CN103772464A - Method for preparing 16-dehydropregnenolone alcohol acetate compounds by utilizing blue LED light source photosensitive oxidation - Google Patents
Method for preparing 16-dehydropregnenolone alcohol acetate compounds by utilizing blue LED light source photosensitive oxidation Download PDFInfo
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- diacetate
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- 238000007254 oxidation reaction Methods 0.000 title claims abstract description 57
- 230000003647 oxidation Effects 0.000 title claims abstract description 30
- 238000000034 method Methods 0.000 title claims abstract description 29
- -1 16-dehydropregnenolone alcohol acetate compounds Chemical class 0.000 title claims abstract description 19
- YLFRRPUBVUAHSR-UHFFFAOYSA-N 16-dehydro-pregnenolone Natural products C1C=C2CC(O)CCC2(C)C2C1C1CC=C(C(=O)C)C1(C)CC2 YLFRRPUBVUAHSR-UHFFFAOYSA-N 0.000 title abstract description 7
- WQLVFSAGQJTQCK-UHFFFAOYSA-N diosgenin Natural products CC1C(C2(CCC3C4(C)CCC(O)CC4=CCC3C2C2)C)C2OC11CCC(C)CO1 WQLVFSAGQJTQCK-UHFFFAOYSA-N 0.000 claims abstract description 52
- 150000003431 steroids Chemical class 0.000 claims abstract description 38
- NWMIYTWHUDFRPL-UHFFFAOYSA-N sapogenin Natural products COC(=O)C1(CO)C(O)CCC2(C)C1CCC3(C)C2CC=C4C5C(C)(O)C(C)CCC5(CCC34C)C(=O)O NWMIYTWHUDFRPL-UHFFFAOYSA-N 0.000 claims abstract description 32
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003504 photosensitizing agent Substances 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 6
- 238000003379 elimination reaction Methods 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 91
- 206010034972 Photosensitivity reaction Diseases 0.000 claims description 45
- 230000005587 bubbling Effects 0.000 claims description 41
- 239000000047 product Substances 0.000 claims description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 20
- DWCSNWXARWMZTG-UHFFFAOYSA-N Trigonegenin A Natural products CC1C(C2(CCC3C4(C)CCC(O)C=C4CCC3C2C2)C)C2OC11CCC(C)CO1 DWCSNWXARWMZTG-UHFFFAOYSA-N 0.000 claims description 20
- WQLVFSAGQJTQCK-VKROHFNGSA-N diosgenin Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)CC[C@H](O)CC4=CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 WQLVFSAGQJTQCK-VKROHFNGSA-N 0.000 claims description 20
- 239000012295 chemical reaction liquid Substances 0.000 claims description 19
- 238000006552 photochemical reaction Methods 0.000 claims description 19
- 238000006356 dehydrogenation reaction Methods 0.000 claims description 17
- WASQWSOJHCZDFK-UHFFFAOYSA-N diketene Chemical compound C=C1CC(=O)O1 WASQWSOJHCZDFK-UHFFFAOYSA-N 0.000 claims description 16
- KFKRXESVMDBTNQ-UHFFFAOYSA-N 3-[18-(2-carboxylatoethyl)-8,13-bis(1-hydroxyethyl)-3,7,12,17-tetramethyl-22,23-dihydroporphyrin-21,24-diium-2-yl]propanoate Chemical compound N1C2=C(C)C(C(C)O)=C1C=C(N1)C(C)=C(C(O)C)C1=CC(C(C)=C1CCC(O)=O)=NC1=CC(C(CCC(O)=O)=C1C)=NC1=C2 KFKRXESVMDBTNQ-UHFFFAOYSA-N 0.000 claims description 13
- 235000008754 Agave americana Nutrition 0.000 claims description 13
- 240000004246 Agave americana Species 0.000 claims description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
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- 239000012043 crude product Substances 0.000 claims description 4
- 230000006837 decompression Effects 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 239000011521 glass Substances 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 2
- 238000002791 soaking Methods 0.000 claims description 2
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 abstract description 22
- 229910052753 mercury Inorganic materials 0.000 abstract description 22
- 239000003814 drug Substances 0.000 abstract description 7
- 238000005516 engineering process Methods 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 abstract description 2
- UJKPHYRXOLRVJJ-MLSVHJFASA-N CC(O)C1=C(C)/C2=C/C3=N/C(=C\C4=C(CCC(O)=O)C(C)=C(N4)/C=C4\N=C(\C=C\1/N\2)C(C)=C4C(C)O)/C(CCC(O)=O)=C3C Chemical compound CC(O)C1=C(C)/C2=C/C3=N/C(=C\C4=C(CCC(O)=O)C(C)=C(N4)/C=C4\N=C(\C=C\1/N\2)C(C)=C4C(C)O)/C(CCC(O)=O)=C3C UJKPHYRXOLRVJJ-MLSVHJFASA-N 0.000 abstract description 2
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Abstract
The invention belongs to the field of organic photochemical synthesis, and particularly relates to a method for preparing a 16-dehydropregnenolone alcohol acetate compound by utilizing photosensitive oxidation of a blue LED light source. In the invention, under the condition that photosensitizer hematoporphyrin, catalyst triethylamine and acetate exist, a blue LED lamp is used as a light source to enable pseudosteroid sapogenin diacetate to undergo photosensitive oxidation reaction, and then the product 16-dehydropregnenolone alcohol acetate compound is obtained through acid elimination reaction. The invention can lead the conversion rate of the pseudosteroid sapogenin diacetate to reach more than 98 percent and the yield of the 16-dehydropregnenolone alcohol acetate compounds to reach 82.6 percent. The invention uses the blue LED lamp to replace a light source high-pressure mercury lamp in photosensitive oxidation, and realizes that the blue LED lamp saves more than 40 times of electric energy and a large amount of water resources on the premise of equivalent yield of target products. The invention provides a new technology for green chemistry in the industrial production of steroid medicines.
Description
Technical field
The invention belongs to the synthetic field of organic photochemistry, particularly utilize blue led light source photosensitized oxidation to prepare the method for the pregnant steroid diketene of 16-dehydrogenation alcohol acetate compounds.
Background technology
Steroid drugs nearly more than 300 is planted, and is widely used in anti-inflammatory, antianaphylaxis, regulation and control internal secretion, suppresses the fields such as aging and contraception, and such medicine is to be only second to antibiotic second largest medicine family.16-dehydrogenation pregnenolone acetic ester (16-Dehydropregnenolone acetate, 16-DPA) is most important Steroid medicine intermediates, and more than 70% steroid drugs is by its production.16-DPA is take diosgenin as raw material, hot cracked, oxidation and eliminate three-step reaction make.Current false diosgenin oxidizing reaction, all adopts chromic anhydride oxidation technology both at home and abroad, and chromic anhydride belongs to the oxygenant of severe toxicity and severe corrosive, and it uses a large amount of discharges containing chromium solid waste and waste water of following to cause serious environmental pollution.
This case applicants in 2005 have invented the method (200510011966.6) of the photosensitized oxidation of the pregnant steroid diketene of synthetic 16-dehydrogenation alcohol acetate ex hoc genus anne thing, and by Anhui Kebao Biology Engineering Co., Ltd's operation of founding the factory.Traditional chromic anhydride oxidation style has been abandoned in this invention, utilizes airborne oxygen as oxygenant, utilizes luminous energy initiation reaction, realizes the Efficient Conversion of false diosgenin diacetate to oxidation products.Landfill leachate substitutes traditional chromic anhydride oxidation style, has eliminated the serious problem of environmental pollution causing containing waste water, the waste residue of chromium from source.This case applicant and Anhui Kebao Biology Engineering Co., Ltd have built up the first large-scale up bubbling style photoreactor that is applicable to prepare 16-DPA in the world jointly, and this photoreactor is using 10 kilowatts of high voltage mercury lamps as light source.Because photosensitizers haematoporphyrin maximum absorption wavelength is positioned at 400nm left and right, this reactor need to be used the optical band below the quartz glass apparatus filtering 380nm adulterating, the luminous energy that this means mercury lamp output only has small part to be effectively utilized, thereby has caused a large amount of energy dissipations; The design of filter system simultaneously and manufacture have also occupied the significant proportion of cost.In addition, the radiant heat of 10 kilowatts of mercury lamp generations needs a large amount of water quench, and this is also to cause water resource waste and the soaring major reason of cost.
With high voltage mercury lamp comparison, LED light source efficiency is higher, and its output spectrum narrow range, and peak width at half height is in about 30nm, and output spectrum almost can be selected arbitrarily at visible light wave range, therefore can realize the well overlapping of itself and sensitiser absorption spectrum.In addition, LED light source also has that volume is little, brightness is high, radiant heat is little, long service life, work-ing life are not are not opened and closed the many advantages such as times influence, environmental protection.LED light source is incorporated into Organic Synthesis of Photochemistry field successively in recent years; LED light source has been saved huge environmental resources compared with traditional mercury lamp; become new technology [the Jens Wegner that promotes industrial photochemistry development; Sascha Ceylan and Andreas Kirschning; Chem.Commun.; 2011,47,4583 – 4592; Joseph W.Tucker, Yuan Zhang, Timothy F.Jamison, and Corey R.J.Stephenson, Angew.Chem.Int.Ed.2012,51,4144 – 4147; Lukas M.Kreis, Simon Krautwald, Nicole Pfeiffer, Rainer E.Martin, and Erick M.Carreira, Org.Lett., 2013,15 (7) 1634-1637].
Summary of the invention
The object of the invention is the problem existing for conventional high-tension mercury lamp, utilize LED light source to substitute high voltage mercury lamp, thereby provide a kind of blue led light source that utilizes to realize the method that photosensitized oxidation is prepared the pregnant steroid diketene of pharmaceutical intermediate 16-dehydrogenation alcohol acetate compounds.
The present invention is under the condition existing at photosensitizers haematoporphyrin, catalyst of triethylamine and acetic ester, utilize blue led lamp to make false steroid sapogenin diacetate generation photosensitized oxidation reaction as light source, then obtain the pregnant steroid diketene of product 16-dehydrogenation alcohol acetate compounds through peracid elimination reaction.
Utilize false steroid sapogenin diacetate to prepare the reaction scheme of the pregnant steroid diketene of 16-dehydrogenation alcohol acetate compounds as follows:
In said structure formula, R is H, C
5～C
6for C-C singly-bound, 1H-C
5when=5 α-H, be false Sisalgenin diacetate, products therefrom is 5 α-pregnene-20-ketone-3 beta-hydroxy acetic esters; R is carbonyl, C
5～C
6for C-C singly-bound, 1H-C
5when=5 α-H, be false american aloe sapogenin diacetate, products therefrom is 5 α-pregnene-12,20-diketone-3 beta-hydroxy acetic ester; R is H, C
5～C
6during for the two key of C=C, be false diosgenin diacetate, products therefrom is 3 beta-hydroxies-pregnant steroid-5 (6), 16 (17)-dienes-20-ketone acetic ester.
First, false steroid sapogenin diacetate generation photosensitized oxidation, in photosensitized oxidation process photosensitizers haematoporphyrin absorb luminous energy from ground state transition to excited state, the haematoporphyrin molecule of excited state and the oxygen molecule of ground state by energy shift generation creating singlet oxygen by using (
1o
2), creating singlet oxygen by using is oxidized false steroid sapogenin diacetate as oxygenant; The oxidation products of false steroid sapogenin diacetate is eliminated reaction through acid and is generated the pregnant steroid diketene of 16-dehydrogenation alcohol acetate compounds.
The method of utilizing blue led light source photosensitized oxidation to prepare the pregnant steroid diketene of 16-dehydrogenation alcohol acetate compounds of the present invention is:
Under room temperature (as 25 ℃), false steroid sapogenin diacetate, photosensitizers haematoporphyrin, triethylamine and acetic anhydride are dissolved in successively and in organic solvent, obtain photochemical reaction liquid;
In above-mentioned photochemical reaction liquid is placed in, soak the container of bubbling style photochemical reactor, and carry out bubbling by the bottom of container to passing into air or oxygen in photochemical reaction liquid, regulate the flow of air or oxygen to make bubble even; In opening, soak the cooling water valve of bubbling style photoreactor, in unlatching, soak the blue led lamp of installing in the heavy trap in bubbling style photoreactor and carry out photosensitized oxidation reaction, regulate the flow velocity of water coolant to make the temperature of photochemical reaction liquid remain on room temperature (as 25 ℃); After photosensitized oxidation has reacted, the underpressure distillation of photosensitized oxidation product is removed to photoresponse organic solvent used, in photosensitized oxidation product, add acetic acid backflow to carry out acid elimination reaction (time of general backflow is 3 hours), make photosensitized oxidation product be converted into the pregnant steroid diketene of 16-dehydrogenation alcohol acetate compounds; Revolve deacidification and eliminate the acetic acid in reaction solution, the product obtaining is dissolved in 60～90 ℃ of sherwood oils, the petroleum ether solution that is dissolved with product is washed till neutrality by water, and decompression steams sherwood oil; Gained crude product is carried out in methyl alcohol to recrystallization, obtain the pregnant steroid diketene of target product 16-dehydrogenation alcohol acetate compounds.Above-mentioned each stage is followed the tracks of reaction by high pressure liquid chromatography (HPLC), and the transformation efficiency of false steroid sapogenin diacetate reaches more than 98%, and the yield of the pregnant steroid diketene of 16-dehydrogenation alcohol acetate compounds is up to 82.6%.
HPLC testing conditions: instrument, Hitachi L-7100; Dalian Yi Lite Spher SiO
2normal phase column, particle diameter 5 μ, the diameter=4.6mm of post, column length 250mm; Moving phase, normal hexane/ethanol=97/3; Detect wavelength, 210nm; Flow velocity is 0.5mL/min.
The volumetric molar concentration of the false steroid sapogenin diacetate in described photochemical reaction liquid is 6 × 10
-2the volumetric molar concentration of mol/L, photosensitizers haematoporphyrin is 3 ‰ (1.8 × 10 of false steroid sapogenin diacetate volumetric molar concentration
-4mol/L), the volumetric molar concentration of triethylamine and acetic anhydride is 2 times (1.2 × 10 of false steroid sapogenin diacetate volumetric molar concentration
-1mol/L).
Described false steroid sapogenin diacetate is false diosgenin diacetate (1), false american aloe sapogenin diacetate (2) or false Sisalgenin diacetate (3), and structural formula is respectively:
The structural formula of the described pregnant steroid diketene of 16-dehydrogenation alcohol acetate compounds is:
Described organic solvent is 2-methyltetrahydrofuran, ethyl acetate, dioxane or acetone etc.
Described blue led lamp is the blue led lamp of the emission wavelength 10W that is greater than 380nm.
In used in the present invention, soaking bubbling style photochemical reactor is to be made up of container, heavy trap and blue led lamp.
Described heavy trap is mounted in described container; Described blue led lamp is placed in the inner chamber of heavy trap; Structure as shown in Figure 1.
The bottom of described container has inlet mouth; Described heavy trap is the U-shaped interlayer container with cooling water intakeoutfall.This interlayer container has the effect of two aspects: one, and filtering wavelength is shorter than the light of 380nm; Two, in interlayer container, logical water coolant, takes away the heat that light source produces.
Described blue led lamp is the blue led lamp of the emission wavelength 10W that is greater than 380nm.
The present invention utilizes blue led lamp (production of Xiamen electricity Tong Electronic Science and Technology Co., Ltd.) as light source, and photosensitized oxidation is prepared the pregnant steroid diketene of 16-dehydrogenation alcohol acetate compounds, compares with conventional high-tension mercury lamp light source.The luminescent spectrum of blue led lamp can be good at mating (as shown in Figure 2) with the maximum absorption spectrum of photosensitizers haematoporphyrin used.And the maximum absorption spectrum of the luminescent spectrum of mercury lamp and photosensitizers haematoporphyrin used exists huge difference, haematoporphyrin can only absorb the small part light of mercury lamp emission spectrum, and most of luminous energy is wasted (as shown in Figure 3).Therefore, use blue led lamp can save huge electric power energy as light source.
In the structure of the false steroid sapogenin diacetate of raw material using in the present invention, contain carbonyl.Because Norrish I type and/or the side reaction of Norrish II type occur carbonyl compound under the illumination of 330～380nm, therefore the present invention wants the light below filtering 380nm.In shown in Fig. 1, soak heavy trap in bubbling style photochemical reactor and be by glass that can the following light of filtering 380nm and make, the blue led lamp that light source is 10W is positioned in the inner chamber of heavy trap, and the trap that will sink directly immerses and in photochemical reaction liquid, carries out illumination reaction.
In addition, the heavy trap using in the present invention is a U-shaped interlayer container, in the process of photosensitized oxidation, in this interlayer container, passes into water coolant, thereby takes away the heat that light source produces, and reaches the object of regulation and control photoresponse temperature.With respect to the high voltage mercury lamp of 500W, the blue led lamp of 10W only produces the heat of minute quantity, and therefore blue led lamp can be saved a large amount of water coolants.
The present invention replaces traditional chromic anhydride oxidation with photosensitive oxidation technology, has eliminated the serious problem of environmental pollution that in traditional production technique, hypertoxic chromium metal causes from source.On this basis, this case applicant is for the critical defect of high voltage mercury lamp light source, utilize blue led lamp to substitute the light source high voltage mercury lamp in photosensitized oxidation, under the suitable prerequisite of target product yield, realized blue led Lantern Festival and economized 40 times of above electric energy and a large amount of water resourcess.The present invention provides new technology for the Green Chemistry in steroid drugs industrial production.
Accompanying drawing explanation
Fig. 1. in used in the present invention, soak the structural representation of heavy trap in bubbling style photochemical reactor.
Fig. 2. blue led lamp luminescent spectrum in the absorption spectrum (--) of the hematoporphyrin photosensitizer in the present invention and the present invention (– – –) figure.
Fig. 3. the utilizing emitted light spectrogram of mercury lamp in the present invention.
Embodiment
Embodiment 1
In used, soak bubbling style photochemical reactor and be and have by bottom the blue led lamp that the container of inlet mouth, heavy trap and emission wavelength be greater than the 10W of 380nm and form.
As shown in Figure 1, the described heavy trap of being made up of glass that can the following light of filtering 380nm is the U-shaped interlayer container with cooling water intakeoutfall, and this heavy trap is mounted in described container; Described blue led lamp is placed in the inner chamber of heavy trap.
Utilize in above-mentioned and soak bubbling style photochemical reactor, the false diosgenin diacetate of oxidative degradation is 3 beta-hydroxies-pregnant steroid-5 (6), 16 (17)-dienes-20-ketone acetic ester:
Under room temperature (as 25 ℃), in the round-bottomed flask of 500mL, haematoporphyrin, the triethylamine of 5.5mL and the acetic ester of 3.7mL of the false diosgenin diacetate of 10g, 37mg are dissolved in the 2-methyltetrahydrofuran of 330mL successively, are uniformly mixed, be mixed with photochemical reaction liquid.In photochemical reaction liquid is transferred to, soak in the container of bubbling style photochemical reactor, and carry out bubbling by the bottom of container to passing into air in photochemical reaction liquid, regulate the flow of air to make bubble even; In opening, soak the cooling water valve of bubbling style photoreactor, in unlatching, soak the blue led lamp of the 10W installing in the heavy trap in bubbling style photoreactor, photosensitized oxidation reaction 19 minutes is carried out in illumination, regulate the flow velocity of water coolant to make the temperature of photochemical reaction liquid remain on room temperature (as 25 ℃), utilize high pressure liquid chromatography (HPLC) monitoring reaction process.When photosensitized oxidation reaction finishes, the transformation efficiency of the false diosgenin diacetate of raw material is 99.2%.
Photosensitized oxidation reaction solution after photosensitized oxidation has been reacted is transferred in the round-bottomed flask of 500mL, vacuum rotary steam is removed 2-methyl-tetrahydrofuran solvent, then add the Glacial acetic acid of 15mL, reflux is termination reaction after 3 hours, and cooling acid is eliminated reaction solution and revolved to steam and removes Glacial acetic acid raffinate.Add 250mL60～90 ℃ petroleum ether dissolution product, wash the extremely neutrality of sherwood oil (60～90 ℃) solution that is dissolved with product for three times with 1000mL saturated common salt moisture, after dry, decompression steams sherwood oil (60～90 ℃), gained crude product is carried out in methyl alcohol to recrystallization, obtain light brown crystallization 3 beta-hydroxies-pregnant steroid-5 (6), 16 (17)-dienes-20-ketone acetic ester is 7.1g(purity 95.8%), yield 82.6%.
HPLC testing conditions: instrument, Hitachi L-7100; Dalian Yi Lite Spher SiO
2normal phase column, particle diameter 5 μ, the diameter=4.6mm of post, column length 250mm; Moving phase, normal hexane/ethanol=97/3; Detect wavelength, 210nm; Flow velocity is 0.5mL/min.
Comparative example 1
In used, soak bubbling style photochemical reactor substantially the same manner as Example 1, the blue led lamp that just emission wavelength is greater than to the 10W of 380nm changes the high voltage mercury lamp of 500W into.
Utilize in above-mentioned and soak bubbling style photochemical reactor, the false diosgenin diacetate of oxidative degradation is 3 beta-hydroxies-pregnant steroid-5 (6), the method of 16 (17)-dienes-20-ketone acetic ester is substantially the same manner as Example 1, in just opening, soak the high voltage mercury lamp of the 500W installing in the heavy trap in bubbling style photoreactor, photosensitized oxidation reaction 22 minutes is carried out in illumination, utilizes high pressure liquid chromatography (HPLC) monitoring reaction process (HPLC testing conditions is identical with embodiment 1).When photosensitized oxidation reaction finishes, the transformation efficiency of the false diosgenin diacetate of raw material is 98.9%.
Gained light brown crystallization 3 beta-hydroxies-pregnant steroid-5 (6), 16 (17)-dienes-20-ketone acetic ester is 6.7 grams (purity 95.3%), yield 78%.
Embodiment 2
Utilize embodiment 1 in soak bubbling style photochemical reactor, the false diosgenin diacetate of oxidative degradation is 3 beta-hydroxies-pregnant steroid-5 (6), 16 (17)-dienes-20-ketone acetic ester:
Under room temperature (as 25 ℃), in the round-bottomed flask of 500mL, haematoporphyrin, the triethylamine of 5.5mL and the acetic ester of 3.7mL of the false diosgenin diacetate of 10g, 37mg are dissolved in the ethyl acetate of 330mL successively, are uniformly mixed, be mixed with photochemical reaction liquid.In photochemical reaction liquid is transferred to, soak in the container of bubbling style photochemical reactor, and carry out bubbling by the bottom of container to passing into oxygen in photochemical reaction liquid, regulate the flow of oxygen to make bubble even; In opening, soak the cooling water valve of bubbling style photoreactor, in unlatching, soak the blue led lamp of the 10W installing in the heavy trap in bubbling style photoreactor, photosensitized oxidation reaction 19 minutes is carried out in illumination, regulate the flow velocity of water coolant to make the temperature of photochemical reaction liquid remain on room temperature (as 25 ℃), utilize high pressure liquid chromatography (HPLC) monitoring reaction process (HPLC testing conditions is identical with embodiment 1).When photosensitized oxidation reaction finishes, the transformation efficiency of the false diosgenin diacetate of raw material is 99.5%.
Photosensitized oxidation reaction solution after photosensitized oxidation has been reacted is transferred in the round-bottomed flask of 500mL, vacuum rotary steam is removed ethyl acetate, then add the Glacial acetic acid of 15mL, reflux is termination reaction after 3 hours, and cooling acid is eliminated reaction solution and revolved to steam and removes Glacial acetic acid raffinate.Add 250mL60～90 ℃ petroleum ether dissolution product, wash the extremely neutrality of petroleum ether solution that is dissolved with product for three times with 1000mL saturated common salt moisture, after dry, decompression steams sherwood oil (60～90 ℃), gained crude product is carried out in methyl alcohol to recrystallization, obtain light brown crystallization 3 beta-hydroxies-pregnant steroid-5 (6), 16 (17)-dienes-20-ketone acetic ester is 7g(purity 95.8%), yield 81.4%.
Comparative example 2
Utilize comparative example 1 in soak bubbling style photochemical reactor, the false diosgenin diacetate of oxidative degradation is 3 beta-hydroxies-pregnant steroid-5 (6), the method of 16 (17)-dienes-20-ketone acetic ester is substantially the same manner as Example 2, in just opening, soak the high voltage mercury lamp of the 500W installing in the heavy trap in bubbling style photoreactor, photosensitized oxidation reaction 22 minutes is carried out in illumination, utilizes high pressure liquid chromatography (HPLC) monitoring reaction process (HPLC testing conditions is identical with embodiment 1).When photosensitized oxidation reaction finishes, the transformation efficiency of the false diosgenin diacetate of raw material is 98.2%.
Gained light brown crystallization 3 beta-hydroxies-pregnant steroid-5 (6), 16 (17)-dienes-20-ketone acetic ester is 6.8 grams (purity 97.2%), yield 79.1%.
Embodiment 3
Utilize embodiment 1 in soak bubbling style photochemical reactor, the false american aloe sapogenin of oxidative degradation diacetate is 5 α-pregnene-12, the method of 20-diketone-3 beta-hydroxy acetic ester is substantially the same manner as Example 1, just 2-methyltetrahydrofuran is changed to dioxane, the false diosgenin diacetate of raw material is changed to false american aloe sapogenin diacetate, utilizes high pressure liquid chromatography (HPLC) monitoring reaction process (HPLC testing conditions is identical with embodiment 1).When photosensitized oxidation reaction finishes, the transformation efficiency of the false american aloe sapogenin of raw material diacetate is 98.8%.
Gained light brown crystallization 5 α-pregnene-12,20-diketone-3 beta-hydroxy acetic ester is 6.4 grams (purity 96.8%), yield 74.4%.
Comparative example 3
Utilize comparative example 1 in soak bubbling style photochemical reactor, the false american aloe sapogenin of oxidative degradation diacetate is 5 α-pregnene-12, the method of 20-diketone-3 beta-hydroxy acetic ester is substantially the same manner as Example 3, in just opening, soak the high voltage mercury lamp of the 500W installing in the heavy trap in bubbling style photoreactor, photosensitized oxidation reaction 22 minutes is carried out in illumination, utilizes high pressure liquid chromatography (HPLC) monitoring reaction process (HPLC testing conditions is identical with embodiment 1).When photosensitized oxidation reaction finishes, the transformation efficiency of the false american aloe sapogenin of raw material diacetate is 98.9%.
Gained light brown crystallization 5 α-pregnene-12,20-diketone-3 beta-hydroxy acetic ester is 6.1g(purity 97.2%), yield 70.9%.
Embodiment 4
Utilize embodiment 1 in soak bubbling style photochemical reactor, the false american aloe sapogenin of oxidative degradation diacetate is 5 α-pregnene-12, the method of 20-diketone-3 beta-hydroxy acetic ester is substantially the same manner as Example 2, just ethyl acetate is changed to acetone, the false diosgenin diacetate of raw material is changed to false american aloe sapogenin diacetate, utilizes high pressure liquid chromatography (HPLC) monitoring reaction process (HPLC testing conditions is identical with embodiment 1).When photosensitized oxidation reaction finishes, the transformation efficiency of the false american aloe sapogenin of raw material diacetate is 98.6%.
Gained light brown crystallization 5 α-pregnene-12,20-diketone-3 beta-hydroxy acetic ester is 6.3g(purity 96.8%), yield 73.3%.
Comparative example 4
Utilize comparative example 1 in soak bubbling style photochemical reactor, the false american aloe sapogenin of oxidative degradation diacetate is 5 α-pregnene-12, the method of 20-diketone-3 beta-hydroxy acetic ester is substantially the same manner as Example 4, in just opening, soak the high voltage mercury lamp of the 500W installing in the heavy trap in bubbling style photoreactor, photosensitized oxidation reaction 22 minutes is carried out in illumination, utilizes high pressure liquid chromatography (HPLC) monitoring reaction process (HPLC testing conditions is identical with embodiment 1).When photosensitized oxidation reaction finishes, the transformation efficiency of the false american aloe sapogenin of raw material diacetate is 98.2%.
Gained light brown crystallization 5 α-pregnene-12,20-diketone-3 beta-hydroxy acetic ester is 6.5g(purity 97.2%), yield 75.6%.
Embodiment 5
Utilize embodiment 1 in soak bubbling style photochemical reactor, the method that the false Sisalgenin diacetate of oxidative degradation is 5 α-pregnene-20-ketone-3 beta-hydroxy acetic ester is substantially the same manner as Example 1, just 2-methyltetrahydrofuran is changed to acetone, the false diosgenin diacetate of raw material is changed to false Sisalgenin diacetate, utilizes high pressure liquid chromatography (HPLC) monitoring reaction process (HPLC testing conditions is identical with embodiment 1).When photosensitized oxidation reaction finishes, the transformation efficiency of the false Sisalgenin diacetate of raw material is 98.3%.
Gained light brown crystallization 5 α-pregnene-20-ketone-3 beta-hydroxy acetic ester is 6.1g(purity 96.8%), yield 70.9%.
Comparative example 5
Utilize comparative example 1 in soak bubbling style photochemical reactor, the method that the false Sisalgenin diacetate of oxidative degradation is 5 α-pregnene-20-ketone-3 beta-hydroxy acetic ester is substantially the same manner as Example 5, in just opening, soak the high voltage mercury lamp of the 500W installing in the heavy trap in bubbling style photoreactor, photosensitized oxidation reaction 22 minutes is carried out in illumination, utilizes high pressure liquid chromatography (HPLC) monitoring reaction process (HPLC testing conditions is identical with embodiment 1).When photosensitized oxidation reaction finishes, the transformation efficiency of the false Sisalgenin diacetate of raw material is 98.6%.
Gained light brown crystallization 5 α-pregnene-20-ketone-3 beta-hydroxy acetic ester is 5.8g(purity 95.2%), yield 67.4%.
Embodiment 6
Utilize embodiment 1 in soak bubbling style photochemical reactor, the method that the false Sisalgenin diacetate of oxidative degradation is 5 α-pregnene-20-ketone-3 beta-hydroxy acetic ester is substantially the same manner as Example 2, just ethyl acetate is changed to 2-methyltetrahydrofuran, the false diosgenin diacetate of raw material is changed to false Sisalgenin diacetate, utilizes high pressure liquid chromatography (HPLC) monitoring reaction process (HPLC testing conditions is identical with embodiment 1).When photosensitized oxidation reaction finishes, the transformation efficiency of the false Sisalgenin diacetate of raw material is 98.3%.
Gained light brown crystallization 5 α-pregnene-20-ketone-3 beta-hydroxy acetic ester is 6.6g(purity 96.8%), yield 76.7%.
Comparative example 6
Utilize comparative example 1 in soak bubbling style photochemical reactor, the method that the false Sisalgenin diacetate of oxidative degradation is 5 α-pregnene-20-ketone-3 beta-hydroxy acetic ester is substantially the same manner as Example 5, in just opening, soak the high voltage mercury lamp of the 500W installing in the heavy trap in bubbling style photoreactor, photosensitized oxidation reaction 22 minutes is carried out in illumination, utilizes high pressure liquid chromatography (HPLC) monitoring reaction process (HPLC testing conditions is identical with embodiment 1).When photosensitized oxidation reaction finishes, the transformation efficiency of the false Sisalgenin diacetate of raw material is 98.1%.
Gained light brown crystallization 5 α-pregnene-20-ketone-3 beta-hydroxy acetic ester is 6.0g(purity 95.2%), yield 69.8%.
Claims (8)
1. utilize blue led light source photosensitized oxidation to prepare a method for the pregnant steroid diketene of 16-dehydrogenation alcohol acetate compounds, it is characterized in that:
Under room temperature, false steroid sapogenin diacetate, photosensitizers haematoporphyrin, triethylamine and acetic anhydride are dissolved in successively and in organic solvent, obtain photochemical reaction liquid;
In above-mentioned photochemical reaction liquid is placed in, soak the container of bubbling style photochemical reactor, and carry out bubbling by the bottom of container to passing into air or oxygen in photochemical reaction liquid; In opening, soak the cooling water valve of bubbling style photoreactor, soak the blue led lamp of installing in the heavy trap in bubbling style photoreactor and carry out photosensitized oxidation reaction in unlatching, in the process of photosensitized oxidation reaction, keeping the temperature of photochemical reaction liquid is room temperature; The underpressure distillation of photosensitized oxidation product is removed to photoresponse organic solvent used, in photosensitized oxidation product, add acetic acid backflow to carry out acid elimination reaction; Revolve deacidification and eliminate the acetic acid in reaction solution, the product obtaining is dissolved in 60～90 ℃ of sherwood oils, the petroleum ether solution that is dissolved with product is washed till neutrality by water, and decompression steams sherwood oil; Gained crude product is carried out in methyl alcohol to recrystallization, obtain the pregnant steroid diketene of 16-dehydrogenation alcohol acetate compounds.
2. method according to claim 1, is characterized in that: the volumetric molar concentration of the false steroid sapogenin diacetate in described photochemical reaction liquid is 6 × 10
-2the volumetric molar concentration of mol/L, photosensitizers haematoporphyrin be false steroid sapogenin diacetate volumetric molar concentration 3 ‰, the volumetric molar concentration of triethylamine and acetic anhydride is 2 times of false steroid sapogenin diacetate volumetric molar concentration.
3. method according to claim 1 and 2, is characterized in that: described false steroid sapogenin diacetate is false diosgenin diacetate, false american aloe sapogenin diacetate or false Sisalgenin diacetate.
4. method according to claim 1, is characterized in that: the structural formula of the described pregnant steroid diketene of 16-dehydrogenation alcohol acetate compounds is:
5. method according to claim 1, is characterized in that: described organic solvent is 2-methyltetrahydrofuran, ethyl acetate, dioxane or acetone.
6. method according to claim 1, is characterized in that: in described, soaking bubbling style photochemical reactor is to be made up of container, heavy trap and blue led lamp;
Described heavy trap is mounted in described container; Described blue led lamp is placed in the inner chamber of heavy trap;
The bottom of described container has inlet mouth;
Described heavy trap is the U-shaped interlayer container with cooling water intakeoutfall.
7. according to the method described in claim 1 or 6, it is characterized in that: described blue led lamp is the blue led lamp of the emission wavelength 10W that is greater than 380nm.
8. according to the method described in claim 1 or 6, it is characterized in that: described heavy trap is to be made up of glass that can the following light of filtering 380nm.
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