DE2110428A1 - New 1,2-diphenyl ethane derivatives and processes for their preparation - Google Patents

Description

Patent attorneys Dipl.-Ing. R We ick ΐνί λ. ν ν,

Dipl.-Ing. H. We ι ckma ν ν, Dipl-Phys.

Dipl.-In'g. R A.W'eιcKiviANN, Dipl.-Ckem. B. Huber

8 MUNICH 86, DEN

PO Box 860 820

MOHLSTRASSE 22, RUFNUAiMER 48 35 21/22

CASE ITo .: F.2376 / P.

BIOREX LABORATORBjS Li ¹ D,,
Beer ex House, Canonbury Villas, London ^1,. IT, 1 /

¹¹ Hot 1,2-Diph.enyläthanderivate and processes for their production "

The present invention relates to new and valuable
1,2-Diphenylethane derivatives which have excellent chemical properties and can be used as contraceptives, and the present invention also relates to the preparation of these new 1,2-diphenylethane derivatives.

The new inventive 1 _f 2-Diphenyläthanderivate are compounds of the general formula:

1 09841/1937

BATH ORIGINAL

_ 2 -

CH - - CH ι ι R ₁ R ₂

O - R

(D

wherein R is a hydrogen atom or an alkyl radical with up% o 6 carbon ens t of fat OD en or a benzyl radical "R, and R p, which may be the same or different, staking antiradical up zxx represents 6 carbon atoms, provided that R . and Rp do not mean methyl or ethyl radicals at the same time, and X means a halogen atom.

If R represents an alkyl radical, it is preferably a methyl radical, but aB can also be an ethyl, n-propyl, isopropyl, η-butyl, tert-butyl, n-pentyl or n-IIexvl radical if R ₁ and Rp are alkyl groups having 3 to 6 carbon atoms, they can be Z ₅ B-. be n-propyl, isopropyl, η-butyl, n-pentyl or n-hexyl.

A preferred group of compounds according to the invention has the following general formula:

X «

■ R ' X ¹ y ι CF I. \ CH ₃ χ '\ Λ C ₂ H ₅

(la)

where R ^{1 is} a hydrogen atom or a methyl, ethyl or benzyl radical and X ^! mean a chlorine or ITuoraton.

1098A1 / 1S37

The new compounds of the invention can be prepared be made by taking an ether of the general formula:

(II)

v / orin R "denotes an alkyl radical with up to 6 carbon atoms and X has the same meaning as indicated above, with a haloketone of the general formula:

Shark - CH - C = 0 (III)

I t

wherein R ^ and Rp have the same meanings as given above have and Hal means a halogen atom, preferably a chlorine atom, converts, so that one is an unsaturated diether the general formula:

X
R "-

receives, wherein R ", R ₁ , Rp and X have the meanings given above j which is then hydrogenated _y to the corresponding

109841/1937

2110423

the saturated diether o the general formula:

CH - ClL

Y / Wn .. p ..

wherein E ", R .., R" and X have the meanings given above, to surrender, and if desired «this connection dealkylated in order to obtain the corresponding hydroxylation to obtain.

According to another flerrjiollungsv / ciBe an ether becomes the general formula (II) with a secondary alcohol of the general formula:

Hal -, CH - CHOH (VI)

ι ι

R, R

implemented, in which Hal. R ₁ and Rp have the meanings given above, σο that a 3) ether of the general formula:

R "

1 0984 1/1937

2110423 5 -

obtained in which R " _5, R ₁ , Rg and X have the meanings given above and this compound can then, if desired, be dealkylated in order to obtain the corresponding bihydroxy compound.

The advantage of this process is that it is unnecessary to carry out the hydrogenation step *

A particularly elegant process for the preparation of the new compounds of the general formula (I) according to the invention, ' in which X denotes a chlorine or bromine atom, consists in that an ether of the general formula:

(VIII)

where R "has the same meaning as above, used for one of the two manufacturing processes described above, so that you get a compound of the general formula:

(ix)

obtained, in which R ", R ₁ , and Rp have the meanings given above, this compound is reacted with bromine in a suitable inert, anhydrous solvent to give the desired compound of the general formula (I) in which X is bromine and R" Mean alkyl radical, or reacted with chlorine or sulfuryl chloride to form the desired compound of the general

1 0 9 B A 1/1 9 3 7

my formula (i) to receive, in which X is chlorine and R ^l! mean an alkyl radical.

If desired, the halogenated product can then be acyliort will. Alternatively, if desired, the 4 * 4 'dihydric tube connection is used to get can connect the general Formula (IX) dealkylated before chlorination or bromination vfer d en.

For the preparation of the new compound of the general S ¹ Or ^ oI (i), in which R- and Rp mean the same alkyl radicals containing 3 to 6 carbon atoms, it is also possible to assume an ether of the general formula (II) , made with an acid halide of the general formula:

R ₅ -CO- EaI (X)

where Hai has the same meaning as above and R _{7 is} an alkyl radical having 3 to 6 carbon atoms; uir ^ eseist so that a ketone of the general formula:

_ o - (/ ^N ) -C0 - R ₃ (XI)

obtained, in which R ", R, and X have the meanings given above possess that to the corresponding secondary alcohol of the general formula:

1098-41 / 1937

(XII)

reduced v. ^r ill, wherein R ', R, and X have the above meanings 3.ngegebenen, is then halogenated such alcohol. " ir, a is the corresponding halide of the general formula:

-CH - IU (XIII)

ι ·>

Shark

to give, in which R ", R- ,, Hai and X the Be given above have interpretations, one has the latter connection with MagneGiu converts in a known manner to the corresponding Grignard compound of the general-Poriael:

_y Hg · Hal
^ R ₃ (XIV)

su obtained, in which R ", R", Hal and X have the meanings given above own, which reacts in statu nascendi with unreacted .halide (XIII), one the reactions ic chung then in a known manner on a connection of the general Porinel (I) worked up, where R. and R "are the same

1 Π ': C i 1 · ■ ·' · £ 7

Alkyl radicals containing 3 to 6 carbon atoms and what you see green if the product is dealkylated can to form the corresponding dihydroxy compound su »

The condensation of the compounds (II) and (Hl) takes place in a delayed manner: in the presence of concentrated seliulfuric acid or anhydrous alurainium chloride at reduced temperature, e.g. at a temperature of -25 ° C to ⁰ ° C, whereas the condensation of the compounds (IJ.) and (Vl) preferably in the presence of anhydrous aluminum chloride at room temperature or at a slightly elevated temperature, such as at a temperature of up to about 40 ⁰ G is performed.

The hydrogenation of the unsaturated diether (IV) is preferred catalytic, in glacial acetic acid in the presence of a palladium or platinum catalyst carried out.

Examples of solvents which can be used for the chlorination or bromination of the compounds (17L) are: glacial acetic acid or anhydrous halogenated crude hydrogens such as methylene chloride or chloroform.

The additional dealkylation of the products obtained can, for example, be caused by the action of hydrobromic acid in Acetic acid.

In some cases, it is seen Wanting sw O2? T, a 4 _f 4 ^J dihydroFK xyverbindung, obtained by the syntheses described above, to convert them into the corresponding diether. This can easily be carried out by reacting the 4 _t 4 '-Dihydroxyverbindung ax a suitable Alley! Halide "in the presence of an alkali metal hydroxide, preferably Katriumhydroxyd, uiasetzt. This etherification v / ith geeigneterv ^ else in an inert solvent, preferably the Alky dera used Halide correspond to alcohol.

1 0 9 PU 1/1 9 3 7

It has been found that some of the 4,4'-hydroxy compounds of the invention are difficult to purify by crystallization. This problem can easily be solved by etherification in the manner described above using an enzyl halide, eg benzyl chloride instead of an alkyl halide yellow. The dibenzyl ethers thus obtained can easily be recrystallized. In addition, the dibenzyl ethers purified in this way can, if desired, then easily be returned to the corresponding Diliydro.xyverbindungen by hydrogenolysis, for example by dissolving the dibenzyl ether in glacial acetic acid and shaking the solution with hydrogen in the presence of a suitable catalyst, such as

Palladium on activated carbon or platinum on activated carbon.

The following examples are intended to explain the present invention further without, however, restricting it «

example

A mixture of 10og redistilled 2-fluoroanisole and 50 g of 3 ~ chloro pentan-2-one (boiling point 134 to 137 ⁰ C) was cooled to -20 C and with stirring was added in the course of 2 hours, added dropwise 125 ml of concentrated sulfuric acid are added. After stirring the reaction mixture further for 6 hours, it was poured into ice water. The mixture was then extracted with diethyl ether, the ether extract was dried and the ether distilled off and the oily residue after 2 hours at 235 to 24O ⁰ C at a pressure of 15 mm Hg was heated and the distillate was discarded. The residue was then distilled at 160 to 1'7O ⁰ C / 0.03 mm Hg to give a main fraction of 20 g of an oil, dan could not be crystallized. This oil was then dissolved in 150 ml of egg soup; gcilöat and in one

1719 3 7

Hydrogen atmosphere in the presence of 1.2g palladium on activated charcoal ($ 10) shaken until the absorption of fuel has ended. The reaction mixture was then filtered and evaporated and one obtained v / a 20 g of a mixture of threo- and erythro-3 »3'-D ifluoro-4,4'-dimethoxy-a-ethyl-a ¹ - methyldibenzyl. After recrystallization of this KiD from methanol, the erythro compound was obtained, which had a melting point of 106 to 107.degree.

The corresponding an-propyl-a'-methyl-; nn ~ propyl-V-ethyl-j σ-n- propyl- cJ -n-hexyl-; and in-pentyl-rx ¹ ·· n-hoxyl compounds are prepared in an analogous manner.

example

(a) A solution of 7.5 g of erythro-3,3'-difluoro-4,4 ^f -dimethoxy-x-ethyl-a'-methyldibenzyl (see Example 1) in 70 ml of glacial acetic acid and 40 ml of hydrobromic acid was added Refluxed under a nitrogen atmosphere for 6.5 hours. After cooling, the reaction mixture was poured into ice and extracted with ether. The ether extracts were washed with water and extracted with 2N sodium hydroxide solution. The alkaline extract was acidified and extracted with ether. Evaporation of the ether extract gave 6 g of a yellowish solid, which was dissolved in benzene and passed through a column which contained 50 g of silica gel. Concentration of the eluate led to the deposition νοϊΐ ery thro-3, 3'-difluoro-4,4'-dihydroxy-ct-ethyl-α ¹ -iaethyldibenzyl, which had a melting point 152-153 ⁰ C.

The corresponding an-propyl- λ ¹ -methyl-: an-Prop2 / l - <* '~ ethyl-; α-n ~ propyl- · ί · -n-hexyl and an-pontyl-i'-n compounds are prepared in an analogous manner.

1 O 9 8 U 1/1 9 3 7

* ■ ι ι * ■ *

(b) 73 ng of erythro-3,3 ^1- difluoro-4,4 ^l -dihydroxy-ci ~ ethyl - cL ^t methyldibenzyl were dissolved in a mixture of 0.5 ml of 1N aqueous sodium hydroxide solution and 5 ml of n ~ butanol and added a slight excess (0.6 ml) of n-butylbrown was added. The reaction mixture was heated on a boiling water bath for 3 hours and ds, nn cooled, after which Pe tr οlather (boiling point 60 to 8O ⁰ C) was added. Ph. Enol In this way, erythro-3,3'-difluoro-4,4 ^f -di-n-butoxy-o-ethylo ^ -methyldibensyl with a point of 61 to 62 ⁰ O was obtained.

Example 3

12.1 g of 3-chloropentan-2-one were mixed into a mixture with stirring of 28.5 g of o-chloroanisole and 26.7 g of anhydrous in Alurainiudchlorid given. The seaction mixture v / urde when the chloroketone was added red and thickened considerably, liach the stirring of the reaction mixture during For hours at room temperature, ether was added and the mixture was poured into ice water. The ether extract was used twice with water, three times with 5% aqueous sodium hydroxide solution and washed three times with water and then dried over anhydrous sodium sulfate, then. the separation of the Solvent gave 29 g of a pale brown oil.

This neutral oil was distilled under a water jet vacuum, us: to separate off the unchanged starting materials and that

109841/1937

resulting viscous oil was then distilled under a higher vacuum. This gave 9.4 g of a fraction which boils at 210 to 225 ° C./0.3 ram Hg.

This material, since it did not crystallize out, was dissolved in 100 ml of glacial acetic acid and then catalytically hydrogenated at room temperature in the presence of 1 $ palladium on activated carbon (10 ^ palladium). One mole of hydrogen was taken up over the course of 4 hours, after which there was no further hydrogen uptake. The catalyst was filtered off and the solution evaporated to give a yellow oil. This oil was treated with hot methanol and upon cooling gave 2.2 g of white crystals. These crystals were crystallized from methanol and 1.9 δ erythro-3,3'-dichloro-4,4'-dimethoxy-a-ethyl-a ¹ -methyläibenzyl in the form of white, shiny flakes with a melting point of 130 bis 132 ⁰ C. The material was, as thin-layer chromatography showed, pure,

Demethylated to these dimethyl ether in an analogous V / else to that described in Example 2, erythro-3 3 ¹ -Diehlor ^^ '- dihydroxy-a-ethyl-a'-methyldibenzyl having a melting point of 76-78 ⁰ C.

Example 4

(a) 461 g of concentrated sulfuric acid was added with stirring over 2 hours to a mixture of 348 g of anisole, and 165 g of 3-chloropentane-one 2-, the overall with the aid of a cooling bath of acetone and solid carbon dioxide at -20 ⁰ C. The resulting dark red viscous oil was kept at this temperature for a further 3 years

109841/1 937

Stirred for hours. Then ice water was added and stirring was continued until the stated color had faded. a white suspension was obtained. The product was extracted with ether and the organic extract was washed successively with water, 2N sodium hydroxide solution and water and then dried over anhydrous sodium sulfate. The solvent was evaporated to give an oil which, after separating off excess hydrogen chloride, at 200 Was distilled up to 250 ⁰ C under water jet vacuum in high vacuum, so that a mixture of 220 g of ice and trans-4 »4'-di- ' gi methoxy-a-ethyl-a'-methylstilbene with a boiling point of 151 was obtained up to 154 ° C / 0.2 mm Hg. "

The oil crystallized on standing and was dissolved in hot methanol and allowed to stand. It divorced 113 g of a crystalline material, and recrystallization of this material from methanol gave 67 g of trans-4 "4 ^{l-dimethoxy-a-ethyl-d l} ~ methylstilbene in the form of white crystals having a melting point of 83-84 ⁰ C. A second batch of 12 g of crystals was obtained which was identical to those of the first batch.

The filtrate from the initial filtration was evaporated M to give 101 g of an almost colorless oil. This oil was a mixture which essentially consisted of cis-4,4 ¹ -dimethoxy-a-ethyl-a'-methylstilbene together with small amounts of other sweet-smelling components.

(b) 30 g of this cis-4,4'-dimethoxy-a-ethyl-cL'-methylstilbene were dissolved in acetic acid and stored at room temperature in the presence of 2.5 g palladium on activated carbon (10 $ palladium) hydrogenated. In about 1 hour, 1 mol of hydrogen was taken up and then the hydrogen uptake was complete.

109841/1937

A small amount of chloroform was added to the hydrogenation mixture to dissolve the large amount of crystals that separated. The catalyst was then filtered off and the piltrate was evaporated to give a pale yellow, semi-solid material. Then methanol / dichloroethane (2/1) was added and the resulting solution was partially evaporated. Then crystallization occurred and 21 g e.rythro-4,4 were obtained ^! - dimethoxy-a-ethyl-c ^ -methyldibenzyl in the form of long white rods, melting at 106-107 ⁰ C. The incrystallization did not increase this melting point.

(c) A mixture of 30 g of erythrd-4,4 ^l -Dinieth.axy - ^ l-äthylct'-methyldibenzyl, 300 ml of glacial acetic acid and 180 ml of concentrated hydrobromic acid was refluxed for 3 hours. After cooling, the solution was poured into ice water and the product extracted with ether. The organic extract was washed with water and the phenolic product was extracted with 1N sodium hydroxide solution. The alkaline extract was washed with ether and then carefully acidified with concentrated hydrochloric acid. The product was extracted with ether, washed successively with water, a saturated aqueous hatriuin carbonate solution and again with water and then dried over anhydrous sodium sulfate. Evaporation of the solvent gave a yellow pest which was recrystallized from benzene to give 23 g of white needles. A further recrystallization from benzene gave 17 g of erythro-4,4 ^f -dihydro>: ya-ethyl-a »_meth.yldibenzyl with a melting point of 187 to 188.degree.

109841/1937

( a ) 5.2g erythro-4- »4 '-dihydroxy-a-ethyl-α? -methyld ibenzyl were mixed under stirring with a 25 5 »strength excess of sulfuryl chloride and the reaction mixture was then stirred for 2 hours at 80 ⁰ C. The Reaktionsisischung vmrde extracted with ether and / petroleum ether obtained after workup, destaining and TJiakristallisation from ether to erythro-3,3 '~ dichloro-4,4-dihydroxy ^l ~ a - ethyl-a ^l -raethyldibenzyl having a melting point from 76 to 78 ° C. This compound was identical to the product obtained in Example 3.

Example 5

(a) 3.5 ml of bromine (25% excess) in 10 ial of chloroform was added dropwise with stirring at tree temperature to a solution of 7.1 g of erythro-4,4'-disethoxy-a-ethyla ^f -isethylobenzyl (cf. Example 4 (b)) added in chloroform. The progress of the reaction was followed by a thin layer or omatographically. When samples were taken after a quarter of an hour, after half an hour, after three quarters of an hour and after all the bromine had been added. The reaction mixture was then stirred for an additional hour at room temperature. The pale brown solution was diluted with diehlomethane, washed with an aqueous sodium carbonate solution and then with water and then dried over anhydrous sodium sulfate. After the solvent had been separated off, a yellow oil which crystallized out easily from methanol was obtained. The oil crystallization from methanol gave 6.2 g of a white crystalline solid which, after a further recrystallization from ether / methanol, contained 4.3 g of erythro-3 »3 ^f -dibr orn-4,4 ^f -d in ethoxy-a-ethi / l-a ¹ -ine thy 1-dibensyl resulted, which has a melting point of 133 to 134 ° G onv-ies.

109841/1937

(b) To prepare the corresponding 4,4 ^t -Dihydi'oxyverbindimg, the dimethoxy compound described above is demethylated in a manner analogous to that described in Example 2.

Alternatively, the corresponding 4,4 ^f -dihydroxy compound is prepared by reacting erythro-4,4 * -dihydroxy-ci-ethyl-cr'-methyldibenzyl (see Example 4 (c)) with a 25% excess of bromine in chloroform in a manner analogous to that described in Example 5 (a) «

The erythro-3i3 ^l * -dibromo-4 »4 ^t -dihydroxy-a-ethyl-a ^l methyldibenzyl, which was produced with these two procedures, has a melting point of 125 to 126 ^° C.

Example 6

About 70 g of butyryl chloride were taken over the course of 30 minutes Stir to a mixture of 81 g of o-fluoranisole, 100 g Aluminum chloride and 100 ml carbon disulfide added. After stirring an additional 4 hours, the reaction mixture became poured into ice water and then extracted with ether. The ether extract was dried over anhydrous sodium sulfate and evaporated and the residue was recrystallized from methanol, so that o-fluoranisylbutyrophenone was obtained. "

A solution of 4 g of sodium borohydride in 20 ml of Y / water was added to a solution of about 40 g of o-uoranisylbutvrophenone in 200 ml of methanol, which had cooled to ^{0 ° C., with stirring.} The reaction mixture was stirred for 3 hours, diluted with water and extracted with benzene. The benzene extract yielded 1-o-fluoranisyl-n-butanol.

10 9 8 41/19 3 7

A 0.2 m solution of io-1-fluoranisyl-n-butanol in dry benzene was added to a cooled suspension of 86 g of phosphorus pentabromide in 50 ml of dry ether. The reaction mixture was poured into ice water for 1.5 hours of stirring. The 1-o-tuoranisyl-n-butyl bromide thus prepared was extracted with benzene and the benzene solution, after drying thoroughly, was poured into a mixture of 4 g of magnesium, 0.01 g Iodine and 20 ml of dry ether were added dropwise. The reaction mixture was refluxed for 15 hours and then poured into a mixture of ice and dilute hydrochloric acid. The mixture was extracted with ether, the ether extract was dried and evaporated and the residue was recrystallized from Ohloroform / petroleum ether (boiling point 40 to 60 ° 0). In this way, 5.5 g of nieso-3>3'-difluoro-4,4'-dimethoxyajCt'-dipropyldibenzyl, which had a melting point of 168 to 169 ⁰ O, were obtained.

After demethylating this compound with hydrobromic acid in glacial acetic acid in a manner analogous to that described in Example 2, the corresponding meso-3, 3'- £ ⁾ ifluoro ~ 4.4 ^l -dihydroxy-ct, a ^f -aipropyldibenzyl, was obtained had a melting point 139-140 ⁰ C.

The corresponding ci, cL'-di-n-butyl-; 3, ci. ^f -Di-n-pentyl ~ and α, α'-di-n-hexyl compounds are obtained in an analogous manner.

109841/19 3

Example 7

26 g of alurainiuaclilorid were raised in the course of 1 hour to a stirred position of 26 g of fluorine sol and 12.5 g of 3-chloropentariol in a nitrogen atmosphere. The reaction mixture was heated to 35 ° C. for 60 positions and then in ice water poured The reaction was extracted with ether and then shaken with an aqueous solution of sodium carbonate in order to separate off the undesired acidic phenolic material. The ether phase remaining was dried and evaporated so that a neutral material was obtained fractionated destiJ - was lated. The fraction which boiled at 165 to 175 ° C / 0.2 mm Hg (10 g) was ucikristaliisiert from methanol so that 1 _s 3 g of erythro-3> 3 ^! ~ Dif luor '~ 4,4 * -dincthox ^ -a-äthyld. ^f -methyldibenzyl obtained, which had a very high value of 106 to 107 ° G and was identical to the product of Example 1.

This dimethoxy compound was demethylated by heating in a mixture of 25 ml of glacial acetic acid and 10 ml of hydrobromic acid in an atmosphere of nitrogen at 140 ° C. for 5 hours. Thereafter, the solution was cooled ¹ "and diluted with water. Kan received to serve way 1.05 g of erythro-3,3 '~ dif luor-4,4' -dihydroxy-tt-ethyl-o. -Nethyldibenzyl which, after Recrystallization from benzene had a melting point of 152 to 153 ° C and was identical to the product of Example 2.

The non-crystalline mother liquor was demethylated in a similar manner. 7 _f 5 g of the product obtained were (g 6, boiling point 180 to 19O ° C / O, 2 mm Hg) with the phenolic fraction combined with 13 g of benzyl chloro id mixed in a solution of 4 g Uatriumhydroxyd in 100 ml of alcohol . The reaction was kept under reflux during

109841/1937

. Cooked hours ", and then cooled and diluted with water to obtain 1.9 g of a Ifiedersehlages of _erythro-3} 3 * - Di £ luor-4,4 -dibenzyloxy ^f-o-ethyl-o * -methyldibenzyl which, after Uratrictallisation from benzene / petroleum ether had a melting point of 1J1 to 132.5 ° C. This compound can be debenzylated v / earth _f by dissolving them in 50 ml acetic acid and add 0.5 g of palladium on charcoal and shaken with Ifasserstoff for 1 hour. After the catalyst had been filtered off and the filtrate had been worked up, 1.1 g of erythro-3.3 ^l -difluoro-4.4 ^{l of} diydroxy-ct-ethyl-a ^r -methyiaibeiizyl were obtained.

The present invention also relates to pharmaceuticals Compositions containing one or more of the novel compounds. These pharmaceutical compositions can be administered orally or parenterally in conjunction with a solid or liquid pharmaceutical carrier be o

Solid compositions for oral administration include compressed tablets, pills, dispersible powders and granules. In such solid compositions, at least one active compound according to the invention is mixed with at least one inert diluent, such as tribasic calcite saphosphate (Ca ^ (PO,) p) f starch, lactose, gelatin, akasia, sucrose, stearic acid, talc, alginic acid or 2iatrium alginate. The compositions also jiiönnen "as is normal practice, additional substances other than inert Liehe diluents, _# eg lubricants such as Kagnesiumstearat and fresh or odor substances.

The percentage of active ingredient in the compositions of the invention can be varied, but it is not \\ 'eniii, g that it makes up such a proportion,

1098A1 / 1937

that a suitable dosage for the desired therapeutic effect is achieved. In general, the he - inventive preparations in an effective dose of etvrs. 0.00001 mg to 1 kg of active substance per kg of body weight administered daily.

The following example illustrates a pharmaceutical according to the invention Composition:

Be game 8 ₍

Ingredients for the production of 100,000 tablets, oils each containing 20 / Ug of active material:

erythro ~ 3, 3 '~ difluoro-4 ₁ 4 ^f -dihydroxy-a-ethyl-a ^f ■ - methyldibenzyl 2.00 g

Lactose '3900.00 g

Starch '998.00 g

Kagnesian stearate 100.00 g

The lactose is first ground to a fine powder and into the bowl of a planetary mixer or straight-through mixer sifted. The dibenzyl derivative vnarde dissolved in 100 ml of ethanol and mixed with the lactone and mixing was carried out for an additional 30 minutes. The starch was sifted and enough pure water was added to to get a 10% by weight starch paste the amount required for granulation, the rest of the starch paste was added to the mixing vessel and the Mixing continued for 15 minutes. Then the granulation was carried out with the calculated amount of starch paste at room temperature carried out and mixing continued for a further 15 minutes.

109 8 A 1/1937

The granulate obtained was passed through a sieve with a K "- UZT width of 1 min _r QO3 (16 mesh), n in a thin layer, V;. And spread for 12 hours with compressed air at a
Temperature from 35 to 40 ⁰ C dried. The dried granulate was then dead through a sieve with a mesh size; 0.776 mm (20 meoh) sifted and returned to the planetary or straight-through mixer. The magnesium stearate was then sieved through a sieve with a mesh size of 0.251 ivl (60 mesh), added to the granules and the M: Lsc ":; .- ri continued for a further 30 minutes. The granules were then made into tablets Pressed with a weight of 50 rag, from el en on
each contained 20 µg of the dibenzyl derivative.

Administer the above tablets after coitus
human prawns, this is how they prevent pregnancy "

^109841/1937

Claims (1)

PA T E Ή IA IT SP SEARCH: 1. 1,2-pipheiiyläthanderivate of the general Pormol v / C - O-i 'VV-CH CH - // Λ-0 - where R denotes a hydrogen atom or an alkyl radical with up to 6 carbon atoms or a benzyl radical, R- «and R», which can be identical or different, denote alkyl radicals with up to 6 carbon atoms, with the proviso that R ₁ and R “Do not represent methyl and ethyl radicals at the same time and X means an ealogen atom. 2. 1,2-Diphenyläthanderivate the general Poriael; CH - // t \ where R * is a hydrogen atom or a methyl, ethyl or benzyl radical and X ^{1 is} a chlorine or fluorine atom ". 1 0 9 8 A 1/1 9 3 7 3 _e Erytlii-o-3.3 ^t -Di methyldibenzyl. 4. Erythro-3,3 ^t -dichlor ~ 4,4'-dihydroxy-o'-lltliyl-cl ¹ ~ methyldibenzyl. 5. ■ Erythro-3 _> 3 ^f- difluoro-4,4 ^l -diraethoxy-a-ätliyl-a ^t inethyldibensyl 6. Erythro-313 ■ -Difluoro-4,4 ^f -dihydroxy-oc-ethyl- -α ¹ -nethyldibensyl. ₍ 7. Erytlir o ~ 3.3 ^f -dibron-4,4' -d irnet.hoxy-a-ethyl-α ^! ~ κ ethyld iben sy1. 8 ο Erythro-3.3 ^l -Dibroa-4,4 '-et! Hydroxy- ri ~ äthyl- .α ¹ - raetliyldibensyl. S. Ke go- 3,3 ^f -D if luor-4,4 '-d ime tlioxy- a, a * -a ipr opyld i- benzyl. 10. Meso-3,3 ^f -Dii ^> luoro-4,4 ^t -dihydroxy-c £, a ^t -dipropyläibenzyl. 11. Erythro-3,3 * -Dif: iiior-4,4 ^f -dibenByloxy-J.-ethyl-c'i. ^t · ro e thy ld ib en zyl « 12. Erythro-3,3 ^f -DiflTsor-4,4 ^! -di-nb-utoxy- a-ethyl-a methyldibenzyl. 1 0 9 8 U 1/1 9 λ 13. Process for the preparation of the compounds according to Claim 1, characterized in that an ether of the general formula in which R "denotes an alkyl radical with up to 6 carbon atoms and X has the same meaning as in claim 1, with a haloketone of the general formula Shark - CH - C = 0 I t R ₁ R ₂ converts, in which R- and Rp have the same meanings as in Own claim 1 and Hai means a halogen atom, so that one is an unsaturated diether of the general Γ ο ras el R " obtained, in which R ^, Rg and X have the meanings given in claim 1 have and R "has the meaning given above, this compound is hydrogenated to give the corresponding 10 9-841 / 19-37 general formula saturated dieters -0 - R " to obtain, wherein R-, Rp and X are those given in claim 1 Have meanings and R "has the meaning given above and then, if desired, this compound dealkylated to the corresponding dihydroxy compound. 14. Process for the preparation of the compound according to Claim 1, characterized in that an ether the formula given in claim 13 with a secondary Alcohol of the general formula ' Hal - CH CHOH
t converts, in which R. and Rp have the meanings given in claim 1 possess and Hai means a halogen atom, so that to become a dieter of the general formula 10 9 8 41/19 3 -CH - obtained in which R ₁ , R ₂ and χ have the meanings given in claim 1 and R "has the meaning given in claim 13, after which this compound is dealkylated, if desired, in order to obtain the corresponding dihydroxy compound., 15. A process for the preparation of the compounds of the general formula given in claim 1, wherein X is a Chlorine or bromine atom means, characterized in that an ether of the general formula R "- O- wherein R "has the meaning given in claim 15, according to the method specified in claim 12 or H instead of the halogenated ether is used, so that one has a compound of the general formula R "- 0- -O - R " 109841/1937 obtained, in which R .. and R _{2 have} the meanings given in claim 1 and R "has the meaning given in claim 13, this compound is then either brominated by reaction with bromine or chlorinated by reaction with chlorine or sulfuryl chloride and if desired, the dealkylation is carried out before or after the halogenation. 16 «A method for preparing the compounds of the general formula given in claim 1, wherein R ^ and R p have the same meanings and are alkyl radicals having from 3 to 6 carbon atoms, characterized m that an acid halide of the general! Formula R ₅ -CO- shark wherein Hal is an Ilalogenatom and R, an alkyl radical with 3 to 6 Means carbon atoms, with an ether of the general formula given in claim 13, so that one eiii Ketone of the general formula Ε «- 0-Γ ^N VC0 - obtained, wherein X is in claim 1, R "is in claim 13 and R-z have the meanings given above, one this compound reduced to the corresponding secondary alcohol and halogenated this alcohol to the corresponding halide, that with magnesium with formation of the corresponding 10 9 8 41/19 3 7 Crignard.-Verbinching is implemented, this Grignard compound in statu nascendi with unreacted halide ur ^ ctzt, so that the desired 1,2 ~ Diphenyläthanderivat, wherein R ₁ and R _? have the same meanings, and, if desired, the derivative is then dealkylated from the resulting dihydroxy compound. 17. The method according to any one of claims 13 to 16, characterized gekennzGich.net that, if the product obtained is a 4,4'-dihydroxy compound, this compound is then mixed with an alky! Halide containing up to 6 carbon atoms in ^{1 the} presence of an alkali metal hydroxide and an inert solvent reacts so that laan receives the corresponding dialkyl ether, 18. The method according to any one of claims 13 to 16, characterized in that v / enn the product obtained is a 4,4 '"dihydroxy compound, this compound is then reacted with a benzyl halide in the presence of an alkali metal hydroxide and an inert solvent, so that the corresponding dibenay ether is obtained, which can then be recrystallized and, if necessary, converted into the dihydroxy compound by hydrogenolysis _o 19. Pharmaceutical compositions, characterized in that it comprises at least an A ^r Getting Connected to the general formula given in claim 1 together with a solid or liquid pharmaceutical diluents barren carrier material contained. 1 0 9 8 U 1/1 9 3 7