CS203913B2 - Process for preparing derivatives of estradiene - Google Patents

Abstract

Steroids of formula (I) are new: (R1 = H, trialkylsilyl or acyl. R2 = ethynyl, chloroethynyl or propynyl. X is oxo, or NOR4. R3 = H or acyl. R4 = H, acyl, alkyl or tetrahydropyranyl). They are prepd. e.g. from corresp. 3-oxo cpds. by reaction with an organometallic cpd. able to introduce R2 giving a tert. carbinol. (I) have powerful progestational activity and inhibit ovulation and implantation; the higher esters have delayed-release activity. The oral doses contain 0.01-0.5 mg and parenteral solns. about 100 mg/ml. In the Clauberg test 17 alpha-ethynyl-17 beta-hydroxy-18-methyl-4,15-oestradien-3-one is more active orally than the corresp. -4-oestren-3-one.

Description

The present invention relates to a process for the production of estradien derivatives of the general formula I,

O/? ¹

where

R ¹ represents a hydrogen atom or an acyl group having 2 to 11 carbon atoms, R ^{2 a} chloroethyl or propynyl group, X an oxygen atom or a moiety

H useful in pharmacy. They are characterized by a strong gestagenic effect and an ovulation and depressant effect. The higher esters of the compounds of the formula I are characterized by a protracted action.

The compounds of the formula I can be used, for example, in contraceptives, being added as a gestagen component in combination with an estrogenically active component, for example ethinylestradiol, or used as the sole active compound. However, the novel compounds can also be used in gynecological disorders.

For application, the compounds of formula (I) are formulated with conventional pharmaceutical ingredients, carriers and flavorants by known methods into conventional dosage forms. For oral administration, in particular tablets, capsules, dragees, pills, suspensions or solutions are suitable. For parenteral administration, particularly suitable are oily solutions, for example in sesame or castor oil, which may optionally contain a diluent, for example benzylbenzoate or benzyl alcohol. The concentration of the active ingredient is dependent on the form of application. Tablets for oral administration contain, for example, 0.01 to 0.5 mg of active ingredient and solutions for parenteral administration preferably contain 1 to 100 mg of active ingredient per ml of solution.

OH or NOR ³ , wherein R ³ represents a hydrogen atom, an acyl group having 1 to 7 carbon atoms or a methyl group.

The compounds of formula I possess valuable steroid hormone properties and are

'Dávktíváni drugs may měnijxpddlecformý ^а г application purposes. For example, the oral contraceptive dose is 0.01 to 0.5 mg.

According to the invention, the estradiene derivatives of the general formula (I) are prepared by the process of 17-oxo-ene-terene of the general formula (II),

where

Y denotes an oxo group preferably protected in the form of a ketal and one of the bonds in the 4,5-, 5,6- or 5,10 position means a carbon-carbon double bond and the other carbon-carbon single bonds, chloro-ethynyl or propynyl, the initially introduced protecting group is cleaved and, depending on the desired meaning of R ¹ а. In the final product of formula (I), optionally the 17-hydroxy group is esterified and / or is esterified before or after cleavage of the ketal group. The 3-keto group is reduced or reacted with a hydroxylamine salt in the presence of a base to give the 3-oxime which is optionally esterified or etherified.

The introduction of the chloroethyl or propynyl group can be carried out by known methods using organometallic compounds of chloroethyl or propynyl. Such organometallic compounds are, for example, alkali metal chloroacetylides or methylacetylides, for example lithium chloroacetylide or lithium methylacetylide.

The organometallic compounds can also be formed in situ and react with the 17-ketone of formula II. Thus, for example, the 17-ketone 1,2-dichloroethylene can be treated in the presence of an ethereal solution of methyl lithium or a methyl ether. methylacetylene in the presence of tibutyllithium in a tetrahydrofuran solution.

, p.ro ^; optionally, the following esterification is contemplated by methods commonly used in the chemistry of steronide esterification.

For esterification of the 17-hydroxy group, for example, reaction with an acid or anhydride is mentioned. an acid in the presence of a strong acid, for example trifluoroacetic acid, at room temperature or elevated, or reaction with an acid anhydride in the presence of a tertiary amine at a temperature of about 20 to 200 ° C.

When pyridine and 4- (dimethylamino) pyridine are used together as tertiary amines, the esterification can be carried out at room temperature.

. The cleavage of the protecting group at the 3-position, which can take place before or after the optional assembly, is carried out by known metalworking. Suitable for the retal cleavage are, for example, mineral acids such as tartaric acid, sulfuric acid or hydrochloric acid, or organic acids, such as oxalic acid. The ketal cleavage is preferably carried out in an alcoholic solution or in another polar solvent such as acetone at a temperature in the range of 20 to 100 ° C.

The reduction can be carried out in a known manner by hydrogenation with a metal hydride. Especially the most complex hydrides have proved to be hydrogen donors. For example sodium borohydride and lithium tri- (tert-butoxy) aluminum hydride The reduction with sodium borohydride is preferably carried out in an aqueous-alcoholic solution and the reduction; The carbon-carbon double bonds are operated under mild reaction conditions, i.e. the reduction / reaction takes place at temperatures in the range of 0 to 50 ° C.

The reaction of 3-ketone with hydroxylamine salt to 3-oxime is carried out in the presence of a base such as. a base _of ; for example, pyridine, collidine or sodium bicarbonate, sodium acetate and sodium hydroxide in an aqueous-alcoholic solution are suitable. Hydrochloride or hydrogen sulphate are preferred as hydroxylamine salts. The reaction is carried out at a temperature in the range of 20 ° C ^; to ^R i50 ^'o C.

3-0xlm can be esterified or etherified using conventional methods. The esterification takes place, for example, with the desired acid or its halides or anhydrides in the presence of a tertiary amine, for example pyridine or collidine, at room temperature. Also suitable as a tertiary amine is 44 dimethylamino) pyridine in pyridine.

The 3-oxime etherification with the alkyl group is preferably carried out by: an appropriate alkyl halide in the presence of a strong base, for example sodium hydroxide, and in the presence of a polar solvent; for example hexamethylphosphoric triamide, at a temperature in the range of 0 to 30 ° C, or in the presence of a strong base such as sodium hydride in the presence of an ether such as tetrahydrofuran or a polar solvent such as dimethylsulfoxide at a temperature of 30 to 100. C. ^the etherification of the 3-oxime is also possible with a diazoalkane, especially diazomethane.

The preparation of 17-oxosteroids of formula II used as starting products is described in the following examples:

A. 15α-Hydroxy-18-methyl-4-estene-3,17-dione

500 ml Erlenmeyer flask containing 500 ml of a nutrient solution composed of 3.0 ml. glucose, 1.0% corn extract, 0.2% sodium nitrate, 0.1% sodium phosphate dibasic, tertiary, 0.2% potassium hydrogenphosphate, 0.05% magnesium sulfate. , '0,002 -%' of ferrous sulphate 'and - 0,05%' of potassium chloride and 'sterile': - 'for - 30 - minutes' in. of an autoclave at a temperature of 120 ° C, inoculated with a culture of Penicillium raistrici (ATCC 10 490) and shake in a rotary shaker for 72 hours at 30 ° C. A two liter flask filled with 15 liters of medium of the same composition, which was sterilized at 121 ° C and 0.11 MPa, was seeded with 250 ml of culture prepared as described above. With the addition of silicone antifoam was cultivated 'at' a temperature of 29 - C - 'for poovzdušňování (10' L 'for' - minute), "pressure" of 70 mbar and stirring ^(; 220 'turns' per minute)' after 24 hours; The 1.8 liter culture slurry is transferred under sterile conditions to 26 liter liters of the above-sterilized nutrient solution and cultured. - under the same conditions. After 12 hours, 2 liters of fine suspension of g20 g of 18-methyl-4-estrene-3,17-dione in distilled water are added. the addition of a wetting agent and 'cultivates' further.

Progress 'is' monitored - by chromatography on '-' thin ^'layer' - methyl isobutyl ketone extract of sample from the fermentor. - About - after - 70 hours of 'contact time' - is 'conversion'. complete. Now the mycelium - 'filtered' a. - the culture broth is extracted twice, after 20 liters of methyl isobutyl ketone. At the same time, the filtered mycelium is mixed several times. with a mixture of methyl isobutyl ketone, acetone and water, and no sterile substance is detectable.

The organic extraction solutions were combined and evaporated to dryness under vacuum at a bath temperature of 50 degrees Celsius. The residual brown crystals are washed several times with hexane to remove silicone oil, dried, and finally, after treatment with activated carbon, recrystallize from ethyl acetate, recovering 97.5 g (76.5 why, " - " of theory) - pure: 15? -Hydroxy-18-methyl-4-estrone-3,1,7-dione with - temperature; mp 175-177 ° C.

B.15a-Hydroox-18-methyl-3,3- (2 ', 2'-dimethyl-1,3' - propylenedioxy) -5-estren-17-one and -5 (10'-bis-methyl) - 15-Hydroxy-18-methyl-4-styrene-13,17-dione is stirred in 150 ml of methylene chloride and 40 ml of formic acid triethyl chloride with 60 g of 2,2-dimethyl-1-carboxylic acid. 3-propanediol and 200 mg of p-toluenesulfonic acid for 20 hours at room temperature The solution was diluted with ethyl acetate, neutralized with sodium bicarbonate solution and washed with water, then the solution was dried over sulfate. The crude product is chromatographed on silica gel with an acetone-hexane gradient (0 to 20% acetone), 20% acetone eluting with 10.0 g -15a. - (2 ', 2'-Dimethyl-1', 3'-propylcyclohexyl) -18-methyl-5-estren-17-one - with 'melting point' 206 DEG-209 DEG. 'Further' afforded 15 'g of an oily mixture' hydooxy 15α-18-methdl-3 _and 3- (2 ', 2'-di.rňbtthyll', 3'-propylendi.oxy) -5-estreh - 17-one and -5 (10) estren-17-one.

.C. .alpha.-5α-Meey-ooχ-11-methyl-3,3- (2 ', 2 ' -dimethyl-, 1 ', 3 ' 5 (10) -estren-17-one g '15α-hydroxy-118-methyl-3,3- (2', 2'-dimethyl-3 ', 3'-propylenedioxy) -5, -estren-17-one; and The -5- (10) -piperidin-17-one was treated with 27.1 ml of methanesulfochloride under ice cooling and then stirred for 3 hours at an ice bath temperature. The reaction mixture is then mixed into ice-water, the precipitate is filtered off with suction and washed. It is then taken up in methylene chloride and dried. A mixture (40 g) consisting of 15α-mesyloxy-18-methyl-3,3- (2 ', 2') dimethyl-33'-propylenedioxide) -51cst-cn-1 · 7 - was obtained. and 5 '(10) -estoen-17-one in the form of an oil.

D. '18-Methyl-3,3- (2', 2'-dimethyl-1 ', 3'-poly-1-ethylenedioxy) -5,15-estoadien-17-one and -5 ( 10), 15 ^and estťadien-17-one 35 g l5α-mesyloxy'-18 '· metňdl-3,3--' (2 ', 2') diMeO-hydroxy-lΓ, 3'-propyiendioxy) --- estoen-n-one -? -? - (5) (10) -estren-17-ol - is stirred. -. in 350 ml of dimethylformamide with 105 g of anhydrous sodium acetate for 20 hours at room temperature. The reaction mixture is then added to ice and water and the precipitate formed is filtered off with suction. The precipitate was washed with water and taken up in methylene chloride. Evaporation of the solvent gave 28.9 g of crude 18-methyl-3,3- (2 ', 2'-dimethyl'-Γ, 3'-propylindioxide)) 5,15-estradien 17-one and -5 (10), 15-estoadien-17-one.

The process for the preparation of the est-adiene derivatives according to the invention is explained in more detail in the following examples:

Example 1 and d 1

17a-C hlorethines (17β-hydroxy-18-methyl) -I-estradien-U-one

To 2.3 ml of 1,2-dichloroacetate. in 40 ml of absolute ether. 'add'<below. protective atmosphere of argon at temperature. 32 ml of a 2M solution of (ether) methyl lithium. After 30 minutes, 18-methyl-3,3- (2 ', 2') dimethyl-d, 3'-propenedenedioxy) -5,15-estradiol-17-one was added dropwise and -5 (10) -, 15-estoadien-17-one in the 1970s. 'ml. . ' of tetrahydrofuran and the reaction mixture is stirred for 1.5 hours at room temperature. After cooling, the solution is carefully mixed with an ammonium chloride solution and diluted. .with ether. The solution is then washed with water. and dried over sodium sulfate. The 'crude' product is - chromatographed - on silica gel with a mixture. acetone / hexane. Obtained 'was - 1.2 - G - 17ατChlorβthi phenyl · 3 · _j 3- (2', 2'1-ethyl--dimё Γ, 3'-poopylcndioxy) -18-metУyl) -5,15-diene-17 З _l) and 01U - 15 (.10) 15 cstoadien-17J-ol, - '- which - .se- stirred at 10- .. -. ml of ethyl alcohol - a. 1 -. ml - water - is -400 g of acidic oxalic acid for 4 hours at 65 ° C. The solution was neutralized with sodium bicarbonate solution and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water and dried over sodium sulfate. Purification by preparative layer chromatography (ether / chloroform - 8: 2) and recrystallization from acetone / hexane gave 170 mg of 17α-chloroethyl-17β-hydroxy-18-methyl-4,15'-estradien-3-one. Mp 153-154 ° C.

Example 2

17β-Acetoxy-17α-chloethinyl-18-methyl-4,15-estradien-3-one

1.0 g of 17α-chloroethynyl-17 / S-hydroxy-18-methyl-4,15-estradien-3-one is stirred in 10 ml of pyridine with 5 ml of acetic anhydride and 50 mg.

Of 4- (dimethylamino) pyridine for 4 hours under a nitrogen atmosphere at room temperature. The solution is then poured into a mixture of ice and water containing sulfuric acid. The precipitated product is filtered off with suction, dissolved in methylene chloride, washed with water and dried over sodium sulfate. Chromatography of the crude product on silica gel with acetone / hexane yields 760 mg of 17.alpha.-acetoxy-17.alpha.-chloroethyl-18-methyl-4,15-estradien-3-one. Melting point - 122 ° C.

Example 3

17.beta.-Butyryloxy-17.alpha.-chloroethyl-18-methyl-4,15-estradien-3-one

400 mg of 17.alpha.-chlorethinyl 17 _g 3-hydroxy-18-methyl-4,15-diene-3-one in 4 ml of pyridine and 2 ml of butyric anhydride and 20 mg of 4- (dimethylamino) pyridine was stirred at room temperature for 8 hours. The reaction product was poured into ice-water containing sulfuric acid and worked up in analogy to Example 2. Chromatography of the crude product on silica gel with acetone / hexane gave 220 mg of 17 _L / 3-butyryloix-17α-chloroethyl-18-methyl -4,15-estradien-3-one as an oily substance.

Example 4

17α-Chloroethyl-18-methyl-17: β-undecanoyloxy-4,15-estradien-3-one

70 ml is distilled from a solution of 3.5 g of nudecylic acid in 300 ml of benzene. After cooling to room temperature, 4 ml of trifluoroacetic anhydride are added. After 30 minutes, 3.2 g of 17α-chloroethynyl-17β-hydroxy-18-methyl-4,15-estradlen-3-one is added. The reaction mixture was stirred for 2.5 hours. 50 ml of acetone water (1: 1) are added under ice-cooling, the mixture is stirred for 30 minutes and finally concentrated in vacuo. The residue was taken up in methylene chloride, washed with sodium bicarbonate solution and water and finally dried over sodium sulfate. The crude product is chromatographed on silica gel. 1.1 g of 17α-chloroethynyl-18-methyl-17β-undecanoyloxy-4,15-estradien-3-one is obtained as an oil.

UV (methanol): γ = 17,900.

Example 5

17α-Chloroethynyl-18-methyl-4,15-estradien-3 $ -17 / 3-diol

To 1.2 g of 17α-chloroethynyl-17 ₁ S-hydroxy-18-methyl-4,15-estradien-3-one in 30 ml of tetrahydrofuran is added slowly a solution of 3.0 g of lithium tri- (tert-butoxy) - of aluminum hydride in 25 ml of tetrahydrofuran and the reaction mixture was stirred for one hour at room temperature under a nitrogen atmosphere. The solution is then poured into a mixture of ice and water containing sulfuric acid. The precipitated product is filtered off, dissolved in ethyl acetate, washed with water and dried over sodium sulfate. Chromatography of the crude product on silica gel with acetone / hexane gave 380 mg of 17α-chloroethynyl-18-methyl-4,15-estradien-3,15,17-diol as a foamy product.

_{[I] = D} of -109.8 ° C.

Example 6

17i / J-Acetoxy-17α-chloroethyl-18-methyl-4,15-estradien-3-ol

900 mg of 17β-acetoxy-17α-ethynyl-18-methyl-4,15-estradlen-3-one in 25 ml of tetrahydrofuran is treated with 2.3 g of lithium tri- (tert-butoxy) aluminum hydride in 20 ml of tetrahydrofuran as described in Example 5. After one hour, the solution is poured into a mixture of ice and water containing sulfuric acid and worked up analogously to Example 5. After purification of the crude product by preparative layer chromatography (ether / chloroform - 8: 2) 410 mg of 17.alpha.-acetoxy-17.alpha.-chloroethyl-18-methyl-4,15-estradien-3.alpha.-J-Oil is obtained.

Melting point 103-108 ° C.

Example 7

17α-Chloroetinyl-18-methyl-3-oximino-4,15-estradien-17i / J-ol

To 2.3 g of 17α-chloroethynyl-17 / S-hydroxy-18-methyl-4,15-estradien-3-one in 60 ml of methanol and 2 ml of water add 1.0 g of hydroxylamine hydrochloride and 1.0 g of bicarbonate sodium. The reaction mixture was stirred for 3 hours at 65 ° C and then concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water and dried over sodium sulfate. Chromatography of the crude product on silica gel with acetone / hexane gave 1.4 g of 17α-chloroethyl-18-methyl-3-oximino-4,15-estradien-17/3-ol as a foam.

UV (methanol): ε24ΐ = 21,800.

EXAMPLE 8 β-Acetoxy-γ-S-chloroethyl-1-methyl-4,15-estradien-3-one oxime

1.2 g of 17.beta.-acetoxy-17.alpha.-chloroethyl-18-methyl-4,15-estradien-3-one in 35 ml of methanol and 1.2 ml of water were reacted as described in Example 7 with 600 mg. hydroxylamine hydrochloride and 700 mg of sodium bicarbonate. After one hour, the reaction mixture was worked up analogously to Example 7. After chromatography of the crude product on silica gel with acetone / hexane, 750 mg of 17β-acetoxy-17α-chloroethyl-18-methyl-4,15-estradien-3-onoxime was obtained. in the form of a foamed product. UV (imethanol): s240-20900.

Example 9

17a-Chlorethinyl heptanoyloximino-3-18-methyl-4,15-estradien- ⁱ 17./í-ol

850 µg of 17α-chloroethynyl-18-methyl-3-oximino-4,15-estradien-17 / S-ol is stirred in 6 ml of pyridine with 3.5 ml of enanthic anhydride for 3 hours at room temperature. The solution is diluted with benzene and subjected to steam distillation. The reaction product was extracted from the aqueous distillation residue with methylene chloride. Chromatography of the crude product on silica gel with acetone / hexane afforded 210 mg of 17? -Chloroetinyl-3-heptanoyloximino-18-methyl-4,15-estradien-17H-ol as an oil.

UV (methanol): ε243 = 20,800.

Example 10

17α-Chloroetinyl-3-methoximino-18-methyl-4,15-estradien-17/3-ol

2.6 g of 17α-chloroethynyl-18-methyl-3-oximino-4,15-estradien-17/3-ol in 50 ml of hexamethylphosphoric triamide are mixed with 2 ml of 25% sodium hydroxide solution under ice-cooling and nitrogen inlet; 5 ml of ethyl iodide. After one hour, the solution was poured into a mixture of ice and water containing hydrochloric acid. Extract with ether, wash the solution with water and dry over sodium sulfate. The crude product is chromatographed on silica gel with acetone / hexane. 510 mg of 17α-chloroethynyl-3-methoximino-18-methyl-4,15-estradien-17/3-ol are obtained as an oil. UV (methanol): ε249 = 22,000.

Example 11

17β-Hydroxy-18-methyl-17α-propyn-1-yl-4,15-estradien-3-one

Methylacetylene was added to a solution of 60 ml of butyllithium (15% in hexane) in 220 ml of tetrahydrofuran, cooled with a mixture of ice and water, for 30 minutes. Then 3.8 g of 18-methyl-3,3- (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -5,15-estradien-17-one and -5 (10) are added dropwise with stirring. 15-estradien-17-one in 60 ml tetrahydrofuran. After two hours the solution was carefully treated with saturated ammonium chloride solution, diluted with ethyl acetate _t, washed with water and dried over sodium sulfate. The solution was concentrated to dryness in vacuo to give 4.6 g of crude 18-methyl-3,3- (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -17α-propyn-1-yl- 5,15-estradien-17β-ol and -5 (10), 15-estradien-17-ol, which is suspended in 50 mL of acetone and treated at room temperature with 0.1 mL of concentrated hydrochloric acid. After one hour, the reaction mixture was poured into ice-water. The precipitated product is filtered off with suction, dissolved in ethyl acetate and dried over sodium sulfate. The crude product is chromatographed on silica gel with acetone / hexane. 1.8 g of 17β / 3-hydroxy-18-methyl-17α-propyn-1-yl-4,15-estradien-3-one is obtained as an oil.

UV (methanol): εζ40 = 17,300.

Example 12

17β-Acetoxy-18-methyl-17α-propyn-1-yl-4,15-estradien-3-one

250 mg of 17β-hydroxy-18-methyl-17α-propyn-1-yl-4,15-estradien-3-one in 2.5 ml of pyridine are stirred with 1 ml of acetic anhydride and 10 mg of 4- (dimethylamino) pyridine after for 2 hours at room temperature and under a nitrogen atmosphere. After working up analogously to Example 2 and chromatographing the crude product on silica gel with acetone / hexane, 110 mg of 17.beta.-acetoxy-18-methyl-17.alpha.-propyn-1-yl-4,15-estradien-3-one is obtained as an oily oil. substances. UV (methanol): εйзэ = 17 300.

Example 13

18-Methyl-3-oximino-17α-propyn-1-yl-4,15-estradien-17-ol

1.2 g of 17β-Hydroxy-18-methyl-17α-propyn-1-yl-4,15-estradien-3-one in 30 ml of methanol and 1 ml of water are mixed with 800 mg of hydroxylamine hydrochloride and 800 mg of hydrogen carbonate sodium for 3 hours at 65 ° C. The reaction mixture was then concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water and dried over sodium sulfate. Chromatography of the crude product on silica gel with acetone / hexane yielded 430 mg of 18-methyl-3-oximino-17α-propyn-1-yl-4,15-estradien-17β-ol as a foamy product.

UV (methanol): ε240 = 21,200.

Example 14

17β-Acetoxy-18-methyl-17α-propyn-1-yl-4,15-estradien-3-one oxime

700 mg of 17? (3-acetoxy-18-methyl-17? -Propiri-1-yl-4,15-estradien-3-one in 30 ml of methyl alcohol and 1 ml of water was reacted analogously to Example 13 600 mg of hydroxylamine hydrochloride and 700 mg of sodium bicarbonate After 1 hour, the reaction mixture was worked up in analogy to Example 13. The crude product was chromatographed on silica gel with acetone / hexane to give 240 mg of 17.beta.-acetoxy-18-methyl-. 17a-propyn-1-yl-4,15-estradien-3-onoxime as an oily substance UV (methanol): ε240 = 20,600.

Claims (1)

OBJECT OF THE INVENTION A process for the production of estradien derivatives of the general formula I, wherein R ¹ represents a hydrogen atom or an acyl group having 2 to 11 carbon atoms, R ^{2 a} chloroethyl or propynyl group, X an oxygen atom or a moiety H У он or NOR ³ , where R ³ represents a hydrogen atom, an acyl group having 1 to 7 carbon atoms or a methyl group, characterized in that the 17-oxoestrene of the general formula II, wherein Y represents an oxo group protected preferably in the form of a ketal and one of the bonds in the 4,5-, 5,6- or position; 5,10- represents a carbon-carbon double bond and other carbon-carbon single bonds, chloroethynylated or propynylated, the initially introduced protecting group is cleaved and, as desired for R ¹ and X in the resulting product of formula I, optionally a 17-hydroxy group before or after cleavage of the ketal group, it is esterified and / or the 3-keto group is reduced or reacted with a hydroxylamine salt in the presence of a base to form a 3-oxime which is optionally esterified or etherified.