JPS5976100A - 16-methylene-17alpha-hydroxy-progestene - 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 BACKGROUND OF THE INVENTION 16-methylene steroids are commonly used in estrone (aromatic A-ring) threads (U.S. Pat. Nos. 3,257,429 and 32,756).
No. 66), corticoids (U.S. Pat. No. 31576)
79, 3878228, 3354184, 3493558 and 3376294) and the progesterone system (U.S. Pat. Nos. 3168537, 3157679, 3284476, 33284)
32 and 3359287). In the anthrostane series, US Pat. No. 3,641,069 and No. 3,300,521
Gazz, Chim, Ital, 91, 672 (1
961), Hungarian Patent No. 019495 and US Patent Application No. 349490 (filed February 17, 1982).

Steroids with a 17α-ethiniIV-17β-hydroxy group are well known to those skilled in the art and are referred to as ethisterone-type steroids. Methyl substitution at the C-16 position is known in these propargyl alcohols. For example, U.S. Pat. No. 4,041,055 discloses various
Although 6α-methyl and 16β-methylethisterone have been disclosed, 16-methyleneethisterone has not been disclosed (Examples 23.24.26.29 and 43).
reference). US Patent No. 3,231,702 generally discloses 16(α and β)-substituted 17α(halothinyl)-,17β-hydroxysteroids.

Methods for converting 17-kedosteroids to the corresponding 17α-ethynyl-17β-hydroxysteroids by reacting 17-kedosteroids with acetylene or acetylene salts in the presence of a base are well known to those skilled in the art and include, for example: U.S. Patent No. 4,041,055 (Preparation Example 1), No. 344
No. 1559, No. 3972906, No. 3759961, No. 3734 (see No. 135, No. 3689512, etc.).

In 17α-hydroxyprogesterone, part 1
The 7-hydroxy group is in the α position and the acetyl group is in the β position. Expressed by formula (V) (see chart below, same below)
Non-natural or opposite configurations (17β-hydroxy-17α-acetyl), such as in 17β-hydroxysteroids, are also known, e.g.
wards Vol ■.

p135. N[15 and He1v, Chim, Act
See a26680 (1943).

Ethisterone-type steroids due to the use of mercury compounds
Conversion to 7β-hydroxy-17α-acetyl type steroids is known and is described in a paper by M.W. Goldberg.

He1v, Chim, Acta 26,680 (19
43) ) See. This report was published almost 40 years ago,
This incorrectly reports 17β-hydroxy as 17α-hydroxide. None of the compounds in the Goldbarb paper have a substituent at the C-16 position. U.S. Pat. No. 4,102,908 discloses a method for converting the nitrate ester of an ethisterone type compound to 17α-hydroxyprogesterone, but all of the compounds exemplified in U.S. Pat. No. 4,102,908 have a substituent at the C-16 position. I don't have it.

Sulfoxides of steroids are known, see, for example, US Pat. Nos. 4,041,055 and 4,342,702. Sulfoxide 20-methoxy-21-(phenylsulfinyl)-Δ in U.S. Pat. No. 4,041,055
17 (20) It is a steroid. U.S. Patent No. 43427
The sulfoxide in No. 02 is 21-chloro-20-methoxy-21-(phenylsulfinyl)-Δ17(2
0) It is a steroid. The sulfoxide of the present invention is 16-
(phenylsulfinylmethyl)-Δ16 steroid (
VI), which is easily converted to 16-methylene-17α-hydroxyprogesterone (■). The prior art sulfoxide of U.S. Pat. No. 4,041,055 is 16
-Methyl (α and β) substituted 17α-hydroxyprogesterone, but the desired 16-methylene-
Does not produce 17α-hydroxyprogesterone. Similarly, the prior art sulfoxides of U.S. Pat.
α-hydroxyprogesterone is produced, but 16-methylene-17α-hydroxyprogesterone, which is desired in the present invention, is not produced. This is a very important matter. This is because even if the present invention's 16-me+L'-17α-
U.S. Patent No. 4041 for hydroxyprogesterone (■)
Melengestrone acetate/
L/(17α-acetyloxy-6-methyl-16-
Melengestrol acetate cannot be produced from the prior art sulfoxides since the 16-methylene group is required for the production of methylenepregna-4,6-diene-3,20-dione.

US Patent No. 4041055 is S/V 7.1111-
Discloses a method for converting ethisterone type steroid to the corresponding sulfoxide by use of a IV agent. The reaction proceeds via an allene sulfoxide intermediate.

Similarly, in U.S. Pat. No. 4,342,702, halogen-substituted ethisterone-type steroids were synthesized via 21-haloalene sulfoxides using sulfenyl inhibitors.
- Converted to halogen-substituted sulfoxide. The sulfenylation reaction of the present invention does not proceed via an allene sulfoxide intermediate.

16-methylene-17α-hydroxyprogesterone is known. For example, J,Chem,SOC,.

2385 (1960) and U.S. Patent No. 304006
No. 9, No. 83130209, No. 3157679, No. 3
No. 168537, No. 3284476 and No. 3359
See No. 287. In US Pat. No. 3,359,287, the compound of formula (X) is closest to the compound of formula (■B) described below. Similarly, the formula (V
Compound 1) is the closest compound to 16-methylene-17α-hydroxyprogesterone (see ①C below). However, the compound of U.S. Pat. No. 3,359,287 has C-11
It requires that both substituents at the positions be hydrogen atoms, which is very different from the functionalized C-11 position in the compounds of the invention.

All of these 16-methylene-17α-hydroxyprogesterone can be used as thioyl as in the present invention.
It is not produced from sulfoxide by reaction with phile.

16-methylenecorticoids are known, see US Pat. No. 3,115,508. The 16-methylenecorticoids disclosed therein are 5α or saturated A-ring corticoids. In the 16-methylenecorticoid of the present invention, the A or B ring is unsaturated.

The claims of U.S. Pat. No. 4,041,055 include 16
A method for converting α- or 16β-methyl-17-ketosteroids to the corresponding 16(α or β)-methyl-17α-hydroxyprogesterone is described. This process involves ethynylating a 17-ketosteroid to produce a 17α-ethynyl-17,θ-hydroxysteroid, which is then sulfenylated to form an allene sulfoxide. Michael addition to this allene sulfoxide produces the corresponding sulfoxide. Reaction of the sulfoxide with thiophyl produces a 17α-hydroxy-2o-alkoxy-2°-unsaturated steroid side chain, which upon acid hydrolysis produces a 17α-hydroxyprogesterone side chain. US Patent No. 404
No. 1055 starts with a 16α- or 16β-methyl 17-ketosteroid and then, when the method is followed, the corresponding 16α- or 16β-methyl-17
Although it is disclosed that α-hydroxyprogesterone is obtained, no mention is made of 16-methylene substitution. Furthermore, the process and intermediates of the present invention are quite different from those of US Pat. No. 4,041,055.

U.S. Pat. No. 4,342,702 describes the conversion of a 17-keto starting material to a halogenated methisterone-type steroid using a halogenated acetylene, a 21-halo 16 of a 16(α or β)-methy/l/-17-ketosteroid. (α
or β)-methyl-17α-hydroxypregnane. A halogen-substituted ethisterone-type steroid is reacted with a sulfenylating agent to form a 21-haloarene sulfoxide, which is combined with the corresponding 21
- halo sulfoxide, finally the 21-halo 16 (
α or β)-methyl-17α-hydroxyprogesterone.

Melengestrol acetate (■) (17α-hydroxy-
6-Methyl-16-methylenepregna-4,6-diene-3,20-dione 1-phoacetate) is known to be useful as a progestin agent in the veterinary field. U.S. Pat. No. 3,359,287 (Example 4) describes the use of 17α-hydroxy-6α-methyl-16 with chloranil.
Discloses the production of melengestrol acetate by dehydrogenation of -methylene pregna-4-ene-3,2o-dione f-acetate.

U.S. Pat. No. 4,154,748 describes an alternative method for producing melengestrol acetate in which the final step is the acetylation of 17α-hydroxy-6-methy,'L'-16-methylene pregner 4,6-diene-3,2o-dione. Reporting.

U.S. Pat. No. 3,705,181 discloses aqueous acetic acid and p-T
17α- by reacting with SA in benzene
Hydroxy-6-methylene pregna-4-ene-3,2
A method is disclosed for the simultaneous isomerization and 17-acylation of 0-dione to 17α-hydroxy-6-methyl pregna-4,6-genine-3,20 dione 1-phoacetate. The steroid in US Patent No. 3705181 is C1
It should be noted that the starting material of the present invention has a reactive methylene group at C16, whereas 6 does not have any substituents.

SUMMARY OF THE INVENTION Provided herein are 17α-ethynyl steroids (IV);
17β-hydroxysteroid (v), sulfoxide (
VI), 16-methylene-17α-hydroxyprogesterone (■) and 16-methylenecorticoid (■)
Disclose.

Herein, a 9-protected 16-methylene-17-ketosteroid (IIIA) is reacted with an excess of monolithium acetylide previously cooled to below about -20'C, and the reaction mixture is reduced to below -20'Q. 1 consisting of maintaining the temperature at a temperature and then contacting the reaction mixture with a quenching agent.
A method for making protected 17α-ethynyl steroids (IVA) is disclosed. Also disclosed is a method for producing 17α-ethynyl steroid (IVA), which comprises first performing the three steps described above and then contacting the reaction mixture of step 3 with a proton source.

The present specification refers to 16-methylene-17 ketosteroids (I
I'IB) with excess monolithium acetylide previously cooled to below about -20°C, maintaining the reaction mixture at a temperature below -20°C, and contacting the reaction mixture with a quenching agent. A method for producing 17α-ethynyl steroid (IVB) is disclosed.

Alternatively, the q-protected 16-methylene steroid (■C) may be contacted with excess monolithium acetylide previously cooled to below about -20°C, the reaction mixture maintained at a temperature below -20°C, and the reaction mixture A method for the preparation of 17α-ethynyl steroids (IVC) is disclosed comprising contacting the 03 protecting group with a hydrolytic means.

Mid herein also refers to 17α-ethynyl steroids (IV
) is disclosed, which comprises contacting 17β-hydroxysteroid (v) with a mercury reagent.

The 1,17β-hydroxysteroid (v) was added to a sulfenylating agent (R22-8-M, R22 and M are shown below) in a solution containing a weak base or a tertiary amine at a temperature below 0 °C. Disclosed is a method for preparing sulfoxide (VI) comprising contacting with sulfoxide (VI).

Furthermore, suf refoxide (VI) was heated at 30°C under pressure.
16 consisting of contacting with 1,000 liters of oil at a temperature of not less than 16
- A method for producing methylene-17α-hydroxysteroid (■) is disclosed.

The present invention also provides 17α-hydroxy-6,16-symethylene pregnar 4-ene-3,20-dione (IX)
1 consisting of contacting with an acyl stopper in the presence of a strong acid.
A method for producing 7α-hydroxy-6-methyl-16-methylenepregna-4,6-genin-3,20-dione 1-fuacetate (■) is provided.

DETAILED DESCRIPTION OF THE INVENTION The 16-methylene-17-ketosteroid (III) starting material is well known to those skilled in the art. See, for example, U.S. Pat. No. 3,275,666, U.S. Pat.
41Q69, Gazz, Chim.

Ital, Ql, 672 (1961), Hungarian Patent No. 0194q5 and U.S. Patent Application No. 349490
No. 1711, filed February 1982.

16-methylene-17-keto (■) starting material is 17-
The ketosteroid (I) can be converted into a 16-methylene-17 ketosteroid (
, [) (See Char) A below. ) This process can be carried out in two different ways: (with isolation of the 1116-substituted intermediate (II) or without isolation of the (2116-substituted intermediate (II). In the first case , 17-ketosteroid (1) is reacted with a C16 activator in the presence of a strong base, intermediate (II) is isolated and then reacted with a formaldehyde generator in the presence of a base. Case 24 , 16
- After forming the substituted intermediate (II), the formaldehyde generator is added without adding any further base. These two methods are considered equivalent to each other.

A 17-ketosteroid (IA-IC) or its frost-protected form is reacted with a C16 activator in the presence of an enolized base. The C16 activator is a 17-ketosteroid (I
) and a compound that activates the 016 position of the 17-ketosteroid CI) when reacted with an enolized base, making it reactive towards the addition of formaldehyde. C1
6 activators include compounds represented by 2X-Go-R, where k is hydrogen or an electron-withdrawing group such as trifluoromethyl, cyano, or COOR16 (R16 is shown below). The leaving group X is ORb (Rb is shown below) and is chlorine, bromine or iodine. The C16 activating group can be an oxalate ester (e.g. methyl or ethyl oxalate), a formate (e.g. methyl or ethyl formate), a trifluoroacetate (e.g. methyl trifluoroacetate or (ethyl).

The enolized salt bale forms an enolate at the C17 position, and the C1
6 is a strong enough base to form the 16-substituted intermediate (II) with the activator. Generally, enolized bases are strong bases with pK values greater than 12. Preferably, the enolizing base is selected from metal-〇Rh, metal hydrides and metal amides. Metals include lithium, sodium, potassium or magnesium, R+
) is argyl or phenyl having 1 to 5 carbon atoms. Enolizing groups include, for example, sodium methoxide, potassium ethoxide, sodium hydride or lithium diisopropylamide. Preferably, the metal is sodium and the base is sodium methoxide, preferably sodium ethoxide. This reaction is carried out in an inert solvent, preferably in an inert solvent selected from solvents such as toluene, terminating methylene, and THF;
It can also be carried out in alcohols such as methanol, ethanol and the like. This reaction should be carried out under an inert atmosphere, preferably under a nitrogen atmosphere, at a temperature ranging from about -20°C to about 50°C.

The reaction is monitored by TLC, as is well known to those skilled in the art. Once the reaction is complete, the 16-substituted steroids ([A to ■C) can be isolated (Example 1) or directly reacted in the reaction system to form the desired 16-substituted steroids.
- Methylene steroids (TI) can be produced (Examples 3 and 4).

In either case, formaldehyde or a formaldehyde generator is then added. It is important to neutralize any excess enolized base before adding the formaldehyde generator. This is preferably done by adding an acid such as acetic acid or hydrochloric acid (Example 1). Formaldehyde generators, when used or reacted,
A compound which acts or generates formaldehyde (11((:HO)) and the formaldehyde generator can be formaldehyde itself, or a compound which forms formaldehyde in the reaction system or which still acts as formaldehyde; The formaldehyde generator is preferably selected from the group consisting of formaldehyde, paraformaldehyde, trioxane and aqueous or alcoholic formaldehyde solutions.

More preferably, the formaldehyde generator is paraformaldehyde or an aqueous formaldehyde solution. 1
Reaction 1 without isolating the 6-substituted steroid (■)
When carried out in the pot method, the reaction mixture is sufficiently basic to cause the conversion of the 16-substituted steroid (II) to the 16-methylene steroid (■). The reaction is carried out with 16-
When carried out in a two-pot method with isolation of substituted steroid (If) intermediates, the second step requires the addition of base.

A strong base such as metal-0Rb or a weak base such as a tertiary amine may be present. Preferred weak bases include, for example, triethylamine, tributylamine or pyridine. Triethylamine is the preferred weak base. The reaction should be carried out in an inert solvent as in the first step.

Weak bases can be used as solvents or cosolvents.

This reaction is carried out under an inert atmosphere, preferably under a nitrogen atmosphere.
The temperature range is 0°C to reflux temperature.

The reaction is monitored by TLC, which is well known to those skilled in the art, and is usually completed in 0.25 to 6 hours, depending on temperature, etc., but usually about 1 hour. Once the reaction is complete, the 16-methylene steroid (III) is isolated and purified using methods well known to those skilled in the art.

When the 16-methylene steroid (ffl) is obtained in the protected form, the protecting group can be easily removed and the functional group of the A ring converted to the formula +Al~(C
It can be easily converted to the unprotected form shown in 1.

16-methylene-17-ketosteroid (lI(A) ~
The starting materials for (IIIC) can have various substituents at positions 1,6,9,10 and 11, as is well known to those skilled in the art. For example, U.S. Patent Application No. 3494
No. 90 (filed on February 17, 1982), Δ1.6-
Fluoro, 6-methyl, 11β-hydroxy, 11-keto, 11α-human 9(11)roxy, Δ, 9β, 11β-epoxy and 9α-
16-methylene-17-ketosteroids having fluoro substituents as well as combinations thereof are disclosed. Preferably RIO is methyl.

In the Δ4-3-keto yarn (A), hydrogen, methyl or methylene is preferable;
In B), hydrogen or fluorine is preferable.

11)-Methylene-17-ketosteroid (I[A)~
(IC) with the appropriate reactive form of acetylene to give the corresponding 17α-ethynyl steroids ((IVA) to (IVA)
Vc). In this case, the active acetylene reagent, monolithium acetylide, was prepared by M.M. Midland, J.

Org, Chem, 40.2250 (1975)).

L i C2H is TI(F, in a dry ether solvent such as dioxane, diethyl ether and dimethyl ether, at a temperature below -20 °C, preferably from about -20 to -
It is produced at a temperature of 80°C, preferably about -60°C.

Alternatively, preferably, monolithium acetylide is produced in a reaction system as described in more detail below and as shown in Example 33 below.

16-methylene-17-ketosteroid (mA) ~(
■ In C), the properties of the steroid A ring (Char) B
There may be cases where it is necessary to protect the q function during ethynylation with (Al-(see q)).

For the Δ4-3-ketosteroid (A), the q-ketone can be expressed as an enol ether (Aa), a ket-Jv (Ab), an enamine (Ac), as is well known in the art.
or protected as an enol ester (see Chart C). In chart C, K3 means alkyl having 1 to 5 carbon atoms, however, in the case of digit-7+z (Ab), the two squares may be bonded. The preferred enol ether 7+z (Aa) is methyl or ethyl ether. A preferred ketal (Ab) is ethylene ketal. Regarding enamine (Ac), 顯 and 顯 are alkyl having 1 to 5 carbon atoms and may be the same or different, and R' and ni' may be bonded. Preferred enamines are selected from the group consisting of pyrrolidine, morpholine and diethylaminoamine. Enol ethers (Aa) are prepared using methods well known in the art.Rell CJ, Org, Chem, 26, 3925 (
1961)), 5teroid Reactions
.

Edited ly Carl Djerassi, H
o1den-Day, 5anFrancisco, 19
63, p42-45 and U.S. Patent No. 351699.
See No. 1 (Preparation Example 1)]. Ketals (Ab) are also produced by well-known methods (the 5teroid
ReaClil)ns, see pil~l4)
. 3-enamine (Ac) is also produced by the well-known method Niyotte (the 5teroid Reac-1).
ii, ons, p. 49-53).

1.4 There is no need to protect frost ketones with Δ-3-ketosteroids (B). The 3-hydroxysteroid (C) should have the 3β-hydroxy group protected as an ether (Ca) or an ester (cb) (Chart C
reference). Preferred protecting groups are methyl and ethyl enoether (Aa), ethyl ketal (Ab), pyrrolidine enamine (Ac), methyl ether (Ca) and acetate ester (Cb)
It is.

q-protected form of Δ4-3-ketosteroid (A) (Aa, A
b and Ac) and 3β-hydroxysteroid (C
) protected forms (Ca and cb), since their q-protecting groups can be easily removed to convert each q-protected form (Aa, Ab, Ac, Ca and cb) to the unprotected form (A and C). Each is considered equivalent to the unprotected or free form (A and C).

Monolithium acetylide and 16-methylene-17-ketosteroids (NAa, IIIAb, I[Ac, N
B, NCa and cb) are brought into contact with the hot water at a temperature lower than -20°C, preferably about -20 to -70°C.

At least 1.5 equivalents of monolithium acetylide are used. Once the reaction is complete, excess acetylide is quenched or destroyed by reacting with any aqueous quenching agent such as water, saline or an aqueous buffer to the desired final pH. A preferred quenching agent is a phosphate buffer. The 17α-ethynyl steroid (IV) is obtained and isolated from the reaction mixture by methods well known to those skilled in the art. Δ-3-ketosteroid (A)
and 17 for 3-hydroxysteroid (C)
α-Ethynyl steroid (IV) is isolated as the 9-protected form (Example 24). The 9 protecting group can be removed by methods well known to those skilled in the art or left for further chemical modification of the 17α-ethynyl steroid (■) as in Example 25. Before isolating the 17α-ethynyl steroid (■), it is hydrolyzed in the reaction system by reacting the protecting group with a proton source such as sulfuric acid or hydrochloric acid to form the unprotected or free 17α-ethynyl steroid (IVA, IVC) can be obtained.

For example, 16-methylene-17-ketosteroid (II
If IA) is protected as enolnial(][Aa), the protecting group can be removed by acid and 17α
- Ethynyl steroid (IV) free Δ-3-keto form (
A) (see Examples 11 and 19).

Since the Δ1°4-3-ketosteroid (B) is unprotected, the 17α-ethynyl (IVB) exists in free or unprotected form. The 9 protecting groups are ether (Ca
) by hydrolysis reaction of the 9-protecting group with an acid with a pKa lower than 4.0, or with a base such as sodium or potassium hydroxide, carbonate or bicarbonate in the case of esters (cb). It is eliminated from the 3-hydroxysteroid (C). Alternatively, monolithium acetylide is preferably generated in the reaction system. Operationally, this is very easy and the reaction can be carried out at -20°C as opposed to -60°C if the reagents are prepared separately. When using this in-system method, an alkali metal amide base such as lithium diethylamide, lithium diisopropylamide and equivalent bases known to those skilled in the art is combined with a suitable amine and an organic compound such as n-butyllithium or phenyllithium. Prepared by reacting with lithium reagent. A saturated solution of acetylene is diluted with a suitable form of 16-methylene-17-ketosteroid (l[
AmHc) containing ethereal solvents (THF, diethyl ether and dioxane) at approximately -20°C.

The lithium amide is then added to the mixture of 16-methylene-17-ketosteroid (III) and acetylene in an ethereal solvent.

The reaction mixture is stirred at about −40° C. until TLC indicates the reaction is complete, typically 0.5 to 2 hours. The reaction mixture is added slowly to a saline/water (1/1) mixture and then worked up in the usual manner.

17α-ethynyl steroids (TVA-IVC) are converted to the corresponding 17β-hydroxysteroids (VA-VC) by reacting with mercury reagents. Oxymercurylation of ethisterone derivatives has been known for a long time (He1v, Ch
im, Acta, 26.680 (1943)). However, the D ring of the present invention is not a simple ethisterone derivative. Here, the 17α-ethynyl-17β-hydroxy substituent is allyl to the 16-methylene group. In the present invention, surprisingly and unexpectedly, a quantitative production of the 17β-hydroxysteroids (VA, VC) is obtained, the allyl alcohol system being the propargyl alcohol system in the oxymercurylation. This shows that they do not match.

Mercury reagents can be prepared by reacting mercuric oxide with a strong acid such as sulfuric acid, hydrochloric acid or nitric acid. The mercuric salts, ie mercuric sulfate, mercuric chloride or mercuric nitrate, can be used directly in an acid medium. Preferred are the salts prepared from mercuric sulfate or mercuric oxide and sulfuric acid. Catalytic amounts of mercury reagent and 17α-ethynyl steroid (VA-V
C) in an aqueous polar solvent for 2 to 24 hours at 20 to 65°C.
make contact with it. Once the oxymercuration reaction is complete, the reaction mixture is filtered through Celite to remove insoluble mercuric salt solids and the 17β-hydroxysteroids (VA, V
C) is recovered from the furnace liquor by means known to those skilled in the art. Alternatively, the oxymercurylation reaction can be carried out using a mercury reagent immobilized on a resin (M, S, Newman, J.
, Am, Chem, Soc, 75°4740 (1953
)reference).

Fortunately, 17β-hydroxysteroids (VA-vC)
was reacted with a sulfenylating agent represented by R22-S-M (XII) to form the corresponding sulfoxide (VIA-
VIC). M is preferably chlorine or bromine;
Chlorine is highly preferred. R22 is methyl, phenyl, P-
Chlorophenyl, P-methoxypheny)V or P-methylphenyl are preferred, more preferably R22 is phenyl.

Optionally substituted sulfenyl stopping agents (xm) are prepared by methods known to those skilled in the art. For example, sulfuryl chloride is added to a thiol predissolved in an organic solvent such as carbon tetrachloride (Chem.

Reviews, 39, 269 (1946), T) 27
9 and US Pat. No. 2,929,820).

The sulfenylation reaction is carried out in a non-polar aprotic solvent such as toluene, chloroform, diethyl ether, methylene chloride, THF, dioxane or mixtures thereof. The preferred solvent is methylene chloride. The reaction is carried out in the presence of at least equimolar amounts of a tertiary amine base such as triethylamine, trimethylamine or pyridine. Trimethylamine is preferred. Any excess base serves as additional solvent for the reaction. The reaction is preferably carried out under an inert dry gas atmosphere such as nitrogen, argon or carbon dioxide. Substituted sulfenylno\lide (Xll) at -20°C to -
Add dropwise to the reaction mixture at a temperature of 40°C. Replacement /L/
Following the addition of the phenyl stopper (XII) to the reaction mixture, excess substituted sulfenylating agent is dissolved in water, various alcohols such as cyclohexane, methanol and ethanol.
) quenched with an enquenching agent such as V or acetone. The sulfoxide (■) can be obtained by standard processing.

Sulfoxide (VI) exists as two double bond isomers, namely compounds of formula (Vl) and compounds in which the unsaturated bond is between the carbon atom bonded to C16 and the sulfur atom. The endocyclic isomer (VI) is very abundant, and the exocyclic isomer is only in trace amounts. However, the ratio of isomeric sulfoxides is not critical for the purposes of the present invention since both pylars are converted to the same product in the next step.

Sulfoxides (■A to ■C) are reacted with thiophyl while heating to convert them into the corresponding 16-methylene-17α-hydroxyprogesterone (■A to ■C). Sulfoxide (-VIA~VIC) in toluene, methanol,
in a suitable solvent such as ethylene dichloride or acetone or a mixture thereof. Certain thiophyls, such as hydroxides, alkoxides, etc., produce unnecessary side reactions;
Others such as trimethyl phosphite, diethylamine and mixtures thereof are well suited. A preferred thiophyl is trimethyl phosphite. Trimethyl phosphite is known as thiophyl. (D.

A, Evans and G, ClAndrews, Acc.
t, of Chem+Res, 7.147 (1974)
, see page 150).

The sulfoxide (VIA-VIC) and child ophyl are contacted and heated to a temperature of about 50-100°C, depending on the solvent used, the sulfoxide (VIA-VIC), thiophyl, and whether the reaction is carried out under pressure. . The reaction mixture was heated to 60
Preferably, heating is carried out in a closed reaction vessel at a temperature of 4 to 24 hours at a temperature of 110°C to 110°C. Once the reaction is complete, 16-methylene-17α-hydroxyprogesterone (■A to ■C)
is isolated and purified by methods known to those skilled in the art.

The 16-methylene-17α-hydroxyproketerone steroids (■A to ■C) are useful as intermediates in the manufacture of commercial pharmaceuticals in two ways.

First, K,16-methylene steroids are intermediates in the production of certain progestin drugs, such as melengestrol acetate; second, when the 16-methylene group is reduced to 16α-methyl or 16β-methyl; Provides a useful intermediate in the production of anti-inflammatory corticoids. For example, androstenedione can be converted to melengestrol acetate with a 16-methylene steroid as follows. (1
) androstenedione (IA) in U.S. Patent No. 3642
L12) converted to 6-methyleneandrost-4-ene-3,17-dione by the method of Example 18 of No. 840.
6-Methyleneandroster-4-ene-3,17-dione was converted to 6-methylandroster-4,6-renine-3, by the method of Example 16 of U.S. Pat. No. 3,117,966.
L1316-methylandrosta-4,6-genin-3,1 fusion (IA) was converted to Hungarian Patent No. 019495 or Gazz, Chim,
Hal, 91, 672 (1961) or the method of converting the 17-ketosteroid to the corresponding 16-methylene-17-ketosteroid (U.S. Patent Application No. 349,490, filed February 17, 1982)
(6-methy)v-16-methyleneandrosta-4,6-genin-3,1 fudione (IIIA) and (416-methyl-16-methyleneandrosta-4,6-renin-3, 1fusion (I[IA) was converted into 17α-hydroxy-6-methyl-16-methylenepregna-4,6- by the method of Examples 20 to 23 of the present invention.
It is converted to diene-3,20-dione (■N), and then (
5117α-hydroxy-6-methyl-16-methylenepregna-4,6-nonine-3,20-dione (■, V
) to 17-acetyloxy-6-methyl-16-methylenepregna-4,6-diene-3,20-dione (
Acylate to melengestrol acetate (■) (see Chart E).

Alternatively, the following reaction can be used. (1116-methyleneandrostenedione (l[A, Hungarian Patent No. 019495, Example 3) was converted into 17α-ethynyl-3,17β-dihydroxy-16-methyleneandrosta-3, 5-diene 3
-Methyl ether diconversion, (2) 17α-ethynyl-
3,17β-dihydroxy-16-methyleneandrosta-3,5-diene 3-methyl ether in U.S. Pat.
17α-ethynyl-17 by the method of No. 642840
β-hydroxy-6,16-symethylene androster-4-en-3-one, and then (3)
Ethynyl-17β-hydroxy-6,16-cymethyleneandroster-4-en-3-one (IVA) was converted to the corresponding 17β-hydroxysteroid (VA) by the method of Examples 27-29 of the present invention, and then 16- unsaturated steroid (VIA), and finally 17α-hydroxy-6,
16-symethylenepregnator was changed to 4-ene-3,20-dione (■A'), and this was converted to 17α-acetyloxy-
6-Methyl-16-methylenepregna-4,6-diene-3,20-dione, melengestrow acetate/I/(■
) (see chart E). 17α-hydroxy-
6,16-cymethylene pregnar 4-ene-3,20-
Dione (■A') is reacted with an acetylating agent in the presence of a strong acid. The acetylating agent is acetic anhydride, acetyl halide (
Preferably, it is selected from the group consisting of equivalent acetylating agents such as acetyl chloride) or isopropyl acetate. A preferred acetylating agent is acetic anhydride. Strong acid is p-TS
A, selected from the group consisting of benzenesulfonic acid, methanesulfonic acid, P-nitrobenzenesulfonic acid, perchloric acid, sulfuric acid, phosphoric acid, hydrochloric acid, and other acids that are substantially dissociated in non-aqueous systems considered to be equivalent to these. . Preferably p
-TSA. Strong acid has a tactile amount (0,001 equivalent)
or up to 10 equivalents, preferably from about 0.05 to about 0.05.
It can be present in 5 equivalents. The reaction is about 20°C~
The reaction can be carried out at a temperature within the reflux temperature of the reaction solvent used, preferably from 50 to 85°C, which results in a reaction time of 2 to 10 hours. Solvents suitable as reaction solvents include benzene, toluene, xylenecyclohexane, penkune, ethylene dichloride and chloroform and mixtures thereof.

After completion of the reaction, 17α-hydroxy-6-methyl-
16-methylenepregna-4,6-genin-3,20-
Dione-1-fu acetate (■) is recovered by methods well known to those skilled in the art. Melengestrol acetate can be further purified by recrystallization from methanol or isopropanol.

Preferably, the following reaction is used. (113-methoxy-16-methyleneandrosta-3,5-diene-
17-one (IIIAa, Example 8) was converted to 17α-ethynyl/L′-17β-hydroxy-16-methyleneandrost-4-en-3-one (
IVA) and (2117α-ethynyl-17β-hydroxy-16-methyleneandrost-4-ene-3
-one (IVA) was converted to 17α- by the method of Example 37.
Change to acetyl-17β-hydroxy-16-methyleneandrosta-4-nin-3-one (VA), (3)1
7α-acetyl-17β-hydroxy-16-methyleneandrost-4-en-3-one (VA) 16-(phenylsulfinylmethyl)pregna-4,16-dinine-3.20- by the method of all Example 38 ')
Changed to oni/, f411 I3- (phenylsulfinylmethyl)pregna-4,16-genin-3,20-
Dione (VIA) was converted to 17α- by the method of Example 39.
hydroxy-16-methylenepregna-4-ene-3,
20-dione (■A), (5117α-hydroxy-16-methylene pregna-4-ene-3,20-dione (■A) was converted to 17α-hydroxy-3β-methoxy-16 by the method of Example 40. -Methylene Pregna-3
,5-die:y-3-)(:y(■Aa), (6
] 17α-hydroxy-3β-methoxy-16-methylenepregna-3,5-dien-3-one (■Aa) was converted to 17α-hydroxy-6,16 by the method of Example 41.
,-dimethylene pregna-4-ene-3,20-dione (■A'), and finally Example 32''!, or 42
17α-hydroxy-6,16-symethylene pregnar 4-ene-3,20-dione (■
) to melengestrol acetate (■).

According to Char I, F, 16-methylene-17α-hydroxyprogesterone (■A-C) id is reacted with iodine, excess calcium oxide, aqueous sodium hydroxide and potassium acetate in acetone, as is well known. , 16-methylenecorticoid (IX) (e.g. HlJ, Ringol
d,et at,,J,Am,Chem.

Soc, 80, 250 (19'58), 0. Ha
lpern.

et al,,J,Am,Chem,Soc,81,.
439 (1959) and J. Org. Chem.
25, 1966 (1060)). 16-methylenecorticoid (■) was then used in U.S. Patent No. 3115
16β-methylcorticoid (
X) or to 16α-methylcorticoid (XI) by the method of US Pat. No. 8,313,0209.

Example Eva, betamethacin (9α-fluoro-11β, 1
7α,21-)dihydroxy-16β-methylpregna-1,4-diene-3,20-dione) is 17α-hydroxy-16-methylenepregna-1,4,Q (1
1)-triene-3,20-dione (■B, Example 19
), first by a known method (J, Am,
Chem, Soc, 80, 250 (1958), J.
Am, Chem, Soc, 81, 439 (1959)
and J, Org, Chem, 25, 1966 (1
960)) 17α,21-dihydroxy-
16-methylenepregna-1,4,9(11)-triene-3,20-dione 21-acet-1-(IX), which was then converted to 17α,21- by the method of U.S. Pat. No. 3,115,508. Dihydroxy-16β-methylpregna-1,4,9(11)-triene-3,20-dione 21-acetate-) (X). 17α, 21-
The conversion of dihydroxy-16β-methyl pregna-1,4-diene-3°20-dione 21-acetate to betamethacin is described in U.S. Pat.

Dexamethacin (9α-fluoro-11β, 17α, 2
1-) Lihydroxy-16α-methylpregna-1,4
-diene-3,20-dione) can still be produced from 17α-hydroxy-16-methylene pregna-1,4,9(11)-triene-3,20-dione (■B, one example), First, it was treated as 17α,21-dihydroxy-16-methylenepregna-1,4,9(1
1)-1 Lien-3,20-dione 21-acetate (
■) and then change it to U.S. Patent No. 3130209
17α,21-dihydroxy-16α by the method of No.
-Methylpregna-1,4,9(11)-triene-3
, 20-dione 21-acetate (XI). This 21-acetate (XI) is then epoxidized to give 9β,1
1β-epoxy-17α, 21-dihydroxy-16α
-Methylpregna-1,4-diene-3,20-dione is formed and converted to dexamethacin 21-acetate by the method of US Pat. No. 3,007,923, Example 2.

Similarly, diflorazone diacetate (6α,9α-difluoro-11β,17α,21-)lihydroxy-16
β-Methylpregna-1,4-diene-3,20-dione 17,21-diacetate) can be prepared using the method of the present invention. First, 6α-fluoro-11β-hydroxyandrosta-1,4-diene-3,17-dione (
U.S. Pat.
j eras s i , Holden-Day, Sa.
n Francisco, 1963, P 238
6α-fluoroandroster (see ~239)
Dehydrate to 1,4,9(11)-triene-3,17-dione. The 16-methylene group was then added to U.S. Patent Application No. 3.
No. 49490 to add 6α-f)V-olor 16-methylene androsta-1,4,9 (11)
-triene-3,17-dione (■B), which is converted into 6α-fluoro-17α-hydroxy-16-methylenepregna-1,4,9 (11) by the method of the invention.
-Change to triene-3,20-dione (■B). Next, the 21-hydroxy group of the corticoid is introduced as described above, and then the 16-methylene group is added to the 16-methylene group as described above.
6α-fluoro-17α, 21- in place of β-methyl group
Hydroxy-16β-methylpregna-1,4゜9(1
1)-) Diene-3,2o-dione 21-acetate was obtained and it was lyacylated by the method described in U.S. Pat. No. 4,154,748, Examples 6 and 7 to give 6α-fluoro-17α,21-dihydroxy -16β-Methyl pregna-1,4,9(11)-1 liene-3,20-
Dione 17.21-diacetate (U.S. Patent No. 3980)
No. 778, Example 6). Then, 6α-fluoro-17α,21-dihydroxy-16β-methylpregna-1,4,9(11)-) citric acid-3,2o-dione-17,21-diacetate was prepared in US Pat. No. 398,077.
No. 8, Examples 7 and 8 to diflorazone diacetate.

Ma Wataru Next, definitions of symbols and terms used in this specification are shown.

"TLC" means thin layer chromatography.

"THFJ means tetrohydrofuran.

"Saline solution" means an aqueous solution of saturated chloride.

[p-TSAJ means p-)luenesulfonic acid.

"NMR" means nuclear (proton) magnetic resonance spectrum, chemical shifts are ppm (ppm) downfield from TMS.
δ).

[TMsJ means tetramethylsilane.

[TEAJ] means ethylamine.

When a mixed solvent is used, the ratio of the solvents used is expressed in volume/volume (V/V).

[Androstenedione]
Means 3,17-dione.

M means boromine or bromine.

k is hydrogen, trifluoromethyl, cyanide or C
It means 00R16.

R3 means alkyl having 1 to 5 carbon atoms; however, in the case of ketal (Ab), two groups may be bonded together.

House means argyl with 1 to 5 carbon atoms.

Shield means alkyl having 1 to 5 carbon atoms.

马 means hydrogen, fluorine, methyl or methylene, and when 铁 is methylene, the 6-7 double bond in formula (A) and the 5-6 double bond in formula (C) do not exist.

The glaze is absent or with hydrogen or fluorine, and
Δ901) and 9β, 11β--boxide.

RIO means hydrogen or methyl.

R11 is 1 or 2 hydrogens or oxygen or α-hydroxy or β-hydroxy, still Δ9(11)
and 9β, 11β-epoxide.

艮16 means alkyl having 1 to 3 carbon atoms.

R22 is alkyl having 1 to 5 carbon atoms, trichloromethyl,
Phenyl, substituted phenyl (substituent is halogen, carbon number 1
-4 alkyl, alkoxy or 1-31 nitro or trifluoromethyl), aralkyl having 7-12 carbon atoms, or [-i'J-Nishi22)2].

R1221d: Alkyl having 1 to 4 carbon atoms and phenylmata mean phthalimide.

2 means a single bond or a double bond.

~ means that the atoms or groups to be bonded are in any K of α'-straddling β configurations.

"Zeng" means lithium, sodium, potassium or magnesium.

Alkyl and the like indicated by the number of carbon atoms include the isomers in which they exist and are practicable.

X means ORb, or chlorine, bromine or iodine.

Rh means alkyl or phenyl having 1 to 5 carbon atoms.

A "formaldehyde generator" is a compound that acts with or generates formaldehyde (HCHO) when used or reacts, and the formaldehyde generator can form formaldehyde itself, or forms formaldehyde in the reaction system. means a compound that acts as formaldehyde or formaldehyde.

"016 activator" forms a 16-substituted intermediate (II) when reacting with a 17-ketosteroid (■) and an enolized base, resulting in the C of 17-ketosteroid (I)
It refers to a compound that activates the 16-position to make it reactive to the addition of formaldehyde.

"Enolized base" means a base that forms a 16-substituted intermediate (II) when reacted with a 17-ketosteroid (I) and a C16 activator.

EXAMPLES Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto.

Example 1 3-Methoxy-13-(methyloxalyl)androsta-3,5,9(11)-)quen-1-fuone (II
) 11.5 f of dimethyl oxalate and 6.5 g of sodium methoxide were added to 3-methoxyandrosta-3°5.9 (
11)-) Quen-1 Huon (■, U.S. Patent No. 351
No. 6991) to a mixture of 17FI and 100 m/tonolenine. This mixture was heated at 20-25° under nitrogen atmosphere.
Stir overnight at C, during which time a precipitate forms. Water, brine, methanol and potassium hydroxide (5%) are added, then the layers are separated and the organic layer is washed with more potassium hydroxide (5%). The aqueous layers are combined, neutralized to pH 5 with 2N hydrochloric acid, and extracted twice with methylene chloride. Combine the organic layers;
Dry over sodium sulfate, filter, concentrate the p-liquid under reduced pressure to an oil and crystallize it from methanol to give the title compound. NMR (CDCI3): 0.99.
1.19.3.18.3.60.3.89.5.20.
5°30 and 5.54δ.

Example 2 3-methoxy-16-methyleneandrosta-3,5,
9(11) -)su,lr-no1fuon(]l[A
a) Paraformaldehyde to a 13:9 mixture of 3-methoxy-16-(methyloxalyl)androsta-3,5,9(11)-trien-17-one (:[Aa, Example 1) in 125 mJ of THF. Add 1.62 g and 7.5 ml of triethylamine. The resulting mixture is refluxed for 1 hour, at which point TLC (dityl acetate/toluene: 1/9) shows the reaction is complete. The reaction mixture was poured into a brine solution and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure to give an oily residue which is crystallized from methanol to give the title compound. NMR (CDC13): 0.90.1
．． 13.3.57.5.17.5.30.5.40.5
．． 56, and 6°80δ.

Example 3 16-(methyloxalyl)androsta-1°4.9
(11)-)triene-3,17-dione (IIB) Androsta-1,4,9(11)-triene-3,17-dione (I13 .US Patent @421615
No. 9, Preparation Example 4) 282#, dimethyl oxalate 175
Add to a mixture of tRg and 3 ml methylene chloride at O'C. The mixture was stirred at 0"C for 4.5 hours, then an additional 0.03 rnl of methoxide solution was added and stirring was continued for a further 2 hours. At this time, the conversion to the title compound was completed using TLC (acetone/methylene chloride). : 5/95
) is substantially completed as indicated by.

Example 4 16-Methyleneandrosta-1,4,9(11)-triene-3,17-dione (IIIB) Sodium bicarbonate 16~, Paraformaldehyde 45~, THF2-
and triethylamine 0°1- were added to 16-(methyloxalyl)androsta-1,4,9(11)-)liene-3,17-dione (■B, reaction mixture of Example 3) and o'c After stirring for 1 hour, conversion to the title compound is complete as shown by TLC. The reaction mixture is poured into a pf (7) buffer and the mixture is extracted with ethyl acetate. The organic extract is washed with water and sulfuric acid), dried over IJum, filtered and the filtrate is concentrated under reduced pressure. The title compound is obtained. NMR (CDC13): 0.90.1,
44.3.87.5, 40.5.58.6.03.6.
21 and 7.21δ0 Example 5 3-methoxy-16-methylene androsta-3,5,
9(11)-1s:r-:/-17-oy(][Aa)
3-Methoxy-16-(methyloxalyl)androsta-3,5,9(11)-)cien-1-fuone (]'
[Aa, Example 1) 385# in paraformaldehyde 4
5 ■, triethylamine 0.2 ml and THF4r
Reflux with nl and then leave at 20-25°C for 48 hours. The reaction mixture is extracted with ethyl acetate-water and the organic layer is dried and concentrated under reduced pressure to give the title compound.

Example 6 3-methoxy-16-methyleneandrosta-3,5,
9(11)-)xn-17-one(l[Aa)TH
3-Methoxy-16-(methyloxalyl)androsta-3,5,9(11)-I in Fl 00 rnt
10 g of Jen-17-oy ([Aa, Example 1), 1.17 g of paraformaldehyde and 5.4-g of triethylamine are refluxed for 1 hour under a nitrogen atmosphere.

The reaction mixture should preferably be extracted with ethyl acetate/water and not with methylene chloride/water, which would result in emulsification. Treatment with chlorine gives the title compound.

Example 7 3-methoxy-16-methyleneandrosta-3,5,
9(11)-tri:'-:/-17-one (l[Aa)
Ti (3-methoxyandrosta-3 in F22Oml)
,5,9(11)-) Lee':n-17-on(■Aa
) 20g of dimethyl silicate 11 at 0''C under nitrogen atmosphere.
．． 8g and 25% sodium methoxide 18°4rn
Mix with l. After mixing the reactants, remove the ice. After 1 hour, TLC clearly shows that the reaction is complete. 7.0 m/l of triethylamine, 1.0 m/l of acetic acid, 3.0 g of paraformaldehyde and 28 rnl of methanol are added and the mixture is stirred overnight at 20-25°C. TLC
indicates that the reaction is complete. The reaction mixture is washed with 121 ml of phosphate buffer and 202 ml of water. The mixture was extracted with 48 d of methylene chloride and again with 40 d of methylene chloride.
Extract with The methylene chloride extracts are combined and back-extracted with 80 ml of water and 10 ml of brine. The organic mixture is concentrated under reduced pressure to give the title compound.

Example 8 3-Methoxy-16-methyleneandrosta-3,5-
Dien-17-one (mAa) 3-methoxyandrosta-3,5-dien-17-one (■Aa) 2.
Mix Of/ with THF22rnl. 1.45 ml of diethyl oxalate is added and the mixture is cooled in a water bath. 2
1.83 rnl of sodium methoxide form 5 are added dropwise with stirring. After removing the water bath, the mixture is stirred for 1 hour and TLC shows the reaction is complete. The reaction mixture was cooled in a water bath and treated with 0.1-1 acetic acid, followed by 0.7 rnl of triethylamine and 2.8 ml of methanol. Add nl. Add 0.3 g of 37% formaldehyde and stir the mixture for 40 minutes. Then 0.61 g of 37% aqueous formaldehyde was added and the mixture was heated at 20-25°C for about 45 minutes.
Stir at C. -r r-c indicates the end of the reaction. water 1
0rnl and 10-ethyl acetate are added and the mixture is stored at about -20°C overnight. The mixture is warmed, the layers are separated and the organic layer is washed twice with brine. The aqueous layer is extracted with ethyl acetate, the ethyl acetate is washed with brine, the organic extracts are combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound.

Example 9 16-methyleneandrosta-1,4,9(11)-triene-3,17-dione (fflB)THF 8
-Medium, androsta-1,4,9(11)-triene-
0.7 g of 3,17-dione (IB) and 0.449 g of dimethyl oxalate are mixed and cooled to 3°C in a water bath. 0.6851 nl of 25 sodium methoxide in methanol
is added dropwise while increasing the temperature. Approximately 0
．． After 5 hours, TLC1/i: indicates that the reaction is almost complete. Acetic acid 0.05rnl, triethylamine 0.26
- and 1 rnl of methanol are added. Add 0.28 ml of 37Φ formaldehyde and reduce the reaction mixture to 20-2
Stir at 5°C. After about 1.5 hours, TLC indicates the reaction is complete. The reaction mixture is added to water and extracted with ethyl acetate. Separate the layers, extract the aqueous layer with ethyl acetate, and combine the organic extracts. The combined organic extracts are washed with water and separated from the organic layer. Add methylene chloride and dry the mixture over sulfuric acid. The mixture is filtered and the filtrate is concentrated to an oil under reduced pressure. Addition of acetone and crystallization give the title compound. Melting point: 157-160°C.

Example 10 16-methyleneandrosta-1,4,9(11)-triene-3,17-dione (I[B) 2 in methanol
6.85 m/s of 5% sodium methoxide was heated at 4°C in advance.
THF8 containing 4°38g of dimethyl oxalate cooled to
Androsta-1 in 01nl and methylene chloride 8d
,4,9(11)-triene-3,17-dione (IB
)7.0'5g of the mixture dropwise. After 1 hour at 4°C, the formation of 16-oxalate is complete and the following reagents are added in sequence: 0°5-acetic acid, 2.6 mj triethylamine.
1 methanol 10- and 37% aqueous formalin 2.8
The +n16 reaction mixture is warmed to 20-25°C and the reaction is complete after 1 hour. The reaction mixture is poured into water and extracted twice with ethyl acetate. The ethyl acetate extracts are combined, washed with water, dried over sodium sulfate, and concentrated under reduced pressure to give a solid. This solid is dissolved in 2.5 m/m of methylene chloride and the methylene chloride is then evaporated. The solid is dissolved again in 25 m/d dry THF and the THF is then evaporated. The solid is then dissolved in THFQ- for use in the next reaction.

Example 11 6-Methyl-16-methyleneandrosta-4°6-diene-3,1 fudione (II[A) 6-methylandrosta-4,6-diene-3,1 fudione (Ibe U.S. Pat. No. 3177966, Example 16) 3.0g in T1
1.64g dimethyl oxalate dissolved in 1F32rnl
Add. The mixture is cooled to O″C under nitrogen atmosphere.

25% sodium methoxide in methanol 2.75rn
Add 1 dropwise. The mixture is stirred at 0° C. for about 2 hours and then neutralized with 0.12 d of acetic acid. Triethylamine 1.2 fnl and methanol 5. Om/, then 1.13- of 37% formaldehyde solution is added. After all reactants have been added, the water bath is removed and the reaction mixture is stirred at 20-25°C for 1.5 hours. 50 tnl of water are added, followed by ethyl acetate and methyl tert-butyl ether. Separate these layers,
Wash the organic layer twice with brine.

The aqueous layers are combined and back-extracted once with ethyl acetate, and the organic extracts are combined and dried over sodium sulfate after addition of a small amount of methylene chloride. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to give an oil, silica/l/(230
~400 meshes) Chromatographed on 140f. The relevant fractions are combined and concentrated to give the title compound.

Example 12 17α-ethynyl-17β-hydroxy-16-methyleneandrosta-4,9(11)-dien-3-one (
IVA) Acetylene was heated to 70°C for 0.5 hours using a gas sparger.
Add 156 m/1.6 N butyllithium dropwise to this acetylene mixture.
-methylene androsta-3,5,9(11) -trix:y-17-oy (-1[Aa, Example 2) 82α
The 6mM @ solution is cooled to -40°C and added to the steroid solution over a period of 10 minutes while maintaining the lithium-added acetylene solution 500°C at a temperature of -30 to -40°C. Next, add 100-20% of the acetylide solution to the colander.
Add it in a few minutes. By this time 2.5 equivalents have been added and the reaction is complete. The reaction mixture was diluted with 10% phosphate
Pour into liquid 550-.

Concentrate the mixture to 6001 nl and add 200 methylene chloride.
Extract twice with
Treat with 20rnl of 6Nl acid. When the hydrolysis of the 3-enol ether is indicated by TLC, the aqueous layer is separated and the organic layer is washed with 100% of water and sulfuric acid).
Dry over a vacuum and concentrate to a solid. The solid is triturated with methanol and the title compound is isolated in three portions. Melting point 216-217°C, NMR (CDCl3):
0.78.1.32.2.57.5.07.5.36
．． 5,60 and 5.72δ0 Example 13 17α-acetyl-17-β-hydroxy-16-methyleneandrosta-4,9(11)-Ien-3-one (V,A) Mercury oxide (red ) 1.21 in 1.6 ml of concentrated sulfuric acid and 25 m of water, 17α-ethynyl-17β-hydroxy-16-methyleneandrosta-4°9 (11) in methanol/L'600- and 125 mJ of THF.
- Add to a solution of 10 g of dien-3-one (IVA, Example 12). The reaction mixture is stirred at 20-25°C overnight, at which point the reaction is complete as determined by TLC. Solids are removed by filtration through a Celite pad. The filtrate was concentrated under reduced pressure to a solid, which was dissolved in methanol 25
Tritrate with -. The mixture is F3a and the solid is dried to give the title compound. Melting point 147-162°C, N
MR (CDCl3): 0.88.1.35.2.35
．． 5.02.5,50 and 5.75δ0 Example 14 16-(phenylsulfinylmethyl)pregna-4,
9(11), 16-driene-3,20-dione (VI
A) 2.5N phenylsulfenyl chloride/L' in methylene chloride
1.4 ml of the solution was added to 10 rnl of methylene chloride containing 0.82-triethylamine, precooled to -55°C.
The solution of 17α-acetyl-17β-hydroxy-16-methyleneandroster-4,9(11)-dien-3-one (vA, Example 13) 11 was added dropwise over 1.5 hours. Add water to the reaction mixture, separate the organic layer,
Wash with water, dry over sodium sulfate, and concentrate under reduced pressure to obtain a partially crystalline material. Crystallization from toluene gives the title compound. Melting point 160-163°Q, N M
R(CDCl3): 0.87.1, 36.2.1
1,4.03.5.50 and 5.75δ0 Example 15 17α-hydroxy-16-methylenepregna-4,9
(11)-Diene-3,20-dione (■A) 16-(phenylsulfinylmethyl)phlebna-4,9(11),16- in toluene In4 containing 53 μl of trimethyl phosphite and 0.14 rnl of methanol. ) Quen-3,20-dione (VIA1 Example 14) 100η
Heat the mixture in a sealed vial at 65°C for 16 hours. TLC shows the reaction is complete. Methylene chloride is added, the reaction mixture is washed with water, the organic layer is separated, dried and concentrated under reduced pressure to give the title compound. NMR(
CDC13): 0.77.1.35.2.31.5.1
0.5.27.5°57 and 5.75δ.

Example 16 17α-ethynyl-17β-hydroxy-16-methyleneandrosta-1,4,9(11)-)suene-3-
On (IVB') Dry acetylene gas @ THF166i at 20-25°C
Disperse for 0.5 hour to saturate the solution. acetylene/
The THF solution was cooled to -70°C and diluted with 1.55% in hexane.
N-butyllithium 3-2.25- was added dropwise over 20 minutes to obtain a transparent thium acetylide solution. 150 m/ml of lithium acetylide solution is placed in another flask at -70'C. 16-methyleneandrosta-1,4,9(11)-triene-3,17-dione (l [B, Example 10) in Tl (F50+r+7) is added dropwise to the remaining lithium acetylide over a period of 35 minutes. Further storage or addition of thium acetylide solution 25- and after 0.5 h at -70 °C, the reaction is stopped in 400 ml of phosphate buffer. The product is extracted with ethyl acetate/methylene chloride, The layers are separated and the organic layer is dried over sodium sulfate and concentrated under reduced pressure to give a solid which is crystallized from ethyl acetate to give the title compound, mp 234-237°C, NMR (CDC
l5): Q, 83.1.43.2.47.5.12.
5.42.5.65.6. ]0.6.32 and 7.2
2 Example 17 17α-acetyl-17β-hydroxy-16-methyleneandrosta-1,4,9(11)-triene-3-
On (VB) 0.4 g of mercuric oxide in 8.3 d of water and 0.53 d of concentrated sulfuric acid was added to 100 ml of methanol and 21 d of THF.
Among them, 17α-ethynyl-17β-hydroxy-16-methyleneandrosta-1,4,9(11)-triene-
Add 3-one (■B, Example 16) to a solution of 3.2F. The reaction mixture is stirred at 20-25°C for 5°5 hours.

IN carbonic acid) IJum 20rnl and ethyl acetate IV
Add 50 ml. Filter the mixture through Celite. Filter the filtrate under reduced pressure. The product was converted into ethyl acetate/L.
//Extract from the aqueous layer using methylene chloride. Dry the ethyl acetate/methylene chloride extract over sodium sulfate,
Concentration to a solid, which is recrystallized from methanol, yields the title compound.

Melting point 185□~190°C, NMR (CDCI3) 0
．． 91.1.42.2, 23.5.20.5.56.6
．． 10.6°27 and 7623δ0 Example 18 16-(phenylsulfinyl)prefuner-1°4.9
(11), 16-tetraene-3,20-dione (VI
B) 2.5N1 m-phenylsulfenyl 2 in methylene chloride
．． 4 ml of 17.alpha.
-acetyl-17β-hydroxy-16-methyleneandrosta-1,4,9(11)-trien-3-one (
VB, Example 17) Add to 1 g of the mixture over a period of 2 hours. The reaction mixture was poured into phosphate buffer (pH 7), the layers were separated, the aqueous layer was extracted with methylene chloride, the organic layers were combined, dried over sulfuric acid, and dried over vacuum. The title compound is concentrated to an isomeric mixture. isomer mixture,
Separation by chromatography on silica gel (50 g) eluting with acetone/hexane (5/95) gives the title compound. NMR (CDCI3): 0.89
．． 1.42.2.11), 4.03.5.5.6.0.
6.27.7.20δ.

Example 19 17α-hydroxy-16-methylene pregna-1,4
,9(11′)-”)diene-3,20-dione (■B
) 0.31 nl of trimethyl phosphite and 0.3 m of triethylamine in 5 rnl of toluene and 0.3 m/m of methanol.
Add to a solution of (7) 16-(phenylsulfinylmethyl)phlebnar-1,4,9 (11), 15-tetraene-3°20-dione (VIB, Example 18, isomer mixture) 538# in 7mj. The mixture is heated at 85° C. in a closed vial until the reaction is complete. The reaction mixture is poured into buffer and extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried over sodium sulfate and concentrated to a solid, which is recrystallized from ethyl acetate to give the title compound. N'MR(CDCI3): 0
．． 70.1.36.2.26.5.10.5゜51.6
．． 00.6.20 and 7.17δ.

Example 20 17α-ethynyl-17β-hydroxy-6-methyl-16-methylene androstar 4,6-genin-3
-one (IVA) 45 ml (4.2 eq.) of acetylene saturated 44]T HF @ solution are cooled to -72° C. over 5 minutes with continued addition of acetylene. Stop blowing acetylene, and
．． 55Mn-butyllithium 1.0m/(4.0 equivalent)
is added over a period of 15 minutes while maintaining the temperature below -65°C, mostly -68°C. -90” mixture
"I" HF1 previously cooled to -105°C
0mZ in
A, Example 11) Add 2.0 g via an insulated Teflon cannula over about 3 minutes. The mixture is heated exothermically to -87°C and recooled to -90°C (bath temperature -93°C). After 3.5 hours, TLC shows the reaction is complete. 1.84 ml (5 equivalents) of acetic acid are added to 1° Fnl of methanol previously cooled to -98°C. Warm the mixture to 20-25°C and add 20 ml of phosphate solution.
Add m/and ethyl acetate 20-. Separate the layers.

Wash the organic layer with buffer/saline (1/1). Back extract the aqueous layer with ethyl acetate and wash it with brine. The organic extracts are combined, dried over sodium sulfate, filtered, and concentrated to an oil under reduced pressure. Ethyl acetate is added with seed crystals and the mixture is left at 20-25°C overnight and then at -20°C for 4 hours. The crystals are added and washed with ethyl acetate/L'/hexane (1/1) to obtain the title compound.

Example 21 17α-acetyl-17β-hydroxy-6-methyl-
16-methyleneandrosta-4,6-genin-3-one (VA) Mercury oxide dissolved in 18 rnl of water containing 0.11 m/m of sulfuric acid was added to 19 ml of methanol-zlz -T HF.
3. B - 17α-ethynyl-17 dissolved in the mixture
β-hydroxy-6-methy/L'-16-methyleneandrosta-4,6-genin-3-one (■A, Example 2
0) Add to 1.30g. Mixture at 40°C (bath temperature)
Heat for 6 hours, then leave at 20-25°C overnight. Cely 1-, 1,79 and phosphate buffer 2- are added, the mixture is stirred and filtered. Wash the solid with methanol and THF. The p-liquid is concentrated under reduced pressure until a solid precipitates out. Add methanol, heat the mixture,
Seed. The mixture is concentrated under reduced pressure and methylene chloride is added. The mixture is washed with buffer, dried over IJ sulfate and filtered. The p solution is concentrated under reduced pressure to obtain the title compound.

Example 22 6-methyl-16-(phenylsulfinylmethyl)pregna-4,6,16-driene-3,20-dione (
VIA) 17α-acetyl-17β-hydroxy-6-methyl-
200 g of 16-methylene androsta-4,6-cyen-3-one (VA, Example 21) were mixed with 2 g of methylene chloride.
Add 0 mK and store at -20°C overnight. The steroid mixture is then cooled to -37°C under a nitrogen atmosphere. Gaseous triethylamine 29- is added directly to the steroid mixture over a period of approximately 10 minutes. 2.5 in methylene chloride
M Phenylsulfenyl chloride 0.45m! (2 eq.) at -40°C over 1.3 hours. TLC shows the reaction to be approximately 98% complete. 10% naric acid 3rnl
and warm the mixture to 20-25°C. Separate the layers and back-extract the aqueous layer. The organic layers are combined, washed with 10% phosphate buffer, and the buffer is back extracted. Combine the organic layers;
Dry over sodium sulfate, filter, and concentrate under reduced pressure. The product was converted into acetone/methylene chloride (10/90)
Purification on a silica gel plate (20×20) eluting with gives the title compound.

Example 23 17α-hydroxy-6-methyl-16-methylenepregna-4,6-genin-3,20-dione (■N) 6-methy/L'-16-(fersulfinylmethyl)
Pregna-4,6-genin-3,20-dione (VI
A, Example 22) 150q,) Toluene 1.25d, Methanol-tVo, 216 ml, Triethyl rmine 0
．． 011-1 Finally, add 0.076-trimethyl phosphite to the vial, seal it, stir, and heat to 4°7 at 100°C.
Heat for 5 hours. The mixture is concentrated under reduced pressure to an oil, which is subjected to TLC on silica gel, eluting with acetone/methylene chloride (5/95) to give the title compound.

Example 24 17α-hydroxy-6-methyl-16-methylenepregna-4,6-diene-3,2o-dione 1-phoacetate (■) Using the method of Example 12 of U.S. Pat. No. 4,154,748, 17α- Hydroxy-6-methyl-16-methylenepregna-4,6-thien-3,2o-dione (■A',
Example 23) is converted into the title compound.

Example 25 3-methoxy-16-methyleneandrosta-3,5-
Dien-17-one (TIIAa) 50 g of 3-methoxyandrosta-3,5-dien-17-one (I) was added to T
Dissolve in T-F containing E A 1-. 55.5 m/dimethyl oxalate are added and the mixture is cooled to 2°C.

Sodium methoxide (2
5%) slowly over 10 minutes. The water bath is removed and the reaction mixture (83) is warmed to 24° C. over 5 minutes with stirring.

The mixture was stirred at 20-25 °C for 55 min, then 1
Cool to 5°C over 0 min. Acetic acid 2.4 rnl
was added, immediately followed by 17.4rnl of TEA, then 1.499ml of paraformaldehyde, and then 63ml of methanol.
Add -. The water bath is removed and the reaction mixture is warmed to 20-25°C over 5 minutes. The mixture is stirred for 5 hours at 2-8°C and stored overnight at -20°C in a fritchie. Warm the mixture to 20-25°C and incubate at 25°C for 4 hours.
Stir at 0-28°C for a total of about 9 hours.

300 ml of water and 300 ml of ethyl acetate are added, the mixture is stirred and the layers are separated. Add the organic layer to 100rnl of saline solution.
Wash twice with The aqueous layer is ethyl acetate/I/100rn
Back-extract twice with l and washed with 50 ml of brine each time. The organic layers were combined, concentrated to an oil under reduced pressure, and diluted with methylene chloride 4
Take up in 50ml/and 200ml of ethyl acetate. The mixture is dried over sulfuric acid, filtered, and concentrated to a solid under reduced pressure. Trituration of the solid with boiling methanol/L'100 containing 1% TEA gives the title compound in crystalline form.

(84) Example 26 17α-ethini/L'-17β-hydroxy-3-methoxy-16-methyleneandrosta-3,5-diene (
]'%rAa) Add acetylene to HF450- for 45 minutes at 20-25°C.
ventilate. The mixture is cooled to -70°C over a period of 15 minutes with continued acetylene saturation.

1,5 M n-butyllithium 150- at -68°
It takes about 45 minutes to drip while maintaining the temperature below C.

The mixture is then warmed to -35°C over a period of 30 minutes. 3-Methoxy-16-methyleneandrosta-3,5-diene-17-oy(l[Aa,
Example 25) 3([1) is added dropwise over 15 minutes while maintaining the temperature at about -25°C.

The mixture is stirred for 10 minutes and then slowly added with 80 lrnl of INIJ salt buffer and 300 m/KO''C of ice water. The conversion takes approximately 1 hour and the mixture is then stirred. The ethyl acetate layer is washed twice with 300ml of brine.The aqueous layer is back-extracted twice with 300ml of ethyl acetate.The ethyl acetate back extracts are combined and extracted once with 200ml of brine. Wash. Combine the organic layers, dry over anhydrous sodium sulfate,
Filter and concentrate to a solid under reduced pressure. The solid was triturated with hot methanol 100 m/m for 10 min, 20-25°
Cool to -20°C for 2 hours. The mixture is filtered and the crystals are washed with cold methanol containing TEA and dried under reduced pressure to give the title compound.

Example 27 17α-ethini IV-17β-hydroxy-6β-(N
-Phenyl-N-ethyl9-aminomethyl)-16-methyleneandrost-4-en-3-one17α-ethini)V-17β-hydroxy-3-methoxy-16-methyleneandrost-3,5-sil- J
(IVA, Example 26) 5g, ethylaniline 2.0
' Mix 5 ml, THE 37.5 ml and 1.33 g 37% formaldehyde. p --r S A
140° C. and the mixture is stirred at 20-25° C. overnight. TLC indicates that the reaction is complete. water 10
0- was added, the mixture was filtered and the solid was dissolved in water/THF (2/
Wash twice with 1) and dry the solid material under nitrogen atmosphere for 5 hours to obtain the title compound. NMR (CDCl2): 0.
85.1.31.2.52.5.23.5.82.6.
7 and 7.2δ.

Example 28 17α-ethini)V-1′7β-hydroxy-6,16
-cymethylene androster-4-en-3-4-en (IV
A) 17α-ethynyl-17β-hydroxy-6β-(N-
phenyl-N-ethylaminoethyl)-16-methyleneandrost-4-en-3-t (Example 27)
Mix with 20m/HF. Degassed 6Nl11a acid 55
Add rnl and 20 rnl of THF. The mixture was stirred overnight at 20-25 °C under a nitrogen atmosphere, at which point T
LC indicates that the reaction is complete. Add 110 d of water, filter the mixture and remove the solid with 10% hydrochloric acid, twice with water and 5%
Wash once with sodium bicarbonate and then three times with water to neutralize.

The solid is dried overnight under a nitrogen atmosphere to give the title compound.

Example 29 17α-acetyl-17β-hydroxy-6,16-symethyleneandroster-4-en-3-one (VA') 0.329 of red mercuric oxide was dissolved in 0.4 of sulfuric acid and 6 of water.
．． Mix with 0 and set aside overnight. 17α-ethynyl-1
7β-hydroxy-6,16-cymethyleneandroster-4-en-3-one (■A, Example 28) 5.0 g
is mixed with THF15-. The mercuric sulfate solution is added and the reaction mixture is heated to 41-49°C for 6 hours, at which point TLC shows the reaction is complete. water 1
Add 0.799 of sodium carbonate in
Stir for a minute. Add 5g of celite and mix the mixture to 20-2
Stir at 5°C for 0.5 hour. The mixture was filtered through 5 g of Celite and the solid was dissolved in methanol/THF (1/1) 1
Wash twice with 0rnl, once with THFIO- and then with 10-methylene chloride. Heat the furnace liquid and washing liquid under reduced pressure for about 30 minutes.
5-, at which point crystal formation begins. 50° of methanol is added and the mixture is concentrated again under reduced pressure and left overnight at 20-25"C under nitrogen atmosphere. 500" of water.
m/ is added slowly at first over 15 minutes while stirring. The mixture is filtered and the solid is washed three times with 20 ml of water and twice with 10 ml of hexane. Dry the solid under a nitrogen atmosphere to obtain the title compound.

Example 30, 6-methylene-16-(phenylsulfinylmethyl) pregna-4,16-genin-3,2o-dione (
VIA) 17α-acety/L'-17β-hydroxy-6,1
6-cymethyleneandroster 4-en-3-one (V
A, Example 29) 8.0 g is dissolved in 66 rnl of methylene chloride and cooled to -20°C. Combine 2.56 yd of trimethylamine and 5 yd of methylene chloride and add the trimethylamine mixture to the steroid solution using a syringe. Phenylsulfenyl chloride (1.0 equivalents) is added to the cooled steroid solution for 1 hour. Add using syringe pump. TLC indicates approximately 80-85% reaction.
Indicates completion. Phenylsulfenyl chloride (o,
25Mft) tJJ Add in 0 minutes. TLC shows the reaction to be approximately 95% complete. Phenylsulfenyl chloride (0.10 equivalents) was then added to give a total of 1.35
equivalence, at which point TLC indicates the reaction is complete. When 400i of 10% oxalic acid is added at once, the temperature is 7.
°C and then stir the mixture for about 10 minutes.

Separate the layers. The aqueous layer portion is back-extracted with 10 m/m of methylene chloride. The organic extract is washed with phosphate buffer 25rnI and back-extracted with 10-methylene chloride. Combine the organic extracts and dry over +3 um of sulfuric acid at 20-25°C overnight. The mixture is filtered and the liquid f is concentrated under reduced pressure to the title compound as an oil.

Example 31 17α-hydroxy-6,16-symethylene pregner 4-ene-3,20-dione (■A″) 6-methylene-
16-phenylsulfinylmethylpregna-4,16
-Genin-3,20-dione (VIA, Example 30)
2.0 g was placed in a 3° vial under a nitrogen atmosphere.

Toluene 20m/, methanol-z+z2.89m/, TE
Ao, 181m/and trimethyl phosphite 1.02-
Add. After 1 hour at 20-25°C, the sealed vial was placed in a hot oil bath with a bath temperature of 90'C and stirred at 90°C for 4 hours, at which point TLC indicated that the reaction was essentially complete. show. Transfer the reaction mixture to a flask and add 10 m/ml of water. Add 10ml of ethyl acetate to the organic mixture, add 1ml of water
-Wash twice. The aqueous part was replaced with toluene/ethyl chloride (
1/1). After separating the layers, the organic layer was filtered through sulfuric acid (IJ), and the added liquid was heated under reduced pressure for about 80 minutes.
Concentrate to a volume of . This concentrate was heated at 20-25°C to approx.
．． Leave it for 5 hours. The resulting crystals were washed into a flask with 2 rnl of toluene and incubated at 5°C for 2 hours, then at -2
Cool at 0°C for 48 hours. Cool the crystals to -20°C (7))
Collect with toluene, wash three times with hexane, and dry under nitrogen atmosphere to give the title compound.

Example 32 17α-hydroxy-6-methyl-16-methylene pregnar-4,6-diene-3,2o-dione 1-phoacetate (compound) 17α-hydroxy-6,16-symethylene pregnar 4-ene- 3,20-dione (■A', Example 31) 5
01! If is slurried in 1.5m/ml of toluene.

Acetic anhydride 95μ7i (7 equivalents) and p-T SA/
Add 8~(0.3 equivalents) of water. 8. Cover the reaction vessel with a lid.
Heat at 5° C. for 3 hours and 20 minutes, remove from heat and allow to cool, TLC indicates the reaction is approximately 70% complete. The reaction mixture is heated for an additional 3 hours and left at 20-25°C overnight, at which point TLC shows the reaction is complete. Add 200μl of 6N hydrochloric acid and mix the mixture for 20~
Stir at 25°C for 1 hour. After working up the title compound is obtained.

Example 33 17α-ethynyl-17β-hydroxy-3-methoxy-16-methyleneandrosta-3,5-diene (■A
a) Cool 400 m/of THF to -40°C. Acetylene is dispersed in this THF. The temperature is -28°C''!

It takes 0.5 hours to cool down to -36°C.

Continue acetylene bubbling for an additional 0.5 hour. The mixture is cooled to -43°C and acetylene is bubbled through for an additional 0.5 hour. 3-Methoxy-16-methyleneandrosta-3
,5-dien-17-one (l [Aa, Example 8) 40
g under stirring, maintaining the cooling bath at -50°C5) (
Add.

Mix 44ml of diisopropylamine and 501n/ml of THF and cool to 8°C. 791.5 Mn-butyllithium 194 m/hex are added at a rate such that the exotherm is maintained below 25°C. Once the addition is complete, the lithium diisopropylamide mixture is transferred via the cannula to the drop tube and then added dropwise to the steroid acetylene mixture while maintaining the reaction temperature below -38°C (bath 711! -50'C). .

Once the addition is complete (65 minutes), TLC shows approximately 98% reaction.
Indicates completion. The reaction mixture was diluted with brine/water (1/1
) 171 and stir. Separate the layers. The aqueous layer is extracted with 200ml of ethyl acetate. The organic layers were combined, washed with brine, added with 1 rnl of triethylamine, dried over sodium sulfate, and diluted with about 801 rnl under reduced pressure.
Concentrate to a volume of . 200 m/ml of methanol and 1 rnl of triethylamine are added and the mixture is heated under reduced pressure to approx.
Enrich rnlK.

Add 200 ml of methanol and bring the mixture back to approx.
Concentrate to –. Filter the mixture and wash the solid with cold methanol to give the title compound.

Example 34 17α,21-dihydroxy-16-methylene pregna-4,9(11)-diene-3,2o-dione 21-acetate (IXA) 17α-hydroxy-16-methylene pregna-4,9
(11)-Diene-3,20-dione (■ A1 Example 1
5) 400 Da to THF (THFl-per iodine o, oi
(with a peroxide content of about 100 g) and dissolved in 1.8 rnl of methanol with stirring. Calcium oxide (fine powder) 600~ and then add iodine 6009. When the reaction is complete for about 3 hours, methylene chloride is added, the mixture is filtered and the added liquid is diluted with aqueous sodium iodide solution,
Wash successively with thiosulfate solution and water, dry and concentrate under reduced pressure without heating. The 21-iodo intermediate was dissolved in 10 ml dry acetone I/Cr'ff and anhydrous potassium acetate 1. Heat to reflux with Og for 18 hours. Water is added and the product is extracted with methylene chloride. The methylene chloride extract is washed with water, dried and concentrated under reduced pressure to give the title compound.

Example 35 17α,21-dihydroxy-16-methylenepregna-1,4,9(11)-)diene-3,20-dione 2
1-Acetate (IXB) Following the general method of Example 34, but with the exception of 17α-hydroxy-16-methylenepregna-1,4°9(11)
-triene-3,20-dione (■B.

Using Example 19) as starting material, the title compound is obtained.

Example 36 17α-ethynyl-17β-hydroxy-16-methyleneandrost-4-en-3-one (■A) Triethylamine (0.63 mol) was dissolved under nitrogen atmosphere at -2
Add to 100 ml of dry THF at 0°C. 1,5N n-butyllithium (0.62 mol) in hexane is then added. This cold solution was dissolved in acetylene saturated TI (F solution) (dry THF) at 10°C.
/) and cooled to -20 °C). 3-Methoxy-16-methyleneandrosta-3,5-dien-17-one (■A
, Example 8.0.32 mmol) is added to the monolithium acetylide solution while maintaining the temperature at -20<0>C. Add 300mZ of 6N hydrochloric acid to the reaction mixture and heat at 30°
Hydrolyze by mixing for 1.5 hours at C. Add methanol and water and isolate the precipitate to give the title compound. N.M.
R: (CDC13) 0.83.1.20.2.52.5
．． 07.5.35 and 5,68δ.

Example 37 17α-acetyl-17β-hydroxy-16-methyleneandrost-4-en-3-one (VA) Mercury oxide (4,
17α-ethynyl-17β-hydroxy-16-methyleneandrost-4-en-3-one (IVA, Example 36) 30.6 mmol) in 300 mZ of acetone under nitrogen atmosphere. Add to the slurry of &. Mixture at 50°
Heat overnight at 20°C, then cool to 20-25°C.

Neutralize the mixture with sodium bicarbonate and filter through Celite. Add acetone and water. After working up, a crude product is obtained. This crude product was heated at 25°C for 2-3 hours.
Purification by stirring in a 2% acetic acid-methylene chloride mixture with 5% zinc dust for an hour. The mixture is filtered through magnesium silicate and then concentrated to a solid. This crude material is crystallized from acetone to give the title compound. N
MR (CDC13): 0.93.1.20.2.26
．． 3.2.5.12 and 5.70δ.

Example 38 16-(phenylsulfinylmethyl)hlebnar-4+
16-Dinin-3,20-dione (VIA) Trimethylamine (0.39 mol) was dissolved in 17α-acetyl-17β-hydroxy-16-methyleneandrost-4-ene-3-t in 450 mZ of methylene chloride, dried over a nitrogen atmosphere. (VA, Example 37) Add to 45 g of mixture (-20°C). A solution of 2M phenylsulfenyl chloride (0.18 mol) in methylene chloride was then added at a temperature of -20°.
While maintaining the temperature at C, the solution is added dropwise over a period of 0.5 hours. -20
After another 20 minutes at °C, add 4.5 rn methanol to the mixture.
I.

The reaction is then stopped by adding hydrochloric acid (10% v/v). After treatment with water, drying over sodium sulfate and removal of the solvent gives the title compound, which is used in the next step without further purification. NMR (CDCl2): 0.9
6.1.02.1.20.2.08.2.18.3.9
．． 5.7 and 7.5δ.

Example 39 17α-hydroxy-16-methylenepregna-4-ene-3,20-dione (■A) Crude [16-(phenylsulfinylmethyl)pregna-4,16-diene-3,
20-dione (VIA, Example 38) under nitrogen atmosphere,
Slurry in 300ml of toluene. Methanol (2
mmol), triethylamine (0.13 mmol),
Then trimethyphosphite tV (0.79 mmol)
Add. The reaction mixture is sealed and heated under pressure at 90°C for 4 hours, then cooled to 20-25°C. Acid hydrolysis of the reaction mixture with trimethyl phosphite, washing with base and buffer and finally crystallization from toluene/heptane gives the title compound. NMR (CDC13): 0
．． 82.1.20.1.30.3.5.5.04.5.
21 and 5.68δ.

Example 40 17α-hydroxy-3β-methoxy-16-methylenepregna-3,5-dien-20-one (■Aa) Trimethyl orthoformate (180 mmol) and pyridine hydrochloride 1% (8,7 17α-hydroxy-16-methylenepregna-4-M'-3,20 mmol) in ethyl acetate/meta/-zv (1/1) mixture
-dione (vIIA1 Example 39) to a mixture of 30.0 g. Heat this slurry at 4°C for 2 hours.

Change the solvent to ethyl acetate and continue heating at 50°C for 1 hour. Triethylamine (16 mmol) is added followed by 30 ml hexane. The slurry is cooled and filtered to obtain the title compound. NMR (CDCl2): 0. +33
．． 0.98.2.28.3.2.3.52.5.1 and 5.2δ.

Example 41 17α-hydroxy-6,16-symethylene pregner 4-ene-3,20-dione (■A') under nitrogen atmosphere,
N-ethylaniline (8 mmol) and THF12d
37% aqueous formaldehyde (8 mmol) and Oxalic acid (0.7 mm)
V) is added. The mixture was stirred at 20-25 °C overnight, at which point the solvent was removed under reduced pressure and diluted with methylene chloride 25°C.
Change to d. After treatment with water, the organic layer was removed under a nitrogen atmosphere.
5 at 40'C in a closed container with degassed 6N glucoic acid 25-
Stir for an hour. Neutralization with water and crystallization from ethyl acetate gives the title compound. NMR (CDCl2): 0.
83, ■, 10.2.31.3.3.4゜90.5,0
2.5.23 and 5.85δ.

Example 42 17α-hydroxy-6-methyl-16-methylene pregnar-4,6-diene-3,20-dione 1-phacetate (■) 17α-hydroxy-6,16-symethylene pregnar 4-ene- 3,20-dione (■A#, Example 41) 0
．． Slurry 5g with 14- toluene under a total nitrogen atmosphere. 0.95 rnl of acetic anhydride, then P-T S A
Add 80 #. The mixture is heated in a sealed vial at 85° C. for 6.5 hours, at which point TLC shows the reaction is complete. The mixture is concentrated to an oil under reduced pressure. Approximately 10-1 methanol is then added, followed by 1.5-10% oxic acid, and the mixture is stirred for 1 hour under a nitrogen atmosphere. Add water and strain mixture. The solid was washed with bicarbonate, then distilled water, and dried under a nitrogen atmosphere overnight to give the title compound 515 (yield 9).
2%).

Chart A Chart B ~ (103) Chart C (104) Chart D Chart E l-13 ■ I3 H3 (107) Q (2 Patent applicant The Upjohn Company agent Patent attorney Aoyama Bohaga 2 people ( 108) -103・

Claims (1)

[Scope of Claims] R6(H [wherein, is hydrogen, fluorine, methyl or methylene, and is absent or hydrogen, fluorine, or R1
together with 1 to form Δ9(11) or 9β,11β-epoxide, RIO is hydrogen or methyl, R11(j l or two hydrogens, oxygen, α-hydroxy or β-hydroxy, or R together with Δ9(1
1), or 9β, 11β-epoxide, ~ indicates that the attached atoms or groups can have either the α or β configuration, = means a single bond or a double bond] A 17α-ethynyl steroid or its q-protected form selected from the group consisting of the compounds represented by: phase is absent or together with hydrogen, fluorine or R11 forms Δ9(11) or 9β,11β-epoxide, RIO is hydrogen or methyl, R11 is one or two hydrogens, oxygen, α-hydroxy or -Hydroxy, or with he, Δ9 (11)
4 or 9β, 11β-forming epoxide ~ indicates that the attached atoms or groups can take either the α or β configuration, 2 means a single bond or a double bond] 17β selected from the group consisting of
-Hydroxysteroids or their 9-protected forms. (3) Formula: ? □3 Sho? ``3 also l'i, phase is absent or forms Δ9(11) or 9β, 11β-epoxide with hydrogen, fluorine or R11, R1oFi hydrogen or methyl, R11 is one or two hydrogen, oxygen , α-hydroxy or β-hydroxy, or both Δ9 (11)
or 9β, 11, θ-epoxide is formed, ~ indicates that the bonding claw or group can take either the α or β configuration, = is a double bond, R221d has 1 carbon number ~5 alkyl, trichloromethyl, phenyl, substituted phenyl (substituent is halogen, alkyl or alkoxy having 1 to 4 carbon atoms, or 1 to 3 nitro or trifluoromethyl), aralkyl having 7 to 12 carbon atoms or -N -(R122)2, R122
means an alkyl having 1 to 4 carbon atoms, phenyl or phthalimide]. H2 ~ or CH3 ions are absent or not yet together with hydrogen, fluorine or R11 to form Δ9(11) or 9β,11β-epoxides, RIO is hydrogen or methyl, R11 is one or two hydrogens, oxygen, α-Hydroxy is also β-hydroxy, or together with Δ9 (11)
and 9β, 11β-epoxides, 〜 indicates that the attached atoms or groups can take either the α or β configuration, = means a single bond or a double bond] 16-methylene-17α-hydroxyprogesterone selected from the group consisting of: (Formula 51+11: [wherein, Rt+R1o, ~ and = are as shown below] If the protected 16-methylene-17-kedosteroid is (1)) contacting the reaction mixture with monolithium acetylide;
maintained at a temperature below 0 °C; RIO is hydrogen or methyl, R11 is one or two hydrogens, oxygen, α-hydroxy or β-hydroxy, or Δ(1(11
) or 9β, 11β-epoxide, 9 indicates that the attached atom or group can have either the α or β configuration, and : means a single or double bond. Method for producing protected 17α-ethynyl steroids. [Formula 11: [In the formula, square, RIO, R11~ and 2 are as shown below.] (contacting the reaction mixture with a quenching agent; then contacting the reaction mixture with a quenching agent; then contacting the reaction mixture with a proton source) characterized in that the formula: ] is absent or forms a Δ9(11) or 9β, 11β-epoxide with the drench, fluorine or R11, RIO is hydrogen or methyl, R11 is 1 or 2 hydrogen, oxygen, α-hydroxy or β-hydroxy, or Δ9(1
1) or 9β, 11β-epoxide is formed, ~ indicates that the attached atoms or groups can take either the α゛ or β configuration, = means a single bond or a double bond] A method for producing 17α-ethynyl steroid. f7) Iil formula: [In the formula, R6, R9, R11, ~ and =2 are the same as below] 16-methylene-17-kedosteroid represented by
(g) maintaining the reaction mixture at a temperature below -20°C, and (iii) contacting the reaction mixture with a quenching agent. characterized by the formula: [wherein the phase is hydrogen or fluorine or methyl or methylene, the phase is absent or hydrogen or I is fluorine, or Δ9 (11 and 9β, 11β-epoxide is formed, R11 is 1 or 2 hydrogen or oxygen or (-1:
α-hydroxy or β-hydroxy, or Δ9(1
1) and 9β, 11β-epoxide needle, ~ indicates that the attached atom or group can take either the α or β configuration, = means a single bond or a double bond] is indicated. Method for producing 17α-ethynyl steroid. A method for producing a 17β-hydroxysteroid represented by the formula: which comprises contacting a 17α-ethynylsteroid represented by the formula with a mercurial agent. A 17β-steroid of formula
-8-M (wherein M means chlorine, bromine or phenylsulfone, phthalimide or imitasol group, R2
2 is shown below), H3 is characterized by contacting with a sulfenylating agent represented by formula 1% formula% [wherein R22 is an alkyl having 1 to 5 carbon atoms, trichloromethyl, phenyl, substituted phenyl ( @substituent d halogen,
Alkyl or alkoxy having 1 to 4 carbon atoms or 1 to 4 carbon atoms
3 nitro or trifluoromethyl) 7-1 carbon atoms
Aralkyl of 2 -N-(R122)2, R122
means alkyl having 1 to 4 carbon atoms, phenyl or phthalimide]. 00) Formula: CI(3) [In the formula, R22 is alkyl having 1 to 5 carbon atoms, trichloromethyl, phenyl, substituted phenyl (tf&I!1fJf
Halogen, alkyl or alkoxy having 1 to 4 carbon atoms or 1 to 3 nitro or trifluoro, l, t
V), 9$ number 7 to 12 aralkyl or -N-(
R122)2, R122 means alkyl having 1 to 4 carbon atoms, phenyl or phthalimide] The sulfoxide represented by thiophyl was heated at 30°C under pressure.
Characterized by contacting at a higher temperature, the formula:
A method for producing 16-methylene-17α-hydroxyprogesterone represented by CH3. C11) 17α-hydroxy-6,16-symethylenepregnator 4-ene-3,20-dione is brought into contact with an acylating agent in the presence of a strong acid. 17α-hydroxy-6-methyl-16- Methylene pregna-4,6
-Production method of genin-3,20-dione 1-fuacetate.