CN114409717A - Tibolone intermediate etherate and preparation method of tibolone - Google Patents
Tibolone intermediate etherate and preparation method of tibolone Download PDFInfo
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- CN114409717A CN114409717A CN202111554331.6A CN202111554331A CN114409717A CN 114409717 A CN114409717 A CN 114409717A CN 202111554331 A CN202111554331 A CN 202111554331A CN 114409717 A CN114409717 A CN 114409717A
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- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0081—Substituted in position 17 alfa and 17 beta
- C07J1/0088—Substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
- C07J1/0096—Alkynyl derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0059—Estrane derivatives substituted in position 17 by a keto group
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J21/005—Ketals
- C07J21/006—Ketals at position 3
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Abstract
The invention relates to a tibolone intermediate etherate and a tibolone preparation method, in the presence of a compound of a formula (II), ethylene glycol and the compound of the formula (I) are subjected to ketal reaction, so that the ethylene glycol can be selectively subjected to ketal reaction with 3-carbonyl of the compound of the formula (I), and 5-10 double bonds are constructed at the same time to obtain a compound of the formula (III); further carrying out a first hydrolysis reaction and an etherification reaction on the compound of the formula (III) by a one-pot method to obtain a high-purity tibolone intermediate etherate of the compound of the formula (IV). The tibolone can be obtained by carrying out an alkynylation reaction and a hydrolysis reaction on the compound of the formula (IV), a new synthetic route is provided for preparing the tibolone, the steps are less, the reaction condition is mild, and the yield and the purity are higher.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to tibolone intermediate etherate and a tibolone preparation method.
Background
Tibolone (Tibolone) is a steroid drug with the chemical name of 17 beta-hydroxy-7 alpha-methyl-19-nor-17 alpha-pregna-5 (10) -en-20-yn-3-one, has androgen activity and progestational hormone activity, and has the effect of promoting synthesis and metabolism, and can prevent osteoporosis of women after menopause, and relieve climacteric symptoms such as facial flush, sweating, etc. Tibolone belongs to the class of anabolic hormones and androgens, and is used for the treatment of menopause and postmenopausal syndromes, as well as for the clinical use in natural or surgically induced menopause.
A traditional method for synthesizing tibolone is to take dehydroepiandrosterone as an initial raw material, obtain a 7 alpha-methyl compound through 7 steps of reaction, and then obtain a target product tibolone through four steps of reaction of Birch reduction, Oppenauer oxidation, acetylene addition and oxalic acid hydrolysis. However, the synthesis method has more steps; meanwhile, when the 5, 10-position double bond is constructed, four-step reaction of Birch reduction, Oppenauer oxidation, acetylene addition and oxalic acid hydrolysis is needed, the reaction condition is severe, and the synthesis difficulty is high. In the other method, 19-nor-4-androstenedione is used as an initial raw material, and tibolone is obtained through alkynylation, acylation, debromination, methylation, transposition and hydrolysis; according to the synthesis method, acetyl chloride is adopted to simultaneously protect the 3-position and the 17-position, and chloride ions in the acetyl chloride are easy to perform addition reaction with double bonds in reactants, so that more byproducts are generated; and acetyl chloride is easy to smoke, strong in corrosivity and strong in irritation; and meanwhile, a lithium bromide reagent is used for brominating and debrominating, and a bromine-containing reagent has high irritation and is extremely unfriendly to the environment. And using diester group protection (10S,13S,17S) -17-acetoxyl group-13-methyl-3-oxyl-1, 2,3,8,9,11,12,13,14,15,16, 17-dodecahydro-10H-cyclopentane [ a ] phenanthrene-10-yl) methyl acetate as a starting material, performing Grignard, hydrolysis, oxidation and preparative chromatography purification to obtain a 7 alpha-methyl aldehyde compound, and then performing aldehyde removal, 3-bit acetal protection, acetylene addition and hydrolysis reaction to obtain a tibolone product. The synthesis method needs to remove aldehyde groups in magnesium methoxide and liquid ammonia when constructing the 5,10 double bonds, and the reaction conditions are severe, thus being not beneficial to the industrial production.
Therefore, the development of a tibolone synthesis method with few steps and mild conditions is of great significance.
Disclosure of Invention
Based on the method, the tibolone intermediate etherate and the tibolone preparation method with few steps are provided, and the method does not need to carry out reaction steps with violent reaction conditions such as aldehyde removal or Birch reduction and the like when 5 and 10 double bonds are constructed.
The technical scheme of the invention for solving the technical problems is as follows.
A preparation method of tibolone intermediate etherate comprises the following steps:
performing ketal reaction on the compound of the formula (I), the compound of the formula (II) and ethylene glycol to prepare a compound of a formula (III);
carrying out a first hydrolysis reaction on a compound shown in a formula (III), and then carrying out an etherification reaction on the compound with an etherification reagent to prepare a tibolone intermediate etherate; the structural formula of the tibolone intermediate etherate is shown as a formula (IV);
in some embodiments, in the method for preparing tibolone intermediate etherate, the ketal reaction is carried out under the action of a first catalyst, and the first catalyst is at least one selected from hydrogen chloride and hydrobromic acid.
In some embodiments, in the method for preparing tibolone intermediate etherate, the solvent for the ketal reaction is at least one selected from the group consisting of diethyl ether, dioxane and tetrahydrofuran.
In some embodiments, in the preparation method of tibolone intermediate etherate, the temperature of the ketal reaction is-10 ℃ to-5 ℃.
In some embodiments, the first hydrolysis reaction is performed in a solvent selected from at least one of methanol, isopropanol, tetrahydrofuran, acetonitrile, ethanol, and acetone.
In some embodiments, the second catalyst of the first hydrolysis reaction is at least one selected from the group consisting of boron trifluoride diethyl etherate, anhydrous aluminum trichloride methanol solution, anhydrous aluminum trichloride ethanol solution, hydrogen chloride methanol solution, hydrogen chloride tetrahydrofuran solution, hydrogen chloride ethanol solution, and hydrogen chloride dioxane solution.
In some embodiments, in the preparation method of tibolone intermediate etherate, the solvent for etherification reaction is selected from at least one of methanol, isopropanol, tetrahydrofuran, acetonitrile, ethanol and acetone.
In some of these embodiments, in the process for preparing tibolone intermediate etherate, the etherification reagent is selected from at least one of methanol and trimethyl orthoformate.
In some embodiments, the preparation of the tibolone intermediate etherate comprises the following steps:
carrying out addition reaction on a compound shown in a formula (V) and a Grignard reagent to generate the compound shown in the formula (I);
in some embodiments, the temperature of the addition reaction in the preparation method of the tibolone intermediate etherate is-10 ℃ to-5 ℃.
In some of these embodiments, in the process for preparing tibolone intermediate etherate, the grignard reagent is selected from at least one of methyl magnesium chloride and methyl magnesium bromide.
In some embodiments, the solvent for the addition reaction is at least one selected from the group consisting of diethyl ether, dioxane, tetrahydrofuran, and 2-methyltetrahydrofuran.
In some embodiments, the tibolone intermediate etherate is prepared by a method in which the addition reaction is carried out under the action of a third catalyst selected from at least one of cuprous chloride, copper acetate, cuprous bromide and cuprous iodide.
In some embodiments, in the preparation method of the tibolone intermediate etherate, the ratio of the mass of the compound of the formula (V) to the volume of the solvent is (0.13 mmol-0.20 mmol):1 mL.
In some embodiments, the preparation of the tibolone intermediate etherate comprises the following steps:
and (3) carrying out condensation reaction on ethylene glycol, a dehydrating agent and a fourth catalyst to obtain the compound of the formula (II).
In some embodiments, in the preparation method of tibolone intermediate etherate, the dehydrating agent is at least one selected from triethyl orthoformate and trimethyl orthoformate
In some embodiments, the tibolone intermediate etherate is prepared by a method wherein the fourth catalyst is selected from at least one of p-toluenesulfonic acid, pyridinium hydrochloride, and methanolic hydrogen chloride.
The invention also provides a preparation method of tibolone, which comprises the following steps:
the compound shown in the formula (IV) is prepared by the preparation method;
carrying out an ethynylation reaction on the compound of the formula (IV) to prepare a compound of a formula (VI);
subjecting said compound of formula (VI) to a second hydrolysis reaction to produce said tibolone; the tibolone is shown as a formula (VII);
in some embodiments, in the tibolone preparation method, the alkynylation reagent of the ethynylation reaction is trimethylsilylacetylene.
In some of these embodiments, in the tibolone production process, the solvent of the ethynylation reaction is selected from at least one of tetrahydrofuran, 2-methyl-tetrahydrofuran, and dehydrated ether.
In some of these embodiments, the ethynylation reaction is carried out under the action of an organic base, which is butyl lithium.
In some embodiments, the solvent for the second hydrolysis reaction is at least one selected from methanol, isopropanol, tetrahydrofuran, acetonitrile, ethanol, and acetone.
In some embodiments, the second hydrolysis reaction is performed under the action of a sixth catalyst selected from at least one of hydrochloric acid, oxalic acid, sulfuric acid, and propionic acid.
Compared with the prior art, the preparation method of the tibolone intermediate etherate has the following beneficial effects:
in the preparation method of the tibolone intermediate etherate, the compound of the formula (I), the compound of the formula (II) and ethylene glycol are subjected to ketal reaction, and because 13-site angular methyl exists beside 17-site carbonyl of the compound of the formula (I), the steric hindrance is larger; in the presence of a compound of formula (II) and ethylene glycol, enabling the compound of formula (II) to selectively perform ketal reaction with the 3-carbonyl of the compound of formula (I) and simultaneously constructing a 5-and 10-double bond to obtain the compound of formula (III). Further, the first hydrolysis reaction and the etherification reaction of the compound shown in the formula (III) are carried out one-pot reaction to obtain the high-purity tibolone intermediate etherate (the compound shown in the formula (IV)), the mass yield is 95%, and the purity is more than or equal to 99%.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 is a hydrogen spectrum of the compound of formula (IV) synthesized in example 1.
Detailed Description
The technical solution of the present invention will be described in further detail with reference to specific examples. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. It is to be understood that these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
In the description of the present invention, it is to be understood that the terms "first", "second" and "first" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implying any number of indicated technical features. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.
The weight of the related components mentioned in the description of the embodiments of the present invention may not only refer to the specific content of each component, but also represent the proportional relationship of the weight among the components, and therefore, it is within the scope of the disclosure of the description of the embodiments of the present invention to scale up or down the content of the related components according to the description of the embodiments of the present invention. Specifically, the weight described in the description of the embodiment of the present invention may be a unit of mass known in the chemical industry field, such as μ g, mg, g, and kg.
The invention provides a preparation method of tibolone intermediate etherate, which is characterized by comprising the steps of S30-S40.
Step S30: performing ketal reaction on the compound of the formula (I), the compound of the formula (II) and ethylene glycol to prepare a compound of a formula (III);
wherein, the chemical name of the compound of formula (I) is (7R,13S) -7, 13-dimethyl-1, 6,7,8,9,10,11,12,13,14,15, 16-dodecahydro-3H-cyclopentane [ a ] phenanthrene-3, 17(2H) -diketone, the chemical name of the compound of formula (II) is 2, 2'- [1, 2-ethanediylbis (oxy) ] -bis-1, 3-dioxolane, and the chemical name of the compound of formula (III) is (7R,13S) -7, 13-dimethyl-1, 4,6,7,8,9,11,12,13,14,15, 16-dodecahydro spiro [ a ] phenanthrene-3, 2' - [1,3] dioxacycloalkane ] -17(2H) -ketone.
In some examples, in step S30, the solvent for the ketal reaction is selected from at least one of diethyl ether, dioxane, and tetrahydrofuran.
In some preferred examples, in step S30, the solvent for the ketal reaction is tetrahydrofuran or any combination of tetrahydrofuran with diethyl ether or dioxane.
It is understood that the solvent of the ketal reaction contains tetrahydrofuran, which facilitates better dissolution and stabilization of the substrate, thereby facilitating the reaction.
In some examples, in step S30, the ketal reaction is performed under the action of a first catalyst selected from at least one of hydrogen chloride and hydrobromic acid.
It can be understood that the first catalyst is diluted by the solvent and then added into the reaction system, which is beneficial to controlling the reaction rate and avoiding other impurities generated due to too fast reaction speed.
In some examples, in step S30, the first catalyst is selected from at least one of a hydrogen chloride methanol solution, a hydrogen chloride tetrahydrofuran solution, a hydrogen chloride ethanol solution, and a hydrogen chloride dioxane solution.
Preferably, the first catalyst is a hydrogen chloride tetrahydrofuran solution.
In some examples, in step S30, the mass concentration of the first catalyst when added is 18% to 38%; optionally, the concentration of the first catalyst when added is from 28% to 35%.
In some examples, in step S30, the mass percentage concentration of the compound of formula (ii) in the reaction solution is 3.5% to 6.7%; optionally, the mass percentage concentration of the compound of formula (ii) is 4.5% to 5.5%. In some examples, the temperature of the ketal reaction is-10 ℃ to-5 ℃ in step S30.
By controlling the temperature and substrate concentration of the ketal reaction, in the presence of the compound of formula (II), the glycol is promoted not to react with the 17-carbonyl group of the compound of formula (I), and the compound of formula (II) is further promoted to protect the 3-carbonyl group of the compound of formula (I).
In some specific examples, in step S30, the compound of formula (I) and a solvent are mixed, and the compound of formula (II) and a first catalyst are added at the above-mentioned specific temperature to perform a ketal reaction to produce the compound of formula (iii).
In some of these examples, in step S30, the preparation of the compound of formula (I) comprises step S10.
Step S10: carrying out addition reaction on the compound shown in the formula (V) and a Grignard reagent to generate a compound shown in the formula (I);
wherein, the chemical name of the compound of the formula (V) is (13S) -13-methyl-1, 8,9,10,11,12,13,14,15, 16-decahydro-3H-cyclopentane [ a ] phenanthrene-3, 17(2H) -diketone.
In some examples, the temperature of the addition reaction is-20 ℃ to-60 ℃ in step S10; optionally, the temperature of the addition reaction is-20 ℃ to-45 ℃; further, the temperature of the addition reaction is-35 ℃ to-45 ℃.
By controlling the temperature of the addition reaction, the 17-carbonyl of the compound shown in the formula (V) does not react with a formula reagent, and the 17-carbonyl is protected without a protecting group, so that the intermediate compound shown in the formula (I), namely the 7 alpha-methyl compound, with higher purity is prepared, and the selectivity is higher.
In some examples, in step S10, the grignard reagent is selected from at least one of methyl magnesium chloride, methyl magnesium bromide, and ethyl magnesium chloride; alternatively, the grignard reagent is methyl magnesium chloride.
In some examples, in step S10, the mass concentration of the grignard reagent when added is 10% to 20%; optionally, the grignard reagent is added at a mass percentage concentration of 15% to 20%.
In some examples, in step S10, the solvent for the addition reaction is selected from at least one of diethyl ether, dioxane, tetrahydrofuran, and 2-methyltetrahydrofuran; alternatively, the solvent for the addition reaction is tetrahydrofuran or any combination of tetrahydrofuran with diethyl ether, dioxane, 2-methyltetrahydrofuran.
In some examples, in step S10, the ratio of the mass of the compound of formula (V) to the volume of the solvent is (0.13 mmol-0.20 mmol):1 mL; alternatively, the concentration of the compound of formula (V) (0.15 mmol-0.18 mmol) is 1 mL.
In some examples, in step S10, the addition reaction is performed under the action of a third catalyst, and the third catalyst is at least one selected from cuprous chloride, cupric acetate, cuprous bromide, and cuprous iodide. Optionally, the third catalyst is a ketone acetate.
In some specific examples, in step S10, the compound of formula (V) and the solvent are mixed, the third catalyst is added, and the grignard reagent is added dropwise at the above-mentioned specific temperature to cause an addition reaction to produce the compound of formula (I).
In some of these examples, in step S30, the preparation of the compound of formula (II) includes step S20.
Step S20: and (3) carrying out condensation reaction on ethylene glycol, a dehydrating agent and a fourth catalyst to obtain the compound shown in the formula (II).
It is understood that the step numbers only represent specific steps, and are not related to the sequence, such as steps S10 and S20, which can be performed simultaneously, or step S10 can be performed first and step S20 can be performed first, and step S20 can be performed first and step S10 can be performed second.
In some examples thereof, in step S20, the dehydrating agent is selected from at least one of triethyl orthoformate and trimethyl orthoformate; optionally, the dehydrating agent is triethyl orthoformate.
In some examples, in step S20, the fourth catalyst is selected from at least one of p-toluenesulfonic acid, pyridinium hydrochloride, and methanolic hydrogen chloride; optionally, the fourth catalyst is p-toluenesulfonic acid.
Step S40, carrying out a first hydrolysis reaction on the compound shown in the formula (III), and carrying out an etherification reaction on the compound with an etherification reagent to prepare a tibolone intermediate etherate; the tibolone intermediate etherate is shown as a formula (IV);
the chemical name of the compound of the formula (IV) is (7R,13S) -3, 3-dimethoxy-7, 13-dimethyl-1, 2,3,4,6,7,8,9,11,12,13,14,15, 16-decatetrahydro-17H-cyclopentan [ a ] phenanthren-17-one.
In some examples, in step S40, the second catalyst of the first hydrolysis reaction is selected from at least one of boron trifluoride diethyl etherate, an aluminum trichloride methanol solution, an aluminum trichloride ethanol solution, a hydrogen chloride methanol solution, a hydrogen chloride tetrahydrofuran solution, a hydrogen chloride ethanol solution, and a hydrogen chloride dioxane solution; further, the second catalyst of the first hydrolysis reaction is absolute aluminum trichloride ethanol solution.
In some specific examples, in step S40, the second catalyst of the first hydrolysis reaction is a hydrogen chloride tetrahydrofuran solution.
In some examples, in step S40, the solvent of the first hydrolysis reaction is selected from at least one of methanol, isopropanol, tetrahydrofuran, acetonitrile, ethanol, and acetone.
In some preferred examples, the solvent of the first hydrolysis reaction is methanol in step S40.
In some examples, in step S40, the solvent for the etherification reaction is selected from at least one of methanol, isopropanol, tetrahydrofuran, acetonitrile, ethanol, and acetone.
In some preferred examples, the solvent for the etherification reaction in step S40 is methanol.
In some examples, in step S40, the etherification reagent is selected from at least one of methanol and trimethyl orthoformate.
It will be appreciated that in the presence of the second catalyst, the compound of formula (iii) is first hydrolysed to intermediate (iii) -1; the intermediate (III) -1 has poor stability and is easy to generate etherification reaction with an etherification reagent; the hydrolysis and the etherification can be realized by a one-pot method without separation, thereby simplifying the operation procedures and saving the cost. Further, when the solvent of the first hydrolysis reaction is methanol, the methanol can be directly used as an etherification reagent, a large amount of methoxyl groups are liberated from the methanol in the second catalyst acid solution, and the large amount of methoxyl groups rapidly react with the intermediate (III) -1 to form the compound of the formula (IV); (III) -1 has the following structure:
in some specific examples, in step S40, the compound of formula (iii) and the solvent are mixed, the second catalyst is added, and the addition of the etherification agent is continued to produce the compound of formula (IV).
One embodiment of the present invention provides a tibolone preparation method, which includes the following steps S50-S60.
Step S50: the compound shown in the formula (IV) is prepared by the preparation method;
carrying out an alkynylation reaction on the compound of the formula (IV) to prepare a compound of a formula (VI);
in some examples, in step S50, the alkynylating agent of the alkynylation reaction is trimethylsilylethynyl.
Acetylene gas is flammable and explosive and is very unsafe, and trimethyl silicon acetylene is adopted to replace alkynyl of acetylene gas frequently used in the traditional process, so that the method is green and environment-friendly, and the production safety is improved.
In some examples, in step S50, the solvent for the ethynylation reaction is selected from at least one of tetrahydrofuran, 2-methyl-tetrahydrofuran, and dehydrated ether; alternatively, the solvent for the ethynylation reaction is tetrahydrofuran.
In some examples, in step S50, the ethynylation reaction is performed under the action of an organic base, which is butyl lithium.
In some examples, in step S50, the mass ratio of the compound of formula (IV), the alkynylating agent and the organic base is 1 (2-3.1): 4.2-4.8; alternatively, the mass ratio of the compound of formula (IV), the alkynylating agent and the organic base is 1:2.4: 4.4.
In some examples, the ethynylation reaction is performed under nitrogen in step S50.
In some examples, the temperature of the ethynylation reaction is-25 ℃ to-60 ℃ in step S50; optionally, the temperature of the ethynylation reaction is-30 ℃ to-50 ℃.
In some specific examples, in step S50, the compound of formula (IV) and a solvent are mixed, and an alkynylating agent and an organic base are added under nitrogen protection at the above-specified temperature to prepare the compound of formula (VI).
Step S60: carrying out a second hydrolysis reaction on the compound shown in the formula (VI) to prepare tibolone; tibolone is shown as formula (VII);
in some examples, in step S60, the solvent of the second hydrolysis reaction is selected from at least one of methanol, isopropanol, tetrahydrofuran, acetonitrile, ethanol, and acetone; alternatively, the solvent of the second hydrolysis reaction is selected from acetone or any combination of acetone with methanol, isopropanol, tetrahydrofuran, acetonitrile, ethanol.
In some examples, in step S60, the second hydrolysis reaction is performed under the action of a sixth catalyst selected from at least one of hydrochloric acid, oxalic acid, sulfuric acid, and propionic acid; optionally, the sixth catalyst is oxalic acid.
In some examples, in step S60, the sixth catalyst is selected from at least one of 5% to 10% hydrochloric acid, 5% to 15% oxalic acid aqueous solution, 3% to 5% sulfuric acid aqueous solution, and 5% to 15% propionic acid aqueous solution by mass; optionally, the sixth catalyst is 5% to 15% oxalic acid.
In some examples, the temperature of the second hydrolysis reaction is 0 ℃ to 5 ℃ in step S60.
In some specific examples, tibolone is prepared by mixing the compound of formula (VI) with a solvent and adding a sixth catalyst in step S60.
The compound of formula (V) and Grignard reagent are subjected to addition reaction, and the intermediate compound of formula (I) with higher purity can be prepared by one-step reaction through the concentration of the compound of formula (V) and the temperature of the addition reaction, the selectivity is higher, the 7 beta-methyl isomer can be controlled within 2 percent, purification is not needed, the reaction step is shortened, the operation process is simplified, the byproducts are less, and the yield is improved. And further performing ketal reaction on the compound of the formula (I) and the ethylene glycol compound of the formula (II), wherein the steric hindrance is large due to the existence of a 13-position angle methyl group beside the 17-position carbonyl group of the compound of the formula (I), and in the presence of the compound of the formula (II), the ethylene glycol can be selectively subjected to ketal reaction with the 3-position carbonyl group of the compound of the formula (I) to simultaneously construct a 5-and 10-position double bond, so as to obtain the compound of the formula (III). Further, after the compound of the formula (III) is subjected to a first hydrolysis reaction and an etherification reaction, a tibolone intermediate etherate (the compound of the formula (IV)) with high purity is obtained. And (3) carrying out an alkynylation reaction and a hydrolysis reaction on the compound shown in the formula (IV) to obtain the tibolone.
The invention provides a new synthetic route for preparing tibolone, and has the advantages of fewer steps, mild reaction conditions and higher yield and purity.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Hereinafter, the tibolone intermediate etherate and tibolone preparation method according to the present invention are exemplified, and it is understood that the tibolone intermediate etherate and tibolone preparation method according to the present invention are not limited to the following examples.
Example 1
1) Addition reaction
Adding 350g of tetrahydrofuran, 20g of acid dehydrogenation product (compound shown in formula (V)), and 0.1g of anhydrous ketoacetate into a reaction bottle, reducing the temperature to-20 to-45 ℃ under the protection of nitrogen, dripping 50g of methyl magnesium chloride solution with the mass concentration of 18%, keeping the temperature for reaction until the raw materials disappear, controlling the temperature to be not more than-10 ℃, slowly dripping 8.6g of concentrated hydrochloric acid for quenching reaction, pouring the reaction liquid into 450mL of water, standing for liquid separation, extracting the water phase once with 60mL of tetrahydrofuran, combining the organic phases, washing the organic phases with saturated saline, standing for layering, concentrating the organic phases to be viscous under reduced pressure, reducing the temperature to-5 to 0 ℃ for crystallization, filtering and drying to obtain 16g of white powder solid, wherein the mass yield is 80%, the purity is 96.7%, and the maximum single impurity content is 1.04%, and the white powder solid can be directly put into the next reaction without purification.
2) Ketal reaction
Preparation of the Compound of formula (II)
Adding 14g of triethyl orthoformate, 6.5g of ethylene glycol, 0.1g of p-toluenesulfonic acid and 100mL of cyclohexane into a reaction bottle, and heating to 65-80 ℃; and evaporating cyclohexane, and cooling to room temperature for later use.
Dissolving 15g of a compound shown in a formula (I) by 230mL of tetrahydrofuran, reducing the temperature to 0-5 ℃ under the protection of nitrogen, dropwise adding 8g of a compound shown in a formula (II), 4.2g of ethylene glycol and 2g of 33% hydrogen chloride tetrahydrofuran solution, keeping the temperature for reaction until the raw materials disappear, adding 0.5g of triethylamine for quenching reaction, concentrating the mixture under reduced pressure to be thick, reducing the temperature to 0-5 ℃ for crystallization, filtering and drying the product at 50 ℃ to obtain 13.5g of white crystalline solid, namely the compound shown in the formula (III); the yield is 90 percent, the purity is more than or equal to 97 percent, and the maximum single impurity content is 0.7 percent.
3) Hydrolysis and etherification
Adding 13g of the compound shown in the formula (III) and 140mL of methanol into a reaction bottle, reducing the temperature to 5-8 ℃ under the protection of nitrogen, dropwise adding 1.2g of a 30% hydrogen chloride tetrahydrofuran solution, keeping the temperature at 5-15 ℃ for reaction for 0.5h, adding 0.5g of boron trifluoride diethyl etherate, and reacting until the raw materials disappear; pouring the reaction solution into 20% sodium bicarbonate solution for water precipitation, filtering, vacuum drying at 30-45 deg.C to obtain a product with purity of 95% or more and purity of 99% or more after refining with methanol, to obtain 12.35g of compound of formula (IV) with yield of 95%, wherein the hydrogen spectrogram of the compound of formula (IV) is shown in figure 1.
4) Ethynylation reaction
Adding 12.3g of the compound shown in the formula (IV) and 206mL of tetrahydrofuran into a reaction bottle, reducing the temperature to-30 to-50 ℃ under the protection of nitrogen, adding 53mL of n-butyl lithium by using an injector, dropwise adding 29.5g of trimethylsilylacetylene, and reacting for 0.5h at the constant temperature. After the raw materials completely react, saturated saline solution is dripped to quench the reaction, 10% hydrochloric acid is used for regulating the pH value of a system to be 8-9, the mixture is kept stand for layering, a water phase is extracted once by 30mL of tetrahydrofuran, an organic phase is combined, the organic phase is concentrated to be thick under reduced pressure, cooled to 0-5 ℃ for crystallization, filtered and dried at 50 ℃ to obtain 12.5g of the compound shown in the formula (VI), the yield is 104%, the purity is not less than 96%, and the compound can be directly put into the next reaction without purification.
5) Deprotection of the amino acid
Adding 12.5g of the compound shown in the formula (VI) and 160mL of acetone into a reaction bottle, stirring and dissolving under the protection of nitrogen, and dropwise adding 3.0g of 10-15% oxalic acid aqueous solution at 0-5 ℃. After the reaction is completed, pouring the reaction solution into a 20% sodium bicarbonate aqueous solution, adjusting the pH value to 7-8, adding 100mL of dichloromethane for extraction, layering, concentrating the organic phase under reduced pressure, adding methanol for replacement, continuously concentrating to a thick state, cooling to 0-5 ℃ for crystallization, and filtering to obtain a tibolone crude product; the purity is more than or equal to 97 percent, the methanol is refined once, the purity is more than or equal to 99 percent, 9.5g of white crystalline solid is obtained, the yield is 76 percent, and all single impurities are less than 0.10 percent.
From the compound of formula (v) the final mass yield of tibolone was 54% (product of yield per step: 80% 90% 95% 104% 76%).
Example 2
The other steps are the same as example 1, only step 2) is different, step 2) is as follows:
2) ketal reaction
Preparation of the Compound of formula (II)
Adding 14g of triethyl orthoformate, 6.5g of ethylene glycol, 0.1g of p-toluenesulfonic acid and 100mL of cyclohexane into a reaction bottle, and heating to 65-80 ℃; and evaporating cyclohexane, and cooling to room temperature for later use.
Dissolving 15g of a compound shown in a formula (I) by 230mL of dioxane, reducing the temperature to 0-5 ℃ under the protection of nitrogen, dropwise adding 8g of a compound shown in a formula (II), 4.2g of ethylene glycol and 2g of 30-35% hydrogen chloride dioxane solution, keeping the temperature to react until the raw materials disappear, adding 0.5g of triethylamine to quench the reaction, concentrating under reduced pressure to be thick, reducing the temperature to 0-5 ℃ to crystallize, filtering, and drying at 50 ℃ to obtain 13.2g of white crystalline solid, namely the compound shown in the formula (III); the mass yield is 88 percent, the purity is more than or equal to 97 percent, and the maximum single impurity content is 0.3 percent.
Example 3
The other steps are the same as example 1, only step 2) is different, step 2) is as follows:
preparation of the Compound of formula (II)
Adding 14g of triethyl orthoformate, 6.5g of ethylene glycol, 0.1g of p-toluenesulfonic acid and 100mL of cyclohexane into a reaction bottle, and heating to 65-80 ℃; and evaporating cyclohexane, and cooling to room temperature for later use.
Dissolving 15g of a compound shown in a formula (I) by using a mixed solvent containing 100mL of tetrahydrofuran and 130mL of diethyl ether, reducing the temperature to 0-5 ℃ under the protection of nitrogen, dropwise adding 8g of a compound shown in a formula (II), 4.2g of glycol and 2g of hydrogen chloride tetrahydrofuran solution, keeping the temperature for reaction until the raw materials disappear, adding 0.5g of triethylamine for quenching reaction, reducing the pressure and concentrating to be thick, reducing the temperature to 0-5 ℃ for crystallization, filtering, and drying at 50 ℃ to obtain 13g of white crystalline solid, namely the compound shown in the formula (III); the yield is 85 percent, the purity is more than or equal to 97 percent, and the maximum single impurity content is 0.6 percent.
Example 4
The other steps are the same as example 1, only step 3) is different, step 3) is as follows:
3) hydrolysis and etherification
Adding 13g of a compound shown in a formula (III) and 140mL of acetone into a reaction bottle, reducing the temperature to 5-8 ℃ under the protection of nitrogen, dropwise adding 1.2g of anhydrous aluminum trichloride ethanol solution with the mass concentration of 30%, keeping the temperature at 5-15 ℃ for reaction for 0.5h, adding 0.5g of boron trifluoride diethyl etherate and 4.6g of trimethyl orthoformate, and reacting until the raw materials disappear; pouring the reaction solution into 20% sodium bicarbonate solution for water precipitation, filtering, and vacuum drying at 30-45 ℃ to obtain a crude product with purity of more than or equal to 90% and refined methanol with purity of more than or equal to 97%. To obtain 12g of a refined product of the compound of the formula (IV) with a yield of 92.3%.
Example 5
The other steps are the same as example 1, only step 4) is different, and step 4) is as follows:
4) ethynylation reaction
Adding 12g of the compound shown in the formula (IV) and 150mL of tetrahydrofuran into a reaction bottle, reducing the temperature to-30 to-50 ℃ under the protection of nitrogen, adding 58mL of n-butyllithium by using an injector, dropwise adding 37g of trimethylsilylacetylene, and reacting for 0.5h under the condition of heat preservation. After the raw materials completely react, saturated saline solution is dripped to quench the reaction, 10% hydrochloric acid is used for regulating the pH value of a system to be 8-9, the mixture is kept stand for layering, a water phase is extracted once by 20mL of tetrahydrofuran, organic phases are combined, the organic phases are concentrated to be thick under reduced pressure, cooled to 0-5 ℃ for crystallization, filtered and dried at 50 ℃ to obtain 11g of the compound shown in the formula (VI), the yield is 90%, the purity is not less than 95%, and the compound can be directly put into the next reaction without purification.
Comparative example 1
Firstly, alkynyl a compound of a formula (I) to obtain a formula (VIII); the other steps are the same as example 1, as follows:
1) ethynylation reaction
Adding 20g of the compound shown in the formula (I) and 260mL of tetrahydrofuran into a reaction bottle, reducing the temperature to-30 to-50 ℃ under the protection of nitrogen, adding 82mL of n-butyllithium by using an injector, dropwise adding 52g of trimethylsilylacetylene, and reacting for 0.5h under the condition of heat preservation. After the raw materials completely react, saturated saline solution is dripped to quench the reaction, 10% hydrochloric acid is used for adjusting the pH value of a system to be 8-9, the mixture is kept stand for layering, a water phase is extracted once by 30mL of tetrahydrofuran, organic phases are combined, the organic phase is concentrated to be thick under reduced pressure, cooled to 0-5 ℃ for crystallization, filtered and dried at 50 ℃ to obtain 14g of a compound shown in the formula (VIII), the yield is 70%, the purity is not less than 96%, and the compound can be directly put into the next reaction without purification.
2) Preparation of a compound of formula (IX)
Adding 13g of triethyl orthoformate, 6.0g of ethylene glycol, 0.1g of p-toluenesulfonic acid and 100mL of cyclohexane into a reaction bottle, and heating to 65-80 ℃; and evaporating cyclohexane, and cooling to room temperature for later use.
Dissolving 14g of a compound shown in a formula (VIII) by 200mL of tetrahydrofuran, reducing the temperature to 0-5 ℃ under the protection of nitrogen, dropwise adding 6.5g of a compound shown in a formula (II), 4.2g of ethylene glycol and 2g of 30% hydrogen chloride tetrahydrofuran solution, keeping the temperature for reaction until the raw materials disappear, adding 0.5g of triethylamine for quenching reaction, concentrating under reduced pressure to be thick, reducing the temperature to 0-5 ℃ for crystallization, filtering, and drying at 50 ℃ to obtain 8.4g of white crystalline solid, namely the compound shown in the formula (IX); the yield is 60 percent, the purity is more than or equal to 95 percent, and the maximum single impurity content is 1 percent.
3) Hydrolysis and etherification
Adding 8.2g of a compound of the formula (IX) and 90mL of methanol into a reaction bottle, reducing the temperature to 5-8 ℃ under the protection of nitrogen, dropwise adding 0.9g of a 30% hydrogen chloride tetrahydrofuran solution at the mass concentration, keeping the temperature at 5-15 ℃ for reaction for 0.5h, adding 0.3g of boron trifluoride diethyl etherate, and reacting until the raw materials disappear; pouring the reaction solution into 20% sodium bicarbonate solution for water precipitation, filtering, and vacuum drying at 30-45 ℃ to obtain crude product with purity not less than 93% and refined methanol with purity not less than 99%, to obtain 6.2g of the compound of formula (X) with yield of 75%.
4) Deprotection of the amino acid
Adding 4.8/6g of the compound of the formula (X) and 85mL of acetone into a reaction bottle, stirring and dissolving under the protection of nitrogen, and dropwise adding 1.4g of 10-15% oxalic acid aqueous solution at 0-5 ℃. After the reaction is completed, pouring the reaction liquid into 20% sodium bicarbonate aqueous solution, adjusting the pH value to 7-8, adding 40mL of dichloromethane for extraction, layering, decompressing and concentrating the organic phase, adding methanol for replacement, continuously concentrating to be thick, cooling to 0-5 ℃ for crystallization, filtering, and obtaining 4.5g of white crystalline solid with the yield of 75%, wherein the purity of the crude product is more than or equal to 90%, the purity of the methanol is more than or equal to 95% and the maximum single impurity content is 1.5%.
The compound of formula (V) is used as raw material, and the final mass yield of the tibolone prepared is 19 percent (the reaction yield in each step is multiplied).
Comparative example 2
The other steps are the same as example 1, only step 3) is different, and step 3 is divided into two steps of reaction, which are specifically as follows:
3) hydrolysis
Adding 25g of the compound shown in the formula (III) and 300mL of acetone into a reaction bottle, reducing the temperature to 5-8 ℃ under the protection of nitrogen, dropwise adding 1.2g of a 30% hydrogen chloride tetrahydrofuran solution, keeping the temperature at 5-15 ℃ for reaction for 0.5h, and reacting until the raw materials disappear; pouring the reaction solution into 20% sodium bicarbonate solution for water precipitation, filtering, wherein the purity of a crude product is more than or equal to 90%, the maximum single impurity is 6% of the compound shown in the formula (I), and the purity of the refined methanol is more than or equal to 93%, so that 17g of the compound shown in the formula (III) -1 is obtained, and the mass yield is 68%.
4) Etherification
Adding 17g of a compound of a formula (III) -1 and 170mL of methanol into a reaction flask, cooling to 5-8 ℃ under the protection of nitrogen, adding 0.6g of boron trifluoride diethyl etherate, and reacting until the raw materials disappear; pouring the reaction solution into 20% sodium bicarbonate solution for water precipitation, filtering, and obtaining 10g of the compound of the formula (IV) with the purity of more than or equal to 83% after refining methanol and the mass yield of 59% (the mass ratio of the compound of the formula (IV) to the compound of the formula (III) -1).
Through analysis, hydrolysis and etherification of the compound of the formula (III) are carried out in two steps, the compound of the formula (III) -1 is not as stable as the compound of the formula (III) -2, and the compound is easy to convert, so that the yield of the compound of the formula (III) -1 is lower;
therefore, the etherification and hydrolysis of the compound shown in the formula (III) are carried out by a one-pot reaction, which is more beneficial to the improvement of the yield of the compound shown in the formula (IV).
Comparative example 3
Otherwise the same as example 1, except that no ethylene glycol was added in the ketal reaction.
Preparation of the Compound of formula (II)
Adding 10g of triethyl orthoformate, 4.7g of ethylene glycol, 0.07g of p-toluenesulfonic acid and 80mL of cyclohexane into a reaction bottle, and heating to 65-80 ℃; and evaporating cyclohexane, and cooling to room temperature for later use.
Dissolving 11g of the compound shown in the formula (I) by 150mL of tetrahydrofuran, reducing the temperature to 0-5 ℃ under the protection of nitrogen, dropwise adding 5.7g of the compound shown in the formula (II) and 1g of 33% hydrogen chloride tetrahydrofuran solution, carrying out heat preservation reaction, carrying out TLC (thin layer chromatography) intermediate control, generating no target product, and adding other impurities.
Comparative example 4
Otherwise the same as in example 1 except that the compound of formula II was replaced with triethyl orthoformate.
Ketal reaction:
dissolving 10g of a compound shown in a formula (I) by using 150mL of tetrahydrofuran, reducing the temperature to 0-5 ℃ under the protection of nitrogen, dropwise adding 6.6g of triethyl orthoformate, 2.8g of ethylene glycol and 1g of 33% hydrogen chloride tetrahydrofuran solution, keeping the temperature for reaction until the raw materials disappear, adding 0.5g of triethylamine for quenching reaction, concentrating the mixture under reduced pressure to be thick, reducing the temperature to 0-5 ℃ for crystallization, filtering the mixture, and drying the mixture at 50 ℃ to obtain 5g of a white-like solid, namely the compound shown in the formula (III); the yield is 50%, the purity is more than or equal to 60%, and the maximum single impurity content is 23%.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, so as to understand the technical solutions of the present invention specifically and in detail, but not to be understood as the limitation of the protection scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. It should be understood that the technical solutions provided by the present invention, which are obtained by logical analysis, reasoning or limited experiments, are within the scope of the present invention as set forth in the appended claims. Therefore, the protection scope of the present invention should be subject to the content of the appended claims, and the description and the drawings can be used for explaining the content of the claims.
Claims (10)
1. A preparation method of tibolone intermediate etherate is characterized by comprising the following steps:
carrying out ketal reaction on the compound of the formula (I), glycol and the compound of the formula (II) to prepare a compound of the formula (III);
carrying out a first hydrolysis reaction on a compound shown in a formula (III), and then carrying out an etherification reaction on the compound with an etherification reagent to prepare a tibolone intermediate etherate; the structural formula of the tibolone intermediate etherate is shown as a formula (IV);
2. the method of claim 1, wherein the ketal reaction is carried out over a first catalyst selected from at least one of hydrogen chloride and hydrobromic acid; and/or
The solvent for ketal reaction is at least one selected from diethyl ether, dioxane and tetrahydrofuran; and/or
The ketal reaction temperature is-10 ℃ to-5 ℃.
3. The method for preparing tibolone intermediate etherate according to claim 1, wherein the solvent of the first hydrolysis reaction is selected from at least one of methanol, isopropanol, tetrahydrofuran, acetonitrile, ethanol and acetone; and/or
The second catalyst of the first hydrolysis reaction is at least one selected from boron trifluoride diethyl etherate, anhydrous aluminum trichloride methanol solution, anhydrous aluminum trichloride ethanol solution, hydrogen chloride methanol solution, hydrogen chloride tetrahydrofuran solution, hydrogen chloride ethanol solution and hydrogen chloride dioxane solution; and/or
The solvent for etherification reaction is at least one selected from methanol, isopropanol, tetrahydrofuran, acetonitrile, ethanol and acetone; and/or
The etherification reagent is at least one of methanol and trimethyl orthoformate.
4. The method for preparing tibolone intermediate etherate according to any one of claims 1 to 3, wherein the preparation of the compound of formula (I) comprises the following steps:
carrying out addition reaction on a compound shown in a formula (V) and a Grignard reagent to generate the compound shown in the formula (I);
5. the method for preparing tibolone intermediate etherate according to claim 4, characterized in that the temperature of the addition reaction is-10 ℃ to-5 ℃; and/or
The Grignard reagent is selected from at least one of methyl magnesium chloride and methyl magnesium bromide; and/or
The solvent for the addition reaction is at least one of diethyl ether, dioxane, tetrahydrofuran and 2-methyltetrahydrofuran; and/or
The addition reaction is carried out under the action of a third catalyst, and the third catalyst is at least one selected from cuprous chloride, ketone acetate, cuprous bromide and cuprous iodide.
6. The method for producing tibolone intermediate etherate according to claim 4, wherein the ratio of the mass of the compound of formula (V) to the volume of the solvent is (0.13mmol to 0.20mmol):1 mL.
7. The method for preparing tibolone intermediate etherate according to any one of claims 1 to 3, wherein the preparation of the compound of formula (II) comprises the following steps:
and (3) carrying out condensation reaction on ethylene glycol, a dehydrating agent and a fourth catalyst to obtain the compound of the formula (II).
8. The method for producing tibolone intermediate etherate according to claim 7, wherein the dehydrating agent is at least one selected from triethyl orthoformate and trimethyl orthoformate; and/or
The fourth catalyst is at least one selected from p-toluenesulfonic acid, pyridinium hydrochloride and methanol hydrogen chloride.
9. A preparation method of tibolone is characterized by comprising the following steps:
preparing a compound of formula (IV) by the preparation method of any one of claims 1 to 10;
carrying out an ethynylation reaction on the compound of the formula (IV) to prepare a compound of a formula (VI);
subjecting said compound of formula (VI) to a second hydrolysis reaction to produce said tibolone; the tibolone is shown as a formula (VII);
10. the tibolone production method of claim 9, wherein the alkynylating agent of the alkynylation reaction is trimethylsilylacetylene; and/or
The solvent for the ethynylation reaction is at least one of tetrahydrofuran, 2-methyl-tetrahydrofuran and anhydrous ether; and/or
The ethynylation reaction is carried out under the action of organic base, and the organic base is butyl lithium; and/or
The solvent of the second hydrolysis reaction is selected from at least one of methanol, isopropanol, tetrahydrofuran, acetonitrile, ethanol and acetone; and/or
The second hydrolysis reaction is carried out under the action of a sixth catalyst, and the sixth catalyst is selected from at least one of hydrochloric acid, oxalic acid, sulfuric acid and propionic acid.
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