JPS6187637A - Preparation of intermediate for synthesis of steroid - Google Patents

Abstract

PURPOSE:To produce a compound useful as a synthetic intermediate of steroid, from an easily available raw material, economically, by oxidizing a terminal olefin group of a compound corresponding to the objective compound to methyl ketone in the presence of a palladium and copper catalyst and water. CONSTITUTION:The compound of formula I [R<1> is lower alkyl; R<2> is H or lower alkyl; Y is oxo, H or (protected) OH; X is CH2 or C2H4] is oxidized in the presence of a palladium and copper catalyst and water to obtain the objective compound of formula II useful as an intermediate of e.g. 19-nor- testosterone-type steroid. The starting compound of formula I can be produced by reacting the compound of formula III producible easily from butadiene with the compound of formula IV, subjecting the resultant compound of formula V to dehydrative cyclization reaction, optionally carrying out the selective reduction of the oxo group of the resultant compound of formula I (Y is oxo), and if necessary, protecting the produced OH group.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing steroid synthetic intermediates.

In addition to being isolated from natural products, steroids have been developed in recent years through various total synthesis methods, particularly >517. ] The method via O′ − is attracting attention as a promising method, but [
Dokraday, Akademi-Nauk, Nisnisnisar (
Journal of the Academy of Sciences of the Soviet Union) Vol. 17, p. 880, 1966], the synthesis of this intermediate (1) requires multiple steps, or the starting materials are expensive, and furthermore, it includes steps with relatively poor yields. It has some shortcomings and is not sufficient.

As a result of various studies in view of these points, the present inventors found that 1,7-octadien-3-one (II) C1ly = Cll C(C)IJ-CI which is easily obtained from butadiene,
(II) is reacted with a compound represented by the general formula (in the formula, R1 represents a lower alkyl group, R3 represents hydrogen or a lower alkyl group, and X represents a methylene or ethylene group) to form a compound represented by the general formula. This is subjected to a dehydration ring-closing reaction to obtain a compound represented by the general formula, optionally subjected to a selective reduction reaction of the oxo group, and if necessary, after protecting the generated hydroxyl group, palladium and copper are removed. By oxidizing the terminal olefin to a methyl ketone in the presence of a catalyst, water, and oxygen, a compound of the general formula (wherein Y represents an oxo group or hydrogen and an optionally protected hydroxyl group, and the others are the same as above a) It was discovered that a compound represented by the following formula could be obtained, and the present invention was completed based on these findings.

That is, the present invention is a method for producing a compound represented by general formula (Vl) characterized by oxidizing a compound represented by general formula (V) in the presence of a palladium and copper catalyst and water. .

In the above general formula, lower alkyl in R1 and R* is, for example, methyl, ethyl, n-propyl, i-
It means a substance having 1 to 3 carbon atoms such as propyl. Also, Y
As the protecting group for the protected hydroxyl group shown in
Any substance that can be removed under relatively mild conditions, such as acidic conditions such as hydrochloric acid or sulfuric acid, or catalytic reduction, may be used. Examples include tertiary butyl, tetrahydropyranyl, benzyl, acetyl, etc. In the case of a ketone, 1,3-dioxolane or the like can be used as a protecting group.

As such a compound represented by the general formula (V),
There are the following.

(+) 7.7a-dihydro a-7a-methyl-4-(
3-butenyl)-1-t-butoxy-5(6H)-indanone (2)? , 7a-dihydro-2-methyl-7a-methyl-4-(3-butenyl)-1-L-butoxy-5(
6H)-indanone (3) (±)-7,7a-dihydro-7a-ethyl-4
-(3-butenyl)-1,5(6H)-indanedione (4)(±)-7,7a-dihydro-2-ethyl-7a
-Methyl-4-(3-butenyl)-1-hydroquine-5
(611)-Indanone(5)(±)-7,7a-dihydro-7a-isopropyl-4-(3-butenyl)-1-hydroquino-5(61
t)-indanone (6) (±)-7,7a-dihydro-7a-methyl-4
-(3-butenyl)-1,5(6H)-indanedione (7)(±)-7,7a-dihydro-7a-methyl-4
-(3-Butenyl)-1-hydroxy-5(6H)-indanone (8) 3.4.8.8a-tetrahydro-5-(3
-butenyl)-8aβ-methyl-1,6(2H,7H)
Naphthalenedione (9) 5-t-butoxy-4aβ-methyl-1-(3-
butenyl)-2,3,4,4a,5.6.7.8 octahydronaphthalen-2-one.

(1G) 3,4.8.8a-tetrahuman o-5-(
3-butenyl)-8aβ-ethyl-1,6(2H,7H
) Naphthalenedione In addition, the above 1,7-octacyen-3-one (II)
Dimerized butadiene in the presence of acetic acid to obtain 3-acetoquine-1,7-diene, which was then hydrolyzed to give 1.7
-octacyen-3-ol and Tetrahedron Letters 1967, Vol. 2, 451), then chromic anhydride, complexes of chromic anhydride and pyridine, etc., and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. (DDQ
), manganese dioxide, silver carbonate, copper oxide, and other oxidizing agents.

Further, the cyclobentanone derivative represented by the general formula (I [
43), Journal on Organic Chemistry, Vol. 32, p. 1236 (1967), Brecan de.
Société Gimmique de France 1955 1
It can be produced by the method described on page 036.

In the method of the present invention, the condensation reaction of (U) and ([I) is usually carried out using sodium hydride, triethylamine, tributylamine, sodium hydroxide, or potassium hydroxide.

This is preferably carried out in the presence of a basic compound such as pyridine. The reaction is preferably carried out using a compound capable of dissolving the starting material, such as benzene, ethyl acetate, or ethanol.

The reaction is preferably carried out in an inert solvent such as methanol, tetrahydrofuran, dimethylformamide, nomethogynoethane, dioxane, etc., and the reaction proceeds satisfactorily even at temperatures below room temperature, about 0°C to 10°C, but may be added, heated or cooled if necessary.

Compound (IV) thus obtained is preferably subjected to a selective reduction reaction to reduce one oxo group on the noclopentane ring so that R1 becomes β-coordinated during the ring-closing reaction in the next step. . For such selective reduction reactions, for example, Cancida spp.

Debaryomyces, Pichia, Schizosatucharomyces,
A microorganism or a culture of a microorganism belonging to the genus Petasosvora, Hansenisula, Torulopsis, Satucharomycodes, etc., which has the ability to reduce compound (IV) to a compound represented by the general formula in which R1 is β-coordinated, This is carried out by acting on compound (IV). Specific examples of microorganisms that can be used include Cancida solani, Cancida robusta, Cancida krusei, Cancida utilis,
Cannoda Fabiani.

Cansida tenuis, Cansida scotchii.

Debaryomyces nicotianae, Debaryomyces bini, Debaryomyces vanrisi, Debaryomyces globozusus, Debaryomyces fatshuii.

Pichia wickerhamii, Vitia echernoi, Pygia biperi, Pichia quercume, Betasosvora thambarno, Satucharomycodes lutwigii, Torulopsis aeria, Torulopsis coryculosa, Torulopsis cansida, Torulopuns globosa, Torulopsis vinacea.

Torlopuns Nyudaeria, Hansenisula wingei, Hansenisula φhorstii, Hansenysula bainilinkii, Hansenisula kabusurata Hansenisula.
Examples include Saturnus.

The raw material compound (
IV) to lead to the target compound (■'). Here, the term "microbial culture" refers to a culture containing microorganisms, crushed bacterial cells, enzyme systems extracted from these, and the like. For example, after culturing microorganisms by a conventional method, the microorganisms may be separated from the culture, or the microorganisms may be brought into contact with the raw material compound without separation. It is also a commonly used method to simultaneously culture the microorganism and reduce the raw material compound by culturing the microorganism in a medium containing the raw material compound.

As a nutrient medium suitable for the growth of microorganisms, one containing a carbon source and a nitrogen source that can be assimilated by the microorganism, inorganic salts necessary for growth, various hydamino-amino acids, etc. is used. That is, examples of carbon sources include glucose, soyosugar, and dextrino.

Nitrogen sources that can be assimilated by bacteria, such as starch and glycerin, include nitrogen-containing organic substances such as pebton, meat extract, caseino, edamine, corn steep liquor, yeast or yeast extract, and ammonium nitrate, phosphorous, etc. Inorganic nitrogen compounds such as ammonium acid, ammonium sulfate, and sodium nitrate, as well as inorganic salts such as potassium phosphate, sodium chloride, and magnesium sulfate, are appropriately added to form a culture medium.

As a method for culturing microorganisms, any of static culture methods, shaking culture methods, deep culture methods involving stirring and aeration, etc. may be used. The time of addition of the starting compound (IV) is selected at the beginning of cultivation or at an appropriate time in the middle of cultivation. The raw material compound (IV) is in the form of a fine powder and can be used as it is or, for example, acetone, methanol, ethanol, ethylene glycol, propylene glycol 2-tumedelporumamide,
As a solution or suspension dissolved in a suitable solution of Nookizano, or as a suspension in which a surfactant and a dispersant are added, either all at once or continuously over a certain period of time. Added periodically or intermittently.

In addition, after separating the microbial cells obtained by culturing or the reductase involved in the desired reduction reaction from the culture medium or the cells, they are suspended or dissolved in a buffer solution or water with an appropriate pH and ionic strength. raw material compound and water
This can also be carried out by contacting the donor and reducing the composition.

Acidity in the reduction reaction using the above (IV) as a substrate,
Since the temperature, reaction time, and other conditions vary depending on the type of raw material compound added, the type of microorganism used, etc., it is desirable to select the most appropriate conditions for each reaction.

The compound (■') produced and accumulated in this way can be separated and collected by various means.

For example, there are adsorption methods in which the target substance is adsorbed on a suitable absorbent such as alumina or activated carbon, and then eluted with a suitable solvent such as methanol or ethanol, or halogenated hydrocarbons such as chloroform, methylene chloride, ethylene chloride, or acetate esters. Direct extraction using an organic solvent that can form a two-liquid phase with water, such as countercurrent distribution, or a method that utilizes the difference in distribution ratio between the two liquid phases, or a suitable carrier such as alumina, silica gel, cellulose pulp, etc. Various separation means can be selected and used as desired, such as a chromatographic method using a chromatographic method or a method using a difference in solubility. The above-mentioned protecting group may be introduced into the obtained compound (■') by a conventional method, if necessary.

The ring-closing reaction of compound (IV) can be carried out using, for example, β-alanino,
It proceeds easily in the presence of weakly basic compounds such as brolino and phenylalanine. The presence of trace amounts of strong acids, such as perchloric acid, gives favorable results.

The reaction involves water, methanol, ethanol, propatool,
The reaction is preferably carried out in a solvent such as acetonitrile, methylene chloride, benzene, or tetrahydrofuran, and can be carried out at room temperature or under heating (for example, under reflux).

The oxidation reaction of compound (V) is carried out using, for example, a balanium chloride catalyst and a reoxidizing agent such as cuprous chloride.

It can be carried out in an elementary atmosphere. The reaction consists of trimethylformamide, methanol, ethanol, propatool,
The reaction can be carried out in the presence of an inert solvent such as sulfolano, nomethoquinoethane, nooxano, etc., and the reaction temperature is sufficient at room temperature, but the reaction temperature may be increased if necessary. The reaction is carried out under atmospheric pressure or pressurized oxygen with efficient stirring or shaking.

The compound (Vl) obtained in this way is published in Angebano de Hemi-vol. 72 (+960), pages 725-730, vol. 108 (
+9-true testosterone type steroids, estrone type steroids, 9.11-dehydrotestosterone type steroids, anotrosterone type steroids, corchidino type steroids, etc. are derived by the method described in pages 2673-2679 etc. It is extremely useful as a synthetic intermediate for various steroids.

Reference Example 1 3.1 g of 1.7-octarenin-3-ol is dissolved in 100 cc of carbon tetrachloride, 10 g of activated manganese dioxide is added, and the mixture is stirred at room temperature for 4 days. After filtration, the solvent was
Distill under reduced pressure of ~30 mmHg to obtain 2 g of 30-b nonin-3-one.

It is confirmed from the analysis results below that the above fraction is 1,7-octanonin-3-one.

Infrared spectrum analysis 1695cm''-', 1680cm-', 16
40cm-', 910cm-'NMR (CC1,)
Spectral analysis 609~1.8 (411, methylene) 2.49 (21+, triple line, -C tan, -C0) 47~
63 (611, olefin) Reference Example 2 (+) Triketone(+, cu
ug) permanent methanol solution (methanol IO+d)
, orthoformic acid medyl ester (0,924d) and p-
Methanol solution of toluenesulfic acid (0.5w [%,
Add 0.5 rnfl of p-1-luenosulfuric acid and stir for 15 minutes at room temperature. The reaction solution was passed through a Nori-Gel column and the solvent was removed, yielding the crude product of (+)-7,7a-nohydro7aS-methyl-4-(3,3-nomethoxybutyl)-1°5(6H)-indangio7. get.

NMR (henozeno, external standard trimethyl norane) δ value (
ppm) 0.48 (3H,s, angular methyl)Q, 38
(311,s, terminal methyl) 2.68(611,3,OCI+,) l R: 1660cm-', 1750cm-'(2
)” Ketal compound (1.32g) obtained from Biped (1)
is dissolved in dry benzene and heated to the boiling point temperature of benzene, then malonic acid (5 mg) is added and about 273 volumes of solvent are removed by distillation (over about 20 minutes).
. After the reaction, the mixture is returned to room temperature, made basic with a saturated aqueous solution of sodium carbonate, and extracted with benzene. The extract was washed with saturated brine, dried over Mg5O, and the solvent was distilled off to give (-)-3-methoquino-3,6aS-tmethyl-
A crude product (t, tag) of 1,2,3,5,6°6a,7,8-octahydrocyclopenta[f][1]benzohyrano-7-one is obtained.

NMR (CC1,) δ value (Ppm): 1.08 (311
, s, angular methyl), 138 (311, s, terminal methyl), 3.20 (311, s, -1It :1
The crude product (1.16 g) obtained in (2) above was dissolved in 20 d of dry tetrahydrofuran and cooled with water.

The above solution is added dropwise with stirring to 3/4 equivalents of 18 il+ dissolved in 10<-> of dry tetrahydrofuran and cooled with water. After 15 minutes after the completion of dripping, add water to 0.1F.
W, 15% Na0I-1 aqueous solution 0.1W and water 0.4
5d was gradually added under water cooling. After the reaction, the solid matter was filtered off, extracted with ether, dried with MgSO4, and the solvent was distilled off to give (-)-3-methoquino-3°6a-tmethyl-1,2,3,5,13 , 6a, 7.8-octahito [
A crude product of J noclobenta[rcolo]benzohylanoa β-ol (1,olg) is obtained.

NMR (benzene) δ value (ppm): 1.20 (3
t1. s, Angu I R: 3400cm-', 1
640cm-'(4) Above (3) Tei'J Rale)'
: tll product (1.01 g) Add 5% pd/c to a solution of ethyl acetate (ethyl acetate 20 am) and stir at room temperature under 1 atm of hydrogen for 1.5 hours. After the reaction, remove pd/c with celite. c was removed and the solvent was distilled off to give (-)-3-methquin-3,6a-tmethyl-1,2,3°5.6,6a
S, 7.8.9.9a α-decahytronocrohenc [f
1 product of H,Il henozopyran-7β-ol (0,
97 g).

NMR (benzene), δ value (ppm): 0.90 and 0.95 (3+1°2s, angular methyl)
, 1.38 (311,s, terminal methyl), 3.28 and 3.22 (311,2s, -0CII-)I n :
3420cm-', 1680cm-' (5) Above (4)
The crude product (0.97 g) obtained above was dissolved in ethanol (20%), 3N hydrochloric acid (5-) was added, and the mixture was stirred for 5 minutes. Next, 6N sodium hydroxide solution (20 in 1) was added and heated to 80°C for 15 minutes, then pl-1 was added with IN-sulfuric acid.
4 to 5, and the solvent was distilled under reduced pressure. The residue was dissolved in methylene chloride (6C1me), washed with water, and subjected to silica gel column chromatography to give (-)-Desu A-!
7β-Hydroquine-9-nystren-5-one 460B
get.

Yield ((1) to (5)) 50% mp・113°C N M n (CD CIs) δ (ppm): 0.9
2 (311,s, angular methyl) 3.78 (2
H, m, -0[1), 5.87 (lH, m, enone) I R: 3400 cm-', 1650 cm-' Example I (+) 2--Methyl-2-(3-oxo-7- octenyl)-1,3-nochlorohexanedione! , 7-octadinin-3-one (o, 24g), 2-methyl-1
, 3-cyclohexanedione (0.5 g) and triethylamine (Id) are added to ethyl acetate (lod) and stirred at room temperature for 24 hours. After removing triethylamine and acetic acid using an evaporator, the title compound was purified by silica gel column chromatography (methylene chloride).
get g. (Ir1 1700~1730ce-', 9
20 cm-'; NMR1, 10 ppm UII, -double line-C11,), 4.6-6. OpI+1 (3+1. multiplet, vinyl)) (2) 3.4,8.8a-tetrahydro-5-(3-butenyl)-8a.-methyl-1,6
(2H17H)-Triketone (2,732 g) obtained in 2(1) above naphthalenedione, β
-alanino (3,6 g), l N-perchloric acid (16-
) was added to acetonitrile (load) for 7 days.
Reflux. After cooling to room temperature, water was added, six layers were extracted with methylene chloride, washed with water and brine, dried over magnesium W acid, filtered, and the solvent was removed.

Purification by column chromatography on silica gel (methylene chloride) yields 1.838 g of the title compound.

(IR, 1715cm-', 1665c-', 9
20c+e-'; NMRl, 31 ppm (311,
- multiplet, CHs), 4.6-6.1 (311, multiplet,
vinyl)) (3) 3.4.8.8a-tetrahydro-5-(3
-oxobutyl)-8a-methyl-1,6(2H,7H
)-naphthalenedione palladium chloride (0,18g), cuprous chloride (1,0g
), water (2 glasses) is added to dimethylformamide (20d), and the mixture is stirred at room temperature in an oxygen atmosphere for 2 hours. Add the olefin Q obtained in (2) above, 761 g) to the solution,
Ili! Stir under double atmosphere for 24 hours. After adding dilute hydrochloric acid, the organic layer was extracted with ether, washed with water and brine, dried over magnesium sulfate, filtered, and the solvent was removed using an evaporator. Purification by column chromatography on silica gel (hexane:ether 3:1) yields 1.40 g of the title compound. (IR11710cm-'
, 1663c hook-'; NMR1,40pp+5(31
1, - double line.

CIjs), 2. IOppm (311, - heavy line, C
OCl15)) Example 2 (1) 2-Methyl-2-(3-oxo-7-octenyl)-1,3-cyclopentanedione 1,7-octadien-3-one (1,782 g) and 2-methyl -1,3
-Cyclopentanedione (2g) and triethylamine (
4d) was added to ethyl acetate (40 ml) and stirred at room temperature for 30 ml.
Stir for an hour. After removing triethylamine and ethyl acetate with an evaporator, the title compound 2.7 was purified by silica gel column chromatography (methylene chloride).
Obtain 44g.

(IR, 1723cm-', 1641cn-', 91
8 cm-': NMll, 02 ppm (311, -multiplet, -CI+3), 4.7-6.2 (311, multiplet.

vinyl)) (2)(L)-7,7a-dihydro-7a-methyl-4
-(3-Butenyl)-1,5(6H)-indandione Triketone (2,744g) obtained in (1) above, β
~Alanine (2.2 g), IN perchloric acid (5-) are added in acetonitrile (50 m?,) and heated to reflux for 5 days. After cooling to room temperature, water was added, the organic layer was extracted with methylene chloride, washed with 9 parts of water and brine, dried over magnesium sulfate, filtered, and the solvent was removed. Purification by column chromatography on silica gel (methylene chloride) yields 1.838 g of the title compound. I R, 1745cm-
', 1662cm-', 911cm-'; NMR1,
25ppm (311, - heavy line, CI+3), 4.7-6
．． 1 (3 + 1. multiplet, vinyl) (3) (±) -7,7
a-Nohydro7a-methyl-1-(3-oxbutyl)-1,5(6H)-indanedione Palladium chloride (lOOmg), cuprous chloride (500m
g) , water (5d) to trimethylformamide (50d)
and stir for 2 hours at room temperature under an oxygen atmosphere. Above (2
) is added to the solution and stirred for 5 hours under oxygen atmosphere. After adding dilute hydrochloric acid, the organic layer was extracted with ether, washed with water and brine,
After drying with magnesium sulfate and filtering, the solvent is removed. Silica gel column chromatography (ether/
Purification with hexane 3) yields 588 mg (solid) of the title compound. (IR.

1745cm-', 1715cm-', 1665cm-
': NMR1,25I)l)m(3■, - double line,
CL, ), 2.02 (3H, - double line, COC focus, )
) Example 3 (1) 2-methyl-2- obtained in Example 2 (+)
(3-oxo-7-octenyl)-1,3-enclopentanone (3.0g), phenylalanine (12 bodies)
(2.5 g), IN-perchloric acid (5d) in acetonitrile (100 hf) and heated under reflux for 4 days.

After cooling to room temperature and filtering off most of the precipitated phenylalanine, water was added, and the organic layer was extracted with methylene chloride, washed with water and brine, dried over magnesium sulfate, filtered, and the solvent was removed. To leave. By column chromatography on silica gel (hexane:ether-3:1), (+)-7,7a-dihydro-7a-methyl-4
2.38 g of -(3-butenyl)-1,5((IH)-indanedione are obtained.

[α] 2+4' (chloroporum) (2) Add palladium chloride (177 mg), cuprous chloride (990 mg), and water (ld) to dimethylformamide (15 Ml),
Stir for 2 hours at room temperature under oxygen atmosphere. The olefin obtained in (1) above (2.38 g) is added to the solution and stirred for 12 hours under an oxygen atmosphere. After adding dilute hydrochloric acid, the organic layer is extracted with ether, washed with water and brine, dried over magnesium sulfate, filtered, and the solvent is removed. Purified by silica gel column chromatography (ether:hexane = 1.3), (+)-7,7a-dihydro-
7aS-Mejiru 4-(3-oxobutyl)-1,5(
2.0 g of 61-υ-indanone is obtained.

Recrystallize from ether to obtain the following customary product.

Claims (1)

[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ (In the formula, R^1 is a lower alkyl group, R^2 is hydrogen or a lower alkyl group, Y is an oxo group or hydrogen and a protected There are general formulas, chemical formulas, tables, etc. that are characterized by oxidizing a compound represented by a hydroxyl group, which may be ▼ A method for producing a compound represented by (the symbols in the formula have the same meanings as above).