JPS5874697A - Manufacture of 1,3-oxidated 8 alpha-estratriene - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] R' a R'' is a hydrogen atom, 〇-alkanoyl group having 1 to 8 atoms, C-alkylsulfonyl group having 1 to 3 atoms,
represents a methyl, cyclopentyl or tetrahyproviranyl group; HR represents a methyl or ethyl group; R4 represents a hydrogen atom or an ethynyl or coolethynyl group]
1.3-Oxygenated Ba,-estratriene production method.

o - Alkanoyl group having t to 8 atoms and if C - Alkylsulfonyl group having 1 to 3 atoms include physiologically tolerable acids such as the following cardanic acids: formic acid, acetic acid, Zoropionic acid, butyric acid, inobutyric acid, noglerianic acid, isonorerianic acid, casillonic acid, enanthic acid, caprylic acid, trimethylacetic acid, diethylacetic acid,
tert-butylacetic acid.

Examples of the alkyl sulfonic acids include methanesulfonic acid, ethanesulfonic acid, and pro/e sulfonic acid.

The compounds according to the invention have an advantageous dissociated biological action. Due to their strong pro-vaginal and -weak pro-uterine effects, compounds are suitable for the treatment of postnatal women. Therefore, these effects on the vagina are desirable, but they do not affect the uterus.
The compounds according to the invention may also be used as intermediates for the production of pharmacologically useful steroids. Useful! Yes.

Advantageous estrogen dissociation can be demonstrated, for example, in the sialic acid test in mice. Compounds according to the invention are shown in the table! ! Known estrogens 17a-z 1.3.5 (
10)-Estratriene-3,17β-diol (f
) and l,3.5(1G)-estratriene-3,1
7β-diol (1) and new steroid 1°3.1′
7/-) diacetoxy-8a-estra-1,3,5(
1G)-triene, 1.

3-Diacetoxy-8a-nistora-1,3゜5 (1G
)-) Lien-17-fluor (mV), l,3-diacetoxy-8a-estra-1,s,5(lo)-) Lien-17-yt:/(V), 1. ．． 3-d cyclopentyl-oleic acid Ba-estra-1,3,5(1G)-1
1J en-17-one (■), 1,3-dihydroxy-
8a-estra-h3-5(10)-)diene-1-fuon (Vl), Example 1, has a dissociation coefficient that far exceeds that of the standard compound shown.

Table 1 The sialic acid test is carried out as follows: the ovaries of mice are removed. This animal was treated from lO day 0 to 3 after ovariectomy.
Day 1 [day 04 of ingesting the substance to be tested] The animal is dead Immediately the vagina and uterus are dissected and collected and weighed into test tubes for hydrolysis. The measurement of sialic acid is carried out by the Flvennarholm method (Bioch@m, Biophys, Acta).
Volume 24, page 604 (1957)]. The dose-induced increase in vaginal and uterine tissue IT and the decrease in sialic acid content are determined, and the relative potency of the substance to be tested is then determined in comparison with the reference substance estradiol. The relative activity is expressed as 1, and the degree of dissociation is q. 'be. Compounds with Q>1 are relatively provaginal! Yes, those with q〈1 are relatively pro-uterine! Are the threshold values listed in Table 1 consistent with the commonly used Allen-Doisy Test in rats?
Measured.

Furthermore, the present invention relates to a medicament containing 8α-estratriene of the general formula 1 as an active substance. , the active substance is used as a pharmaceutical agent, commonly used excipients,
the desired dosage form, e.g. tablets, together with diluents, flavoring agents, etc.
Dragee-coated tablets, capsules, solutions, etc. (carried out with two substitutions. The concentration of active substance in the medicament thus formed depends on the dosage form. Tablets preferably contain 0.01-101% F and are suitable for parenteral administration. The solution contains 0.1 to 20 μ/we of solution.

The dosage of the medicament according to the invention may be adjusted depending on the processed form and the compound chosen. The history can be characterized by the person being treated at the time. Generally, the compounds according to the invention are processed at concentrations that will yield effective crystals without causing any adverse or deleterious side effects. For example, about 0.0219 to about 20M9
Although the dosage is within the range of 20 cm, depending on the circumstances, it may be prudent to use a dosage higher than 20 cm, for example, 50 cm or 1. However, dosages within the range of about 0.05 volts to about 51 volts are advantageously used.

General ceremony! The compound is also 3-hydroxy-13-R”-
8α-estra-1,3,5(10)-triene-17
-On lead tetraacylate! Oxidize, rearrange the reactant in the presence of a strong acid, and optionally ) continue! and R
The 17-keto group is reduced and/or the ether- or acyl group is eliminated and/or the free hydroxy group is esterified and/or etherified by the desired one.

The novel compounds are produced by methods known per se.

Oxidation with lead acetate and subsequent rearrangement in the presence of a strong acid results in 3-
Hydroxy-8β-estra-1°3.5 (1G)-)
Regarding Lien, it is known from the literature, but the corresponding 3
- Diverted to hydroxy-8α-estratriene! It didn't happen [by Rufer Sen: Liebigs Annalen der Hiemi (LIEBIGS)
^nn, Ohem, ) Vol. 752, p. 5 (1971)) 0 Contrary to Rufuer et al., oxidation with lead tetraacylate can be carried out successfully if carried out in the conventional manner; Stop after 3 minutes, for example. Subsequently, post-treatment and rearrangement are carried out by the known method 1.

The 17-keto group can subsequently be reduced (!:), for which there are a number of methods known per se.

Reduction can be carried out by reaction with hydrogen in benzene in the presence of conventional catalysts such as Raney nickel. Particularly (= hydrogen can be transferred from metal hydrides to 17-keto groups) Hydrogen donors include especially complex hydrides, such as sodium hydride, P-late, lithium and tridoaluminate, sodium hydride. ``Trimethquine dilate, lithium hydridotri-t-zotoxoaluminate, etc. have been found to be advantageous.

The reduction can also be carried out by known methods with metal-organic compounds in which the organic group represents R4, the core compound being an alkynylmagnesium degenide, ethynylmagnesium bromide, or an alkali metal acetylide, such as potassium acetylide. The metal-organic compounds used as reducing agents may then be formed, and the 17-
Reacting with a ketone, for example an alkyne, chloralkyne or alkadiine, and an alkali metal in a suitable solvent for the ketone, preferably in the presence of a tertiary alcohol or ammonia, optionally enriched for the reaction with a metal-organoalkynyl compound. It can be operated under pressure.

The free hydroxy groups can subsequently be esterified or etherified. An esterified or etherified hydroxy group can be converted to a hydroxy group.
The acylation of the 1- and 3-positions 1 is preferably carried out at room temperature using pyridine/acid anhydride or pyridine/acid chloride.The etherification of the O1- and 3-positions f is carried out using compounds with alkyl action. Preference is given to using diazomethane, dialkyl sulfates, cycloalkyl halides P and dihydrobilanes.

1,3-diester and 1,3-J) 17 in ether
For esterification of β- and droxy groups, a strong acid such as p-toluenesulfonic acid, HC
Presence of ZO4 or pyridine/acid anhydride 0IIk when activated at heat The method listed below can also be used to convert free trihydroxy compounds directly to tri/acylates! Wear. From triacylates it is possible to liberate the 1- and 3-0H groups by careful partial saponification.

1s' 3-diester and 1,3-diether can be converted to the corresponding 17-tetrahydropyranyl ether using dihydropyran in the presence of a strong acid, such as p-toluenesulfonic acid. l according to the invention using an alkyl group.

The etherification of the 17-0R group in the 3-diether is advantageous when the 17-0R group is etherified in liquid ammonia using an alkyl halide.
implement. The two methods mentioned above make it possible to etherify all the OH groups of the hydroxy compounds according to the invention in one operating step.

The 1- and 3-Oil- groups can be liberated from the 1,3-thia-2-syl-17-titrahydrobilanyl derivative by alkaline saponification.

The ether decomposition is carried out in a manner known per se.

Decomposition of enriched temperature 1j (180-220 °C) t% using pyridine hydrochloride or pyridine/concentrated hydrochloric acid or the presence of lower carminic acids % below 150 °C using hydrohalic acid The decomposition of S degree f is mentioned,
Decomposition of the tetrahydropyranyl ether is carried out under mild conditions by addition of monoacid.

In order to increase the yield, it is advantageous to start from compounds whose hydroxyl groups in the l- and 3-positions are esterified or etherified. For example, if an ether group has to be introduced only as an intermediate protecting group, it may be advantageous to etherify dihyropyran, since this group can be removed particularly easily after the reaction has taken place. It's empty.

Residues can also be carried out in a trowel in which the ester groups present in the starting product are retained. On the other hand, the 1- and/or 3-position hydroxyl groups liberated during the reduction can be selectively reacylated.

3-Hydroxy-8a-estra-1,3°5 (10)
-) Diene-1-fuon is known from the literature! be.

Next, the present invention will be explained in detail with reference to examples. The compound according to the invention can be obtained both as a racemate and as an enantiomer.It is not known to experts that the racemate can be divided into the enantiomers by a generally known method for separating the optical enantiomers. It's obvious.

Accordingly, the present invention encompasses racemic and mirror forms.

Example 1 1.3-diacetoxy-8α-estra-1゜3.5・
(10)-) Lien-17-one 3-Hydroxy-Ba-Tora-1,3,5 (r'0
)-) 120 g of lead tetraacetate was added to a suspension of 42 g of diene-1 fluorine, and then side-pressed at room temperature for 3 minutes while excluding water, and then 1 cup was poured into 600 g of ice water.

The sediment is filtered off with suction, washed with water and the filter cake is taken up in methylene chloride. The substance solution is neutralized by washing with hydrogen carbonate solution and water, dried and concentrated. The concentrate is filtered through silica gel (10 s of earth water) using methylene chloride. Combine the substance-containing hexalactones and remove the solvent. lOβ-acetoxy-86-esdlar 1.4
7 g of -diene-3°17-diene are obtained as an oil.

lOβ-acetoxy-8α-estra-1,4-diene-307-dione in 125d acetic anhydride 3. 0.1 ml of concentrated sulfuric acid is added in portions to the Og suspension and stirred for 3 hours at room temperature, during which time the substance gradually goes into solution. Next, put the Nogutsuchi in 10 times the amount of ice water, add 7 g of sodium carbonate, stir for 1 hour, and then filter the mixture. The washed and dried residue is recrystallized from methanol. 7g is obtained.

Melting point: 208~21 t”c (α]D=+89°(
0) for, , c = 0.5).

Analogously, the following is obtained: Ze3-diacetoxy-18-methyl-8α-estra-1,3,5(10)-trixone-17-one. Melting point: 136-137°C Example 2 1.3.17β-triacetoxy-8α-estra-1
,3,5(1G)-) diene methanol #1.3- in 240 d and THF 100 d
Diacetoxy-8a-estra-1,3,5(10)-
) NaB was gradually added to a solution of 6 g of citric acid at room temperature.
Add H4600III and stir for 30 minutes in room ml under N2. - Neutralize the zeta with glacial acetic acid, acetylate and work up according to Example 5. Yield: 4.8g6 Melting point: 1497
50~151'O()(')D =+4.2
(0HQt, *e” 0-5) UV(CI'1
30) i) Su @ 5 = 446 e 'Snow, 3 = 405
, Jg book=SO0 Similarly, the following is obtained: 1.3.17β-triacetoxy-18-methyl-8σ
-estra-1,3,5(1G)-)diene. Melting point = 8
5-89°C Example 3 1.3-diacetoxy-17α-ethynyl-8-estra-1,3,5(10)-)diene-17β-ol 1.3-diacetoxy-8α-estra-1,3, 5(
1G)-)Diene-1Fuon 750■ according to Example 81)
Ethynylation and work-up.

Yield*: Foam that does not crystallize 24019° (a) g0 = -3
3,8° (OHO#3, c = 0.5).

Similarly, the following is obtained: 1,3-diacetoxy-18-methy-17-loethynyl-8α-estra-1,3.5(10)-triene-
17β-ol. Amorphous substance: nv (acetonitrile)
z s s = 5601g * @ 9 = 525 Example 4! , 3-bis-cyclopentyloxy-8-estra-1,3,5(1G)-triene-17β to 8α-estra-1,3,5(10
)-) Lien-1. 3.17
A solution of β-t+1 ol 850"fi is boiled in N21F with 2.5 d of cyclopentyl bromide and 2.5 g of potassium carbonate for 5 hours. It is then placed in ice water, taken up in ether, and the organic phase is washed. Dry and concentrate by evaporation. After purification by chromatography on silicic acid gel, 365 Da is obtained as an oil.

UV (methanol) #Hs = 2270. )example
5 1,3-bis-butyloxy-8a-estra-1,3
, 5(10)-) diene-1 β-O example! 8α-estra-1,3,5(10)-triene-1 in the same manner as in 2.
,3,17β-triol SOOda to n-butyl bromide 1
．． 5 mg and post-treatment. 230Q is obtained. ) Oily substance. UV (methano) ”*5s=20
150 Example 6 1.3.17β-tris-tetrahydropyranyloxy-8α-estra-1,3,5(1G)-triene anhydrous benzene 40-8a-varnished door 1°3.5(1
0)-triene-1,,3,l 7β-triol 80
Distilled dihydropyran 1.4 mzN (jp-
) Add luenesulfone IItOMg. Pour the solution,
S time room temperature! Stirring, then washing with sodium bicarbonate solution and water, neutralization, drying and evaporation gives 700 μl of crude product. Oily substance. nv (methanol)
2g, 76=1? 50, g,, = 176 o
0 Example 7 1.3.17-) Lis-hexanoyloxy-@cl
-Etra-1,3,5(1G)-)8α-Estra-1,3,5(lO) in dienepyridine 3d
-triene-1,3,17β-triol 450111
Add anhydrous turnip 071vt, ssl to the solution of step 9 and heat to 90° C. for S hours under nitrogen. Then pour into ice water, add some methanol and stir for 1 hour to decompose excess anhydride.

Take up in ether, wash the ethereal solution with dilute sulfuric acid, sodium bicarbonate solution and water to neutrality, dry and evaporate. After purification by chromatography through silicic acid gel, 320w9 is obtained. As an oil, U'V (methanol) '16@ = 485 +
1275 =421, Example 8 1.3-dimethoxy-17α-chloroethynyl-8α
-est -1, 3, 5 (IQ)
A methyl-lithium solution is prepared from 1.39 g of lithium and 6.9 g of methyl iodide in 50 ml of anhydrous ether by heating to reflux (45 min under N).

After cooling to 0° C., 3.75 m/ml of dichloroethylene in 15 d of anhydrous ether are added dropwise.

Within 30 minutes after stirring for 1.5 hours at room temperature - 1'THF5
1,3-dimethoxy-8-estra-1 in 0Wll,
Add a solution of 1.3 g of 3,6(10)-)diene-1-fuon and heat to boiling for 1 hour. After cooling with ice, add saturated sodium chloride solution, dilute with ether, wash and make neutral. , dry and evaporate. 475ap is obtained by a-coating through silica gel. Melting point = 185~1
95℃0 Example 9 1.3-diacetoxy-8a-estra-1゜3.5(
10)-) Diene-1f! -1,3-diacetoxy=Be-xxtra-1,3,5(
30) A solution of -triene-17-one Ig was added to lithium-tri-t-butoxyaluminum hydroxide under water cooling.P2
Stir for 45 minutes with g and add 1 haot of ice water of acetic acid to ether! Extract. The organic phase is washed neutral, dried and concentrated by evaporation. Remaining f(Ig)
(crystal) N is prepared by thin layer chromatography treatment. 1,3-Diacetoxy-8α-estra-1,3,5 (melting point = 210-211°C after recrystallization from hexane/acetone)
10)-,) Diene-1-fluor β-ol 380M9 is obtained.

Example 10 1.3-dihydroxy-8a-estra-1°3.5(
10) -) Citric-1-fuone 3 g of 1,3-diacetoxy-8α-estra-1°3.5(10)-trien-17-one in 9 parts of methylene chloride and 18 d of methanol
Add 0.23 d of Nakabori chloric acid (70%) in methanol (1 me) to the solution at 0°C under 1% nitrogen and stir at room temperature for 3 days.UV (methanol) 12.4 = 1950
0th order! Dilute with acetic acid ester and wash neutral with saturated sodium chloride solution. After drying and evaporation, 3
-dihyroxy-8g-estra-1,s,5(10)
2.9 g of -trien-17-one are obtained as an oil.

Example 11 1,3-bis-mesyloxy-8a-estra-1,3
,5(1G)-)diene-1fuonpyridine 1411
1,3-dihydroxy-8-monoestra-1,3,5
(10)-To a solution of triene-17 monoion Ig was added 1.9 m of 1 methanesulfone chloride at 0°C, and G-
10℃! Stir. Then, put it in ice water (hot and acidic) and separate it! ! I! Dissolve the supernatant in methylene chloride. 1,3-bis-mesyloxy-8a-estra-1,3 by chromatography with 8102
,5(1G)-)diene-1Fuon 800 capes are obtained. Melting point: 128-132°C.

Example 12 1.3-bis-mesyloxy-8e1~estra-1,
3,5(10)-) citric acid-1 fluorine A solution of 400 μl of 1,3-bis-mesyloxy-8α-1,3,5(10)-)diene-1 fluorine in anhydrous THF I Oml 800~ of t-butoxy-aluminum hydride is added and stirred for 60 minutes at 0<0>C. Water the n phase! The crude product (4ooQ) obtained is washed, dried and evaporated and purified by thin layer chromatography. 1.3-bis-mesyloxy-8α
-estra-1,3,5(10)-)diene-1fuβ-
All 320 ~ is obtained.

UV (methanol) #, , = 527. ε27%
= '4 Example 13 1.3-bis-mesyloxy-17β-acetoxy-8
1,3-bis-mesyloxy-Ba-estra-1*3*5(ro)-triene-17 in α-estra-1,3,5(10)-trienepyridine 3-
Add acetic anhydride 2- to a solution of /-ol 200IIy,
Leave at room temperature for 3 days. Next, put 1 no Yatsuchi in ice water, extract with methylene chloride, and water! Wash, dry and evaporate. ! ! The +2 residue (180IIIF) is purified by thin layer chromatography. 1.3-L'su-syloxy-17β-acetoxy-8a-estra-1,3
,5(10)-)diene 15G■ is obtained, melting point=6
0-68°C Example 14 1,3-dihydroxy-B a in anhydrous 45d
-Estra-1,3,5(10)-triene-17-
To a solution of 5 ooq. Extract. The extract is washed, dried and concentrated by evaporation. The crude product is purified by column chromatography. Melting point 134-13
1,3-bis(2-propyl-sulfonyloxy)-ga-:c at 6°C (hexane/acetone) 1.
700 Mg of 3.5(10)-trien-17-one are obtained.

Continuing from page 1 Priority claim @ May 31, 1974 ■ West Germany (D
E) ■ P2426777.4 0 Inventor Rudolf Wiechert, Federal Republic of Germany Berlin 39 Endestraße Road 0 Inventor Friedmund Neumann Federal Republic of Germany Berlin 22 Grampnitzer Weeg 7-79 @ Inventor Uxige Herring Federal Republic of Germany Berlin 22 Landsendorfer Veeg

Claims (1)

[Claims] 1. General formula 1! [In the formula, I represents an oxygen atom, and R1 is a C-atom number of 1-8
represents an alkanoyl group or an alkylsulfonyl group having 1 to 3 carbon atoms, and RM represents a methyl or ethyl group. R"-11a-z □
Tora-1,3,5(10)-trien-17-one as lead tetraacylate! A process for producing 1.3-oxygenated 8α-estratriene, characterized by oxidizing and rearranging the reaction product in the presence of a strong acid. 2 General expression do! R1 represents an alkanoyl group having 1 to 8 carbon atoms, an alkylsulfonyl group having 1 to 3 carbon atoms, a methyl or ethyl group, R3 represents a hydrogen atom, and 14 represents a hydrogen atom or an ethynyl or chloroethynyl group] 1.3-
In producing oxygenated 8a-estratriene, 3-
Hydroxy-13-R''-8a-zx tora-1,3,5
(10)-Trien-17-one is oxidized with lead tetraacylate 1, the reaction product is rearranged in the presence of a strong acid, followed by
A process for the preparation of 1,3-oxygenated 8a-estratriene, characterized in that the 17-keto group is reduced by the final desired one. 1 General formula i: ! R1 represents a hydrogen atom, an alkanoyl group having 1 to 8 atoms, a furkylsulfonyl group having 1 to 3 atoms, R2 represents a methyl or ethyl group, R1 represents a hydrogen atom, and H4 represents a hydrogen atom. 3-hydroxy-13-R”-
8g-estra-1゜j, 5(to)-triene-17
-one is oxidized with lead tetraacylate 1, the reaction product is rearranged in the presence of a strong acid, and then! and the final desired one of R1.11? - A method for producing 1.3-oxygenated 8a-estratriene, which is characterized by reducing a keto group and eliminating an acyl group. and R1 and R3 represent a hydrogen atom, a 0-JjA furucyl group having 1 to 8 atoms, an alkylsulfonyl group having 1 to 3 C atoms, methyl, cyclopentyl, or tetrahydrobyrenyl, and R2 represents a methyl or ethyl group. and R4 represents a hydrogen atom or an ethynyl or chloroethynyl group]
In producing 1.3-oxygenated 8α-estratriene, 3-hydroxy-13-H! -'9 g -!
, Xtolar 1.3.5(10)-trien-17-one is oxidized to lead tetraacylate, and the reaction product is rearranged in the presence of a strong acid, followed by! 1.3- characterized in that the 17-keto group is reduced and the acyl group is eliminated and the free PCI group is esterified or etherified by the desired final Pjr of - and R1; Dyeing method of oxygenated 8a-estratriene.