KR20120039344A - A novel method of making endoxifen - Google Patents

Abstract

PURPOSE: A manufacturing method of endoxifen is provided to lower manufacturing cost and obtain high purity edoxifen with high yield. CONSTITUTION: A manufacturing method of Z-form edoxifen which is represented by chemical formula 1 comprises the following steps: a first step of protecting one -OH in 4,4- hydroxybenzophenone using a protective group; a 2nd step of coupling the outcome of the first step with propiophenone; a 3rd step of O-alkylating hydroxyl group in the outcome of the 2nd step; a 4th step of unprotecting the protective group which is attached to the hydroxyl group; a 5th step of unprotecting a protective group of alkyl moiety which is combined by the O-alkylation; and a 6th step of fractional crystallizing the outcome of the 5th step using an organic solvent.

Description

A novel method of making Endoxifen

The present invention relates to a novel process for preparing endoxifen, and more particularly, using 4,4'-hydroxybenzophenone as a starting material, high yield and high yield of Z form endoxifen having anticancer effect It relates to a method for producing in purity.

Breast cancer is the second most common cancer among domestic female cancers, and 60-70% of all breast cancer patients are subject to hormone therapy.

Tamoxifen is a representative hormone therapy that has been used in premenopausal and postmenopausal breast cancer patients for more than 30 years. Tamoxifen does not exert its own effects, but is converted to endoxifen, an active metabolite by CYP2D6, a metabolite present in the liver, and the converted endoxifen has an anti-hormonal effect. However, about 30% of estrogen receptor-positive breast cancer patients are genetically deficient in CYP2D6, and thus do not convert to endoxifene, which is an activator of tamoxifen.

Recently, a lot of third-generation aromatase inhibitors are used for hormonal treatment, but this drug also has many side effects and cannot be used in premenopausal patients.

Tamoxifen has been proven to be safe for a long time compared to aromatase inhibitors, and has the merits of tamoxifen, such as cardioprotective function and bone mineral augmentation. Breast cancer patients are expected to benefit.

Various methods have been proposed for synthesizing endoxifen, known as an active metabolite of tamoxifen, a breast cancer drug. US 2009/0291124 A1 describes a process for preparing endoxifen from 4-hydroxybromobenzene.

In addition, WO 2009 / 120999A2 describes the preparation of the endoxifen as follows.

By the way, the two manufacturing methods are using a high-cost reaction material, the manufacturing cost is high, and does not provide a method of separating the endoxifen of pure Z form.

In addition, WO 2008/070463 describes a process for preparing endoxifen as follows.

Bioorganic & Medical Chemistry Letters, 2010, describes a process for preparing endoxifen for separating Z form endoxifen by RP-HPLC, which is not suitable for mass production.

As described above, the conventional endoxifen manufacturing methods are not purely manufactured Z form endoxifen, the manufacturing cost is high even if the production is possible, or the separation and purification technology is not suitable for mass production. None of the documents discloses a process for producing endoxifen from 4,4′-hydroxybenzophenone.

The present invention uses a 4,4'-hydroxybenzophenone as a starting material to reduce the production cost of the endoxifen, while at the same time the production method suitable for mass production in which Z form endoxifen can be obtained in high purity and high yield To provide.

According to the present invention, there is provided a method for preparing Z form endoxifen or a salt thereof using 4,4′-hydroxybenzophenone as a starting material:

According to the present invention, there is also provided a method comprising the first step of protecting one hydroxy group in 4,4′-hydroxybenzophenone by a protecting group.

According to the present invention, there is further provided a method comprising the second step of coupling the compound obtained in the first step with propiophenone.

Also provided is a method comprising the third step of O-alkylating the hydroxy group in the compound obtained in the second step.

The present invention also provides a method comprising a fourth step of deprotecting a protecting group bound to a hydroxy group.

Also provided is a method comprising the fifth step of deprotecting a protecting group of an alkyl moiety bound by O-alkylation.

The present invention also provides a method comprising the sixth step of fractionating the material obtained in the fifth step with an organic solvent.

In the sixth step, the organic solvent is selected from the group consisting of ethyl acetate, methanol, ethanol, propanol, benzene, acetone, acetonitrile, toluene, dichloromethane, 1,2-dichloroethane and chloroform, or used alone or It provides a method characterized by being used in combination with water, diethyl ether.

In addition, the obtained E / Z endoxifene mixture is treated with an acid or base to provide a method characterized in that the conversion of the E form endoxifene in the mixture to Z form endoxifen.

Also provided is a process characterized in that the obtained endoxifene is reacted with water and citric acid to obtain an endoxifen citrate salt.

According to the production method of the present invention, 4,4'-hydroxybenzophenone can be used to obtain a high purity, for example, 99% or more of the endoxifen, while lowering the manufacturing cost compared to the conventional endoxifen production method. In addition, Z form endoxifen showing an anticancer effect can be obtained in a higher yield.

In the present invention, an endoxifen of Z form represented by Chemical Formula 1 may be prepared by the following Scheme 1:

Scheme 1

Where

P is benzyl, p-methoxybenzyl, acetate, tetrahydropyran or pivalate,

P 'is ethyl carbamate or t-butyl carbamate.

In the preparation method of the present invention, 4,4'-hydroxybenzophenone (compound of formula 2) is used as a starting material.

One of the two hydroxy groups bound to the compound of formula 2 is protected by introducing various protecting groups such as benzyl, p-methoxybenzyl, acetate, tetrahydropyran, pivalate and the like to obtain a compound of formula 3 .

Preferably, after dissolving the compound of formula 2 in acetone, potassium carbonate and a protecting group-containing compound are added, heated and stirred at 60 ° C. for 48 hours, filtered after cooling to room temperature, and the pH of the reaction mixture is adjusted to 1 with hydrochloric acid. 2 to 2, extracted with ethyl acetate and washed with water and brine, followed by drying, filtration and distillation under reduced pressure to obtain a compound of formula (3).

The compound of formula 3 is coupled with propiophenone by a Mcmurry reaction using zinc and titanium chloride to obtain a compound of formula 4.

Preferably, zinc is added to tetrahydrofuran, stirred at −10 ° C., followed by addition of titanium chloride, followed by heating and stirring at 80 ° C. for 2 hours, cooling to 0 ° C., followed by the compound of formula 3 and propiope The paddy is added and dissolved, and the mixture is heated and stirred at 80 DEG C for 16 hours. After cooling to room temperature, an aqueous solution of potassium carbonate was added, extracted with ethyl acetate, washed with brine, dried, filtered and dried under reduced pressure to obtain a compound of formula (4).

At this time, the compound of formula 4 is a mixture of the E / Z form of the geometric isomer around the alkene bond, and is alkylated by the compound of formula 10 obtained from Scheme 2.

Scheme 2

Wherein P 'is as defined above,

X is chloro, bromo, iodine, methanesulfonyl, toluenesulfonyl or trifluoro toluenesulfonyl.

The compound of formula 8 is protected with ethyl carbamate or t-butyl carbamate to give the compound of formula 9.

Preferably, the compound of formula 8 is dissolved in dichloromethane, then triethylamine is added and cooled and stirred at 0 ° C. After adding ethylchloroformmate, the mixture is stirred at room temperature for 1 hour. The pH of the reaction mixture is adjusted to 1-2 with 1M hydrochloric acid, extracted with dichloromethane, washed with water and brine, followed by drying, filtration and distillation under reduced pressure to afford the compound of formula 9.

The compound of formula 9 is converted into a hydroxy group leaving group by a halogenation reaction such as chloro, bromo, iodide, or sulfonylation reaction such as methanesulfonyl, toluenesulfonyl, and trilotoluenesulfonyl. It becomes a compound of.

Preferably, the compound of formula 9 is dissolved in tetrahydrofuran, cooled and stirred at 0 ° C. and dissolved by addition of imidazole, and dissolved by addition of triphenylphosphine. Subsequently, after adding and dissolving iodine, the mixture was stirred at room temperature for 1 hour, and the reaction mixture was adjusted to pH 7-8 by adding saturated sodium bicarbonate solution, extracted with ethyl acetate, and then the organic layer was washed with saturated sodium thiosulfate solution. Drying, filtration and distillation under reduced pressure yield the compound of formula 10.

The hydroxy group in the compound of Formula 4 is subjected to O-alkylation reaction with the compound of Formula 10 to obtain a compound of Formula 5.

Preferably, the compound of formula 4 is dissolved in N, N-dimethylformamide, cesium carbonate is added and stirred at room temperature, and after adding the compound of formula 10, the mixture is heated and stirred at 70 ° C. for 2 hours. The reaction mixture pH is adjusted to 7-8 by addition of saturated ammonium chloride solution, extracted with diethyl ether, washed with brine, dried, filtered and distilled under reduced pressure to afford the compound of formula 5.

The compound of formula 5 becomes a compound of formula 6 by deprotection (eg, debenzylation) reaction with borontribromide.

Preferably, the compound of formula 5 is dissolved in dichloromethane, stirred at −40 ° C. and stirred after addition of borontribromide. The pH of the reaction mixture is adjusted to 7-8 by addition of saturated sodium bicarbonate solution, extracted with dichloromethane, washed with brine, dried, filtered and distilled under reduced pressure to afford the compound of formula (6).

Alternatively, the compound of formula (5) is deprotected by a hydrogenation reaction using palladium as a catalyst to give a compound of formula (6).

Preferably, the compound of formula 5 is dissolved in ethyl acetate, charged with 5% palladium / carbon catalyst, stirred under 1 atmosphere of hydrogen, filtered through celite, dried, filtered and dried under reduced pressure to obtain a compound of formula 6 .

Alternatively, the compound of formula 5 is converted into the compound of formula 6 by deprotection reaction with acid.

The compound of formula 6 becomes a compound of formula 7 by deprotection reaction with hydrazine.

Preferably, the compound of formula 6 is added to ethylene glycol and stirred, and after addition of hydrazine monohydrate, potassium hydroxide is added thereto, heated and stirred at 160 ° C. for 2 hours, water is added, and extracted twice with diethyl ether, The organic layer is washed with water and brine, dried, filtered and dried under reduced pressure and then recrystallized with ethanol / water to obtain a compound of formula 7.

The compound of Formula 7 is obtained in higher yield by fractional crystallization using an organic solvent alone or in combination.

Preferably, the compound of Formula 7 is added to an organic solvent, dissolved at a constant temperature, and then stirred at room temperature for 1 hour. The resulting solid was filtered and dried under reduced pressure to give Z form endoxifen.

As the organic solvent, ethyl acetate, methanol, ethanol, propanol, benzene, acetone, acetonitrile, toluene, dichloromethane, 1,2-dichloroethane or chloroform may be used, and depending on the solvent used, E / E of endoxifen Z ratio is different.

The endoxifene mixture obtained mainly from the fractionation crystals was treated as shown in Scheme 3 below to convert the mixture into a 1: 1 E / Z mixture, and then separated the endoxifen of Z-form through fractionation crystals. Increased yield of Z-form endoxifen.

Scheme 3

Preferably, the endoxifene mixture mainly containing E form is added to the dichloromethane and trichloroacetic acid mixture and stirred at room temperature for 1 hour. A saturated sodium hydrogen carbonate solution was added to adjust the pH of the reaction mixture to 7 to 8, extracted twice with dichloromethane, washed with brine, dried, filtered and dried under reduced pressure to give an endotoxin having an E / Z ratio of 1/1. Obtain a pen.

Hereinafter, the present invention will be described in more detail with reference to Examples, which are intended to illustrate the present invention and are not intended to limit the scope of the present invention.

Example  1: (4- Benzyloxy - Phenyl )-(4-hydroxy- Phenyl ) - Methanone

After dissolving 50 g (233.4 mmol) of 4,4'-hydroxybenzophenone in 500 ml of acetone, 35 g (252.1 mmol) of potassium carbonate were added and 30.5 ml (252.1 mmol) of benzylbromide, followed by 60 ° C The mixture was heated and stirred for 48 hours at. After cooling to room temperature, potassium carbonate was filtered and 1M hydrochloric acid solution was added to adjust the pH of the reaction mixture to 1-2. After extracting twice with 200 ml of ethyl acetate, the organic layer was washed twice with 200 ml of water and then with 200 ml of brine, dried over anhydrous magnesium sulfate, filtered and dried under reduced pressure. 150 ml of ethanol and 50 ml of water were added thereto, and the mixture was heated and stirred at 60 ° C. for 1 hour, followed by cooling to room temperature. The resulting solid was filtered and dried under reduced pressure to give 32 g (45%) of (4-benzyloxy-phenyl)-(4-hydroxy-phenyl) -methanone.

mp 169 ° C .; IR (cm- ¹ ) 3347, 1600, 1249; 1 H NMR (400 MHz, DMSO) δ 7.69 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.49-7.31 (m, 5H), 7.16 (d, J = 12.0 Hz, 2H), 6.89 (d, J = 12.0 Hz, 2H), 5.21 (s, 2H)

Example  2: 4- (1- (4- Benzyloxy - Phenyl )-2- Phenyl - Boot -1-enyl) -phenol

58 g (887.0 mmol) of zinc was added to 600 ml of tetrahydrofuran, stirred at −10 ° C., and 44 ml of titanium tetrachloride was slowly added thereto. After adding all titanium chloride, the mixture was heated and stirred at 80 ° C. for 2 hours. After cooling to 0 ° C., 20 g (65.7 mmol) of (4-benzyloxy-phenyl)-(4-hydroxy-phenyl) -methanone and 28.2 g (210.2 mmol) of propiophenone were dissolved in 900 ml of tetrahydrofuran. The solution was added slowly, followed by heating and stirring at 80 ° C. for 16 hours. After cooling to room temperature, 500 ml of 10% aqueous potassium carbonate solution was added, extracted with 700 ml of ethyl acetate, washed with 700 ml of brine, dried over anhydrous magnesium sulfate, filtered, and dried under reduced pressure. The obtained residue was separated and purified through column chromatography (ethyl acetate / n-hexane = 1/10), and 21.4 g of 4- (1- (4-benzyloxy-phenyl) -2-phenyl-but-1-enyl) -phenol (80%) was obtained.

mp 118 ° C .;

IR (cm- ¹ ) 3516, 1507, 1238;

1 H NMR (400 MHz, CDCl ₃ ) δ 7.47-7.26 (m, 5H), 7.18-7.07 (m, 7H), 6.96 (d, J = 8.0 Hz, 1.2H), 6.82-6.71 (m, 2.8H), 6.62 (d, J = 8.0 Hz, 0.8H), 6.47 (d, J = 8.0 Hz, 1.2H), 5.07 (s, 1.2H), 4.91 (s, 0.8H), 2.48 (m, 2H), 0.92 (m, 3 H)

Example  3: ethyl-2- Hydroxyethyl (methyl) carbamate

After dissolving 50 g (665.7 mmol) of 2- (methylamino) ethanol in 500 ml of dichloromethane, 92.5 ml (665.7 mmol) of triethylamine was added thereto, and the mixture was cooled and stirred to 0 ° C. 65 ml (665.7 mmol) of ethylchloroformmate were added slowly, followed by stirring at room temperature for 1 hour. 1 M hydrochloric acid solution was added to adjust the pH of the reaction mixture to 1-2, extracted with 500 ml of dichloromethane, washed with 500 ml of water and 500 ml of brine, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness under reduced pressure. 83.3 g (85%) of 2-hydroxyethyl (methyl) carbamate was obtained.

IR (cm- ¹ ) 3398, 2936, 1679;

1 H NMR (400 MHz, CDCl ₃ ) δ 4.16 (q, 2H, J = 7.0 Hz), 3.76 (brs, 2H), 3.44 (brs, 2H), 2.97 (s, 3H), 1.27 (t, 3H, J = 7.0 Hz).

Example  4: ethyl-2- Ethyl iodide (methyl) carbamate

30 g (203.8 mmol) of ethyl-2-hydroxyethyl (methyl) carbamate was dissolved in 1500 ml of tetrahydrofuran, and then cooled to 0 ° C. 77.6 g (1019.3 mmol) of imidazole was added and dissolved, followed by 69.4 g (305.7 mmol) of triphenylphosphine. 80.2 g (305.7 mmol) of iodine were added thereto, and then dissolved. Then, the mixture was stirred at room temperature for 1 hour. A saturated sodium bicarbonate solution was added to adjust the pH of the reaction mixture to 7-8, and extracted with 2000 ml of ethyl acetate. The organic layer was washed with 500 ml of saturated sodium thiosulfate solution, dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. The obtained residue was separated and purified through column chromatography (ethyl acetate / n-hexane = 1/3) to obtain 41.9 g (80%) of ethyl-2-iodine iodide (methyl) carbamate.

IR (cm- ¹ ) 2979, 1697, 1194;

1 H NMR (400 MHz, CDCl ₃ ) δ 4.15 (brd, J = 4.0 Hz, 2H), 3.61 (brd, J = 4.0 Hz, 2H), 3.25-3.20 (brm, 2H), 2.95 (s, 3H), 1.28 (t, J = 12.0 Hz, 3H).

Example  5: (2- (4- (1- (4- Benzyloxy - Phenyl )-2- Phenyl - Boot -1-enyl) Phenyloxy )-ethyl)- methyl Ka Bamic  Acid ethyl ester

20 g (49.2 mmol) of 4- (1- (4-benzyloxy-phenyl) -2-phenyl-but-1-enyl) -phenol was dissolved in 500 ml of N, N-dimethylformamide, followed by cesium carbonate (48 g, 147.7 mmol) and stirred strongly at room temperature. 37.8 g (147.7 mmol) of ethyl-2-iodine ethyl (methyl) carbamate were added and then heated and stirred at 70 ° C. for 2 hours. A saturated ammonium chloride solution was added to adjust the pH of the reaction mixture to 7-8 and extracted twice with 500 ml of diethyl ether. The organic layer was washed with 500 ml of brine, dried over anhydrous magnesium sulfate, filtered and dried under reduced pressure. The obtained residue was recrystallized from ethyl acetate / n-hexane = 5/95 to give (2- (4- (1- (4-benzyloxy-phenyl) -2-phenyl-but-1-enyl) -phenyloxy) -ethyl 21.9 g (83%) of methyl-carbamic acid ethyl ester was obtained.

mp 91 ° C .;

IR (cm- ¹ ) 1689, 1508. 1238;

1 H NMR (400 MHz, CDCl ₃ ) δ 7.46-7.29 (m, 5H), 7.16-7.10 (m, 7H), 6.96 (d, J = 8.0 Hz, 1.5H), 6.86 (d, J = 8.0 Hz, 0.5 H), 6.77 (d, J = 8.0 Hz, 2H), 6.62 (d, J = 8.0 Hz, 0.5H), 6.52 (d, J = 8.0 Hz, 1.5H), 5.07 (s, 1.5H), 4.91 (s, 0.5H), 4.13 (brs, 0.5H), 3.96 (brs, 1.5H), 3.66 (brs, 0.5H), 3.55 (brs, 1.5H), 3.05 (s, 0.7H) 2.97 (s, 2.3H), 2.49 (q, J = 8.0 Hz, 2H), 1.33-1.24 (m, 5H), 0.94 (t, J = 8.0 Hz, 3H)

Example  6: (2- (4- (1- (4-hydroxy-) Phenyl )-2- Phenyl - Boot -1-enyl) Phenyloxy )-ethyl)- methyl Ka Bamic  Acid ethyl ester

20 g of (2- (4- (1- (4-benzyloxy-phenyl) -2-phenyl-but-1-enyl) -phenyloxy) -ethyl) -methyl-carbamic acid ethyl ester in 140 ml of dichloromethane (37.3 mmol) was dissolved and then stirred at -40 ° C. 74.6 ml (74.6 mmol) of 1.0M borontribromide solution in dichloromethane were added slowly and stirred for 1 hour. A saturated sodium bicarbonate solution was added to adjust the pH of the reaction mixture to 7-8, and extracted twice with 200 ml of dichloromethane. The organic layer was washed with 200 ml of brine, dried over anhydrous magnesium sulfate, filtered and dried under reduced pressure. The obtained residue was crystallized from diethyl ether / hexane = 5/95 to give (2- (4- (1- (4-hydroxy-phenyl) -2-phenyl-but-1-enyl) -phenyloxy) -ethyl) 14.1 g (85%) of methyl-carbamic acid ethyl ester was obtained.

IR (cm ⁻¹ ) 3520, 2972, 1675, 1508, 1240, 1172;

1 H NMR (400 MHz, CDCl ₃ ) δ 7.18-7.08 (m, 7H), 6.91-6.70 (m, 4H), 6.53-6.46 (m, 2H), 4.13 (brs, 0.8H), 3.96 (brs, 1.2H ), 3.66 (brs, 0.8H), 3.55 (brs, 1.2H), 3.06 (s, 1.2H) 2.97 (s, 1.8H), 2.48 (q, J = 8.0 Hz, 2H), 1.34-1.21 (m , 5H), 0.92 (t, J = 8.0 Hz, 3H)

Example  7: (2- (4- (1- (4-hydroxy- Phenyl )-2- Phenyl - Boot -1-enyl) Phenyloxy )-ethyl)- methyl Ka Bamic  Acid ethyl ester

To 400 ml of ethyl acetate (2- (4- (1- (4-benzyloxy-phenyl) -2-phenyl-but-1-enyl) -phenyloxy) -ethyl) -methyl-carbamic acid ethyl ester 20 g After dissolving (37.3 mmol), 15.9 g (3.7 mmol) of 5% palladium / carbon catalyst was added thereto, and the mixture was stirred for 10 minutes under 1 atmosphere of hydrogen. After filtration through celite, the mixture was dried over anhydrous magnesium sulfate, filtered and dried under reduced pressure. The obtained residue was crystallized from diethyl ether / hexane = 5/95 to give (2- (4- (1- (4-hydroxy-phenyl) -2-phenyl-but-1-enyl) -phenyloxy) -ethyl) 14.1 g (85%) of methyl-carbamic acid ethyl ester was obtained.

IR (cm ⁻¹ ) 3520, 2972, 1675, 1508, 1240, 1172;

1 H NMR (400 MHz, CDCl ₃ ) δ 7.18-7.08 (m, 7H), 6.91-6.70 (m, 4H), 6.53-6.46 (m, 2H), 4.13 (brs, 0.8H), 3.96 (brs, 1.2H ), 3.66 (brs, 0.8H), 3.55 (brs, 1.2H), 3.06 (s, 1.2H) 2.97 (s, 1.8H), 2.48 (q, J = 8.0 Hz, 2H), 1.34-1.21 (m , 5H), 0.92 (t, J = 8.0 Hz, 3H)

Example  8: 4- (1- (4- (2- Methylamino - Ethoxy ) - Phenyl )-2- Phenyl - Boot -1-enyl))-phenol

To 500 ml of ethylene glycol (2- (4- (1- (4-hydroxy-phenyl) -2-phenyl-but-1-enyl) -phenyloxy) -ethyl) -methyl-carbamic acid ethyl ester 20 g ( 44.9 mmol) was added and stirred. After adding 76.2 ml (1.57 mol) of hydrazine monohydrate, 120.7 g (2.15 mol) of potassium hydroxide was added thereto, and the mixture was heated and stirred at 160 ° C. for 2 hours. 500 ml of water was added, followed by extraction twice with 500 ml of diethyl ether. The organic layer was washed with 500 ml of water and 500 ml of brine, dried over anhydrous magnesium sulfate, filtered and dried under reduced pressure. The obtained residue was recrystallized from ethanol / water = 5/5, and 4- (1- (4- (2-methylamino-ethoxy) -phenyl) -2-phenyl-but-1-enyl))-phenol 16.0 g ( 95%).

mp 141 ° C .;

IR (cm- ¹ ) 3516, 1507, 1238;

1 H NMR (400 MHz, CDCl ₃ ) δ 7.18-7.05 (m, 7H), 6.85 (d, J = 8.0 Hz, 1.3H), 6.77 (d, J = 8.0 Hz, 0.7H), 6.75 (d, J = 8.0 Hz, 0.7H), 6.70 (d, J = 8.0 Hz, 1.3H), 6.51 (d, J = 8.0 Hz, 0.7H), 6.44 (d, J = 8.0 Hz, 1.3H), 4.09 (t, J = 4.0 Hz, 1.3H), 3.94 (t, J = 4.0 Hz, 0.7H), 3.00 (t, J = 4.0 Hz, 1.3H), 2.90 (t, J = 4.0 Hz, 0.7H), 2.53 ( s, 1.8H), 2.47 (m, 3.2H), 0.92 (t, J = 8.0 Hz, 3H)

Example  9: Z-4- (1- (4- (2- Methylamino - Ethoxy ) - Phenyl )-2- Phenyl - Boot -1-enyl))-phenol

10 g (26.7 mmol) of 4- (1- (4- (2-methylamino-ethoxy) -phenyl) -2-phenyl-but-1-enyl))-phenol was added to 100 ml of methanol, and heated to 40 ° C. After dissolving, the mixture was stirred at room temperature for 1 hour. The resulting solid was filtered and dried under reduced pressure to obtain Z-4- (1- (4- (2-methylamino-ethoxy) -phenyl) -2-phenyl-but-1-enyl having an E / Z ratio of 1/99. 4.7 g (47%) of))-phenol was obtained. (E / Z ratio of filtrate 63/37)

mp 141 ° C .;

IR (cm- ¹ ) 3516, 1507, 1238;

1 H NMR (400 MHz, CDCl ₃ ) δ 7.18-7.05 (m, 7H), 6.85 (d, J = 8.0 Hz, 2H), 6.70 (d, J = 8.0 Hz, 2H), 6.44 (d, J = 8.0 Hz , 2H), 4.09 (t, J = 4.0 Hz, 2H), 3.00 (t, J = 4.0 Hz, 2H), 2.53 (s, 3H), 2.47 (m, 2H), 0.92 (t, J = 8.0 Hz , 3H)

Example  10: Z-4- (1- (4- (2- Methylamino - Ethoxy ) - Phenyl )-2- Phenyl - Boot -1-enyl))-phenol

In 100 ml of ethyl acetate, 10 g (26.7 mmol) of 4- (1- (4- (2-methylamino-ethoxy) -phenyl) -2-phenyl-but-1-enyl))-phenol was added to 40 ° C. After dissolving by heating, the mixture was stirred for 1 hour at room temperature. The resulting solid was filtered and dried under reduced pressure to obtain Z-4- (1- (4- (2-methylamino-ethoxy) -phenyl) -2-phenyl-but-1-enyl having an E / Z ratio of 5/95. 6.0 g (60%) of))-phenol was obtained. (E / Z ratio of filtrate 87/13)

Example  11: Z-4- (1- (4- (2- Methylamino - Ethoxy ) - Phenyl )-2- Phenyl - Boot -1-enyl))-phenol

10 g (26.7 mmol) of 4- (1- (4- (2-methylamino-ethoxy) -phenyl) -2-phenyl-but-1-enyl))-phenol was added to 100 ml of ethanol and heated to 40 ° C. After dissolving, the mixture was stirred at room temperature for 1 hour. The resulting solid was filtered and dried under reduced pressure to obtain Z-4- (1- (4- (2-methylamino-ethoxy) -phenyl) -2-phenyl-but-1-enyl having an E / Z ratio of 1/99. 2.3) (23%) of phenol) was obtained. (E / Z ratio of the filtrate 61/39)

Example  12: Z-4- (1- (4- (2- Methylamino - Ethoxy ) - Phenyl )-2- Phenyl - Boot -1-enyl))-phenol

10 g (26.7 mmol) of 4- (1- (4- (2-methylamino-ethoxy) -phenyl) -2-phenyl-but-1-enyl))-phenol was added to 100 ml of isopropanol and heated to 40 ° C. After dissolving, the mixture was stirred at room temperature for 1 hour. The resulting solid was filtered and dried under reduced pressure to obtain Z-4- (1- (4- (2-methylamino-ethoxy) -phenyl) -2-phenyl-but-1-enyl having an E / Z ratio of 4/96. 4.1) (41%) of phenol) was obtained. (E / Z ratio of filtrate 75/25)

Example  13: Z-4- (1- (4- (2- Methylamino - Ethoxy ) - Phenyl )-2- Phenyl - Boot -1-enyl))-phenol

10 g (26.7 mmol) of 4- (1- (4- (2-methylamino-ethoxy) -phenyl) -2-phenyl-but-1-enyl))-phenol was added to 100 ml of acetonitrile and heated to 40 ° C. After dissolving, the mixture was stirred at room temperature for 1 hour. The resulting solid was filtered and dried under reduced pressure to obtain Z-4- (1- (4- (2-methylamino-ethoxy) -phenyl) -2-phenyl-but-1-enyl having an E / Z ratio of 37/63. 6.7 g (67%) of))-phenol were obtained. (E / Z ratio of the filtrate 84/16)

Example  14: 4- (1- (4- (2- Methylamino - Ethoxy ) - Phenyl )-2- Phenyl - Boot -1-enyl))-phenol

50 ml of dichloromethane was added to 50 ml of trichloroacetic acid, and dissolved. 4- (1- (4- (2-methylamino-ethoxy) -phenyl) -2-phenyl- having an E / Z ratio of 87/13. Butyl-1-enyl))-phenol 10 g (26.7 mmol) was added thereto and stirred at room temperature for 1 hour. A saturated sodium bicarbonate solution was added to adjust the pH of the reaction mixture to 7-8, and extracted twice with 100 ml of dichloromethane. The organic layer was washed with 100 ml of brine, dried over anhydrous magnesium sulfate, filtered and dried under reduced pressure, thereby having 4- (1- (4- (2-methylamino-ethoxy) -phenyl) having an E / Z ratio of 1/1. 9.5 g (95%) of 2-phenyl-but-1-enyl))-phenol were obtained.

Example  15: Z-4- (1- (4- (2- Methylamino - Ethoxy ) - Phenyl )-2- Phenyl - Boot -1-enyl))-phenol Citrate salt

31 g (160.2 mmol) of citric anhydride were added to 60 ml of water, and then dissolved. Z-4- (1- (4- (2-methylamino-ethoxy) -phenyl) -2-phenyl-but-1-enyl) It was added to 10 g (26.7 mmol) of) -phenol, and the mixture was heated to 40 ° C. to dissolve all of them, followed by stirring at room temperature for 12 hours. The resulting solid was filtered and dried under reduced pressure to yield 9.1 g of Z-4- (1- (4- (2-methylamino-ethoxy) -phenyl) -2-phenyl-but-1-enyl))-phenol citrate salt (60%) was obtained.

Claims (10)

Process for preparing Z form endoxifen or a salt thereof using 4,4′-hydroxybenzophenone as starting material:

The method according to claim 1,
And a first step of protecting one hydroxy group in the 4,4′-hydroxybenzophenone by a protecting group. The method according to claim 2,
And a second step of coupling the compound obtained in the first step with propiophenone. The method according to claim 3,
And a third step of O-alkylating the hydroxy group in the compound obtained in the second step. The method of claim 4,
And a fourth step of deprotecting the protecting group bound to the hydroxy group. The method according to claim 5,
And a fifth step of deprotecting the protecting group of the alkyl moiety bound by O-alkylation. The method of claim 6,
And a sixth step of fractionating the material obtained in the fifth step with an organic solvent. The method according to claim 7,
The organic solvent is selected from the group consisting of ethyl acetate, methanol, ethanol, propanol, benzene, acetone, acetonitrile, toluene, dichloromethane, 1,2-dichloroethane and chloroform or used alone or in hexane, water, diethyl ether. Characterized in that it is used in combination with. A process according to claim 7, wherein the E / Z endoxifene mixture obtained in claim 7 is subjected to acid or base treatment to convert the E form endoxifene in the mixture to Z form endoxifen. The method of claim 1, wherein the endoxifene obtained in claim 1 is reacted with water and citric acid to obtain an endoxifene citrate salt.