CN100551929C - The preparation method of Δ 9 (11) steroid compounds - Google Patents
The preparation method of Δ 9 (11) steroid compounds Download PDFInfo
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- CN100551929C CN100551929C CNB2005100144795A CN200510014479A CN100551929C CN 100551929 C CN100551929 C CN 100551929C CN B2005100144795 A CNB2005100144795 A CN B2005100144795A CN 200510014479 A CN200510014479 A CN 200510014479A CN 100551929 C CN100551929 C CN 100551929C
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Abstract
The present invention relates to the preparation method of formula (I) steroid compound.It is to react in organic solvent with formula (II) compound and acidic dehydration agent to obtain compound (I), wherein R
1Be selected from H, halogen, C
1-5Acyloxy or OH; R
2During=OH, 1,2 is not two keys; R
2=C
1-5Acyloxy; R
2, R
3=O; R
2R
3=two keys; R wherein
4Be selected from α, β position C
1-3Alkyl or halogen.The highest yield of Δ 9 (11) steroid compounds reaches 99%, and impurity Δ 11 (12) content generally are lower than 3%.Product content improves, and has reduced cost, has reduced pollution.
Description
Technical field
The present invention relates to the preparation of steroid compound, particularly a kind of preparation method of Δ 9 (11) steroid compounds.
Background technology
Δ 9 (11) steroid compounds be make 9 fluorine-containing steroid hormones and introduce 11 hydroxyl functional groups the constituent that must have.People such as G.Arth, J.Fried [J.Am.Chem.Soc last 1958 (80) 3160,3161] has reported that to make 9 halogen-containing as F, and 11 is that the steroidal compounds of β-OH will usually be used Δ 9 (11) compounds.
Δ 9 (11) compounds can make 9 by known method (as J.A.M.C, 1958 (80) 6687) suc as formula (I), the 11-epoxy material, and then can make 9 halogen-containing cortin such as becort acetates as F.
People such as R.Rausser, A.M.Lyncheski (J.O.C.1966 (31), 26) has reported and has utilized CH
3SO
2Cl carries out the sulphur esterification to 11 α-OH steroidal compounds, utilize NaOAc again, HOAc eliminates reaction and forms Δ 9 (11) compounds, but this elimination reaction will inevitably with the impurity of an about 8-15%, this be because 11 α-when the OH methanesulfonate ester is eliminated, since 9,12 all have a H, though portion's generation Δ 9 (11) compounds greatly also can generate a small amount of Δ 11 (12) compounds.Since this impurity in follow-up reaction, treating process all difficulty remove, cause the final product quality obviously to descend.In order to solve this impurity problem, many chemists have carried out big quantity research.As far back as 1954, S.Lenhard, R.H..Williams. (J.O.C.1954 (19), 41) reported and have utilized 3, two alpha-hydroxy these compounds of ketal-11 of 17-and POCl
3Reaction obtains Δ 9 (11) compounds, crude product yield about 90% in pyridine; Shoppee, and C.W.Nemorin etc. [J.C.S (Perkin, Trans) 1973,542.] reported that 5 α-androstane-11 Alpha-hydroxy utilizes PCl
5At CHCl
3In, obtaining 5 α-androstane-9 (11)-alkene, its yield is 65%, and has one 9, the main by product of the two chlorine of 11-.The little brave people such as grade of Fu (T.L 2001 (42) 2639) has reported from formula (III) compound, utilizes PCl
5With THF production (IV) Δ 9 (11) compounds at low temperatures, its problem is that 21 continuous hydroxyls will utilize Vinyl chloroformate to generate carbonic ether earlier, because Vinyl chloroformate is a violent in toxicity, has increased operator's danger and labour intensity, has also increased corresponding cost simultaneously.
Present industrial classic methods is that 11 α oxy-compound are utilized CH
3SO
2Cl carries out the sulphur esterification, utilizes NaOAc, HOAc to eliminate reaction again and forms Δ 9,11 compounds, and the content of impurity Δ 11 (12) compounds is 8～15%, and obtaining qualified product needs to make with extra care repeatedly, and cost is expensive more; In addition owing to can use pyridine, acetic acid equal solvent and need two-step reaction to finish in the reaction process.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of Δ 9 (11) steroid compounds.It is to obtain formula (I) compound with the dehydration of formula (II) compound, and yield reaches 99%, and impurity Δ 11 (12) content generally are lower than 3%.The method for preparing Δ 9 (11) steroid compounds provided by the invention, product content improves, and has reduced cost, has reduced pollution.
The preparation method of Δ 9 (11) steroid compounds of the present invention comprises the steps: that it is to react in organic solvent with formula (II) compound and acidic dehydration agent to obtain compound (I):
Wherein, R
1=H, halogen, OH, or C
1-5Acyloxy.
R
2=H, α-OH, or C
1-5Acyloxy.
R
3=H, OH, or α, β C
1-3Alkyl.
R
2, R
3=α epoxy or two key.
R
4=H, α, β C
1-3Alkyl or α, β halogen.
R
5, R
6=H or two key.Or
R
2=OH and R
3C is contained in=α, β position
1-3During alkyl, R
4Be α, β C
1-3Alkyl or α, β halogen or R
5, R
6=H.
(serpentine in the molecular formula be expressed as substituents alpha, β all can)
The described mol ratio that contains 11 α-OH formula (II) compound and organic solvent is 1: 6～60, and organic solvent is: 1, and 4-dioxane, tetrahydrofuran (THF), DMF, pyridine, C
1-3Chloroparaffin, acetonitrile, toluene, benzene, C
1-4Ether, or their mixing, the described mol ratio that contains 11 α-OH formula (II) compound and acidic dehydration agent is 1: 0.1～5, reacts under temperature-108～O ℃ of (preferred-90～-50 ℃) condition, reaction is finished, and is diluted in following alkali NaOH, NaHCO
3, KOH, S-WAT or ammoniacal liquor the aqueous solution in or be diluted in and regulate neutrally in the water again with the aqueous solution that contains described alkali, filter drying; Or pour the methyl alcohol redilution in water behind the organic layer underpressure distillation removal solvent, filter drying.
Described formula (II) compound that contains 11 α-OH refers in particular to:
R
1=H, halogen, OH, or C
1-5Acyloxy.
R
2＝OH，
R
3=H or α, β methyl,
R
2, R
3=α epoxy or two key.
R
4=H, α methyl or α halogen.
R
5, R
6=H or two key; Or
R
2=OH and R
3When=α, β methyl, R
4Be α methyl or α halogen or R
5, R
6=H.
(serpentine in the molecular formula be expressed as substituents alpha, β all can).
Described formula (II) compound that contains 11 α-OH especially refers in particular to:
R
1=H, halogen
R
2＝OH
R
3=H or α, β methyl
R
2, R
3=α epoxy or two key.
R
4=H, α methyl or α fluorine.
R
5, R
6=H or two key; Or
R
2=OH and R
3When=α, β methyl, R
4Be α methyl or α fluorine or R
5, R
6=H.
(serpentine in the molecular formula be expressed as substituents alpha, β all can)
Describedly contain formula (II) compound of 11 β-OH and the mol ratio of organic solvent is 1: 6～60, organic solvent comprises 1,4-dioxane, tetrahydrofuran (THF), N, dinethylformamide (DMF), pyridine, C
1-3Chloroparaffin, acetonitrile, toluene, benzene, C
1-5Ether or their mixing; Describedly contain formula (II) compound of 11 β-OH and the mol ratio of acidic dehydration agent is 1: 0.2～3, react under 0～60 ℃ of (preferred 15～40 ℃) condition of temperature, reaction is finished, and is diluted in following alkali NaOH, NaHCO
3, KOH, S-WAT or ammoniacal liquor the aqueous solution in or be diluted in and regulate neutrally in the water again with the aqueous solution that contains described alkali, filter after drying, or the organic layer underpressure distillation, pour the methyl alcohol redilution in water, filtration drying after removing solvent.
Described acidic dehydration agent is PCl
5, PCl
3, POCl
3, SO
2Cl
2, triphenyl phosphorus (PPh
3), preferred PCl
5, PCl
3, POCl
3The mol ratio of formula (II) compound and acidic dehydration agent is 1: 0.8～and 2.
Described organic solvent is 1,4-dioxane, tetrahydrofuran (THF), DMF, pyridine, acetonitrile, toluene or benzene; Or their mixing.Preferably: 1,4-dioxane, tetrahydrofuran (THF) or acetonitrile, or their mixing.
The described mol ratio that contains 11 α-OH formula (II) compound and acidic dehydration agent is 1: 0.8～2, organic solvent is: 1, and 4-dioxane, tetrahydrofuran (THF), DMF or their mixing are-90～-50 ℃ of reactions down, reaction is finished, and is diluted in following alkali NaOH, NaHCO
3, KOH, S-WAT or ammoniacal liquor the aqueous solution in or be diluted in regulate neutrality with the aqueous solution that contains described alkali again in the water after, filter drying.
The present invention has used the proper raw material compound in appropriate solvent, under appropriate reaction conditions, can obtain formula (I) compound with formula (II) compound, and yield is up to 99%, and impurity Δ 11 (12) content can be lower than 3%.The invention provides the method that several 11-oxy-compound are prepared into Δ 9 (11) compounds, product content improves, and has reduced cost, has reduced pollution.
Embodiment
Below will the invention will be further described by embodiment, these descriptions are not that content of the present invention is done further to limit.One skilled in the art will understand that to be equal to replacement to what technical characterictic of the present invention was done, or corresponding the improvement, still belong within protection scope of the present invention.11 α or β hydroxy-steroids used in following examples all are that Tianjin Tianyao Pharmaceutical Co., Ltd. produces.
Embodiment 1
With the pregnant steroid-1,4 of 10Kg shown in the following formula, 16 (17)-triolefins-3,20-diketone-11 Alpha-hydroxy, 110L tetrahydrofuran (THF) drop in the reaction flask, stir, and are cooled to below-50 ℃ in 20 minutes, the 7Kg phosphorus trichloride is added reaction flask, and stirring reaction is after 2 hours, and thin-layer chromatography is identified (TLC), reaction is not after have raw material point, be diluted in the 550L0.05% ammoniacal liquor, regulate pH value to neutral with 5% ammoniacal liquor again, leave standstill 1 hour after, filter the back in going into baking box, get 9.3Kg.The product of the Δ 9 (11) that obtains and the product of Δ 11 (12), measuring the content ratio through high performance liquid chromatography (HPLC) is 98: 2.[Δ 11 (12) represents 11,12 to be two keys, and it is two keys that Δ 9 (11) is represented 9,11].
Embodiment 2
With the pregnant steroid-1 of 10Kg shown in the following formula, 4-diene-3,20-diketone-11 Alpha-hydroxy-16,17 α-epoxy, 80L tetrahydrofuran (THF) drop in the reaction flask, stir, and are cooled to-85 ℃ in 20 minutes, the 20Kg phosphorus pentachloride is added reaction flask, and-85 ℃ of following stirring reactions are after 3.5 hours, TLC, reaction is not after have raw material point, be diluted in the 350L water, regulate pH value to neutral with KOH, leave standstill 1 hour after, filter back 60 ℃ and go into baking box, get 9.4Kg.Δ 9 (11) products that obtain and Δ 11 (12) products, measuring the content ratio through high performance liquid chromatography (HPLC) is 98.8: 1.2.
Table 1: the dehydration results of this 11 α oxy-compound in THF is as follows under the differing temps:
| Temperature of reaction | Reaction times (h) | Δ9(11)(％) | Δ11(12) (％) |
| 0℃ | 1 | 85.1 | 8.7 |
| -10℃ | 1 | 88.4 | 5.9 |
| -30℃ | 1.5 | 91.6 | 4.1 |
| -50℃ | 2 | 95.5 | 2.6 |
| -70℃ | 3 | 97.8 | 1.3 |
| -85℃ | 3.5 | 98.5 | 1.2 |
Embodiment 3
With the pregnant steroid of 10Kg shown in the following formula-1-alkene-3,20-diketone-11 β, 17 α-two hydroxyls, pyridine 60L drop in the reaction flask, stirred 10 minutes, controlled temperature adds reaction flask at 20 ℃ with the 10Kg phosphorus pentachloride, 25 ℃ of following stirring reactions are after 1 hour, TLC, reaction is diluted in the 800L water after do not have raw material point, regulate pH value to neutral with NaOH, after leaving standstill 1 hour, filter 60 ℃ and go into baking box, get 8.5Kg.Obtain Δ 9 (11) products and Δ 11 (12) products, measuring the content ratio through high performance liquid chromatography (HPLC) is 94.4: 5.6.
Embodiment 4
With the pregnant steroid-1 of 10g shown in the following formula, 4-diene-3,20-diketone-11 α, 17 α-two hydroxyls-6 Alpha-Methyl, 35ml tetrahydrofuran (THF) drop in the reaction flask, stir, and are cooled to-60 ℃ in 20 minutes, the 15g phosphorus pentachloride is added reaction flask,-60 ℃ of following stirring reactions are after 3 hours, TLC, and reaction is not after have raw material point, be diluted in the 280ml water, regulate pH value to neutral with NaOH again, leave standstill 1 hour after, filter back 60 ℃ and go into baking box.Get 9.2g, Δ 9 (11) products that obtain and Δ 11 (12) products, measuring the content ratio through high performance liquid chromatography (HPLC) is 98.5: 1.5.
Embodiment 5
With the pregnant steroid of 10g shown in the following formula-1-alkene-3,20-diketone-11 α, 17 α, 21-trihydroxy-, 30ml tetracol phenixin and 30ml acetonitrile drop in the reaction flask, stir, and are cooled to 0 ℃ in 20 minutes, with 4g PPh
3Add reaction flask, stirring reaction below 0 ℃ is after 24 hours,, TLC, reaction in the dilution water, is regulated pH value to neutral with NaOH after do not have raw material point, pours the methyl alcohol redilution in 70ml water after getting the organic layer underpressure distillation, and filtration is gone into baking box in 60 ℃.Get Δ 9 (11) products and Δ 11 (12) products that 7.7g obtains, measuring the content ratio through high performance liquid chromatography (HPLC) is 94.9: 5.1.
Embodiment 6
With the pregnant steroid of 10g shown in the following formula-1-alkene-3,20-diketone-11 Alpha-hydroxy-16,17 α-epoxy, 60ml1, the 4-dioxane drops in the reaction flask, stirs, and is cooled to-30 ℃ in 20 minutes, the 25.5g phosphorus oxychloride is added reaction flask, and-30 ℃ of following stirring reactions are after 2 hours, TLC, reaction is not after have raw material point, in the dilution 140ml water, regulate pH value to neutral with NaOH, leave standstill 1 hour after, filter, go into baking box in 60 ℃.Get Δ 9 (11) products and Δ 11 (12) products that 8.6g obtains, measuring the content ratio through high performance liquid chromatography (HPLC) is 94.2: 5.8.
Embodiment 7
With the pregnant steroid of 10g shown in the following formula-1-diene-3,20-diketone-11 α, 17 α-two hydroxyls-6 Alpha-Methyl, 80ml tetrahydrofuran (THF) drop in the reaction flask, stir, and are cooled to below-70 ℃ in 20 minutes, the 9g phosphorus pentachloride is added reaction flask, stirring reaction below-60 ℃ is after 2 hours, TLC, and reaction is not after have raw material point, be diluted in the 150ml water, use NaHCO
3Regulate pH value to neutral, leave standstill 1 hour after, filter, go into baking box in 60 ℃.Get Δ 9 (11) products and Δ 11 (12) products that 8.2g obtains, measuring the content ratio through high performance liquid chromatography (HPLC) is 96.3: 3.7.
Embodiment 8
With the pregnant steroid of 10g shown in the following formula-1-alkene-3,20-diketone-11 β, 17 α-two hydroxyls-16 Beta-methyl, pyridine drop in the reaction flask, stirred 10 minutes, and reduced the temperature to 0 ℃, phosphorus oxychloride is added reaction flask, 10 ℃ of following stirring reactions are after 1 hour, TLC, and reaction is not after have raw material point, be diluted in the 200ml2% ice NaOH/ water of 0 degree, regulate pH value to neutral, leave standstill 1 hour after, filter, massive laundering dries, go into baking box in 60 ℃, obtain 8.5g.Obtain Δ 9 (11) products and Δ 11 (12) products, measuring the content ratio through high performance liquid chromatography (HPLC) is 94.6: 5.4.
Embodiment 9
With the pregnant steroid of 10g shown in the following formula-1-alkene-3,20-diketone-11 α, 17 α-two hydroxyls, 80ml tetrahydrofuran (THF) drop in the reaction flask, stir, be cooled to below-70 ℃ in 20 minutes, the 17.8g phosphorus pentachloride is added reaction flask, stirring reaction is after 2 hours below-70 ℃, TLC, reaction is diluted in the 500ml water after do not have raw material point, regulate pH value to neutral with S-WAT, after leaving standstill 1 hour, filter, go into baking box in 60 ℃.Δ 9 (11) products that obtain and Δ 11 (12) products, measuring the content ratio through high performance liquid chromatography (HPLC) is 98.2: 1.8.
Embodiment 10
With the pregnant steroid-1 of 10g shown in the following formula, 4-diene-3,20-diketone-11 α, 17 α-two hydroxyls, 100ml tetrahydrofuran (THF) drop in the reaction flask, stir, and temperature adjustment is to below-70 ℃ in 20 minutes, the 17.8g phosphorus pentachloride is added reaction flask, and stirring reaction below-60 ℃ is after 6 hours, TLC, reaction is diluted in the 1000ml frozen water after do not have raw material point, regulates extremely neutrality of pH value with 5% ammoniacal liquor, after leaving standstill 1 hour, filter, go into baking box in 60 ℃, 9.4g.Δ 9 (11) products that obtain and Δ 11 (12) products, measuring the content ratio through high performance liquid chromatography (HPLC) is 97.1: 2.9.
Embodiment 11
With the pregnant steroid-1,4 of 10g shown in the following formula, 16 (17)-triolefins-3,20-diketone-11 α, two hydroxyl-21 acetic esters of 21-, 80ml tetrahydrofuran (THF) drop in the reaction flask, stir, be cooled in 20 minutes below-70 ℃, the 17.8g phosphorus pentachloride is added reaction flask, stirring reaction is after 2 hours below-70 ℃, TLC, reaction is diluted in the 1000ml water after do not have raw material point, regulate pH value to neutral with S-WAT, leave standstill 1 hour after, filter, go into baking box in 60 ℃, 9.1g.Δ 9 (11) products that obtain and Δ 11 (12) products, measuring the content ratio through high performance liquid chromatography (HPLC) is 97.2: 2.8.
Claims (9)
1, the preparation method of a kind of formula (I) steroid compound is characterized in that it comprises the steps: to react in organic solvent with formula (II) compound and acidic dehydration agent to obtain compound (I):
Wherein, R
1=H;
R
2＝H、OH；
R
3=H, OH or α, β C
1-3Alkyl; Or
R
2, R
3=α epoxy, two key;
R
4=H, α, β C
1-3Alkyl or α, β halogen;
R
5, R
6=H, two keys;
When containing 11 α-OH formula (II), temperature of reaction is-108～0 ℃; The described mol ratio that contains 11 α-OH formula (II) compound and organic solvent is 1: 6～60;
Organic solvent is 1,4-dioxane, tetrahydrofuran (THF), DMF, pyridine, chloro C
1-3Alkane, acetonitrile, toluene, benzene, C
1-5Ether at interior single or mixed organic solvents;
The described mol ratio that contains 11 α-OH formula (II) compound and acidic dehydration agent is 1: 0.1～5, and reaction is finished, and is diluted in following alkali NaOH, NaHCO
3, KOH, S-WAT or ammoniacal liquor the aqueous solution in or be diluted in and regulate neutrally in the water again with the aqueous solution that contains described alkali, filter and pour the methyl alcohol redilution in water after solvent is removed in after drying or organic layer underpressure distillation, filter drying;
When containing 11 β-OH formula (II), temperature of reaction is 0～60 ℃; Describedly contain formula (II) compound of 11 β-OH and the mol ratio of organic solvent is 1: 6～60;
Organic solvent is 1,4-dioxane, tetrahydrofuran (THF), DMF, pyridine, C
1-3Chloroparaffin, acetonitrile, toluene, benzene, C
1-5Ether at interior single or mixed organic solvents, containing formula (II) compound of 11 β-OH and the mol ratio of acidic dehydration agent is 1: 0.2～3, reaction is finished and to be diluted in following alkali NaOH, NaHCO
3, KOH, S-WAT or ammoniacal liquor the aqueous solution in or be diluted in and regulate neutrally in the water again with the aqueous solution that contains described alkali, filter drying; Or pour the methyl alcohol redilution in water behind the organic layer underpressure distillation removal solvent, filter drying.
2. in accordance with the method for claim 1, it is characterized in that R
2=OH and R
3=α, β C
1-3During alkyl, R
4Be α, β C
1-3Alkyl or α, β halogen; R
5, R
6=H.
3, in accordance with the method for claim 1, when it is characterized in that containing 11 α-OH formula (II), temperature of reaction is-90～-50 ℃.
4, in accordance with the method for claim 1, it is characterized in that: described formula (II) compound that contains 11 α-OH is:
R
1＝H，
R
2＝OH，
R
3=H or α, β methyl;
R
2, R
3=α epoxy, two key;
R
4=H, α methyl, α halogen;
R
5, R
6=H, two key.
5, in accordance with the method for claim 1, it is characterized in that: described formula (II) compound that contains 11 α-OH is: R
1=H, R
2=OH and R
3When=α, β methyl; R
4=α methyl, α fluorine or R
5, R
6=H.
6, in accordance with the method for claim 1, it is characterized in that described organic solvent is 1,4-dioxane, tetrahydrofuran (THF), DMF, pyridine, acetonitrile; Or their mixing.
7, in accordance with the method for claim 6, it is characterized in that described organic solvent is: 1,4-dioxane, tetrahydrofuran (THF) or acetonitrile; Or their mixing.
8, in accordance with the method for claim 1, it is characterized in that described acidic dehydration agent is PCl
5, PCl
3, POCl
3, SO
2Cl
2Or PPh
3The mol ratio of formula (II) compound and acidic dehydration agent is 1: 0.8～2.
9, in accordance with the method for claim 8, it is characterized in that described acidic dehydration agent is PCl
5, PCl
3Or POCl
3
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105348351A (en) * | 2015-11-16 | 2016-02-24 | 浙江仙琚制药股份有限公司 | Method for preparing tetraene methyl CAS |
| CN107286215A (en) * | 2016-03-31 | 2017-10-24 | 天津金耀集团有限公司 | A kind of steroidal compounds preparation method of multiple olefin groups |
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| KR101591482B1 (en) | 2008-05-28 | 2016-02-03 | 레베라겐 바이오파마 인코포레이티드 | - non-hormonal steroid modulators of nf-b for treatment of disease |
| EP2556083A4 (en) | 2010-04-05 | 2013-12-04 | Validus Biopharma Inc | Non-hormonal steroid modulators of nf- kappa b for treatment of disease |
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| CN107540719B (en) * | 2016-06-26 | 2020-02-21 | 浙江仙琚制药股份有限公司 | Preparation method of 17 α -acetoxyl- (8,13) -alkene-11 α -hydroxyprogesterone |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105348351A (en) * | 2015-11-16 | 2016-02-24 | 浙江仙琚制药股份有限公司 | Method for preparing tetraene methyl CAS |
| CN107286215A (en) * | 2016-03-31 | 2017-10-24 | 天津金耀集团有限公司 | A kind of steroidal compounds preparation method of multiple olefin groups |
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