JPS5821639B2 - 1,3- Sansoca 8 Alpha-Estratrienno Seihou - Google Patents

Description

Detailed Description of the Invention The present invention relates to the general formula I: [wherein X represents an oxygen atom or a group, R1 and R3 are a hydrogen atom, an alkanoyl group having 1 to 8 C atoms, a group having 1 to 8 C atoms, 3 represents an alkylsulfonyl group, methyl, cyclopentyl or tetrahydropyranyl group, R2 represents a methyl or ethyl group, and R4 represents a hydrogen atom or an ethynyl or chloroethynyl group].
This invention relates to a method for producing 3-oxygenated 8α-estratriene.

Alkanoyl group having 1 to 8 C atoms or 1 C atom number
The alkylsulfonyl group of ~3 includes physiologically tolerated acids.

For example, the following carboxylic acids may be mentioned: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, enanthic acid, caprylic acid, trimethylacetic acid, diethylacetic acid, tert-butylacetic acid.

Examples of the alkylsulfonic acids include methanesulfonic acid, ethanesulfonic acid, and propanesulfonic acid.

The compounds according to the invention have an advantageous dissociated pharmacological action.

Due to the strong pro-vaginal and -weak pro-uterine effects, the compounds are suitable for the treatment of postmenopausal women.

They can therefore act in the treatment of estrogen deficiency, where effects on the vagina are desirable, but centrally controlled effects on the uterus must be avoided.

The compounds according to the invention are furthermore useful as intermediates for the production of pharmaceutically useful steroids.

Advantageous estrogen dissociation can be demonstrated, for example, in sialic acid tests in mice.

The compounds according to the invention are listed in Table 1 as known estrogens 17α-
Ethynyl-1,3,5 (10)-estratriene-
3,17β-diol (I) and 1,3,5(10)-
Elatratriene-3,17β-diol (II) and new steroidoid 3-diacetoxy-8α-estra-
1,3,5(10)-trien-17β-ol (IV
), 1,3-dimethoxy-8α-estra-1,3,5
(10)-trien-17-one (VI), ■・3-dicyclopentyloxy-8α-estra-1.3.5 (
10)-) Diene-1-fuon (■), l.3-dihydroxy-8α-estra-1.3.5 (10)-) Diene-1-fuon (■), l.3-simethoxy-17α-
Ethynyl-8α-estra-1,3,5(10)-trien-17β-ol (IX), 1,3-diacetoxy-17α-ethynyl-8α-estra-1,3,5(1
0)-trien-17β-ol (X) and 1,3-dimethoxy-8α-estrogen 3,5(10)-trien-17β-ol (Xl). It has a higher dissociation coefficient.

The sialic acid test is performed as follows: remove the ovaries of the mouse.

Starting from day 10 after ovariectomy, the animals receive the substance to be tested once daily for 3 days.

On the fourth day the animal died. Immediately dissect and collect the vagina and uterus.
Weigh into test tubes for hydrolysis.

Measurement of sialic acid was performed using Svennerform.
holm) method [Biochem, B 1ophy
s.

Acta) Vol. 24, p. 604 (1957)].

The dose-induced increase in vaginal and uterine tissue weight and the decrease in sialic acid content are determined, and from this the relative potency of the substance to be tested is determined in comparison with the reference substance estradiol (II).

The relative activity is expressed as a percentage and the degree of dissociation Q is obtained.

For the standard compound estradiol, Q=1.

Compounds with Q>1 are relatively provaginal;
those with are relatively uterotropic.

The thresholds listed in Table 1 were determined in the routine Allen-Toisy test in rats.

The invention furthermore relates to medicaments containing 8α-estratriene of the general formula I as active substance.

The preparation of pharmaceuticals is carried out in a conventional manner by converting the active substance together with the excipients, diluents, flavoring agents etc. customary in galenic pharmaceuticals into the desired dosage form, for example tablets, dragees, capsules, solutions and the like.

The concentration of active substance in the medicament thus formed depends on the dosage form.

Tablets advantageously contain from 0.01 to 101 n9, solutions for parenteral administration contain from 90.1 to 201 v/mj of solution.

The dosage of the medicament according to the invention may vary depending on the processed form and the compound chosen in each case.

Furthermore, it may vary depending on 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, dosages in the range of about 0.02 to about 201 n9 are processed, although variations are permitted depending on circumstances, and dosages greater than 20 Tng, for example up to 50 Tng, are also used.

However, dosages within the range of about 0.057Q to about 59Q are advantageously used.

The compound of the general formula (1) can be prepared by a method known per se to obtain the estra-oligo-
hydrogenating the ene and optionally subsequently reducing the 17-keto group and/or eliminating the ether- or acyl group and/or esterifying the free hydroxyl group with the final desired one of X and R1; and/or etherify.

The novel compounds are produced by methods known per se.

Hydrogenation of the estra-oligoene of general formula (1) can be carried out, for example, by catalytic hydrogenation.

Catalysts include in particular heavy metal catalysts, such as palladium or Raney-N, optionally on carriers such as calcium carbonate, activated carbon or barium sulfate.
ickel ) is applicable.

During the hydrogenation, unsaturated hydrocarbon radicals R4 which are optionally present in the molecule can also be partially hydrogenated.

When the compound in which R4 represents an unsaturated hydrocarbon group is the final desired compound, the hydrogenation to the compound of formula (3) in which X is an oxygen atom is first carried out, and then the organic group R4 is It is advantageous to carry out the reduction with a metal-organic compound, in which represents an unsaturated hydrocarbon group.

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.

In particular, hydrogen can be transferred from the metal hydride to the 17-keto group.

Complex hydrides, such as sodium hydridoborate, lithium hydridoaluminate, sodium hydridotrimethoxoborate, lithium hydridotri-tert-butoquinoaluminate, etc., have proven particularly advantageous as hydrogen donors.

The reduction can also be carried out by known methods with metal-organic compounds in which the organic group represents R4, such as allylmagnesium bromide, for example methylmagnesium bromide or -iodide, alkenylmagnesium- and/or alkenylzinc-10genide. , for example vinylmagnesium bromide or allylmagnesium bromide, alkynylmagnesium halides such as ethynylmagnesium bromide, propynylmagnesium bromide or propynylzinc bromide or alkali metal acetylides such as potassium acetylide.

The metal-organic compound used as the reducing agent may be formed in situ and reacted with the 17-ketone of formula (1).

For example, for reaction with metal organic alkynyl compounds, alkynes, chloralkynes or alkadiines and alkali metals are treated in a suitable solvent for ketones, preferably in the presence of tertiary alcohols or ammonia, optionally under elevated pressure. can be done.

Free hydroxy groups can subsequently be esterified or etherified.

Esterified or etherified hydroxy groups can be converted to hydroxy groups.

Acylation in the 1- and 3-positions is preferably carried out using pyridine/acid anhydride or pyridine/acid chloride at room temperature.

For the etherification in the 1- and 3-1 positions, compounds with alkyl action are preferably used, preferably diazomethane, dialkyl sulfates, cycloalkyl halides and dihydropyran.

■ 17β in 3-diester and 1,3-diether
- For esterification of hydroxyl groups, the steroid is mixed with a strong acid such as acid anhydride, e.g. p-toluenesulfonic acid, HCl.
Act hot in the presence of O4 or pyridine/anhydride.

The last-mentioned method can also be used to convert free trihydroxy compounds directly into triacylates.

1- and 3 from triacylates by careful partial saponification
-OH- group can be liberated.

1,3-diester and 1,3-diether can be converted into the corresponding 17-tetrahydropyranyl ether using dihydropyran in the presence of a strong acid, for example pt-luenesulfonic acid.

The etherification of the 17-OH group in the 1.3-diether according to the invention with an alkyl group is preferably carried out using an alkyl halide in liquid ammonia.

The two last-mentioned methods make it possible to etherify all the OH groups of the hydroquine compounds according to the invention in one operating step.

The 1- and 3-OH groups can be liberated from the 1,3-diacyl-17-titrahydropyranyl derivative by alkaline saponification.

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

For example, decomposition at elevated temperatures (180-220°) with pyridi/hydrochloride or pyridine/concentrated hydrochloric acid or at temperatures below 150°C in the presence of lower carboxylic acids using hydrologonic acid. Decomposition of tetrahydropyranyl ether is carried out under mild conditions by addition of acid.

In order to increase the yield, it is advantageous to start the esterification from a compound in which the hydroxy groups at the l- and 31-positions have been etherified.

For example, ether. If a group has to be introduced only as an intermediate protection, etherification with dihydropyran is advantageous, since this group can be removed particularly easily after the reaction has taken place. .

Reduction also reduces the ester groups present in the starting product.

It can be implemented in such a way that it is maintained.

On the other hand, the 1- and/or 3-position hydroxy groups liberated during the reduction can be selectively reacylated.

Other starting compounds are 1,3-dimethoxylate 3,5 (1
0)・8・14-estrapentaene-1 fuon (A
), 1,3-dimethoxy-17β-acetoxylate 3.
5 (10), 8, 14-estrapentaene (B) and 1, 3-dimethoxy-17β-acetoxet 3, 5 (
10) It can be produced as described in the example of 8-estratetraene (C).

A: 1, 3-dimethoxy sheet 3, 5 (10), 8, 14
-To Estra/Quen anhydrous Huon anhydrous THF15rr
Trace amounts of iodine and 2 rnl of ethyl bromide are added to a suspension of 17 g of Mg pieces in Ll, and after warming to 50 DEG C., vinyl chloride is gradually introduced until the temperature falls to room temperature.

250 ml of anhydrous THF are added dropwise during the introduction.

Anhydrous THF8 was added to this vinyl Grignard solution at 20°C.
A solution of 52.4 P of 6,8-dimethoxy-tetralone in 4 ml and 82 ml of anhydrous benzene is slowly added dropwise and left under N2 in a cooling room overnight.

After warming to room temperature, add 84 ml of glacial acetic acid and 350 ml of ice water to the batch.
After 30 minutes, the mixture is stirred, the aqueous phase is separated off and the mixture is further extracted with benzene.

The combined organic extracts are washed neutral with NaHCOa-solution and water and dried.

38 tons of 2-methyl-cyclopentane-dione-(1.3) in this pinol compound solution? and potassium hydroxide (powdered 160 Iv), concentrated to half, carefully added dropwise with methanol 170 rILl and heated to boiling under N2 for 3 hours.

Cool to room temperature, dilute with ether and remove excess 2-methylcyclopentanedione (1.3) by extraction with 10% caustic soda solution.

Wash to neutrality with water, dry and evaporate and recrystallize from ethanol.

1,3-dimethoxy-8,14-seco-1,3,5 (1
0)・9(11)-Estratetraene-14・17-
66g of Zion is obtained.

Melting point: 87788-89°C.

1,3-dimethoxy-8 in distilled benzene 940ml
14-Secote 3.5(10).9(11)-estratetraene-14.17-dione 69S#)
Add 3 g of t-toluenesulfonic acid and heat to boil for 20 minutes.

After cooling, it is extracted with a hot Na He solution, washed with water to neutralize it, and dried.

r by recrystallization over activated carbon from acetone/hexane.
ac, (racemic)-1,3-dimethoxy-1,3.
5(10).8.14-estrapentaen-17-one 601 is obtained.

Melting point: 120-121°C0B: 1,3-dimethoxy-
17β-acetoxylate 3,5(10),8,14-estrapentaenemethano-/lz2.4, J and THFl, r in OJ
ac.

-1,3-dimethoxylate 3,5(10),8,14-
Slowly add NaBH46,0? to a solution of estrapentaen-17-one 601 at room temperature. and stir at room temperature under N2 for 30 minutes.

The batch is neutralized with glacial acetic acid, concentrated, taken up in ether, washed neutral with saturated NaCl solution, dried and concentrated by evaporation.

The residue is dissolved in 140 Tl of pyridine, 801 rL of acetic anhydride is added to the solution and stirred for 1 hour at 80° C. under N2.

After cooling, place in ice water, take a portion of the precipitate, and absorb in ether.

The ethereal solution is washed neutral with saturated NaCl solution, dried and concentrated by evaporation.

rac via activated carbon by recrystallization from methanol
.

-1,3-dimethoxy-17β-acetoxylate 3,5
(10)・8・14-Estrapentaene61. Of is generated.

Melting point: 122-124°co
.

C: 1,3-dimethoxy-17β-acetoxy-1,3
・5 (10)・8-Estratetraene distilled THF1
raCl-1,3-dimethoxy-17β-acetoxylate 3,5(10),8,14-estrapentaene in 0 ml was dissolved in N246.6 rnl over Pd/CaCO3 (5%) 2007Q at room temperature and normal pressure. Hydrogenate until absorbed.

After drying and evaporative concentration from the catalyst, rac, -1,3-dimethoxy-17β-acetoxylate 3.□5(10).8-estratetrae/447■ is obtained from methanol.

Melting point: 11.1/112-113℃ 02-Ethyl-cyclopentane-dione (1-3) using 2-7'ropyrunclopentane-dione-(1.3), and further A, B and later by C.

When processing, 1,3-dimethoxy-18-methyl-
1, 3, 5 (10), 8, 14-Estrapentaene-
17-one or 1,3-diftquin-18-ethyl-1,3,5(10).8,14-estrapentaen-17-one and 1.

3-dimethoxy-17β-acetoxy-18-methylto 3,5(10),8,14-estrapentaene or 1,3-dimethoxy-17β-acetoxy-18-
Ethyl-1,3,5 (10) 8,14-estrapentaene and 1,3-diftquine-1, β-acetoxy-
18-methyl-1,3,5(10),8-estratetraene or 1,3-dimethoxy-17β-acetoxy-18-ethyl-1,3,5(10),8-estratetraene is obtained. .

Next, the present invention will be explained in detail with reference to examples.

The compounds according to the invention can be obtained both as racemates and as enantiomers.

It is clear to the expert that racemates can be resolved into enantiomers by separation methods commonly known for the separation of optical antipodes.

Accordingly, the present invention includes racemates and enantiomers.

Example 1 rac, -1,3-dimethoxy-8α-estra-1.
3.5(10)-triene-17-one THF50mA
'Medium rac, -1,3-dimethoxylate 3,5 (10)
・8.14-Estrapenta: r-7-17-o70.
3Y to Paradium A /Ca CO3 (5%) 0.15
? Hydrogenation in the presence of 50 atmospheres (gauge) of N2 at room temperature within 17 hours.

Next, one portion of the catalyst is taken, the liquid f is concentrated by evaporation, and the residue is recrystallized from isopropyl ether.

40~ is obtained.

Melting point: 158-160°C. Example 2 rac, -1,3-dimethoxy-17β-acetoxy-8α-estra-1,3,5(10)-triene (a) rac, -1,3- in 400 ml of benzene
Dimethoxy-17β-acetoxylate 3.5(10).8.14-estrapentaene 612 was synthesized in the presence of 14 g of Raney nickel at room temperature within 17 hours.
Hydrogenate under atmospheric (gauge) N2 pressure.

The catalyst is then separated, the P solution is concentrated by evaporation, and the residue is recrystallized from methanol over activated carbon.

50ft is obtained. Melting point: 136-138°C.

(b) rac, -1,3-dimethoxy-17β
-acetoxylate 3.5(10).8-estratetraene 100m? Distill Pd in 1.4 ml of THF.
/CaCO3 (5%) 301n9 under normal pressure at room temperature until no more hydrogen is absorbed.

44~ is obtained from methanol after one filtration and evaporative concentration.

Melting point: 126/130-131°C.

Similarly, the following is obtained: rac, -1,3-dimethoxy-17β-acetoxy-
13-methyl-8α-estra-1, 3, 5 (10)
-t-liene, as oil; UV (methanol) ε2
□6 =4090゜rac, -1,3-dimethoxy-17β-acetoxy-18-ethyl-8α-estra-1,3-5(10
)−) Lien.

Example 3 rac, -1,3,17β-triacetoxy-8α-estra-1,3,5(10) -triene rac, -1,3-dimethoxy-17β-acetoxy-
A mixture of 8α-estra-1.3.5(10)-) linear 1t and pyridine-hydrochloride 101 is heated to 200° C. under N2 and stirring for 3 hours.

After cooling, the melt is dissolved in 50 ml of pyridine and stirred with 5 rnl of acetic anhydride for 1 hour at room temperature under N2.

After precipitation in ice water, the crude product is collected and purified by gradient liquid chromatography (methylene chloride/acetone=9+1).

930~ is obtained.

Melting point: 146/147-148°C0 The following can be obtained in the same way: rac, -1,3,17β-triacetoxy-18
-Methyl-8α-estra-1,3,5(10)-) linear, oil, UV (methanol) ε268 (-48
5; ε275 = 429o) When using caproic anhydride or caprylic anhydride instead of acetic anhydride, the following is obtained: rac, -1°3·17β-tris-
Hexanoyloxy-8α-estra-1, 3, 5 (1
0)-triene raCl-1,3,17β-tris-octanoyloxy-8α-estra-1,3,5(10)-triene,
Oily substance.

UV (methanol) ε264-481; ε2□o = 4
12゜Example 4 rac, -1,3-dimethoxy-8α-estra-1.
3,5(10)-t-linear 17β-ol rac, -1,3-dimethoxy-17β-acetoxy-8α-estra-1,3,5(10)-) linear 4
．． 5fI was dissolved in 100 ml of methanol in an aqueous potash solution (1
0%) saponified by heating at reflux for 1.5 h under N2 at 13 rnl.

After cooling, carefully neutralize with glacial acetic acid, concentrate to half the volume, precipitate in ice water/NaCl and work up.

Crude product 4.11 is obtained.

Recrystallize 500rv from methanol to obtain 330.

Melting point: 153/153.5-154°C. Similarly, the following is obtained: rac, -1,3-dimethoxy-18-methyl-8
α-estra-1,3,5(10)-triene-17β
-Oar, foam.

UV (methanol) ε283-2120゜Example 5 raCo-1,3-dimethoxy-17β-acetoxy-
8α-estra-1,3,5(10)-trienemethanol 3rrLl and THF 1. Qmlml
Medium e, -1s3-dimethoxy-8α-est-y
-1・3・5(10)-) Linear 17-on 601v
NaBH46Om& was gradually added to the solution at room temperature for 30
Stir at room temperature under N2 for minutes.

The batch is neutralized with glacial acetic acid, concentrated, taken up in ether, washed neutral with NaCl-saturated solution, dried and concentrated by evaporation.

The residue is dissolved in 1 yr Ll of pyridine, 0.5 ml of acetic anhydride is added to the solution and kept under N2 at 80° C. for 1 hour.

After cooling, place in ice water, take a portion of the precipitate, and absorb in ether.

The ethereal solution is washed neutral with NaC1-saturated solution, dried and concentrated by evaporation.

Recrystallization from methanol via activated carbon yields 42.

Melting point: 131-134°C. Example 6 rac, -1,3-dimethoxy-17α-ethynyl-8
α-estra-1,3,5(10)-triene-17β
-all potassium-t-butyrate 1.2f (10 mmol),
t-butano-/L/2.5 rul and anhydrous THF2
Place 0 ml into an autoclave, flush with nitrogen, and fill with acetylene to 4.5 atmospheres (gauge pressure).

rac in 5 ml of anhydrous HF after 30 minutes, -1-3-
Dimethoxy-8α-estra-1, 3, 5 (10)-)
Add 740 Da of Linear 17-one and react under acetylene pressure for 45 minutes.

Precipitate in 401 rLl of dilute sulfuric acid (20%) and ice, extract with methylene chloride and work up.

The crude product is purified by column chromatography.

4301n9 is obtained from hexane/acetone.

Melting point 177/178-179°C.

Similarly, but without using t-butanol as solvent during ethynylation, the following is obtained: raC0-1
・3-dimethoxy-18-methyl-17α-ethynyl-
8α-varnish) Ra-1, 3, 5 (lo)-) Linear 17
β-ol, melting point: 95-98°C, UV (CH30H)
: '284 = 2050° Example 7 rac, -1,3-diacetoxy-8α-estra-1,3,5(10)-) diene-1-fuone pyridine-hydrochloride 25f and 1,3-dimethoxy-8α- Estra-1, 3, 5 (10)-triene-
A mixture of 2.51 ml of 17-one is heated to 200° C. for 3 hours under N2 and stirring.

After cooling, adding 120 r/L of pyridine and 12 ml of acetic anhydride and stirring for 1 hour at room temperature, the solution was dissolved in ice water/N a Cl.
Stir for 10 hours, take out and post-process.

The crude product (2.5f?) was subjected to gradient concentration liquid chromatography (SiO260P: methylene chloride/acetone 10%)
Purify by processing.

After recrystallization from methanol 710 rnI/ is obtained.

Melting point: 179-180.5°C0 Example 8 rac, -1,3-diacetoxy-17α-ethynyl-
8α-estra-1, 3, 5 (10)-triene-17
β-ol Potassium-t-butyrate in anhydrous THF2 (Il 8.3
? A mixture of 2.5rrLl of t-butanol was washed with N2 and placed in a stirring bomb under acetylene.
) for 1 hour at room temperature.

Then rac, -1·3- in ml of anhydrous THFS
Diacetoxy-8α-estra-1,3-5(10)-
) Add 740 μl of diene-1 fuon and rock under acetylene for 2 hours at room temperature.

The batch was placed in 40 ml of dilute sulfuric acid (20%) to remove P.
Post-process.

The crude product is postacetylated with 2 rnl of acetic anhydride in 5 ml of pyridine.

After precipitation with water and work-up, the crude product (from 850) is purified by gradient concentration chromatography (SiO□201, 25% hexane/acetone).

152 da is obtained.

Melting point: 154-155°C. Analogously, but without using tert-butanol as solvent during ethynylation, the following is obtained: rac, -1,3-diacetoxy-18-methyl-17
α-ethynyl-8α-varnish), 7-1, 3, 5 (10)
-trien-17β-ol, foam, UV (acetonitrile) ε265 = 587, ε2□2 = 549゜Example 9 1,3-bis-cyclopentyloxy-8α-estra-1,3,5 (10)-) Diene-1 fluorine β-ol 8α-varnish in 30ml ethanol) 7-1 ・3・5(
10)-) Liento 3.17β-triol 8501
Add 2.5 rn of cyclopentyl bromide to the solution of n9 under N2.
1 and potassium carbonate for 5 hours.

It is then placed in ice water, taken up in ether, and the organic phase is washed, dried and concentrated by evaporation.

After purification by chromatography on silicic acid gel 36
You will get 5 Da.

Oily substance. UV (methanol) ε285-2270゜Example 10 1,3-bis-butyloxy-8α-estra-1,3
・5(10)-trien-17β-ol 8α-estra-1, 3, 5(10
)-triene-1,3,17β-triol 500rn
9 is reacted with 1.5 TrLl of n-butyl bromide and worked up.

230~ is obtained. Oily substance. UV (methanol) ε,
28. =2015゜Example 11 1,3,17β-tris-tetrahydropyranyloxy-8α-estrato 3,5(10)-triene 8α-estra-1,3,5(10) in 40 ml of anhydrous benzene
10)-trient 3.17β-triol 8001
r1f? Dihydrobilane l, 4 ml and p
-) Add luenesulfonic acid 1oIn&.

The solution is stirred for 1.5 hours at room temperature, then washed neutral with sodium bicarbonate solution and water, dried and concentrated by evaporation.

A crude product 700rn9 is obtained. Oily substance.

Uv (methanol): ε2□6=175o1ε279=
1760° Example 12 1,3,17-Dolis-hexanoyloxy-8α-estra-1,3,5(10)-) 8α-estra-1,3,5(1) in 3rrll of lienepyridine
0)-)Lient 3.17β-triol 450m
Add 1.5 ml of caproic anhydride to the solution of 9 and heat to 90'C under nitrogen for 5 hours.

Then pour it into ice water, add some methanol,
Stir for 1 hour to destroy 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, 320~ are obtained.

Oily substance.

UV (methanol) ε268-485, ε275 = 4
2'.

Example 13 1,3-dimethoxy-17α-chloroethynyl-8α-
Estra-1.3.5(10)-) diene-1-fluor β-ol from 1.39P of lithium and 6.9 ml of methyl iodide in 50 ml of anhydrous ether by heating to reflux (45 min under N2). -Preparing a methyl-lithium solution by preparing a lithium solution.

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

After stirring for 1.5 hours at room temperature, 50m of THF was added within 30 minutes.
1,3-dimethoxy-8α-estrate 3,5 (
10) Add a solution of 1.31 -trien-17-one,
Heat to boil for 1 hour.

After cooling with water, saturated sodium chloride solution is then added, diluted with ether, washed neutral, dried and concentrated by evaporation.

Purification via silica gel yields 4751n9.

Melting point 2: 185-195°C Example 14 1,3-diacetoxy-8α-estra-1,3,5 (
10)-) Diene-1F β-ol Anhydrous THF”30m
1 in 1,3-diacetoxy-8α-estra-1,3.
A solution of 1 g of 5(10)-) diene-1 phion was stirred with 2 g of lithium-tri-t-butoxy-aluminum hydride for 45 minutes under water cooling.

The batch is then placed in acetic acid/water ice/NaCl and extracted with ether.

The organic phase is washed neutral, dried and concentrated by evaporation.

Residue 1 (tP) is purified by thin layer chromatography.

Melting point 2210-211 after recrystallization from hexane/acetone
1,3-diacetoxy-8α-estra-1,3-diacetoxy-8α-estra-1,3-
380 Iv of 5(10)-)diene-1-fur β-ol are obtained.

Example 15 1,3-dihydroxy-8α-estra-1,3,5 (
10)-) Lien-17-one 1 in 91 rLl of methylene chloride and 18 ml of methanol
・3-Diacetoxy-8α-estra-1, 3, 5 (1
0) Perchloric acid (70%) 0.23 in 1 ml of methanol under nitrogen at 0°C to a solution of 3v of -1-diene-1-fuon
Add m1 and stir at ice temperature for 3 days.

It is then diluted with acetic acid ester and washed neutral with saturated sulfur chloride solution.

After drying and evaporative concentration, 1,3-dihydroxy-8α-estra-1,3,5(10)-)diene-1fuone2.
91 is obtained as an oil.

UV (methanol) ε284-1950゜Example 16 1,3-bis-mesyloxy-8α-estra-1,3
・5(10)-trien-17-onepyridine 14rn
1,3-dihydroxy-8α-estra-1,3.
A solution of 5(10)-trien-17-one 11 at 0 °C.
Add 1.91 Ll of methanesulfonic acid chloride and stir at 0 to io'c for 3 days.

It was then placed in ice water (acidified with HCI) for 1 hour.
Separate and dissolve the residue in methylene chloride.

1.3.5 (10
)-) 800 μm of diene-1-fuon are obtained.

Melting point: 128-132°C. Example 17 1,3-bis-mesyloxy-8α-estra-1,3
・5(10)-)luene-17β-ol 1,3-bis-mesyloxy-8 in 10 ml of anhydrous THF
α-1・3・! 5(10)-trien-17-one 40
800 m9 of lithium-tri-t-butoxy-aluminum hydride is added to the solution of 0~ and stirred for 60 minutes at O<0>C.

The organic phase is washed with water, dried and concentrated by evaporation.

The crude product obtained (400~) is purified by thin layer chromatography.

■・3-bis-mesyloxy-8α-estra-1,3
-5(10)-trien-17β-ol 3207Q is obtained.

Uv (methanol)! -267=527. 5275
=4640 Example 18 1,3-bis-mesyloxy-17β-acetoxy-8
α-Estra-1,3,5(10)-1,3-bis-mesyloxy-8α- in 3 ml of trienepyridine
Add 2 ml of acetic anhydride to a solution of 2001 vol of estra-1.3.5(10)-trien-17β-ol and leave it at room temperature for 3 days.

The batch was then placed in ice water and extracted with methylene chloride,
Wash with water, dry and evaporate.

The residue (180Iv) is purified by thin layer chromatography.

1,3-pisumesyloxy-17β-acetoxy-8
150 Da of α-estra-1.3.5(10)-triene is obtained.

Melting point = 60-68°C Example 19 1,3-dihydroxy-8α in 45 ml of anhydrous benzene
14 ml of triethylamine are added to the solution of 900In9 of -estra-1.3.5(10)-)diene-1-fuon.

5.4 ml of isofuropylsulfonyl chloride are then added with vigorous stirring and the mixture is stirred for 2 days at room temperature.

Then pour on ice and extract with ether.

The extract is washed, dried and concentrated by evaporation.

The crude product is purified by column chromatography.

1.3 with melting point 134-136℃ (hexane/acetone)
-bis(2-propyl-sulfonyloxy)-8α-estra-1·3·5 (10)-)diene-1 phoon 700~ is obtained.

Claims (1)

[Scope of Claims] 1 General formula I [wherein, X represents an oxygen atom or a group; alkylsulfonyl group,
methyl, cyclopentyl or tetrahydropyranyl group, R2 represents a methyl or ethyl group, R4 represents a hydrogen atom or an ethynyl or chloroethynyl group]. By a method known per se, the general formula (1) [wherein R1, R2 and
---B represents a single bond or a double bond]
1.3, characterized by hydrogenating oligoenes.
Method for producing oxygenated 8α-estratriene. 2 General formula I, 10-R'' [wherein, , methyl, cyclopentyl or tetrahydropyranyl group, R2 represents a methyl or ethyl group, R3 represents a hydrogen atom, R
4 represents a hydrogen atom or an ethynyl or chloroethynyl group], the general formula where X represents an oxygen atom and the estra-oligoene of A---B&"! A method for producing 1,3-oxygenated 8α-estratriene, which is characterized by reducing the group. 3 General formula I [wherein, represents an alkanoyl group, an alkylsulfonyl group having 1 to 3 C atoms, methyl, cyclopentyl or tetrahydropyranyl group, R2 represents a methyl or ethyl group, R3 represents a hydrogen atom, R
4 represents a hydrogen atom or an ethynyl or chloroethynyl group], the general formula where X represents an oxygen atom and A=B represents a single bond or a double bond], followed by hydrogenation of X and R1
Process for the preparation of 1,3-oxygenated 8α-estratriene, characterized in that the 17-keto group is reduced by the final desired one and the ether- or acyl group is removed. 4 General formula I [wherein, R2 represents a methyl or ethyl group, R4 represents a hydrogen atom or an ethynyl or chloroethynyl group]
In producing α-estratriene, a method known per se is used to produce α-estratriene using the general formula [representing a heavy bond] is hydrogenated, followed by reduction of the 17-keto group by the final desired one of X and R1, and elimination of the ether- or acyl group and removal of the free hydroxyl group. A method for producing 1,3-oxygenated 8α-estratoriae, which is characterized by esterification or etherification.