CN112409433B - Preparation method of U18666A - Google Patents
Preparation method of U18666A Download PDFInfo
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- CN112409433B CN112409433B CN202011332691.7A CN202011332691A CN112409433B CN 112409433 B CN112409433 B CN 112409433B CN 202011332691 A CN202011332691 A CN 202011332691A CN 112409433 B CN112409433 B CN 112409433B
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- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0038—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 with an androstane skeleton, including 18- or 19-substituted derivatives, 18-nor derivatives and also derivatives where position 17-beta is substituted by a carbon atom not directly bonded to a further carbon atom and not being part of an amide group
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Abstract
The invention relates to a preparation method of U18666A, which comprises the following steps: placing dehydroepiandrosterone in a round-bottom flask, adding an organic solvent for dissolving, sequentially adding pyridine and a catalytic amount of DMAP, adding p-toluenesulfonyl chloride in batches, reacting and carrying out aftertreatment to obtain a yellow solid; placing the yellow solid in a round-bottom flask, adding N, N-diethylethanolamine to dissolve the yellow solid, adding p-toluenesulfonic acid into the round-bottom flask under the condition of ice-water bath, stirring at room temperature, heating for reaction, and performing aftertreatment and separation to obtain a light yellow solid; placing the light yellow solid in a round-bottom flask, adding an organic solvent for dissolving, dropwise adding a 2M HCl dioxane solution in an ice water bath, and performing after-treatment to obtain a white solid product U18666A. The preparation method has mild reaction conditions, no special high-temperature high-pressure extreme reaction conditions, easily controlled reaction process, suitability for industrial production, high yield and total yield up to 72 percent.
Description
Technical Field
The invention relates to a preparation method of U18666A, belonging to the technical field of drug synthesis.
Background
Currently, a plurality of roles of U18666A have been made to be important findings in lipid research, and U18666A helps researchers to understand the pathophysiology of various diseases. Ha Li ludney (Harry Rudney) inhibits oxidosqualene cyclase using U18666A, a pathway for polar sterol formation was discovered, and U18666A proved to be an important regulator of 3-hydroxy-3-methyl-glutaryl-coa reductase. Laura Liscam (Laura Liscum) found that U18666A inhibited late endosome and lysosome release of cholesterol, thus having clear recognition of the major pathway of intracellular cholesterol transport. The inhibition of cholesterol transport by U18666A mimics the loss of the functional Niemann-Pick type C protein responsible for NPC disease, thus providing a model for this disease. U18666A subsequently became a tool to assess the importance of molecular trafficking through the lysosomal pathway in other conditions (e.g., atherosclerosis, alzheimer's disease and viral infections).
U18666A also provides two animal models for important diseases: small-sized epilepsy and cataract. This is the first chronic model of absence epilepsy. U18666A was also used to address the role of oxidative stress in apoptosis. Perhaps because U18666A acts as a structure of an amphophilic cationic amine that can interact and inhibit a variety of proteins. Limiting the availability of cholesterol in membrane formation by inhibiting cholesterol synthesis and intracellular transport may also be a mechanism that widely affects many processes. Another possibility is that the order of the membranes can be changed by intercalation into membrane U18666A, thereby changing the function of the resident protein. The similarity of the effects of native and enantiomer U18666A on cells and the ability of intercalating U18666A to increase membrane order are arguments that favor this possibility.
Relatively few reports on the synthesis of U18666A exist at present, and the synthesis method of U18666A reported in the early literature is as follows:
the synthesis method has poor repeatability and low yield, and is not suitable for application in production.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides the preparation method of U18666A, and the preparation method of U18666A has the advantages of mild reaction conditions, easy control of reaction and high yield.
The technical scheme for solving the technical problems is as follows: a preparation method of U18666A, the process principle of said preparation method is as follows:
a preparation method of U18666A, the preparation method of U18666A comprising the steps of:
(1) Placing dehydroepiandrosterone in a round-bottom flask, adding an organic solvent for dissolving, sequentially adding pyridine and a catalytic amount of DMAP (4-dimethylaminopyridine), cooling to-5 ℃, adding p-toluenesulfonyl chloride (TsCl) in batches, stirring at normal temperature for reaction, detecting the disappearance of the dehydroepiandrosterone by TLC, adding the organic solvent for dilution, washing an organic phase by using a saturated sodium bicarbonate solution, washing by using a water solution and a saturated sodium chloride solution in sequence, separating the organic phase, drying by using anhydrous sodium sulfate, and concentrating under negative pressure to obtain a yellow solid;
(2) Putting the yellow solid obtained in the step (1) into a round-bottom flask, adding N, N-diethylethanolamine for dissolving, adding p-toluenesulfonic acid into the round-bottom flask under the condition of ice-water bath, stirring at room temperature, heating for reaction, detecting disappearance of a substrate by TLC, cooling to room temperature, pouring into water, adjusting pH =8 by using sodium bicarbonate, stirring vigorously, precipitating a white solid, performing suction filtration, dissolving the solid in a post-treatment solvent, washing with water, washing with a saturated sodium bicarbonate solution, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography separation to obtain a light yellow solid;
(3) And (3) placing the light yellow solid obtained in the step (2) into a round-bottom flask, adding an organic solvent for dissolving, dropwise adding a 2M HCl dioxane solution in an ice water bath, separating out the solid, stirring at room temperature after dropwise adding, performing suction filtration, leaching with an organic solvent, and performing vacuum drying to obtain a white solid product U18666A.
Preferably, in the step (1), the mass ratio of the dehydroepiandrosterone to the pyridine to the p-toluenesulfonyl chloride is 1:1 to 1.5:1 to 1.5.
Preferably, in the step (1), the organic solvent is dichloromethane, and the reaction time is 8 to 12 hours under stirring at normal temperature.
Preferably, in the step (2), the mass ratio of the yellow solid obtained in the step (1), the N, N-diethylethanolamine and the p-toluenesulfonic acid is 1: 4.0-5.0: 0.5 to 1.0.
Preferably, in the step (2), the stirring time at room temperature is 20min, the heating reaction temperature is 95 ℃, and the heating reaction time is 1 hour.
Preferably, in step (2), after adjusting pH =8 with sodium bicarbonate, stirring vigorously for 3 hours; the post-treatment solvent is dichloromethane; the developing solvent used in the column chromatography separation operation is a mixed solvent of dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol in the developing solvent is 50-100: 1.
preferably, in the step (3), the mass-to-volume ratio of the light yellow solid obtained in the step (2) to the dioxane solution of 2M HCl is 1g.
Preferably, in the step (3), the organic solvent is methyl tert-butyl ether, the stirring time at room temperature is 30min, and the vacuum drying temperature is 40 ℃.
The invention has the beneficial effects that: the preparation method of U18666A is completed through three steps of reaction, and U18666A is rapidly synthesized by taking dehydroepiandrosterone as a starting material. The reaction condition is mild, no special high-temperature high-pressure extreme reaction condition exists, the reaction process is easy to control, the method is suitable for application in industrial production, the yield is high, and the total yield can reach 72%.
Drawings
FIG. 1 is a mass spectrum of Compound 3 described in the examples;
FIG. 2 is a nuclear magnetic detection map of the U18666A product described in the example.
Detailed Description
The present invention will be described in detail with reference to the following embodiments in order to make the aforementioned objects, features and advantages of the invention more comprehensible. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.
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 herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
(1) Placing dehydroepiandrosterone (12.9g, 44.7mmol) in round-bottom flask, adding dichloromethane (100 mL) to dissolve, sequentially adding pyridine (17.6 g, 223.6mmol) and catalytic amount of DMAP, and cooling to T Inner part P-toluenesulfonyl chloride (17g, 89.5 mmol) was added portionwise at < 0 ℃. The ice-water bath was removed and stirred for 12 hours. TLC detects that dehydroepiandrosterone disappears, dichloromethane is added for dilution, organic phase is washed by saturated sodium bicarbonate solution, water is washed by saturated sodium chloride solution, organic phase is separated, anhydrous sodium sulfate is dried, and negative pressure concentration is carried out to obtain yellow solid 18g, and the yield is 91%. Used in the next step without purification.
(2) Taking 10g of the yellow solid product obtained in the step (2), adding 44g of N, N-diethylethanolamine into a round-bottom flask for dissolving, adding 7.3g of p-toluenesulfonic acid under an ice water bath, stirring at room temperature for twenty minutes, and reacting at 95 ℃ for 1 hour. TLC detecting substrate disappearance, cooling to room temperature, pouring into water (1.5L), adjusting pH =8 with sodium bicarbonate, vigorously stirring for 3 hours, precipitating a white solid, performing suction filtration, dissolving the solid in dichloromethane, washing with water, washing with a saturated sodium bicarbonate solution, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography (dichloromethane: methanol = 50-100) to obtain 7g of a product as a light yellow solid, wherein yield is 80%, M + =388.6, mass spectrum as shown in fig. 1.
(2) Taking 7g of the light yellow solid product obtained in the step (2) to a round-bottom flask, adding methyl tert-butyl ether to dissolve the product, and dropwise adding 40mL of a 2M HCl dioxane solution under ice water bath. After the addition of the solid, the mixture was stirred at room temperature for 30 minutes and filtered. The methyl tert-butyl ether was rinsed and dried under vacuum at 40 ℃ to give U18666A 7.6g (100% yield) as a white solid.
The nuclear magnetic spectrum of U18666A is shown in FIG. 2, and the nuclear magnetic detection data is as follows:
1 H NMR(400MHz,DMSO-d 6 )δ13.02(d,J＝5.8Hz,1H),8.12–8.07(m,1H),6.50(t,J＝5.2Hz,2H),5.92(s,3H),5.83(d,J＝18.3Hz,4H),5.09(d,J＝8.7Hz,2H),4.91–4.64(m,3H),4.65–4.50(m,3H),4.43–4.28(m,4H),4.21(t,J＝12.4Hz,1H),4.10(s,2H),4.00(s,1H),3.92(d,J＝14.5Hz,7H),3.69(s,5H),3.51(s,3H).
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, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that various changes and modifications can be made by those skilled in the art without departing from the spirit of the invention, and these changes and modifications are all within the scope of the invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (6)
1. A preparation method of U18666A is characterized in that the preparation method of U18666A comprises the following steps:
(1) Taking dehydroepiandrosterone to a round-bottomed flask, adding an organic solvent for dissolving, sequentially adding pyridine and a catalytic amount of DMAP, cooling to-5 ℃, adding paratoluensulfonyl chloride in batches, stirring and reacting at normal temperature, detecting the disappearance of the dehydroepiandrosterone by TLC (thin layer chromatography), diluting with the organic solvent, washing an organic phase with a saturated sodium bicarbonate solution, washing with water, washing with a saturated sodium chloride solution in turn, separating the organic phase, drying with anhydrous sodium sulfate, and concentrating under negative pressure to obtain a yellow solid;
(2) Putting the yellow solid obtained in the step (1) into a round-bottom flask, adding N, N-diethylethanolamine for dissolving, adding p-toluenesulfonic acid into the round-bottom flask under the condition of ice-water bath, stirring at room temperature, heating for reaction, detecting disappearance of a substrate by TLC, cooling to room temperature, pouring into water, adjusting pH =8 by using sodium bicarbonate, stirring vigorously, precipitating a white solid, performing suction filtration, dissolving the solid in a post-treatment solvent, washing with water, washing with a saturated sodium bicarbonate solution, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography separation to obtain a light yellow solid;
(3) Placing the light yellow solid obtained in the step (2) into a round-bottom flask, adding an organic solvent for dissolving, dropwise adding a 2M HCl dioxane solution in an ice water bath, separating out the solid, stirring at room temperature after dropwise adding, performing suction filtration, leaching with an organic solvent, and performing vacuum drying to obtain a white solid product U18666A;
in the step (2), the mass ratio of the yellow solid obtained in the step (1), the N, N-diethylethanolamine and the p-toluenesulfonic acid is 1: 4.0-5.0: 0.5 to 1.0;
in the step (2), the stirring time at room temperature is 20min, the heating reaction temperature is 95 ℃, and the heating reaction time is 1 hour.
2. The method of claim 1, wherein in step (1), the mass ratio of dehydroepiandrosterone to pyridine to p-toluenesulfonyl chloride is 1:1 to 1.5:1 to 1.5.
3. The method according to claim 1, wherein the organic solvent is dichloromethane, and the reaction time is 8-12 hours under stirring at room temperature in step (1).
4. The method of claim 1, wherein in step (2), after the pH of sodium bicarbonate is adjusted to =8, the mixture is vigorously stirred for 3 hours; the post-treatment solvent is dichloromethane; the developing solvent used in the column chromatography separation operation is a mixed solvent of dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol in the developing solvent is 50-100: 1.
5. the preparation method of U18666A according to claim 1, characterized in that, in step (3), the mass-to-volume ratio of the pale yellow solid obtained in step (2) to the dioxane solution of 2M HCl is 1 g.
6. The method according to claim 1, wherein in step (3), the organic solvent is methyl tert-butyl ether, the stirring time at room temperature is 30min, and the vacuum drying temperature is 40 ℃.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3000910A (en) * | 1961-04-07 | 1961-09-19 | Upjohn Co | 17-isonitrose-3-aminoethers of the androstane series |
| US3389051A (en) * | 1961-01-09 | 1968-06-18 | Upjohn Co | Method for reducing cholesterol in the body |
| CN101759740A (en) * | 2009-12-31 | 2010-06-30 | 深圳万乐药业有限公司 | Method for synthesizing 3-alpha-acetoxy-deoxidized androstane-5-17-ketone |
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2020
- 2020-11-24 CN CN202011332691.7A patent/CN112409433B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3389051A (en) * | 1961-01-09 | 1968-06-18 | Upjohn Co | Method for reducing cholesterol in the body |
| US3000910A (en) * | 1961-04-07 | 1961-09-19 | Upjohn Co | 17-isonitrose-3-aminoethers of the androstane series |
| CN101759740A (en) * | 2009-12-31 | 2010-06-30 | 深圳万乐药业有限公司 | Method for synthesizing 3-alpha-acetoxy-deoxidized androstane-5-17-ketone |
Non-Patent Citations (2)
| Title |
|---|
| Ketones as directing groups in photocatalytic sp3 C-H fluorination;Bume, Desta Doro;《Chemical Science》;20170811;第8卷(第10期);6918-6923页 * |
| Synthesis, antiproliferative activity, acute toxicity and assessment of the antiandrogenic activities of new androstane derivatives;Dhingra, Neelima;《Archives of Pharmacal Research》;20111231;第34卷(第7期);1055-1063页 * |
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Effective date of registration: 20230821 Address after: 264006 plant 6 in Jinhuan Industrial Park, No. 3, Nanchang Street, Yantai Development Zone, China (Shandong) pilot Free Trade Zone, Yantai, Shandong Province Patentee after: Yantai Haoyuan Biomedical Technology Co.,Ltd. Address before: No.60, Jinhe Road, Fushan District, Yantai City, Shandong Province Patentee before: Yantai Gongjin Medical Technology Co.,Ltd. |
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