CN114230627A - Preparation method of betamethasone epoxy hydrolysate intermediate - Google Patents
Preparation method of betamethasone epoxy hydrolysate intermediate Download PDFInfo
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- CN114230627A CN114230627A CN202111676952.1A CN202111676952A CN114230627A CN 114230627 A CN114230627 A CN 114230627A CN 202111676952 A CN202111676952 A CN 202111676952A CN 114230627 A CN114230627 A CN 114230627A
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- reaction
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- tetrahydrofuran
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- acetylene
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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
Abstract
The invention belongs to the technical field of steroid hormone preparation, and particularly relates to a preparation method of a betamethasone epoxy hydrolysate intermediate, wherein a compound A is subjected to methyl treatment and then subjected to ethynylation reaction to obtain a compound C, and the reaction route is as follows:
Description
Technical Field
The invention belongs to the technical field of steroid hormone preparation, and particularly relates to a preparation method of a betamethasone epoxy hydrolysate intermediate.
Background
The betamethasone epoxy hydrolysate is an important intermediate for synthesizing betamethasone, is a main raw material for synthesizing the betamethasone, and has the molecular formula: c22H28O5And the product is named as: DB 11; the chemical name is 9 beta, 11 beta-epoxy-16 beta-methyl pregna-1, 4-diene-17 alpha, 21-diol-3, 20-diketone; betamethasone epoxide. CAS No. is 981-34-0, and the molecular structural formula is as follows:
in the synthesis of betamethasone epoxy hydrolysate, a more important intermediate is provided, and the structural formula is as follows:
at present, no better way is available for synthesizing the intermediate.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a preparation method of betamethasone epoxy hydrolysate intermediate, which has simple process, high product yield and purity, and can convert 16-bit alpha methyl into beta methyl while alkynylating the upper alkynyl.
The invention relates to a preparation method of a betamethasone epoxy hydrolysate intermediate, which comprises the following steps of carrying out ethynylation reaction on a methyl group on a compound A to obtain a compound C (namely the betamethasone epoxy hydrolysate intermediate), wherein the reaction route is as follows:
the ethynylation reaction comprises the steps of adding a compound B into an acetylene solution, reacting and processing to obtain a compound C, wherein the acetylene solution is a mixture of tetrahydrofuran or methyltetrahydrofuran dissolved with acetylene, absolute ethyl alcohol or isopropanol and potassium hydroxide (namely the acetylene solution is composed of at least three raw materials which are tetrahydrofuran or methyltetrahydrofuran, absolute ethyl alcohol or isopropanol and potassium hydroxide respectively).
Preferably, the weight ratio of tetrahydrofuran or methyltetrahydrofuran, absolute ethyl alcohol or isopropanol to potassium hydroxide is 10:1-1.5: 2-2.5.
Preferably, the reaction temperature for the ethynylation reaction is from 0 to 5 ℃.
Preferably, in the ethynylation reaction, the reaction product is kept stand, the organic phase is concentrated, filtered and recrystallized to obtain the betamethasone epoxy hydrolysate intermediate.
Preferably, the preparation method of the compound B comprises the steps of mixing the compound A and a reaction solution at a temperature of-40 to-35 ℃, heating to 0-10 ℃ for reaction, cooling to-45 to-40 ℃, adding methyl bromide, controlling the temperature to-20 to 10 ℃ for reaction, and treating to obtain the compound B;
the preparation method of the reaction solution comprises the step of mixing the Grignard solution with tetrahydrofuran and hexamethylphosphoramide, wherein the Grignard solution is prepared by adding a mixed solution of styrene and tetrahydrofuran into a mixed solution of diisopropylamine and metallic lithium.
Preferably, the mixture of styrene and tetrahydrofuran is added into the mixture of diisopropylamine and lithium metal, and the temperature is controlled to be 40-50 ℃.
Preferably, the weight ratio of styrene, tetrahydrofuran, diisopropylamine and metallic lithium is 1:2.5-3.5:1.5-2: 0.1-0.2.
Preferably, the weight ratio of the tetrahydrofuran to the hexamethylphosphoramide is 1:0.1-0.2
The invention has the beneficial effect that the invention discloses a preparation method of a key intermediate of betamethasone epoxy hydrolysate. The preparation method takes the compound A as a raw material, and prepares the key intermediate of the betamethasone epoxy hydrolysate through methylation reaction, acetylization transposition reaction and refining in sequence.
In the parent ring of steroid hormone, if the 16-position is firstly substituted by beta methyl, then LDA (lithium diisopropylamide) or butyllithium and other reagents are needed to carry out the ethynylation reaction, the cost is obviously increased; in the invention, the 16-position alpha methyl is firstly used for carrying out the ethynylation reaction, and the acetylene solution dissolved with acetylene is used for carrying out the ethynylation reaction and transposition, thereby obviously reducing the cost.
The ethynylation reaction generally requires acetylene to be dissolved in an aprotic solvent such as acetone to increase the solubility of acetylene and improve the reaction efficiency. According to the invention, solvents such as acetone and the like are not added in the ethynylation reaction, but ethanol is added, so that 16-site alpha methyl is transposed into beta methyl during the ethynylation reaction, the 16-site methyl can be simultaneously transposed without extra operation, the efficiency is higher, and the cost is lower.
Detailed Description
Example 1
0.8kg of diisopropylamine is pumped into a reaction tank, after nitrogen gas is replaced for 2 times, 0.051kg of metallic lithium is added, the system is heated to 40-45 ℃, the temperature is controlled to be 40-45 ℃, about one-thirtieth of mixed solution of 0.48kg of styrene and 1.5kg of tetrahydrofuran is dripped into the reaction tank, and the reaction is initiated (the temperature is raised by 2-5 ℃ for fogging). After the initiation, the temperature is controlled to be 40-50 ℃, and the residual mixed solution of styrene and tetrahydrofuran is dripped. After the dropwise addition is finished, the temperature is kept between 40 and 50 ℃ for reaction for about 2 hours until no metallic lithium is left. Cooling the prepared Grignard solution to 0-10 ℃ for later use.
4.5kg of tetrahydrofuran and 0.78kg of hexamethylphosphoramide were pumped into the low temperature kettle, and then cooled to 0-5 ℃ after 2 times of nitrogen substitution. And slowly pumping the prepared Grignard solution into the main reaction kettle. After the addition, nitrogen is replaced for 2 times, and the temperature is kept between 5 and 10 ℃ for reaction for 1 hour. The temperature of the system is reduced to-35 to-40 ℃ under the protection of nitrogen. Adding 1.0kg of compound A in 4-5 times, each time at 5-10min intervals. After the addition, the temperature is kept between 0 and 10 ℃ for reaction for 2 hours. The temperature of the system is reduced to-40 to-45 ℃ under the protection of nitrogen, a small amount of methyl bromide is firstly introduced, the heat release is violent, and after the temperature is stable, the residual methyl bromide (total 0.9kg) is quickly introduced. And after the introduction is finished, keeping the system at the temperature of-20-10 ℃ for reaction for at least 2 h. After the raw materials are completely reacted, 0.25kg of water is added to stop the reaction, and the temperature is controlled to be 10-20 ℃ and the stirring is carried out for at least 2 h. Concentrating the system at 45-55 deg.C under negative pressure (vacuum less than or equal to-0.08 MPa) until there is no fraction, adding 5kg of dichloromethane, stirring, washing with 2kg of water and 1kg of water sequentially, adding 0.5kg of sodium sulfate into the system, drying, filtering, concentrating the filtrate at 45-55 deg.C under negative pressure (vacuum less than or equal to-0.08 MPa) until there is no fraction, adding 3.5kg of tetrahydrofuran, dissolving to obtain tetrahydrofuran solution of compound B, and directly adding into the next step.
Under the protection of nitrogen, 10kg of tetrahydrofuran, 1.2kg of absolute ethyl alcohol and 2kg of powdered potassium hydroxide are added into a reaction kettle, the temperature is reduced to 0-10 ℃, acetylene gas is introduced, and the acetylene gas is introduced at a constant speed for 2 hours until the acetylene gas is not absorbed any more. Cooling the system to 0-5 deg.C, stirring for 10min, maintaining the temperature at 0-5 deg.C, slowly adding above tetrahydrofuran solution dropwise, maintaining the temperature at 0-5 deg.C, reacting for 3.5h until the raw materials react completely, adding 2kg water, quenching, and stirring for 30-60 min. Standing, separating, extracting the lower water layer with 1kg tetrahydrofuran, mixing the tetrahydrofuran layers, concentrating at 50 deg.C under negative pressure (vacuum less than or equal to-0.08 Mpa) until no fraction, replacing with 4kg water, concentrating again until no fraction, cooling to 30 deg.C, filtering to obtain crude product, and repeatedly recrystallizing with 10kg ethyl acetate for 3-4 times to obtain refined product. Purity 99% and total yield 80%.
Comparative example 1
Compared with the example 1, 2kg of acetone is used for replacing 1.2kg of absolute ethyl alcohol, the rest is the same as the example 1, the yield of the target product compound C is 60 percent, the purity is 98.5 percent, and the structural formula of other main products is shown in the specification
Those of ordinary skill in the art will understand that: the discussion of any embodiment above is meant to be exemplary only, and is not intended to imply that the scope of the application is limited to these examples; within the context of the present application, features from the above embodiments or from different embodiments may also be combined, steps may be implemented in any order, and there are many other variations of different aspects of one or more embodiments in the present application as described above, which are not provided in detail for the sake of brevity.
It is intended that the one or more embodiments of the present application cover all such alternatives, modifications, and variations as fall within the broad scope of the present application. Therefore, any omissions, modifications, substitutions, improvements, and the like that may be made without departing from the spirit and principles of one or more embodiments of the present application are intended to be included within the scope of the present application.
Claims (8)
1. A preparation method of a betamethasone epoxy hydrolysate intermediate is characterized in that a compound A is subjected to methyl treatment and then is subjected to ethynylation reaction to obtain a compound C, and the reaction route is as follows:
the ethynylation reaction comprises the steps of adding a compound B into an acetylene solution, reacting and processing to obtain a compound C, wherein the acetylene solution is a mixture of tetrahydrofuran or methyltetrahydrofuran dissolved with acetylene, absolute ethyl alcohol or isopropanol and potassium hydroxide.
2. The process according to claim 1, wherein the weight ratio of tetrahydrofuran or methyltetrahydrofuran, absolute ethanol or isopropanol to potassium hydroxide is 10:1-1.5: 2-2.5.
3. The process according to claim 1, wherein the reaction temperature for the ethynylation is 0 to 5 ℃.
4. The process according to claim 1, wherein the reaction is carried out by allowing the reaction mixture to stand, concentrating the organic phase, filtering, and recrystallizing to obtain the intermediate betamethasone epoxy hydrolysate.
5. The process according to any one of claims 1 to 4, wherein the compound B is prepared by mixing the compound A with the reaction solution at-40 to-35 ℃, heating to 0 to 10 ℃ for reaction, cooling to-45 to-40 ℃, adding methyl bromide, controlling the temperature to-20 to 10 ℃ for reaction, and treating to obtain the compound B;
the preparation method of the reaction solution comprises the step of mixing the Grignard solution with tetrahydrofuran and hexamethylphosphoramide, wherein the Grignard solution is prepared by adding a mixed solution of styrene and tetrahydrofuran into a mixed solution of diisopropylamine and metallic lithium.
6. The method according to claim 5, wherein the mixture of styrene and tetrahydrofuran is added to the mixture of diisopropylamine and lithium metal at a temperature of 40-50 ℃.
7. The process according to claim 5, wherein the weight ratio of styrene to tetrahydrofuran to diisopropylamine to lithium metal is 1:2.5-3.5:1.5-2: 0.1-0.2.
8. The process according to claim 5, wherein the weight ratio of tetrahydrofuran to hexamethylphosphoramide is 1: 0.1-0.2.
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2021
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| US4707358A (en) * | 1984-01-30 | 1987-11-17 | The University Of Chicago | Vaccine against Epstein-Barr Virus |
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