CN101085803A - Androstane compound and its preparation method and application - Google Patents
Androstane compound and its preparation method and application Download PDFInfo
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- CN101085803A CN101085803A CN 200610027375 CN200610027375A CN101085803A CN 101085803 A CN101085803 A CN 101085803A CN 200610027375 CN200610027375 CN 200610027375 CN 200610027375 A CN200610027375 A CN 200610027375A CN 101085803 A CN101085803 A CN 101085803A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 37
- -1 Androstane compound Chemical class 0.000 title claims description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 36
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims description 36
- 230000006103 sulfonylation Effects 0.000 claims description 13
- 238000005694 sulfonylation reaction Methods 0.000 claims description 13
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical group CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 5
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 6
- QGXBDMJGAMFCBF-UHFFFAOYSA-N Etiocholanolone Natural products C1C(O)CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CCC21 QGXBDMJGAMFCBF-UHFFFAOYSA-N 0.000 abstract 3
- 229940061641 androsterone Drugs 0.000 abstract 3
- 125000004391 aryl sulfonyl group Chemical group 0.000 abstract 1
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 11
- 238000001035 drying Methods 0.000 description 11
- 229910052760 oxygen Inorganic materials 0.000 description 11
- 239000001301 oxygen Substances 0.000 description 11
- 238000010792 warming Methods 0.000 description 7
- QZLYKIGBANMMBK-UGCZWRCOSA-N 5α-Androstane Chemical compound C([C@@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CCC[C@@]2(C)CC1 QZLYKIGBANMMBK-UGCZWRCOSA-N 0.000 description 6
- 229960001208 eplerenone Drugs 0.000 description 6
- JUKPWJGBANNWMW-VWBFHTRKSA-N eplerenone Chemical compound C([C@@H]1[C@]2(C)C[C@H]3O[C@]33[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)C(=O)OC)C[C@@]21CCC(=O)O1 JUKPWJGBANNWMW-VWBFHTRKSA-N 0.000 description 6
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 6
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 5
- 229940083712 aldosterone antagonist Drugs 0.000 description 5
- 239000002170 aldosterone antagonist Substances 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000001632 sodium acetate Substances 0.000 description 5
- 235000017281 sodium acetate Nutrition 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 229960000890 hydrocortisone Drugs 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- WFIZEGIEIOHZCP-UHFFFAOYSA-M potassium formate Chemical compound [K+].[O-]C=O WFIZEGIEIOHZCP-UHFFFAOYSA-M 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 241000872931 Myoporum sandwicense Species 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
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- Steroid Compounds (AREA)
Abstract
The invention provides a compound that is demonstrated in general formula I. The R in formula I can be low- grade alkyl sulfonyl, aryl sulfonyl chloride or relevant halosulfonyl. Said compound is prepared by taking 11 alpha- hydroxy- 4- ene- 3, 17- androsterone and through sulfoacylation process. The invention aslo discloses the application of said compound in preparation of medical intermediate 4, 9(11) - diene- 3, 17- androsterone. The productivity for 4, 9(11) - diene- 3, 17- androsterone is above 92%, and the cost is low. The invention is suitable for large- scale production.
Description
Technical field
The present invention relates to the preparation method and the purposes of this compounds in the preparation medicine of a compounds and this compounds thereof, the preparation method of androstane compound and this class androstane and this class androstane are at the medicine intermediate 4 of preparation selectivity aldosterone antagonists eplerenone specifically, 9 (11)-diene-3, the application in the 17-androstanedione.
Background technology
Androstane is a steroid-like, its steroide comprises and contains the also luxuriant and rich with fragrance skeleton of [a] hydrogenation of pentamethylene, or by its deutero-ring structure: androstane belongs to the ormal steroids that contains carbon, hydrogen, halogen or oxygen, and 17 β are not replaced by carbon atom in the position.
4,9 (11)-diene-3 in the androstane, 17-androstanedione (III) are a kind of important medicine intermediates of selectivity aldosterone antagonists eplerenone for preparing, and eplerenone has been used for the treatment of the medicine of hypertension and heart failure by drugs approved by FDA.
Described 4,9 (11)-diene-3, the structural formula of 17-androstanedione is as follows:
Bibliographical information (Tetrahedron Letters, 1996,37 (34): 6141 and Steriods, 2003,68:139) preparation 4,9 (11)-diene-3, the method for 17-androstanedione is: with hydrocortisone (IV) is raw material, with NaBH
4And NaIO
4Reaction obtains 11 beta-hydroxies-4-alkene-3, the 17-diketone, and the latter and tosic acid reflux in benzole soln makes 4,9 (11)-diene-3, the 17-androstanedione.Hydrocortisone in this method (IV) market cost is higher, and has used a large amount of benzene in the reaction.
Summary of the invention
Purpose of the present invention provides a kind of formula (I) compound, this formula (I) compound is that androstane compound can be used to prepare a kind of important medicine intermediate 4 of selectivity aldosterone antagonists eplerenone for preparing, 9 (11)-diene-3,17-androstanedione (III) has the high and low characteristics of cost of yield.
Another object of the present invention provides the preparation method of a kind of formula (I) compound.
Also purpose of the present invention provides a kind of purposes of a kind of formula (I) compound.
Purpose of the present invention can be achieved through the following technical solutions.
Provided by the invention a kind of with following general formula (I)
R can be low alkyl group alkylsulfonyl, fragrant alkylsulfonyl or corresponding halogen alkylsulfonyl in the compound of expression, its Chinese style (I).Formula (I) compound is an androstane compound, has another name called 11 alpha-hydroxy sulfonates.
The preparation method of above-mentioned formula (I) compound is that the 17-androstanedione is prepared from through sulfonylation with formula (II) compound 11 alpha-hydroxy-4-enes-3; Its reaction formula is as follows.
Formula provided by the invention (I) compound can be applied in the 17-androstanedione (III) at important medicine intermediate 4,9 (11)-diene-3 of a kind of selectivity aldosterone antagonists eplerenone of preparation.Be that its formula (I) compound is obtained 4,9 (11)-diene-3 through eliminating reaction during concrete the application, 17-androstanedione (III), its reaction formula is as follows:
(I) of the present invention compound is at preparation 4,9 (11)-diene-3, and during 17-androstanedione (III), yield is more than 92%, and has the low advantage of cost.Owing to need not to use a large amount of benzene in the reaction process, protected environment, so the present invention is fit to scale operation.
Embodiment
For technique means, creation characteristic that the present invention is realized, reach purpose and effect is easy to understand, below in conjunction with embodiment, further set forth the present invention.
Following general formula (I)
The compound of expression is an androstane compound, has another name called 11 alpha-hydroxy sulfonates, and R can be low alkyl group alkylsulfonyl, fragrant alkylsulfonyl or corresponding halogen alkylsulfonyl among its Chinese style I.Wherein the low alkyl group alkylsulfonyl is that carbonatoms is a 1-4 low alkyl group alkylsulfonyl, as methylsulfonyl, and ethylsulfonyl, third alkylsulfonyl etc.The fragrance alkylsulfonyl is p-toluenesulfonyl, benzenesulfonyl, is preferably tosyl group.Corresponding halogen alkylsulfonyl is preferably the halogeno-benzene alkylsulfonyl.
The preparation method of above-mentioned formula (I) compound is that the 17-androstanedione is prepared from through sulfonylation with formula (II) compound 11 alpha-hydroxy-4-enes-3; Its reaction formula is as follows.
Above-mentioned preparation method is with 11 alpha-hydroxy-4-enes-3,17-androstanedione (II) is dissolved in the exsiccant organic solvent, add de-acidying agent, add sulfonylation agent at low temperatures, reacted 5～40 hours, and separated out solid in subsequently that the reaction solution impouring is a large amount of water, be formula (I) compound, be androstane, have another name called 11 alpha-hydroxy sulfonates; Wherein temperature of reaction is-20～50 ℃, the pH=8.0-11.0 of reaction solution; 11 alpha-hydroxy-4-enes-3,17-androstanedione (II): the mol ratio of sulfonylation agent is 1: 1.0～1: 4.0.
In above-mentioned preparation method, selected sulfonylation agent is low alkyl group SULPHURYL CHLORIDE, aromatic sulfonyl chloride or corresponding halogen sulphonyl thing, is preferably Tosyl chloride.Selected organic solvent is toluene, methylene dichloride, ethyl acetate, pyridine or its their mixed solvent.Be preferably the exsiccant pyridine.
Selected de-acidying agent is triethylamine, yellow soda ash, sodium bicarbonate, sodium hydroxide and potassium hydroxide etc.
Its temperature of reaction is preferably-10～30 ℃.Adding the concrete reaction process of sulfonylation agent is: under-10～30 ℃ of conditions, stirring reaction 1-5 hour, reacted 10-24 hour after being warming up to room temperature then again.Its stirring velocity also is to select easily to those skilled in the art.What adopt when separating out solid is frozen water, with separating out of accelerating solid.
11 alpha-hydroxy-4-enes-3,17-androstanedione (II): the mol ratio of SULPHURYL CHLORIDE is preferably 1: 1.5.
Above-mentioned formula (I) compound can be used for preparing important medicine intermediate 4,9 (11)-diene-3 of a kind of selectivity aldosterone antagonists eplerenone, 17-androstanedione (III).
Be that its formula (I) compound is obtained 4,9 (11)-diene-3 through eliminating reaction during concrete the application, 17-androstanedione (III), its reaction formula is as follows:
Its concrete reaction process is as follows;
Formula (I) compound dissolution in lower fatty acid, is added the organic salt of alkalescence then, and reflux is after 0.5～20 hour, remove 11 α-leavings group and form two keys at 9-and 11-carbon atom effectively, obtain 4,9 (11)-diene-3,17-androstanedione (III); Wherein temperature of reaction is 40～180 ℃, formula (I) compound: the mol ratio of the organic salt of alkalescence is 1: 1.0～1: 10.0.
In above-mentioned concrete application process, the lower fatty acid that is adopted is generally the alkyl carboxylic acid of carbonatoms 1～5.The organic salt of the alkalescence that is adopted is the univalent metal salt of low alkyl fatty acid, as sodium formiate, and sodium acetate, potassium formiate, potassium acetate etc.
In above-mentioned concrete application process, after back flow reaction is complete, be cooled to room temperature, in reaction solution impouring frozen water, separate out solid, filter the dry product that gets.
Further specify the present invention by the following examples, but should be understood that these embodiment are exemplary, the present invention does not limit to this.
Embodiment 1
11 α-tolysulfonyl oxygen base-4-alkene-3, the preparation of 17-androstanedione (Ia)
With 11 alpha-hydroxy-4-enes-3,17-androstanedione (II) 435.0g (1.44mol) is dissolved among the exsiccant pyridine 3L, adds Tosyl chloride 420.0g (2.20mol) down at-20 ℃, stirs 3 hours, be warming up to the room temperature afterreaction 12 hours, with among the reaction solution impouring frozen water 10L, separate out solid subsequently, filter, obtain 622.0g off-white color solid after the drying, this compound is 11 α-tolysulfonyl oxygen base-4-alkene-3,17-androstanedione (Ia), yield 94.7%.138～140 ℃ of fusing points.
Embodiment 2
11 α-tolysulfonyl oxygen base-4-alkene-3, the preparation of 17-androstanedione (Ia)
With 11 alpha-hydroxy-4-enes-3,17-androstanedione (II) 43.5g (0.15mol) is dissolved among the exsiccant triethylamine 300ml, adds Tosyl chloride 42.0g (0.22mol) down at-10 ℃, stirs 5 hours, be warming up to the room temperature afterreaction 24 hours, with among the reaction solution impouring frozen water 1L, separate out solid subsequently, filter, obtain 61.0g off-white color solid after the drying, this compound is 11 α-tolysulfonyl oxygen base-4-alkene-3,17-androstanedione (Ia), yield 87.5%.138～140 ℃ of fusing points.
Embodiment 3
11 α-tolysulfonyl oxygen base-4-alkene-3, the preparation of 17-androstanedione (Ia)
With 11 alpha-hydroxy-4-enes-3,17-androstanedione (II) 43.5g (0.15mol) is dissolved among the exsiccant methylene dichloride 300ml, add sodium bicarbonate 10.5g, add Tosyl chloride 42.0g (0.22mol) down at-5 ℃, stirred 3 hours, be warming up to the room temperature afterreaction 24 hours, subsequently with among the reaction solution impouring frozen water 1L, separate out solid, filter, obtain 60.2g off-white color solid after the drying, this compound is 11 α-tolysulfonyl oxygen base-4-alkene-3,17-androstanedione (Ia), yield 90.0%.138～140 ℃ of fusing points.
Embodiment 4
11 α-tolysulfonyl oxygen base-4-alkene-3, the preparation of 17-androstanedione (Ia)
With 11 alpha-hydroxy-4-enes-3,17-androstanedione (II) 23.5g (0.08mol) is dissolved among the exsiccant ethyl acetate 150mlL, add triethylamine 100ml, add Tosyl chloride 22.8g (0.12mol) down at 5 ℃, stirred 3 hours, be warming up to 30 ℃ of afterreactions 18 hours, subsequently with among the reaction solution impouring frozen water 1L, separate out solid, filter, obtain 33.9g off-white color solid after the drying, this compound is 11 α-tolysulfonyl oxygen base-4-alkene-3,17-androstanedione (Ia), yield 91.0%, 138～140 ℃ of fusing points.
Embodiment 5
11 α-mesyloxy-4-alkene-3, the preparation of 17-androstanedione (Ib)
With 11 alpha-hydroxy-4-enes-3,17-androstanedione (II) 23.5g (0.08mol) is dissolved among the exsiccant pyridine 200ml, adds methylsulfonyl chloride 14.0g (0.12mol) down at-20 ℃, stirs 3 hours, be warming up to the room temperature afterreaction 18 hours, with among the reaction solution impouring frozen water 1L, separate out solid subsequently, filter, obtain 27.4g off-white color solid after the drying, this compound is 11 α-mesyloxy-4-alkene-3,17-androstanedione (Ib), yield 93.2%.
Embodiment 6
11 α-mesyloxy-4-alkene-3, the preparation of 17-androstanedione (Ib)
With 11 alpha-hydroxy-4-enes-3,17-androstanedione (II) 23.5g (0.08mol) is dissolved among the exsiccant methylene dichloride 200ml, adds sodium bicarbonate 15.0g; Add methylsulfonyl chloride 14.0g (0.12mol) down at-20 ℃, stirred 3 hours, be warming up to the room temperature afterreaction 18 hours, with among the reaction solution impouring frozen water 1L, separate out solid subsequently, filter, obtain 26.2g off-white color solid after the drying, this compound is 11 α-mesyloxy-4-alkene-3,17-androstanedione (Ib), yield 89.4%.
Embodiment 7
4,9 (11)-diene-3, the preparation of 17-androstanedione (III)
With 11 α-tolysulfonyl oxygen base-4-alkene-3,17-androstanedione (Ia) 622.0g (1.36mol) is dissolved among the acetate 3.5L, adds sodium acetate 250.0g (3.05mol) again, after the reflux 1 hour, be cooled to room temperature, in reaction solution impouring frozen water 10L, separate out solid, filter, obtain 355.0g after the drying, this solid is 4,9 (11)-diene-3,17-androstanedione (III), yield 92.0%.196～198 ℃ of fusing points.
Embodiment 8
4,9 (11)-diene-3, the preparation of 17-androstanedione (III)
With 11 α-tolysulfonyl oxygen base-4-alkene-3,17-androstanedione (Ia) 35.8g (0.08mol) is dissolved among the acetate 200ml, adds sodium acetate 15.2g (0.18mol) again, 80 ℃ of heating are after 1 hour, be cooled to room temperature, in reaction solution impouring frozen water 500ml, separate out solid, filter, obtain 18.8g after the drying, this solid is 4,9 (11)-diene-3,17-androstanedione (III), yield 86.0%.196～198 ℃ of fusing points.
Embodiment 9
4,9 (11)-diene-3, the preparation of 17-androstanedione (III)
With 11 α-mesyloxy-4-alkene-3,17-androstanedione (Ib) 22.5g (0.06mol) is dissolved among the acetate 150ml, adds sodium acetate 12.3g (0.15mol) again, after the reflux 30 minutes, be cooled to room temperature, in reaction solution impouring frozen water 500ml, separate out solid, filter, obtain 14.9g after the drying, this solid is 4,9 (11)-diene-3,17-androstanedione (III), yield 88.1%, 195～198 ℃ of fusing points.
Embodiment 10
4,9 (11)-diene-3, the preparation of 17-androstanedione (III)
With 11 α-mesyloxy-4-alkene-3,17-androstanedione (Ib) 22.5g (0.06mo1) is dissolved among the formic acid 100ml, adds potassium formiate 12.5g (0.15mol) again, after the reflux 1 hour, be cooled to room temperature, in reaction solution impouring frozen water 10L, separate out solid, filter, obtain 14.5g after the drying, this solid is 4,9 (11)-diene-3,17-androstanedione (III), yield 86.0%, 196～198 ℃ of fusing points.
Embodiment 11
4,9 (11)-diene-3, the preparation of 17-androstanedione (III)
With 11 α-mesyloxy-4-alkene-3,17-androstanedione (Ib) 22.0g (0.06mol) is dissolved among the acetate 100ml, adds sodium acetate 5.0g (0.06mol) again, after the reflux 1 hour, be cooled to room temperature, in reaction solution impouring frozen water 500ml, separate out solid, filter, obtain 14.1g after the drying, this solid is 4,9 (11)-diene-3,17-androstanedione (III), yield 85.0%, 196～198 ℃ of fusing points.
More than show and described ultimate principle of the present invention and principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; that describes in the foregoing description and the specification sheets just illustrates principle of the present invention; the present invention also has various changes and modifications without departing from the spirit and scope of the present invention, and these changes and improvements all fall in the claimed scope of the invention.The claimed scope of the present invention is defined by appending claims and equivalent thereof.
Claims (16)
1, with following general formula (I)
R can be low alkyl group alkylsulfonyl, fragrant alkylsulfonyl or corresponding halogen alkylsulfonyl in the compound of expression, its Chinese style (I).
2, according to the described compound of claim 1 (I), wherein said low alkyl group alkylsulfonyl is that carbonatoms is a 1-4 low alkyl group alkylsulfonyl, as methylsulfonyl, and ethylsulfonyl, third alkylsulfonyl.
3, according to the described compound of claim 1 (I), wherein said fragrant alkylsulfonyl is p-toluenesulfonyl, benzenesulfonyl.
4, according to the described compound of claim 1 (I), the halogen sulphonyl thing base of wherein said correspondence is the halogeno-benzene alkylsulfonyl.
5, a kind of preparation method of formula (I) compound is according to claim 1 wherein used formula (II) compound 11 alpha-hydroxy-4-enes-3, and the 17-androstanedione is prepared from through sulfonylation; Its reaction formula is as follows.
6, preparation method according to claim 6, wherein the sulfonylation agent that sulfonylation adopted is low alkyl group SULPHURYL CHLORIDE, aromatic sulfonyl chloride or corresponding halogen sulphonyl thing.
7, preparation method according to claim 6, wherein selected sulfonylation agent is a Tosyl chloride.
8, preparation method according to claim 5, its Chinese style (II) compound 11 alpha-hydroxy-4-enes-3, the 17-androstanedione: the mol ratio of sulfonylation agent is 1: 1.0～1: 4.0.
9, preparation method according to claim 5, its Chinese style (II) compound 11 alpha-hydroxy-4-enes-3, the 17-androstanedione: the mol ratio of sulfonylation agent is 1: 1.5.
10, preparation method according to claim 5, the temperature of reaction of sulfonylation-20～50 ℃ wherein, the pH=8.0-11.0 of reaction solution reacted 5～40 hours.
11, preparation method according to claim 5, wherein elder generation is with formula (II) compound 11 alpha-hydroxy-4-enes-3 before sulfonylation, and the 17-androstanedione is dissolved in the exsiccant organic solvent and adds de-acidying agent and regulates.
12, preparation method according to claim 11, wherein selected exsiccant organic solvent is toluene, methylene dichloride, ethyl acetate, pyridine or its their mixed solvent.
13, preparation method according to claim 11, wherein selected exsiccant organic solvent is the exsiccant pyridine.
14, preparation method according to claim 11, wherein selected de-acidying agent is triethylamine, yellow soda ash, sodium bicarbonate, sodium hydroxide and potassium hydroxide.
15, preparation method according to claim 10, wherein said temperature of reaction are-10～30 ℃.
16, a kind of formula as claimed in claim 1 (I) compound is at preparation medicine intermediate 4,9 (11)-diene-3, application in the 17-androstanedione (III), be that employing formula (I) compound makes medicine intermediate 4 through eliminating reaction, 9 (11)-diene-3,17-androstanedione (III), its reaction formula is as follows.
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| CN102531955A (en) * | 2011-09-16 | 2012-07-04 | 浙江众益药业有限公司 | Preparation method of olsalazine disodium and postprocessing method of methyl sulfonation reaction |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102531955A (en) * | 2011-09-16 | 2012-07-04 | 浙江众益药业有限公司 | Preparation method of olsalazine disodium and postprocessing method of methyl sulfonation reaction |
| CN102531955B (en) * | 2011-09-16 | 2014-02-19 | 浙江众益制药股份有限公司 | Preparation method of olsalazine disodium and postprocessing method of methyl sulfonation reaction |
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