DE2429644C3 - Process for the preparation of desmosterol, the hydroxyl group of which is optionally protected in the 3-position - Google Patents

Description

IO

R-hO

wherein R denotes a hydrogen atom and η 1 or R denotes a monovalent or divalent protective group and η 1 or 2, characterized in that 24-hydroxycholesterol, the hydroxyl group of which is protected in the 3-position, or a bis-form derivative thereof of the following formula 1

OH

R +

(1)

R-r-O-

where R is a monovalent or divalent protective ring and η is 1 or 2.

HO

where R is a monovalent or divalent protective group and η is 1 or 2, with (A) phosphorus pentoxide or acidic potassium sulfate or (B) phosphorus oxychloride, thionyl chloride or sulfonyl chlorides in the presence of a tertiary amine and the desmosterol derivative optionally with elimination of the protective group (- R or - R -) hydrolyzed or reduced.

and its derivatives are valuable compounds as intermediates for biologically active steroids or for active forms of vitamin D ₃ such as 1,23-dihydroxycholecalciferol, 24,25-dihydroxycholecalaferol and 25-hydroxycholecalciferol.

It is known that Desmosterol or its derivatives can be prepared from 3 / i-acetoxy-5-cholenic acid by Srf-acetoxy-S-cholenaldehyde from the starting material via the acid chloride of S / i-acetoxy-S-cholenic acid and synthesized ethyl 3 / i-acetoxythiol-5-cholenate and then subjecting the aldehyde to the Wittig reaction with isopropyl bromide, with desmosterol-3-acetate is formed (see. J. Am. Chem. Soc, 79. S 6473) It is also known that desmosterol-3-acetate from Can produce methyl 3 / f-hydroxy-5-cholenate via a six-step process (cf. US-PS 11 52 152) or that it can be made from methyl 3 / ί-acetoxychol-5-en-24-carboxylate can be produced in five stages (cf. J. C. S. Perkin, I [1973]. 2423 to 2425). . .

In all of these known processes, however, 3 / i-hydroxycholenic acid of the following formula 4 is used as Starting material used:

COOH

The invention relates to a process for the preparation of desmosterols and their derivatives. the The invention relates in particular to a method which is characterized in that 24-hydroxycholesterol, whose hydroxyl group is protected at the 3-position, or a bis-form derivative thereof, such as expressed by the following formula 1, dehydrated to form desmosterol, its hydroxyl group is protected at the 3-position, or whereby the bis-form derivative thereof is obtained by the following formula 2

This connection is very expensive. These known methods are also many and complex Stages are required until the desired product is obtained, and this will only be insufficient Yields obtained. These processes are therefore not very suitable for industrial practice.

It has also been suggested that 25-ketone cholesterol of the following formula 5

to use as a starting material, which in 25-hydroxycholesterol converted by Grignard reaction and then dehydralisicrt in the presence of sulfuric acid or phosphorus oxychloride, whereby Desmosterol or an ester thereof is obtained (cf.. 1. Org. Chem., 23 p.459, and J. Lipid Research, 8, p. 152). However, this method again has such disadvantages that that as a starting material

25-ketone cholesterol used is expensive and that The yields in the dehydration reaction are low. Especially when phosphorus oxychloride Used in the reaction, substantial amounts of 25-dehydrocholesterol-3-acetate are by-produced educated. Thus, the method cannot be regarded as industrially advantageous.

The present invention is therefore based on the object of a new process for the production of Desmosterol derivatives to be created by a reaction that contains fewer steps, whereby the desired product is obtained in high yield. Another object of the present invention is therein, a process for the preparation of desmosterol derivatives in high yield from 24-hydroxycholesterol to create whose hydroxyl group is protected in the 3-position, or from the bis-form derivatives of this through a simple dehydration reaction.

The technical progress achieved according to the invention can be seen in the fact that compared to the prior art higher yields are possible and that the starting material used according to the invention is easy is obtained from fucosterol, which occurs in large quantities in empty plants.

The invention thus provides a process for the preparation of Desmostcrol, its hydroxyl groups is optionally protected in the 3-position, or a bis-form derival thereof of the following formula

group is protected in the 3-position, or a bis-form derivative thereof of the following formula 1

R-r-O

(D

in which R is a monovalent or divalent protective group and »3 is 1 or 2, with (A) phosphorus pentoxide or acid potassium sulfate or (B) phosphorus oxychloride thionyl chloride or sulfonyl chlorides in the presence of a tertiary amine and the desmosterol derivative, optionally with elimination the protecting group (—R or —R-) hydrolyzed or reduced.

Output connections

With reference to the definitions given in formula 1 above, there can be used as starting materials in the present invention: Compounds in which, when 11 is 1, R is a monovalent protecting group and, when η is 2 , R is a divalent group. Accordingly, formula 1 includes two groups of compounds of the following formulas 1-a and 1-b

OH

35

wherein R is a hydrogen atom and η 1 or R is a monovalent or divalent protective group and η 1 or 2, which is characterized in that 24-Hydroxycholestcrol, whose hydroxyl

(1-a)

wherein R is a monovalent protecting group, and

OH

(1-b)

O R -

wherein R is a divalent protecting group.

The formula 1-a corresponds to the cases where in the formula 1 η denotes 1, and the formula 1-b corresponds to the cases in which in the formula 1/1 denotes 2.

The group R in the above formula 1 may be any protecting group as far as appropriate Process such as by hydrolysis, reduction or the like after the compounds of formula 2 according to the invention can be converted back into a hydroxyl group without affecting the structures the compounds of formula 2 or their derivatives are destroyed or changed.

The group R in formula 1-a means cin-

55 valent protecting groups, and in formula 1-b it means divalent protecting groups.

Preferred examples of such protecting groups R include the following:

A. Substituted or unsubstituted, saturated or unsaturated and monovalent or divalent hydrocarbon radicals having 1 to 12 carbon atoms and

B. substituted or unsubstituted and saturated or unsaturated carboxylic acid residues with 1 to 12 carbon atoms, for example the acyl groups derived from such carboxylic acids.

That R is such a hydrocarbon residue in the Group A is above, means that the hydroxyl group in the 3-position of the 24-hydroxycholesterol gc-

protects and forms an ether. If, on the other hand, R represents a radical from group B, it means that the hydroxyl group is protected by a carboxylic acid.

The protective groups are explained below using specific examples. The group A hydrocarbon radicals can be roughly divided into two large subgroups, namely aliphatic hydrocarbon radicals and aromatic hydrocarbon radicals. In both cases the hydrogen atom or the atoms of the radicals can be substituted with inert substituent groups such as halogen atoms, alkoxy, nitro, acyl, carboxyl, esters of carboxyl, alkyl (only for aliphatic hydrocarbon radicals ) and aromatic groups (only for aromatic hydrocarbon radicals) being. In addition, the methylene groups of the aliphatic hydrocarbon radicals can be substituted with oxygen atoms and form ethers.

Specific examples of aliphatic hydrocarbons include alkyl groups such as methyl, ethyl, n-propyl, η-butyl, n-pentyl, n-hexyl, heptyl, octyl, nonyl, dodecyl, isopropyl, isobutyl, sec-butyl, t-butyl , isopentyl, neopentyl, terpentyl, isohexyl, cyclopentyl and cyclohexyl; Alkenyl groups * 5 such as allyl, butenyl, isopropenyl, hexenyl and cyrlohexenyl; Alkylene groups such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene; aliphatic hydrocarbon radicals substituted with monovalent inert substituent groups such as chloromethyl, / i-chloroethyl, benzyl, nitrobenzyl, cinnamyl, chlorobenzyl and phenethyl; and aliphatic hydrocarbon radicals in which the methylene group is substituted with an oxygen atom such as tetrahydropyranyl and methoxymethyl.

Of the examples given above, particularly preferred are alkyl groups having 1 to 6 carbon atoms and benzyl groups. Specific examples of aromatic hydrocarbon groups include aryl groups such as phenyl and naphthyl; Arylene groups. such as phenylene and substituted aromatic hydrocarbon radicals such as ToIyI, ethylphenyl, cumenyl, chlorophenyl and methoxyphenyl.

The carboxylic acid residues of group B can further be divided into two large subgroups, namely aliphatic carboxylic acid residues and aromatic carboxylic acid residues, in which the hydrogen atom or the atoms with monovalent, inert substituent groups such as halogen atoms, alkoxy, nitro, acyl, carboxyl, esters of carboxyl, alkyl (only for aromatic carboxylic acid residues) and aromatic groups (only for aliphatic carboxylic acid residues) can be substituted.

Specific examples of such carboxylic acid residues include: saturated aliphatic monocarboxylic acid residues such as acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, capronyl, capryryl, laurayl, cyclohexanoyl and cyclopentanoyl; unsaturated aliphatic monocarboxylic acid residues such as acrylyl, methacrylyl, n-ethylacrylyl. / i-methylcrotonyl, crotonyl, heptanoyl and algcloyl; substituted uliphatic carboxylic acid residues such as fluoroacetyl, chloroacctyl, bromoacctyl, dichloroacetyl. Trichloroacetyl, -chloropropanoyl, -bromocapronyl, phenylacetyl. Phenylpropanoyl, cinnamoyl. Naphthylacetyl, m-nitrocinnamoyl. p-nitrophenyl- <> 5 acetyl, nitrophenylpropanoyl, acctoacetyl, levulinoyl. C'arboxyacetyl, methoxycarboxyacetyl, m-carboxypropyl octyl, carboxyphenyl octyl and carboxynaphthyl acetyl; saturated and unsaturated dicarboxylic acid residues such as oxalyl, malonyl, succinyl, glutaryl. Adipoyl, Sebacyl, Malcyl, Fumaryl, Glutaconoy! and dihydromuconoyl, and substituted aliphatic dicarboxylic acid residues such as chloromalonyl, bromomalonyl. Dichloromalonyl, chlorosucciny! and bromosuccinyl.

As specific examples of aromatic carboxylic acid residues, the following should be mentioned: aromatic monocarboxylic acid residues such as benzoyl and naphthoyl; aromatic carboxylic acid radicals substituted with monovalent, inert substituent groups such as ethylbenzoyl, toluyl, trimethylbenzoyl, methylnaphthoyl, Fluorobenzoyl, chlorobenzoyl, dichlorobenzoyl, chloronaphthoyl. Nitrobenzoyl. Dinitrobenzoyl. Methoxybenzoyl, carboxybenzoyl. 2,4-dicarboxylbenzoyl, Carboxynaphlhoyl and methoxycarbonylbenzoyl; aromatic dicarboxylic acid residues such as phthaloyl, Isophthaloyl, terephthaloyl and naphtholoyl. and aromatic dicarboxylic acid residuesc. substituted with monovalent, inert substituent groups such as chlorophthaloyl, Chlorotercphthaloyl. Dichlorterephthaloyi and Nitroierephthaloyl.

The 24-hydroxycholestcrol derivatives. as a starting point can be used in the method according to the invention can easily in high Yields can be synthesized from fucosterol, which is found in large quantities in marine plants that grow too belongs to the brown algae, occurs and in large quantities in industrial wastewater from industrial plants, how sodium alginate is produced occurs. An example of a synthesis process exists in that one oxidizes a fucosterol derivative with ozone in the usual way, with 24-KelocholestcroI -derivate are easily formed, and this 24-octocholestcrol derivative with a suitable reducing agent treated, whereby the desired 24-Hydroxycholcslcrolderivat in high yields is obtained

Dehydration agent and dehydration reaction conditions

According to the invention, compounds of the aforementioned formula, i.e. those of the formula 1-a or 1-b, with a dehydrating agent. which is described below, treated as well as possible to cause the hydration reaction.

The following dehydrating agents have been found to be effective in the present invention are:

Phosphorus pentoxide.
acidic potassium sulfate.
Phosphorus oxychloride.
Thionyl chloride and

AI
A-2
BI
B-2
B-3 sulfonyl chlorides.

It has also been found that other known dehydrating agents other than those listed above five ways that are essentially ineffective.

Of the above-mentioned agents, preferred are dehydrating agents A-I. A-2, B-I and B-2 used, phosphorus pentoxide (A-I) is the cheapest agent.

The starting mark used in the present invention, i.e. H. 24-hydroxycholeslcrol, whose hydroxyl group is protected in the 3-position. or a bis-form derivative thereof

by Formula 1, can not be in the Dcsmosterolderivat of the formula 2, which is to be represented according to the invention, with known dehydrating agents, such as with sulfuric acid, polyphosphoric acid and the like. It is surprising that the same starting material is used in Dcsmostcroldcrivate can be convicted with high bulges if the above five types of dehydrating products. in particular and preferably phosphorus pentoxide can be used. the specified dehydration agents are in proportions from 0.5 to 100 mol times. preferably the 1 to 50 molfachcn, the starting compound of Formula 1 used to advantage.

If phosphorus pentoxide (AI) or acidic potassium sulfate (A-2) is used as the dehydration agent, the dehydration reaction is preferably carried out in an inert solvent at temperatures in the range from -10 to 150.degree. C., preferably from -5 to 130.degree. In particular when phosphorus pentoxide is used, the optimum reaction temperature is in the range from -5 to 50 C. The dehydration conversion can usually be completed within 5 minutes to 20 hours. The reaction time is variable within this range depending on such factors as the reaction temperature and the type and amount of the dehydrating agent.
If either

30th

(B-I) phosphorus oxychloride.

(B-2) thionyl chloride or

(B-3) sulfonyl chlorides

should be used as a dehydrating agent the Dchydralisieriingsreaktion carried out in the presence of a tertiary amine as an acid acceptor will.

As sulfonyl chlorides, those of the following formula can be used

R SO ₂ Cl

wherein R 'is a monovalent organic group, is preferred an aromatic or aliphatic group having 1 to 10 carbon atoms, means with favorable Results are used. Methanesulfonyl chloride in particular is more precise. Toluenesulfonyl chloride and benzene sulfonyl chloride, for example, are preferred.

Alinhatisehe, for example, can be used as tertiary amines tertiary amines such as triethylamine. Tri-n-propyiamine. Tri-n-butylamine. Triisohutylamine. Dimethylethylamine. 1,4-diaza-bicyclof 2.2.2] octane and 1.5-diaza-bicyclof4.3.0] -5-nonane; aromatic amines such as dimethylaniline. Diethylaniline and Triphcnylamine: Pyridines: picolines; Lutidines: Collidines: Quinolines and heterocyclic compounds such as pyridazine and pyrimidine. preferably Ί riälhylamine. Tri-n-propylamine. Pyridines. Lutidine and collidine, can be used. 6c

Of the tertiary amines mentioned above, the act. those at the temperatures at which the cr Dehydration reactions are carried out, are liquid, also as inert solvents, except for the fact that they act as acid accretors.

The Dchydratisierungsumsel / uni; under use the Delndratisicrunüsmille (B-H. (B-2 | or (B-3) is used in the presence of 0.5 to 100 moles, preferably from 1 to 50 moles per mole of starting compound of formula 1 at -10 to ISO C. preferably 0 to 150 C. carried out with advantage. The reaction is usually completed within 5 minutes to 30 hours.

The dehydration reaction of the invention is preferably carried out in an inert solvent. Using phosphorus oxychloride (B-I). Thionyl chloride (B-2) or sulfonyl chlorides (B-3) as dehydrating agents. so should the implementation in The presence of a tertiary amine can be carried out as indicated above, If the tertiary amine at the reaction temperature is liquid. all or part of the inert solvent should pass through the tertiary amine be replaced.

The type of inert solvent is not critical, as long as it is a liquid medium. which is the dehydration reaction. based on the invention Manner is carried out, does not interfere and the output connections Formula I. the dehydrating agent and. if used, the tertiary Amine dissolves.

Such inert solvents can be mentioned, for example: aliphatic hydrocarbons, like petroleum ether. Ligroin. Hexane. Pentane. Cvclohcxan. Decalin and methylcvcyelohexane; aromatic hydrocarbons such as benzene. Toluene. Xylene and Ethylbenzene: halogenated hydrocarbons such as carbon tetrachloride. Tetrachloroethane and TeUachioethylene: Ether, such as ethyl ether. Tetrahydrofuran and dioxane. and esters such as ethyl acetate and butyl acetal. can be used to advantage.

In a preferred embodiment according to the invention, 24-hydroxycholesterol-3-aceteate is therefore used of the following formula 1-c

OH

11-el

CH ₃ COO -Λ

for example with phosphorus pentoxide in an inert Solvent reacted at a temperature in the range from -5 to 50 C, with a simple one-run reaction Dcsmosterol-3-acetate of the following formula 2-c

V "

(2-c)

CH ₁ COO -J _x

is formed with high yield.
The product, its separation and its purification

In the above-described dehydration implementation will be Dcsmosterol. its hydroxyl group in 3-SleIlun>: is protected. as it is by the 1-ormcl 2-;

is expressed

forms when the aforementioned 24-hydroxycholestcrol. whose hydroxyl group is protected in the 3-position. as it is expressed by the formula l-a,

the starting material is. In contrast, when bis-mold (2-a) 5 derivatives of the compound of the formula I-adh the compound of formula lh · ^{1 's} be used starting material, the corresponding bis-form

\ / \ / Dcsmoslerol derivative. its hydroxyl group in

3 position is protected. of the formula 2-b as follows, where R is a monovalent protective group

I L--

(2 B)

wherein R is a divalent protecting group.

After the reaction has ended, the reaction mixture contains if it contains the formed, desired product of the formula 2-a or 2-b, likewise the dehydrating agent or the decomposition product thereof in the form of a solid, and the Mixing is then usually a separation process for separating liquids and solids such as filtration, centrifugation, sedimentation or decantation. When the dehydrating agent is dissolved in the reaction mixture, the dehydrating agent! or decomposition products thereof separated by other stages for example, water can be added to the reaction mixture in order to remove the dehydrating agent or to extract the decomposition products thereof in water, and one can use the aqueous phase from the inert solvent phase containing the desired product, separate.

Of course, the solid and the liquid can also be separated by aqueous extraction or the separation of solid and liquid can be carried out together with aqueous extraction be performed.

The desired product can be obtained from the reaction mixture from which the dehydrating agent or the decomposition products were separated therefrom, separated by distilling off the inert solvent or you can focus the system in a suitable way first and if necessary then recrystallize the product from other suitable solvents, or the system can be used submit to column chromatography. Through these measures, the desired product can be separated will also be cleaned.

According to the invention, the reaction mixture containing the desmosterol thus formed or the bis-form derivatives thereof, in which the hydroxyl group is protected in the 3-position, is expressed by the formula 2-a or 2-b, hydrolyzed or reduced, either directly or after the removal of the dehydrating agent or the decomposition product thereof, choosing suitable conditions. The protective group can then be removed and the desired product can be converted into Desmosterol. For example, if the hydroxyl group in the 3-position is protected by a carboxylic acid residue. For example, the product can be converted into desmosterol by hydrolysis under conditions customarily used for esters, ie hydrolysis can be carried out using acids or alkali. In a specific embodiment, a caustic potash-methanol solution containing a sufficient amount of caustic potash is added to the reaction mixture. which contains desmosterol, the hydroxyl group of which is protected in the 3-position by a carboxylic acid residue. and the system is then hydrolyzed at a temperature in the range from room temperature to 60 ¹ C, optionally in the presence of an inert solvent such as benzene. This gives you free desmosterol.

The carboxyl compounds can also be mixed with a suitable metal hydride such as with excess lithium aluminum tetrahydride be reduced to free desmosterol.

When the hydroxyl group is in the 3-position with a

Hydrocarbon residue is protected. can such Desmosterol derivatives easily converted into desmosterol by treatment with hydrochloric acid provided that the hydrocarbon radical is chosen so that it can be easily eliminated with acid for example tetrahydropyranyl, methoxymethyl or the like

Other hydrocarbon residues that act as protective groups act, can be split off, for example by treating the desmosterol derivative with what hydrogen iodide, aluminum bromide. Boron tribromide or the like

The desmosterol thus formed can again easily be separated off from the above reaction mixture

be purified such as by recrystallization

cation or column chromatography.

According to the invention, Desmosterolderi derivatives of the formula 2-a or 2-b can thus be used as Desmosterol be separated.

The usability of the specified five kinds of compounds (A-R (A-2), (B-I). (B-2) un < (B-3) as a dehydrating agent is known per se of the numerous compounds which are known as dehydrating agents The specified five types of compounds show the unique Rt activity in the dehydration reaction vo 24-Hydroxvcholcsterol and the bis-form derivatives

thereof, with the hydroxyl groups in the 3-position are protected and the Dcsmoslerol derivatives with high yields by simple conversion can be obtained. Implementation for the production of Dcsmosterolderivaten using such dehydrating agent is completely new.

According to the invention, Desmosterol. its hydroxyl group is protected in 3-position, (2-a) or the bis-form derivative thereof (2-b) or Desmoslcrol in high bulges.

The invention is particularly characterized in that desmosterol derivatives which have a double bond in the 24-position, as indicated by the formula 2-a or 2-b is given, can be formed selectively.

The studies confirm that when dehydrated of 25-Hydroxycholstcrol derivatives, for example with phosphorus oxychloride. the connection with a double bond in the 25-position and desmosterol derivatives (which contain the double bond in the 24-position included) in a ratio of approximately 1: 1. With regard to this In fact, it is particularly surprising that in the dehydration of 24-hydroxycholeslerol accordingly the desmosterol derivatives are selectively formed in the process according to the invention.

As can be seen from the comparative experiment described later, it is obtained by dehydration of 25-hydroxycholesterol with sulfuric acid Dcsmoslerol derivatives, but it is very difficult to the desmosterol derivatives according to the invention by dehydrating the 24-hydroxycholesterol rivals to produce the formula 1, which is used as a starting material in the process according to the invention when using sulfuric acid.

In the process according to the invention, olefins are also formed by elimination the group RO, which is bound to the 3-position of the A ring, hardly takes place.

According to the invention, Desmosterolderivaic can be obtained in high purity and Dcsnioslerol produced therefrom produce in high yields according to a simple reaction scheme.

The following examples illustrate the invention without restricting it.

example 1

350 mg of phosphorus pentoxide are added to 24 ml of benzene and the system is kept at 10 ° C. 440 mg of 24-hydroxycholestcrol-3-acetate are added with stirring over a period of 3 minutes. One stirs another 35 minutes, and then 30 ml of water are added to the reaction mixture to break the benzene phase to separate. The benzene phase is washed with water and dried with sodium sulfate. then the benzene is distilled off under reduced pressure, with 430 mg of colorless solid remaining.

The product is separated off and purified by column chromatography using a column which is filled with 0.74 mm (200 mesh) silica gel (the elution takes place with a solvent mixture from benzene and η-hexane.) 360 mg (yield 85%) of the product with those listed below are obtained physical properties:

Melting point 93 to 94 C;

[><] :, "= -42.7 (C = -0.48, CHCl ₃ );

IR (, ·, "", cm ' ^1. KBr): 1730, 1370, 1250, 800:

NMR (CDCl _1. t) [ppm]): 0.67 (3H, singlet, C 18-H. S). 1.01 (3H. S. C-19-H, S). 1.60 (3H, S. C-26-H. S or C-27-H. S). 1.69 (3H, S. C-26-H. S or C-27-H, S), 2.01 (3H. S, CH ₃ CO-), 4.63 (IH, b. C-3- H).

5.08 (1 H. T, J = 6.5 Hz. C-24-H), 5.35 (1 H,

■ ο M, C-6-H);

S: singlet, b: broad, T: triplet, M: multiple;

Mass spectrum (m'e): 366 (M-CH ₃ COOH). 351, 253, 145.93, 69.

From the above values, the product obtained is identified as desmosterol-3-acetal.

According to J. Org. Chem., 23, 459 (1958), desmosterol-3-acelate has a melting point of 92.5 to 93 "C and [«] ' _n ⁵ of -40.6 " (c = 0.9, CHCl ₃ ).

Examples 2 to 11

24-Hydroxycholesterol-3-acetate and phosphorus pentoxide are prepared in a manner similar to that in Example 1 in the reaction solvent and at the temperature listed in Table I during the times given in this table.

With the exception of Example 10, the reaction products are separated off by the following stages: water is added to the reaction system to separate the organic phase, and the organic phase is washed Phase with water and dried with sodium sulfate and the organic solvent is distilled at reduced Pressure off. In example 10, water and ethyl ether are added instead of water alone, to separate the ether phase.

The product that is separated in each experiment is first mixed with a solvent from benzene and n-hexane through a column filled with 0.074 mm (200 mesh) silica gel. clues. The product (I) is thus obtained. Further elution with a solvent mixture of benzene and Ethyl acetate gives the product (U).

The product (I) was called DesmosciOl-3-acetal from the melting point. [«ΙΌ ⁹ , IR. NMR and mass spectra identified.

The product (II) was identified as desmosterol, as the results of gas chromatography (1.5% OV-I on Chromosorb WHP) correspond to that of Desmosterol, and the product showed the melting points listed below and the NMR spectrum given below.

Melting point: 120 to 121 C.

NMR (CDCl3, Λ [ppm]): 0.67 (3H. S. C-18-H. S).

1.00 (3 H. S, C-19-H, S), 1.60 (3 H. S. C-26-H, S or C-27-H, SV 1.68 (3 H. S. C-26-H, S or C-27-H. S). 3.50 (IH, b, C3-H). 5.08 (IH. T.

J = 6.5 Hz, C-24-H), 5.30 (IH, M. C-6-H).

According to the literature reference J. Org. Chem. 23, 459 (1958), a desmosterol has an melting point of 120.5 to 121 C.

The results of the reaction are shown in Table I.

14th

"abclle

! example 24-hy- Type of solvent (20) IMK te reaction time Howl (l'roduki I) Dcsmoslci'ol '' droxy
chole- (20) Tempe Desmosterol (l'roduki II) slcrol- (30) ra itir 3-acctai (""1 3-ucctal (18) I min.) 73 (mg) ("« 1 (mg) ImI) 125) (Cl 50 I mg I. 52 2 300 Methyl chloride (40) 310 -5 40 210 48 3 1.2 3 300 benzene (28) 280 25th 20th 150 44. 7.8 3.0 4th 300 benzene (25) 150 50 20th 138 78 3.6 2.8 5 150 toluene (10) 70 90 20th 63 66 6th 440 Methylene chloride (10) 400 5 40 330 71 7th 300 Cyclohexane 300 10 50 190 63 8th 300 Trachlorethylene 260 5 40 204 43 9 300 Chlorobenzene 300 5 320 181 45 10 100 Tetrahydrofuran 600 60 240 41 Γ »ΐΊ ΊΙΙΙΙΛΙΙΙ · 11th 100 Ethylene acetate 600 60 c 11 η nctii ι 43 Example 12 11 M 1-wi A

A solution of 30 ml of toluene. 440 mg of 24-Hydroxycholcsterol-3-Acctate and 3.0 g of acid potassium sulfate were stirred for 3 hours at 110 ° C. After completion 40 ml of water are added to the reaction mixture in order to separate off the toluene phase, which is then treated in a manner similar to that described in Example 1. 300 mg of purified are obtained Product. Yield 70%. the product having identical physical properties like desmoslerol-3-acetate. that in example 1

received. _. . . ,,, ■ _1O

Examples 13-18

24-Hydroxycholsterol-3-acetal and acid potassium sulfate are listed in the tables below implemented during the specified Zeil.

With the exception of Example 18, the reaction products were separated by adding water / u
added to the reaction system to make the organic

Separate phase, the organic phase with water
washed and dried with sodium sulfate and adding
one the organic solvent at reduced
Distill off pressure lc. In example 18 the water
as extraction agent through water and ethyl ether

replaced, and the ether phase was separated. the
Purification of the product was carried out in the same way
as described in example 1.

The results obtained are shown in Table II.

Table II 24-Hy solvent (30) sow example dro χ y- (18) K; il No. ehol- (20) suit stcrol- (30) 3-ai: clal (30) (mg) I ml I (15) IgI 300 benzene 3 13th 150 toluene 1.5 14th 150 o-xylene 1.5 15th 300 Tetrachlorethylene 3 16 300 Chlorobenzene 3 17th 100 Dioxane 1.5 18th

Acid reaction

Potassium sulfate temperature / s

Howl
Dcsmostcrol-J-accial

(Ci

iSul.i

mm

"..1

60 12th 80 10 144 3 110 3 105 4th 100 25th

138 48 82 57 95 66 178 62 156 52 39 41

Example 19

A mixture of 460 mg of 24-hydroxycholsterol-3-propionate and 30 ml of trachlorethylene was kept at 110 ° C., and 2.0 g of acid potassium sulfate were added with stirring. After stirring for a further 4 hours, 30 ml of water were added to separate the trachlorethylene phase, which was treated in a manner similar to that described in Example 1, giving 300 ms: of the excess product. The yield was 67%. The
The product shows the following NMR spectra:

NMR (CDCl3, Λ [ppm]): 0.67 (3H, S, C-18-H. S).

1.02 (3H. S. C-19-H. S). 1.60 (3H. S, C-26-H. S

or C-27-H, S). 1.68 (3H, S, C-26-H. S or

C-27-H, S). 4.62 (IH. B. C-3-H). 5.07 (IH. T.

.1 = 6.5 Hz. C -24-H). 5.35 (1 H.M. C-6-H).

If the product was reduced with lithium aluminum tetrahydride in ethyl ether at room temperature,
so one got a l'roduki with an ep. of 119

up to 120 C with the Aus den V Identify product d

One Li 250 mg 24 5 C under phosphorus] "30 minute egg as in the at so 242 mg phase. Dci a woman medium: lo

Hexane) according to the following: booty re.

NMR (C 1.05 (3 H.: or C-1 C-27-11. C-24-H). Benz.oat-or and -para-I

The picx of kausli · hour hy <with a 1 das idenlisi. play 3 until this example

A solution: 100 mg of 24- "IOC under 100 mg of Phc in the following manner as ^c . A solution was obtained from chromatography, yield Iv the NMR ^

NMR (C 1.02 (3 H. S or C- 2 C- 27-H. J = 6.5 Hz.

The product as used in the case of the product obtained and NMR-

From this Dcsmosterc

A lo: 100 mg bis was used in I.

to 120 C and an NMR. which was identical to that of the desmosterol of Examples 3 to 5. From the values of the qualitative analyzes, the product of this example was identified as Dcsmosterol-3-propional identified.

Example 20

A solution prepared from 30 ml of benzene and 250 mg of 24-hydroxycholesterol-3-benzoate was kept at 5 ^: C with stirring, and 200 mg of phosphorus oxide were added. After stirring for 30 minutes, the system was treated in a manner similar to that described in Example 1. This gave 242 mg of a pale yellow solid from the benzene phase. The solid was purified by chromatography with a column filled with silica gel (eluent: mixed solvent of benzene and "n-Hxane), whereby 162 mg of product were obtained with the following NMR spectrum. The yield was 67%.

NMR (CDfI _1. Λ [ppm]): 0.68 (3H. S. C "-18-H, S), 1.05 (3H. S. C-19-H, S), 1.60 (3H, S. C-26-H. S or C-27-H. S). 1.68 (3H. S. C-26-H, S or C-27-H. S). 4.70 (IH b. C -3-H) 5.00 (IH. M. C "24-H). 5.37 (IH. M. C-6-H). 7.49 (3H. M. Benzoate-ortho-H, S). 8.02 (2 H. M, benzoate-meta- and -para-H. S).

The product was in a methanolic solution of caustic potash at 60 C for a Hydrolyzed hour. A product with a melting point of 120 ° C. and an NMR spectrum was obtained in this way. this was identical to that of the desmosterol of Examples 3 to 5. The product was obtained from these values identified in this example as desmosterol-3-benzoate.

Example 21

A solution prepared from 20 ml of benzene and 100 mg of 24-hydroxycholesterol-3-caprylal was used in Maintained 10 ° C with stirring, and 100 mg of phosphorus pentoxide were added. After 30 minutes of the following With stirring, the system was treated in a manner similar to that described in Example 1. Man thus obtained 96 mg of a light yellow, oily compound from the benzene phase, which on silica gel by column chromatography has been purified (eluent: a solvent mixture of benzene and n-hexane), 56 mg of purified product were obtained. The yield was 58%. The product showed the following NMR values:

NMR (CDCl ₃ , Λ [ppm]): 0.67 (3H, S, C-18-H, S), 1.02 (3H, S, C-19-H, S), 1.60 (3 H, S, C-26-H, S or C-27-H, S), 1.68 (3H, S, C-26-H, S or C-27-H, S), 4.63 ( IH.b, C-3-H). 5.08 (IH. T. J = 6.5 Hz, C-24-H), 5.35 (IH, M, C-6-H).

The product was prepared under identical conditions to those used in the hydrolysis of the product of Example 20 were used, hydrolyzed to give a product which, according to melting point (119 to 120 C) and NMR spectrum corresponds to Dcsmostcrol.

From these results the product was identified as desmosterol-3-caprylate.

Example 22

A solution made from 30 ml of benzene and 100 mg of bis- (24-hydroxycholestero!) - 3.3'-terephthalal. was kept at 10 C with stirring, and 70 mg of phosphorus pentoxide were added. The system was stirred for a further 40 minutes and then treated in a manner similar to that described in Example 1. Out 97 mg of a colorless solid were obtained from the benzene phase, and that of a filled with silica gel Column chromatography was performed (eluent:

Benzene); 53 mg of the product were obtained, yield 55%. The product showed the following NMR analysis:

NMR (CDCl _3, ö [ppm]): 0.68 (6H, S, C-18 H, S).

ίο 1.04 (6H, S, C-19-H, S). 1.60 (6H, S, C-26-H. S or C-27-H. S). 1.67 (6H. S. C-26-H. S or C-27-H, S), 4.70 (2H. B, C -3-H), 5.10 (2H. B, C-24-H), 5.38 (2H. M, C-6-H), 8.03 (4H, S. benzene ring-H, S).

The same product was hydrolyzed in a methanol-benzene solution from caustic potash at 60 ° C. for 1.5 hours, a product having a melting point of 118 to 120 ^° C. and an NMR spectrum which was perfectly matched to that in the Examples 3 to 5 described Desmosterol corresponds.

From these results, the product of this example was identified as bis (desmosterol) -3,3'-terephthalate.

Example 23

A solution made from 15 ml of toluene. 150 mg of 24-hydroxycholesterol-3-benzoate and 1.5 g of acid Potassium sulfate was kept at 110 ° C. for 3 hours with stirring. After completion of the implementation the system was treated in a manner similar to that described in Example 12, and 150 mg of one pale yellow solid became from the toluene phase

won. The same solid was purified by column chromatography using a column which was filled with silica gel, cleaned (eluent: solvent mixture of benzene and n-hexane), 75 mg of desmosterol-3-benzoate, which has the same NMR spectrum, were obtained as the product of Example 20. The yield is 52%.

Example 24

0.40 g of phosphorus pentoxide were added to 25 ml of η-hexane. and then stirred at OC. Then were 420 mg of 3-methoxy-24-hydroxy-cholest-5-ene were added to the solution over the course of 1.5 minutes, and then the mixture was stirred for a further 30 minutes. Then 25 ml of water and 25 ml of ethyl ether were added, to separate the organic phase. Distilling off the η-hexane and ether from the organic phase under reduced pressure gave 400 mg of a colorless, crystalline product. the Solid was separated off and column chromatographically using silica gel (eluent: Solvent mixture of benzene and n-hexane) purified, 250 mg being purified Product received. The bulge was 59%. The product had the following NMR spectrum. and from these values it was called 3-melhoxy-cholesta-5.24-diene identified.

NMR (CDCI, Λ [ppm]): 0.67 (3 H. S. C 18-H. S). 1.01 (311. S. C 19-H. S). 1.60 (311. S. C 26-H. S or C 27-H. S). 1.69 (3H. S. C 26-H. S or C-27-11. S). 3.00 (111. b. C 3-H). 3.31 (311. p.

609 643,302

CH ₃ O-), 5.04 (IH, T, J = i
(IH, M, C-6-H).

JjQ

Hz C-? 4-H), was 5.34, a fp. And an N M R, which is the same as that of desmosterol and thus it was identified as Dcsmosterol.

Example 25

A solution prepared from 20 ml of methylene chloride and 150 mg S / in-butoxy ^ -hydroxycholest-S-ene, was at \ 0 ^c C held, and thereto was added 150mg Phosphorpenloxyd. The system was stirred for an additional 30 minutes and treated in a manner similar to that described in Example 1. 142 mg of a colorless solid were obtained in this way from the methylene chloride phase. The solid was purified by column chromatography (absorbent: silica gel, eluent: solvent mixture of benzene and n-hexane). 79 mg of the purified product were obtained, yield 55%.

The product had the following NMR spectrum, it was found to be 3 / i-n-butoxy-cholesta-5,24-diene was.

NMR (CDCl ₃ ,.) [Ppm]): 0.65 (3 H, S, C-18-H, S), 0.98 (3 H, S, C-29-H, S), 1, 58 (3 H, S, C - 26-H, S or C - 27-H, S), 1.62 (3 H, S, C - 26-H, S or - C-27-H, S) , 3.00 (1H, b. C-3-H), 3.37 (2H, M, -CH ₁ -O-). 5.04 (IH. M, C-24-H). 5.30 (IH, M, C-6-H).

B e i s ρ i e 1 26

A solution prepared from 50 mg of 24-hydroxycholest-5-en-3 / * - (2'-tetrahydropyranyl) ether and 10 ml of benzene was kept at 24 ° C., and 150 mg of phosphorus pentoxide were added. The system was Stirred for a further 60 minutes and, after the reaction has ended, with 1% strength aqueous sodium carbonate solution and ethyl ether extracted. The separated organic phase was washed well with water and dried over anhydrous sodium sulfate. The benzene and ethyl ether were at reduced Distilled pressure.

The residue was passed through a column filled with silica gel, which was deactivated with water, given, and then it was first eluted with a solvent mixture of benzene and η-hexane. 14.4 mg of product (III) were obtained. The yield was 30%. The further elution with a Mixed solvent of benzene and ethyl acetate gave 5 mg of the product (IV). The yield was 13%. The NMR spectrum of the product was as follows:

NMR (CDCl 1, <> [ppm]): 0.67 (3H, S, C-18-H, S), 1.00 (3H, S, C-19-H, S), 1.60 (3H, S-C-26-H, S or C-27-H, S), 1.69 (3 H, S, C-26-H, S or C-27-H, S), 3, 10 to 3.90 (4H, b, C- 3-H and the proton in the 2-position of the pyranyl group), 5.08 (1 H. M, C-24-HO), 5.35 (IH, M . C-6-H).

Became the product (III) with hydrochloric acid treated, a product was obtained with the same melting point (119 to 120 ° C.) and NMR as Dcsmosterol, which was prepared in Examples 3 to 5.

On the basis of these results, the product (III) was identified as Cholesta-5,24-diene-3 / i- (2'-tetrahydropyranylj-ether identified.

The product (IV) which is the decomposition product with hydrochloric acid of the above product (III)

Example 27

A solution made from 15 ml of toluene. 5 (J mg ίο 3 ^ -n-butoxy-24-hydroxycholest-5-en and 700 mg of acid potassium sulfate, was stirred at 110 C Held for 2 hours. After the completion of the reaction, the system was operated in a manner similar to that in Example 12 treated, and 47 mg of solid were obtained from the toluene phase. To clean of the solid by column chromatography on silica gel (eluent: solvent mixture from benzene and η-hexane) gave 23 mg of the product ". The yield was 48%. Since the NMR spectrum of the product was completely identical to that of the product of Example 25, the product was identified as 3 / i- (n-Butoxy! -Cholesta-5,24-diene identified.

Example 28

440 mg of 24-hydroxycholesterol-3-acetate were dissolved in 11 ml of pyridine, and while the solution was in 22 ° C was kept, 1.1 ml of phosphorus oxychloride was slowly added dropwise, and then was Stirred for 1 hour. Then the reaction solution was poured into ice-water and extracted with 50 ml of ether, here.

The ether phase was treated with dilute hydrochloric acid washed, then washed repeatedly with water and finally with sodium sulfate dried. Distilling off the ether under reduced pressure gave 420 mg of white, crystalline product. The solid was separated and treated with a column filled with silica gel (eluent: mixed solvent of Benzene and n-hexane) chromatographed, 260 mg of purified product being obtained. yield 61%.

The product had a melting point of 92 to 93 ° C. and the NMR spectrum corresponded well to that of the product from Example 1. The product was thus identified as desmosterol-3-acetate.

Examples 29 to 36

24-Hydroxycholesterol-3-acetal was made with phosphorus oxychloride or thionyl chloride in the presence implemented by tertiary amine. The amount of reactants, the type of tertiary amine and the reaction temperature and time used in each experiment are given in Table III. The reaction mixtures were treated in a manner similar to that described in Example 28, and the products were separated and purified.

The results are also given in Table III.

All of these products were called Desmoslcrol-3-Acetate identified from the melting points and NMR analysis values.

Table UI example

24-hydroxychulesterol-3-acetal

(possibly

POCI ₃ or SOCI,

(ml)

I. amines

ImIl reaction
Temperature time

<Cl

Dent on Desmoslero] -3-acetate

(Still I mg I

200
200
440
100
100
220

440
100

POCl ₃
POCl ₃
SOCl ₂
SOCl ₂
SOCK
POCl ₃

POCl ₃
SOCl ₂

(0.3)

(0.3)

(1.1)

(0.25)

(0.20)

(1.0)

(0.6)
(0.28)

Pyridine

Pyridine

Pyridine

Pyridine

Pyndin

Triethylamine

(trichylamine)

s-collidine «picoline

(Ii)
(2.5)
(2.8)
(10)

(13)
(3)

50
98
15th
50
76

0-18
(slow
increasing)
22nd
20th

2.5

109

105

230

48

50

140

279

47

57 55 55 50 52 66

66 49

Example 37

^ 50 mg of 24-Hydroxycholcsterol-3-benzoate were in 15 ml of pyridine dissolved and heated to 20 C. 1.0 ml of phosphorus oxychloride is added dropwise to the solution given, and then stirred for 20 hours. After that, the reaction liquid is in water poured and extracted with a solvent mixture of benzene and ether.

The organic phase is separated off, washed with water, dried over sodium sulfate, and that organic solvent is distilled off.

The residue is purified in a manner similar to that described in Example 1 and obtained 150 mg of a product which has an NMR spectrum which is very similar to that of the product of Example 20 (Desmosterol-3-benzoate) corresponds. The yield is 62%. Will the product with a methanolic Solution of caustic potash hydrolyzed at 60 ° C. for one hour, a product is obtained with a melting point (119 to 120 C) and an NMR spectrum, which are identical to those of Desmostcrol.

From the previous results, the product of this example can be described as desmosterol-3-benzoate be identified.

Example 38

100mg 3 / i'-n-butoxy-24-hydroxycholest-5-en will be dissolved in 3 ml of pyridine. While the solution is kept at 20 C, 0.30 ml of thionyl chloride are added, then it is stirred for 3 hours. The reaction mixture is prepared in a manner similar to that in Example 28 treated, and 94 mg of a colorless solid are obtained, which is column chromatographically using a solvent mixture of benzene and η-hexane and silica gel is cleaned. 50 mg of a product are obtained. Yield 52%.

From the results of the NMR analysis it became Product identified as 3 / i '- (n-butoxy) -cholesta-5,24-diene.

Example 39

58 mg 24 - hydroxycholesl - 5 - en - 3 /> '- (2' - tetrahydropyranyl) - ether are dissolved in 1.5 ml of pyridine.

and while the solution is held at 18C.

0.1 ml of phosphorus oxychloride are slowly added, and the mixture is then stirred for 2 hours. The reaction mixture is treated in a manner similar to that described in Example 28, and from the ethyl ether phase 49 mg of a light yellow solid are separated off.

The solid is purified by column chromatography using silica gel mixed with water was deactivated, and purified with a solvent mixture of benzene and η-hexane as the eluent.

23 mg of a product are obtained with an NMR spectrum similar to that of Cholcsta-5,24-diene-3, ;- (2'-tetrahydropyrany!) Ether is equivalent to. The yield is 42%.

Treatment of this product with hydrochloric acid gives a material with a m.p. (118.5-120 ° C) and an NMR spectrum similar to that of Dcsmosterol. From these results, the product of this example as cholesta-5.24-dien-3-tetrahydropyranyl _i M2 ') ether is identified.

Example 40

To a solution made from 0.44 g of 24-hydroxycholesterol-3-acetate and 13 ml of pyridine. 0.50 g of p-toluenesulfonyl chloride at room temperature given. After 3 hours of reaction at 110 ° C., the reaction liquid is poured into ice-water and extracted with 100 ml of ether. The ether phase is mixed with 5% aqueous sodium carbonate solution and 1N hydrochloric acid and washed several times with water. Then the ether phase treated in a manner similar to that described in Example 28 to separate 193 mg of the product, Yield 46%. The product has a melting point of 93.5 to 94 ° C. and its NMR spectrum corresponds well that of Desmostcrol-S-acctat.

Examples 41 to 45

24-Hydroxycholestcrol-3-acetate is combined with various sulfonyl chloride in the presence of tertiary Amines implemented. The amount of reaction participants, the type of amine and the reaction temperature and time you spend on each attempt

used are listed in Table IV. the Reaction mixtures are treated in a manner similar to that described in Example 40, and the products are separated and cleaned.

The results are shown in Table IV. All Products were called Desmostcrol-3-acelal from their Melting points and NMR analysis values identified.

Table IV

example

24-hy-

drox \ -

chole-

sterol-

3-acetate

(mg)

Sulfonyl chlorides

(mgi

t.-Annn

ι ml I

Response
Tcmperaiur zx-ii

I Cl

iSld.l

Yield to

Desmoslerol

3-acetal

Ulli!)

Pyridine pyridine s-collidine

P \ ritiiii

DMF

Pxridine

4! 150 p-toluoisulfonyl- (240)

chloride

42 100 p-toluenesulfonyl- (150)

chloride

43 KK) p-toluenesulfonyl- (120)

chloride

44 150 methanesulfonyl- (4 (X))

chloride

45 100 benzenesulfonyl- (110)

chloride

Example 46

120 mg of 24-hydroxycholesterol-3-ben / .oat graze in 6 ml of pyridine dissolved, and while the solution is at 110 C 150 mg of p-toluenesulfonyl chloride are used added, and then stirred for 3 hours. The reaction mixture is processed in a similar manner treated as described in Example 40, through a chromatography column filled with silica gel. passed and purified by extraction with a solvent mixture of benzene and η-hexane. 51 mg of product are obtained, yield 44%.

The product shows an NMR spectrum. which is identical to that of the product of Example 20. and after hydrolysis with a solution of caustic potash and methanol at 60 C during one hour it has a melting point (118.5 to 120 ° C.) and is in an NMR spectrum. soft are identical to those of Dcsmosterol.

From these results the product of this example is identified as desmostcrol-3-benzoate.

Example 47

43 mg of 3 / i'-n-butoxy-24-hydroxycholest-5-ene dissolved in 2 ml of pyridine, and 60 mg of p-toluenesulfonyl chloride are added to the solution, which is kept at 110.degree and implements for 6 hours. The reaction mixture is prepared in a manner similar to that in Example 40 described, separated and treated by column chromatography with silica gel and a Purified solvent mixture of benzene and n-hexane as eluent. You get 16 me one Product which has an NMR spectrum which is identical to that of 3,; - n-Buloxycholesta-5.24-diene. The bulge is 38%.

Example 48

130 mg of phosphorus oxide become K) ml of benzene given and then kept at -5 C with stirring. Then there are 200mg of 24-1 hydrocholesterol-3-acetal zuueueben. and the Svslem will be another 40 minutes

(5) (4) (4t (4) (4)

40 50

83
158
OK
110

3.5 4th

56

38
41

72
44

stirred at the temperature and reacted. Then the solid and the benzene phase separated by decanting. 10 ml of methanol and 10 ml of 2-n caustic are added to the benzene phase Potlasche Meihanol Solution, and by refluxing, the hydrolysis is during one hour. After the reaction, ethyl ether and water are added to the system, and dicÄlhylätherphase is separated and then washed with 1N hydrochloric acid and then several times with water and dried over anhydrous Dried Glauber's salt. The ethyl ether is distilled off under reduced pressure. being 168 mg of a light yellow solid remain. The solid is separated and filtered by column chromatography Purified over silica gel using a solvent mixture of benzene and allyl acetate cluieri. One receives 13HiIg Dcsmosterol, which the has the same properties as the products of Examples 3 to 5. The yield is 78%.

Comparative example

A sulfuric acid-dioxane system. which for synthesis of desmoslerol from 25-hydroxycholesleroi-3-acetate is said to be effective (cf. J. Org. ("hem. 23.456 I 1958]). was in the implementation of 24-Hydroxycholestcrol-3-acetate used.

25 mg of 24-hydroxycholesterol-3-acetate are added to 6 ml of 2% strength sulfuric acid / dioxane mixture (percent by weight) and stir 2 layers at room temperature.

The reaction mixture is then poured into water and extracted with ether. The extract is acelylierl and analyzed in an acetic anhydride-pyridine system. It is found that the desired Desmosterol-3-acelal in one yield below 5 "egg is obtained.

The above is carried out at 50 ° C. for 30 minutes carried out, a larger amount of by-products is obtained, and the yield of desmoslerol-3-acetate entrusts only 10 "/».

Claims (1)

Desmosterol of the following formula 3 Claim: Process for the preparation of desmosterol, whose hydroxyl group in the 3-position may be or a bis-form derivative thereof of the following formula