DK165785B - PROCEDURE FOR THE PREPARATION OF TRIPHENYL BUTEN DERIVATIVES AND PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALTS AND INTERMEDIATES FOR USING THE PROCEDURE - Google Patents

Description

in

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The present invention relates to a particular process for the preparation of (Z) -1,2-diphenyl-1- [4- [2- (N, N-dimethylamino) -ethoxy] -phenyl] -1-butene or tamoxifen with Formula I below, or acid addition salts thereof and intermediates 5 for use in the process.

CH ..

/ 3

OCH-, CH_, N

φ "c" s I 2 CH3

Tamoxifen has antiestrogenic effect. Because of this property, the compound is used therapeutically to treat hormone-dependent breast cancer.

The preparation of tamoxifen of formula I is described in four patents (GB 1,013,907 and 1,354,939, AT 347,929 and DE 2,704,690), which disclose four methods 2q for their preparation. Three of these processes (GB 1,013,907, AT 347,929 and DE 2,704,690) include a Grignard or equivalent reaction that is difficult to perform on an industrial scale. The fourth process (GB 1,354,939) does not include any Grignard reaction, but the last step of the process is difficult to complete in other respects. It is used as a reagent namely either potassium or sodium amide and as solvent either liquid ammonia or dimethylformamide. When ammonia is used, the temperature is between -40 and -20 ° C and when dimethylformamide is used 120-150 ° C.

3q In addition to this, in each of the four processes described in the patent documents, the tamoxifen core must be built blunt by blunt in a number of successive steps. The same applies to α-ethylene oxybenzoins which are used as starting materials according to the patent specifications. Finally, it can be mentioned that with the exception of one side chain in one of the processes, either all high (>> 100 C) or low (<< 0 C) temperatures must be used in at least one reaction step in all processes.

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2

In the process of the present invention, tamoxifen is prepared without any Grignard reaction and at temperatures of 0-100 ° C. However, if desired, lower or higher temperatures may be used. The tamoxifen core itself is prepared very readily and contrary to the known processes directly in one step in a 60-80% yield from cinnamaldehyde (II) and 4 - [2- (N, N-dimethylamino) -ethoxy] -benzophenone (IV). Thereafter, the tamoxifen core is built up in 2-5 very simple and easily completed reaction steps to obtain 10 tamoxifen as the final product. These reactions proceed with virtually quantitative yields without side reactions. However, as 1/3 of the (E) isomer is formed in the dehydration step just as in the known processes, the theoretical yield is only approx. 67%. In addition, loss, primarily in connection with the removal (E) isomer, reduces the yield from 67% to approx.

50%. In other words, the yield of (Z) -amoxifene of formula I, calculated from the amount of 4- [2- (N, N-dimethylamino) -ethoxy] -benzophenone of formula IV is 30-40%.

The process of the invention for the preparation of tamoxifen or an acid addition salt thereof is characterized in that a triphenylbutene derivative of the formula OCH

25 Q VHI

Or O

CH-, ifi2x 30 where X is a functional group such as F, Cl, Br, I or?

-O-S-R

& where R is 4-tolyl or methyl is reduced by a metal hydride reducing agent such as lithium aluminum hydride in e.g. tetrahydrofuran at elevated temperature, sodium borohydride at form 3

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elevated temperature or in an organic solvent such as dimethyl sulfoxide, or using phase transfer technique, wherein the organic phase e.g. is toluene, or sodium bis (2-methoxyethoxy) aluminum dihydride e.g. in toluene at elevated temperature.

The process of the invention uses as starting material cinnamaldehyde (II) and 4- [2- (N, N-dimethylamino) -ethoxy] -benzophenone of formula IV. First, cinnamal aldehyde of formula II is hydroaluminated

10

<^^ y_CHCHCH0 II

to form an Al complex of formula III: 15 "/ CH2CvH2 / TVdH b W \ A1 / m NCH2CH2 w

20 When reacting this Al complex with the benzophenone derivative IV

CH3 OCH3 CHN3 + - 1,2-diphenyl-1- {4- [2- (Ν, Ν-dimethylamino) -ethoxy] phenyl} -butane-1,4-diol or triphenyldiol is formed of formula V: 30 CH-, / ^

0CHnCHo * T

φ 2oh ch2oh

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4 In the next step, the triphenyl diol V is dehydrated to give 4-acetoxy-1,2-diphenyl-1- {4- [2- (Ν, Ν-dimethylamino) -ethoxy] -

phenyl} -1-butene or triphenyl acetate of formula VI

CH, 3

ς OCH-.CH, N

5 I 2 2 \ 1 CH.

0

O-R-O

, ° <p2 J

CH2OCCH3 In the following steps, the triphenyl acetate VI is hydrolyzed to 1,2-di-phenyl-1- [4- [2- (Ν, Ν-dimethylamino) -ethoxy] -phenyl} -1-buten-4-ol ^ or triphenyl alcohol VII : CH-, / 3

OCH, CH, N

i 2 2 \ L X CH-, »n

Or O

CH, I 2

CH 2 OH

25

The hydroxy group of triphenyl alcohol VII is substituted with halogen to give 4-halogen-1,2-diphenyl-1- {4- [2- (N, N-dimethylamino) -ethoxy] -phenyl} -1-butene, i.e. the triphenyl halide VIII where X represents F, Cl, Br or I: CH, OCH, CH, N ^ 1 2 2 ^ '30 O0 O3 CH2 ch2-x

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Instead, a sulfonic acid ester can be prepared from the triphenyl alcohol VII to give 4-sulfonyloxy-1,2-diphenyl-1- [{4 - [2- (N, N-dimethylamino) -ethoxy] -phenyl } - 1 - butene or trifinylsulfonate IX where R represents 4-tolyl or methyl:

5 ^ CH

OCH-CHON ^ J

φ "

γ-λ \ r ~ \ IX

, o Otc ~ 0 CH_ 1 0 li

CH-OSR

2 II

o 15

Triphenyl halides of formula VIII may also be prepared from triphenylsulfonates IX or from another triphenyl halide VIII.

In the final step, the triphenyl halide VIII or triphenylsulfonate IX is reduced to tamoxifen I.

20

The triphenyl diol V can also be dehydrated in such a way as to form 2,3-diphenyl-2- {4- [2- (Ν, dim-dimethylamino) -ethoxy] -phenyl] -tetrahydrofuran, i.e. the triphenylfuran compound X: ^ CH3

25 0CHoCH „N

1 CH3

Q

O / 'VO

When the tetrahydrofuran ring in the triphenylfuran X is opened under appropriate conditions, triphenyl acetate VI is obtained. The opening of the tetrahydrofuran ring as well as the dehydration of triphenyldiol V can also be accomplished in such a way that the triphenyl alcohol VII is directly obtained.

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6

The dehydration and conversion of the primary hydroxy group to a halogen atom or a sulfonyloxy group may also occur in the reverse order of that described above. Thus, from the triphenylthiol V can be prepared either 4-halo-5-1,2-diphenyl-1- {4- [2- (Ν, Ν-dimethylamino) -ethoxy] -phenyl} -butane 1-ol or the hydroxy halide XI: .CH,

0CHoCHotr J

3 "3, 0 Lj

Ln nti ^ CH 2 hal 2 wherein hal represents F, Cl, Br or I, or the hydroxysulfonate XIX, namely 4-sulfonyloxy-1,2-diphenyl-1- [4- (2-, Ν-dimethylamino) -ethoxy] -phenylj-butan-1-ol: au

OCH-CIUNC

20 I 2 ^ CH, p /Λ-.ΟΗ XI1

W CH, 0H W

25 I 2 ΐ

CH20-C₅-: R

ISLAND

wherein R represents 4-tolyl or methyl. When the hydroxy halide XI or hydroxy sulfonate XII is dehydrated, the triphenyl halide VIII or the corresponding triphenylsulfonate IX is obtained.

Furthermore, triphenyl halides VIII can be prepared directly in a reaction step from the triphenyl diol V as well as from the triphenylfuran X. In fact, this process for dehydrating the triphenyl diol V is the very best and most practical because it can omit one or more reaction steps and thus reduce the reaction sequence to three steps. . Flow

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In other words, the procedure for preparing tamoxifen is most convenient and advantageous to carry out according to the following reaction series: In the first step, the triphenyldiol V is prepared from cinnamaldehyde II and 4- [2- (N, N-dimethylamino) ~ 5 ] -benzophenone IV. In the second step, the triphenyl diol V is dehydrated to give as a final product a triphenyl halide XI which is then reduced in the third and final reaction step to tamoxifen I.

All of the intermediates V-XIII of the present reaction series are novel compounds.

The invention therefore also relates to a (Z) -1,2-diphenyl-1- [4- [2- (N, N-dimethylamino) -ethoxy] -phenyl} -1-butene derivative of the formula 15 ^ N- ^ I 1 1 ^ CH3 wine O ^ c— ^ 3 20 CH- I 2

CH 2 X

C) wherein X represents F, Cl, Br, I or -O-S-R, where R is 4-tolyl & 25 or methyl for use as starting material in the process of claim 1.

The hydroalumination of cinnamal aldehyde II is carried out with some aluminum hydride reducing agent, for example lithium aluminum hydride or sodium bis (2-methoxyethoxy) aluminum dihydride, and the resulting aluminum complex III is reacted with 4- [2- (N, N- the dimethylamino-ethoxy-benzophenone IV. The reaction is preferably carried out at room temperature in, for example, an ether or a hydrocarbon solvent or a mixture thereof. An example of an ether solvent may be mentioned tetrahydrofuran.

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8 robberies and on a hydrocarbon toluene.

The triphenyl diol V can be dehydrated in many different ways, including with an acidic catalyst either in an alcoholic solvent or in an organic acid or with a mixture of an acid anhydride and an acid chloride.

When using a mixture of acetic anhydride and acetyl chloride, the reaction is preferably carried out at a temperature of 80-100 ° C as follows: First, the triphenyl diol V is reacted with acetic anhydride 10 to form 4-acetoxy-1,2-diphenyl-1- {4- [2- (N, N-dimethylamino) -ethoxy] -phenyl] -butan-1-ol or the hydroxyacetate XIII: CH

AND-CH-N ^ J

Φ2 2 CH-,

XIII

I 20 CH 2 O-CH 3

Acetyl chloride is then added to dehydrate hydroxy acetate XIII.

Hydrolysis of the resulting triphenyl acetate VI is carried out in a suitable solvent under either acidic, alkaline or neutral conditions. In acidic and alkaline hydrolysis, an alcoholic solvent, e.g. ethanol, is conveniently used and the reaction is carried out either at the boiling point of the mixture or at a lower temperature. For example, in alkaline hydrolysis, sodium hydroxide can be used as a catalyst and in acidic hydrolysis, for example hydrochloric acid.

The triphenyl halides VIII are prepared from triphenyl alcohol VII, for example in the following ways: By treating the triphenyl alcohol VII in a suitable solvent with, for example, diethylamino nosulfur trifluoride ((C 2 H 2 As a solvent, inter alia, halogenated hydrocarbons or ethers may be used and as special examples may be mentioned methylene chloride and dimethoxyethane.

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at room temperature or at lower temperature.

When treating the triphenyl alcohol VII in a suitable solvent with, for example, thionyl chloride or triphenylphosphine carbon tetrachloride reagent, the triphenyl chloride VIII is formed (X = 5 Cl). Using thionyl chloride, the reaction can be carried out in, for example, chloroform, and when using the triphenylphosphine carbon tetrachloride reagent, for example, acetonitrile or a mixture of acetonitrile and carbon tetrachloride can be used. The reaction is most conveniently carried out at the boiling point of the reaction mixture or at a lower temperature. When treating the triphenyl alcohol VII in a suitable solvent with, for example, phosphorus tribromide or triphenylphosphine carbon tetrabromide, the triphenyl bromide VIII (X = Br) is similarly formed. For example, when phosphorus tribromide is used, the reaction can be carried out in methylene chloride and when the triphenylphosphine carbon tetrabromide reagent is used, for example, in acetonitrile or a mixture of acetonitrile and methylene chloride.

In both cases, the reaction is preferably carried out at ca. room temperature. When treating triphenyl alcohol VII in a suitable solvent with, for example, triphenylphosphite methiodide 20, the triphenyl iodide VIII is formed (X = I). As a solvent, hexamethylphosphorous triamide is used and as the reaction temperature room temperature. The triphenyl halides VIII can also be converted to other triphenyl halides VIII by refluxing or heating them in a suitable solvent together with, for example, an alkali metal or alkaline earth metal halide.

In this way, for example, the triphenyl chloride VIII (X = Cl) can be prepared from the triphenyl bromide VIII (X = Br) and from the triphenyl bromide VIII (X = Br) the triphenyl iodide VIII (X = I) can be prepared. As a solvent, for example, N-methyl-2-pyrrolidone can be used. Triphenyl halides VIII can also be prepared from triphenyl sulfonates IX by refluxing or heating them in a suitable solvent together with, for example, an alkali metal or alkaline earth metal halide. In this way, for example, from the triphenyl tosylate IX (R = 4-toyl) the triphenyl iodide VIII (X = I) can be prepared. The reaction is preferably carried out using sodium iodide as a reagent and boiling acetone as the solvent.

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10

The triphenylsulfonates IX are prepared from the triphenylalcohol VII, for example, by the following processes: When treating the triphenyl alcohol VII with 4-toluenesulfonic acid chloride under appropriate conditions, the triphenyl tosylate IX is formed (R = 4-tolyl). The reaction can be carried out either in an organic solvent, for example pyridine, in a solvent mixture or by phase transfer technique using, for example, toluene as an organic solvent. When the reaction is carried out in pyridine, it is advantageous to use a temperature in the vicinity of 0 ° C. When phase transfer technique is used, the reaction is preferably carried out at ca. room temperature. When treating the triphenyl alcohol VII with methanesulfonic acid chloride under appropriate conditions, the corresponding triphenyl mesylate IX (R = methyl) is formed. The reaction can be carried out either in an organic solvent, for example pyridine 15 or a mixture of methylene chloride and triethylamine, or by phase transfer technique using, for example, methylene chloride as an organic solvent. In either case, the reaction is preferably carried out at a temperature in the vicinity of 0 ° C.

The triphenyl halides VIII are reduced to tamoxifen 20 I, for example, with a metal hydride reducing agent, catalytically, by a dissolved metal, via a Grignard-type intermediate or by desulphoring a thioether prepared from a halide.

As examples of useful metal hydride reducing agents 25 mention is made of lithium aluminum hydride, sodium borohydride, sodium bis (2-methoxyethoxy ·) aluminum dihydride, sodium cyanoborohydride and tributyltin hydride. For example, when lithium aluminum hydride is used, ether or hydrocarbons such as tetrahydrofuran or toluene or mixtures thereof are useful as solvents.

When sodium borohydride is used, the reaction is carried out either in a suitable solvent, for example dimethyl sulfoxide, a solvent mixture or by phase transfer technique using, for example, toluene as an organic solvent.

When sodium bis (2-methoxyethoxy) aluminum hydride is used, the reaction is preferably carried out in toluene, although many other solvents and solvent mixtures can be used. For example, hexamethylene phosphorus triamide is suitable as a solvent when sodium cyanoborohydride is used and, for example, toluene when 1 1

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tributyltin hydride is used.

The metal hydride reduction is usually carried out at a temperature slightly above room temperature, e.g. 50 ° C. The catalytic hydrogenation is carried out by hydrogenolysis in the presence of, for example, a precious metal catalyst. Among metal catalysts are palladium on coal and palladium on barium sulfate and, among other catalysts, for example Raney nickel. The hydrogenation is carried out under either acidic, neutral or alkaline conditions. As the solvent, for example, some alcohol is used, such as methanol or ethanol or some carboxylic acid, for example acetic acid. The reaction is preferably carried out at room temperature or slightly above. The reduction with a dissolved metal is carried out with zinc / acetic acid treatment which is best suited for the reduction of triphenyl iodide and bromide (VIII, X = I or 15 Br). The reaction is preferably carried out at a temperature above room temperature. As another example for reduction with a dissolved metal, mention may be made of an alkali metal such as lithium dissolved in liquid ammonia. Among the intermediates in the reduction via Grignard-type intermediates may be mentioned the Grignard-20 or the magnesium complex (VIII, X = Mghal) and the lithium salt (VIII, X = Li). The Grignard complex is prepared from the triphenyl halide VIII with magnesium in a suitable ether solvent such as tetrahydrofuran or a solvent mixture containing some ether. The reaction is preferably carried out at room temperature. The lithium salt can be prepared either directly from lithium metal or by an exchange reaction with a suitable lithium salt, for example, butyllithium. As a solvent, for example, either a hydrocarbon solvent, eg hexane, or an ether solvent such as diethyl ether or a mixture thereof is used.

The magnesium complex or lithium salt which breaks down as an intermediate is decomposed into tamoxifen I, for example by means of a solvent containing a hydroxy group, for example water. The desulphurization of a thioether prepared from the halide to tamoxifen is carried out as follows: First, the trifanyl halide VIII is reacted with a thioalcohol or thiophenol, preferably in the form of a sodium salt thereof, to form a thioether. For example, when the sodium salt of ethyl mercaptan reacts with

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When the phenyl halide VIII in a suitable solvent, e.g., dimethylsulfoxide, is formed, the corresponding ethylthioether VIII (X = sch2ch3).

In the subsequent reaction, the thioether VIII 5 (X e.g. SCE ^ CH 2) is reduced to tamoxifen. The reduction is carried out with, for example, Raney nickel in ethanol.

The triphenyl sulfonates IX are reduced to tamoxifen I with, for example, a metal hydride reducing agent or by desulfurization of a thioether prepared from a sulfonate. The metal hydride reduction and the preparation and desulfurization of the thioether are carried out in substantially the same manner as mentioned above in connection with the reduction of the triphenyl halides V.III.

The dehydration of triphenyl diol V to the triphenylfuran X can be carried out, for example, as follows: When treating the triphenyl diol V with an acidic catalyst under appropriate conditions, water is decomposed and the triphenyl furan X is formed. Examples of suitable acidic catalysts include hydrochloric acid and sulfuric acid, and examples of suitable solvents are alcoholic ones. When sulfuric acid is used as acid catalyst and ethanol 20 as the solvent, the reaction is preferably carried out at slightly above room temperature. By acidifying the reaction mixture in connection with the preparation of the triphenyl diol V with, for example, hydrochloric acid, the triphenylfuran X can be recovered without any isolation of the triphenyl diol V.

If the triphenyl diol V is treated with an acidic catalyst under appropriate conditions in a suitable solvent, the triphenyl alcohol VII is obtained by dehydration. Under the same conditions, the tetrahydrofuran ring in the triphenylfuran X is also opened and the triphenyl alcohol VII is also formed.

As an acid catalyst, dry hydrogen chloride or concentrated hydrochloric acid is used and as a solvent alcohols such as ethanol. The reaction is preferably carried out at the boiling point of the mixture or at a lower temperature.

Furthermore, when the triphenylfuran X is treated with an acidic catalyst under appropriate conditions in an organic acid, in this case acetic acid, the tetrahydrofuran ring is opened and the triphenyl acetate VI is formed. Under the same conditions, the triphenyl acetate VI is also formed from the triphenyl diol V. As 1 3

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acid catalyst can be used, for example, hydrogen bromide. The reaction is preferably carried out either at the boiling point of the mixture or at a lower temperature.

Preparation of the hydroxy halides XI and hydroxy sulfonates XII from the triphenyl diol V as well as the dehydration to the triphenyl halides VIII and the triphenyl sulfonates are carried out using similar reactions as described above. Preparation and dehydration of the hydroxy sulfonates XII can also be carried out in one combined reaction step.

Preparation of the triphenyl halides VIII from the tri phenyl diol V or triphenylfuran X in one reaction step can be carried out, for example, by the following methods. When the triphenyl diol V is reacted with thionyl chloride in a suitable solvent, e.g., chloroform or toluene, the triphenyl chloride VIII (X = Cl) is formed. The reaction is preferably carried out as a two-step reaction. In the first step, cooling is used and in the second stage heating is used. When the corresponding triphenylfuran X is reacted with triphenylphosphine dibromide in a suitable solvent, for example acetonitrile, the triphenyl bromide VIII is formed (X = Br). The reaction is preferably carried out by heating.

The reaction sequence described in connection with the present invention is preferably carried out in such a way that only part of the intermediates is purified. For example, if the triphenyl diol V is purified by recrystallization, the remainder of the reaction can be carried out without purification of the intermediates. The operation can also be done in such a way that instead of the triphenyl diol V, only the triphenyl chloride VIII (X = Cl) or triphenyl alcohol VII is purified. If desired, separation of the isomers can also be carried out in the same context. In fact, purification 30 and isomer separation are preferably performed in one and the same context.

The (Z) isomer can be isolated from the mixture of the (Z) and (E) isomer, both in triphenyl acetate stage VI, triphenyl alcohol stage VII, triphenyl halide stage VIII and triphenyl sulfonate stage. The reaction can also be carried out in such a way that the (Z) isomer is not isolated before the tamoxifen stage.

The (Z) isomer can also be isolated as well when the isomers are free bases as when in salt form. The isolation of the (Z) isomer from the isomer mixture is carried out either by fraction 14

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ionized crystallization, fractional solution, chromatographically or by a combination of these methods.

In the process of preparing tamoxifen according to the present invention, the functional group is removed at the end of the ethyl group in the last step. In principle, acetoxytamoxifen VI and tamoxifen alcohol V I can also be reduced directly to tamoxifen. In the literature, such processes are even described in which, by reducing alcohols, esters or ethers, the corresponding hydrides 10 are obtained (see, e.g., Compendium of Organic Synthetic Methods, Vols 1-4,

sections 153, 158 and 159). The reductions in question generally succeed poorly in normal cases and often require very severe conditions. ISLAND

The group -CH₂OH or -Cf₂O-C-CH₂ can be more easily reduced to the CH₂ group via the corresponding halide or sulfonic acid ester, but other esters such as thiocarbamates (see Chem. Commun. 1979, 1175) may also be used.

Simple halides and sulfonates can be readily prepared from the corresponding alcohols in high yields. In addition, 20 simple halides and sulfonates can be readily reduced in high yields to the corresponding hydrides by various processes (see, e.g., Compendium of Organic Synthetic Methods, Vol. 1-4, Section 160, and Synthesis 1980, 425-452).

The truly inventive 25 lies in the extreme ease with which, above all, the triphenyl halides VIII and, in particular, the triphenyl chloride (X = Cl) can be prepared in two very simple and technically feasible reactions in good yields. The third and final step in which the triphenyl halide VIII or triphenyl sulfonate IX is reduced to tamoxifen is also inventive because it could not be anticipated that a compound having such a complex structure as compounds VIII and IX, dys. containing a double bond so as to be readily reduced to tamoxifen and in practically quantitative yield.

35 15

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Example 1 1,2-Diphenyl-1- {4- [2- (N, N-dimethylamino) -ethoxy] -phenyl} -butane-1,4-diol (triphenyldiol V; RR, SS? RS, SR) To a reaction flask containing 20 g of lithium aluminum hydride dissolved and dispersed in 500 ml of dry tetrahydrofuran, add, with stirring, 132 g of cinnamal aldehyde dissolved in 750 ml of dry tetrahydrofuran. The temperature is maintained between 25 and 35 ° C during the addition. When the entire amount of cinnamon aldehyde 10 is added, the mixture is stirred for an additional 30 minutes at room temperature. Then, with stirring, 269 g of 4- (2- (N, N-dimethylamino) -ethoxy) -benzophenone (IV) dissolved in 1000 ml of dry tetrahydrofuran are added and the temperature is maintained at 35-45 ° C during the addition. The mixture is stirred for an additional 2 hours at 45 DEG C. Then, with stirring, the reaction mixture is first added with 20 ml of water, then 20 g of 15% sodium hydroxide solution and finally 60 ml of water. The precipitated lithium and aluminum hydroxide are removed by filtration. The solvent is then distilled off and the residue recrystallized from toluene The yield of pure isomer mixture is 243-324 g (60-80%) and the melting point 127-151 ° C. The isomer mixture contains about 60% for solubility reasons (RR, SS) -enan-thiomer pairs, although both pairs are formed in the reaction. Upon recrystallization of the isomer mixture from acetone 25, the (RR, SS) -enantiomer pair is obtained, mp 165-167 ° C (from toluene). by recrystallization twice of the residue from acetone, the (RS, SR) enantiomer pair is obtained with m.p. 139-141 ° C (from toluene). 1 2 3 4 5 6 4-Acetoxy-1,2-diphenyl-1- [4- [2- (N, N-dimethylamino) -ethoxy] -phenyl} -2-butene (triphenylacetate VI; Z and Z, E) 3 405 g of triphenyl diol V, either pure enantiomer pair 4 or mixture thereof, are dissolved in 1500 ml of hot acetic anhydride.

anhydride. The mixture is stirred for 1 hour at a temperature of 90 ° C

6 whereby the primary hydroxy group is acetylated (as intermediate, the hydroxy acetate XIII is formed; the melting point of the (RR, SS) enantiomer pair is 97-99 ° C). Then, with stirring, 318 g of acetyl chloride dissolved in 500 ml of acetic anhydride 16 are added.

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whereupon the reaction mixture is kept at 90 ° C for 3 hours. Finally, the solvent is evaporated to give the hydrochloride salt of (Z, E) triphenyl acetate VI in quantitative yield.

In the residue, which has m.p. 114-122 ° C, 2/3 is the desired (Z) -5 isomer and 1/3 (E) isomer. (Z) -Isomer m.p. as free base is 67-69 ° C.

1,2-Diphenyl-1- {4- [2- (Ν, Ν-dimethylamino) -ethoxy] -phenyl] -1-buten-4-ol (triphenyl alcohol VII; Z and Z, E) - The residue containing the hydrochloride of The (Z, E) triphenyl acetate VI (Z: E = 2: 1) obtained in the previous step is dissolved in 2000 ml of ethanol. The solution is then neutralized with 20% sodium hydroxide solution. Add 300 ml or more of 20% sodium hydroxide solution and 200 ml of water to reflux for 1 hour. The reaction mixture is neutralized with 2M hydrochloric acid. The solvent is evaporated and water is added to the residue. The product is then extracted with a mixture of toluene and ethyl acetate 8.2. After washing with water, the solvents are evaporated to give the (Z, E) triphenylalcohol VII (Z: E = 2: 1) in quantitative yield. M.p. is 93-100 ° C. The desired (Z) isomer is isolated, for example, as follows: Method a. The above-obtained (Z, E) triphenyl alcohol-VII (Z: E = 2: 1) is recrystallized from toluene to give 157 g (Z) triphenyl alcohol. VII, which corresponds to 41% calculated from the amount of triphenyl diol used. of the (Z) triphenyl alcohol is 110-112 ° C. Then, the isomer mixture remaining in the toluene mother liquor is 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. The residue is dissolved in boiling acetone whereby the (Z) isomer dissolves completely and the majority of the (E) isomer remains undissolved. The cooled solution is filtered to remove precipitated (E) triphenyl alcohol VII. After evaporation of the acetone, the residue is dissolved in boiling ethanol. Upon cooling the solution, an additional 47 g (11%) of (Z) -trifertyl alcohol VII is crystallized in the form of its hydrochloride salt. Thus, the total yield of triphenyl alcohol VII is 52% by calculation

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17 from the amount of triphenyl diol V. The melting point of the (Z) triphenyl alcohol VII hydrochloride is 166-168 ° C (from acetone). If desired, the (Z) isomer can be released from its hydrochloride salt as follows.

5 First, the hydrochloride salt is dissolved in hot water and then 10% s sodium carbonate solution is added. Then, the released (Z) isomer is extracted from the cooled solution in a mixture of toluene and ethyl acetate. Finally, wash with water and evaporate. The (Z) isomer is obtained as a free base without extraction loss.

Method b. (Z, E) -The triphenyl alcohol residue (VII, Z: E = 2: 1) obtained above is dissolved in acetone and then converted to the hydrochloride salt thereof by introducing hydrogen chloride into the solution. Then, the hydrochloride isomer mixture 15 is treated with acetone and recrystallized as described under Method a. The yield of hydrochloride of (Z) -riphenyl alcohol VII is 195 g, which is 41%, based on the amount of triphenyldiol V used.

Method c. The (Z, E) -trifertyl alcohol residue (VII, Z: E = 2: 1) obtained as described above is dissolved in ethanol and the isomer mixture is converted to the hydrochloride salt thereof by introducing hydrogen chloride into the solution. When the heated solution is allowed to cool, a precipitate forms, which is recrystallized again from ethanol. In this way, 123 g of hydrochloride salt of (Z) -riphenyl alcohol VII is obtained, which corresponds to 29% based on the amount of triphenyldiol V used.

Method d. (Z) Tamoxifen is readily isolated from the (Z) and (E) isomer mixture, for example, by column or layer chromatography for the (Z) isomer moving remarkably faster with many solvents than the (E) isomer. In isolation by column or layer chromatography, as a mobile solvent, for example, either toluene-Et 1 N 90:10 (R 2 / Z 0.20; R 2 / E 0.05) or CHCl 3 / MeOH / concentrated NH 3 90 is used: 95: 0.5 (R f / Z 0.49; R f / E 0.33).

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Example 2 4-Chloro-1,2-diphenyl-1- {4- [2- (Ν, Ν-dimethylamino) -ethoxy] -phenyl] -1-butene (triphenyl chloride VIII; X = Cl; (Z)) 387 g of (Z) triphenyl alcohol VII either as free base, hydrochloride salt or a mixture thereof is dissolved in 2400 ml of chloroform. 238 g of thionyl chloride are added and then the mixture is refluxed for 3 hours. After evaporation of the solvent, 10% of sodium carbonate solution is added and the product is extracted with toluene. After washing with water, the solvent is distilled off to give the (Z) triphenyl chloride VIII (X = Cl) in quantitative yield. The melting point of this (Z) triphenyl chloride VIII as free base after recrystallization from acetone is 108-110 ° C and the melting point of the hydrochloride salt 194-196 ° C after recrystallization from acetone.

15

Tamoxifen (Z) (I)

To a reaction flask containing 76 g of lithium aluminum hydride dissolved or dispersed in 1000 ml of dry tetrahydrofuran is added the (Z) triphenylchloride mixture (VIII, X = Cl) obtained in the previous section in 1500 ml of dry tetrahydrofuran and refluxed for 4-5 hours. hours. Excess reagent is decomposed by the addition of ethyl acetate. Then, with stirring, first 76 ml of water and then 76 g of 15% sodium hydroxide and finally 228 ml of water are added. The precipitated lithium and aluminum hydroxide are removed by filtration and the solvent is evaporated. The residue is dissolved in toluene. After washing with water and drying over sodium sulfate, the toluene is distilled off to give (Z) tamoxifen I in quantitative yield. Then, the (Z) tamoxifen is converted to the citrate salt in a conventional manner with ^ citric acid in acetone. The thus obtained (Z) -amoxifene citric acid salt melts at ca. 142 DEG C. and the yield is 507-535 g, which corresponds to 90-95% calculated from the amount of (Z) triphenyl alcohol VII used.

The triphenyl chloride (Ζ, Ε) (VIII, X = Cl) (Z, E) -The triphenyl chloride VIII (X = Cl; Z: E = 2: 1) is prepared from the toluene-ethyl acetate residue from (Z, E) 19

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the alcohol VII (Z: E = 2: 1) in the same manner as the pure (Z) isomer as described above. The yield after evaporation of toluene is quantitative.

Tamoxifen (Ζ, Ε) (I) The toluene residue from the (Z, E) triphenyl 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 described above. The (Z) isomer is isolated from the isomer mixture by known methods and converted to the citrate salt as described above. The melting point of the thus obtained (Z) -amoxifene lemon salt is approx. 142 ° C and the yield 225-253 g, which corresponds to 40-45% based on the amount of triphenyl diol V used.

Example 3 4-Tosyloxy-1,2-diphenyl-1- {4- [2- (Ν, Ν-dimethylamino) -ethoxy] -phenyl] -1-butene (Z and Z, E; the triphenyl tosylate IX, R = 4-tolyl) 387 g (Z) triphenyl alcohol VII either as a free base, as a hydrochloride salt or as a mixture thereof is dissolved in 1000 2Q ml of dry pyridine. While stirring the reaction mixture, 572 g of 4-toluenesulfonic acid chloride dissolved in 1000 ml of dry pyridine are added. The temperature is kept at 0 ° C during the addition. The reaction mixture is then stirred for 4 hours at 0 ° C. then with stirring and with maintaining the temperature of 0-2 ° 10 ° C, add 200 ml of cold water first and then cold 10% hydrochloric acid until the reaction mixture is acidic. The precipitated hydrochloride of (Z) triphenyl tosylate IX (R = 4-tolyl) is collected by filtration, washed with water and dried. The precipitate m.p. is 122-124 ° C and the yield quantitative. The melting point of the corresponding β (Z, E) triphenyl tosylate IX (Z: E = 2: 1; R = 4-tolyl) is 80-105 ° C.

The melting point of the (Z) isomer released by treatment with toluene / base and recrystallized from petroleum ether is 85-87 ° C. 1

Tamoxifen (Z) (I)

The hydrochloride obtained above (Z) triphenyltosylate IX (R = 4-tolyl) is triturated with 10% sodium carbonate solution 20

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whereupon it is extracted as free base with toluene. After washing with water, the toluene is distilled off to dry the solution until its volume is 2000-2500 ml. The toluene solution obtained is added to 720 ml of 70% sodium bis (2-methoxyethoxy) aluminum hydride-toluene solution while maintaining the temperature at 75 ° C during the addition. Thereafter, stirring is continued at the same temperature for 3 hours. Excess reagent is digested with ethyl acetate and then the reaction solution is washed twice with water. After drying over sodium sulfate, the solvent is evaporated to give (Z) tamoxifen I in quantitative yield.

The citrate salt is prepared as described above. The melting point of the (Z) -tamoxifen-citric acid salt obtained is about, 142 ° C and the yield is 479-507 g, which corresponds to 85-90% based on the amount of (Z)-triphenylalcohol V used.

Example 4 2,3-Diphenyl-2- [4- [2- (N, N-dimethylamino) -ethoxy] -phenyl] -tetrahydrofuran (triphenylfuran X; RR, SS; RS, SR) - 405 g of triphenyldiol V , either a pure enantiomer pair or a mixture thereof, is dissolved in a solution containing 4000 ml of ethanol, 150 ml of concentrated sulfuric acid and 750 ml of water. The reaction mixture is stirred for 3 hours at a temperature of 45 ° C. The solution is neutralized with 2M sodium hydroxide and the ethanol is evaporated. Water is added to the residue and the product is extracted with toluene. After drying over sodium sulfate, the toluene is evaporated to give the triphenylfuran X in quantitative yield, wherein the (RR, SS) enantiomer pair is remarkably enriched at the expense of the (RS, SR) pair. The melting point of the (RR, SS) triphenylfuran X is 83-85 ° C after recrystallization from ethanol.

30

Triphenyl Alcohol VII (Z, E) Dissolve 387 g of triphenylfuran X or 405 g of triphenyl diol V, either as a pure enantiomer pair or a mixture thereof, in 2500 ml of dry ethanol containing excess hydrogen chloride gas. The mixture is refluxed for 4 hours and the solvent is evaporated. The yield of the hydrochloride salt of the triphenyl alcohol

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21 VII (Z: E = 2: 1) is quantitative, but it contains as impurity approx. 5% 2,3-diphenyl-2- [4- (Ν, Ν-dimethylamino) -ethoxy] -phenyl-tetrahydrofuran. The isolation of the (Z) isomer is carried out as in Example 1.

5

Example 5 4-Bromo-1,2-diphenyl-1- {4- [2- (Ν, Ν-dimethylamino) -ethoxy] -phenyl} -1-butene (Z) (the triphenyl bromide VIII, X = Br) - 387 g (Z) -riphenyl alcohol VII is dissolved in 3000 ml of dry acetonitrile. With stirring, 395 g of triphenylphosphine are added to the mixture first and then in small portions 498 g of carbon tetrabromide. The reaction mixture is stirred at room temperature for 2 hours. The solution is cooled to crystallize the desired product and collected by filtration. The yield is 306 g (68%) and the melting point 114-116 ° C (from methanol). More pure product can be obtained from the mother liquor if desired.

Tamoxifen (Z) (1) 2Q 306 g (Z) triphenyl bromide VIII (X = Br) and 51 g hexadecyltributylphosphonium bromide are suspended in 340 ml of toluene. Then 103 g of sodium borohydride dissolved in 270 ml of water are added. The mixture is stirred for 24 hours at a temperature of 50 ° C. Water is added and then the product is extracted with toluene. The toluene solution is dried and the solvent is evaporated.

2 5

Most of the residue consists of the boron complex of the desired product, but also contains some complex-free product. The residue is dissolved in 1700 ml of absolute methanol and 340 ml of concentrated hydrochloric acid is added. The mixture is stirred for 2 hours at 2 ° C at 50 ° C, thereby decomposing the boron complex. The solvent is distilled off and the product is suspended in toluene. Then 2M sodium hydroxide solution is added to release the product from the HCl salt thereof. The aqueous layer is discarded and the toluene layer is washed with water. The solvent is then evaporated to give (Z) tamoxifen I in almost quantitative yield. The citrate salt is prepared as described above.

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22

Example 6 Tamoxifen (Z) (I) Dissolve 40.6 g (Z) triphenyl chloride VIII (X = Cl) in 1000 ml of ethanol and then 41.4 g of dry potassium carbonate 5 and 12 g of 5% palladium / carbon are added. The reaction mixture is shaken at 50 ° C in a hydrogen atmosphere until the reaction is complete, ca. 3 hours. The catalyst is removed by filtration and the solvent is distilled off. The residue is converted to the citrate salt thereof as described above. The yield is almost quantitative.

Example 7 4-Chloro-1,2-diphenyl-1- {4 - [2- (N, N-dimethylamino) -ethoxy] -phenyl] -1H-butene (Z) (the triphenyl chloride VIII, X = Cl) 405 g of triphenyl diol V are suspended in 2500 ml of toluene and then 250 ml of toluene is distilled off to dry the solution. The mixture is cooled with stirring to 0 ° C. With continued stirring and keeping the temperature at 0 ° C or slightly below 2q, 476 g of good quality thionyl chloride is added. The mixture is stirred for 1 hour at 0 ° C and then allowed to rise to 22 ° C.

Then the mixture is stirred at 80 ° C until the reaction is complete, ca. 3 hours. Water is added to decompose 2, - excess thionyl chloride, and then 20% to obtain anhydrous oxide solution to release the product from its hydrochloride salt.

Discard the aqueous layer. The toluene layer is washed with water. Then, the solvent is juxtaposed to give the (Z, E) triphenyl chloride (Z: E = 7: 3) in quantitative yield. The residue is recrystallized from methanol. 182 g (45%) of pure (Z) isomer is obtained.

Tamoxifen (Z) (I) 182 g of the (Z) triphenyl chloride and 51 g of sodium borohydride are dissolved in 900 ml of dimethyl sulfoxide and the reaction mixture is kept at 85 ° C for 5 hours. Water is added to precipitate the product as a boron complex. The precipitate is filtered off and washed 23

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with water. The precipitate is then dissolved in 1125 ml of absolute ethanol and 225 ml of concentrated hydrochloric acid is added. The mixture is stirred for 2 hours at 50 ° C, which degrades the complex. The solvent is evaporated and then the product 5 is suspended in toluene. 2M sodium hydroxide solution is added to release the product from its hydrochloride salt. The aqueous layer is discarded and the toluene layer is washed with water. The solvent is then evaporated. Finally, the residue is converted to the citrate salt thereof as described above. The yield is almost quantitative and the melting point approx. 142 ° C.

Claims (2)

A process for the preparation of (Z) -1,2-diphenyl-1- {4- [2- (N, N-dimethylamino) -ethoxy] -phenyl] -1-butene (tamoxifen) of formula I or an acid addition salt thereof 5 / CH3 OCHoCH, N ^ 1 2 2 ^ CH3 I 2 CH3 characterized in that a triphenylbutene derivative of the formula 15 ^ CH .. OCH-CH ^ NC j I 2 * ^ CH3 fj Or ^ -O CH Ϊη2χ where X is a functional group such as F, Cl, Br, I or 25 $ -OSR II where R is 4-tolyl or methyl is reduced with a metal hydride reducing agent such as lithium aluminum hydride in e.g. tetrahydrofuran at elevated temperature, sodium borohydride at elevated temperature or in an organic solvent such as dimethyl sulfoxide, or using phase transfer technique, where the organic phase e.g. is toluene, or sodium bis (2-methoxyethoxy) aluminum dihydride e.g. in toluene at elevated temperature. 2. (Z) -1,2-Diphenyl-1- {4- [2- (Ν, Ν-dimethylamino) -ethoxy] -phenyl} -butan derivative of the formula CH ^ Wherein X represents F, Cl, Br, I or -O-S-R, wherein R is 4-tolyl tt or methyl for use as the starting material of the method of claim 1.