FI67538C - PROCEDURE FOR FRAMSTATION OF AV (Z) -1,2-DIPHENYL-1- (4- (2- (N N-DIMETHYLAMINO) ETHOXY) PHENYL) -1-BUTEN - Google Patents

Description

67538

Process for the preparation of (Z) -1,2-diphenyl-1- 4- [2- (N, N-dimethylamino) ethoxy] -phenyl] -1-butene - For the preparation of (Z) -1,2-diphenyl- The present invention relates to (Z) -1,2-diphenyl-1- [4- [2- (N, N-dimethylamino) ethoxy] phenyl] -1-butene. A new process for the preparation of N-dimethylamino) ethoxy] phenyl-1-butene, i.e. tamoxifen (i) and its acid addition protection.

10 CHo / 3 och9ch7n _ (S '"· <2> - ^ g>

Tamoxifen (i) has antiestrogenic activity. Based on these 20 properties, it is used therapeutically in the treatment of hormone-dependent breast cancers.

The preparation of tamoxifen (i) is described in four patents (GB 1 013 907, GB 1 354 939, AT 347 929 and DE 2 704 690), in which a total of four methods for its preparation are disclosed. Three of these methods (GB 1 013 907, AT 347 929 and DE

2,704,690) contains a Grignard reaction or the like, which is difficult to perform on an industrial scale. The fourth method (GB 1 354 939) does not involve a Grignard reaction, but the last step of the method is otherwise difficult to perform. Namely, it uses either potassium or sodium amide as the reagent and either liquid ammonia or dimethylformamide as the solvent. The temperature is -40 to -20 ° C when using ammonia and 35 to 120 ° C to 150 ° C when using dimethylformamide.

2 67538

In addition, of each of the four methods described in the patents, the frame must be constructed piece by piece in several successive steps. The same applies to the (X-ethyl-idesoxybenzenes used as starting materials in the patents. Finally, with the exception of the second side branch of one process, each process requires the use of high (0 ° C) or low (0 ° C) temperatures in at least one reaction step.

In the process of this invention, tamoxifen (i) is prepared without a Grignard reaction at a temperature of 0 to 100 ° C. However, lower and higher temperatures can be used if desired. The tamoxifen backbone itself is prepared very conveniently and, in contrast to known methods, directly from cinnamic aldehyde (II) and 4- [2- (N, N-dimethylamino) ethoxy] benzophenone (IV) in one reaction step in 60-80% yield. . The tamoxifen backbone is then modified in 2-5 very simple and easy reactions to give tamoxifen (1). The modification reactions are practically successful in quantitative yields without side reactions. However, since 1/3 of the (E) -isomer is formed in the water quenching step, as in other known methods, the theoretical yield remains at about 67%. In addition, the losses mainly due to the removal of the (E) -isomer reduce the yield from 67% to about 50%. That is, the yield of (Z) -tamoxifen (i) based on the amount of 4- [2- (N, N-dimethylamino) ethoxy] benzophenone (IV) used is 30 to 40%.

The process of this invention uses 30 cinnamaldehyde (II) and 4- [2- (N, N-dimethylamino) ethoxy] benzophenone (IV) as starting materials. First, cinnamic aldehyde (II) CH = CHCHO (II) is hydroalurained to form the Al complex (lii).

Il 3 67538 "CH, cHo m> \ r (m) (V® 5 CH2dH2

When reacted with a benzophenone derivative (IV), / H3

10 0CH2Ch2N

rQl CH3 (IV) 0¾ 15 gives 1,2-diphenyl-1- [4- [2- (N, N-dimethylamino) ethoxy] phenyl] butan-1,4-diol] or triphenyl idiol (V).

/ * 3 och2ch2n 20 j ^ j XCH3 (V) ®rr®

N- 'CH90H

I 1 CH2OH 25

Next, water is cleaved from the triphenyldiol (V) to give 4-acetoxy-1,2-diphenyl-1- [4- [2- (N> N-dimethylamino) ethoxy] phenyl] -1-butene, i.e. triphenyl acetate (VI).

30 och2ch2n r ^ i Xch3 (vi) 35 CH2 O

I J

CH2OCCH3 4 67538

In the next step, triphenyl acetate (VI) is hydrolyzed to 1,2-diphenyl-1- [4- [2- (N, N-dimethylamino) ethoxy] phenyl] -1-buten-4-ol, i.e. triphenyl alcohol (VII).

/ Ch3 5 0CH2cH2n fQ "! ™ 3 <VII> <o> -rKo> CH?

10 CH2OH

The hydroxyl group of triphenyl alcohol (VII) is replaced by halogen to give 4-halo-1,2-diphenyl-1- | 4- [2- (N, N-dimethylamino) ethoxy] phenyl] -1-butene or triphenyl halide (VIII), where X = F, Cl, Br or I.

CHo / 3 ÖC ^ 2 C ^ n J »X“ 3 (»HI) CH2

CH 2 "X

Alternatively, a sulfonic acid ester is prepared from triphenyl alcohol (VII) to give 4-sulfonyloxy-1,2-diphenyl-1- [4- [2- (N, N-dimethylamino) ethoxy] phenyl] -1- butene or triphenyl sulfonate (IX), where R = 4-tolyl or methyl.

/ «3

30 OCH2CH2N

Xch3 dx) 35 Sjojl, o 5 67538

Trifenyyliha! Ideas (Vili) can also be prepared from triphenyl sulfonates (IX) or other triphenyl halides (VIII).

In the last step, triphenyl halide (Vili) or triphenyl isulfonate (IX) is reduced to tamoxifen (i).

Water can also be cleaved from triphenyldiols (V) to give 2,3-diphenyl-2- | 4- [2- (N, N-dimethylamino) ethoxy] phenyl} tetrahydrofuran or triphenylfuran (x).

10 ^ PH3 och2ch2n V) (X) ®rv® 15 v °

Upon opening the tetrahydrofuran ring of triphenylfuran (X) under suitable conditions, triphenyl acetate (VI) is obtained. The opening of the tetrahydrofuran ring as well as the water cleavage of the triphenyldiol (V) can also be carried out directly to the triphenyl alcohol (VII).

Water cleavage and conversion of the primary hydroxyl group to a halogen or sulfonyloxy group can also be performed in the reverse order as above. Thus, either 4-halo, 2-diphenyl-1- 4- [2- (N, N-dimethylamino) ethoxy] phenyl butan-1-ol can be prepared from triphenyl idiol (V) 25, i.e. hydroxy ihalide (XI), yCH3 och2ch2 ^ r ^ i ™ 3 (xi) 30 / _0¾ OH d; H2hal 35 where hal = F, Cl, Br or I, or 4-sulfonyloxy-1,2-diphenyl-1 - [4- [2- (N, N-dimethylamino) ethoxy] phenyl] butan-1-ol or hydroxysulfonate (XII), I; 6 67538 ch3 OCH2cH2n \ h3 (XII) 5 ch2 oh 1 °

CH, 0-S-R

2 II

0 10 where R = 4-tolyl or methyl. Cleavage of water from the hydroxyhalide (X1) or hydroxysulfonate (XII) yields triphenyl halide (VIII) or triphenylsulfonate (IX), respectively.

The triphenyldiol (V) as well as the triphenylfurons (X) are also directly obtained in the triphenyl halides (VIII) by one reaction step 1a.

In fact, water purification of triphenyldiol (V) is best and most conveniently carried out in this way, since one or more steps are then omitted from the reaction series, and the reaction sequence is truncated to three steps. That is, the process for preparing tamoxifen (I) disclosed in the present invention is most conveniently and most advantageously carried out according to the following series of reactions. In the first step, triphenyl idiol (V) is prepared from cinnamon aldehyde (II) and 4- [2- (N, N-dimethylamino) ethoxy] benzophenone (IV). In the second step, water is cleaved from the triphenyldiol (V) to give the triphenyl halide (X1), which is reduced in the third or final step to tamoxen-30 (i).

All of the intermediates (V to XIII) disclosed in this invention are novel compounds.

67538

Hydroalumination of cane] aldehyde (II) is carried out with an α 1 -amine hydride reducing agent, e.g. 1-aluminum fluoride or sodium bis (2-methoxyethoxy) aluminum dihydride, and the resulting aluminum complex (III) is reacted with 4- [2- (N, N-dimethyl- 5 (amino) ethoxy] with benzophenone (IV). The reaction is most preferably carried out near room temperature, e.g. in an ether or hydrocarbon solvent or a mixture thereof. Ether solvents include tetrahydrofuran and hydrocarbon solvents include toluene.

10

Water can be cleaved from triphenyldiol (V) by a wide variety of methods, e.g. hapokatal yyt il 1 a vagy ai koho! In a solvent or an organic acid or a mixture of acid anhydride and acid chloride. When using a mixture of acetic anhydride and acetyl chloride, it is preferable to carry out the reaction at a temperature of 80 to 100 ° C as follows.

First, triphenyldiol (V) is reacted with acetic anhydride to give 4-acetoxy-1,2-diphenyl-1- | 4- [2- (N, N-dimethylamino) ethoxy] phenyl tert-but-1-ol, i.e. hydroxy-20-acetate (XIII).

ch3 och2ch2n j "Q ^ | ^ 0Η3 (XIII) I f C ^ O-C-CHj 30

Acetyl chloride is then added to cleave water from the hydroxyacetate (XIII).

I. - 8 67538

The hydrolysis of the resulting triphenyl acetate (VI) is carried out in a suitable solvent under either acidic, basic or neutral conditions. In acid and base hydrolysis, it is most convenient to use an alcohol solvent, e.g. ethanol, and to carry out reaction 5 either at or below the boiling point of the mixture. In the case of base hydrolysis, e.g. sodium hydroxide can be used as a catalyst, and in acid hydrolysis, e.g. hydrochloric acid.

Triphenyl halides (VIII) are prepared from triphenyl alcohol 10 (VII), e.g., by the following methods. Treatment of triphenyl alcohol (VII) in a suitable solvent, e.g. diethylamino sulfur trifluoride, gives triphenyl fluoride (VIII, X = F). As the solvent, e.g. a halogenated hydrocarbon solvent or an ether solvent such as methylene chloride or dimethoxyethane. The reaction is most preferably carried out either at room temperature or below.

Treatment of the triphenyl alcohol (VII) in a suitable solvent with, for example, thionyl chloride or triphenylphosphine-carbon tetrachloro-20 is used to give triphenyl chloride (VIII, X-Cl). When thionyl chloride is used, the reaction can be carried out, for example, in chloroform and, when using a triphenylphosphine-carbon tetrachloride reagent, e.g. in acetonitrile or in a mixture of acetonitrile and carbon tetrachloride. The reaction is most conveniently carried out at or below the boiling point of the reaction mixtures. Treatment of triphenyl alcohol (VII) in a suitable solvent, e.g. phosphorus tribromide 1a or triphenylphosphine-carbon tetrabromide 1a, gives triphenylbromide (VIII, X = Br), respectively. When phosphorus tribromide is used, the reaction can be carried out, for example, in methylene chloride and triphenylphosphine-carbon tetrabromide reagent, e.g. in acetonitrile or in a mixture of acetonitrile and methylene chloride.

9,67538

In the case of both reagents, the reaction is preferably carried out near room temperature. Treatment of triphenyl alcohol (VII) in a suitable solvent, e.g. triphenyl phosphite methiodide, gives triphenyl iodide (VIII, X = I). As the solvent 5, e.g. hexamethylphosphoric triamide and room temperature as the reaction temperature. Triphenyl halides (Vili) can also be converted to other triphenyl halides (Vili) by boiling or heating them in a suitable solvent, e.g. with alkali or earth or aliquots. In this way, for example, triphenyl bromide (VIII, X * Br) and triphenyl bromide (VIII, X = Br) triphenyl iodide (VIII, X = I) can be prepared from, e.g., triphenyl bride (VIII, X = Cl). As the solvent, for example, N-methyl-2-pyrrolidone can be used. Triphenyl halides (VIII) can also be prepared from triphenyl sulfonates (IX) by boiling or heating in a suitable solvent, e.g. alkali metal or alkaline earth metal. imetal with 1 ihal id in. In this way, e.g. Triphenyl iodide (VIII, X = i) can be prepared from triphenyl itosylates (IX, R = 4-tolyl). The reaction is most conveniently carried out using sodium iodide as the reagent and boiling acetic acid as the solvent.

Triphenyl isulfonate (IX) is prepared from triphenyl and elevated! (VII) e.g. by the following methods. Treatment of triphenyl with elevated (VII) 4-toluenesulfonic acid chloride under appropriate conditions affords triphenyl tosylate (IX, R = 4-tolyl). The reaction can be carried out either in an organic solvent, e.g. pyridine, in a solvent mixture or in a phase transfer technique using e.g. toluene as the organic solvent. When carrying out the reaction in pyridine, it is preferable to use a temperature close to 0 ° C. When using a phase transfer technique, it is preferable to carry out the reaction close to room temperature. Treatment of triphenyl with elevated (VII) methanesulfonic acid chloride under appropriate conditions affords triphenyl mesylate (IX, R = methyl), respectively.

- 1 '__ 10 67538

The reaction may be carried out either in an organic solvent, e.g. pyridine or in a mixture of methylene chloride and triethylamine, or by a phase transfer technique using e.g. methylene chloride as the organic solvent. In each case, the reaction is preferably carried out at a temperature close to 0 ° C.

Triphenyl halides (Vili) are reduced to tamoxifen (i), e.g., either by one of the metal 1 dihydride games or by catalytic. Among the useful metal hydride reducing agents are e.g.

10 l of lithium aluminum hydride, sodium borohydride and sodium bis (2-methoxyethoxy) aluminum dihydride. When lithium aluminum hydride is used as a solvent, e.g. an ether or hydrocarbon solvent, e.g. tetrahydrofuran or toluene or a mixture thereof. When sodium borohydride is used, the reaction is carried out either in a suitable solvent, e.g. dimethyl sulfoxide, in a solvent mixture or by a phase transfer technique using e.g. toluene as the organic solvent. When sodium bis (2-methoxyethoxy) -aluminum dihydride is used, the reaction is most conveniently carried out in toluene, although many other solvents and solvent mixtures may be used. Metal 1 dihydride reduction is generally most preferably performed at a temperature somewhat above room temperature, e.g., about 50 ° C. Kata! The reduction is carried out by hydrogenation, for example in the presence of a solvent or a catalyst. The palladium carbon is preferably 25. The hydrogenation is carried out under either acidic, neutral or, preferably, basic conditions. As the solvent, for example, an alcohol such as methanol or ethanol or a carboxylic acid such as acetic acid is used. The reaction is most preferably carried out near or slightly above room temperature.

The triphenyl sulfonates (IX) are reduced to tamoxifen (I), e.g. with a metal hydride reducing agent. The metal hydride reduction is carried out in substantially the same manner as described above for the reduction of triphenyl halides (VIII).

11 67538

The purification of the water of triphenyldiol (V) to triphenylfuran (suorittaa) can be performed e.g. as follows. When the acid catalyst is administered to the triphenyldione (V) under suitable conditions in a suitable solvent, triphenyluran 5 (x) is formed by cleavage of water. Suitable acid catalysts include hydrochloric acid and sulfuric acid, and suitable solvents include an alcoholic solvent. When sulfuric acid is used as the acid catalyst and ethanol is used as the solvent, it is preferable to carry out the reaction slightly above room temperature. By acidifying the reaction mixture in between the preparation of triphenyldiol (V), e.g. with hydrochloric acid, triphenyl ifuran (X) is obtained directly without first having to isolate the triphenyldiol (V).

If the acid catalyst is allowed to act on triphenyldiol (V) under suitable conditions in a suitable solvent, triphenyl alcohol (VII) is formed by cleavage of water. Under the same conditions, the tetrahydrofuran ring of triphenylfuran in (X) also opens and triphenyl alcohol (VII) is also formed. The acid Kata! yyt tin can be used e.g. dry hydrogen chloride or concentrated hydrochloric acid and an alcoholic solvent such as ethanol as solvent. The reaction is most conveniently carried out either at or below the boiling point of the mixture.

In addition, when the acid catalyst acts on triphenyluran (X) under suitable conditions in an organic acid, in this case acetic acid, the tetrahydrofuran ring opens and triphenyl acetate (VI) is formed. Under the same conditions, triphenyldiol (V) is also formed triphenyl acetate (VI).

30 Acid kata] can be used e.g. hydrogen bromide. The reaction is most conveniently carried out either at or before the boiling point of the mixture.

Preparation of hydroxyhalides (XI) and hydroxysulfonates (XII) from triphenyldiol (V) and trituration of water to triphenyl halides (VIII) and triphenylsulfonates (IX) are performed using the corresponding reactions described above.

12 67538

The preparation of hydroxysulfonates (XII) and the control of water can also be carried out as one combined reaction step.

Preparation of triphenyl idols (Vili) from triphenyl idiol (V) or triphenylfuran (X) in one reaction step can be carried out e.g. by the following methods. When triphenyldiol (V) is reacted with thionyl chloride in a suitable solvent, e.g. chloroform or toluene, triphenyl chloride (VIII, X * Cl) is formed. The reaction is most preferably carried out in two steps, in the first step using cooling and in the second step using heating. Similarly, upon reaction of triphenylfuran (X) with triphenylphosphine dibromide in a suitable solvent, e.g. acetonitrile, triphenyl bromide (VIII, X = Br) is formed. The reaction is preferably carried out using stirring.

It is preferred to carry out the reaction sequence described in this invention in such a way that only a part of the intermediates is purified. For example, if the triphenyldiol (V) is purified by recrystallization, the remainder of the reaction sequence can be performed without purification of intermediates. It is also possible to purify only triphenyl chloride (VIII, X = Cl) or triphenylchloride (VII) instead of triphenyldiol (V). If desired, the separation of the isomers can also be carried out in the same context. In fact, purification and separation of isomers are preferably carried out in the same context.

The (Z) -isorazine can be isolated from a mixture of (Z) - and (E) -isorazine as well as triphenyl acetate (VI), triphenyl and elevated compounds. i- (VII), triphenyl halide- (VII) and triphenylsulfonate in step 30 (IX). It is also possible to carry out the reaction sequence by isolating the (Z) -isomer only in tamoxifen step (I).

The (Z) -isomer can be isolated both when the isomers are free bases and when they are in salt form. Isolation of the (Z) -35 isomer from the isomer mixture is performed either by fractional crystallization, fractional leaching, chromatography, or a combination thereof.

67538 In the process for the preparation of tamoxifen (i) according to the present invention, the functional group at the end of the ethyl group is removed in the last step. In principle, triphenyl acetate (VI) and triphenyl alcohol (VII) are also obtained by reduction directly to tamoxifen (i). Methods in which alcohols, esters or ethers are obtained by reduction of the corresponding hydrides have even been reported in the literature (see, e.g., Compendium of Organic Synthetic Methods, Vol. 1-4, sections 153, 158 and 159). However, these reductions 10 are usually cumbersome in normal cases and often require 0 ....... Λ quite harsh conditions. Much more conveniently, or the Cl 2 OCCH 2 group can be reduced to the CH 2 group via the corresponding halide or sulfonic acid ester, although e.g. some other esters such as thiocarbamates (see Chem. Commun. 1979, 1175) may be used.

Simple sharks and sulfonates can be readily prepared from the corresponding alcohols in high yields. In addition, simple sharks and sulfonates can also be easily and in high yields reduced to the corresponding hydrides by a wide variety of methods (see, e.g., Compendium of Organic Synthetic Methods, Vol. 1-4, section 160 and Synthesis 1980, 425-52).

The real inventive step of the present invention is how it is extremely easy and convenient to prepare mainly triphenyl halides (VIII) and in particular triphenyl chloride (VIII, X = Cl) by two very simple, technically easy-to-carry and high-yield reactions. The third and final step of reducing the triphenyl halide (VIII) or triphenyl sulfonate (IX) to tamoxifen (i) is also inventive. It was not expected that multifunctional compounds such as triphenyl halides (VIII) and triphenyl sulfonates (IX), which contain, for example, a double bond, could be reduced so easily and in practice in quantitative yield to tamoxifen.

67538 14

Example 1 1,2-Diphenyl-1- [4- [2- (N, N-dimethylamino) ethoxy] phenyl | -butane-1,4-diol (triphenyldiol) (RR, SS; RS, SR) (V): 5

To a reaction vessel containing 20 g of lithium aluminum hydride dissolved or slurried in 500 ml of dry tetrahydrofuran is added, with stirring, 132 g of cinnamon aldehyde dissolved in 750 ml of dry tetrahydrofuran. The temperature is maintained between 25 and 35 ° C during the addition 10. After complete addition of the cinnamon, the mixture is stirred for a further 30 minutes at room temperature. 269 g of 4- [2- (N, N-dimethyl) amino) ethoxy] benzophenone (IV) dissolved in 1000 ml of dry tetrahydrofuran are then added with stirring. The temperature is maintained between 35 and 45 ° C during the addition. After the benzophenone derivative is completely added, the mixture is stirred for a further 2 h at 40 ° C. The reaction mixture is then added with stirring, first to 20 ml of water, then to 20 g of 15% sodium hydroxide solution and finally to 60 ml of water. The precipitated lithium and aluminum hydroxide are removed by filtration. The solvent is then evaporated off and the evaporation residue is recrystallized from toluene. The yield of the pure isomer mixture is 243 to 324 g (60 to 80%) and m.p. 127-51 ° C. The mixture of isomers contains, for reasons of solubility, about 60% of the (RR, SS) enantiomeric pair, although the reaction itself produces the same number of both pairs. Recrystallization of the isomer mixture from acetone gives the (RR, SS) enantiomeric pair, m.p. 165-7 ° C (from toluene). Evaporation of the acetone mother liquor obtained above to dryness and recrystallization of the evaporation residue twice from acetone gives a pair of (RS, SR) enantiomers, m.p. 139-41 ° C (from toluene).

4-Acetoxy-1,2-diphenyl-1- [4- [2- (N, N-diraethylamino) ethoxy] phenyl] -1-butene (triphenyl acetate) (Z and Z, E) ( vl):

Dissolve 405 g of triphenyldiol (V), either pure enantiomeric ribs or a mixture thereof, in 1,500 ml of warm acetic anhydride. The mixture is stirred for 1 h at 90 ° C, whereupon the primary hydroxyl group is acetylated. [The intermediate is hydroxyacetate (XIII); (RR, SS) enantiomer pair m.p. is 97-9 ° C].

15 67538

318 g of acetyl chloride dissolved in 500 ml of acetic anhydride are then added with stirring, after which the reaction mixture is kept at 90 [deg.] C. for a further 3 h. Finally, the solvent is evaporated off to give the hydrochloride salt of (Z, E) -triphenyl-5-acetate (VI) in quantitative yield. The evaporation residue, m.p. is 114-22 ° C, contains 2/3 part of the desired (Z) isomer and 1/3 part of the (E) isomer. The free base (Z) -isomer m.p. is 67 - 9 * C.

1,2-Diphenyl-1- [4- [2- (N, N-dimethylamino) ethoxy] phenyl] | -1-buten-4-ol (triphenyl alcohol) (Z and Z, E) (VII):

Dissolve the evaporation residue of the hydrochloride salt of (Z, E) triphenylacetate (VI, Z: E 2: 1) obtained in the previous step in 2,000 lanes of ethanol. The solution is then neutralized with 20% sodium hydroxide solution. An additional 300 mL of 20% sodium hydroxide solution and 200 mL of water are added, after which the mixture is refluxed for 1 h. The reaction mixture is neutralized with 2M chlorohydrochloric acid. The solvent is evaporated off and water is added to the evaporation residue. The product is then extracted into a mixture of toluene and ethyl acetate (8: 2). After washing with water, the solvents are evaporated off to give (Z, E) -triphenylalcohol. and (VII, Z: E 2: 1) in quantitative yield. The m.p. is 93-100eC. The desired (z) -isomer is isolated, e.g., as follows: 25

Method a. The evaporation residue of the (ZE) -triphenyl alcohol (VII, Z: E 2: 1) obtained above is recrystallized from toluene to give 157 g of (Z) -triphenyl alcohol (VII), corresponding to 41% of the triphenyldiol (V) used. in the order of. (Z) -triphenyl-30 alcohol m.p. is 110 - 2®C. The remaining isomeric mixture is then converted to the hydrochloride salt either by introducing hydrogen chloride gas into the solution or by adding a mixture of ethanol and concentrated hydrochloric acid. The solvent is then evaporated off. The residue is dissolved in boiling acetone, whereby the (Z) -isomer 35 is completely soluble and the (E) -isomer remains largely insoluble. The cooled solution is filtered to remove (E) -triphenylal alcohol (VII). After evaporation of the acetone, the evaporation residue is dissolved in boiling ethanol.

__ Il ___ 16 67538

As the solution cools, 47 g (11%) of additional (Z) -triphenyl alcohol (VII) crystallizes out as its hydrochloride salt. Thus, the total yield of (Z) -trophenyl alcohol (VII) becomes 52% based on the amount of triphenyldiol (V) used. (Z) -triphenyl alcohol 5 (VII) hydrochloride salt m.p. is 166-8 ° C (from acetone). If desired, the (Z) -isomer can be liberated from its hydrochloride salt from the following i.

First, the hydrochloride salt is dissolved in hot water, followed by the addition of 10% sodium carbonate solution. The liberated (Z) -isomer is then extracted from the cooled solution into a mixture of toluene and ethyl acetate. Finally, water washing and evaporation are carried out to give the (Z) -isomer as the free base without extraction losses.

Method b. The evaporation residue of the (Z, E) -triphenyl alcohol (VII, Z: E 2: 1) obtained above is dissolved in acetone, after which it is converted into its hydrochloride salt by introducing hydrogen chloride gas into the solution. The mixture of isomers converted to the hydrochloride salt is then subjected to acetone treatment and recrystallization as described in a). Yield of the hydrochloride salt of (Z) -triphenyl] alcohol (VII) en 195 g, corresponding to 46% based on the amount of triphenyldiol (V) used.

Tapa c. The evaporation residue of the (Z, E) -trienyl alcohol (VII, Z: E 2: 1) obtained above is dissolved in ethanol, after which the isomer mixture is converted into its hydrochloride salt by introducing hydrogen chloride gas into the solution. When the hot-heated solution is allowed to cool, a precipitate forms, which is recrystallized a second time from ethanol. In this way, 123 g of the hydrochloride salt of (z) -triphenyl alcohol (VII) are obtained, corresponding to 29% based on the amount of triphenyldiol (V) used.

Tapa d. The (Z) -triphenyl alcohol (VII) is easily isolated from a mixture of the (Z) - and (E) -isomers, e.g., column or plate chlorate-35 graphesis, since the (Z) -isomer moves considerably faster than (E) in many driving solvents. isomer. For column or plate chromatographic isolation, for example, either toluene -Et3N (90:10) (Rf / Z 0.20; Rf / E 0.05) or CHCl3-MeOH conc. NH 3 (90: 9.5: 0.5) (Rf / Z 0.49; Rf / E 0.33).

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Example 2 4-Chloro-1,2-diphenyl-4- [2- (N, N-dimethylamino) ethoxy] -phenyl | -1-butene (triphenyl chloride) (Z) (VIII, X * Cl): 5

Dissolve 387 g of (Z) -triphenylalcohol (VII) either as the free base, the hydrochloride salt or a mixture thereof in 2,400 ml of chloroform. 238 g of thionyl chloride are added, after which the mixture is refluxed for 3 h. After evaporation of the solvent, 10% sodium carbonate solution is added, after which the product is extracted into toluene. After washing with water, the solvent is evaporated off * to give (Z) -triphenyl chloride (VIII, X = Cl) in quantitative yield. 15 g of (Z) -triphenyl chloride (VIII, X = Cl) recrystallized from acetone as the free base. is 108-10 ° C and m.p. of the hydrochloride disalt recrystallized from acetone. 194 - 6 ° C.

Tamoxifen (Z) (i): To a reaction vessel containing 76 g of 1 lithium aluminum hydride dissolved or slurried in 1000 ml of dry tetrahydrofuran is added the evaporation residue of the (Z) -trophenyl oride (VIII, X = Cl) obtained above. In 500 ml of dry tetrahydrofuran, after which the mixture is refluxed for 4 to 5 h. The excess reagent is decomposed by adding 25 ml of ethyl acetate. The mixture is then added with stirring, first to 76 ml of water, then to 76 g of 15% sodium hydroxide and finally to 228 ml of water. The precipitated lithium and aluminum hydroxide are removed by filtration, after which the solvent is evaporated off. The evaporation residue is dissolved in toluene. After washing with water and drying over sodium sulfate, the toluene is evaporated off to give (Z) -tamoxifen (i) in quantitative yield. The (Z) -tamoxifen (i) is then converted to the citrate salt by normal procedures with citric acid in acetone. The citric acid salt of (Z) -tamoxifen (I) thus obtained m.p. is about 142 ° C and the yield is 507-535 g, which corresponds to 90-95% based on the amount of (Z) -triphenyl alcohol (VIl) used.

67538 18

Triphenyl chloride (Ζ, Ε) (VIII, X = Cl): (ZE) -triphenyl chloride (VIII, X = Cl, Z: E 2: 1) is prepared with (Z, E) -triphenyl alcohols (VII, Z : E 2: 1) to! uene-ethyl acetate-5 from the evaporation residue in the same manner as the pure Z-isomer above. The yield after toiuene evaporation is quantitative.

Tamoxifen (Z, E) (i): The toluene evaporation residue of 10 (Z, E) -trophenyl chloride (VIII, X - Cl, Z: E 2: 1) is reduced to (Z, E) -tamoxifen (i, Z: E 2: 1) in the same manner as the pure (Z) -isomer above. The (Z) -isomer is isolated from the isomer mixture by known methods and converted to the citrate salt as above. The citric acid salt of (Z) -tamoxifen (i) thus obtained m.p. is about 142 ° C and the yield is 225-253 g, which corresponds to 40-45% based on the amount of triphenyl idol (V) used.

Example 3 20

Tosyloxy-1,2-diphenyl-1- [4- [2- (N, N-dimethylamino) ethoxy] phenyl] -1-butene (triphenyl tosylate) (Z and Ζ, Ε) (IX, R = 4-tolyl ): Dissolve 387 g of (Z) -triphenyl alcohol (VII), either as the free base, the hydrochloride salt or a mixture thereof, in 1 000 ml of dry pyridine. With stirring, 572 g of 4-toluenesulfonic acid chloride dissolved in 1000 ml of dry pyridine are added. The temperature is maintained at 0eC during the addition. The reaction mixture is then stirred for a further 4 h at 0 ° C. The mixture is then added with stirring and maintaining the temperature between 0 and 10 ° C, first with 200 ml of cold water and then with cold 10% hydrochloric acid until the reaction mixture becomes acidic. The precipitated hydrochloride salt of (Z) -triphenyl itosylate (IX, R = 4-tolyl) is filtered off, washed with water and dried. Sakan sp. is 122 - 4 * C and the yield is quantitative.

19 67538

The corresponding (Z, E) triphenyl tosylate (IX, R = 4-tolyl, Z: E 2: 1) m.p. is 80-105 ° C. The (Z) -isone liberated by toluene-base treatment and recrystallized from petroleum ether m.p. is 85-7 ° C.

5

Tamoxifen (Z) (I):

The hydrochloride salt of (Z) -triphenyl tosylate (IX, R = 4-tolyl) obtained above is slurried in 10% sodium carbonate, after which it is extracted as the free base into toluene. After washing with water, the toluene is evaporated to dry the solution until the volume of the solution is 2,000 to 2,500 ml. The resulting toluene solution is added to 720 ml of a 70% toluene solution of sodium bis (2-methoxyethoxy) aluminum dihydride, the temperature of which is maintained at 75 ° C during the addition. Stirring is then continued for a further 3 h at the same temperature. The excess reagent is quenched with ethyl acetate, after which the reaction solution is washed twice with water. After drying over sodium sulfate 1a, the solvent is evaporated off to give (Z) -tamoxifen (i) in quantitative yield. The preparation of the citrate salt is performed as above. The citric acid salt of (Z) -tamoxifen (i) thus obtained m.p. is about 142 ° C and the yield is 479-507 g, which corresponds to 85-90% based on the amount of (Z) -tamoxifen alcohol (VII) used.

Example 4 2,3-Diphenyl-2- [4- [2- (N, N-dimethylamino) ethoxy] phenyl] -tetrahydrofuran (triphenylfuran) (RR, SS; RS, SR) (X): Dissolve 405 g of triphenyldiol (V), either pure enantiomeric pairs or a mixture thereof, in a solution of 4,000 ml of ethanol, 150 ml of concentrated sulfuric acid and 750 ml of water. The reaction mixture is stirred for 3 h at 45 ° C. The solution is neutralized with 2 M sodium hydroxide, after which the ethanol is evaporated off. 35 Water is added to the evaporation residue and the product is extracted into toluene.

20 67538

After drying over sodium sulfate 1a, the toluene is evaporated off to give, in quantitative yield, triphenylfuran (X), where the (RR, SS) enantiomeric pair is considerably enriched at the expense of the (RS, SR) pair. The recrystallized (RR, SS) -triphenylfuran (X) from ethanol 5 m.p. is 83-5 ° C.

Triphenyl alcohol (Z, E) (VII): Dissolve 387 g of triphenylfuran (X) or 405 g of triphenylidene (V), either pure enantiomeric pairs or a mixture thereof, in 2500 ml of dry ethanol containing an excess of hydrogen chloride gas. The mixture is refluxed for 4 h, after which the solvent is evaporated off. The yield of the hydrochloride-15 salt of triphenylalcohol (VII, Z: E 2: 1) is quantitative, but it contains about 5% of 2,3-diphenyl-2- | 4- [2- (N, N-dimethylamino) ethoxy] -phenyl} tetrahydrofuran. Isolation of the (Z) -isomer is performed in the same manner as in Example 1.

Example 5 4-Bromo-1,2-diphenyl-1- 4- [2- (N, N-dimethylamino) ethoxy] -phenyl] -1-butene (triphenyl bromide) (Z) (VIII, X = Br): Dissolve 387 g of (Z) -triphenyl alcohol (VII) in 3000 ml of dry acetonitrile. With stirring, 395 g of triphenylphosphine are added first and then 498 g of carbon tetrabromide in small portions. The reaction mixture is stirred at room temperature for 2 h. The solution is cooled, whereupon the desired product crystallizes and is filtered off. The yield is 306 g (68%) and m.p. 114-6 ° C (methanol list). If desired, more pure product can be isolated from the mother liquor.

21 67538

Tamoxifen (Z) (i):

306 g of (Z) -triphenyl ibromide (VIII, X = Br) and 51 g of hexadecylribribyl ifosonium bromide are slurried in 340 ml of toluene.

5 103 g of sodium borohydride dissolved in 270 ml of water are then added. The mixture is stirred at 50 ° C for 24 h. Water is added, after which the product is extracted into toluene. After drying the toluene solution, the solvent is evaporated off. The evaporation residue is mainly a boron complex of the desired product, but it also contains some of the desired product in free form. The evaporation residue is dissolved in 1700 ml of absolute ethanol and 340 ml of concentrated hydrochloric acid are added. The mixture is stirred for 2 h at 50 ° C, whereupon the boron complex decomposes. The solvent is evaporated off, after which the product is slurried in toluene. A 2 M sodium hydroxide solution is then added to release the product into the hydrochloride salt. The aqueous layer is removed and the other layer is washed with water. The solvent is then evaporated off to give (Z) -tamoxifen (I) in almost quantitative yield. The preparation of the citrate salt is performed as above.

20

Example 6 Tamoxifen (Z) (I): Dissolve 40.6 g of (Z) -triphenyl chloride (VIII, X = Cl) in 1000 ml of ethanol, then add 41.4 g of dry potassium carbonate and 12 g of 5% solution. 1adiumhiiltä. The reaction mixture is stirred at 50 DEG C. under an atmosphere of hydrogen until the reaction is complete, about 3 h. The catalyst is removed by filtration, and the residual solvent is evaporated off. The evaporation residue is converted into the citrate salt as above. The yield is almost quantitative.

22 67538

Example 7 4-Chloro-1,2-diphenyl-1- [4- [2- (N, N-dimethylamino) ethoxy] -phenyl] -1-butene (triphenyl chloride) (Z) (VIII, X = Cl): 5

405 g of triphenyl idiol (V) are slurried in 2500 ml of toluene, followed by distilling off 250 ml of toluene to dry the solution. The mixture is cooled to 0 ° C using stirring. 476 g of good quality thionyl chloride are added with further stirring and keeping the temperature at or slightly below 0 ° C. The mixture is stirred for 1 h at 0 ° C and then the temperature is allowed to rise to 22 ° C. The mixture is then stirred at 80 ° C until the reaction is complete, n 3 h. Water is added to decompose the excess thionyl chloride and then 20% sodium hydroxide solution to liberate the product from its hydrochloride salt. The aqueous layer is removed. The toluene layer is washed with water. The solvent is then evaporated off to give (Z, E) triphenyl chloride (Z: E 7: 3) in quantitative yield. The evaporation residue 20 is recrystallized from methanol to give 182 g (45%) of the pure (z) -isomer.

Tamoxifen (Z) (I):

Dissolve 182 g of (Z) -triphenyl chloride and 51 g of sodium borohydride in 900 ml of dimethyl sulfoxide and keep the reaction mixture at 85 ° C for 5 h. Water is added to precipitate the product as a boron complex. The precipitate is filtered off and washed with water. The precipitate is then dissolved in 1125 ml of absolute ethanol and 225 ml of concentrated hydrochloric acid are added. The mixture is stirred for 2 h at 50 ° C, whereupon the boron complex decomposes. The solvent is evaporated off, after which the product is slurried in toluene. A 2 M sodium hydroxide solution is then added to liberate the product from its hydrochloride salt. The aqueous layer is removed and the toluene layer is washed with water. The solvent is then evaporated off. Finally, the evaporation residue is converted into its citrate salt as above. The yield is almost quantitative and m.p. about 142eC.

Il

Claims (6)

67538 A process for the preparation of therapeutically active (Z) -1,2-diphenyl-1- [4- [2- (N, N-dimethylamino) ethoxy] phenyl] -1-butene (i) and its acid addition salts ch3 och2ch2n (O) "<5Hm5> CHo (! η3 15 characterized in that the triphenylbutene derivative of the formula / Ch3 OCH2CH2n" ιό) ν · CH2X 25 wherein X is a functional group such as F, Cl, Br, I or O . -OSR, where R is 4-tolyl or methyl, is reduced to a compound of formula (I) with a metal hydride reducing agent such as lithium aluminum hydride in, for example, tetrahydrofuran at elevated temperature, sodium borohydrohydride at elevated temperature in either an organic solvent such as an organic solvent, using a phase transfer technique, the organic phase being, for example, toluene or sodium bis (2-methoxyethoxy) aluminum hydride, for example in toluene at elevated temperature li __ 67538, or if X is F, Cl, Br or I, is catalytically hydrogenated in, for example, an alcohol such as ethanol, elevated At 1 ° C, preferably in the presence of a base, the catalyst being preferably palladium on carbon, after which the product can be converted into acidification salts. A novel compound, characterized in that it is a (Z) -1,2-diphenyl-1- [4- (2- (N, N-dimethylamino) ethoxy] phenyl] -1-butene derivative of the formula CH3 OCH9Ch9N 15 JL NNvCH3 ¥ CH0 I 2 CH2x0 II wherein X is F, Cl, Br, I or -O-S-R11 wherein R is 4-tolyl or methyl. 67538 A process for the preparation of therapeutically active (Z) -1,2-diphenyl-1- [4- [2- (N, N-dimethylamino) ethoxy] phenyl] -1-butene (i) / ¾ OCH2CH2N .0 ύ Xc% ch2 k3 15 kännetecknat därav, att ett triphenylbutenderivat rned forme In / ¾ och2ch2i5 "(6] ^ p CH2X d'ar X betyder en funkt ione] O-Ο-ϋ-R, when R is 4-tolyl or methyl, II or 30 reducers for the preparation of the formula (i) with a metal 1-hydride reduction medium, to give 1-aluminum aluminum hydride and t.ex. in tetrahydrofuran at room temperature, sodium borohydride in the case of organic and organic solvents, 35 parts of dimethyl sulfoxide, or genomic alternatives to organic solvents, such as organic toluene or toluene or sodium bis (2-methoxyethoxy) aluminum hydride or other toluene