CN100345862C - Steroid compounds preparation method - Google Patents
Steroid compounds preparation method Download PDFInfo
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- CN100345862C CN100345862C CNB2004100088061A CN200410008806A CN100345862C CN 100345862 C CN100345862 C CN 100345862C CN B2004100088061 A CNB2004100088061 A CN B2004100088061A CN 200410008806 A CN200410008806 A CN 200410008806A CN 100345862 C CN100345862 C CN 100345862C
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Abstract
The present invention discloses a method for preparing a steroid compound by using phytosterol microbial degradation products as raw materials. The method comprises the following steps: firstly, phytosterol microbial degradation products and new distillated nitromethane are mixed, and are heated under the protection of inert gas, and nitromethane which accounts for 0% to 15% of the volume total amount of the added nitromethane is vaporized; subsequently, organic alkali is added to the mixture, obtained mixed liquid reflows for 0.5 to 40 hours under the protection of inert gas, and whether reaction is finished or not is displayed by TLC (ethyl acetate/ligarine with a ratio of 2: 1); finally, a reaction product is concentrated to be dried and purified to obtain a steroid compound by pressure reduction.
Description
Technical field
The present invention relates to the preparation method of steroid, relating in particular to plant sterol microbiological deterioration product is the method for feedstock production steroid.
Background technology
Since the naturally occurring steroidal compounds of microbiological deterioration draws the method practicability of its derivative, swift and violent (the Sih C.J. of the synthetic method of steroidal compounds structure of modification development; Wang K.C.J.Am.Chem.Soc.1965,87,1387; Sih C.J.; Lee S.S.; Tsong Y.Y.; Wang K.C.; Chang F.N.J.Am.Chem.Soc.1965,87,2765; Nagasawa M.; Hashiba H.; Tamura G.; Arima K.Agric.Biol.Chem.1969,33,1644.).Naturally occurring steroidal can be converted into valuable medicine, for example: cortisone etc.Produce a tempting field of intermediate 17-oxo steroidal research becoming of cortisone.In this field, the synthetic method of relevant steroidal compounds becomes the focus of research, and has obtained a series of achievements, for example, in the presence of quadrol, the reaction high productivity of trans-dehydroandrosterone and Nitromethane 99Min. generates corresponding 17-nitro alkene steroid (Barton D.H.R.; Motherwell W.B.; Zard S.Z.J.Chem.Soc., Chem.Commun.1982,551).After this, this method is developed into from 17-oxo steroidal and is made up cortisone hydroxyketone side chain (Barton D.H.R. through 17-nitro alkene steroid; Motherwell W.B.; Zard S.Z.Bulletin de la Societe Chimique de France 1983,3-4, II-61).
Owing to do not have amino usually in the steroidal structure, so when preparation steroidal-conjugation of polypeptides hormone, have to connect steroidal and polypeptide by ester bond.Ester bond in the molecule can not tolerate polypeptide synthetic HF deprotection, and the structure diversity of steroidal-conjugation of polypeptides hormone is restricted (Chao Wang, Weina Cui, Ming Zhao, Jian Yang and Shiqi Peng, Bioorg Med Chem Lett, 2003,13,143-146; Wang Chao, Zhao Ming, Peng Shiqi, Steroids.2001,6,811-815; Chao Wang, Ming Zhao, WeinaCui, Jian Yang and Shiqi Peng, Synthetic Communications, 2003,33,1633-1641).A series of nitre methylation reactions of 17-oxo-steroidal can be used to prepare the steroidal compounds that contains amino.Nitroreduction is that amino is easy to realize, and 17-nitro en steroids not only can make preparation steroidal-conjugation of polypeptides hormone become easily after being reduced to the amino en steroids of 17-, and can realize the structure diversity target of steroidal-conjugation of polypeptides hormone.
The nitrogen mustards alkylating agent is the important antitumor drug of a class, and application potential is very big clinically, but the shortcoming of nitrogen mustards alkylating agent maximum is to lack selectivity, thereby has limited its clinical application.The nitrogen mustards alkylating agent is conjugated on the suitable carrier, is to improve optionally one of strategy of nitrogen mustards alkylating agent.Verified, steroidal compounds can distribute and tissue bond by high selectivity ground organ, is one of optimal candidate carrier of nitrogen mustards alkylating agent.Emcyt and PM according to this strategy invention are the representatives of two successes, are used as selectivity antitumor drug and immunosuppressor (Hiroshi, Kosano, et al., Cancer Research 52,1187-1191,1992; USP 4,921, and 849; USP 4,885, and 290).But, taking for a long time as the medicine of carrier with estradiol and prednisone can the side effect of generation estrogens.If use the 1-methyl estradiol, not only can keep high selectivity ground organ to distribute and tissue bond, and not have the estrogens side effect as carrier.
Summary of the invention
It is the method for the following 5 kinds of steroids of feedstock production by plant sterol microbiological deterioration product that the object of the invention provides a kind of:
(1) 11-Alpha-hydroxy-17-Nitromethylene androstane-1,4-diene-3-ketone, (2) 1-methyl-3-hydroxy-estra-1,3,5 (10), 9 (11)-tetraenes-17-ketone, (3) 17-Nitromethylene androstane-1,4,11 (12)-triolefins-3-ketone, (4) 11-α-tolysulfonyl oxygen androstane-1,4-diene-3,17-diketone, (5) androstane-1,4,9 (11)-triolefins-3, the 17-diketone;
The present invention seeks to realize by following approach:
A kind of is feedstock production 11-Alpha-hydroxy-17-Nitromethylene androstane-1 by plant sterol microbiological deterioration product, the method for 4-diene-3-ketone;
May further comprise the steps:
1) plant sterol microbiological deterioration product is mixed with new distillatory Nitromethane 99Min.; under protection of inert gas heating and boiling off account for add the Nitromethane 99Min. of Nitromethane 99Min. volume total amount 0%～15%; then in mixture, add organic bases, with the said mixture 0.5～40h that under protection of inert gas, refluxes.
2) show with TLC (ethyl acetate/petroleum ether, 2: 1) whether reaction is finished.
3) reaction product is evaporated to dried, purifying promptly gets above-mentioned formula I steroid.
Wherein the feed ratio of plant sterol microbiological deterioration product and new distillatory Nitromethane 99Min. is 1g: 30～70ml in the step 1), is preferably 1g: 50ml; Described organic bases is an amine, is preferably quadrol; The add-on of described organic bases account for add 0.05%～1% of Nitromethane 99Min. volume total amount, be preferably account for add 0.1% of Nitromethane 99Min. volume total amount.
Described rare gas element is nitrogen or argon gas, is preferably argon gas.
Described product purification mode is recrystallization purifying or purification by silica gel column chromatography, is preferably purification by silica gel column chromatography.
A kind of preparation 1-methyl-3-hydroxyl is female-1,3,5 (10), 9 (11)-tetraenes-17-ketone, 17-Nitromethylene androstane-1,4,11 (12)-triolefins-3-ketone, 11-α-tolysulfonyl oxygen androstane-1,4-diene-3,17-diketone and androstane-1,4,9 (11)-triolefins-3, the method for 17-diketone;
May further comprise the steps:
1) with 5g 11-Alpha-hydroxy-androstane-1,4-diene-3, the solution of 17-diketone and 40ml pyridine is cooled to 0-5 ℃, Dropwise 5 3mmol Tosyl chloride in this cold soln; Reaction mixture room temperature reaction 24h shows with thin-layer chromatography whether reaction is finished; In reaction product impouring 120ml frozen water, leach the precipitation of generation; Precipitation obtains 11-α-tolysulfonyl oxygen androstane-1,4-diene-3,17-diketone with distilled water wash, drying;
2) mixture of 45ml diacetyl oxide and 5g sodium acetate is heated to sodium acetate in 90 ℃ and dissolves fully, mixing solutions 1;
3) in mixing solutions 1, add the prepared 5g 11-α-tolysulfonyl oxygen androstane-1 of step 1), 4-diene-3,17-diketone; With the reaction mixture 2h that refluxes under argon shield, thin-layer chromatography shows whether reaction is finished; Reaction product is cooled to after the room temperature in the impouring 120ml frozen water, leaches the precipitation of generation; Precipitation is used ethyl alcohol recrystallization, obtains androstane-1,4,9 (11)-triolefins-3,17-diketone;
4) 1g androstane-1,4 that step 3) is prepared, 9 (11)-triolefins-3, the solution of the new distillatory Nitromethane 99Min. of 17-diketone and 50ml reflux under argon shield boils off the 5ml Nitromethane 99Min. after 20 minutes; Add the 0.05ml quadrol in the remaining reaction solution, the reaction mixture 1h that under argon shield, refluxes, thin-layer chromatography shows whether reaction is finished; Reaction product is evaporated to dried, and the residue purification by silica gel column chromatography obtains 1-methyl-3-hydroxy-estra-1,3, and 5 (10), 9 (11)-tetraenes-17-ketone; Or getting 1g step 3) prepared androstane-1,4,9 (11)-triolefins-3, the mixing solutions of 17-diketone and 0.05ml quadrol and the new distillatory Nitromethane 99Min. of the 50ml 4h that refluxes under argon shield, thin-layer chromatography show whether reaction is finished; Reaction product is evaporated to dried, the residue purification by silica gel column chromatography obtains 17-Nitromethylene androstane-1,4,11 (12)-triolefins-3-ketone.
Plant sterol microbiological deterioration product described in the present invention comprises: 11-Alpha-hydroxy-androstane-1,4-diene-3,17-diketone, androstane-1,4,9 (11)-triolefins-3,17-diketone etc.Described plant sterol microbiological deterioration product can be bought and obtain, and also can make as embodiment 2 described methods.
Embodiment
Specify the preparation method of steroid of the present invention by following examples, present embodiment is only in order to explanation the present invention, not in order to limit the scope of the invention.
General rule
All reagent is commercially available, and purity is analytical pure, and solvent is by standard operation purifying or drying in case of necessity.Reaction process, intermediate and degree of purity of production are confirmed with TLC or HPLC.Specific rotation uses the polarimeter polarimeter in 25 ℃ of mensuration.EI-MS measures with the Trace MS System mass spectrograph of U.S. Thermo Finnigan company.Infrared spectrum (IR) adopts Avatar 360 Fourier transformation infrared spectrometers of U.S. Nicolet company to measure.Nuclear-magnetism spectrum (NMR) adopts NEC AL-300FT NMR System to measure.The micro-fusing point instrument of the X75 that fusing point adopts Beijing instrument electric light instrument plant of section to produce is measured, and thermometer is not proofreaied and correct.Silica gel for chromatography is produced by Haiyang Chemical Plant, Qingdao.
Embodiment 1 11-Alpha-hydroxy-17-Nitromethylene androstane-1, the preparation of 4-diene-3-ketone (2)
Fig. 1 .11 Alpha-hydroxy-17-Nitromethylene androstane-1, the synthetic route .a of 4-diene-3-ketone (2)). Nitromethane 99Min., quadrol;
With 1g 11-Alpha-hydroxy-androstane-1,4-diene-3, the solution of the new distillatory Nitromethane 99Min. of 17-diketone and 50ml heat under argon shield and boil off about 5ml Nitromethane 99Min..In remaining reaction solution, add the 0.05ml quadrol.The reaction mixture 30h that refluxes under argon shield, TLC (ethyl acetate/petroleum ether, 2: 1) show whether reaction is finished.Reaction mixture is evaporated to dried, and residue obtains 560mg (49%) 11 Alpha-hydroxies-17-Nitromethylene androstane-1,4-diene-3-ketone (2) with silica gel column chromatography (ethyl acetate/petroleum ether, 1: 2) purifying.
Products therefrom is identified: colorless solid.MP：90-96℃.[α]＝70°(C＝1.2，CHCl
3)；FAB/MS(m/e)：344[M+H]
+；IR(KBr，cm
-1)：3394(OH)，1659(CO)，1511(NO
2)cm
-1；
1HNMR(CDCl
3)δ＝7.76(d，J＝10.2Hz，1H)，7.24(t，J＝2.4Hz，1H)，6.14(dd，J＝10.2Hz，J＝1.8Hz，1H)，6.06(s，1H)，1.31(s，3H)，0.98(s，3H)；
13C?NMR(CDCl3)δ＝186.9(C
3)，168.4(C
5)，167.5(C
20)，159.3(C
1)，131.5(C
17)，124.9(C
2)，124.4(C
4).Anal.calcd?for?C
20H
25O
4C，69.94；H，7.34；N，4.08；Found?C，69.79；H，7.56；N，3.94.
Embodiment 2 1-methyl-3-hydroxy-estra-1,3,5 (10), the preparation of 9 (11)-tetraenes-17-ketone (6)
Fig. 2 .1-methyl-3-hydroxy-estra-1,3,5 (10), the synthetic route .a of 9 (11)-tetraenes-17-ketone (6)). pyridine, Tosyl chloride; B) diacetyl oxide, sodium acetate; C). Nitromethane 99Min., quadrol, heating;
With 5g 11-Alpha-hydroxy-androstane-1,4-diene-3, the solution of 17-diketone and 40ml pyridine is cooled to 0-5 ℃, Dropwise 5 3mmol Tosyl chloride in this cold soln.Reaction mixture room temperature reaction 24h, TLC (ethyl acetate/petroleum ether, 1: 1) demonstration reaction is finished.In reaction mixture impouring 120ml frozen water, leach the precipitation of generation.Precipitation obtains 7.1g (94%) 11-α-tolysulfonyl oxygen androstane-1,4-diene-3,17-diketone with distillation washing, drying.11-α-tolysulfonyl oxygen androstane-1,4-diene-3,17-diketone (4) is not purified, is directly used in the next step.
The mixture of 45ml diacetyl oxide and 5g sodium acetate (60mmol) is heated to sodium acetate in 90 ℃ to be dissolved fully.In this hot solution, add 5g (11mmol) 11-α-tolysulfonyl oxygen androstane-1,4-diene-3,17-diketone.With the reaction mixture 2h that refluxes under argon shield, TLC (ethyl acetate/petroleum ether, 1: 1) shows that reaction finishes.Reaction mixture is cooled to after the room temperature in the impouring 120ml frozen water, leaches the precipitation of generation.Filter the solid ethyl alcohol recrystallization, obtain 2.5g (80%) androstane-1,4,9 (11)-triolefins-3,17-diketone (5), its physicochemical property are clear crystal.MP：161-164℃.ESI/MS(m/e)：283[M+H]
+.[α]＝118°(c＝2.3，CHCl
3).IR(KBr，cm
-1)：1737?and?1658(CO)
1H?NMR(CDCl
3)δ＝7.16(d，J＝10.2Hz，1H)，6.25(dd，J＝10.2Hz，J＝1.8Hz，1H)，6.05(s，1H)，5.55(m，1H)，1.40(s，3H)，0.88(s，3H)；
13C?NMR(CDCl
3)δ＝220.6(C
17)，186.2(C
3)，166.1(C
5)，154.2(C
1)，143.4(C
9)，127.4(C
11)，124.0(C
2)，119.9(C
4)，26.6(C
19)，13.8(C
18).Anal.calcd?for?C
19H
22O
2：C，80.81；H，7.85；Found?C，80.74；H，7.99.
With prepared 1g (3.5mmol) androstane-1,4,9 (11)-triolefins-3, the solution of the new distillatory Nitromethane 99Min. of 17-diketone and 50ml reflux under argon shield boils off about 5ml Nitromethane 99Min. after 20 minutes.Add the 0.05ml quadrol in remaining reaction solution, reaction mixture becomes yellow immediately.The reaction mixture 1h that refluxes under argon shield, TLC (ethyl acetate/petroleum ether, 1: 1) show that reaction finishes.Reaction mixture is evaporated to dried, and residue obtains 960mg (96%) 1-methyl-3-hydroxy-estra-1,3 with silica gel column chromatography (ethyl acetate/petroleum ether, 1: 2) purifying, and 5 (10), 9 (11)-tetraenes-17-ketone (6), it is colourless bubble gum sample thing.Physicochemical property is as follows: MP:168-170 ℃ of .MS:282[M]
+.[α]=276 ° of (C=1.4, CHCl
3) .IR (KBr, cm
-1): 3323 (OH), 3018,2959 and 2941 (aromatic H), 1716 (CO), 1609,1587,1463 (aromatic C=C), 1373 (CH
3).
1H NMR (CDCl
3) δ=6.56 (d, 1H, J=2.7Hz, 1H), 6.45 (d, J=2.7Hz, 1H), 5.62 (m, 1H), 2.34 (s, 3H), 0.99 (s, 3H).
13C NMR (CDCl
3) δ=222.09 (C
17), 153.54 (C) .Anal.calcd for C
19H
22O
2: C, 80.81; H, 7.85; Found:C, 80.23; H, 7.97.
Embodiment 3 17-Nitromethylene androstanes-1,4, the preparation of 11 (12)-triolefins-3-ketone
Fig. 3 .17-Nitromethylene androstane-1,4, the synthetic route .a of 11 (12)-triolefins-3-ketone (7)). pyridine, Tosyl chloride; B). diacetyl oxide, sodium acetate; C). Nitromethane 99Min., quadrol.
Get the androstane-1,4 of 1g embodiment 2 preparation, 9 (11)-triolefins-3, the mixing solutions of 17-diketone (5) and 0.05ml quadrol and the new distillatory Nitromethane 99Min. of the 50ml 4h that refluxes under argon shield, TLC (ethyl acetate/petroleum ether, 1: 1) show that reaction finishes.Reaction mixture is evaporated to dried, residue is with silica gel column chromatography (ethyl acetate/petroleum ether, 1: 2) purifying, obtain 520mg (45%) 17-Nitromethylene androstane-1,4,11 (12)-triolefins-3-ketone (7), it is a colourless syrup sample thing, a couple of days after fixing.Physicochemical property is as follows: MP:206-208 ℃ of .MS:325[M]
+.[α]=59 ° of (C=1.6, CHCl
3) IR (KBr, cm
-1):
1H NMR (CDCl
3) δ 7.06 (d, 1H), 6.93 (t, J=2.4Hz, 1H), 6.24 (dd, J=10.2Hz, J=1.8Hz, 1H), 6.08 (s, 1H), 6.02 (dd, J=9.9Hz, J=2.7Hz, 1H), 5.69 (dd, J=9.9Hz, J=1.8Hz, 1H), 1.17 (s, 3H), 1.01 (s, 3H);
13C NMR (CDCl
3): δ 186.03 (C
3), 166.64 (C
20), 164.72 (C
5), 153.86 (C
1), 134.04 (C
12), 131.22 (C
17), 128.11 (C
11), 125.81 (C
2), 125.44 (C
4) .Anal.calcd for C
20H
23NO
3: C, 73.82; H, 7.12; N, 4.30.Found:C, 73.50; H, 6.28; N, 4.18.
Claims (6)
1, a kind of method for preparing following 3 kinds of steroids by plant sterol microbiological deterioration product:
(1) 11-Alpha-hydroxy-17-Nitromethylene androstane-1,4-diene-3-ketone, (2) 1-methyl-3-hydroxy-estra-1,3,5 (10), 9 (11)-tetraenes-17-ketone, (3) 17-Nitromethylene androstane-1,4,11 (12)-triolefins-3-ketone;
May further comprise the steps:
1) plant sterol microbiological deterioration product is mixed with the feed ratio of new distillatory Nitromethane 99Min. according to 1g: 30～70ml, under protection of inert gas heating and boiling off account for add the Nitromethane 99Min. of Nitromethane 99Min. volume total amount 0%～15%, then in mixture, add quadrol, the add-on of quadrol account for add 0.05%～1% of Nitromethane 99Min. volume total amount; The gained mixing liquid was refluxed under protection of inert gas 0.5～40 hour; Wherein, described plant sterol degraded product is selected from 11-Alpha-hydroxy-androstane-1,4-diene-3,17-diketone or androstane-1,4,9 (11)-triolefins-3,17-diketone;
2) finish with thin-layer chromatography demonstration reaction, wherein, the condition of thin-layer chromatography is: ethyl acetate/petroleum ether=2: 1;
3) reaction product is evaporated to dried, is purified promptly.
2, preparation steroid method according to claim 1, wherein the feed ratio of plant sterol degraded product and new distillatory Nitromethane 99Min. is 1g: 50ml in the step 1).
3, preparation steroid method according to claim 1, wherein said rare gas element is nitrogen or argon gas.
4, the method for preparing steroid according to claim 1, wherein the add-on of quadrol account for add 0.1% of Nitromethane 99Min. volume total amount.
5, preparation steroid method according to claim 1, wherein the purifying mode described in the step 3) is recrystallization purifying or purification by silica gel column chromatography.
6, preparation steroid method according to claim 1, the plant sterol degraded product androstane-1 described in the step 1) wherein, 4,9 (11)-triolefins-3, the 17-diketone prepares in accordance with the following methods: with 5g11-Alpha-hydroxy-androstane-1,4-diene-3, the solution of 17-diketone and 40ml pyridine is cooled to 0-5 ℃, Dropwise 5 3mmol Tosyl chloride in this cold soln; Reaction mixture room temperature reaction 24h, thin-layer chromatography demonstration reaction is finished, and wherein, the condition of thin-layer chromatography is: ethyl acetate/petroleum ether=1: 1; In reaction mixture impouring 120ml frozen water, leach the precipitation of generation; Precipitation obtains 7.1g 11-α-tolysulfonyl oxygen androstane-1,4-diene-3,17-diketone with distillation washing, drying; 11-α-tolysulfonyl oxygen androstane-1,4-diene-3, the 17-diketone is not purified, be directly used in the next step: the mixture of 45ml diacetyl oxide and 5g 60mmol sodium acetate is heated to sodium acetate in 90 ℃ dissolves fully, in this hot solution, add 5g 11mmol 11-α-tolysulfonyl oxygen androstane-1,4-diene-3, the 17-diketone; With the reaction mixture 2h that refluxes under argon shield, thin-layer chromatography shows that reaction finishes, and wherein, the condition of thin-layer chromatography is: ethyl acetate/petroleum ether=1: 1; Reaction mixture is cooled to after the room temperature in the impouring 120ml frozen water, leaches the precipitation of generation, filter the solid ethyl alcohol recrystallization, obtain 2.5g androstane-1,4,9 (11)-triolefins-3,17-diketone.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4490296A (en) * | 1982-02-18 | 1984-12-25 | Roussel Uclaf | Compositions and method |
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|---|---|---|---|---|
| US4490296A (en) * | 1982-02-18 | 1984-12-25 | Roussel Uclaf | Compositions and method |
Non-Patent Citations (1)
| Title |
|---|
| "A Simple Construction of the Hydroxy-ketone Side ChainofCorticosteroids from 17-Oxo-steroids via Nitro-olefins" Derek H.R.Barton,et al,J.Chem.Soc.,Chem.Commun.,No.10 1982 * |
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