CN101759740B - Method for synthesizing 3-alpha-acetoxy-deoxidized androstane-5-17-ketone - Google Patents
Method for synthesizing 3-alpha-acetoxy-deoxidized androstane-5-17-ketone Download PDFInfo
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- CN101759740B CN101759740B CN2009102395067A CN200910239506A CN101759740B CN 101759740 B CN101759740 B CN 101759740B CN 2009102395067 A CN2009102395067 A CN 2009102395067A CN 200910239506 A CN200910239506 A CN 200910239506A CN 101759740 B CN101759740 B CN 101759740B
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Abstract
The invention discloses a method for synthesizing 3-alpha-acetoxy-deoxidized androstane- -5-17-ketone through two steps by taking dehydroepiandrosterone as material. The first step of reaction of the method has high conversion ratio and little impurity, the intermediate of dehydroepiandrosterone p-toluenesulfonate produced in the first step can directly participate in the reaction of the second step without being separated and purified, and the final products can be separated and purified to obtain 3-alpha-acetoxy-deoxidized androstane-5-17-ketone with purity above 96% through only one silica gel chromatography column. Compared with the prior art, the method simplifies the process, shortens the synthesis period, avoids heavy use of pyridine, saves cost and reduces pollution, therefore, the method is suitable for industrial production.
Description
Technical field
The present invention relates to organic chemistry filed, further relate to the synthetic method of 3-α-acetoxyl group-deoxidation androstane-5-alkene-17-ketone.
Background technology
3-α-acetoxyl group-deoxidation androstane-5-alkene-17-ketone is the diastereomer of 3 optical siomerisms of acetic acid dehydroepiandros-sterone.The acetic acid dehydroepiandros-sterone is the important intermediate of steroid hormone class medicines such as synthetic various hormones, birth control necessities, can synthesize Testosterone, methyltestosterone, estradiol, trihydroxy-oestrin by it, and anticarcinogen acetic acid Abiraterone etc., its chemistry 3-β-acetoxyl group by name-deoxidation androstane-5-alkene-17-ketone.3-α-acetoxyl group-deoxidation androstane-5-alkene-17-ketone can be used for comparative study in steroid compound research, for example research of the optical isomer impurity of anticarcinogen acetic acid Abiraterone, or be used for the synthetic of optically active isomer medicine.Its structural formula is as follows:
This compound can not be bought from the market and obtain, and can only synthesize voluntarily as needs.Document " The scope and limitationsofthe reaction of Δ
5-steroids with mercury (II) trifluoroacetate " Steroids.1998 Dec; 63 (12): 650-664. discloses the reaction method by dehydroepiandros-sterone p-toluenesulfonic esters and the synthetic 3-α-acetoxyl group of tetrabutylammonium acetate ammonium reaction-deoxidation androstane-5-alkene-17-ketone, this method is solvent refluxing reaction 9 hours with the butanone, then earlier after two kinds of chromatographic column purifying obtain target product.The dehydroepiandros-sterone p-toluenesulfonic esters can not be bought from the market and obtain, and document " Experimental Evidence forEnzyme-Enhanced Coupled Motion/Quantum Mechanical Hydrogen Tunneling by KetosteroidIsomerase. " J.Am.Chem.Soc., 2008,130 (20), pp 6577-6585 discloses the method by dehydroepiandros-sterone and the synthetic dehydroepiandros-sterone p-toluenesulfonic esters of Tosyl chloride, this method with pyridine not only as organic alkali catalyst but also as solvent, room temperature reaction 20 hours, reaction solution concentrates after treatment, and enriched material obtains tosylate with the chromatographic column purifying.Can obtain 3-α-acetoxyl group-deoxidation androstane-5-alkene-17-ketone by following reaction formula as can be known according to above-mentioned document:
Find in the research, react according to the document disclosed method, reaction conversion ratio is low, impurity causes separating very difficult more, and two steps all needed silica gel chromatographic column, and the chromatographic column purifying time is long, and the intermediate dehydroepiandros-sterone p-toluenesulfonic esters instability that the first step obtains is decomposed in the chromatographic column purge process easily; The second step reaction needed is crossed twice silica gel chromatographic column and just can be obtained target product.
Summary of the invention
The technical problem that the present invention solves has provided the method for a kind of synthetic 3-α-acetoxyl group-deoxidation androstane-5-alkene-17-ketone, this method transformation efficiency height, and impurity is few, need not intermediate is carried out separation and purification, simplify technology, shortened synthesis cycle, be fit to industrial production.
The method of a kind of synthetic 3-α-acetoxyl group provided by the invention-deoxidation androstane-5-alkene-17-ketone, this method comprises the steps:
1) mol ratio is that 1: 2～4 dehydroepiandros-sterone and Tosyl chloride are in anhydrous methylene chloride, 4～20 hours synthetic dehydroepiandros-sterone p-toluenesulfonic esters of room temperature reaction in the presence of organic bases, reaction solution is concentrated except that desolvating, described organic bases is N, N-dimethyl aminopyridine, triethylamine, pyridine, 2, one or more in the 6-lutidine;
2) the reaction solution enriched material and the tetrabutylammonium acetate ammonium heating reflux reaction in 2-butanone or tetrahydrofuran (THF) that obtain of step 1), reaction solution is concentrated except that desolvating, and gained reaction solution enriched material obtains 3-α-acetoxyl group-deoxidation androstane-5-alkene-17-ketone through the silica gel chromatography column separating purification.
Further optimize, organic bases described in the described step 1) is N, N-dimethyl aminopyridine and triethylamine, and the mol ratio of they and dehydroepiandros-sterone is respectively 0.5～1.5: 1 and 2～6: 1, preferred 0.9～1: 1 and 4～5: 1.
The mol ratio of dehydroepiandros-sterone and Tosyl chloride is preferred 1: 3 in the described step 1), preferred 8～10 hours of reaction times.
Reaction solution is used 10%Na earlier in the described step 1) before concentrating
2CO
3The aqueous solution is washed, and washes with 10% oxalic acid aqueous solution again.Mode of washing is a stirred for several minute, leaves standstill phase-splitting, aqueous phase discarded, and organic phase is filtered with anhydrous sodium sulphate or anhydrous magnesium sulfate drying.
Described step 2) reaction times is 2～8 hours.
Described step 2) reaction solution is used saturated NaHCO in before concentrating
3Solution washing, the same step 1) of mode of washing.
Described step 2) silica gel chromatography column separating purification described in is that the mixed solvent with ethyl acetate and sherwood oil carries out gradient elution.Mixed solvent is that the per-cent of ethyl acetate in sherwood oil is 4%, 6%, 10% mixed solvent successively during gradient elution.
The method of preferred synthetic 3-α-acetoxyl group-deoxidation androstane-5-alkene-17-ketone comprises the steps:
1) mol ratio is that 1: 3 dehydroepiandros-sterone and Tosyl chloride are in anhydrous methylene chloride, at organic bases N, there are 8～10 hours synthetic dehydroepiandros-sterone p-toluenesulfonic esters of room temperature reaction down in N-dimethyl aminopyridine and triethylamine, N, the mol ratio of N-dimethyl aminopyridine and triethylamine and dehydroepiandros-sterone is respectively 0.9～1: 1 and 4～5: 1, and reaction solution is used 10%Na earlier
2CO
3The aqueous solution is washed, washes with 10% oxalic acid aqueous solution again, and aqueous phase discarded, organic phase is filtered with anhydrous magnesium sulfate or anhydrous sodium sulfate drying, and filtrate decompression concentrates to remove and desolvates.
2) the reaction solution enriched material that obtains of step 1) and tetrabutylammonium acetate ammonium heating reflux reaction 2～8 hours in 2-butanone or tetrahydrofuran (THF), reaction solution adds the ethyl acetate dilution after being chilled to room temperature, uses saturated NaHCO
3The aqueous solution is washed, aqueous phase discarded, and organic phase is with anhydrous sodium sulphate or anhydrous magnesium sulfate drying, filter, filtrate decompression concentrates to remove and desolvates, and gained reaction solution enriched material is through the silica gel chromatography column separating purification, and ethyl acetate-sherwood oil gradient elution obtains 3-α-acetoxyl group-deoxidation androstane-5-alkene-17-ketone.
Synthetic method provided by the invention is raw material with the dehydroepiandros-sterone, through the synthetic 3-α-acetoxyl group of two-step reaction-deoxidation androstane-5-alkene-17-ketone, the first step reaction conversion ratio height, impurity is few, the intermediate dehydroepiandros-sterone p-toluenesulfonic esters that obtains need not the reaction that separation and purification can participate in for second step directly, and the finished product only need can separation and purification go out purity greater than 3-α-acetoxyl group-deoxidation androstane-5-alkene-17-ketone of 96% through a kind of chromatographic column of silica gel chromatographic column.Compared with prior art simplify technology, shortened synthesis cycle, avoided a large amount of use pyridines, saved cost, reduced pollution, be fit to industrial production.
Embodiment below in conjunction with embodiment is described in further detail the present invention.
Embodiment
Embodiment 1
1) the dehydroepiandros-sterone p-toluenesulfonic esters is synthetic
In exsiccant 1000ml reaction flask, add 20g (0.07mol) dehydroepiandros-sterone, add the 200ml methylene dichloride, stirring and dissolving adds N, N-Dimethylamino pyridine (DMAP) 8g (0.066mol), triethylamine 40ml (0.28mol), stir after 5 minutes, add Tosyl chloride 40g (0.21mol), stirred 9 hours, adding 10% yellow soda ash water liquid 400ml stirred 10 minutes, phase-splitting, aqueous phase discarded, organic phase add 10% careless acid liquid 400ml and stirred 10 minutes, phase-splitting, aqueous phase discarded, organic phase adds the anhydrous magnesium sulfate powder for drying, filters, filtrate decompression concentrates, and gets yellow solid 28.5g.
2) 3-α-acetoxyl group-deoxidation androstane-5-alkene-17-ketone is synthetic
In the yellow solid of step 1) gained, add 114g tetrabutylammonium acetate ammonium, add the 142ml 2-butanone again, connect prolong, 85 ℃ of oil bath heating reflux reactions 3 hours, reaction is finished, and is chilled to room temperature, add ethyl acetate 570ml and saturated sodium bicarbonate water liquid 570ml, stirred 10 minutes, water is abandoned in phase-splitting, organic phase drying, filtration, concentrated get oily matter.With this oily matter silica gel chromatography column purification,, get white crystals 8g with ethyl acetate-sherwood oil gradient elution (4%, 6%, 10%).HPLC purity 97.4%, fusing point 169.8-173.7 ℃, specific rotatory power [α]
D+ 35 ° (c=0.2g/100ml ethanol), yield: 40.0%.
1H-NMR(CDCl
3)：δ0.90(3H，s)，1.02(3H，s)，2.02(3H，s)，4.99(1H，t，J＝3Hz)，5.30(1H，dd，J＝2.5Hz).
Embodiment 2
1) the dehydroepiandros-sterone p-toluenesulfonic esters is synthetic
In exsiccant 500ml reaction flask, add 10g (0.035mol) dehydroepiandros-sterone, add the 100ml methylene dichloride, stirring and dissolving adds N, N-Dimethylamino pyridine (DMAP) 4g (0.033mol), triethylamine 20ml (0.14mol), stir after 5 minutes, add Tosyl chloride 20g (0.11mol), stirred 5 hours, adding 10% yellow soda ash water liquid 200ml stirred 10 minutes, water is abandoned in phase-splitting, and organic phase adds 10% careless acid liquid 200ml and stirred 10 minutes, phase-splitting, abandon water, organic phase adds anhydrous sodium sulfate drying, filters, filtrate concentrates, and gets yellow solid 14.6g.
2) 3-α-acetoxyl group-deoxidation androstane-5-alkene-17-ketone is synthetic
In the yellow solid of step 1) gained, add 58.4g tetrabutylammonium acetate ammonium, add the 75ml tetrahydrofuran (THF) again, connect prolong, 70 ℃ of oil bath heating reflux reactions 5 hours, reaction is finished, and is chilled to room temperature, add ethyl acetate 300ml and saturated sodium bicarbonate water liquid 300ml, stirred 10 minutes, water is abandoned in phase-splitting, organic phase drying, filtration, concentrated get oily matter.This oily matter is crossed silica gel chromatographic column,, get white crystals 3.9g with ethyl acetate-sherwood oil gradient elution (4%, 6%, 10%).HPLC purity 96.9%, fusing point 171.5-172.5 ℃, specific rotatory power [α]
D+ 38 ° (c=0.2g/100ml ethanol), yield: 39%.
Embodiment 3
1) the dehydroepiandros-sterone p-toluenesulfonic esters is synthetic
In exsiccant 500ml reaction flask, add 10g (0.035mol) dehydroepiandros-sterone, add the 100ml methylene dichloride, stirring and dissolving adds N, N-Dimethylamino pyridine (DMAP) 2.5g (0.02mol), triethylamine 30ml (0.21mol), stir after 5 minutes, add Tosyl chloride 27g (0.14mol), stirred 20 hours, adding 10% yellow soda ash water liquid 200ml stirred 10 minutes, water is abandoned in phase-splitting, and organic phase adds 10% careless acid liquid 200ml and stirred 10 minutes, phase-splitting, abandon water, organic phase adds anhydrous sodium sulfate drying, filters, filtrate concentrates, and gets yellow solid 15.0g.
2) 3-α-acetoxyl group-deoxidation androstane-5-alkene-17-ketone is synthetic
In the yellow solid of step 1) gained, add 58.5g tetrabutylammonium acetate ammonium, add the 75ml tetrahydrofuran (THF) again, connect prolong, 70 ℃ of oil bath heating reflux reactions 8 hours, reaction is finished, and is chilled to room temperature, add ethyl acetate 300ml and saturated sodium bicarbonate water liquid 300ml, stirred 10 minutes, water is abandoned in phase-splitting, organic phase drying, filtration, concentrated get oily matter.This oily matter is crossed silica gel chromatographic column,, get white crystals 4.1g with ethyl acetate-sherwood oil gradient elution (4%, 6%, 10%).HPLC purity 96.5%, fusing point 171.0-172.6 ℃, specific rotatory power [α]
D+ 38 ° (c=0.2g/100ml ethanol), yield: 41%.
Embodiment 4
1) the dehydroepiandros-sterone p-toluenesulfonic esters is synthetic
In exsiccant 500ml reaction flask, add 10g dehydroepiandros-sterone (0.035mol), add the 100ml methylene dichloride, stirring and dissolving adds N, N-Dimethylamino pyridine (DMAP) 6g (0.05mol), triethylamine 10ml (0.07mol), stir after 5 minutes, add Tosyl chloride 13.5g (0.07mol), stirred 20 hours, adding 10% yellow soda ash water liquid 200ml stirred 10 minutes, water is abandoned in phase-splitting, and organic phase adds 10% careless acid liquid 200ml and stirred 10 minutes, phase-splitting, abandon water, organic phase adds anhydrous sodium sulfate drying, filters, filtrate concentrates, and gets yellow solid 14.2g.
2) 3-α-acetoxyl group-deoxidation androstane-5-alkene-17-ketone is synthetic
In the yellow solid of step 1) gained, add 58.0g tetrabutylammonium acetate ammonium, add the 75ml 2-butanone again, connect prolong, 70 ℃ of oil bath heating reflux reactions 8 hours, reaction is finished, and is chilled to room temperature, add ethyl acetate 300ml and saturated sodium bicarbonate water liquid 300ml, stirred 10 minutes, water is abandoned in phase-splitting, organic phase drying, filtration, concentrated get oily matter.This oily matter is crossed silica gel chromatographic column,, get white crystals 3.8g with ethyl acetate/petroleum ether gradient elution (4%, 6%, 10%).HPLC purity 96.2%, fusing point 171.6-172.8 ℃, specific rotatory power [α]
D+ 38 ° (c=0.2g/100ml ethanol), yield: 38%.
The comparative example
1) the dehydroepiandros-sterone p-toluenesulfonic esters is synthetic
In exsiccant 500ml reaction flask, add 10g dehydroepiandros-sterone (0.035mol), add the dry pyridine of crossing of 100ml, stirring and dissolving stirred after 5 minutes, added Tosyl chloride 10g (0.05mol), stirring at room 20 hours, pressure reducing and steaming pyridine, enriched material are dissolved in the 300ml ethyl acetate, successively add 1N hydrochloric acid soln 100ml, water 200ml, saturated sodium bicarbonate aqueous solution 200ml, water 200ml washing, phase-splitting, abandon water, organic phase adds anhydrous magnesium sulfate drying, filters, and filtrate concentrates, enriched material silica gel chromatography column purification, normal hexane-ethyl acetate (1: 1) wash-out will contain the elutriant evaporate to dryness of dehydroepiandros-sterone p-toluenesulfonic esters, obtain the 9.2g yellow solid, yield 57%, HPLC purity 73%.
2) 3-α-acetoxyl group-deoxidation androstane-5-alkene-17-ketone is synthetic
In the yellow solid of step 1) gained, add 50g tetrabutylammonium acetate ammonium, add the 75ml tetrahydrofuran (THF) again, connect prolong, 70 ℃ of oil bath heating reflux reactions 9 hours, reaction is finished, be chilled to room temperature, the pressure reducing and steaming solvent gets oily matter, this oily matter is carried out the chromatographic column purifying, use the silica gel chromatography column purification, with acetone-sherwood oil gradient elution, the elutriant of collecting that only contains product, evaporated under reduced pressure obtains the 1.7g white solid, yield 17%, HPLC purity 89%.
By the comparative example as can be known, method of the present invention is synthesized 3-α-acetoxyl group-deoxidation androstane-5-alkene-17-ketone and the method for prior art, and to compare reaction conversion ratio higher, and yield and purity are all higher.
Claims (7)
1. the method for synthetic 3-α-acetoxyl group-deoxidation androstane-5-alkene-17-ketone is characterized in that comprising the steps:
1) mol ratio be 1: 2～4 dehydroepiandros-sterone and Tosyl chloride in anhydrous methylene chloride, 4～20 hours synthetic dehydroepiandros-sterone p-toluenesulfonic esters of room temperature reaction in the presence of organic bases, the reaction afterreaction liquid 10%Na that finishes
2CO
3The aqueous solution is washed, and washes with 10% oxalic acid aqueous solution again, concentrates to remove to desolvate, and described organic bases is N, N-dimethyl aminopyridine, triethylamine, pyridine, 2, one or more in the 6-lutidine;
2) the reaction solution enriched material and the tetrabutylammonium acetate ammonium heating reflux reaction in 2-butanone or tetrahydrofuran (THF) that obtain of step 1), the reaction saturated NaHCO of afterreaction liquid that finishes
3Solution washing, concentrate to remove and desolvate, gained reaction solution enriched material obtains 3-α-acetoxyl group-deoxidation androstane-5-alkene-17-ketone through the silica gel chromatography column separating purification, uses the mixed solvent of ethyl acetate and sherwood oil to carry out gradient elution during described silica gel chromatography column separating purification.
2. the method for a kind of synthetic 3-α-acetoxyl group according to claim 1-deoxidation androstane-5-alkene-17-ketone, it is characterized in that the described organic bases of step 1) is N, N-dimethyl aminopyridine and triethylamine, the mol ratio of they and dehydroepiandros-sterone is respectively 0.5～1.5: 1 and 2～6: 1.
3. the method for a kind of synthetic 3-α-acetoxyl group according to claim 2-deoxidation androstane-5-alkene-17-ketone is characterized in that N, and the mol ratio of N-dimethyl aminopyridine and triethylamine and dehydroepiandros-sterone is respectively 0.9～1: 1 and 4～5: 1.
4. the method for a kind of synthetic 3-α-acetoxyl group according to claim 1-deoxidation androstane-5-alkene-17-ketone is characterized in that the mol ratio of dehydroepiandros-sterone and Tosyl chloride is 1: 3 in the step 1).
5. the method for a kind of synthetic 3-α-acetoxyl group according to claim 1-deoxidation androstane-5-alkene-17-ketone, the reaction times that it is characterized in that step 1) is 8～10 hours.
6. the method for a kind of synthetic 3-α-acetoxyl group according to claim 1-deoxidation androstane-5-alkene-17-ketone is characterized in that step 2) reaction times be 2～8 hours.
7. the method for a kind of synthetic 3-α-acetoxyl group according to claim 1-deoxidation androstane-5-alkene-17-ketone is characterized in that comprising the steps:
1) mol ratio is that 1: 3 dehydroepiandros-sterone and Tosyl chloride are in anhydrous methylene chloride, at organic bases N, there are 8～10 hours synthetic dehydroepiandros-sterone p-toluenesulfonic esters of room temperature reaction down in N-dimethyl aminopyridine and triethylamine, N, the mol ratio of N-dimethyl aminopyridine and triethylamine and dehydroepiandros-sterone is respectively 0.9～1: 1 and 4～5: 1, and reaction solution is used 10%Na earlier
2CO
3The aqueous solution is washed, washes with 10% oxalic acid aqueous solution again, and aqueous phase discarded, organic phase is filtered with anhydrous magnesium sulfate or anhydrous sodium sulfate drying, and filtrate decompression concentrates to remove and desolvates
2) the reaction solution enriched material that obtains of step 1) and tetrabutylammonium acetate ammonium heating reflux reaction 2～8 hours in 2-butanone or tetrahydrofuran (THF), reaction solution adds the ethyl acetate dilution after being chilled to room temperature, uses saturated NaHCO
3The aqueous solution is washed, aqueous phase discarded, and organic phase is with anhydrous sodium sulphate or anhydrous magnesium sulfate drying, filter, filtrate decompression concentrates to remove and desolvates, and gained reaction solution enriched material is through the silica gel chromatography column separating purification, and ethyl acetate-sherwood oil gradient elution obtains 3-α-acetoxyl group-deoxidation androstane-5-alkene-17-ketone.
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