CN111187326A - Preparation method of nomegestrol acetate - Google Patents
Preparation method of nomegestrol acetate Download PDFInfo
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- CN111187326A CN111187326A CN202010035562.5A CN202010035562A CN111187326A CN 111187326 A CN111187326 A CN 111187326A CN 202010035562 A CN202010035562 A CN 202010035562A CN 111187326 A CN111187326 A CN 111187326A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
- C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
- C07J7/004—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa
- C07J7/0045—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa not substituted in position 16
Abstract
The invention relates to the field of organic synthesis, in particular to a preparation method of nomegestrol acetate. The invention provides a preparation method of nomegestrol acetate, which comprises the following steps: reacting the compound shown in the formula 5 in the presence of a catalyst to prepare the compound shown in the formula 1, wherein the catalyst is selected from Rh-Binap catalysts. In the preparation method of nomegestrol acetate provided by the invention, the Rh-Binap catalyst is innovatively used for preparing nomegestrol acetate, the method is mild in reaction condition and simple to operate, and the catalyst used in the reaction can be recycled and reused simply and repeatedly.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a preparation method of nomegestrol acetate.
Background
Nomegestrol Acetate (Nomegestrol Acetate) was developed by thermex corporation and marketed in france in 1985, primarily for the treatment of uterine disorders (5mg single dose) and combined with estradiol for the treatment of a range of post-menopausal symptoms. The modified 19-demethyl pregnane based structure is a fourth generation synthetic progestogen with high selectivity, and nomegestrol acetate has obvious characteristics of pituitary gonad inhibition and ovulation inhibition, and has very small toxic and side effects. The progestogen activity is 4 times stronger than medroxyprogesterone acetate and 1.4 times stronger than medroxyprogesterone acetate, and the structural formula is as follows:
at present, the most classical synthesis route in the prior art is to obtain a target product by taking pregnenolone acetate as a raw material through multi-step reaction. The compound (2) is obtained by protecting 3-carbonyl by using pregnenolone acetate, then the compound (2) reacts with Vilsmeier reagent to obtain a compound (3), the compound (3) is subjected to reduction reaction to obtain a compound (4), then the substance is dehydrated and deprotected under acidic condition to obtain a compound (5), and the substance is subjected to double bond migration isomerization to obtain a target product nomegestrol acetate. The reaction formula is as follows:
for example, U.S. Pat. Nos. 4544555, org. Process Res.Dev.2014,18,431-436 all provide processes for preparing compound (1) from pregnanone acetate, which are carried out in the course of the key step double bond migration isomerization (the reaction step from compound (5) to the desired product) using palladium on carbon as a metal catalyst. According to the known literature reports, the chemical synthesis route for preparing nomegestrol acetate by using the compound (5) has the problems of low yield, large use of noble metal catalysts, excessively high raw material cost, poor reaction repeatability and the like, the product yield is only about 50-60%, side reactions exist, a large amount of impurity A (the structure of the impurity A is shown in the figure below) is generated, and the content of the impurity A is 8-10 wt% of the product system.
Disclosure of Invention
In view of the above-mentioned disadvantages of the prior art, the present invention aims to provide a method for preparing nomegestrol acetate, which solves the problems of the prior art.
In order to achieve the above objects and other related objects, the present invention provides a method for preparing nomegestrol acetate, comprising:
reacting a compound shown in a formula 5 in the presence of a catalyst to prepare a compound shown in a formula 1, wherein the catalyst is selected from Rh-Binap catalysts;
in some embodiments of the invention, the chemical structure of the Rh-Binap catalyst is as follows:
[Rh(Binap)2]+Y-；
wherein, Y-Is selected from ClO4 -、PF6 -、BF4 -；
Binap is 2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl.
In some embodiments of the present invention, the reaction is performed at a temperature ranging from room temperature to the boiling point of the solvent, preferably, the reaction temperature is 50 to 80 ℃.
In some embodiments of the invention, the reaction is carried out under a gas blanket.
In some embodiments of the present invention, the reaction is carried out in the presence of a reaction solvent selected from one or more of alkanes, haloalkanes, alcohol solvents, ether solvents, and ketone solvents.
In some embodiments of the invention, the reaction solvent is selected from the group consisting of n-hexane, n-heptane, dichloromethane, dichloroethane, methanol, ethanol, tetrahydrofuran, methyltetrahydrofuran, acetone, and combinations of one or more thereof.
In some embodiments of the invention, the molar ratio of the Rh-Binap catalyst to the compound of formula 5 is 1:6000 to 10000.
In some embodiments of the present invention, the catalyst has a TON of 7500-8000.
In some embodiments of the invention, the loss of catalyst during the reaction is less than or equal to 3 wt%.
In some embodiments of the invention, the post-treatment of the reaction comprises: separating the catalyst, and recrystallizing to provide the nomegestrol acetate.
In some embodiments of the invention, at least a portion of the separated catalyst recovery package is used in the reaction of the compound of formula 5 to produce the compound of formula 1.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments, and other advantages and effects of the present invention will be apparent to those skilled in the art from the disclosure of the present specification.
The inventor of the invention has conducted a great deal of practical research, and unexpectedly found that the compound shown in the formula 5 can be effectively promoted to generate the compound shown in the formula 1 in a double bond migration isomerization reaction by using the Rh-Binap catalyst, and an extremely small amount of impurity A is generated at the same time, and the Rh-Binap catalyst has small loss in the reaction, so that the invention provides a high-efficiency preparation method of nomegestrol acetate, and the invention is completed on the basis.
The invention provides a preparation method of nomegestrol acetate, which comprises the following steps: reacting a compound shown in a formula 5 in the presence of a catalyst to prepare a compound shown in a formula 1, wherein the catalyst is selected from Rh-Binap catalysts;
in the preparation method of nomegestrol acetate provided by the invention, the Rh catalyst is coordinated with the C2 symmetric bidentate phosphine ligand to carry out double bond migration isomerization of the compound shown in the formula 5, surprisingly, in the double bond migration isomerization process of the compound shown in the formula 5, the Rh-Binap catalyst shows more excellent catalytic activity and selectivity compared with other catalysts, and only a very small amount of impurity A compound is generated in the reaction process, so that the post-treatment of the reaction becomes simpler, and the reaction product does not need to be repeatedly refined and purified to remove the impurity A like other processes in the prior art.
In the preparation method of nomegestrol acetate provided by the invention, the Rh-Binap catalyst is a complex formed by metal rhodium and a bidentate phosphine ligand, and the chemical structural formula of the complex is as follows:
[Rh(Binap)2]+Y-；
wherein, Y-Can be selected from ClO4 -、PF6 -、BF4 -Anion of the root;
binap is 2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl. Methods of providing the Rh-Binap catalyst should be known to those skilled in the art, and for example, the Rh-Binap catalyst may be provided with reference to the disclosure in US 4605750. The amount of the Rh-Binap catalyst added to the reaction system during the reaction is usually a catalytic amount, which is greatly reduced relative to the amount of other catalysts (e.g., 5 wt% palladium on carbon catalyst) used in the prior art for preparing the compound of formula 1, for example, the molar ratio of the Rh-Binap catalyst to the compound of formula 5 may be 1:6000 to 10000, 1:6000 to 7000, 1:7000 to 8000, 1:8000 to 9000, or 1:9000 to 10000, and further, for example, the TON (the amount of TON being the amount of the substance of the substrate/the amount of the substance of the catalyst) of the catalyst during the reaction may be 7500 to 8000, 7500 to 7600, 7700 to 7800, 7800 to 7900, or 7900 to 8000, while the amount of other catalysts used in the prior art for preparing the compound of formula 1 may be as high as 40 to 80% by weight of the substrate. In addition, as mentioned above, the Rh-Binap catalyst loss in the reaction of the present invention is very small, the catalyst loss in a single batch reaction (i.e., the loss of the mass of the catalyst recovered after the reaction relative to the mass of the catalyst charged in the reaction) is less than or equal to 3 wt%, less than or equal to 2.5 wt%, less than or equal to 2.2 wt%, or less than or equal to 2 wt%, and the recovered catalyst can still substantially maintain the original catalytic activity during the application process, and the activity of the catalyst is not substantially lost, for example, the total TON of the catalyst can be greater than or equal to 350,000, 375,000, or greater than or equal to 400,000, and for example, the application of the catalyst can be performed more than 2 times, more than 3 times, more than 4 times, more than 5 times, or more than 6 times, thereby realizing multiple recycling applications. In the process of applying the catalyst, the recovered catalyst can be combined with a fresh catalyst so as to ensure the sufficient proportion of the catalyst in a reaction system. Other catalysts (for example, 5 wt% palladium carbon catalyst) in the prior art have poor effect in the recycling experiment, and have almost no value in recycling.
In the preparation method of nomegestrol acetate provided by the invention, the reaction can be generally carried out under the condition from room temperature to the boiling point temperature of the solvent, preferably under the heating condition, and more preferably, the reaction temperature can be 50-80 ℃, 50-60 ℃, 60-70 ℃ or 70-80 ℃. The reaction time can be adjusted by those skilled in the art according to the reaction progress, for example, the reaction progress can be judged by TLC, chromatography, etc., and for example, the reaction time can be 0.5 to 2 hours, 0.5 to 1 hour, 1 to 1.5 hours, or 1.5 to 2 hours, and an excessive reaction time may cause the formation of impurities.
In the preparation method of nomegestrol acetate provided by the invention, the reaction can be carried out under the condition of gas protection, so that the loss of activity of the catalyst active intermediate can be avoided. Methods of providing suitable gas blanketing conditions will be known to those skilled in the art, for example, the reaction may be carried out under generally closed conditions; for another example, the gas protection condition may be provided by a gas such as nitrogen, an inert gas, and the like, and the inert gas may specifically be helium, neon, argon, krypton, xenon, or the like.
In the preparation method of nomegestrol acetate provided by the invention, the reaction is usually carried out in the presence of a reaction solvent, the reaction solvent used in the reaction is usually selected from organic solvents, and the reaction solvents are usually good solvents of a reaction system, so that all substances in the reaction system can be fully mixed, and a certain concentration is ensured to ensure that the reaction is smoothly carried out. For example, the reaction solvent may be selected from one or more of alkanes, halogenated alkanes, alcohol solvents, ether solvents, ketone solvents, and the like, and specifically may be one or more of n-hexane, n-heptane, dichloromethane, dichloroethane, methanol, ethanol, tetrahydrofuran, methyltetrahydrofuran, acetone, and the like.
In the preparation method of nomegestrol acetate provided by the present invention, a person skilled in the art can select a suitable method to perform post-treatment on the reaction product, for example, the post-treatment of the reaction may include: separating the catalyst, and recrystallizing to provide the nomegestrol acetate. After the reaction is finished, a proper solvent can be added to dissolve the reaction product, solid-liquid separation is carried out, the separated solid phase substance is the catalyst, and the liquid phase substance is desolventized and recrystallized to obtain the target product, namely the compound shown in the formula 1. As mentioned above, the recovered catalyst can still substantially maintain the original catalytic activity during the process of recycling, the activity of the catalyst is not substantially lost, and at least part of the catalyst obtained by separation can be further recycled and reused for the reaction of the compound of formula 5 for preparing the compound of formula 1.
In the preparation method of nomegestrol acetate provided by the invention, the Rh-Binap catalyst is innovatively used for preparing nomegestrol acetate, the method is mild in reaction condition and simple to operate, and the catalyst used in the reaction can be recycled and reused simply and repeatedly. In addition, the reaction has the characteristics of high selectivity, high yield and the like, the product yield can reach more than 95.0, more than 96.0, more than 97.0, more than 98.0 or more than 99.0 percent, the product purity can reach more than 99.0 percent by weight, and the content of the impurity A compound which is similar to the target product, namely the compound shown in the formula 1 in structure is usually not more than 0.2 to 0.3 percent by weight. Therefore, the preparation method of nomegestrol acetate provided by the invention avoids the problems of large use of noble metal catalysts, no catalytic activity after the catalysts are recovered, harsh reaction conditions, incapability of reproducing the reaction and the like existing in the traditional synthesis process of the compounds, is greatly superior to the traditional process in terms of reaction yield, harsh degree of reaction conditions, simplicity of process routes, atomic economy, environmental friendliness, safety, price cost and the like, and has good industrial prospect.
The invention of the present application is further illustrated by the following examples, which are not intended to limit the scope of the present application.
Example 1
Preparation of chiral catalyst:
under the protection of nitrogen gas, [ Rh (COD) Cl]2(500mg,1mmol) Dissolved in 20 ml of dry tetrahydrofuran, 1, 5-cyclooctadiene COD (0.54ml,4mmol) was added, and after the reaction mixture was stirred for 5 minutes, AgClO was added4(420mg, if necessary to prepare other anion catalysts, AgClO4Replacing with corresponding silver salt anion), reacting for 1 hour at room temperature;
under nitrogen protection, BINAP (2.58g) was added to the reaction mixture, nitrogen was replaced with hydrogen, and the reaction was stirred at room temperature under 3atm hydrogen pressure and detected by thin layer chromatography for about 12 hours until the reduction of BINAP was no longer observed. The reaction was stopped, dry acetone was slowly added, and then the reaction flask was placed in a 0 ℃ freezer for crystallization. After the solvent was removed, a small amount of acetone was used for washing, and vacuum drying was carried out to obtain 2.15g of red crystals, which were the catalyst, in a yield of 80%, and had a chemical structural formula of [ Rh (Binap) ]2]+[ClO4]-。
The nuclear magnetic resonance method and the infrared spectrum are characterized, and the results are as follows:
31P NMR((CD3)2CO，162MHz):24.48(d,J(P-Rh)＝138.5Hz)；27.65(d,J(P-Rh)＝141.5Hz)ppm；
IR(solid)νmax3048.5,2926.1,1702.6,1433.2,1238.7,813.9.
example 2
Preparation of nomegestrol acetate (1):
a dry 100mL closed-loop reactor was charged with the catalyst prepared in example 1 and the system was replaced with dry high-purity nitrogen for 3 iterations. Then adding tetrahydrofuran and a compound shown in a formula 5, sealing the system, heating to 80 ℃, continuing to perform heat preservation reaction for 0.5 hour, cooling the system to room temperature after the reaction is finished, then recovering the solvent from the reaction solution under reduced pressure, then adding acetone to dissolve the product, filtering to remove the catalyst, and performing adsorption decoloration, reduced pressure concentration and methanol recrystallization purification on the residual liquid through activated carbon to obtain the target product, namely the compound shown in the formula 1, wherein the yield is 98.0%. Drying scale for filtering, washing and recovering catalystHeavy, its loss is 2.1%, product HPLC content is greater than 99.6%, impurity A content is less than 0.1%, [ α ]]D 25-63.5°(c 2.0,EtOH)。
Example 3
Preparation of nomegestrol acetate (1):
adding the catalyst prepared in example 1 into a dry 100mL closed-loop reactor, replacing the system with dry high-purity nitrogen for 3 times, then adding methanol and the compound of formula 5, sealing the system, heating to 60 ℃, continuing to perform heat preservation reaction for 1.0 hour, cooling the system to room temperature after the reaction is finished, then recovering the solvent from the reaction liquid under reduced pressure, then adding acetone to dissolve the product, filtering to remove the catalyst, performing adsorption decoloration, reduced-pressure concentration and recrystallization purification on the residual liquid through activated carbon to obtain the target product of the compound of formula 1, wherein the yield is 95.8%, filtering, washing, recovering the catalyst, drying and weighing, the loss is 1.9%, the HPLC content of the product is more than 99.6%, and the A content of the impurity is less than 0.1%, [ α ]]D 25-63.0°(c 2.0,EtOH)。
Example 4
Preparation of nomegestrol acetate (1):
adding the catalyst prepared in the example 1 into a dry 100mL closed-loop reactor, replacing the system with dry high-purity nitrogen, repeating for 3 times, then adding acetone and the compound of the formula 5, sealing the system, heating to 60 ℃, continuing to perform heat preservation reaction for 2.0 hours, cooling the system to room temperature after the reaction is finished, then filtering the reaction liquid to remove the catalyst, adsorbing and decoloring the residual liquid by activated carbon, concentrating under reduced pressure, recrystallizing and purifying to obtain the target product of the compound of the formula 1, wherein the yield is 95.0%, filtering, washing, recovering the catalyst, drying and weighing, the loss is 2.2%, the HPLC content of the product is more than 99.5%, the content of the impurity A is less than 0.1%, and the [ α% ]]D 25-62.8°(c 2.0,EtOH)。
Example 5
Preparation of nomegestrol acetate (1):
adding the catalyst prepared in the example 1 into a dry 100mL closed-loop reactor, replacing the system with dry high-purity nitrogen for 3 times, then adding tetrahydrofuran and the compound of the formula 5, sealing the system, heating to 80 ℃, continuing to perform heat preservation reaction for 0.5 hour, cooling the system to room temperature after the reaction is finished, then recovering the solvent from the reaction liquid under reduced pressure, then adding acetone to dissolve the product, filtering to remove the catalyst, adsorbing and decoloring the residual liquid by activated carbon, concentrating under reduced pressure, recrystallizing methanol to purify to obtain the target product of the compound of the formula 1, wherein the yield is 99.0%, filtering, washing, recovering the catalyst, drying and weighing, the loss is 2.0%, the HPLC content of the product is more than 99.8%, the content of the impurity A is less than 0.1%, and the content of the impurity is less than α]D 25-63.8°(c 2.0,EtOH)。
Example 6
Preparation of nomegestrol acetate (1):
the catalyst used in this example was the catalyst recovered in example 5, and the deficit was additionally supplemented with fresh catalyst.
The recovered catalyst was added to a dry 100mL closed-loop reactor and the system was replaced with dry high-purity nitrogen for 3 iterations. Then adding tetrahydrofuran and a compound shown in the formula 5, sealing the system, heating to 80 ℃, continuing to perform heat preservation reaction for 1.5 hours, cooling the system to room temperature after the reaction is finished, then recovering the solvent from the reaction solution under reduced pressure, then adding acetone to dissolve the product, filtering to remove the catalyst, and performing adsorption decoloration, reduced pressure concentration and methanol recrystallization purification on the residual liquid through activated carbon to obtain the target product, namely the compound shown in the formula 1, wherein the yield is 97.0%. The catalyst is filtered, washed, recovered, dried and weighed, the loss rate is calculated, and the obtained catalyst is used for the next application. The experimental conditions used in each set of experiments refer to the reaction conditions given in this example, the reaction system needs an oxygen-free system, and the specific experimental results of the set of experiments are shown in table 1.
TABLE 1
In conclusion, the present invention effectively overcomes various disadvantages of the prior art and has high industrial utilization value.
The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.
Claims (10)
1. A method for preparing nomegestrol acetate, comprising:
reacting a compound shown in a formula 5 in the presence of a catalyst to prepare a compound shown in a formula 1, wherein the catalyst is selected from Rh-Binap catalysts;
2. the method of claim 1, wherein the Rh-Binap catalyst has a chemical structure as follows:
[Rh(Binap)2]+Y-；
wherein, Y-Is selected from ClO4 -、PF6 -、BF4 -；
Binap is 2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl.
3. The method for preparing nomegestrol acetate according to claim 1, wherein the reaction is carried out at a temperature ranging from room temperature to the boiling temperature of the solvent, preferably at a temperature ranging from 50 ℃ to 80 ℃.
4. The method of claim 1, wherein the reaction is carried out under a gas blanket.
5. The method for preparing nomegestrol acetate according to claim 1, wherein the reaction is carried out in the presence of a reaction solvent selected from one or more of alkanes, haloalkanes, alcohol solvents, ether solvents, and ketone solvents.
6. The method of claim 5, wherein the reaction solvent is selected from the group consisting of n-hexane, n-heptane, dichloromethane, dichloroethane, methanol, ethanol, tetrahydrofuran, methyltetrahydrofuran, and acetone.
7. The method of claim 1, wherein the molar ratio of the Rh-Binap catalyst to the compound of formula 5 is 1:6000 to 10000.
8. The method of claim 1, wherein the catalyst has a TON of 7500-8000.
9. The method of claim 1, wherein the loss of catalyst during the reaction is less than or equal to 3 wt%.
10. The method of claim 1, wherein the post-treatment of the reaction comprises: separating the catalyst, recrystallizing to provide said nomegestrol acetate, and preferably, at least partially recovering the separated catalyst for use in the reaction of the compound of formula 5 to prepare the compound of formula 1.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4605750A (en) * | 1983-09-16 | 1986-08-12 | Takasago Perfumery Co., Ltd. | Rhodium-phosphine complex |
| WO2008148473A2 (en) * | 2007-06-06 | 2008-12-11 | Bayer Schering Pharma Ag | Method for the production of 17 alpha-acetoxy-6-methylenepregn-4-ene-3,20-dione, medroxyprogesterone acetate, and megestrol acetate |
| US20090012321A1 (en) * | 2007-06-06 | 2009-01-08 | Klaus Annen | Process for preparing 17alpha-acetoxy-6-methylenepregn-4-ene-3,20-dione, medroxyprogesterone acetate and megestrol acetate |
| CN107501375A (en) * | 2017-09-04 | 2017-12-22 | 江苏远大信谊药业有限公司 | A kind of preparation method of megestrol acetate |
| WO2018109508A1 (en) * | 2016-12-16 | 2018-06-21 | Richter Gedeon Nyrt. | Industrial process for the synthesis of nomegestrol-acetate |
-
2020
- 2020-01-14 CN CN202010035562.5A patent/CN111187326B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4605750A (en) * | 1983-09-16 | 1986-08-12 | Takasago Perfumery Co., Ltd. | Rhodium-phosphine complex |
| WO2008148473A2 (en) * | 2007-06-06 | 2008-12-11 | Bayer Schering Pharma Ag | Method for the production of 17 alpha-acetoxy-6-methylenepregn-4-ene-3,20-dione, medroxyprogesterone acetate, and megestrol acetate |
| US20090012321A1 (en) * | 2007-06-06 | 2009-01-08 | Klaus Annen | Process for preparing 17alpha-acetoxy-6-methylenepregn-4-ene-3,20-dione, medroxyprogesterone acetate and megestrol acetate |
| WO2018109508A1 (en) * | 2016-12-16 | 2018-06-21 | Richter Gedeon Nyrt. | Industrial process for the synthesis of nomegestrol-acetate |
| CN107501375A (en) * | 2017-09-04 | 2017-12-22 | 江苏远大信谊药业有限公司 | A kind of preparation method of megestrol acetate |
Non-Patent Citations (2)
| Title |
|---|
| HE-LIN LU 等: "An Improved Synthesis of Nomegestrol Acetate", 《ORG. PROCESS RES. DEV.》 * |
| TETSUO OHTA 等: "BINAP-Ru(II) and BINAP-Rh(I)-catalyzed asymmetric hydrogenation of olefins without heteroatom-functionalities", 《JOURNAL OF ORGANOMETALLIC CHEMISTRY》 * |
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