CN101759742A - Preparation method of 16 Alpha-methyl steroidal compound - Google Patents
Preparation method of 16 Alpha-methyl steroidal compound Download PDFInfo
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- CN101759742A CN101759742A CN200810152875A CN200810152875A CN101759742A CN 101759742 A CN101759742 A CN 101759742A CN 200810152875 A CN200810152875 A CN 200810152875A CN 200810152875 A CN200810152875 A CN 200810152875A CN 101759742 A CN101759742 A CN 101759742A
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Abstract
A preparation method of a 16 Alpha-methyl steroidal compound comprises: taking a formula (I) compound as a substrate, reacting with 0.2 to 0.1 time catalyst, 1 to 1.5 times trimethyl chlorosilane, 1 to 1.5 times Grignard reagent and 2 to 4 times triamine phosphate in organic solvent to obtain a formula (I) compound, and taking the formula (I) compound to react with 1 to 5 times alkali and 1 to 3 times meta-chloroperoxybenzoic acid in organic solvent to obtain a formula (III) compound.
Description
Technical field:
The present invention relates to the preparation method of steroidal compounds, particularly a kind of preparation method of 16 Alpha-methyl steroidal compounds.
Background technology:
The steroid drugs molecule is introduced effect and the raising anti-inflammatory activity that 16 Alpha-Methyls can reduce the retention of sodium ion greatly, the common adrenocortical hormone with 16-α methyl has dexamethasone, diflucortolone etc. at present, be crucial potent adrenocortical hormone, the patent application WO8707612 of World Intellectual Property Organization discloses a kind of synthesis technique of 16 Alpha-methyl steroidal compounds, employing formula (1) compound is under the catalysis of copper (II) salt, carry out grignard reaction with trimethylchloro-silicane ether, Grignard reagent, obtain formula (2).Yet said synthesis route is only disclosed in this application, through our experiment, discovery is in carrying out the grignard reaction process, because the strong basicity of Grignard reagent, make 21 ester bond dissociate easily, thereby make according to the method described above the 16 Alpha-methyl steroidal compound yields that obtain with technology lower, and impurity is difficult to make with extra care.
Summary of the invention:
By research to the synthetic preparation of formula (I) compound 16 Alpha-methyl steroidal compounds, the discovery that we are surprised, by, adopting 21 is the reaction substrate of methyl.Copper (II) salt catalyst is changed into copper (I) salt catalyst and add HMPA in reaction solvent, can in suc as formula the steroidal compounds structure of (1), introduce 16 Alpha-Methyls, 17 Alpha-hydroxies and 21-hydroxyl continuously by highly selective.
The invention provides a kind of new 16 Alpha-methyl steroidal compounds (III) preparation method, react as follows:
R
1Be selected from H, a kind of in the ketone group, R
2Be selected from H, perhaps preferred R
1, R
2Link to each other with two keys or oxo bridge key, most preferably R
1, R
2Link to each other with two keys.
(1) with the catalyzer of formula (I) compound and 0.02～0.1 times, 1～1.5 times of trimethylchlorosilane, 1～1.5 times Grignard reagent and 2～4 times HMPA are reacted in organic solvent, described multiple is a mol ratio, temperature of reaction is-50 ℃～-10 ℃,, obtain compound (II).Described organic solvent is an ether solvent, one or more in preferred ether, tetrahydrofuran (THF), the dioxane, and the reaction times is 3～15 hours, and reaction is preferably carried out under the condition of anhydrous, logical rare gas element, and described rare gas element is preferably N
2Described catalyzer is selected from one or more in cuprous bromide dimethyl sulphide (CAS:54678-23-8), cuprous acetate, cuprous bromide, cuprous chloride, cuprous iodide, the lithiumbromide, described Grignard reagent is a methylmagnesiumhalide, be selected from methylmagnesium-chloride, methylmagnesium-bromide, the iodate methyl magnesium one or more, preferable methyl magnesium bromide.Described multiple is the amount of substance multiple.
(2) formula (II) compound and 1～5 times alkali, 1～3 times metachloroperbenzoic acid are reacted in organic solvent, temperature of reaction is-30～-5 ℃, and reaction is finished, and with acid for adjusting pH value to 1～4, obtains compound (III).Described multiple is a mol ratio.Described organic solvent is one or more in methylene dichloride, chloroform, ethylene dichloride, tetracol phenixin, benzene, the toluene, described alkali is one or more in sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate, the saleratus, acid is one or more in hydrochloric acid, sulfuric acid, the phosphoric acid, preferred hydrochloric acid.
Described ratio is mol ratio.
As everyone knows, ketone group, two key and oxo bridge key all can react with Grignard reagent, compared with prior art, we are surprised to find, under technical scheme condition provided by the invention, above-mentioned group and Grignard reagent do not react substantially, simultaneously compared with prior art, be the raw material of methyl by selecting 21, avoid the destruction of 21 ester bonds of reaction process neutral and alkali Grignard reagent, reduced the generation of impurity, therefore at compound of the present invention (I) preferably from R
1Be H or ketone group, R
2Be H; And R
1, R
2During several compound of linking to each other with two keys or oxo bridge key, resultant compound can press above-mentioned steps (1), (2) reaction, simultaneously owing to added HMPA in solvent, makes the reaction yield raising.Thereby realized can be in suc as formula the steroidal compounds structure of (1) highly selective introduce the purpose of 16 Alpha-Methyls, 17 Alpha-hydroxies and 21-hydroxyl continuously
Embodiment:
Ratio described in the present embodiment is mol ratio, and described reacting completely is to disappear to raw material point to usefulness TLC detection reaction process, and the used various raw materials of described grignard reaction, reaction vessel, solvent all should keep anhydrous
The reaction of comparative example 2 when R1 is hydroxyl
(1) with 11-hydroxyl-pregnant steroid-1,4,16-triolefin-3,20-diketone 5.0g (compound (I-0), content 95.1%) with 0.02 times of cuprous bromide dimethyl sulphide, 1.1 times trimethylchlorosilane, 2 times HMPA are dissolved in the 50ml tetrahydrofuran (THF), slowly add 1.2 times the methylmagnesium-bromide that is dissolved in tetrahydrofuran (THF) and carry out grignard reaction, temperature of reaction is-30～-20 ℃, logical N during reaction
2Protection is monitored reaction process with TLC, and to reacting completely, dilute with water filters, drying, obtains product 4.5g, detects through HPLC, and compound (II-0) content is 35.2%, and amounting to yield is 30.1%
Embodiment 1
1) with pregnant steroid-1,4,16-triolefin-3,11,20-triketone (compound (I-1)) 5.0g and 0.02 times of cuprous bromide dimethyl sulphide, 1.2 times trimethylchlorosilane, 2 times of HMPA join in the 60ml tetrahydrofuran (THF), slowly add 1.2 times of methylmagnesium-bromides that are dissolved in tetrahydrofuran (THF) and carry out grignard reaction, temperature of reaction is-30～-20 ℃, logical N during reaction
2Protection, reaction finish back dilute with water, separation, drying, obtain Ge Shi thing (compound (II-1));
2) above-mentioned Ge Shi thing and 3 times of saleratus, 1.5 times of metachloroperbenzoic acids are reacted in methylene dichloride, temperature of reaction is-30～-25 ℃, and reaction is to complete.With hydrochloric acid conditioning solution pH value to 1, concentrating under reduced pressure, refrigerated separation, drying obtain compound (III-1), total recovery 78.2%
Embodiment 2
1) with pregnant steroid-1,4,16-triolefin-3,20-diketone (compound (I-2)) is dissolved in the 40ml tetrahydrofuran (THF) with 0.05 times of cuprous bromide, 1.5 times trimethylchlorosilane, 3 times of HMPA, slowly add 1.4 times of methylmagnesium-bromides that are dissolved in tetrahydrofuran (THF) and carry out grignard reaction, temperature of reaction is-15～-10 ℃, logical N during reaction
2Protection, reaction finish back dilute with water, separation, drying, obtain Ge Shi thing (compound (II-2));
2) above-mentioned Ge Shi thing and 1.1 times of sodium hydroxide, 2.5 times of metachloroperbenzoic acids are reacted in chloroform, temperature of reaction is-25～-20 ℃, and reaction is to complete.With hydrochloric acid conditioning solution pH value to 2, concentrating under reduced pressure separation, refrigerated separation, drying obtain compound (III-3), total recovery 80.5%
Embodiment 3
1) pregnant steroid-1,4,9 (11), 16-tetraene-3,20-diketone (compound (I-3)) 5.0g and 0.08 times of cuprous chloride, 1.5 times trimethylchlorosilane, 4 times of HMPA are dissolved in the 30ml tetrahydrofuran (THF), slowly add 1.4 times of methylmagnesium-chlorides that are dissolved in tetrahydrofuran (THF) and carry out grignard reaction, temperature of reaction is-25～-15 ℃, logical N during reaction
2Protection, reaction finish back dilute with water, separation, drying, obtain Ge Shi thing (compound (II-3));
2) above-mentioned Ge Shi thing and 1.5 times of yellow soda ash, 3 times of metachloroperbenzoic acids are reacted in chloroform, temperature of reaction is-20～-15 ℃, and reaction is to complete.With sulfuric acid regulation solution pH value to 3, separation, drying obtain compound (III-3), total recovery 77.9%.
Embodiment 4
1) 9,11-epoxy-pregnant steroid-1,4,16-triolefin-3,20-diketone (compound (I-4)) 5.0g and 0.03 times of cuprous acetate, 1.2 times trimethylchlorosilane, 3 times of HMPA are dissolved in the 20ml tetrahydrofuran (THF), slowly add 1.2 times of methylmagnesium-bromides that are dissolved in tetrahydrofuran (THF) and carry out grignard reaction, temperature of reaction is-25～-15 ℃, logical N during reaction
2Protection, reaction finish back dilute with water, separation, drying, obtain Ge Shi thing (compound (II-4));
2) above-mentioned Ge Shi thing and 2 times of yellow soda ash, 3 times of metachloroperbenzoic acids are reacted in benzene, temperature of reaction is-30～-25 ℃, and reaction is to complete.With hydrochloric acid conditioning solution pH value to 3, separation, drying obtain compound (III-4), total recovery 80.1%.
Claims (10)
1. the preparation method of a formula (III) compound is shown below:
R
1Be selected from H, a kind of in the ketone group, R
2Be selected from H, perhaps preferred R
1, R
2Link to each other with two keys or oxo bridge key.
2. preparation method as claimed in claim 1 is characterized in that:
(1) with the catalyzer of formula (I) compound and 0.02～0.1 times of mole multiple, 1～1.5 times of mole multiple trimethylchlorosilane, 1～1.5 mole of multiple doubly Grignard reagent and the HMPA of 2～4 times of mole multiples in ether solvent, react, temperature of reaction is-50 ℃～-10 ℃,, obtain compound (II).
(2) alkali of formula (II) compound and 1～5 times of mole multiple, the metachloroperbenzoic acid of 1～3 times of mole multiple are reacted in organic solvent, temperature of reaction is-30～-5 ℃, and reaction is finished, and with acid for adjusting pH value to 1～4, obtains compound (III).
3. preparation method as claimed in claim 2 is characterized in that the used catalyzer of described step (1) is selected from one or more in cuprous bromide dimethyl sulphide, cuprous bromide, cuprous acetate, cuprous chloride, cuprous iodide, the lithiumbromide.
4. as claim 2 or 3 described preparation methods, it is characterized in that the used Grignard reagent of described step (1) is selected from one or more in methylmagnesium-chloride, methylmagnesium-bromide, the iodate methyl magnesium.
5. preparation method as claimed in claim 4 is characterized in that the preferred methylmagnesium-bromide of described Grignard reagent.
6. as the arbitrary described preparation method of claim 2 to 5, it is characterized in that in the preferred ether of described ethers reagent, tetrahydrofuran (THF), the dioxane one or more.
7. as arbitrary described preparation method in the claim 2 to 6, it is characterized in that the used organic solvent of described step (2) is one or more in methylene dichloride, chloroform, ethylene dichloride, tetracol phenixin, benzene, the toluene.
8. as arbitrary described preparation method in the claim 2 to 7, it is characterized in that the used alkali of described step (2) is selected from one or more in sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate, the saleratus.
9. as arbitrary described preparation method in the claim 2 to 8, it is characterized in that the used acid of described step (2) is selected from one or more in hydrochloric acid, sulfuric acid, the phosphoric acid.
10. as arbitrary described preparation method in the claim 2 to 9, it is characterized in that the preferred hydrochloric acid of the used acid of described step (2).
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| US20150011519A1 (en) * | 2011-11-29 | 2015-01-08 | Reveragen Biopharma, Inc. | Non-hormonal steroid modulators of nf-kappa beta for treatment of disease |
| CN104974210A (en) * | 2014-04-08 | 2015-10-14 | 天津金耀集团有限公司 | Preparation method of 17,21-dihydroxy steroid derivative |
| CN104974209A (en) * | 2014-04-08 | 2015-10-14 | 天津金耀集团有限公司 | Synthetic method of 17, 21-double-hydroxyl steroid derivatives |
| US9198921B2 (en) | 2010-04-05 | 2015-12-01 | Reveragen Biopharma, Inc. | Non-hormonal steroid modulators of NF-κB for treatment of disease |
| US9649320B2 (en) | 2008-05-28 | 2017-05-16 | Reveragen Biopharma, Inc. | Non-hormonal steroid modulators of NF-κB for treatment of disease |
| US10799514B2 (en) | 2015-06-29 | 2020-10-13 | Reveragen Biopharma, Inc. | Non-hormonal steroid modulators of NF-kappa beta for treatment of disease |
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Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU7480187A (en) * | 1986-06-04 | 1988-01-11 | Upjohn Company, The | 16alpha-methylation process |
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2008
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| US20150011519A1 (en) * | 2011-11-29 | 2015-01-08 | Reveragen Biopharma, Inc. | Non-hormonal steroid modulators of nf-kappa beta for treatment of disease |
| US10464967B2 (en) * | 2011-11-29 | 2019-11-05 | Reveragen Biopharma, Inc. | Non-hormonal steroid modulators of NF-κβ for treatment of disease |
| CN103772210B (en) * | 2012-10-22 | 2015-03-25 | 沈阳药科大学 | Method for catalysis synthesis of 1,3-diaminobenzene derivative by using cuprous dimethyl sulfide coordination compound |
| CN103772210A (en) * | 2012-10-22 | 2014-05-07 | 沈阳药科大学 | Method for catalysis synthesis of 1,3-diaminobenzene derivative by using cuprous dimethyl sulfide coordination compound |
| CN104974210B (en) * | 2014-04-08 | 2018-01-23 | 天津金耀集团有限公司 | A kind of preparation method of 17,21 pairs of hydroxy steroid derivatives |
| CN104974209B (en) * | 2014-04-08 | 2018-01-19 | 天津金耀集团有限公司 | A kind of synthetic method of 17,21 pairs of hydroxy steroid derivatives |
| CN104974209A (en) * | 2014-04-08 | 2015-10-14 | 天津金耀集团有限公司 | Synthetic method of 17, 21-double-hydroxyl steroid derivatives |
| CN104974210A (en) * | 2014-04-08 | 2015-10-14 | 天津金耀集团有限公司 | Preparation method of 17,21-dihydroxy steroid derivative |
| US10799514B2 (en) | 2015-06-29 | 2020-10-13 | Reveragen Biopharma, Inc. | Non-hormonal steroid modulators of NF-kappa beta for treatment of disease |
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| CN101759742B (en) | 2012-07-04 |
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