JPH0480920B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing estrone acetal, which is a precursor of estrone. Estrone is an important female hormone and is useful as an intermediate material for treating benign prostatic hyperplasia and other steroidal drugs. Conventionally, androstar-1,4-diene-3,17
A method for producing estrone acetal from -dione-17-acetal (hereinafter abbreviated as "ADDK") is described, for example, in JP-A-55-51099, which was proposed by one of the present inventors. There is a way. In the above method, a radical anion is prepared from sodium and a polycyclic aromatic compound in a mixed solvent of tetrahydrofuran and a small amount of polyether, and then a tetrahydrofuran solution of ADDK is supplied into the resulting reaction mixture. This is a method for producing estrone by reducing estrone to acetal and then deacetalizing it. However, this method is still at a basic stage of invention and cannot achieve a sufficient yield when implemented on an industrial scale, requiring further investigation. That is, according to the examples of this published patent, a yield of 80 to 86% of estrone is achieved on a laboratory scale on the order of grams (g). However, when this method is carried out on an industrial scale, for example, even on a scale of about 25, even under the conditions of Example 9, which achieves the highest yield, the yield is 40% as shown in Comparative Example 6 below. Only around the same yield can be achieved. In view of this point, the present invention is an improvement on the invention disclosed in the published patent, and its purpose is to provide a method for producing estrone acetal in a high yield and economically advantageous manner on an industrial scale. It is in. That is, the gist of the present invention is to prepare a radical anion by reacting sodium with a polycyclic aromatic compound in a reaction solvent, and to prepare a radical anion with a low boiling point feed solvent in the resulting reaction mixture. Androsta-1,4-diene-3,17-dione-17
- In a method of supplying a solution or slurry of acetal (hereinafter abbreviated as "ADDK") and reducing it to estrone acetal, (a) as a reaction solvent, () a polyether having three or more ether bonds; 1.5 for all ADDKs supplied
~5 (V/W) times, () the concentration of the polyether is 35 (V/V)
% or more, () The amount of other solvents other than the polyethers is 5 (V/W) times or less with respect to the total ADDK supplied, () The total amount of the reaction solvent is 3 (V/W) times or less with respect to the total ADDK. (b) Radical anion preparation reaction and ADDK
The temperature of the reduction reaction is above the melting point of sodium 105
(c) The supply solvent of ADDK is distilled out of the reaction system as necessary so that the reaction solvent can always maintain the conditions () to () above. It depends on the manufacturing method. The present invention will be explained in detail below. As the raw material ADDK used in the present invention, for example, androsta-1,4-diene-3,17-dione-17,17 represented by the general formula []
- dialkyl acetal and androsta-1,4-diene-3,17-dione-17-alkylene acetal represented by the general formula []. (In the formula, R represents a lower alkyl group having 1 to 6 carbon atoms.) (In the formula, R ¹ represents a lower alkylene group having 2 to 6 carbon atoms.) Specific examples of these ADDKs include the following compounds. Androsta-1,4-diene-3,17-dione-17,17-dimethylacetalandrosta-1,4-diene-3,17-dione-17,17-diethylacetalandrosta-1,4-diene -3,17-dione-17,17-dipropylacetal androsta-1,4-diene-3,17-dione-17-ethyleneacetal androsta-1,4-diene-3,17-dione-17- As sodium propylene acetal, metallic sodium is usually used, but sodium alloys containing small amounts of other alkali metals or alkaline earth metals can also be used as long as they have a melting point of about 105°C or lower. For such a sodium alloy, for example, when the alloy component is potassium, the content can be up to about 20% by weight. Polycyclic aromatic compounds that can be used as radical anion precursors include biphenyl,
Naphthalene, methylnaphthalene (2 isomers), dimethylnaphthalene (10 isomers), ethylbiphenyl (3 isomers), phenanthrene, terphenyl (3 isomers), anthracene, acenaphthene, fluoranthene, dibenzofuran, benzophenone, etc. Either can be used. Among these, particularly preferred are biphenyl,
Naphthalene, ethylbiphenyl, phenanthrene, and terphenyl. Examples of polyethers having three or more ether bonds include the following. (a) Polyethylene glycol dialkyl ethers represented by the general formula []. R ² O(CH ₂ CH ₂ O) _o R ³ [] (In the formula, R ² and R ³ represent a lower alkyl group, and n represents an integer of 2 or more. In the formula, R ² and R ³ may be the same ) Polyethylene glycol dialkyl ethers include, for example, diglyme, triglyme, tetraglyme and pentaglyme. (b) Polyethylene glycol monoalkyl ethers represented by the general formula []. HO (-CH ₂ CH ₂ O) - _o R ⁴ [] (In the formula, R ⁴ represents a lower alkyl group, and n represents an integer of 3 or more.) (c) General formula [] (CH ₂ CH ₂ O) A cyclic polyether (another name: crown ether) represented by _n [] (wherein, m represents an integer of 4 to 6). Examples of cyclic polyethers include, for example, 15-
Crown-5 (m=5) and 18-crown-6
(m-6) is mentioned. Also forms a solution or slurry of ADDK
A low boiling point solvent is used as the supply solvent for ADDK, and usually has a boiling point of 110°C or less, preferably 105°C or less.
A solvent below ℃ is used. Specifically, tetrahydrofuran, dioxane, 1,2-dimethoxyethane (ethylene glycol dimethyl ether)
Examples include low-boiling ether solvents such as ethereal solvents, and low-boiling hydrocarbon solvents such as benzene and hexane, but it is preferable to use low-boiling ethereal solvents. Particularly preferred is 1,2-dimethoxyethane. One of the features of the method of the present invention is that the radical anion preparation reaction and the ADDK reduction reaction are carried out at a temperature above the melting point of sodium and below 105°C. Adoption of such temperature conditions prevents sodium agglomeration and achieves a high yield of estrone acetal in industrial scale implementation. That is, according to the findings of the present inventors, the generation rate of radical anions is proportional to the "total surface area of sodium per unit volume of the reaction system." When the pre-dispersed sodium particles are subjected to a radical anion production reaction at a temperature below the melting point of sodium, unexpectedly they aggregate into a single lump. As a result, the "total surface area of sodium per unit volume of the reaction system" decreases significantly as it changes from a dispersed state to a lumpy state, but the extent of this decrease is not a problem on a gram (g) scale. However, it increases as the scale of the reaction system increases. Therefore, in industrial-scale implementation, the agglomeration of sodium greatly reduces the production rate of radical anions, making it difficult to form a high concentration of radical anions, resulting in a decrease in the yield of estrone acetal. Regarding the temperature of the reduction reaction of ADDK, the above-mentioned published patent states that the temperature is usually 30 to 150°C, preferably 60 to 120°C.
There is a general statement that it is. However, this description regarding the reaction temperature is not a result of careful consideration, and is not a description that discloses a technique useful for the present invention. This is because the Examples of the same patent all employ a reaction temperature of refluxing conditions of tetrahydrofuran (66° C.), and the specification does not mention agglomeration of sodium at all. Not only that, but
For example, Special Publication No. 42-10226 (USP No. 3274182)
Column 2 of the publication, lines 36-42, states that ``The high melting points of sodium and sodium prevent their melting in many organic solvents at temperatures below the reflux range and control access of the steroid to be converted.'' According to the state of the art at the time of the application, in order to maintain the initial dispersion state (particle size) of the alkali metal and conduct the planned reaction in a controlled manner, the alkali metal must be used at a temperature that does not melt it. The common method was to do so. In connection with this, for example, in the case of lithium, there is no problem of agglomeration, and the predetermined dispersion state does not substantially change even if lithium is used at temperatures below its melting point. It is a phenomenon peculiar to sodium that it becomes agglomerated when used. Furthermore, it is generally difficult to generate a high concentration of radical anions at high temperatures; for example, 110-115
℃, the yield of estrone is extremely low to 30% as shown in Comparative Example 4 below, but the general description of the reaction temperature in this published patent does not include this. It also includes temperatures that can be considered meaningful. The reaction temperature of the process of the present invention is a relatively high temperature selected to maintain the sodium in a molten state from the temperature range generally disclosed in the published patents. Adoption of such high temperature conditions, combined with the reaction solvent conditions described below, makes it possible to achieve the objectives of the present invention. That is, one of the other characteristics of the present invention is that, as a reaction solvent, () polyethers having 3 or more ether bonds are used in an amount of 1.5 to 5 with respect to the total ADDK supplied.
(V/W) times, () The concentration of the polyethers is 35 (V/V)
% or more, () The amount of other solvents other than the polyethers is 5 (V/W) times or less relative to the total ADDK supplied, and () The total amount of the reaction solvent is 3 times or less relative to the total ADDK.
(V/W) times or less, and if necessary, distill the ADDK supply solvent out of the reaction system to obtain the reaction solvent () ~
The point is to always maintain the conditions in parentheses. Generally, it is difficult to generate a high concentration of radical anions at high temperatures such as those employed in the method of the present invention. In addition, the radical anion once generated is
Since it is consumed in the reduction reaction of ADDK, it is necessary to regenerate a high concentration of radical anions within the reaction system in order to continue the reaction. Therefore, when polyethers are used in large quantities, it is relatively easy to prepare and regenerate high-concentration radical anions even at relatively high temperatures, but it is difficult to implement on an industrial scale. 1.5 to 5 for ADDK due to the following reasons:
It is necessary to limit the range to (V/W) times. In other words, the recovery operation for estrone is generally similar to the method described in the above-mentioned published patent.
The method includes an extraction operation in which an insoluble organic solvent and water are added to the reaction mixture, and polyethers having three or more ether bonds can dissolve estrone and have mutual solubility with water. Therefore, if the amount of polyether used exceeds the above-mentioned ratio, a recovery loss will occur as estrone migrates to the aqueous layer, and the final estrone yield will be low even in an economically advantageous recovery operation. In addition, polyethers are generally expensive and have a high boiling point, making recovery difficult. Therefore, it is economical to select the amount of polyether to be used within the above range. Therefore, in order to prepare and regenerate a high concentration of radical anions under the high reaction temperature conditions adopted by the method of the present invention under such a limited amount of polyethers used, the above () and () must be carried out. This necessitates the use of a reaction solvent with certain conditions. Condition () is that the concentration of polyether in the reaction solvent is gradually reduced by the feeding solvent of ADDK.
It has particular significance in the reduction reaction of ADDK, and in the radical anion preparation reaction, it shows the tolerance range as a solvent necessary to prepare a high concentration of radical anions. Further, the condition () defines the limit of the slurry concentration that can be stirred. In the above-mentioned published patent, there is a general statement that the amount of polyether used is 5 to 50% to tetrahydrofuran, which is 5 to 20 (V/W) times as much as ADDK, and The amount of ethers used includes the same amount as in the present invention. However, the reaction solvent described in the same patent contains polyethers in an amount of 1.5 to ADDK.
The above conditions () for the solvent of the present invention that are 5 (V/W) times and the concentration of polyethers are
It does not simultaneously satisfy the above condition () of being 35 (V/V)% or more. Moreover, there is no description of carrying out the reduction reaction of ADDK while distilling the ADDK supply solvent out of the reaction system, which means that the above condition () regarding the solvent of the present invention is also satisfied. do not. For example, in all of the Examples of the same publication, as described above, the reaction is carried out by refluxing tetrahydrofuran. Specifically, 10 for ADDK
(V/W) times tetrahydrofuran and 2.5 (V/W)
A solution of ADDK dissolved in tetrahydrofuran in an amount 5 (V/W) times as much as ADDK is supplied to a reaction solvent containing twice as much polyether as the amount of ADDK, and the reaction is carried out under reflux of tetrahydrofuran. In other words, the method described in the published patent requires that the concentration of polyethers be
20 (vol)% and other solvent other than polyether (tetrahydrofuran) is 10% relative to ADDK.
(V/W) times the radical anion is prepared in the reaction solvent, and in the process the former value decreases to 14 (vol)% and the latter value increases 15 (V/W) times, the radical anion regeneration and ADDK reduction reaction. Under these reaction solvent conditions,
Even if the temperature conditions of the present invention are adopted, as shown in Comparative Examples 2 and 5 below, the yield of estrone is only low. The amount of metallic sodium used is usually 2 to 10 mol, preferably 3 to 8 mol, per mol of ADDK (however, when polyethylene glycol monoalkyl ether represented by the formula [] is used as the polyether, the amount of this (Excluding the mole of sodium consumed in alcoholate production.) In addition, the amount of polycyclic aromatic compounds used is
Usually 1 to 10 moles per mole of ADDK. Preferably it is 1.5 to 8 mol. The ratio of the ADDK feed solvent used can be selected from a wide range, but considering the distillation load mentioned above, it is best to use a ratio of 20 (V/W) or less to ADDK, and usually It is selected from the range of 2 to 15 (V/W) times. The reaction is carried out by feeding a solution or slurry of ADDK into the reaction mixture containing the radical anion at a rate that does not cause the coloration derived from the radical anion to disappear. Further, the reaction is carried out under stirring in an inert gas atmosphere, and the stirring is carried out so that the molten sodium is sufficiently dispersed. The ADDK supply time is selected from a range of 15 minutes to 5 hours. Therefore, in the present invention, the ether bond is
As other solvents that form a reaction solvent together with a polyether having at least 100% ether, hydrocarbon solvents, ether solvents, etc., as exemplified as the supply solvent for ADDK, can be used. Preferred other solvents are ether solvents, especially ether solvents. , 1,2-dimethoxyethane are preferred. The sodium salt of estrone acetal produced by contacting ADDK with a radical anion is obtained by decomposing the radical anion and excess sodium with methanol, ethanol, water, etc., and then acidifying it with an appropriate mineral or organic acid. It can be an acetal. When the estrone acetal shown by the general formula [] is used as ADDK, the one shown by the general formula [] is obtained. (In the formula, R has the same meaning as above.) Furthermore, when the ADDK represented by the general formula [] is used, the product represented by the general formula [] is obtained. (In the formula, R ¹ has the same meaning as above.) Estrone acetal can be completely deacetalized by heating as it is (in the presence of an acid catalyst), and estrone can be produced. Examples of acids that can be used are hydrochloric acid, sulfuric acid, para-toluenesulfonic acid. According to the method of the present invention, it is possible to prevent the agglomeration of sodium and the reduction of radical anions, and it is possible to improve the yield of estrone. This effect becomes particularly noticeable when implemented on a large scale, and from this fact as well, the industrial value of the present invention can be found. Next, the present invention will be explained in more detail with reference to examples, but the present invention is not limited to the following examples unless it exceeds the gist thereof. Note that "ADDK" used in the following Examples and Comparative Examples is androsta-1,4-diene-3,17-dione-17-ethylene acetal. Example 1 A mixture of 3.36 kg (146 gr-mole) of sodium, 15.0 kg (97.4 gr-mole) of biphenyl, 16.0 kg of diglyme, and 20.0 kg of 1,2-dimethoxyethane was heated with stirring at 98 to 102°C under a nitrogen atmosphere. The reaction mixture took on a dark green color. After stirring for 30 minutes, 1 or 2 of ADDK8.0Kg (24.4gr-mole)
- Dimethoxyethane 80.0 solution was added at such a rate that the dark green color did not disappear while maintaining the reaction temperature of 98 to 102°C.
It was gradually fed (the feed rate was controlled in accordance with the distillation rate of 1,2-dimethoxyethane which was distilled out of the system. Required time: 1.5 hours). Next, 50 kg of water was gradually supplied in a nitrogen stream. After cooling to room temperature, 20.5 kg of concentrated hydrochloric acid was gradually added. The resulting mixture is heated to 60~
The mixture was heated and mixed at 65°C for 1 hour. After cooling to room temperature
While stirring, 7.99 kg of a 25 wt% caustic soda aqueous solution was gradually added to neutralize the mixture. Next, the mixture was allowed to stand for about 30 minutes to separate an organic layer and an aqueous layer. The aqueous layer was extracted with 40 g of tetrahydrofuran. The resulting tetrahydrofuran solution was combined with the organic layer and concentrated under reduced pressure. Add 80% heptane, 80% toluene, and 40% water to the residue.
The mixture was stirred at 80°C for 1 hour. After standing overnight at room temperature, the crystals were collected, washed with heptane and water, and dried to obtain crude crystals of estrone. Estrone yield 5.92Kg (yield
90.0moie%). Example 2 An experiment was conducted under the same conditions as in Example 1 except that tetraglyme was used instead of diglyme as the polyether, and estrone was obtained in a yield of 88 mole%. Example 3 An experiment was conducted in the same manner as in Example 1 using ethylbiphenyl as a radical anion precursor. Sodium 3.59Kg (156gr-mole), Ethylbiphenyl 13.3Kg (73.1gr-mole), Diglyme
When a mixture of 16.0 and 20.0 of 1,2-dimethoxyethane was heated at 98-102° C. with stirring under a nitrogen atmosphere, the reaction mixture took on a dark green color. 30
After stirring for a minute, ADDK8.0Kg (24.4gr−mole)
A solution of 1,2-dimethoxyethane (80.0%) was fed at a rate that kept the dark green color from disappearing, while keeping in mind the rate at which 1,2-dimethoxyethane was distilled out of the system (reaction temperature: 98-102°C, Time required: 1.0 hours). After post-treatment in the same manner as in Example 1, estrone was obtained in a yield of 85 mole%. Example 4 Sodium 3.59Kg (156gr-mole), biphenyl 22.5Kg (146gr-mole) and diglyme 40.0
When the mixture was heated with stirring at 98-102°C under a nitrogen atmosphere, the reaction mixture took on a dark green color. After continued stirring for 30 minutes, a solution of 8.0 kg of ADDK dissolved in 40.0 kg of tetrahydrofuran was supplied at a rate that did not cause the dark green color to disappear, and while keeping pace with the distillation rate of tetrahydrofuran that was distilled out of the system (reaction Temperature: 98-102°C, time required: 0.75 hours, amount of recovered tetrahydrofuran: ca.32). After post-treatment in the same manner as in Example 1, estrone was obtained in a yield of 86 mole%. Example 5 Example 4 except that the ADDK supply solvent was changed from tetrahydrofuran to benzene (amount used: 40).
An experiment was conducted under the same conditions as (however, the amount of distilled benzene after ADDK supply was ca.28), and 83 mole of estrone was
% yield. Example 6 Sodium/potassium alloy (potassium 20wt%)
4.80Kg (Na=167gr-mole, K=24.6gr-mole),
Biphenyl 15.0Kg (97.4gr−mole), diglyme
When a mixture of 28.0 and 40.0 of 1,4-dioxane was heated with stirring at 98-104°C under a nitrogen atmosphere, the reaction mixture took on a dark green color. After stirring for 30 minutes, it was dissolved in 1,4-dioxane 80.0
A solution of 8.0 kg of ADDK was gradually fed at a rate that did not cause the dark green color to disappear, and while taking into account the rate of distillation of 1,4-dioxane out of the system (reaction temperature: 101-104°C, required time). 1.0 hours). After post-treatment in the same manner as in Example 1,
Estrone was obtained with a yield of 85 mole%. Example 7 An experiment was conducted under the same conditions as Example 1, except that the amount of diglyme used was reduced from 16.0 to 12.0.
Estrone was obtained with a yield of 83 mole%. Comparative Example 1 An experiment was conducted under the same conditions as in Example 1, except that the amount of diglyme used was reduced from 16.0 to 8.0. The estrone yield was 67 mole%. Comparative Example 2 After preparing a radical anion under the same reaction conditions as in Example 1, ADDK was supplied using the supply solvent 1,
The reaction was carried out without distilling 2-dimethoxyethane out of the system (reaction temperature: 98 to 102°C, reaction pressure: normal pressure to 1.0 Kg/cm ² G, ADDK supply time: 1.5 hours).
The estrone yield was 70 mole%. Comparative Example 3 A reaction was carried out under the same conditions as in Example 1, except that the reaction temperature was changed to 110 to 115°C. The estrone yield was 60 mole%. Comparative Example 4 The reaction temperature was changed to the tetrahydrofuran reflux temperature (66
℃) to 110 to 115℃.
The reaction was carried out under the same conditions as in Example 9 of 51099. That is, when 0.92gr (40mmole) of sodium and 5.55gr (36mmole) of biphenyl were added to a solution of 20ml of tetrahydrofuran and 5ml of diglyme and heated to 110°C while stirring in an argon stream, the reaction mixture took on a dark green color (pressure: 2.5Kg). / ^cm2G ).
ADDK1.971gr (6mmole) of tetrahydrofuran
10 ml of the solution was added dropwise while maintaining the reaction temperature at 110 to 115°C without distilling tetrahydrofuran out of the system (required time: 50 minutes, pressure: 2.5 kg/cm ²
G). However, under these temperature conditions, it was difficult to maintain the color of the reaction mixture black-green at all times during the supply of ADDK. After completion of the dropwise addition, estrone was isolated by post-treatment according to a conventional method (the same method as in Example 1) (yield: 30 mole%). Comparative Example 5 The reaction temperature was changed to the tetrahydrofuran reflux temperature (66
℃) to 98 to 102℃.
The reaction was carried out under the same conditions as in Example 9 of 51099. That is, when 0.92 gr (40 mmole) of sodium and 5.55 gr (36 mmole) of biphenyl were added to a solution of 20 ml of tetrahydrofuran and 5 ml of diglyme and heated to 98 to 102°C while stirring in an argon stream, the reaction mixture took on a dark green color. ADDK1.971gr
(6 mmole) of tetrahydrofuran was added dropwise at a reaction temperature of 98 to 102°C without distilling the tetrahydrofuran out of the system (required time
1.0 hours). After dropping, estrone was isolated by post-treatment in the same manner as in Example 1 (yield 65 mole).
%). Comparative Example 6 This comparative example is based on the experiment of Example 9 in JP-A-55-51099 using ADDK1.971gr (6×10 ^-3 gr-mole).
This is an experiment in which the scale was increased from 328gr (1gr-mole) to 328gr (1gr-mole). 30wt% pre-prepared in toluene solvent
Sodium Disperdiene 513gr (Sodium
154gr (6.7gr−mole)), tetrahydrofuran 3.3
, diglyme 0.82 and biphenyl 924gr
(6 gr-mole) were added one after another and heated under reflux in a nitrogen stream while stirring, and the reaction mixture turned dark green. However, as the solution took on a strong dark green color, the dispersed sodium particles agglomerated into a single mass, making it necessary to stop stirring from time to time. Then ADDK328gr dissolved in tetrahydrofuran 1.6
A solution of (1 gr-mole) was fed over 1 hour at a rate such that the dark green color did not disappear under tetrahydrofuran reflux temperature (66°C). After the supply was completed, the mixture was heated under reflux for 10 minutes, then cooled to room temperature, and 2.5 hours of water was gradually added and mixed in a nitrogen stream. Post-treatment was performed in the same manner as in Example 1, and estrone was isolated (yield: 40 mole%). The results of Examples 1 to 7 and Comparative Examples 1 to 6 are summarized in Table 1 and Table 2, respectively.

【table】

【table】

Claims (1)

[Scope of Claims] 1 A radical anion is prepared by reacting sodium with a polycyclic aromatic compound in a reaction solvent, and androstabyl prepared in a low-boiling point feed solvent is added to the resulting reaction mixture. -1,4-diene-3,17-dione-17-acetal (hereinafter referred to as
In the method of supplying a solution or slurry of ADDK (abbreviated as “ADDK”) and reducing it to estrone acetal, (a) as a reaction solvent, () all ADDK supplied with polyethers having three or more ether bonds; 1.5 against
~5 (V/W) times, () the concentration of the polyether is 35 (V/V)
% or more, () The amount of other solvents other than the polyethers is 5 (V/W) times or less relative to the total ADDK supplied, () The total amount of the reaction solvent is 3 (V/W) times or less relative to the total ADDK. (b) Radical anion preparation reaction and ADDK
The temperature of the reduction reaction is above the melting point of sodium 105
(c) The supply solvent of ADDK is distilled out of the reaction system as necessary so that the reaction solvent can always maintain the conditions () to () above. Production method. 2. The method for producing estrone acetal according to claim 1, wherein the reaction solvent is an ether solvent consisting of polyethers having three or more ether bonds and other ethers. 3. The method for producing estrone acetal according to claim 2, wherein the other ether is 1,2-dimethoxyethane. 4. The method for producing estrone acetal according to claim 1 or 3, wherein the ADDK feeding solvent is a solvent consisting of ethers. 5. The method for producing estrone acetal according to claim 4, wherein the ether is 1,2-dimethoxyethane.