the organic phase is chromatographed on silica gel in benzene / ethyl acetate (1: 1) solution. This results in 100 rag crystals of the (14- * 18) acetonide of 3ß-methoxy-3a ₃ 90> oxido-7a, lla-diacetoxy- ^ ß, 18-dihydroxy-20-οχο-Δ -5ß-pregnens ( Mp, 194-195 °, recrystallized once) [otf _D = -65 ° (0.60), IR .: 1730, 1665, 1620, 1240. UV .: 236 (9580).

309850/1209

Example 12

40 mg of the (14 * -> 18) acetonide of 3ß-methoxy-3 ", 9a-oxido-7a, 11a-diacetoxy-14ß, 18-dihydroxy-20-oxo-A -5ß-pregnen in 3 ml of abs . Dioxane with 160 mg Li [Al (t-amyloxy) H]. Reduced at 80 for 15 minutes. Then it is added to saturated aqueous (NHj-JpSOu solution, extracted with ethyl acetate and then washed neutral with saturated aqueous NaCl solution. After drying and evaporation of the organic phase, 40 mg of crude product are obtained, which are dissolved in methylene chloride-methanol (100: l) solution are chromatographed on silica gel. 23 mg (14- ^ 18) -aeetonide of (20R) -3ß-methoxy-3a, 9a-oxido-7 <x, Ila-diacetoxy-14ß, 18, 20-trihydroxy-Δ -5β-pregnen, which melt after crystallization at 206-207. [Α] _β - - 33 ° (0.45). IR .: 3460 (broad), 1730, 1240.

Later fractions yield 7 mg (14-9-18) -acetonide of (20S) -3ß-methoxy-3a, 9a-oxido-7a, Ila-diaoetoxy-14ß, 18,20-trihydroxy-Δ -5ß-pregnen, the melt at I6O-I6I after crystallization. [aI _D = -36 ° (0.50). IR,: 3590, 3450 (broad), 1730, 1240.

200 mg of the starting material used are in 15 ml of abs. Methanol at -30 with 200 mg of solid NaBH ₂ , added. Then it is left with stirring for 24 hours at -3Q , after 5 hours a further 100 mg of NaBEL are added. It is then diluted with ethyl acetate and washed neutral with saturated aqueous NaCl solution. After drying and evaporation of the organic phase, like chromatographed above, initially 50 mg of the above-described (20R) -compound eluted, later fractions yield 120 mg of the above-described (2OS) -compound.

309850/1209

Example I3

120 mg (14- * 18) -acetonide of (20S) -3ß-methoxy ~ 3a, 9aoxido-7otj Ila-diacetoxy-14ß, 18,20-trihydroxy-A -5ß-pregnen in 5 ml of acetic anhydride-pyridine (1: 1) mixture for 3 hours at room temperature acetylated. Then it is evaporated in vacuo., With 125 mg (14 - *. 18) -Apetonide of (20S) -3-ft-MethoÄy-3ai9a-oxido-7a, lla, 20-

triacetoxy-14ß, 18-dihydroxy-A -5ß-pregnen (IR .: 1730.1240) can be obtained, which without purification in 6 ml of abs. Methanol with a solution of 6 mg of p-toluenesulfonic acid in a further 6 ml of abs. Methanol are reacted for 15 min. At room temperature. It is then diluted with ethyl acetate, washed neutral with saturated aqueous NaCl solution, evaporated in vacuo and the crude product (II5 mg) crystallized from ether-hexane. This gives (2OS) -3β-methoxy-3a, 9a-oxido-7a, 11a, 20-triacetoxy-14β, 18-dihydroxy-A -5β-pregnen with a melting point of 172-173 °. [a] _D = + 48 ° (0.35), IR: 3580, 3460 (broad), 1730, 1240.

Example l4

160 mg (20S) -3ß-methoxy-3a, 9a-oxido-7a, lla, 20-triaeetoxyl4ß, 18-dihydroxy-A -5ß-pregnen are in 3 ml of abs. Dissolved dimethyl sulfoxide, with 3 ^ffl l abs. Acetic anhydride is added and left at room temperature overnight. Then it is poured into ice-cold aqueous NaHCO solution, extracted with ethyl acetate and washed neutral with plenty of water. The crude product obtained after drying and evaporation of the organic phase is chromed in benzene-ethyl acetate (3: l) solution on silica gel

309850/1209
OBIGJNALSNSPSGtED

- -ze -

rnatographed. 130 mg of crystals of (20S) -3ß-methoxy-3o > 9a-oxido-70, llo, 20-triac8toxy-14ß-0-: methyl-thlomethoxy-18-oxo-Δ -5ß-pregnen obtained after crystallization at 125-126 .melt. ...... . '

[ _{α] β} = + 25 ° (0.40) .. IR .: 2740, 173O, 1240.

Example 15

• The starting material of Example 11 can be as follows will be obtained:

720 mg of 3ß-methoxy-3a, 9a-oxido-7a-hydroxy-lla, 18-diacetoxy-20-oxo-5ß-pregnane [HeIv. 54, 2879 (1971) 3 are acetylated in 30 ml of acetic anhydride-pyridine (1: 1) mixture under an N "atmosphere at I30 ^{0 for 6 hours.} Then it is evaporated in vacuo and chromatographed in ethyl acetate-chloroform (1: 1) solution on silica gel. This results in 47O mg of 3ß-methoxy-3, a _J 9a-oxido-7a _i Ila, 18-triacetoxy-20-oxo-5ß-pregnane, which once recrystallized melt at 146-147. [a] _D = + 81 ° (0.64). IR: 1735, 1710, 1245.

470 mg 3ß-methoxy-3a, 9a-oxido-7a, 11a, 18-triacetoxy-20-oxo-5ß-pregnane are dissolved in 40 ml CCIk with 200 mg N-bromosuccinimide with the addition of 10 mg azobisisobutyronitrile under external irradiation with a 1000 W Incandescent lamp cooked for 45 minutes. Then the precipitated succinimide is filtered off and evaporated in vacuo. The resulQ ₀ animal crude bromination product was dissolved in 40 ml abs. Dimethyl-ο formamide and heated with 470 mg LiBr and 470 mg Li CO_ for 2 1/2 hours under N "to 130. Then you concentrate in a vacuum, dilute with

«Essigester and washes several times with water. That after drying and evaporation of the organic phase resulting crude product is chromatographed one in ethyl acetate-chloroform (1: 1) mixture on silica gel.

This gives 2β5 mg crystals of 3β ~ meth'oxy-3a, 9a-oxido-7a ,, lla _i 18-triacetoxy-20-οχο-Δ -5β-pregnens, which ^{melt once recrystallized at 187-188 0} , [ a] ^ = + 53 ⁰ (0.54). IR .: 1730, 1070, 1595, 1240; UV. 235 (855Ο).

265 mg of the product thus obtained and 110 mg of N-bromosuccinimic

and 10 mg of azobisisobutyronitrile are boiled under external irradiation with a 1000 W incandescent lamp in 4θ ml of CCl ₂ for 20 minutes. It is then cooled, the precipitated succinimide is filtered off and the filtrate is evaporated in vacuo. The crude bromination product is heated under N _? with '265 mg LiBr and 265 mg Li CO in 20 ml abs. Dimethylformamide 15 minutes to 130. It is then evaporated in vacuo, taken up in ethyl acetate and washed several times with water. The crude product obtained after evaporation in vacuo is chromatographed in benzene-ethyl acetate " ¹ (1: 1) solution on silica gel. 185 mg crystals of 3ß-methoxy-3a, 9a-oxido-7a, hex, 18-triacetoxy- 20-oxo-A > ^l6 -5ß-

pregnadiens are obtained which melt once recrystallized at 209 ° «[a] _D = + 227 ° (0.60). ir .. 1735, χ64θ, 1530, 1465, 1240. UV .: 309 (10900).

187 of the product thus obtained are epoxidized in 18 ml of CHCl - methanol (. 100: 1) mixture with 185 mg of p-nitroperbenzoic acid in the dark for 24 hours at room temperature. Then it is diluted with ethyl acetate and washed successively with aqueous solutions of NaI, Na ₂ SgO-, NaCl, NaHCO and again NaCl ₀ It is then dried over MgSO ^, evaporated in vacuo and in ethyl acetate-chloride

-. 309850/1201

roform (lil) solution chromatographed on silica gel. This elutes 10 9 rag crystals of 3ß-methoxy-3a., 9a; 14ß, 15ß-dioxido-7a, 11α, 18-triacetoxy-20-oxo-A -5, ß-pregnens, which recrystallizes once at 199-200 ° melt. [a] _D = + 33 ° (0.65). IR .: 1735, 1670, I605, 1250. UV .: 244 (7850).

25Ο mg of the product thus obtained are in the presence of 375 mg of 5-ρΐΌΖ. Pd-BaSOju catalyst in a mixture of 28 ml of methanol and 2 ml of cyclohexene boiled with vigorous stirring for 3 hours at an oil bath temperature of 120. The catalyst is then filtered off through Celite, evaporated in vacuo and chromatographed in benzene-methanol (40: l) mixture on silica gel. 155 mg of 3β-methoxy-3a _J 9a-oxido-7a _J 11a, 18-triacetoxy-14β-hydroxy-20 ~ οχο ~ Δ -5β-pregnen are obtained in amorphous form. IR: 3580, 1735 * 1670j 1615 _f 125Ο; UV ": 836 (9860).

205 mg of the product thus obtained are .in 20 ml 0.1 MaHCO ^ 'in 90 percent. aqueous methanol boiled for 15 minutes under Np (oil bath temperature 80). Then it is diluted with ethyl acetate, washed neutral with saturated aqueous NaCl solution and evaporated in vacuo and chromatographed on silica gel in ethyl acetate. 140 mg of crystals of 3ß-methoxy-3ä, 9a-oxido-7a, Ila-diacetoxy-14ß, 18-dihydroxy-20-οχο-Δ -5ß-pregnens are obtained, which melt after two crystallizations at 222 °, [α ] = - 41 ° (0.5O) ₀ IR .: 36ΟΟ / ■ 3450, 1730, 1655, ιβιο, I24o, uv. Ϊ 236 (9960).

308850 / 120S

Example ΐβ-

The conversion of the product obtained in Example 14 in batrachotoxinin A occurs in the following manner

220 mg (2OS) - ^ ß-methoxy- ^ a, 9a-oxide-7G, 11a, 20-triaeetoxyl4ß-methyl-thiornethoxy-18-oxo-A '-5p-pregnen are in 4.ml abs. Dissolved benzene, heated to 85 for 9 hours in a sealed tube together with 1.5 ml of a saturated benzene methylamine solution. It is then cooled and evaporated in vacuo. ¹ '3.beta.-methoxy-3a, 9 <i-oxido-7a, Ha, 20-triacetoxy-l4ß-methyl-thiomethoxyla-methylimino-A ~ 5ß-pregnene (IR .; 2770, I73O - in this case be 220 mg (20S) , 1665, 1240), which are reduced without purification in 18 ml of methanol at room temperature with 220 mg of NaBEL in 2 ml of water for 10 minutes. Then it is diluted with ethyl acetate, washed neutral with saturated aqueous NaCl solution, dried over MgSOu and evaporated in vacuo. This results in 210 mg (20S) -3ß-methoxy ~ 3a, 9a-oxido-7a, IIIa.

triacetoxy- ^ ßO-methyl-thiomethoxy-lS-methyla ^ ino-A '-5ß-pregnen (IR .: 3340, 2800, I73O, 1240), which in turn without purification at 0 ° in 20 ml of alcohol-free chloroform are added one after the other with 1.5 ml of chloroacetyl chloride and 0.28 g of NaOH in 20 ml of water. The two-phase system is then left with vigorous stirring 15 Minutes at 0 °, then add to saturated aqueous NaHCO solution, extracted with ethyl acetate and washed neutral with saturated aqueous NaCl solution. After drying and afterwards Evaporation of the organic phase gives 220 mg (20S) ~ 3ß-methoxy-3a, 9a-oxido-7a, Ila, 20-triacetoxy-14ß-methyl-thiomethoxy-18-

3098 50/1209

(N-methyl-N-chloroacetyl-amino ^ -A -5ß-pregnerij which are left in 10 ml of a 0.05 W HCl solution in absolute methanol for 1 J> / K hours at room temperature without prior purification and characterization. Then it is added to aqueous NaHCO - solution, extracted with ethyl acetate and washed neutral with saturated aqueous MaCl solution. The crude product obtained after drying and evaporation of the organic phase is finally chromatographed on silica gel in benzene / ethyl acetate (isl) solution. 150 mg of crystals of (20S) -3ß-methoxy-3a, 9a-oxido-7a, α-20-triacetoxyl4ß-hydroxy-18- (N-methyl-N-chloroacetyl-ainino) -A -5ß-pregnen are obtained , whose melting point after crystallization is 203-204 °. [a] L = + 39 ° (0.40). IR .: 3350 (broad), 1730, 1645, 1245.

I70 mg of NaH dispersion are freed from adhering mineral oil by washing four times with absolute pentane. Benzene and gives 80 mg (20S) -3ß-methoxy-3a _J 9a-oxido-7a _f

^ -Methyl-N-chloroacetyl-amino ^ A ~ 5ß-pregnene in 5 val abs. Tetrahydrofuran too. Finally, a drop of a solution of 20 mg of ethanol in 10 ml of abs is added. Benzene boils to nand under argon and stirring for 2 hours. O ₅ H ml of methanol are then added and the mixture is boiled for a further hour to hydrolyze the acetate groups on C-7 * C-II and C-20. Then it is added to saturated aqueous (NH] I) o ^s0 4 "solution, extracted with ethyl acetate. ,, washed neutral with saturated aqueous NaCl solution, dried and evaporated the organic phase in vacuo ) _r 3ß-methoxy-3a, 9a-oxido-7o, 11a, 20-trihydroxy-14ßO, 18N- [ep (oxy

309850/1203 '

2 '-oxo-ethano) -N-methylimino) 3-A -5ß-pregnen (IR .: 3500 (broad) ,,

j oils can be acetylated in 4 ml acetic anhydride-pyridine (1: 1) mixture overnight at room temperature without purification. It is then evaporated in vacuo and chromatographed in ethyl acetate-methanol (9: 1) solution: 47 mg of crystals of (20S) -3β-methoxy-3a, 9a-oxido-7a-hydroxy-IIIa, 20-diacetoxy are thereby obtained -14βO, 18N- [ep (oxy- (2 ^l -oxo-ethano) -N-methylimino)] - A -5β-pregnens, which melt after crystallization at 254-255 °, [α] = + 114 ° (0.40). IR.:. 3510, 286O ₃ 2840, 1730, 1635, 1240.

30 mg of the product thus obtained are in 0.9 ml of abs. Leave pyridine with 0.02 ml SOCl for 2 hours at room temperature. Then pour into aqueous NaHCO solution and extract with ethyl acetate and washes neutral with saturated aqueous NaCl solution. That obtained after drying and evaporation of the organic phase The crude product becomes ethyl acetate in the solvent system by means of preparative Purified thin layer chromatography. 15 mg thin layer are chromatographed uniform (20S) -3ß-methoxy ~ 3 &, 9ß-oxido-lla, 20-

7 l6 diacetoxy-l4ßO, l8 N-ep [(oxy- ^(2-oxo-f äthano) -N-methylimino)] - A '5ß-pregnadiene obtained in amorphous form. IRs 2840, I73O, I65O and I635 (double band) 125Ο.

19 mg of this product are in 3 nil abs. Ether with 40 mg LiAlHi, cooked for 5 hours. Then the excess hydride is destroyed by carefully adding saturated, aqueous (NH ^) SO ^ solution and then gives 5-proζ. aqueous NH -, - solution. Then extracted it is washed with ethyl acetate, washed neutral with saturated aqueous NaCl solution, dried and the organic phase is evaporated in vacuo

309850/1209

a. The resulting crude product is purified by means of preparative thin-layer chromatography in the system cyclohexane-chloroform-triethylamine-methanol (ΐ6ϊ4: 1: ΐ). In this case 10 mg of the resulting einheitliche.n (20S) -3ß-methoxy-3a.9a-oxido-.lla, 20-dihydroxy-l4ßO _J 18 N- [epoxyäthano-N-methyllmino) 3-A--5ß pregnadiens in amorphous Shape. IR: 33 ^ 0, 2840, 1100 ,. 99Ο.

10 mg of this product are in Ij5 ^m l 90 ₅ percent strength aqueous acetone with I ₃ 5 mg p-toluenesulfonic acid 1 hour cooked. Then you add to dilute aqueous 5 percent. NH -, - solution., Extracted with ethyl acetate and washed neutral with saturated aqueous NaCl solution. The crude batrachotoxinin A resulting after drying and evaporation of the organic phase is purified preparatively on thin-layer plates in the system cyclohexane-chloroform-triethylamine-methanol- (16: 4: 1: 1). This results in 5 mg of batrachotoxin A in amorphous form, which, according to thin-film chromatograms, turns out to be identical to natural batrachotoxin A in the systems cyclohexane-chloroform-triethylamine-methanol-ilG: ² ) -;!:! or 16: 4-: 1: 2) and ethyl acetate-methanol {4: 1), - as well as IR, mass and NM R spectrum ^ proves to be identical.

In the case of Witkop (Journal of the American Chemical Society 91j 3931 (1969) published NMR spectrum of natural batrachotoxinin A is the spectrum of the corresponding deuterochloride, which was recorded before the NMR contaminated deuterochloroform is formed. Moreover In addition, various signal assignments had to be changed .. The NMR values for synthetic and natural batrachotoxin A are:

Oj88 / s CH, -19, l * 40 / d / u ~ = 7 CH -21, 2.32 + 3.2l / 2d / j, _Ί = 19 (to-

309850/1209

Additional fine structure through J _χ6 = each 'approx. 2) CHg-15, 2.35 / s 2.71 / s CH ₂ -18.

3-, 78 / d / J ..., _ΊΟ = 9 (additional fine structure through J _{11 1i3fi} = 4) CH-Il, 4.46 / q / J = 7 CH-20, 5.66 / ra GH-16 , 6.2Vm CK-7, in the range of 2-4.2 ppm there are also the complex signals of the four bridge protons (CDCl ^ + D ₃ O) ₀ . . ·. ·

Example 1?

The conversion of the product obtained in Example 9 in 3-0-methyl-7,8-Dihydroepi batrachotoxinin-A can be carried out as follows ι

200 mg of (20R) -3ß-methoxy-3.beta. _J 9a-oxido-lla _i-20 diaeet © xyl4ß-methyl-thiomethoxy-lS-öXo ~ A -5ß-pregnene are dissolved in 4 ml of abs. Benzene with 2 ml of saturated benzene methylamine solution for 7 hours

heated to 80 ° in the bomb tube. Then you cool down and steam in Vacuum a. The resulting 205 mg of the crude marine base of the aldehyde used are reduced in 15 ml of methanol with 200 mg of sodium borohydride in 1 ml of water at 15 ° for 10 minutes. Then work up and then dissolve the amine obtained (200 mg) in 20 ml of alcohol-free chloroform. At 0, 1.5 ml of chloroacetyl chloride and 140 mg are added to this solution while stirring frequently Sodium hydroxide in 20 ml of water. Do 15 minutes to work up. This results in 250 mg of crude 3ß-methoxy-3 ©, 9a-oxido-lla, 20-diacetoxy-14ß-methyl-thiomethoxy-18- (N-methyl-N-chloroacetylamino) ' -Δ- -5ß-pregnen this again without cleaning for 2 hours in the room

- 3098S0 / 1209

temperature in 20 ml 0.05 N-abs. HCl is left in methanol. Repeated work-up and chromatography in benzene-ethyl acetate (1: 1) solution finally yields 80 mg. methyl-N-chloroacetyl-amino) -Δ -5β-pregnen _J after purification by crystallization, the melting point 176-178 °, the rotation [α] = + 35 ° (0.29) and the IR bands 335Ο (broad ), 1725, 1640, 1245, and which with that described in Helvetica Chimica Acta 5 ^, P-2793 (1971) as 3ß-methoxy-3a _J 9a-oxido-lla _J 20 | -diacetoxy-14ß-hydroxy-18 - (N-methyl N-chloroacetyl-amino) -A -5ß-pregnen designated compound is identical.

The transfer of this product according to the information in HeIv. Chimica Acta loc. cit. in the compound described there as 3-0-methyl-2oi-7 _JS 8-dihydrobat'rachotoxinin, the 2OR epimer of 3-O-methyl-7,8-dihydroepi-batra.chotoxinin A _{3 is obtained} from which one can saponify the etherified The 7j8-dihydrorepi-batrachotoxinin A is obtained in a manner known per se from the hydroxy group in the 3-position.

Example l8

The conversion of the product obtained according to Example 10 in 7i8-Dihydrobatrachotoxinin A can be carried out as follows will:

The (2OS) -3ß-methoxy-3a, 9α-οχίαο-11α, 20-diacetoxy-l4ß-

methyl-thiome.thoxy-IS-oxo-A 5ß-pregnen is according to the above Example given instructions in the (20S) ~ 3ß-methoxy ^ a ^ a-oxido-lla ^ O-diacetoxy- ^ ß-hydroxy-lS-iN-methyl-N-

309850/1209

■ -37 -

chloroacetyl-amino) -A -5β-pregnen), whereby 213 mg of this amorphous compound are obtained by chromatography in benzene-ethyl acetate (1: 1) solution.
IR: 3450 (broad), 1725, 1645, 1250.

320 mg Na Η dispersion are freed from adhering mineral oil by washing four times with absolute pentane. Then overlay with 10 ml abs. Benzene and are under argon 228 mg of the above chlorine acetate in 10 ml of abs. Tetrahydrofuran too. Finally, a drop of a solution of 20 mg of ethanol in 10 ml of abs is added. Benzene and boiled under argon and stirring for about 6 hours. It is then cooled to 0 and the excess hydride is carefully _{decomposed with saturated aqueous (NH 4} ) SO ₄ solution. Customary work-up and chromatography in ethyl acetate finally give 156 mg of crystals of (20S) -3ß-methoxy-3a, 9a-oxido-IIIa, 20-diacetoxy-14ßO, 18N- [ep (oxy- (2 ^J -oxo-ethano) - N-methylimino)] - A ^lo -5β-pregnens. After crystallization 166-168 °. [α] _ = + 12 ° (l, l4). IR .: 1730, 1634, -125 0. ^

40 mg of the compound obtained are then mixed with 100 mg of LiAlH ₄ in 10 ml of boiling abs for 5 hours. Aether reduced. After the excess hydride has been destroyed by careful addition of saturated aqueous (NH _{4 I 3} SO ₄ solution, it is added to 5% aqueous NH, solution and worked up as usual. 16: 4: 1: 1) "gives 30 mg crystals of (20S) -3ß-methoxy-3a, 9a-oxido ~ Ila, 20-dihydroxy-14ß0, 18N- [ep (oxyethano-N-methylimino) 1-Δ -5ß-preg-

[& 1 +57

nen. After crystallization at 151-152. [& 1-Q = +57 (0.33) · IR .: 36OO, 3450 (broad), 2810, IIO5, 1000, 96Ο.

■ - '309850/120 9

36 mg of the compound thus obtained are boiled with 28 mg of p-toluenesulfonic acid in a mixture of 7 ml of acetone and 0.7 ml of water for 1 hour. Then you give 5 percent. aqueous NH solution and works up as usual. Preparative thin-layer chromatography of the crude product in the system cyclohexane-chloroform-triethylamine-methanol- (l6: 4: l: 3) gives 3I mg crystals of (2OS) -3ρ-hydroxy -3α, 9α-oxido-lla ,, 20-dihydroxy-ΐ4βθ ^ 18W- [ep (oxyethano-N-methy! imino)] - Δ ¹ -5βpregnen (= 7,8-Dlhydrobatrachotoxinin A), which melt ^{once recrystallized at 169-170 0.} [a] _D = + 57 ° (0.64), IR .: 3580, 3,000 (broad), 2810, iioo, 1080, 1065, 1030, 1010, 1000, 960, 925, 855.

3 09850/1209

Claims (1)

Patent claims: 1. Process for the preparation of Δ - steroid-14J3,18,2O-triplets and Δ -steroid-14β, 2O-diol-18-alene of the pregnane series and their esters and ethers whose 17-pregnane side chain has one of the following two partial formulas - HR'-D TT ~ - - 20 S configuration 20 R configuration wherein R is a free, esterified or etherified hydroxyl group T 6 represents, characterized in that one δ -20-Oxo * - steroid-14j3,18-diol of the pregnane series, in which the 14,18-diol group is ketalized with a ketone, with a complex light metal hydride, which an Oxogrupp.e to the hydroxyl group reduced but leaves esterified hydroxyl groups intact, treated, and, if desired, in any order and optionally at the same time from the mixture of the 20 S- and 20 R-hydroxy compounds formed or their functional ones Derivatives, at least one of the two epimers isolated in a manner known per se, and / or optionally sets existing protected functional groups free and / or functionally modifies functional groups and / or the 18-hydroxy group is selectively dehydrogenated to the 18-oxo group. 309850/1209 2. The method according to claim 1, characterized in that one an alkali borohydride is used as the complex light metal hydride. 3 · The method according to claim 2, characterized in that one Sodium borohydride is used. 4. The method according to any one of claims 2-3, characterized in that that the reduction is carried out in an alcohol. 5. Process according to one of Claims 2.-K, characterized in that a lower aliphatic alcohol is used. 6. The method according to claim 5 *, characterized in that one Methanol or ethanol used. 7 · The method according to claim 1, characterized in that one a complex alkali-aluminum hydride-of the type (X) X ₀ O-Al ² ι - H Me wherein X- ,, X _p and X ^ each represent a tertiary lower alkyl group and Me an alkali metal, is used. 8. - The method according to claim 7, characterized in that one Tri-tert. butoxy-lithium aluminum hydride or tri-tert. amyloxy-lithi- 309850/1209 H- um aluminum hydride used. 9. Method according to one of claims 7-8, characterized in that that the reduction is carried out in an ether. 10. The method according to claim Q _3, characterized in that diethyl ether, di-isopropyl ether, dioxane or tetrahydrofuran is used as the solvent. 11. The method according to any one of claims 1-10, characterized in that that one reduces above 0. 12. The method according to any one of claims 1-10, characterized in that that one reduces below 0. ' 13. The method according to any one of claims 2-6, characterized in that that one reduces at temperatures between - 50 and 0. 14. The method according to any one of claims 7-10, characterized in, that you reduce between 0 and 100. 15. The method according to any one of claims 1-14., Characterized in, that the separation of at least one of the epimeric 20-hydroxy compounds from the reduction mixture before the modification function © Her groups. 309850/120 l6. Method according to one of Claims 1-14, characterized in that that the separation of at least one of the ,, epimers 20-hydroxy compounds from the reduction mixture after the free Setting of functional groups from functionally modified groups undertakes. 17 · Method according to one of claims 15 or 16, characterized
characterized in that the separation is carried out by crystallization or chromatography. 18. The method according to any one of claims 1-17, characterized in, that ketalized oxo groups or the ketalized 14,18-diol group are cleaved by the action of acidic agents. 19. The method according to claim l8, characterized in that a mineral acid or an organic carboxylic acid is used. 20. The method according to any one of claims I-I8, characterized in that that one cleaves ester groups by the action of basic agents. 21. The method according to claim l8, characterized in that a 14, 18-ketal group is cleaved using p-toluenesulfonic acid. 22. The method according to any one of the preceding claims, characterized in characterized in that, after the 20-epimeric alcohols have been separated off, free hydroxyl groups are esterified or etherified. 27). Process according to Claim 22, characterized in that the 20-hydroxy group is esterified after the separation of at least one of the 20-epimeric alcohols and before the cleavage of a ketalized 14,18-diol group. 2h. Process according to one of Claims 22-23, characterized in that the esterification is carried out by treatment with a carboxylic acid anhydride or carboxylic acid halide in the presence of a tertiary base. 25. The method according to any one of the preceding claims, characterized characterized in that one has the optional etherification of free hydroxyl groups by treatment with an alkyl halide, an alkyl sulfate or dialkyl sulfate in the presence of an organic or inorganic one Base executes. 26. The method according to any one of the preceding claims, characterized in that the selective dehydrogenation of the 18-hydroxy group to the oxo group after previous protection of other oxidizable free ones Makes hydroxyl groups. 27. The method according to claim 26, characterized in that a compound of hexavalent chromium is used for dehydration. 309850/1209 28. The method according to claim 26, characterized in that a mixture of a sulfoxide of one of the formulas is used for the dehydrogenation Yl / CH - V CH - O = s' ^ O = S ^ ^X C - V or 0 C) ^{3 4} D) and a carboxylic acid anhydride, in which formulas V - V are hydrogen or alkyl or aryl groups and 0 is an aryl group. Process according to Claim 28, characterized in that sulfoxides of the formulas given are used in which V - V are lower alkyl groups or phenyl lower alkyl groups and 0 is a phenyl nucleus. 30. The method according to claim 29, characterized in that a compound of formula C) is used in which V-. - V _n . Mean hydrogen or lower alkyl groups and which contains no more than 8 carbon atoms in total. 31 · The method according to claim 3'Oj characterized in that one uses dimethyl sulfoxide. 309850/1209 - «s - 2325808 32 »Method according to one of claims 28, - 31j characterized in that that you have a lower aliphatic carboxylic acid anhydride used. 33 · The method of claim 32, characterized _s that Birnethylsulfoxyd and acetic anhydride characterized used. J) k. Process according to one of the preceding claims , characterized in that a 2-thiapropanol or 2-thiaaryl ethanol of one of the formulas formed in the dehydrogenation according to the method of claims 28-33 with a sulfoxide corresponding to the sulfoxide used ² | ^{B) 0H} egg wherein V, - V ₁ - and fi have the meaning given in claim 28, etherified 14-hydroxyl group is cleaved to the free 14-hydroxyl group by acid treatment or by treatment with chloramine T in dioxane-water. 35 · The method according to any one of the preceding claims, characterized in that "that one compounds of the formula 30385Q / 1209 III producing, in which P has the abovementioned claim 1 -importance and R is a free or protected oxo group or a free, esterified or etherified hydroxyl group together with a hydrogen atom, · Rp represents two hydrogen atoms or a hydrogen atom in addition to J, 8-double bond, a protected oxo group or a hydrogen atom together with a free , esterified or etherified hydroxyl group, R two hydrogen atoms or a hydrogen atom next to a 9 * H ~ double bond or a free or protected oxo group or a free, esterified or etherified hydroxyl group together with a hydrogen atom, R ^ denote a hydrogen atom or a free, esterified or etherified hydroxyl group and Z and Zp each represent a free, esterified or etherified hydroxyl group and Z, and Z _p together represent a ketalized 14 ₅ 18 -diol group and Z but also represent an oxo group, and in which in one of the 4,5 or 5 * 6 gradations and / or optionally in the case that Rp or R ₂ ^ a what hydrogen atom means that double bonds can also be present in one of the 7 * 8- and / or 9.11-position, 36. The method according to claim 35 , characterized in that an esterified hydroxyl group is derived from a carboxylic acid with 1-8 carbon atoms, an etherified hydroxyl group is derived from an alcohol with 1-8 carbon atoms. 3 0 9 8 5 0/1 2 0 9 ORIGINAL INSPEGTHD 37 · Method according to one of claims 35-36; characterized in that compounds of the formula III are prepared in which Z, the aldehyde group and Z _{p is} one of a 2-thia-propanol or 2-thia-aryl ethanol of the general formulas V ν ¹ '3 1 j ~? " ^V 4 ^{or ν} ι - ^c - S ς - OH wherein V-, - Vj- hydrogen "or alkyl, aryl or aralky l groups and 0 signifies an aryl group, denotes etherified hydroxy group derived. 38. The method according to claim 37 *, characterized in that one Preparing compounds wherein Z is one of a 2-thiapropanol with etherified hydroxyl group derived from up to 8 carbon atoms. 39 · The method according to claim 38, characterized in that compounds are prepared in which Z etherified one with 2-thiapropanol Is hydroxyl group. 40. The method according to any one of the preceding claims, characterized characterized in that one compounds of the formula 309850/1209 IV produces, wherein P has the meaning given in claim 1, A represents a hydroxyl group together with a hydrogen atom or a Oxo group X an etherified or esterified hydroxyl group and Y and Z each represent an esterified hydroxyl group and their esters and ethers and ketals of the 14,18-diols. 4l. The method according to claim 40, characterized in that compounds are produced in which the ester groups of lower aliphatic carboxylic acids with 1-6 carbon atoms are etherified hydroxyl groups derive from alcohols with 1-5 carbon atoms or from a 2-thiapropanol with a total of up to 8 carbon atoms and a ketal group is different from a ketone of the formula O = C, derives, in which W and W are two lower aliphatic hydrocarbon radicals with 1-6 carbon atoms or together with the carbon atom that they are bound, an alicyclic hydrocarbon radical with 1-12 carbon atoms and 5-7 ring carbon atoms mean. 309850/1 209 42. The method according to claim 4l, wherein compounds of the formulas. ■ "'* Alk O 3B! AcO _it O OH (VII) 'QAe Alk Ό OAc manufactures., wherein Alk for a lower alkyl group with 1-6 carbon atoms, Ac for a lower aliphatic acyl radical with 1-6 carbon atoms and P ¹ for one of the two partial formulas (VIII) 1? CH
3 .20 S configuration ix OR » 20 R configuration ι t f are, in which .R is hydrogen or a nxederaliphatic acyl group with 1-6 carbon atoms means and 14,18-ketals of the compounds of Formula .VI, in which the ketal group differs from a ketone eier formula derives where W-. and W _p two lower aliphatic hydrocarbon radicals with 1-6 carbon atoms or together with the carbon atom to which 309850 / 12-09 ORIGINAL INSPECTED - YOU ~ "' they are bonded, mean an alicyclic hydrocarbon radical with 1-12 carbon atoms and 5 ~ 1 ring carbon atoms, and 14-ethers of the compounds of the formula VII which are derived from a 2-thiapropanol with a total of up to 8 carbon atoms. · 43? The method according to claim 42, characterized in that an ether group in the 14-position is derived from 2-thiapropanol., 44. The method according to any one of claims 42-43, characterized in that that esterified hydroxyl groups are acetyl groups and Alk represents a methyl group. 45. The method according to any one of the preceding claims 35-44, characterized in that one of l4, l8-ketals of corresponding Δ -20-oxo-pregnane compounds, in which the ketal group is of a ketone of the formula derives, in which W and W "have the meaning given in claim 41 own. 46. The method according to claim 4'5, characterized in that acetonide is used. 3 0 9 8 50/1209 -SA- 47 · Method according to one of the preceding claims, characterized in · characterized in that after the reduction of the 14,18-ketals Δ -SO-oxosteroid-l ^ lS-diols with a complex light metal hydride, the 20-hydroxy group is aylated in the compounds obtained acid treatment cleaves the 14-, 18-ketal group and the 18-hydroxy group dehydrated with a lower aliphatic dialkyl sulfide in the presence of a lower aliphatic carboxylic acid anhydride and optionally at least one of the formed at any stage epimeric 20 R-OH and 20 S OH or -OAc compounds isolated. 48. The method according to claim 47, characterized in that one undertakes the isolation of an epimer immediately after the reduction step. ■ 49. The method according to any one of claims 47-48, characterized in that that one is a Niederaliphatiscb.es 14,18-ketal of a compound of formula p, Alc used as a starting material in which Alk is a lower alkyl group with 1-6 carbon atoms and Ac is a lower aliphatic acyl group with 1-6 Means carbon atoms. '' 309850/1209 - 52 - 7325806 50. The method according to claim Kty, characterized in that acetonides are used as the starting point and 2-thiapropanol and acetic anhydride are used for the dehydrogenation of the 18-hydroxy group. 51. The method according to claim 50, characterized in that to reduce sodium borohydride in absolute methanol at -30 °. 52. The method according to claim 51, characterized in that one of the (14 / J - > 18) -Äcetonid des 3j3-methoxy-3a, 9cc-oxido-IIIa-acetoxy-14 #, 18-dihydroxy-20-oxo-A -5i3-pregnen goes out and the (2OR) - 3/3-methoxy-3a, 9a-oxido-ila, 20-acetoxy-14 £, 18-dihydroxy ~ A -5 / 3-pregnen and the (20S) - Sß-methoxy-Sa, 9a-oxido-IIIa, 20-diacetoxy-14ß, 18-dihydroxy-Δ -5 / 3-pregnen. 53. The method according to claim 5O, characterized in that tri-tert-butoxy-lithium-aluminum hydride for the reduction 70 used in absolute dioxane. 54. The method according to claim 53, characterized in that the (20R) -3 / 3-methoxy-3a, 9, a-oxido ~ llcc, 20-diacetoxy-14j3, 18-dihy ~ droxy-Δ -5β-pregnen and the (20S) -3β-methoxy-3a, 9a-oxido-IIIa, 20-diacetoxy-14j3,18-dihydroxy-A -5ß-pregnen produces. 3 Ü Β 8 ο 0 / i 2 U ■■■. ■■■■■ - ■■■ - 53 - 55 · Method according to one of claims 52 or ^ h ₃ thereby characterized that the 20 R or the 20 S ~ 3ß-methoxy-3a, 9 <~ - oxido-llct, 20-diacetoxy-14β, 18-aihydroxy-A -5 / 3-pregnenmit Treated dimethyl sulfoxide and acetic anhydride and the 20R or 20S ~ 3ß-methoxy-3a, 9a-oxido-lla, 20-diaeetoxy-14ß-0-methylthiomethoxy-18-οχο-Δ -5ß-pregnen isolated. 56. The method according to any one of claims 52 or 54., characterized in that one of the (14-? 18) -acetonide des ^> ß j l8-dihydi ^> oxy-20-oxo-A -5ß-pregnen and the (20S} -33_-methoxy-3a, 9a-oxido-7a, lla, 20-triacetoxy-14j3, 18-dihydroxy-A -5ß-pregnen produces. 57. The method according to claim 56, characterized in that one the (2OS) -3-methoxy-3a, 9a-oxido-7a, 11a, 20-triacetoxy-14j3,18-dihydroxy-Δ -5ß-pregnen with dimethyl sulfoxide and acetic anhydride to (2OS) -3 / 3-methoxy-3a, 9a-oxido-7a, 11a, 20-triacetoxy-14ß-0-methyl-thiomethoxy-18-oxo-Δ -5ß-pregnen produces. OBlQItMAL INSPECTED 30 9 850/1209