CN115028674A - Preparation method of medicine troostine for treating breast cancer - Google Patents
Preparation method of medicine troostine for treating breast cancer Download PDFInfo
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- CN115028674A CN115028674A CN202210618314.2A CN202210618314A CN115028674A CN 115028674 A CN115028674 A CN 115028674A CN 202210618314 A CN202210618314 A CN 202210618314A CN 115028674 A CN115028674 A CN 115028674A
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- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
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Abstract
The invention provides a preparation method of a medicine troostine for treating breast cancer, which comprises the following steps: reacting testosterone and dihydropyran in a solvent under the catalysis of pyridinium p-toluenesulfonate to obtain a compound 1; reacting the compound 1 with ethyl formate in a solvent under the action of sodium methoxide to obtain a compound 2; the compound 2 and hydroxylamine hydrochloride undergo cyclization reaction in a solvent to obtain a compound 3; oxidizing the compound 3 in a solvent by an epoxidizing agent to obtain a compound 4; and carrying out a ring opening reaction on the compound 4 in a solvent by sodium methoxide to obtain trilostane. The preparation method of the medicine troostine for treating breast cancer, disclosed by the invention, is simple to operate, does not use toxic and dangerous reagents, is convenient for post-treatment, safe and mild in reaction conditions, good in product purity and suitable for industrial production.
Description
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a preparation method of a medicine troostine for treating breast cancer.
Background
Trolsteine, 4 alpha, 5 alpha-epoxy-2-cyano-androst-2-ene-3, 17 beta-diol, has the following structure.
It reversibly inhibits 3 beta-hydroxysteroid dehydrogenase and delta 5, 4-isomerase in the adrenal cortex, thereby blocking mineralocorticoid and glucocorticoid biosynthesis. Since trilostane can reduce the production of all endogenous steroids, including estrogen and androgen, its effect on advanced breast cancer in postmenopausal women was studied by scholars who were approved for marketing and subsequently reported to be effective in small trials. For this reason, after the expiration of the trilostane patent, Bioenvsion in the UK decided to investigate it further. The postmenopausal progressive breast cancer women who do not respond to the first-line standard medication tamoxifen (tamoxifen) treatment are taken as objects, 780 patients are registered in Europe, America, Australia and other countries to carry out a series of clinical tests, and the results of the clinical tests show that troostitan has high anti-tumor activity and the total effective rate reaches 42 percent through system analysis, wherein the objective response rate to hormone sensitive part subjects is as high as 55 percent, and the two indexes are obviously superior to the current standard second-line medication aromatase inhibitor.
Trilostane has formally acquired a new and important indication for the treatment of progressive breast cancer in postmenopausal women in the uk for the first time in 2002, 8 months, under the trade name modenal. Trilostane will also undergo large phase iii additional trials in europe and america to confirm its benefit in survival, and then filed a supplementary application for treatment of this indication to the U.S. FDA accordingly.
A method for preparing impurity A and impurity B of trilostane reported in 2016, volume 47, volume 3 of Chinese medicinal industry.
A process for the preparation of an intermediate of trilostane reported in section 4 of volume 46 of 2015, journal of the Chinese medical industry. According to the preparation method, testosterone is directly formylated, so that the reaction of testosterone is incomplete, large impurities are generated, the compound 3 is difficult to purify, and the difficulty of industrial production is increased.
Patent WO2005113577a1 reports a process for the preparation of trilostane from compound 4, which uses a methanolic solution of sodium hydroxide for hydrolysis, but with the occurrence of more cyano hydrolysis impurities, and with increasing batch size, the impurities increase further, making purification difficult.
Disclosure of Invention
In view of the above, in order to solve the above problems, the invention provides a novel preparation method of troostine for treating breast cancer, which is simple to operate, does not use toxic and dangerous reagents, is convenient for post-treatment, has safe and mild reaction conditions and good product purity, and is suitable for industrial production.
In order to achieve the purpose, the technical scheme of the invention is realized as follows:
a preparation method of a medicine troostine for treating breast cancer comprises the following synthetic route:
the synthetic route comprises the following steps:
s1, reacting testosterone with dihydropyran in a solvent under the catalysis of pyridinium p-toluenesulfonate (PPTS) to obtain a compound 1;
s2, reacting the compound 1 with ethyl formate in a solvent under the action of sodium methoxide to obtain a compound 2;
s3, carrying out cyclization reaction on the compound 2 and hydroxylamine hydrochloride in a solvent to obtain a compound 3;
s4, oxidizing the compound 3 in a solvent by an epoxidizing agent to obtain a compound 4;
s5, compound 4 is subjected to ring opening reaction by sodium methoxide in a solvent to obtain the trilostane.
Further, in the S1, adding testosterone into a solvent, stirring, adding pyridinium p-toluenesulfonate after dissolving, controlling the reaction temperature at 0-30 ℃, dropwise adding dihydropyran into the system, and after the reaction is finished, performing post-treatment to obtain a compound 1; wherein the mass ratio of testosterone to the dihydropyriran and pyridinium p-toluenesulfonate is 100: 60-70: 1-3; the solvent is dichloromethane.
Furthermore, in the S1, the mass ratio of the dichloromethane to the testosterone is 6: 1; the reaction temperature is 10-20 ℃.
Further, in S1, after the reaction is completed, the reaction mixture is quenched with water to separate an organic phase, and the organic phase is concentrated, and then substituted with cyclohexane, dispersed, and crystallized to obtain compound 1.
Further, in the step S2, adding a sodium methoxide solution into a solvent, controlling the temperature to be 0-20 ℃, adding the compound 1 into the system, adding ethyl formate, controlling the reaction temperature to be 20-30 ℃, and after the reaction is finished, carrying out post-treatment to obtain a yellow oily compound 2 which is not purified and is directly used for the next operation; wherein the mass ratio of the compound 1 to the ethyl formate is 1: 1.3 to 1.8; the mass fraction of the sodium methoxide solution is more than 50%; the solvent is anhydrous tetrahydrofuran.
Furthermore, in the S2, the mass ratio of the anhydrous tetrahydrofuran to the compound 1 is 3-5: 1.
further, in S2, after the reaction is completed, the system is concentrated, an aqueous hydrochloric acid solution is added dropwise to the concentrated system, extraction is performed with ethyl acetate, and the organic phase is concentrated to obtain compound 2.
Further, in the step S3, the amount of hydroxylamine hydrochloride is 1 to 3 equivalents of the compound 2; the solvent is absolute ethyl alcohol; controlling the reaction temperature to be 0-100 ℃; after the reaction is finished, the compound 3 is obtained through post treatment.
Furthermore, in the S3, the dosage of the hydroxylamine hydrochloride is 1 to 1.2 equivalents of the compound 2; the reaction temperature is 40-50 ℃.
Further, in S3, after the reaction is completed, the anhydrous ethanol is distilled off under reduced pressure, ethyl acetate and water are used for extraction, the organic phase is concentrated, and the concentrated product is replaced, dispersed and crystallized with cyclohexane to obtain compound 3 as a pale yellow solid.
Further, in the step S4, the epoxidizing agent is m-chloroperoxybenzoic acid, and the reaction solvent is dichloromethane; the molar ratio of the compound 3 to the m-chloroperoxybenzoic acid is 1: 1-3; the reaction temperature is controlled to be 0-100 ℃; after the reaction is finished, the compound 4 is obtained through post treatment.
Furthermore, in the S4, the mol ratio of the compound 3 to the m-chloroperoxybenzoic acid is 1: 1 to 1.2; the mass ratio of the compound 3 to the dichloromethane is 1: 10; the reaction temperature is 0-10 ℃.
Further, in S4, after the reaction is completed, water is added to perform extraction, an aqueous solution of sodium bisulfite is added to perform extraction to remove excess oxidizing agent, an aqueous solution of sodium bicarbonate is used to perform extraction to remove participating acidic substances in the organic phase, the organic phase is concentrated, and the concentrated product is subjected to phase inversion with ethyl acetate to obtain compound 4.
Further, in the S5, a ring opening reaction is performed with sodium methoxide, and a solvent is tetrahydrofuran; the molar ratio of compound 4 to sodium methoxide was 1: 1-3; after the reaction is finished, the target product troostine is obtained after post-treatment and refining.
Further, the molar ratio of compound 4 to sodium methoxide is 1: 1.4 to 1.6; the mass ratio of the compound 4 to the tetrahydrofuran is 1: 5 to 10.
Further, in the step S5, after the reaction is finished, water and methyl tert-butyl ether are added to extract impurities, the pH value of a water phase is adjusted to 3-4 by using glacial acetic acid, the water phase is extracted by using ethyl acetate, an organic phase is dried, filtered and concentrated, and a residue is DMF/H 2 And refining the O to obtain a target product troostitan.
Compared with the prior art, the preparation method of the breast cancer treatment drug trilostane has the following advantages:
(1) the preparation method of the medicine trilostane for treating breast cancer, disclosed by the invention, has the reaction steps of 5 steps, adopts dihydropyran to protect testosterone, then carries out subsequent preparation procedures, and is simple to operate and simple in post-treatment; in the preparation process, toxic reagents and dangerous chemicals are not used, so that the reaction conditions are safer and milder;
(2) the preparation method of the medicine troostine for treating breast cancer avoids using cycloisomer impurities and hydrolysis impurities reported in other patents, and the prepared product has high purity and is suitable for industrial production.
Drawings
FIG. 1 is an HPLC chromatogram of Compound 1, described in example 1 of the present invention;
FIG. 2 is an HPLC chromatogram of Compound 3, example 1 of the present invention;
FIG. 3 is an HPLC chromatogram of crude Compound 4 as described in example 1 of the present invention;
FIG. 4 is an HPLC chromatogram of a fine compound 4 described in example 1 of the present invention;
FIG. 5 is a HNMR spectrum of a purified compound 4 of example 1 of the present invention;
FIG. 6 is an HPLC chromatogram of crude trilostane prepared as described in example 1 of the present invention;
FIG. 7 is an HPLC chromatogram of a trilostane top-product prepared in example 1 of the present invention;
FIG. 8 is the HNMR spectrum of the refined trilostane product obtained in example 1 of the present invention.
Detailed Description
Unless defined otherwise, technical terms used in the following examples have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention belongs. The test reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the experimental methods are conventional methods unless otherwise specified.
The present invention will be described in detail with reference to the following examples and accompanying drawings.
A preparation method of a medicine troostine for treating breast cancer comprises the following steps:
s1, adding testosterone into a dichloromethane solvent, stirring, dissolving, adding pyridinium p-toluenesulfonate, controlling the reaction temperature at 10-20 ℃, dropwise adding dihydropyran into the system, quenching with water after the reaction is finished, separating an organic phase, concentrating the organic phase, and performing displacement, dispersion and crystallization by using cyclohexane to obtain a compound 1; wherein the mass ratio of testosterone to the dihydropyridine to the pyridinium p-toluenesulfonate is 100: 60-70: 1-3; the mass ratio of the dichloromethane to the testosterone is 6: 1;
s2, adding a sodium methoxide solution into an anhydrous tetrahydrofuran solvent, controlling the temperature to be 0-20 ℃, adding the compound 1 into the system, adding ethyl formate, controlling the reaction temperature to be 20-30 ℃, concentrating the system after the reaction is finished, dropwise adding a hydrochloric acid aqueous solution into the concentrated system, extracting by using ethyl acetate, and concentrating an organic phase to obtain a yellow oily compound 2, wherein the yellow oily compound is directly used for the next operation without purification; wherein the mass ratio of the compound 1 to the ethyl formate is 1: 1.3 to 1.8; the mass fraction of the sodium methoxide solution is more than 50%; the mass ratio of the anhydrous tetrahydrofuran to the compound 1 is 3-5: 1;
s3, adding an absolute ethyl alcohol solvent into the prepared compound 2, adding hydroxylamine hydrochloride, carrying out cyclization reaction, controlling the reaction temperature to be 40-50 ℃, after the reaction is finished, carrying out reduced pressure distillation to remove absolute ethyl alcohol, extracting by using ethyl acetate and water, concentrating an organic phase, carrying out phase change on the concentrated product by using cyclohexane, dispersing and crystallizing to obtain a compound 3 which is a light yellow solid; wherein the dosage of the hydroxylamine hydrochloride is 1-1.2 equivalent of the compound 2;
s4, adding the compound 3 into a dichloromethane solvent, adding m-chloroperoxybenzoic acid, controlling the reaction temperature at 0-10 ℃, after the reaction is finished, adding water for extraction, adding a sodium bisulfite aqueous solution for extraction to remove excessive oxidant, extracting by using a sodium bicarbonate aqueous solution to remove participating acidic substances, concentrating an organic phase, performing phase change on the concentrated product by using ethyl acetate, and crystallizing to obtain a compound 4; wherein the mol ratio of the compound 3 to the m-chloroperoxybenzoic acid is 1: 1 to 1.2; the mass ratio of the compound 3 to the dichloromethane is 1: 10;
s5, adding sodium methoxide and the compound 4 into a tetrahydrofuran solvent, carrying out ring-opening reaction at the temperature of 20-25 ℃, adding water and methyl tert-butyl ether after the reaction is finished, extracting impurities, adjusting the pH value of a water phase to 3-4 by using glacial acetic acid, extracting by using ethyl acetate, drying an organic phase, filtering and concentrating, and using DMF/H for residues 2 Refining the O to obtain a target product troostine; wherein the molar ratio of the compound 4 to the sodium methoxideIs 1: 1.4 to 1.6; the mass ratio of the compound 4 to the tetrahydrofuran is 1: 5 to 10.
The specific synthetic route is as follows:
example 1
(1) Preparation of Compound 1
600.0kg of methylene chloride was pumped into a 1000L reactor and 100.0kg of testosterone was added to the reactor. After the solution was stirred and dissolved, 2.0kg of pyridinium p-toluenesulfonate was added to the reaction vessel. And (3) stirring and cooling, cooling to 10-20 ℃, pumping the dihydropyrane into a high-level tank, controlling the temperature in the reaction kettle to be 10-20 ℃, and slowly dripping 65.0kg of dihydropyrane. The temperature rise is obvious in the dropping process, and after the dropping is finished, the temperature is controlled to be 10-20 ℃ to react for 2.0-3.0 hours. The reaction was checked using thin layer plates (developing solvent dichloromethane: acetone ═ 9V: 1V). And (3) finishing the reaction after the raw materials disappear, adding 400.0kg of purified water into the system to terminate the reaction, stirring for 30min, and separating out a lower organic phase. The organic phase was concentrated at moderate temperature, and the phases were exchanged twice with cyclohexane, 30.0kg each time. And then adding 300.0kg of cyclohexane into the system, stirring and heating to 50 ℃ until the system is clear, and slowly cooling to 0-5 ℃. A large amount of solid is separated out in the system. The solid was centrifuged to obtain compound 1 as a white solid with a yield of 105.2kg, 81.4% and an HPLC purity of 98.79%, as shown in figure 1.
(2) Preparation of Compound 2
Preparation of high-concentration sodium methoxide: 380.0kg of 30% sodium methoxide methanol solution was charged into a 2000L reactor, and the methanol was distilled under normal pressure, and when the amount of distilled methanol was 80.0kg, the distillation was stopped. To a freshly prepared high-strength methanolic solution of sodium methoxide was added 500.0kg of anhydrous tetrahydrofuran. Controlling the temperature to be 0-20 ℃, slowly adding 100.0kg of compound 1 solid into the system, controlling the temperature to be 0-20 ℃ after the addition is finished, stirring for 1.0h, and then adding 150.0kg of ethyl formate into the system. And after the feeding is finished, controlling the temperature to be 20-30 ℃ and reacting for 16.0 hours. After the reaction, the system was concentrated to substantially no fraction, and 500.0kg of a 4N hydrochloric acid aqueous solution was added dropwise to the concentrated system, followed by extraction with 400.0kg of ethyl acetate. The ethyl acetate phase was concentrated to give compound 2 as a yellow oil. The product was used in the next experiment without further purification.
(3) Preparation of Compound 3
789.0kg of ethanol is added into a reaction kettle for preparing the compound 2, and the mixture is stirred to completely dissolve the compound 2; 23.0kg of hydroxylamine hydrochloride was dissolved in 100.0kg of water; an aqueous solution of hydroxylamine hydrochloride was added dropwise to an ethanol solution of compound 2. After the dropwise addition is finished, heating to 40-50 ℃ for reaction for 16.0 hours; after the completion of the reaction, anhydrous ethanol was distilled off under reduced pressure, and 500.0kg of ethyl acetate and 500.0kg of water were added to the reaction system to conduct extraction. Concentrating the ethyl acetate phase, performing phase change twice by using cyclohexane in the concentrated system, using 50.0kg of cyclohexane for each time, finally adding 500.0kg of cyclohexane dispersed solid into the system, centrifuging the solid to obtain a compound 3 which is a light yellow solid, wherein the yield of the compound 3 in the steps 2 and 3 is 85.1%, the HPLC purity is 83.70%, and the spectrogram is shown in figure 2.
(4) Preparation of Compound 4
Adding 700.0kg of dichloromethane into a 2000L reaction kettle, adding 70.0kg of compound 3 into the dichloromethane, stirring for dissolving, cooling to 0-5 ℃, adding 48.0kg of m-chloroperoxybenzoic acid (with the content of 80%) at a controlled temperature, and after the addition is finished, controlling the temperature to 0-10 ℃ for reaction; after the reaction, 400.0kg of water was added for extraction, and an aqueous solution of sodium hydrogen sulfite was added to the organic phase to remove excess oxidizing agent. The organic phase is extracted with aqueous sodium bicarbonate solution to remove the participating acidic substances. Concentrating the organic phase, performing phase change on the concentrated product by using ethyl acetate, and concentrating until no fraction is generated basically to obtain a crude compound 4. The crude product purity was 91.16%. The spectrogram is shown in figure 3. And adding 100.0kg of ethyl acetate into the crude product, heating to reflux, dissolving all solids, cooling to 0-5 ℃, separating out solids, centrifuging, and drying the product to obtain a refined product of the compound 4, wherein the refined product is a white solid, the yield is 51.3kg, the yield is 69.7%, and the HPLC purity is 96.43%. The spectrogram is shown in figure 4. The product structure is confirmed by HNMR spectrogram, and the HNMR spectrogram of the compound 4 is shown in figure 5.
(5) Preparation of trilostane
Pumping 400.0kg of tetrahydrofuran into a reaction tank, controlling the temperature to be 20-25 ℃, adding 10.0kg of sodium methoxide solid, stirring for 20 minutes, adding 50.0kg of compound 4, controlling the temperature to be 20-25 ℃, and carrying out heat preservation reaction for 1.5 hours. Thin layer assay (developing solvent dichloromethane: acetone ═ 9V: 1V). Detecting the disappearance of the raw material point of the compound 4, adding 300.0kg of water into the reaction kettle, stirring until viscous substances appear, adding 150.0kg of methyl tert-butyl ether into the reaction kettle, and extracting impurities. Temporarily storing the upper organic phase, and adjusting the pH value of the water phase to 3-4 by using glacial acetic acid. 300.0kg of ethyl acetate is added into the reaction kettle, liquid separation is carried out after stirring for 30min, and an upper organic phase is separated. Drying, filtering and concentrating the organic phase, dissolving the residue with 100.0kg of DMF (N, N-dimethylformamide), dropwise adding 200.0kg of purified water at the temperature of 20-25 ℃, separating out white solid in the dropwise adding process, stirring for 30min, filtering, washing the product with water to obtain 45.2kg of crude trilostane with the HPLC purity of 97.46%. The spectrum is shown in figure 6.
Adding the crude product of trilostane into 100.0kg of DMF (N, N-dimethylformamide) and stirring for dissolving, controlling the temperature to be 20-25 ℃, dropwise adding 200.0kg of purified water, separating out white solids in the dropwise adding process, stirring for 30min, filtering, washing the product with water to obtain white solids, and drying to obtain refined trilostane 31.6kg, wherein the yield is 63.2%, and the HPLC purity is 99.90%. The spectrum is shown in figure 7. The product structure is confirmed by HNMR spectrogram, and the HNMR spectrogram of trilostane is shown in figure 8.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (10)
1. A preparation method of a medicine troostine for treating breast cancer is characterized by comprising the following synthetic route:
the synthetic route comprises the following steps:
s1, reacting testosterone with dihydropyran in a solvent under the catalysis of pyridinium p-toluenesulfonate to obtain a compound 1;
s2, reacting the compound 1 with ethyl formate in a solvent under the action of sodium methoxide to obtain a compound 2;
s3, carrying out cyclization reaction on the compound 2 and hydroxylamine hydrochloride in a solvent to obtain a compound 3;
s4, oxidizing the compound 3 in a solvent by an epoxidizing agent to obtain a compound 4;
s5, compound 4 is subjected to ring-opening reaction by sodium methoxide in a solvent to obtain the trilostane.
2. The method for preparing the drug troostine for treating breast cancer according to claim 1, wherein the drug troostine comprises: in the S1, adding testosterone into a solvent, dissolving, adding pyridinium p-toluenesulfonate, controlling the reaction temperature at 0-30 ℃, dropwise adding dihydropyran into the system, and after the reaction is finished, performing post-treatment to obtain a compound 1; wherein the mass ratio of testosterone to the dihydropyridine to the pyridinium p-toluenesulfonate is 100: 60-70: 1-3; the solvent is dichloromethane.
3. The method for preparing the drug troostine for treating breast cancer according to claim 2, wherein the drug troostine comprises: in the S1, the mass ratio of the dichloromethane to the testosterone is 6: 1; the reaction temperature is 10-20 ℃.
4. The method for preparing the drug troostine for treating breast cancer according to claim 1, wherein the drug troostine comprises: in the S2, adding a sodium methoxide solution into a solvent, controlling the temperature to be 0-20 ℃, adding a compound 1 into the system, adding ethyl formate, controlling the reaction temperature to be 20-30 ℃, and performing post-treatment after the reaction is finished to obtain a compound 2; wherein the mass ratio of the compound 1 to the ethyl formate is 1: 1.3 to 1.8; the mass fraction of the sodium methoxide solution is more than 50 percent; the solvent is anhydrous tetrahydrofuran.
5. The method for preparing the drug troostine for treating breast cancer according to claim 4, wherein the drug troostine comprises: in the S2, the mass ratio of anhydrous tetrahydrofuran to the compound 1 is 3-5: 1.
6. the method for preparing the drug troostine for treating breast cancer according to claim 1, wherein the drug troostine comprises: in the S3, the dosage of hydroxylamine hydrochloride is 1-3 equivalents of the compound 2; the solvent is absolute ethyl alcohol; controlling the reaction temperature to be 0-100 ℃; after the reaction is finished, the compound 3 is obtained through post treatment.
7. The method for preparing the drug troostine for treating breast cancer according to claim 6, wherein the drug troostine comprises: in the S3, the dosage of hydroxylamine hydrochloride is 1-1.2 equivalent of the compound 2; the reaction temperature is 40-50 ℃.
8. The method for preparing the drug troostine for treating breast cancer according to claim 1, wherein the drug troostine comprises: in the S4, the epoxidizing agent is m-chloroperoxybenzoic acid, and the reaction solvent is dichloromethane; the molar ratio of the compound 3 to the m-chloroperoxybenzoic acid is 1: 1-3; the reaction temperature is controlled to be 0-100 ℃; after the reaction is finished, the compound 4 is obtained through post treatment.
9. The method for preparing the drug troostine for treating breast cancer according to claim 8, wherein the drug troostine comprises: in the S4, the mol ratio of the compound 3 to the m-chloroperoxybenzoic acid is 1: 1 to 1.2; the mass ratio of the compound 3 to the dichloromethane is 1: 10; the reaction temperature is 0-10 ℃; after the reaction is finished, adding water for extraction, adding sodium bisulfite aqueous solution for extraction to remove excessive oxidant, extracting an organic phase by using sodium bicarbonate aqueous solution to remove participating acidic substances, concentrating the organic phase, and performing phase change on a concentrated product by using ethyl acetate to obtain a compound 4.
10. The method for preparing troostine for treating breast cancer according to claim 1, wherein: in the S5, a solvent is tetrahydrofuran; the molar ratio of compound 4 to sodium methoxide was 1: 1-3; after the reaction is finished, carrying out post-treatment and refining to obtain a target product troostine;
of these, the preferred molar ratio of compound 4 to sodium methoxide is preferably 1: 1.4 to 1.6; the mass ratio of the compound 4 to the tetrahydrofuran is 1: 5-10; after the reaction is finished, adding water and methyl tert-butyl ether, extracting impurities, adjusting the pH value of a water phase to 3-4 by using glacial acetic acid, extracting by using ethyl acetate, drying an organic phase, filtering, concentrating, and using DMF/H as a residue 2 And refining the O to obtain a target product troostine.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3296255A (en) * | 1963-11-29 | 1967-01-03 | Sterling Drug Inc | 2-cyano steroids |
| WO2005113577A1 (en) * | 2004-05-22 | 2005-12-01 | Stegram Pharmaceuticals Ltd | Method for the preparation of trilostane |
-
2022
- 2022-06-01 CN CN202210618314.2A patent/CN115028674A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3296255A (en) * | 1963-11-29 | 1967-01-03 | Sterling Drug Inc | 2-cyano steroids |
| WO2005113577A1 (en) * | 2004-05-22 | 2005-12-01 | Stegram Pharmaceuticals Ltd | Method for the preparation of trilostane |
Non-Patent Citations (2)
| Title |
|---|
| MATTHIAS GRILL 等: "Novel protective group synthesis of androgen receptor modulators with steroidal and nonsteroidal scaffolds", CHEMRXIV * |
| 李永 等: "17β-羟基-4α，5α-环氧雄甾烷并[2，3-d]异噁唑的合成工艺改进", 贵阳医学院 * |
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