DE1134985B - Process for the production of precursors for OEstrons - Google Patents

Description

GERMAN

PATENT OFFICE

J18198 IVb / 12 ο

REGISTRATION DATE: MAY 25, 1960

NOTICE THE REGISTRATION ANDOUTPUTE EDITORIAL: AUGUST 23, 1962

The oestrone molecule has four asymmetric centers. For developing a practically usable Synthesis of this female sex hormone is essential to the steric configuration of one to strive for and realize each of these centers stereospecifically in such a way that from the total possible Number of 8 racemates that are possible for this molecule, only the desired isomer is obtained.

In the following description and in the claims, the characters I, II, etc. are associated with the Figures of the drawing used characters of the same kind identical. The characters A, B etc. refer to the process schemes shown in the drawings.

Johnson et al. (W. S. Johnson and R. G. Christiansen, J. Amer. Chem. Soc, Vol. 73, 1951, p. 5511; W. S. Johnson, R. C. Christiansen and R. E. Ireland, ibid., Vol. 79, 1957, p. 1995) the keto diester of formula XVII stereoselectively into the estrone. In making the mentioned Ketodiesters by Johnson and coworkers (see above) as well as by Turner (D. L. Turner, J. Amer. Chem. Soc, Vol. 73, 1951, p. 3017; ibid., Vol. 73, 1951, p. 1284), however, the formation of other isomers in the step of reducing a double bond linked to the aromatic nucleus and in the stage of methylation of the / 3-ketoester are not avoided, so that the mentioned ß-ketoester of the formula XVII was obtained in relatively low yield.

By the present invention and by the new reactions to be used according to the invention and multi-stage process it was made possible to use the mentioned /? - keto diester of the formula XVII to produce in such a way that all stages are stereospecifically geared to the desired end product as the only isomer to be obtained excluding all other isomers. This creates total synthesis of oestrone in a much more advantageous manner.

It is an object of the present invention to produce the methyl ester of lp-anisyl-4-carbomethoxy-4-methyl-3-ketocyclohexyl- (2) -acetic acid (XVII) in the form of the desired isomer, the isomer produced having the correct configuration which is necessary for the synthesis of estrone. In order to produce the noted isomer, a number of new compounds were made. In particular, the following are used as starting products:
1. that ^ -dimethylamino-p-methoxypropiophenone hydrochloride (corresponding to the general formula XV);

Method of manufacture
of estrone precursors

Applicant:

Indian Institute of Science,
Bangalore (India)

Representative: Dr.-Ing. Dr. jur. F. Redies, patent attorney, Opladen, Rennbaumstr. 27

Claimed priority:
Great Britain April 6, 1960 (No. 12 203)

DiHp Kumar Banerjee
and Kadlebal Matada Sivanandaiah,

Bangalore (India),
have been named as inventors

2. the following compounds of the general formula XVI:

a) j8-ketoadipic acid diethyl ester,

b) (S-ketoadipic acid methyl ethyl ester,

c) ß-ketoadipic acid dimethyl ester,

d) «-Methyl-jS-ketoadipic acid diethyl ester,

e) methyl ethyl a-methyl-ß-ketoadipate,

f) a-methyl-ß-ketoadipic acid dimethyl ester.

The / J-ketoadipic acid dimethyl ester is in a obtained extremely poor yield if one works by the usual procedures for the Synthesis of other jö-ketoadipic acid esters are available. However, the product can be excellent Yield can be obtained if the ιβ-Ketoadipinsäuremethyläthylester, which according to the conventional processes can be produced, transesterified.

The first stages of the process according to the invention consist in that a salt of the ^ -dialkylaminop-methoxypropiophenones preferably the hydrochloride of ^ -dimethylamino-p-methoxypropiophenone, with a ß-ketoadipic acid dialkyl ester, which is in the «position can be substituted by an alkyl group, preferably a methyl group, condensed and the condensation product is cyclized.

209 637/433

R. C ₂ ed R ₂ a) - H - C ₂ H ₅ -C ₂ H ₅ b) - H -CH ₃ -CH ₃ c) - H -C ₂ H ₅ -CH ₃ d) -CH ₃ - C ₂ H ₅ C ₂ ed e) -CH ₃ -CH ₃ -CH ₃ f) -CH ₃ -CH ₃

3 4

The condensation stage will begin in the drawing of the compound of formula III, indicated by arrow A , obtained. There will be a connection.

of the general formula XV with a compound of This series of reactions is shown in the drawing

general formula XVI shown to compounds of the general by the reaction scheme C-1. ₁ The common formula XIV condenses. The condensation 5 lp-anisyl-3-ketocyclohexen- (l) -yl- (2) -acetic acid (III) is esterified by reacting the starting components in the presence of sodium or potassium alcoholates and then forming their methyl ester (V) of the methyl ester of 1-p-ani- and dimethyl sulfate carried out. R, R ₁ and R ₂ in the syl-4-hydroxymethylene-3-ketocyclohexen- (1) -yl- (2) compound of the general formula XIV can be formylated in acetic acid (VI). The method which is selected for the various ways to be substituted as follows: io formylation is that the

Compound of formula V with methyl or ethyl formate treated using petroleum ether, ether or benzene as a solvent and in the presence a sodium or potassium alcoholate is worked 15.

The methyl ester of l-p-anisyl-4-hydroxymethylene-3-ketocyclohexen- (l) -yl- (2) -acetic acid On treatment with hydroxylamine hydrochloride in acetic acid, (VI) is converted into the methyl ester of 6-p-anisyl-4,5-dihydrobenz-20 (2, l-d) -isoxazole-7-acetic acid (XIII) transferred to the

Instead of the methyl and ethyl group, in turn by treatment with a sodium or the compounds of general formula XIV also include potassium alcoholate and a methyl halide other alkyl radicals. Methyl ester of the l-p-anisyl ^ -cyan ^ -mnethyl-S-keto-

By cyclization of the compound of the general cyclohexen- (l) -yl- (2) -acetic acid (VIII) gives the under Formula XIV (a, b or c) becomes a compound of the formation of the l-p-anisyl ^ -cyan ^ methyl-a-keto-cyclo-formula III obtained, which are partially saponified as l-p-anisyl-3-ketocyclohexen- (l) -yl- (2) -acetic acid (X) hexen- (l) -yl- (2) -acetic acid can be designated. can. This product results after reduction with lithium According to a preferred type of cyclization and anhydrous liquid ammonia and the Compounds of the general formula XIV (a, b final treatment with methanolic hydrochloric acid or c) treated with alcoholic or aqueous alkali 30 the methyl ester of l-p-anisyl-4-carbomethoxy, where: 4-methyl-3-ketocyclohexyl- (2) -acetic acid (XVII), the

1. A keto cleavage of the ^ -Ketoestergruppe, whereby the starting product for the synthesis of the estrone is removed by the group —COOR ₁ ; represents.

2. saponification of the -GOOR _{2 group} to COOH; ^{According to} process scheme E ₂ - / ₂ , a

3. the usual aldol condensation, wherein the initial bond ³⁵ of the general formula IV, wherein R occurs followed by water, is whereby the unsaturated hydrogen, obtained when lp-anisyl-3-ketocyclische keto acid of formula III is produced. cyclohexen- (l) -yl- (2) -acetic acid (III) with lithium and

anhydrous, liquid ammonia is reduced.

However, if a compound of the general formula forms lp-anisyl-3-ketocyclohexyl- (2) -acetic acid (IV, formula XIV (a, b or c) with sodium methylate at 4 ° R = H) when treated with diazomethane or methanol If a compound of methanol / sulfuric acid is esterified, the general formula is obtained, in which R stands for water-speaking ester, ie the methyl ester of the 1-p-anisylic substance and R ₁ stands for methyl. When a compound is 3-ketocyclohexyl- (2) -acetic acid (IV, R = H). The Verder general formula XIV (d, e or f) in the same bond of the general formula IVa (R = H) can be treated, in turn a compound 45 is obtained by catalytic reduction of the compound V and the general formula II in the now but R subsequent treatment with methanolic Kali- and R ₁ each stand for a methyl group. Can be obtained in a similar caustic solution. If the compound is treated the all way, if a compound of the general formula IV (R = CH ₃ ) is subjected to a formylation of formula XIV (a or b) with sodium ethylate as described above, the methyl becomes a compound of the general formula II 5 <j ester of lp-anisyl ^ -hydroxymetnylen-S-ketocyclo formed, in which R stands for methyl and R ₁ for ethyl. hexyl (2) acetic acid (VII) formed; this compound. The compounds of the general formulas II and III, when treated with hydroxylamine hydrochloride, are used for two series of reactions. in acetic acid the methyl ester of 6-p-anisyl-4,5,6, the series beginning with compound II leads to 7-tetrahydrobenz- (2, 1d) -isoxazole-7-acetic acid (XII). to the compound of the formula XVIII, which is a 1,2-de-55 If the compound of the formula XII is the action of the hydrocompound of the end product of this invention of a sodium or potassium alcoholate and a meder of formula XVII. After being subjected to customary hydric thylhalides, the merging methods are formed, e.g. B. by catalytic hydrogenation, thyl ester of the lp-AnisyM-cyano ^ -methyl-S-ketocyclo can easily be converted into the saturated compound corresponding to hexyl- (2) -acetic acid (IX), which can be converted with partial saponification according to the formula XVII. The 60 the lp-anisyl-4-cyano-4-methyl-3-ketocyclohexyl (2) series, which begins with the compound of formula III, forms acetic acid (XI). The methyl ester of 1-p-anisyl leads to the formation of the desired end product of 4-cyano-4-methyl-3-ketocyclohexyl- (2) -acetic acid gives formula XVII. under the influence of methanolic chlorinated water

In the following, the series of reactions is first of all the end product, i. H. the methyl ester of the 1-p treated, with the compound of formula III, 65 anisyl ^ -carbomethoxy ^ -methyl-S-ketocyclohexyld. h, the l-p-anisyl-3-ketocyclohexen- (l) -yl- (2) '- acetic- (2) - acetic acid. The l-p-anisyl ^ -cyan ^ -methyl-S-keto acid kick off. The end product of the formula XVII cyclohexyl (2) acetic acid gives under the influence of can after each of the two reaction sequences, which with methanolic hydrogen chloride also the final

5 6

product, i.e. the methyl ester of l-p-anisyl-4-carbo- To a solution of 2.32 g sodium (= 0.101 g-

methoxy-4-methyl-3-ketocyclohexyl- (2) -acetic acid atom) in 120 g of absolute methanol were 20.2 g

(XVII). / 3-Ketoadipic acid methyl ethyl ester (0.1 mol) was added.

The second series of reactions concerns the formation The mixture was left at room temperature for 5 hours of the methyl ester of l-p-anisyl-4-carbethoxy-4-me-5 left to stand. Then there was enough acetic acid ethyl-3-ketocyclohexen- (1) -yl- (2) -acetic acid (XVIII). added to neutralize the sodium methylate.

This compound is based on the compound Most of the methanol was on the water

of the general formula II obtained when distilled off under reduced pressure in their bath. Of the

_a NR = H ^- R = CH residue was in a mixture of ether and

,. _R _ p ' ² _R _ ² p ^S Tj ¹⁰ benzene added and treated with 5% sodium

b) K - LH ₃ ; K ₁ - C ₂ H ₅ bicarbonate solution and then washed with water.

stands. If the compound II a) with diazomethane After removal of the solvent, the esterified and the esterification product with sodium, residue was distilled at 125 to 126 ° C / 4mm Hg. The sodium or potassium alcoholates or sodium hydride yield was 167 g (89%) and if methyl halides are methylated, the formula (XVIII) can be obtained in a corresponding manner. This connects / 3 ketoadipinsäuredimethylester, bp. 136 ° C in ₃ dung will ^he be produced yield strength by esterification of the compound of 83%.

general formula Hb formed with diazomethane. "_ ,, ..

By cyclization, the encryption _J "^ ₁ is preferred. Cyclization of the compound bond of the formula III obtained. The conversion of ^the general formula XIV (compound a, b or c) of this compound into the desired end product ^{with wal3n} S ^{em Alkah}

Formula XVII can be summarized as follows: To a solution of 10% aqueous potassium

that in the 4-position of the cyclohexene ring a hydroxide (11.5 g of potassium hydroxide in 104 ml of water) Methyl and a carboxyl group are introduced, which are in 15.5 g of the compound of general requirements Molecule containing carboxyl groups are given in their 25 mel XIV (compound a, b or c). The Ge methyl ester are transferred and the cyclohexene mixture is 4 hours under nitrogen and reflux ring is reduced to the cyclohexane ring, which is heated. The homogeneous solution obtained is cooled Reduction to the beginning or to the end of and extracted once with ether. The aqueous layer Reaction sequence can be made. is acidified with ice-cold dilute hydrochloric acid,

The following examples explain the invention: 30 whereupon a brownish, resin-like body precipitates,

which becomes firm when standing. The yield of the examples compound of the formula III is 9.65 g. (About 90%, A. Condensation of the compound of the general calculated on the compound of the general For-Formula XV with the compound of the general ^me * ^XV "i ^The conversion from dilute formula XVI (compounds a, b or c): ³⁵ ethanol or a Mixture of benzene and petroleum ^{v 6} ' ether (bp. 40 to 60 C) gives white needles with the addition of a solution of sodium ethylate, which dimorphs from 4 g melting point 136 or 146 ° C (the compound is sodium and 104 ml of absolute ethanol ).

has been, 38.5 g of the compound of all- "",. . ,. ,,, . ,

common formula XVI (compound a, b or c) and 40. ., ^B * cyclization of the compound then 20 g of the compound of ^the general formula XIV (compound a, b or c) of formula XV are added. To the one with an ice cream with sodium methylate

Saline mixture cooled mixture are added to a solution of sodium methylate, which is made from

Stirring 16 ml of dimethyl sulfate via a dropping funnel, 1.25 g of sodium and 60 ml of absolute methanol were added in 45 minutes. After the addition 45 has been formed, 15.5 g of the compound is complete, the mixture is stirred for 2 hours and general formula XIV (compound a, b or c) then left to stand overnight at room temperature. given. The mixture is left under a stick overnight. Most of the alcohol is left to stand under reduced pressure. After acidification, distilled off with ice pressure, 100 ml of water are added, most of the alcohol is vinegar and the oily liquid which precipitates is removed with a 5 ° water bath under reduced pressure. Water extracted from mixture of ether and benzene. The (100 ml) is added and the mixture is removed with a solvent and the residue is extracted from an ether-benzene mixture. The organic distilled 120 to 125 ° C / 1mmHg, approximately layer is washed once with water and then 17.5 g of unchanged compound of the general are extracted repeatedly with saturated sodium bicarbonate solution formula XVI (compound a, b or c) 55 extracted. The entire bicarbonate layer will become one time. The remaining orange colored cone is extracted with ether and then acidified with ice-cold digestion product of the general formula XIV (dilute hydrochloric acid. A yellow, solid bond a, b or c) is a thick liquid and forms immediately. The yield at the weighed 31 g. Yields 79 to 84%, based on the bond of the general formula II (R = H, R _x = CH ₃ ) of the recovered compound of the formula XVI. 60 is 10 g (about 76%, calculated on the hydro

In the same way, the following compounds of the chloride of the compound of the general formula XIV). general formula XIV (d, e and f) produced: After recrystallization from ethyl acetate, R = CH ₃ , R ₁ and R ₂ = C ₂ H ₅ ; Around R ₂ = CH ₃ , white crystals with a melting point of 184 ^° C. are obtained. R ₁ = C ₂ H ₅ ; R, R ₁ and R ₂ = CH ₃ , yields 74 to Compounds can be prepared in a corresponding manner

78 ° / ₀ , based on the recovered compound 65 of the general formula XIV (compound d, e or f) of the formula XVI. with the help of sodium methylate, which is obtained from 1.3 g

The starting materials can be prepared as follows: Sodium and 60 ml of absolute methanol become: has been, cyclize. The product was a resin.

7 8

After recrystallization from benzene petroleum ether (boiling point 40 siert, with white needles from melting point 93 ⁰ C to 60 ⁰ C) z. B. 7.2 g of the compound of the all- can be obtained. The yield is 13 g (95% of the general formula II (R and R ₁ = CH ₃ ) obtained; the theory).

Product forms white needles with melting point _ _f ,., ".., ■ ,,,, ·,, ^, _τττ

127 ° C. The yield is 61%, calculated on the 5th ^ '^ ff ^ ^ compound of the formula III hydrochloride of the compound of the general formula ^{m the} compound of the general formula IV (R == H) mel XIV (compound f; R, R ₁ and R ₂ = CH ₃ ). ^using lithium and ammonia

If you work in the same way with sodium In a 2-1 three-neck bottle, a solution of 3 g

ethylate in ethanol is obtained from a compound of the compound of the formula III in 30 ecm of dry ether of the general formula XIV (compound a or b) and 800 ml of dry, liquid ammonia introduced about 10 g of the compound of the general formula II. With thorough stirring (R = H, R ₁ = C ₂ H ₆ ); the yield is about 240 mg of lithium added. There is a 73%, calculated on the hydrochloride of the compound blue color persists for about 7 minutes, of the general formula XIV developed. The product can completely out after evaporation of the ammonia who-benzene-petroleum ether (bp. 40 to 6O ⁰ C ) recrystallized 15 to the residue added 100 ml of water; they will; it then falls into white needles with the aqueous solution being extracted once with ether. The melting point 106 ⁰ C at. Acidification of the aqueous layer with ice-cold

If a compound of the general thin hydrochloric acid is cyclized, a resinous substance is obtained, the formula XIV (compound d or e) with sodium solidifies on standing; Yield 2.5 g (82 ° / ₀₎ · After ethylate in ethanol, so (40 Kp. Up, a compound of general formula II 6O ⁰ C) obtained in a corresponding 20 recrystallization from benzene-petroleum ether are white crystals with the melting point (R = CH ₃ , R ₁ = C ₂ H ₈ ) as a resin. It is obtained at 111 ° C. Cleared ways of short-path distillation; it boils at ,,,,.,

150 to 160 ° C / 0.15 mm Hg; Yield 6.1 g (about ^D i preparation of compound IV (R = H)

43%, calculated on the hydrochloride of compound 25 ^by catalytic reduction of the compound of general formula XIV (compound d or e). ^the Formula V

The unsaturated keto acid of formula III can also be a solution of 300 mg of the compound of

by hydrolysis of the compound of formula II (compound a formula V in 10 ml of spectroscopically pure alcohol) with 10% aqueous potassium hydroxide solution is obtained catalytically over 100 mg of 10% palladium. 30 chloride reduced to carbon. After the absorption C. Production of the compound ^v ™ hydrogen has ceased, the catalyst of the general formula XVIII is ^{filtered off} from the compound ^ ^{and the} ^ ^k ° ^h _c ^{o1 is} evaporated. The residue of the general formula II (compound a) ? Ρ * & ²⁹ J ^ ^He f ™ around two hours with 4% methano

^{v J} lischer potassium hydroxide solution (0.12 g in 3.5 ml methanol) under

The compound of the formula Ha is esterified to boiling methane with diazo reflux in a nitrogen atmosphere. The ester is heated quantitatively. Most of the alcohol is obtained under consumption. A solution of 1.56 g of this ester is distilled off under reduced pressure; the residue is dissolved in 5 ml of dry benzene in a suspension in water; the aqueous solution is extracted once with 125 mg of sodium hydride in 20 ml of dry benzene ether and then added dropwise with ice-cold, dilute solution. The mixture is acidified in hydrochloric acid for 4 hours. The resulting, resinous, solid water bath is heated under reflux, the sodium body being taken up in ether and the hydride solution being completely removed with the formation of a pale red medium. The residue is converted from benzene-Pe solution. The solution is cooled, 4 ml Me- troläther (Kp. 40 to 6O ⁰ C) recrystallized to yield thyljodid are added and the mixture is the ERAL room temperature allowed to stand for 2 hours at 180 mg = 63% angesättigter keto acid. After 45 NEN formula IV (R = H) with the melting point Hl ⁰ C. 2 hours of refluxing, 2 ml of "_,. ■ ,,,, ■ _ ■

Methyl iodide added, and heating with re- _A J * · Formation of the compound

flow is carried out for a further 2 hours. To that ^{of the formula V} ^ r overall compound of formula VI

ice-cold water is added to the cooled product and the mixture is added to a cooled suspension of sodium methylate

Mixture shaken well. The benzene layer is removed (made from 300 mg sodium and 415 mg methanol) separated and the aqueous layer once with ether in 25 ml of dry, thiophene-free benzene extracted. The entire organic layer is added once to 2.5 ml of dry ethyl formate; the air in washed with water, then the solvent from the apparatus used is removed by nitrogen. The product is purified by distillation. puts. After 30 minutes, 1.6 g of the compound The boiling point is 135 to 140 ° C / 0.006 mm Hg; 55 of the formula V in 5 ml of dry benzene slowly the yield is 1.44 g (89%) added dropwise with thorough stirring. Stirring is 2 hours

" _F · ,, _f .., j ,,,. , _"TTT. ,. continued; then the reaction mixture is at

C ₁ . Transfer of the compound of the formula III at _{room temperature left to stand overnight} .

A mixture of 13 g of l-p-anisyl-3-keto-cyclo- The reaction vessel is cooled (ice and water),

hexen- (l) -yl- (2) -acetic acid (III), 50 ml of absolute Me-60 ice water were added and the vessel was vigorously ethanol and 2.5 ml of concentrated sulfuric acid is shaken. The aqueous layer is separated; the Heated to boiling under the reflux condenser for hours, repeated organic layer with 2%, ice-cold cooled and poured into 480 ml of ice water. The reacted sodium hydroxide solution extracted until no formyl derivative The product is extracted with ether-benzene and more is dissolved in it, the entire aqueous layer once the organic layer with dilute sodium bicarbonate 65 extracted with ether and then diluted with ice cold natlösung and then washed with water. Acidified by hydrochloric acid. The precipitating yellow resinous Removal of the solvent, the residue product was taken up in ether-benzene, with from benzene-petroleum ether (bp 40 to 60 ° C) washed recrystallized ice-cold water and the solvent

removed. The yield of the formyl derivative of the formula VI is 1.7 g.

E ₂ . Methyl ester of lp-anisyl ^ -hydroxymethylene-S-ketocyclohexyl- (2) -acetic acid (VII)

Using sodium methylate (from 0.28 g of sodium and 0.385 g of methanol) suspended in 20 ml of dry benzene, 1.6 ml of dry ethyl formate and 1.42 g of the compound of the general formula IV (R = CH ₃ ) in 5 ml of dry benzene are obtained in the same way as in Example E ₁ 1.5 g of the hydroxymethylene derivative of the formula VII, corresponding to a yield of 96 ⁰ I ₀ , based on the amount of the compound of the formula IV (R = CH ₃ ) consumed.

F ₁ . Methyl ester of 6-p-anisyl-4,5-dihydrobenz- (2,1 -d) -isoxazolyl- (7) -acetic acid (XII)

A solution of 1.7 g of the crude hydroxymethylene derivative of the formula VI in 20 ml of glacial acetic acid is stirred for 8 hours at 70 to 80 ° C. with 800 mg of dry, powdered hydroxylamine hydrochloride. Most of the acetic acid is removed under reduced pressure on the water bath; the residue is diluted with water and extracted with ether-benzene. The organic layer is then washed with 5 ° / _o sodium bicarbonate with water. After removing the solvent, a resinous substance is obtained, which is distilled. The boiling point is 145 to 150 ° C / 0.005 mm Hg; the yield is 650 mg = 37%> calculated on the compound of the formula VI. Recrystallization from dilute methanol gives pale yellow plates of the compound of the formula XII, melting point 77 to 79 ° C.

35 F ₂ . Methyl ester of 6-p-anisyl-4,5,6,7-

tetrahydrobenz- (2,1 -d) -isoxazolyl- (7) -acetic acid (XIII)

A solution of 1.5 g of the hydroxymethylene derivative of the formula VII in 30 ml of glacial acetic acid is mixed with 350 mg of dry hydroxylamine hydrochloride and quickly heated to the boil in an oil bath kept at 170 ° C. (about 3 minutes). It is refluxed for 10 minutes at this temperature, cooled and diluted with 150 ml of water. The resinous substance formed is taken up in ether-benzene, and then washed with 5 ° / _o sodium bicarbonate with water. After removing the solvent and distilling the residue at 145 to 150 ° C / 0.006 mm Hg, 975 mg of the isoxazole of the formula XIII are obtained. The yield is 63%> calculated on compound IV, R = CH ₃ .

G ₁ . Methyl ester of lp-anisyl-4-cyano-4-methyl-3-ketocyclohexen ~ (l) -yl- (2) -acetic acid (VIII)

A solution of 550 mg of the isoxazole of the formula XII in 5 ml of dry tertiary butanol turns into tertiary potassium butylate (made from 220 mg of potassium and 6 ml of dry tertiary butanol); the mixture is refluxed for 15 minutes Boiled heated and then cooled; 3 ml of methyl iodide are added and the mixture is at room temperature Let stand for 1 hour with frequent shaking. Fresh methyl iodide (2 ml) is added and the mixture was refluxed for 4 hours. The alcohol is removed under reduced pressure; 6g the residue is washed with water and ether — benzene treated. The organic layer is washed with water and the solvent is removed. The product of formula VIII is purified by distillation; the boiling point is 130 to 135 ° C / 0.005 mm Hg; Yield 525 mg = 91%.

G ₂ . Methyl ester of lp-AnisyM-cyano ^ -methyl-S-ketocyclohexyl- (2) -acetic acid (IX)

The preparation of the compound of the formula IX is carried out in the same way as the preparation of the compound of the formula VIII, but using 550 mg of the isoxazole of the formula XIII. That Product is recrystallized from benzene - petroleum ether. The yield is 432 mg of the compound of the formula IX = 75%. The product forms white needles with a melting point of 112 and 122 ° C (das Product is dimorphic).

H ₁ . lp-AnisyM-cyano ^ -methyl-3-ketocyclohexen- (l) -yl- (2) -acetic acid (X)

A solution of 1 g of potassium bicarbonate in 3 ml of water is added to a solution of 525 mg of the compound of the formula VIII in 15 ml of methanol. The mixture is refluxed for 2 hours; then it is evaporated in vacuo and treated with water. The aqueous layer is extracted once with ether and then acidified with ice-cold dilute hydrochloric acid to give a resinous product which is taken up in ether. After removal of the solvent, the residue from benzene-petroleum ether is recrystallized (40 to 6O ⁰ C). The yield is 350 mg (7O ° / o) of the unsaturated Cyanoketosäure of formula X, mp 126 ⁰ C.

H ₂ . lp-anisyl-4-cyano-4-methyl-3-ketocyclohexyl- (2) -acetic acid (XI)

A solution of 400 mg of the compound of the formula IX in 12 ml of methanol is refluxed for 2 hours with a solution of 0.8 g of potassium bicarbonate in 2.5 ml of water. The reaction mixture is worked up as described for the compound of the formula X. After recrystallization from benzene-petroleum ether (40 to 6O ⁰ C) white needles of the compound of formula XI, melting point 145 ° C are obtained. The yield is 288 mg = 75%.

I ₁ . Methyl ester of lp-anisyl-4-carbomethoxy-4-methyl-3-ketocyclohexyl- (2) -acetic acid (XVII)

300 mg of the unsaturated cyanoketo acid of the formula X are dissolved in 10 ml of dry ether in a three-necked bottle. Then 200 ml of dry liquid ammonia are introduced with stirring; 21 mg of lithium are added, whereupon a blue color appears, which disappears after about 1 minute. After the ammonia has evaporated, the residue is dissolved in ice-cold water and the solution is extracted once with ether. The aqueous layer is acidified and the resulting resin-like product is extracted with ether-benzene. The solvent is removed and the residue (270 mg) is dissolved in 6 ecm of absolute methanol. The solution is saturated with dry hydrogen chloride at 0 ° C and allowed to stand for 3 days at O ⁰ C. It is then poured into 100 ml of ice-cold water and extracted with ether-benzene. The organic layer is washed with 5% sodium bicarbonate solution and then with water. The solvent is removed and the residue is chromatographed over Brockmann aluminum oxide. After eluting with benzene petroleum ether (1: 1), the crystalline diester of the formula XVII is

209 637/433

keep; Yield 120 mg = 34%. After recrystallization from petroleum ether (bp. 60 to 8O ⁰ C) White needles are obtained with a melting point of 93 ⁰ C.

I ₂ . Methyl ester of lp-AnisyM-carbomethoxy ^ - "methyl-3-ketocyclohexyl- (2) -acetic acid (XVII)

A solution of 400 mg of the compound of formula IX in 8 cc of absolute methanol saturated with dry hydrogen chloride below 0 ° C and allowed to stand for 3 days at 0 ⁰ C. After dilution with ml of ice-cold water, the product is extracted with an ether-benzene mixture. The organic layer is washed with a sodium bicarbonate solution and then with water. After removal of the solvent, the residue from petroleum ether (bp. 40 to 6O ⁰ C) recrystallized. The yield is 353 mg = 12 ⁰ I _{0 of} the compound of the formula XVII. The melting point is 93 ⁰ C.

The same experiment is carried out with the compound of the formula XI, the compound of the formula XVII is obtained in approximately the same yield.

Claims (3)

PATENT CLAIMS: 1. A process for the preparation of precursors of estrone, characterized in that a salt of a jft-dialkylamino-p-methoxypropiophenone with a / 3-ketoadipic acid dialkyl ester, which can be substituted in the α-position by an alkyl group, in the presence of sodium or potassium alcoholates and dimethyl sulfate condensed, the condensation product cyclized by known methods in the presence of alcoholic or aqueous alkali or a sodium alcoholate, the resulting cyclized compounds, if desired, subjecting the cyclohexene ring to a partial reduction of the cyclohexene ring to the cyclohexane ring in the presence of lithium in anhydrous liquid ammonia or by conventional methods converted into the corresponding methyl esters by reaction with diazomethane or methanol-sulfuric acid or hydrolyzed with aqueous potassium hydroxide solution or methylated with methyl halides in the presence of sodium, sodium or potassium alcoholates or sodium hydride, the resulting methyl ester of lp-an isyl-3-ketocyclohexen- (l) -yi- (2> acetic acid, if desired, catalytically reduced, the hydrogenation product optionally treated with aqueous or alcoholic alkali, the resulting lp-anisyl-3-ketocyclohexyl (2) acetic acid or its methyl ester or its 1,2-dehydro compound is formylated with an alkyl formate in the presence of a sodium or potassium alcoholate using ether, petroleum ether or benzene as a solvent, the 4-hydroxymethylene compounds obtained are converted into the corresponding isoxazole compounds by treatment with hydroxylamine hydrochloride in acetic acid, and these are converted with the aid of sodium or potassium alcoholates and a methyl halide are converted into the corresponding 4-methyl-4-cyano compounds, these are partially saponified by heating with methanolic potassium carbonate solution, the resulting lp-anisyl-4-cyano-4-methyl-3-ketocyclohexen- (l) -yl- (2) -acetic acid, if desired, reduced with lithium in anhydrous liquid ammonia and the 1 - ρ - aniseed obtained yl-4-cyano-4-methyl-3-ketocyclohexyl- (2) - or -cyclohexen- (1) -yl- (2) -acetic acid treated with methanolic hydrogen chloride. 2. The method according to claim 1, characterized in that the starting product is the dimethyl ester the / S-ketoadipic acid or the «-methyl- / 3-ketoadipic acid is used. 3. The method according to claim 1 and 2, characterized in that the starting material is the dimethyl ester the a-methyl-ß-ketoadipic acid and (8-ketoadipic acid are used by transesterification obtained the methyl ethyl ester with sodium methylate in methanol and methyl halides became. 1 sheet of drawings © 209 637/433 p.