DE2733116A1 - 3 ALPHA, 5 ALPHA CYCLO 6 BETA ALKOXY DELTA HIGH 22 -25 HYDROXY AND ACYLOXYSTERIN DERIVATIVES AND PROCESSES FOR THEIR PREPARATION - Google Patents

Description

BEIL, WOLFF & BEIL 2t. July 1977

RECHTSANWÄLTE ADELONSTRASSE 58 6230 FRANKFURT AM MAIN

Our no. 21 2l8 D / wl

The Upjohn Company Kalamazoo, Mich., V.St »A.

22 5r <i, 5c * <- Cyclo-6fl-alkoxy- Δ-25-hydroxy- and-acyloxysterine derivatives and processes for their manufacture

Addition to main patent (DOS 2 601 52})

ι -

A new process for the synthesis of 3 <* »> 5oi» -Cyclo-6ßalkoxy-25-hydroxy- and acyloxy derivatives found. These sterols are intermediate products in the production of 25-hydroxycholesterol derivatives and 25-hydroxy vitamin D metabolites and their analogues.

The new process is characterized in that an ylid of the formula

AP

wherein A is the inert part of the reaction medium

12 3

Wittig reagents, R, R and R ^ hydrogen or methyl and D the grouping

0 ^e or

represent, in which R is an alkyl radical having 1 to 6 carbon atoms, denotes the phenyl, benzyl or phenethyl radical, with a> *, S.i-cyclo-oß-alkoxybisnorcholanaldehyde, whose Alkoxy has 1 to 6 carbon atoms, converted to form compounds of the formula

II

OR

709885/0801

wherein R represents an alkyl radical having 1 to 6 carbon atoms and R, R, R and D have the meanings given above.

The invention also relates to the production of a betaine, the methylenephospharane of the formula III

AP = CH ₂ III

wherein A denotes the part of a Wittig reagent which is inert towards the reaction medium, with the epoxide of the formula IV

⁰ R ² IV

12 3

R and Br

12 3
in which R, R and Br are hydrogen or methyl, reacts to form the compound of the formula V

ο I

R ¹ '

The invention also relates to the provision of new cholestans and 1-ethers.

The methyl, ethyl, propyl, butyl, pentyl, H * xyl radical and their Isomers understood. Examples of isomers are the isopropyl, tert-butyl, neopentyl and 2,3-dimethylbutyl radicals.

The betaine of the formula V is made by reacting a methylene phosphorane of the formula III formed with an epoxide of the formula IV.

709885/0801

Group A of the phosphorane is common in Wittig reagents, see for example Tripett, Quart.Rev. XVII, No. 4, pp. 406 (1963) and House, "Modern Synthetic Reactions", 2nd ed., Pp. 682-709. The grouping should be essentially inert to the reaction medium. Examples of such groupings are triphenyl, triphenyl substituted by 1 to 3 alkyl radicals on each phenyl ring, the alkyl radicals being identical or different and being able to have 1 to 4 carbon atoms. Furthermore, A can consist of a monosubstituted phenyl and two unsubstituted phenyl radicals, for example (phenyl) ₂ , p-carboxyphenyl. Further suitable phosphoranes are, for example, dimethylaminoethylene phosphorane (Me ₂ N) ₃ P = CH ₂ .

Phosphorane and epoxide are at room temperature or at any convenient temperature from about 0 to about 40.degree reacted with one another, it being possible occasionally to use higher or lower temperatures. One uses also an inert organic solvent. Regarding suitable solvents, see Tripett and House, loc. Sit. referenced.

Examples of such solvents are tetrahydrofuran, diethyl ether, Hexane, pentane, benzene, heptane, octane, toluene and dioxane.

Once the betaine is prepared it is converted into the ylid using conventional reagents and under conventional conditions of the formula I converted, for example by the action of a strong base. Examples of reagents which are suitable for converting the betaine into the ylide are organo-lithium compounds such as the alkyllithium compounds with 1 to 4 carbon atoms, sodium amide, sodium hydride, lithium amide

709885/0801

and the same. Conditions known per se are used in the reaction, and the preferred reagent consists of n-butyllithium.

The ylide of the formula I, in which D denotes 0, is then reacted with the ^ »Sii-cyclo-α1-alkoxybisnorchalanaldehyde to form a compound of the formula II, in which D denotes 0. The temperature of this reaction is not particularly important. Can be applied to about 40 ° C temperatures of about 0, and the preferred temperature range is from about 15 to about 25 ⁰ C. It should be noted that the cation of the metal of the base is that used for the conversion of Betaine in the ylide became.

0 π h

For the preparation of compounds of the formula I in which D OCR

4 means, the betaine of the formula V is corresponding with the R.

H. Acylating agent acylated. For example, one can write an R -

4th
Use acid anhydride or R acyl halide, preferably the chloride, under standard conditions. The resulting salt is then reacted with a strong base such as, for example, lithium diisopropylamide, the ylide of the formula I (D = acyloxy) being obtained. This is then reacted with the bisnorcholanaldehyde to form a compound of the formula II, wherein

OCR. The compound of formula II, wherein D - OCR

means can also be obtained by using the ylid

Θ '

D-O reacts with the bisnorcholanaldehyde and then the resulting 25-oxyanionic steroid with an acylating agent converting the i-ether with D = «

OCR ^ receives.

The i-ethers can easily be converted into 25-hydroxy-cbiesterine and then into 25-Hydroxycholecalciferol can be converted.

709885/0801

-r-

After the representation of the compounds of formula II, the

22 27>
Double bond between C and C ^ can be saturated in a conventional manner, the intermediate product for 25-hydroxy-vitamin D-, and analogues of the formula VI being obtained:

VI

12 3 In this formula, R, R, R, Br and D have the meanings given above.

A suitable method is catalytic hydrogenation. The hydrogenation is carried out with a noble metal catalyst in a suitable inert organic solvent with appropriate Printing done. Preferred precious metals are platinum or palladium. As inert organic solvents are suitable for Example ethyl acetate, methylene chloride, tetrahydrofuran, with ethyl acetate being preferred. Any hydrogenation pressure which brings a reasonable reaction speed with it,

2 can be used. You can work with pressures as low as 1.05 kg / cm. The upper limit for the bridge depends on the loss of yield which goes back to the opening of the cyclopropane ring.

Pressures up to about 7 kg / cm or more can be easily applied will.

7G9885 / 08G1

example 1
506 "5" t-Cyclo-613-niethoxy-25-hydroxy-26,27-bisnorcholest-22-en

17.9 g of methyltriphenylphosphonium bromide are stirred into 150 ml of tetrahydrofuran, which contains 15 ml of hexaraethylphosphoric acid triamide, under nitrogen. Then 35 ml of a 1.5 molar solution of n-butyllithium in hexane are added dropwise, a bright red solution being formed. This is left to stand for 30 minutes, then approx. 5.0 g of ethylene oxide are added. The reaction vessel is closed and the temperature is ^{increased to 35 °} C. for 1 hour. At this point the nitrogen inlet is used and the reaction vessel is purged with nitrogen to remove excess ethylene oxide. The reaction mixture is then pale yellow. A further 35 ml of n-butyllithium are added, resulting in a bright red color. As the addition progresses, the temperature increases to 35 ° C. 15 minutes after the addition is complete, a solution of 17.0 g of 30U5 ^ -cyclo-6fl-methoxybisnorcholanaldehyde in 150 ml of hexane is added dropwise until the color of the ylid has disappeared. The reaction mixture is then treated with water and extracted with ethyl acetate. The desired product is obtained from the residue after chromatography on neutral clay. When recrystallizing from acetonitrile, platelets with a melting point of 104 to 105 ° C. are obtained. NMR (CDCL ₅ ): 0.3-0.67 m; 0.73 s (3H); 1.01 s (3H); 1.01 d,

J = 6 Hz, (3H; 2.77 b.t. (IH); 3.30 s (3H);

3.60 t (J-6Hz (2H); 5.37 m (2H).

R _f : (5 % CH ^ OH / CHCl ^) 0.58 '

709885/0801

Example 2
Λ, 5o4-Cyclo-6ß-methoxy-25-hydroxy-26,27-bisnorcholestane

2.0 g of the Δ compound according to Example 1 are dissolved in 10 ml of methylene chloride. Then 0.5 g of 5 % platinum / carbon catalyst are added and the mixture is at a ν ^ ΒβΓ-ρ

material pressure of 6.33 kg / cm hydrogenated for two hours. The catalyst is filtered off and the filtrate is concentrated, a crystalline residue being obtained. This is made from acetonitrile recrystallized with displacement of methylene chloride, needles with a melting point of 128 ° -129 ° C.

NMR (CDCl3,): 0.3-0.67 m \ 0.73 s (3H) _; 1.01 s (3H); 2.77 bt (IH); 3.30 s (3H); 3 * 60 t, J = 6Hz (2H). Rf: (5 % CH, QH / CHCl,) 0.52.

Example 3

Po
3o6.53 (.- Cyclo-6ß-methoxy-A ^ S-acetoxy ^ o, 27-bisnorcholestane

6.3 ml of a 15% solution of η-butyllithium in hexane are added to a suspension of 3 * 57 g of methyl triphenylphosphonium bromide in 30 ml of dry tetrahydrofuran with stirring at room temperature under nitrogen. The mixture is then stirred for a further 30 minutes and an excess of isobutylane oxide is then added. After 1 hour, the flask is flushed with a stream of nitrogen to remove excess oxide, then the molar amount of acetic anhydride is added. After 15 minutes, a solution of lithium diisopropylamide in hexane prepared from 6.3 ml of a 15% n-butyllithium solution in hexane and 1.1 g of diisopropylamine in 10 ml of hexane is added, and a solution of ~ 5 is added 30 minutes later , h g bianorcholanaidehyd in 25 ml hexane. After a further 30 minutes, the mixture is poured into methanol and worked up as described in Example 1, 3X ', 5ol-cyclo-6β-25-acetoxy-26,27-bisnorcholest-22-ene being obtained.

709885/0801

Example 4
3uU5dLrCyclo-6ß-methoxy-25-acetoxy-ch) Lest-22-en

To a suspension of 3 »57 g of methyltriphenylphosphonium bromide in 30 ml of dry tetrahydrofuran, 6.3 ml of a are added with stirring at room temperature in a nitrogen atmosphere 15 #igen solution νώη n-butyllithium in hexane was added. then is stirred for a further 30 minutes and then an excess of isobutylene oxide added. After an hour the flask is flushed with a stream of nitrogen, then a further 6.3 ml of the n-Butyllithium solution added. 30 minutes later, a Solution of 3.0 g of bisnorcholanaldehyde in 30 ml of hexane was added. After a further 15 minutes, 1.4 ml of acetic anhydride are added and a further 30 minutes later the mixture is dissolved in methanol poured, then about 200 ml of Skellysolve B and then about 200 ml of water are added. This creates two layers, the lower being mainly the by-product Triphenylphosphine oxide and the upper one contains the desired 25-acetate. By drying the upper phase and evaporation a residue is obtained from the desired 3 ° * »5o ^ cyclo-6β-methoxy-25-acetoxy-cholest-22-ene.

NMR (CDCl ^) iSO.75 s (£ H); 1.03 S (+ H; 1.40 S (OH); 1.93 S (3H); 2.77 m (IH); 3.20 s (3H); 5.30 m (2H).

Example 5
3dU5cjL-Cyclo-6β-methoxy-25-benzoxy-cholest-22-en

According to the procedure of Example 4, when the acetic anhydride is replaced by benzoyl chloride, 3V, 5 ^ -cyclo-6ß-methoxy-25-benzoxy-choles are obtained t-22-en.

The Δ compound shows the following NMR spectrum in deuterochloroform: <f 0.27-0.70 m (3H;, 0.70 s (3H); 0.97 d, J> 6 Hz (3H); 1.02 s ( 3H); 1.55 s (6H); 2.50-2.67 m (IH); 2.77 t (L); 3.30 s (3H); 5.20-5.50 π (2H) ; 7.23-7.63 m;, 7.87-8.17 a (2H).

709885/0801

The A compound shows the following NMR spectrum in deuterochloroform: 0.27-0.73 m (3H); 0.78 s (3H) _; 0.97 d, J = g, (3H); 1.03 s (3H); 1.58 S (6h); 2.67-287 in (2H); 3.32 S (3H); 5.2-5.47 Bl (2H); 7.2-7.58 m (3H); 7.88-8.13 m (2H).

Example6

According to the procedure of Examples 1 to 5, the following can be used Connections are made:

1. R ¹ - H, R ² = ■ R ⁵ = CH-, precursor in the US-PS

3,786,062 compounds claimed

2. R ¹ = R ² = R ⁵ = CH ₃ precursor for 25-OH-D ₂ derivatives

3. R ¹ = H, R ² = R- ⁵ = CH ₃ prep? ^od act for 25-HCC

Example 7

Following the procedure of Examples 1 to 6, further compounds of the above formulas, where R denotes the ethyl, propyl, butyl, pentyl, hexyl, isropyl, tert-butyl, neo-

12 "5 is pentyl or 2,3-dimethylbutyl and R, R and Br are hydrogen or methyl.

Example 8

According to the procedure of Examples 1 to 7, compounds of the above formulas, where R is propionoxy, tert-butyoxy, Hexoxy, phenylacetoxy or 2'-phenylpropionoxy radical represents.

709885/0801

It should be noted that compounds of the formula II, in which D O means to be quenched in an aqueous medium such as water or by customary work-up procedures can, whereby compounds of the formula II are obtained in which D is the hydroxyl group. These connections can be ütech become easily saturated with the formation of i-ether derivatives of 25-hydroxycholesterol and its analogues.

The following is an example of the preparation of a compound of Formula II wherein D is the]
and Yr represent methyl.

1 2

Formula II, where D is the hydroxyl group, R is hydrogen and R

Example 9
3 " ^t " 5 ° t'-Cyclo-6β-methoxy-25-hydroxyeholest-22-en

The procedure of Example 4 is followed for the preparation of the ylide, which is then reacted with the aldehyde. Instead of the further reaction with acetic anhydride, the Reaction mixture of aldehyde and ylide quenched with water and then extracted with ethyl acetate. The extracts are made with Washed water, dried and concentrated to a semicrystalline residue. This is based on neutral clay (Manufacturer Woelm, type IV) chromatographed, whereby one the title compound is obtained, which after crystallization au3 Methanol melts at 123 to 135 ° C.

Example 10

In the same way, analogues of the compound of Example 9 are obtained, in which R denotes the ethyl, propyl, tert-butyl or isohexyl

1 2 ■ = *

represents the rest, while R is hydrogen and R and Br are methyl,

1 2 "3 12

R methyl and R and Br hydrogen or R and R hydrogen and B? Mean methyl.

For: The Upjohn Company Kalamazoo, / Mich., V.St.A.

DrVH.J.Wolff 709885/0801 »« ehteaiwalt

Claims (2)

Patent claims: 1. / Compound of the formula OR where R is an alkyl radical having 1 to 6 carbon atoms and D is one of the groupings 0® or ρ R CO- represent, 4th
wherein R is an alkyl radical having 1 to 6 carbon atoms, the phenyl, benzyl or phenethyl radical. R ¹ 2. Compound of the formula? wherein R is an alkyl radical having 1 to 6 carbon atoms and 12 "5 R, R and Br, which can be identical or different, represent hydrogen or methyl. 3. A compound according to claim 2, characterized in that 1 2 ~ *> R represents hydrogen and R and Yr represent methyl. 70988S / 0801 INSPECTED 4. A compound according to claim J5> characterized in that R represents methyl. 5. Process for the preparation of / i -25-hydroxy-substituted a) · Starine derivatives, characterized in that one is a ylid the formula in which A is the part which is inert towards the reaction medium 12 3 of a Wittig reagent and R, R and Br represent hydrogen atoms, with a y *, 5 ^ -cyclo-6ß-alkoxybisnorcholanaldehyde, the alkoxy group of which has 1 to 6 carbon atoms, and b) the sterol bond formed in step a) in water quenching, forming a compound of the form] R wherein R is an alkyl radical having 1 to 6 carbon atoms 12 ~ * t
and R, R and Br are as defined above. 709885/0801