JPH0536431B2 - - Google Patents

Description

[Detailed description of the invention] Industrial applications The present invention relates to a method for producing tamoxifen.

Prior art Tamoxifen has the formula (1): Z(1,2-diphenyl)-1-[4
-(2-N,N-dimethylaminoethoxy)-phenyl]-1-butene.

Its anti-estrogenic effects have led to its use in the treatment of malignant tumors, particularly estrogen receptive-positive breast cancer, since 1971. The tumor must be pure in that only the Z isomer is effective and no E isomer is present as an impurity. The E isomer is therefore an estrogen agonist and prevents the anti-estrogenic effects of the Z isomer. In this specification, the Z isomer is simply referred to as tamoxifen, the E isomer is referred to as E tamoxifen, and the mixture of the two is referred to as EZ tamoxifen.

British Patent Specification No. 1064629 (ICI) states:
Techniques have been described for separating EZ tamoxifen into individual isomers by crystallizing the EZ mixture or salt (usually citrate) from a suitable solvent. A technique for separating EZ tamoxifen into its isomers by crystallization from methanol and petroleum ether, respectively, was developed by ICI researchers G.R.
Nature by Bethford and D.N. Richardson, 212 , 733.
(1966), in which half-dimethylamide of dibenzoyl D-tartaric acid is used. This method relies on the selective separation of the above salts of the Z isomer in a butyl acetate medium.

The intermediate in the synthesis of tamoxifen is the formula (4): It is 1,2-diphenyl-1-(4-hydroxyphenyl)1-butene represented by

By reacting this EZ mixture of phenols with 2-dimethylaminoethyl chloride, EZ
Methods for converting to tamoxifen are known. See, for example, Example 2 of GB 1013907. Unfortunately, no satisfactory method has been described for separating the EZ isomers of phenols of formula (4). The preparation of this intermediate is therefore not useful in providing a better method for obtaining tamoxifen.

European Patent Application No. 84105719.3 (Bristol-Myers Co.) (filed May 18, 1984,
No. 126470A on November 28, 1984) describes a process for producing EZ tamoxifen in which the Z:E isomer ratio in the crude reaction product is approximately 2:1.
The Bristol-Myers method utilizes the McMurry reaction to prepare olefins from ketones.

The McMurrie reaction has been known since 1974 and was recently reexamined by its discoverer, Dr. G.E. McMurrie (Accounts of Chemical Research).
Chemical Research) 16 , 405-411 (1983)). This reaction involves the simultaneous reductive coupling reaction of two ketone or aldehyde functional groups, thereby producing a molecule in which two carbonyl carbon atoms are coupled together to form an olefinic double bond. This reduction requires a titanium compound such as titanium trichloride and a strong reducing agent such as lithium or potassium. This reaction is primarily used to produce dimers by reaction of two molecules from the same ketone or aldehyde, or by coupling the terminal carbonyl function by cyclization of an aliphatic omega-diketone or dialdehyde. It has been used to make macrocyclic compounds. A few experimental examples of coupling different carbonyl compounds together, i.e., the production of uncontrolled olefins, are known (G. E. McMurley and L. R. Krespski, Journal of Organic Chemistry). of Organic Chemistry) 41 ,
3929-3930 (1976)). Benzophenone or fluorenone was reacted with acetone, cyclohexanone, 3-cholestanone, hexanal, di-t-butylketone, cycloheptanone or acetophenone. In all but one case, the mixed product was superior to the self-coupling compound. The authors assumed that self-coupling proceeds by a free radical mechanism and mixed coupling has a different mechanism. Dianions are formed by one ketone, which is linked to the other by nucleophilic addition. The authors suggest that if benzophenone or fluorenone is reduced to a dianion before the other is reduced to an anion radical, whatever the two ketones are, it should give a mixed conjugated product in excellent yield. I assumed. However, the mixed coupling-McMurrie reaction to obtain olefins did not make much progress, and in the above-mentioned review in 1983, Dr. McMurrie concluded that this part of his reaction could not be used for general synthesis.

In the Bristol-Myers method, propiophenone is reacted with 4-(2-N,N-dimethylaminoethoxy)benzophenone in the following scheme: It is bundled according to . Surprisingly, this mixed coupling reaction yields a product that is predominately of the desired Z-isomer. By working up this reaction product, EZ tamoxifen with a purity of more than 85% and a Z:E isomer ratio of 97.5:1 can be obtained.
was obtained in a reported yield of 51.2%. This Bristol-Myer Co specification specifies that 4-(2-N,
The preparation of N-dimethylaminoethoxy)benzophenone is not described. However, we obtained this compound from 4-hydroxy-benzophenone in 79.3% yield. Therefore, the overall maximum yield of pure product obtained in the Bristol-Meyer process is 79.3 x 51.2 x 85% = 34.5%
It is. If the EZ-tamoxifen mixture is pure
If it is 90%, the maximum yield is 36.5%. However, such yield calculations are optimistic considering that the purification of the EZ tamoxifen mixture will inevitably result in greater than the theoretical yield loss, so the yield of pure product will be 30%. would be an appropriate place.

Summary of the invention First priority claim date of the patent application (June 1984)
The inventors are aware of an earlier and currently ongoing Bristol-Myer Co. application in which propiophenone is coupled with an appropriately substituted benzophenone. The surprising finding is that the mixed coupling reaction gives a product that is substantially much more enriched in the Z isomer than in the E form. As far as the present inventors know, there has been no research on the use of this mixed coupling-McMurrie reaction for stereospecific reactions.

However, our research is not limited to the one-step reaction of propiophenone and 4-(2-N,N-dimethyl-aminoethoxy)benzophenone. The present inventors have demonstrated that the yield of tamoxifen can be improved by carrying out a two-step reaction, namely the MacMulley reaction, between propiophenone and 4-(2-haloethoxy)benzophenone to produce the intermediate 1,2-diphenyl-1-[4-(2- -haloethoxy)phenyl]
It has been found that the yield of tamoxifen can be improved by obtaining -1-butene and then reacting it with dimethylamine. In order to compare this yield with the Bristol-Meyer method, 4-hydroxybenzophenone must be considered as the starting material. We obtained an overall yield of product in analytical purity: 87.5 x 54.2 x 83.0% = 39.4%
I got it. However, the Bristol-Meyer product was not of analytical purity (approximately 15% impurities plus 1% E isomer). Perhaps a fair comparison would be that the yield from the Bristol-Meyer method is
34.5%, and the yield of tamoxifen obtained by the method of the invention before the final chromatography necessary to obtain a product of analytical purity is 87.5 × 54.2
×94.7=44.9%. In any case, it is clear that the process of the invention offers significant yield advantages. It is surprising that the process of the present invention, although ostensibly inferior to the direct process due to the extra steps involved, has a yield advantage, which could never have been predicted. Therefore, the present invention is based on Bristol-
It should be distinguished from the Mayer method, and it seems that it was something that could not be predicted from now on.

That is, the present invention provides (1) propiophenone and formula (2): 4- represented by [X is chlorine, bromine or iodine]
A haloethoxybenzophenone is reacted under a substantially dry inert atmosphere in a medium containing a reducing titanium compound and a reducing agent effective to generate titanium in a substantially zero valence state, formula (3): Intermediate 1 represented by [X has the same meaning as above],
2-diphenyl-1-[4-(2-haloethoxy) phenyl]-1-butene is obtained, and the intermediate represented by formula (2) (3) is reacted with dimethylamine (1). ): Provided is a method for producing tamoxifen represented by

Preferred embodiment 4-(2-haloethoxy)benzophenone reaction reagent is 4-hydroxybenzophenone and 1,
Prepared from 2-dihaloethane. Preferably the reaction was carried out under phase transfer conditions using quaternary ammonium salt phase transfer catalysts known per se. Alternatively, strong proton-attracting reagents such as sodium alkoxides may be used in the reaction.

MacMurry olefin synthesis reaction conditions require a reducible titanium compound and a reducing agent effective to generate a low atomization state, such as what is believed to be substantially zero titanium, usually no more than 1.2 per atom on average. The titanium will be reduced to a valence state of 2 or 0 and typically 0 to 60% of the atoms will be divalent and average 0 to obtain the olefin. The preferred titanium salt is the chloride, with trivalent or tetravalent titanium salts usually being useful. Tetrachloride is usually preferred over trichloride. Examples of reducing agents include lithium, lithium aluminum hydride, potassium, zinc or zinc-copper couples (zinc-copper couples can be prepared from zinc dust and a small amount of copper salt in deoxygenated water). Preferably, the reducible titanium compound is trichloride and the reducing agent is lithium, or the titanium compound is tetrachloride and the reducing agent is zinc. Titanium tetrachloride with zinc, preferably at a temperature of 50~
It is particularly advantageous to pre-prepare the reagent before adding it to the ketones by heating to 100°C.

The MacMurry olefin synthesis reaction used in the present invention is conveniently carried out using a reducing agent in excess (eg, 2:1 to 5:1 molar) with respect to the titanium salt.

The invention is carried out in a substantially inert atmosphere, such as argon or nitrogen, to prevent premature oxidation of the reducing agent. The atmosphere should also be substantially free of moisture.

The reaction may be carried out at room temperature, but heating to 25°C or higher is usually required to speed up the reaction. A temperature range of 15-100°C, preferably 15-70°C, most preferably 40-70°C is used in this step.

The reaction is carried out in an inert liquid medium, usually a solvent for the ketone reactant, preferably 1,2-dimethoxyethane or tetrahydrofuran.

The titanium compound is usually used in large excess over the two ketones. The reducing agent is preferably used in a molar ratio of at least 3:1 to the titanium compound. Preferably the ketones are used in substantially equimolar ratios. Excess ketones usually result in self-coupling and undesirable by-products.

MacMurrie reaction is performed on the 4-position of the appropriate benzene ring with 2
-chloroethoxy, 2-bromoethoxy or 2-
After use to prepare compounds with iodoethoxy substituents, the products are easily converted to tamoxifen or Z-rich EZ tamoxifen mixtures in one step using dimethylamine. This process is usually carried out under sealed conditions, e.g. in a closed container at a temperature of 60 -
It is carried out at 100°C, preferably 70-90°C.

Purification steps, including crystallization, solid phase absorption, chromatography, etc., may vary considerably. It is desirable to remove the dark colored material produced from the McMurrie reaction, which usually requires an absorption or chromatography step. On the other hand, purification from the reaction product with dimethylamine is usually minimal.

The present invention will be explained below with reference to Examples. Temperature is expressed in °C.

The NMR spectrum data are shown in hydrogen atom values indicated by the following symbols, and this was applied mutatis mutandis to the E isomer.

(X=Cl, Br or I) Example 1 Production of tamoxifen (Z 1-[4-(2-dimethylaminoethoxy)phenyl]-1,2-diphenylbut-1-ene): (a) 4-(2 -Chloroethoxy)benzophenone preparation: 4-hydroxybenzophenone (13.23 g,
70 mmol) was added to a solution of sodium (3.2 g) in ethanol (60 ml) and the resulting deep red solution was stirred at room temperature for 1 hour. The solvent was removed on a rotary evaporator leaving the organic sodium salt. Toluene (50ml) and 1-bromo-2-chloroethane (20g, 140mmol) were added and the mixture was stirred at reflux temperature for 18 hours. After cooling to room temperature, the solid material was removed by filtration, and the solvent in the liquid was distilled off to obtain a pale brown oil. Crystallization from ethanol/water gave 4(2-chloroethoxy)-benzophenone. 12.1 g (73%) of light cream-colored flaky crystals (mp 78°C) were obtained.

(b) 1-[4-(2-chloroethoxy)phenyl]
-Preparation of 1,2-diphenylbut-1-ene Lithium pieces (0.45 g, 65 mmol) were added to titanium trichloride (2.87 g, 18.6 mmol) in dry dimethoxyethane (30 ml) under argon atmosphere and refluxed for 1 hour. Stirred. After cooling the black mixture to room temperature, a solution of 4-(2-chloroethoxy)benzophenone (0.54 g, 2.0 mmol) and propiophenone (0.31 g, 2.3 mmol) in dry dimethoxyethane (20 ml) was added and the whole was stirred at room temperature. Stirred for 2 hours. The mixture was then refluxed under stirring for 20 hours.

After cooling the black suspension to room temperature, petroleum ether (bp 60-80 °C, 50 ml) was added and the mixture
Stir for 15 minutes. The organic layer was decanted and the solvent was removed, leaving a brown oil (0.77g).

The oil was purified using a silica gel column eluting with hexane/ethyl acetate 9:1 (v/v). Each fraction was collected and monitored by TLC, the fractions with Rf = 0.44 were combined, the solvent was distilled off and a colorless oil (0.51
g, 68%). NMR showed that the Z:E isomer ratio was 6:1 and 9:1.
This oil was dissolved in isopropanol (20 ml) and the white crystals that separated on standing were filtered off, washed with isopropanol and dried in a desiccator. Yield 0.29g (yield 34%),
mp63−65℃. NMR shows that these compounds are pure Z 1-[4-(2-chloroethoxy)-phenyl]-1,2-diphenylbut-1-ene.

Elemental analysis: C H Measured % 79.7 6.3 C ₂₄ H ₂₃ ClO theoretical % 79.4 6.4 NMR of EZ mixture at 60 mHz E Z a and b 3.53 4.34(m)4H c or e 7.07(s) 7.07(s)5H d 6.53−7.05 6.34−6.85 4H e or c 7.21(s) 7.21(s)5H f 2.38(q) 2.34(q)2H g 0.92(t) 0.88(t)3H IR (nujiol) cm ^-1 :3000− 2800(s), 1610
(m), 1510(m), 1460(m), 1380(s), 1250(m), 1180
(m), 1040(m), 770(m), 705(s), 670(m).

(c) 1-[4-(2-chloroethoxy)phenyl]
Preparation of tamoxifen from -1,2-diphenylbut-1-ene: Z 1-[4-(2-chloroethoxy)phenyl]-1,2-diphenylbut-1-ene (100
mg) was heated with a solution of 30% w/v dimethylamine in ethanol (3 ml) at 75°C in a closed container for 3 days. Solvent and excess amine were removed by rotary evaporation. The product obtained from this reaction (97 mg, 94.7% yield), already in high purity, was chromatographed in chloroform/on silica gel column chromatography to prepare it to analytical purity for NMR spectroscopy.
Chromatographic purification using methanol 9:1 v/v eluent.

Crystallization from chloroform/hexane gave white needle-like crystals (85 mg, yield 83.0%), which was determined by NMR to be Z 1-[4-(2-dimethylaminoethoxy)phenyl]-1,2-diphenylbut- It was identified as 1-ene.

Elemental analysis value: C H N Actual value % 84.2 8.1 3.5 C ₂₆ H ₂₉ NO theoretical value % 84.1 7.9 3.8 Example 2 Preparation of tamoxifen: (a) Preparation of 4-(2-bromoethoxy)benzophenone 1-bromo- 1 in place of 2-chloroethane,
Step (a) of Example 1 using 2-dibromoethane
repeated. 4-(2-bromoethoxy)benzophenone as an off-white solid (mp62~
64°C, yield 70%).

(b) 1-[4-(2-bromoethoxy)phenyl]
Preparation of -1,2-diphenylbut-1-ene 4-(2-bromoethoxy)-benzophenone was used instead of 4-(2-chloroethoxy)benzophenone, stirring was performed for 10 minutes after adding petroleum ether, and Rf = 0.45. Step (b) of Example 1 was repeated with the modification that a fraction having . The product obtained from the chromatography is a colorless syrup (0.45 g, yield
46%). When this syrup was dissolved in isopropanol and allowed to stand, white crystals were formed. This crystal has Z- and E 1-[4
-(2-bromoethoxy)-phenyl]-1,2
-diphenylbut-1-enes in an approximately 4:1 mixture.

Elemental analysis: C H Actual value % 71.0 5.5 C ₂₄ H ₂₃ Bro theoretical value % 70.8 5.7 NMR (EZ mixture, 60 mHz): E Z a and b 3.37 (m) 4.33 (m) c or e 7.05 (s) 7.05 (s)5H d 6.54−7.30 6.35−6.824H e or c 7.21(s) 7.21(s)5H f 2.40(q) 2.37(q)2H g 0.88(t) 0.83(t)3H IR (nujiol) cm ^{- 1} :3000−2800(s), 1610
(m), 1510(m), 1460(s), 1380(s), 1290(m), 1250
(s), 1175(m), 820(m)770(m), 715(s).

(c) 1-[4-(2-bromoethoxy)phenyl]
- Preparation of tamoxifen from 1,2-diphenoxybut-1-ene Tamoxifen was prepared as in step (c) of Example 1, except that the bromoethoxy congener prepared above was used in place of the chloroethoxy compound. .

Example 3 (a) Preparation of 4-(2-chloroethoxy)benzophenone 4-hydroxybenzophenone (19.8 g),
Benzyltri-n-butylammonium bromide (3.6g), sodium hydroxide (8.0g), water (75ml) and 1,2-dichloroethane (75ml)
was stirred vigorously at reflux temperature for 18 hours. The mixture was cooled, the upper aqueous layer was removed, and the organic layer was dried over magnesium sulfate. The solvent was removed in vacuo to obtain a red oil, which was recrystallized from ethanol/water to obtain 4-(2-chloroethoxy)-benzophenone (22.8 g, 88% yield, mp77-78
℃).

(b) 1-[4-(chloroethoxy)phenyl]-1,
Preparation of 2-diphenylbut-1-ene: Titanium tetrachloride (3.4 g, 18 mmol) was dissolved in a stirred suspension of zinc powder (2.36 g, 36 mmol) in tetrahydrofuran (30 cm ³ ) at −10° C. under a dry argon atmosphere. dripped. Stirring the resulting dark mixture yielded 54.2%.

(c) 1-[4-(2-chloroethoxy)phenyl]
Preparation of tamoxifen from -1,2-diphenylbut-1-ene Step (c) of Example 1 was repeated.

Reference Example US Pat. No. 2,914,562, Example 3 describes the process of converting 4-hydroxybenzophenone to 4-(2-N,N-dimethylaminoethoxy) using sodium methoxide and N,N-dimethylaminoethyl chloride. A method for preparing benzophenones is described. The product is stated to have a bp of 176-180°C/0.3 mmHg, but the yield is not stated. Chemical Abstracts 53 11296e states a yield of 17% for the same process. The Bristol-Myers Co. European patent application mentioned above does not describe how to prepare 4-(2-N,N-dimethylaminoethoxy)benzophenone. Our best method for preparing this compound was to heat to reflux and hold at that temperature for 1 hour. Cool the solution to room temperature and
(2-chloroexy)benzophenone (1.59g,
6 mmol) and propiophenone (0.80 g, 6 m
mol) mixture in tetrahydrofuran (20 ^cm3 ) was added. The mixture was refluxed under stirring for 2 hours.

After cooling to room temperature, the dark mixture was poured into 10% potassium carbonate solution (200 cm ³ ) and dissolved in diethyl ether (3×
^100cm3 ), collect the organic extract, dry it,
The solvent was distilled off to obtain a yellow oily substance.

This crude product was generated by column chromatography (silica gel, hexane/ethyl acetate 9:1 eluent), with 1-[4-
(2-chloroethoxy)phenyl]-1,2-diphenylbut-1-ene (1.46 g, 67% yield) was obtained as a colorless oil. This oil was dissolved in 2-propanol and 1-[4-(2-chloroethoxy)phenyl]-1,2-diphenylbut-1-
The ene was precipitated as the pure Z isomer. After evaporation, the temperature was mp64-65°C, and the yield was 1.20 g (the yield from the entire process was as follows).

A solution of the sodium salt of 4-hydroxybenzophenone (10 g), 1-N,N-dimethylamino-2-chloroethane (from its hydrochloride, 25.5 g) in toluene (100 ml) was heated under reflux for 24 hours. After filtering, the solvent was distilled off to obtain a brown oily product. This oily substance was distilled under vacuum and 4-(2-N,N-
dimethylaminoethoxy)benzophenone (9.7
g, yield 79.3%). bp174−179/0.3mm
Hg and yield was 79.3%.

Claims (1)

[Claims] 1 (1) Propiofenone and formula (2): 4- represented by [X is chlorine, bromine or iodine]
A haloethoxybenzophenone is reacted under a substantially dry inert atmosphere in a medium containing a reducing titanium compound and a reducing agent effective to generate titanium in a substantially zero valence state, formula (3): Intermediate 1 represented by [X has the same meaning as above],
2-diphenyl-1-[4-(2-haloethoxy) phenyl]-1-butene is obtained, and the intermediate represented by formula (2) (3) is reacted with dimethylamine (1). ): The manufacturing method of tamoxiphenone expressed as 2. The method according to item 1, wherein in step (1), the reducible titanium compound is titanium tetrachloride. 3. The method according to item 2, wherein the reducing agent is zinc. 4. The method according to item 1, wherein in step (1), the reducible titanium compound is titanium trichloride and the reducing agent is lithium. 5. The method according to any one of items 1 to 4, wherein step (1) is carried out in 1,2-dimethoxyethane or tetrahydrofuran. 6. The manufacturing method according to any one of items 1 to 5, wherein step (2) is carried out in a sealed container at a temperature of 60 to 100°C.