CN116333025A - Synthesis method of 4, 16-androstadiene-3 beta-alcohol - Google Patents
Synthesis method of 4, 16-androstadiene-3 beta-alcohol Download PDFInfo
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- CN116333025A CN116333025A CN202310096152.5A CN202310096152A CN116333025A CN 116333025 A CN116333025 A CN 116333025A CN 202310096152 A CN202310096152 A CN 202310096152A CN 116333025 A CN116333025 A CN 116333025A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
- C07J13/005—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17 with double bond in position 16 (17)
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Abstract
The invention relates to a synthesis method of 4, 16-androstadiene-3 beta-alcohol, which mainly solves the technical problems of harsh reaction conditions, difficult purification, difficult amplification and the like in the existing synthesis method. The technical scheme of the invention is as follows: a method for synthesizing 4, 16-androstadiene-3 beta-alcohol, which comprises the following steps: the steroid (3 beta) -3-hydroxy-17-sterone (CAS 571-44-8) is taken as a starting material and is dissolved in an organic solvent to react with hydrazine hydrate to obtain a compound 2 in the first step, the compound 2 is dissolved in the organic solvent to perform substitution reaction with elemental iodine to obtain a compound 3 in the second step, and the compound 3 is dissolved in the organic solvent to eliminate iodine to obtain a double bond target product in the third step. The invention optimizes and improves the double bond reaction condition, and uses the n-butyl lithium to extract iodine to obtain double bond products, so that the reaction condition is mild and has scalability.
Description
Technical Field
The invention relates to the technical field of preparation of 3 beta-alcohol steroid compounds, in particular to a method for synthesizing 4, 16-androstadiene-3 beta-alcohol, which mainly optimizes and improves double bond reaction conditions, and uses n-butyl lithium to extract iodine to obtain a double bond product, so that the reaction conditions are mild and have scalability.
Background
Many of the steroid compounds are biologically active, such as hydrocortisone for the treatment of allergic diseases, the diuretic Androsultone, and cardiac Digoxin. Wherein 4, 16-androstadien-3 beta-ol is a typical sterol compound, and its classical synthesis is a three-step synthesis starting from testosterone (CAS 58-22-0) (referenceHelvetica Chimica Acta，1983，66(1) 192-217Formula one), but the routeThe second step requires 460 ℃ superhigh temperature reaction, the third step uses lithium tripentylborohydride (CAS 60217-34-7), the reaction condition is harsh, and the content ratio of the alpha alcohol to the beta alcohol after reduction is 1:1, so that the purification is difficult.
Or the similar reaction conditions of lithium-ammonia are severe, and the equipment requirement is high. Based on the problems, the method has poor application prospect and is difficult to process and amplify in practical experiments.
One (I)
Disclosure of Invention
The invention aims to provide a synthesis method of 4, 16-androstadiene-3 beta-alcohol, which mainly solves the technical problems of harsh reaction conditions, difficult purification, difficult amplification and the like in the existing synthesis method. Based on the above problems existing in the prior art, referring to similar compound document CN107236015 (hydrazine hydrate reaction and iodine substitution), CN111454315 (2020, process of deiodination of diethylene glycol monoethyl ether sodium into double bond), journal of chemistry [ Journal of Chemical Research,6, 2008, 314-317 (metallic sodium, ethanol) ] and the like, it has been unexpectedly found through a great deal of research that the use of n-butyllithium can achieve higher yields and very low isomerism rates to obtain double bond target products.
The technical scheme of the invention is as follows: a method for synthesizing 4, 16-androstadiene-3 beta-alcohol, which comprises the following steps: the method comprises the steps of dissolving steroidal (3 beta) -3-hydroxy-17-sterone (CAS 571-44-8) serving as a starting material in an organic solvent for a first step to react with hydrazine hydrate to obtain a compound 2, dissolving the compound 2 in the organic solvent for a second step to perform substitution reaction with elemental iodine to obtain a compound 3, dissolving the compound 3 in the organic solvent for eliminating iodine to obtain a double bond target product; the reaction formula is as follows:
the organic solvent in the three steps is selected from one of ethanol, tetrahydrofuran, diethyl ether, n-hexane or toluene; tetrahydrofuran is preferred.
In step 3), the compound used for iodine elimination is selected from one of n-BuLi, LDA, liHMDS or NaHMDS, preferably n-butyllithium (n-BuLi).
In the step 3), the mass mole ratio of the compound 3 to the n-butyllithium reagent is as follows: 1:0.2-2.0.
The beneficial effects of the invention are as follows: the invention is a synthetic route with low cost and commercial production. Compared with the classical route for reducing ketone to alcohol, the problems of difficult purification and poor selectivity due to the content ratio of alpha to beta alcohol 1:1 are solved, the beta alcohol crude product with high selectivity can be obtained, and impurities are removed by simple column chromatography, so that the product with 99 percent purity (the isomer content is reduced to below 1 percent) is obtained, and the total yield is high. The process flow is simple and is suitable for industrial production.
Drawings
FIG. 1 is a nuclear magnetic characterization of Compound A (4, 16-androstadien-3. Beta. -alcohol) of example 3 of the present invention.
FIG. 2 is an HPLC chart of compound A (4, 16-androstadien-3. Beta. -alcohol) of example 3 of the present invention.
FIG. 3 is a UPLC-MS of compound A (4, 16-androstadien-3. Beta. -alcohol) of example 3 of the present invention.
Detailed Description
The present invention will be described in more detail with reference to examples. It should be understood that the practice of the invention is not limited to the following examples, but is intended to be within the scope of the invention in any form and/or modification thereof.
In the present invention, unless otherwise specified, all parts and percentages are by weight, all equipment, materials, etc. are commercially available or are commonly used in the industry. The methods in the following examples are conventional in the art unless otherwise specified.
Example 1
Preparation of intermediate compound 2 (17-hydrazono-4-dehydroepiandrosterone)
(reference Process epiandrosterone CAS 481-29-8)Journal of Chemical Research;6; (2008); 314 - 317）
4-dehydroepiandrosterone compound 1 (4-DHEA, CAS 571-44-8) (20 g, 69.4 mmol) was dissolved in ethanol (200 ml), and hydrazine hydrate (80% by mass, 15 ml) was added dropwise under nitrogen protection, and the reaction mixture was heated under reflux for 4 hours after the completion of the reaction, as monitored by TLC and MS, at room temperature. The reaction solution was cooled to room temperature, poured into ice water (60 ml), white solid was precipitated, and the obtained solid was slurried with acetonitrile (40 ml), suction filtered, and the solid was dried under vacuum at 40 ℃ to obtain compound 2 (17-hydrazono-4-dehydroepiandrosterone, 17.82 g, white powder, 85% yield). LC-MS: m/z= 302.8 [ m+h] + 。
Example 2
Preparation of intermediate compound 3 (17-iodo-4-dehydroepiandrosterone)
Example 2-1 (refer to CN 107236015)
To a three-necked flask, elemental iodine (1.88 g, 7.4 mmol), anhydrous tetrahydrofuran (6 ml) was added, the temperature was lowered to 0℃and tetramethylguanidine (119.2 mg, 10.35 mmol) was added dropwise thereto, and the temperature was controlled at 0 ℃. After the completion of the dropwise addition, stirring was carried out for 0.5 hour, and a tetrahydrofuran solution (10 ml) of compound 2 (17-hydrazono-4-dehydroepiandrosterone, 694 mg, 2.3 mmol) was added dropwise, the temperature was kept at 0℃and the stirring reaction was continued for 1 hour after the completion of the dropwise addition. The reaction solution was filtered off with suction, the organic phase was concentrated to dryness, N-methylpyrrolidone (0.7 ml) was added, and the mixture was heated to 80℃and reacted for 8 hours. Cooled to room temperature, water (10 ml) and dichloromethane (20 ml) were added, the aqueous phase pH was adjusted to 3-4 with dilute hydrochloric acid, the solution was separated, the organic phase was washed with saturated sodium bicarbonate (2 x 10 ml), the solution was separated, the organic phase was added to saturated sodium thiosulfate solution (10 ml) and stirred for 1 hour, and the solution was separated. The organic phase was washed with saturated brine (10 ml), dried over sodium sulfate, suction filtered, the organic phase was concentrated to dryness, the column chromatography was concentrated, and dried under reduced pressure at 40 ℃ to give compound 3 (17-iodo-4-dehydroepiandrosterone, 600 mg, 65% yield, white powder).
Example 2-2
Compound 2 (17-hydrazono-4-dehydroepiandrosterone, 11.0 g, 36.37 mmol) was dissolved in anhydrous tetrahydrofuran (55 ml) at room temperature in a 250 ml three-necked flask, triethylamine (15.6 ml) was added to control the temperature to not more than 30 ℃, nitrogen was purged, and a solution of elemental iodine (18.8 g, 74 mmol) in anhydrous tetrahydrofuran (55 ml) was slowly added dropwise, followed by stirring for 1.5 hours after the completion of the dropwise addition. The reaction solution was suction filtered, water (70 ml) and dichloromethane (140 ml) were added, the pH of the aqueous phase was adjusted to 3-4 with dilute hydrochloric acid, the solution was separated, the organic phase was washed with saturated sodium bicarbonate (2 x 70 ml), the solution was separated, and the organic phase was added to a saturated sodium thiosulfate solution (70 ml) and stirred for 1 hour, and the solution was separated. The organic phase was washed with saturated brine (70 mmol), the organic phase was separated, dried over anhydrous sodium sulfate, suction filtered, the organic phase was concentrated to dryness, purified by column chromatography (petroleum ether: ethyl acetate volume ratio=10:1 to 1:1, iodine color development), the column chromatography liquid was concentrated, and dried under reduced pressure at 40 ℃ to give compound 3 (17-iodo-4-dehydroepiandrosterone, 11.0 g,76% yield, white powder).
1 HNMR(CDCl 3 )： 6 .16（s,1H）,5.21(s, 1H), 3.62-3.59(m，1H)，3.20-3.09(m ,2H) 2 .07- 2 .06（m ,1H）,1 .95-1.26(m，15H)，1.02 (s, 3H), 0.81-0.80（m, 1H）.0.79-0.78(m,1H）0.78(s, 3H); LC-MS：m/z =399.2[M+H] + 。
The preferable scheme 2-2 has milder and simpler operation condition and high yield compared with the 2-1.
Example 3
Preparation of Compound A (4, 16-androstadien-3 beta-ol)
Example 3-1
Compound 3 (17-iodo-4-dehydroepiandrosterone, 1.0 g, 2.5 mmol) was dissolved in ultra-dry tetrahydrofuran (20 ml), cooled to-50℃in a dry ice bath, and n-butyllithium (2.5M, 2 ml, 5 mmol, 2.0 EQ) was added dropwise at a controlled temperature of not more than-50℃and reacted at room temperature for 2 hours after the addition. TLC/LCMS monitored, isomer 3 a was about 50%.
Example 3-2
Compound 3 (17-iodo-4-dehydroepiandrosterone, 1.0 g, 2.5 mmol) was dissolved in ultra-dry tetrahydrofuran (20 ml), cooled to-50℃in a dry ice bath, LDA (2M, 2.5 ml, 5 mmol, 2.0 EQ) was added dropwise at a temperature of not more than-50℃and reacted at room temperature for 2 hours after the addition. TLC/LCMS was monitored from 0.5 hours to 2 hours, 85% was compound 3.
Examples 3 to 3
Compound 3 (17-iodo-4-dehydroepiandrosterone, 1.0 g, 2.5 mmol) was dissolved in ultra-dry tetrahydrofuran (20 ml), cooled to-50℃in a dry ice bath, liHMDS (1M, 5 ml, 5 mmol, 2.0 EQ) was added dropwise at a temperature of not more than-50℃and reacted at room temperature for 2 hours after the addition. TLC/LCMS did not react.
Examples 3 to 4
Compound 3 (17-iodo-4-dehydroepiandrosterone, 1.0 g, 2.5 mmol) was dissolved in ultra-dry tetrahydrofuran (20 ml), cooled to-50℃in a dry ice bath, naHMDS (2M, 2.5 ml, 5 mmol, 2.0 EQ) was added dropwise at a temperature of not more than-50℃and reacted at room temperature for 2 hours after the addition. TLC/LCMS did not react.
Examples 3 to 5
Compound 3 (17-iodo-4-dehydroepiandrosterone, 1.0 g, 2.5 mmol) was dissolved in ultra-dry tetrahydrofuran (20 ml), cooled to-50℃in a dry ice bath, KHMDS (1M, 5 ml, 5 mmol, 2.0 EQ) was added dropwise at a temperature of not more than-50℃and the mixture was allowed to react at room temperature for 2 hours. TLC/LCMS did not react.
Examples 3 to 6
Compound 3 (17-iodo-4-dehydroepiandrosterone, 1.0 g, 2.5 mmol) was dissolved in ultra-dry tetrahydrofuran (20 ml), cooled to-20℃in a dry ice bath, and n-butyllithium (2.5M, 2 ml, 5 mmol, 2.0 EQ) was added dropwise at a controlled temperature of not more than-50℃and reacted at room temperature for 2 hours after the addition. TLC/LCMS monitored, isomer 3 a was about 50%.
Examples 3 to 7
Compound 3 (17-iodo-4-dehydroepiandrosterone, 1.0 g, 2.5 mmol) was dissolved in ultra-dry tetrahydrofuran (20 ml), cooled to-50℃in a dry ice bath, and n-butyllithium (2.5M, 1 ml, 2.5 mmol, 1.0 EQ) was added dropwise at a controlled temperature of not more than-50℃and reacted at room temperature for 2 hours after the addition. TLC/LCMS monitored, isomer 3 a was about 50%.
Examples 3 to 8
Compound 3 (17-iodo-4-dehydroepiandrosterone, 1.0 g, 2.5 mmol) was dissolved in ultra-dry tetrahydrofuran (20 ml), cooled to-50℃in a dry ice bath, and n-butyllithium (2.5M, 0.5 ml, 1.25 mmol, 0.5 EQ) was added dropwise at a temperature of not more than-50℃and reacted at room temperature for 2 hours. TLC/LCMS monitored, isomer 3 a about 40%.
Examples 3 to 9
Compound 3 (17-iodo-4-dehydroepiandrosterone, 1.0 g, 2.5 mmol) was dissolved in ultra-dry tetrahydrofuran (20 ml), cooled to-50℃in a dry ice bath, and n-butyllithium (2.5M, 1.25 ml, 5 mmol, 0.2 EQ) was added dropwise at a temperature of not more than-50℃and quenched with ice immediately after addition. Monitored by TLC/LCMS, isomer 3. Alpha. Is less than 5%.
Examples 3 to 10
Compound 3 (17-iodo-4-dehydroepiandrosterone, 1.0 g, 2.5 mmol) was dissolved in ultra-dry tetrahydrofuran (20 ml), cooled to-20℃in a dry ice bath, and n-butyllithium (2.5M, 1.25 ml, 5 mmol, 0.2 EQ) was added dropwise at a controlled temperature of not more than-50℃and reacted at room temperature for 2 hours after the addition. TLC/LCMS monitored, isomer 3 a about 10%.
Examples 3 to 11
Compound 3 (17-iodo-4-dehydroepiandrosterone, 1.0 g, 2.5 mmol) was dissolved in anhydrous toluene (20 ml), cooled to-50℃in a dry ice bath, and n-butyllithium (2.5M, 1.25 ml, 5 mmol, 0.2 EQ) was added dropwise at a controlled temperature of not more than-50℃and reacted at room temperature for 2 hours after the addition. TLC/LCMS monitoring, starting material was not reacted.
Examples 3 to 12 (preferred embodiment)
In a 250 ml three-necked flask, compound 3 (17-iodo-4-dehydroepiandrosterone, 10.0 g, 25.0 mmol) was dissolved in ultra-dry tetrahydrofuran (200 ml), cooled to-50℃in a dry ice bath, and n-butyllithium (2.5M, 12.5 ml, 5 mmol) was added dropwiseMolar, 0.2 EQ) was controlled at no more than-50 ℃, after addition, TLC/LCMS monitored the reaction, ice water quenched, and most of the ethyl tetrahydrofuranacetate extracted (200 ml) was concentrated to dryness and purified by column chromatography (petroleum ether: ethyl acetate volume ratio = 100: 1. to 10:1, iodine color) to give compound a (4, 16-androstadien-3 beta-ol, 11.0 g,76% yield, HPLC 99%, isomer 3 alpha content 0.22%, white powder). 1 HNMR(CDCl 3 )： 5.85-5.83（m,1H）,5.71-5.69(m, 1H),5.30(m,w1/2≈5, 1H), 4.15(m,w1/2≈10, 1H),，3.20-3.09(m ,2H) 2 .07- 2 .06（m ,1H）,1 .95-1.26(m，15H)，1.02 (s, 3H),0.81-0.80（m, 1H）,0.79-0.78(m, 1H）0.78(s, 3H); LC-MS：m/z = 255.0[M-H 2 O+H]+
The 4, 16-androstadien-3 beta-alcohol prepared in the above example was tested, the nuclear magnetic hydrogen spectrum was shown in FIG. 1, the HPLC was shown in FIG. 2, and the mass spectrum was shown: m/z, 255.0[ M-H ] 2 O+H]+. The mass spectrum is shown in figure 3.
The invention provides a method for synthesizing 4, 16-androstadiene-3 beta-alcohol, which has low cost and can be commercially produced. The synthetic method has the advantages of easily available reaction raw materials, mild conditions and wide industrial application prospect; the invention optimizes the using condition and equivalent of n-butyl lithium, so that isomerization hardly occurs, and has good reference effect on producing single alpha and beta.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.
Claims (6)
1. A method for synthesizing 4, 16-androstadiene-3 beta-alcohol is characterized in that: the method comprises the following steps: dissolving (3 beta) -3-hydroxy-17-sterone serving as a starting material in an organic solvent to react with hydrazine hydrate to obtain a compound 2, dissolving the compound 2 in the organic solvent to perform substitution reaction with elemental iodine to obtain a compound 3, dissolving the compound 3 in the organic solvent to eliminate iodine to obtain a double bond target product; the reaction formula is as follows:
2. the method for synthesizing 4, 16-androstadien-3 beta-ol according to claim 1, wherein: the organic solvent in the step 1-3 is selected from one of ethanol, tetrahydrofuran, diethyl ether, n-hexane or toluene.
3. The method for synthesizing 4, 16-androstadien-3 beta-ol according to claim 2, wherein: the organic solvent is tetrahydrofuran.
4. The method for synthesizing 4, 16-androstadien-3 beta-ol according to claim 1, wherein: in step 3), the compound used for eliminating iodine in the compound 3 is selected from one of n-BuLi, LDA, liHMDS or NaHMDS.
5. The method for synthesizing 4, 16-androstadien-3 beta-ol according to claim 4, wherein: compound 3 the compound used for iodine elimination was n-BuLi.
6. The method for synthesizing 4, 16-androstadien-3 beta-ol according to claim 5, wherein: in the step 3), the mass mole ratio of the compound 3 to the n-BuLi is as follows: 1:0.2-2.0.
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