CN101759742B - Preparation method of 16 Alpha-methyl steroidal compound - Google Patents
Preparation method of 16 Alpha-methyl steroidal compound Download PDFInfo
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- CN101759742B CN101759742B CN2008101528758A CN200810152875A CN101759742B CN 101759742 B CN101759742 B CN 101759742B CN 2008101528758 A CN2008101528758 A CN 2008101528758A CN 200810152875 A CN200810152875 A CN 200810152875A CN 101759742 B CN101759742 B CN 101759742B
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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 BP98, diflucortolone etc. at present; Be crucial strong effect adrenocortical hormone; The patented claim WO8707612 of World Intellectual Property Organization discloses a kind of synthesis technique of 16 Alpha-methyl steroidal compounds; Employing formula (1) compound carries out grignard reaction with trimethylchloro-silicane ether, Grignard reagent under the catalysis of copper (II) salt, 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 makes 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:
Through research to the synthetic preparation of formula (I) compound 16 Alpha-methyl steroidal compounds, the discovery that we are surprised, through, adopting 21 is the reaction substrate of methyl.Copper (II) salt catalyst is changed into copper (I) salt catalyst and in reaction solvent, adds HMPA, 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 present invention provides a kind of new 16 Alpha-methyl steroidal compounds (III) preparation method, reacts 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 react 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, 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 said 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; Said Grignard reagent is a methylmagnesiumhalide; Be selected from methylmagnesium-chloride, methylmagnesium-bromide, the iodate methyl magnesium one or more, preferable methyl magnesium bromide.Said 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, Pottasium Hydroxide, yellow soda ash, salt of wormwood, sodium hydrogencarbonate, the saleratus; Acid is one or more in hydrochloric acid, sulfuric acid, the phosphoric acid, preferred hydrochloric acid.
Said 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, and under technical scheme condition provided by the invention, above-mentioned group and Grignard reagent do not react basically; Simultaneously compared with prior art, be the raw material of methyl through 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 according to the invention (I) preferably from R
1Be H or ketone group, R
2Be H; And R
1, R
2During several kinds of compounds linking to each other with two keys or oxo bridge key, resultant compound can press above-mentioned steps (1), (2) reaction, simultaneously owing in solvent, having added HMPA, 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 said reacting completely is to disappearing with TLC detection reaction process to raw material point, and the used various raw materials of said 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 THF, slowly add 1.2 times the methylmagnesium-bromide that is dissolved in 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 HMPAs join in the 60ml THF; Slowly add 1.2 times of methylmagnesium-bromides that are dissolved in 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 THF with 0.05 times of cuprous bromide, 1.5 times trimethylchlorosilane, 3 times of HMPAs, slowly adds 1.4 times of methylmagnesium-bromides that are dissolved in THF and carries 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 HMPAs are dissolved in the 30ml THF; Slowly add 1.4 times of methylmagnesium-chlorides that are dissolved in 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 HMPAs are dissolved in the 20ml THF; Slowly add 1.2 times of methylmagnesium-bromides that are dissolved in 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 (11)
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 R
1, R
2Link to each other with two keys or oxo bridge key.
2. preparation method according to claim 1 is characterized in that R
1, R
2Link to each other with two keys or oxo bridge key.
3. according to claim 1 or claim 2 preparation method 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 Grignard reagent and the HMPA of 2～4 times of mole multiples doubly reacts in ether solvent; 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).
4. preparation method as claimed in claim 3 is characterized in that the used catalyzer of said step (1) is selected from one or more in cuprous bromide dimethyl sulphide, cuprous bromide, cuprous acetate, cuprous chloride, cuprous iodide, the lithiumbromide.
5. preparation method as claimed in claim 3 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.
6. preparation method as claimed in claim 4 is characterized in that described Grignard reagent is selected from methylmagnesium-bromide.
7. preparation method as claimed in claim 3 is characterized in that described ethers reagent is selected from one or more in ether, THF, the dioxane.
8. preparation method as claimed in claim 3 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.
9. preparation method as claimed in claim 3 is characterized in that the used alkali of described step (2) is selected from one or more in sodium hydroxide, Pottasium Hydroxide, yellow soda ash, salt of wormwood, sodium hydrogencarbonate, the saleratus.
10. preparation method as claimed in claim 3 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.
11. preparation method as claimed in claim 3 is characterized in that the used acid of described step (2) is selected from hydrochloric acid.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11690853B2 (en) | 2015-06-29 | 2023-07-04 | Reveragen Biopharma, Inc. | Non-hormonal steroid modulators of NF-κβ for treatment of disease |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX2010012976A (en) | 2008-05-28 | 2011-05-31 | Validus Genetics | Non-hormonal steroid modulators of nf-kb for treatment of disease. |
| US9198921B2 (en) | 2010-04-05 | 2015-12-01 | Reveragen Biopharma, Inc. | Non-hormonal steroid modulators of NF-κB 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 |
| 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 |
| US11382922B2 (en) | 2019-03-07 | 2022-07-12 | Reveragen Biopharma, Inc. | Aqueous oral pharmaceutical suspension compositions |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1987007612A1 (en) * | 1986-06-04 | 1987-12-17 | The Upjohn Company | 16alpha-METHYLATION PROCESS |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1987007612A1 (en) * | 1986-06-04 | 1987-12-17 | The Upjohn Company | 16alpha-METHYLATION PROCESS |
Non-Patent Citations (1)
| Title |
|---|
| 赵贞贞.2008101528758.《STN检索记录》.2011, * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11690853B2 (en) | 2015-06-29 | 2023-07-04 | Reveragen Biopharma, Inc. | Non-hormonal steroid modulators of NF-κβ for treatment of disease |
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