CN101429224A - Synthesis of 1,4-diene-6-methylene steroids and midbody thereof - Google Patents
Synthesis of 1,4-diene-6-methylene steroids and midbody thereof Download PDFInfo
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- 230000015572 biosynthetic process Effects 0.000 title description 3
- 238000003786 synthesis reaction Methods 0.000 title description 3
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 24
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000003379 elimination reaction Methods 0.000 claims abstract description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 10
- 230000001476 alcoholic effect Effects 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 229930195733 hydrocarbon Natural products 0.000 claims description 8
- 150000002430 hydrocarbons Chemical class 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 239000012188 paraffin wax Substances 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 238000010189 synthetic method Methods 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 150000005826 halohydrocarbons Chemical class 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 239000005977 Ethylene Substances 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 230000006837 decompression Effects 0.000 claims description 2
- 230000008030 elimination Effects 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
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- 238000000926 separation method Methods 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 claims 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 2
- 239000002994 raw material Substances 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000006683 Mannich reaction Methods 0.000 abstract description 2
- 238000011112 process operation Methods 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 19
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 10
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 8
- 229910052786 argon Inorganic materials 0.000 description 8
- 229960000255 exemestane Drugs 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 229960000935 dehydrated alcohol Drugs 0.000 description 7
- 239000012043 crude product Substances 0.000 description 6
- 238000007670 refining Methods 0.000 description 5
- -1 6-aminomethyl phenyl Chemical group 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 238000006356 dehydrogenation reaction Methods 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 150000003233 pyrroles Chemical class 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 102000014654 Aromatase Human genes 0.000 description 1
- 108010078554 Aromatase Proteins 0.000 description 1
- 229940122815 Aromatase inhibitor Drugs 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 230000003570 biosynthesizing effect Effects 0.000 description 1
- 201000008275 breast carcinoma Diseases 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 238000007269 dehydrobromination reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000001076 estrogenic effect Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
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- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
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- 235000011149 sulphuric acid Nutrition 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing a 1, 4-diene-6-methylene steroid as formula (I) and an intermediate. The method comprises the following steps: substituting the first position and the third position or only the third position of a 1, 4-diene-androstane compound as a raw material by pyrrolidine to generate 5, 6-ethylenic linkage compound; and introducing 6-methylene to the compound through Mannich reaction and elimination reaction to obtain the compound in the formula (I). Particular reaction formulas are shown as the above, and the method has the advantages of cheap and easily obtained raw materials, easily controlled process operation, high yield and low cost, and is suitable for industrialized production.
Description
Technical field
The invention belongs to the pharmaceutical chemistry technical field, be specifically related to synthetic suc as formula (I) 1, the synthetic method and the intermediate of 4-diene-6-methylene sterides.
Background technology
1, representational in 4-diene-6-methylene steroids class medicine have an Exemestane (Exemestane), Exemestane chemistry 6-methylene radical-androstane-1 by name, and 4-diene-3, the 17-diketone, structural formula is as follows:
Exemestane (Exemestane) is by Italian Pharmacia﹠amp; The s-generation aromatase inhibitor of Upjohn company exploitation can irreversibly combine with aromatase enzyme and makes its deactivation, thereby stops estrogenic biosynthesizing.Be used for the treatment of metastatic breast cancer clinically and reach the adjuvant therapy that is used as breast carcinoma of early stage, determined curative effect, better tolerance, side effect is less relatively.
The synthetic route of Exemestane mainly contains following two lines at present:
1, bromo is eliminated route (European patent EP 0326340), sees reaction formula (1):
Reaction formula (1)
2, DDQ dehydrogenation route (seeing US4808616), by intermediate 6-methylene radical-androstane-4-alkene-3,17-diketone direct dehydrogenation obtains Exemestane, sees reaction formula (2):
Reaction formula (2)
Said synthesis route all with 4-alkene-3-ketone compounds as starting raw material, after introducing 6 methylene radical, no matter take the dehydrobromination or the method for dehydrogenation to introduce 1-alkene, react all difficult to carry out, yield is lower, have only about 40%, and the impurity that this step side reaction causes is difficult to remove by crystal refining, makes production cost higher.
Summary of the invention
Technical problem to be solved by this invention is to overcome above-mentioned weak point, the method and the intermediate of the more rational synthetic Exemestane of research and design.
Technical problem to be solved by this invention can be achieved through the following technical solutions:
A kind of suc as formula (I) 1, the synthetic method of 4-diene-6-methylene sterides, with 1,4-diene-androstane compound is a raw material, with 1 and 3 or only 3 replace through tetramethyleneimine, generate 5,6-ethylene linkage compound is introduced 6 methylene radical through Mannich reaction, elimination reaction then and is obtained formula (I) compound.Concrete reaction formula is as follows:
R1 in the formula, R2 independently are selected from hydrogen, halogen, perhaps alkyl; R3, R4 independently are selected from hydrogen, hydroxyl, and halogen, alkoxyl group, acyl group, hydroxyalkyl, alkoxyalkyl, the hydroxycarbonyl group alkyl, alkoxycarbonyl alkyl, the acetyl oxyalkyl, cyano group, aryloxy, perhaps R3, R4 is selected from oxygen jointly; R5, R6 is selected from lower paraffin hydrocarbons, the hydroxyl lower paraffin hydrocarbons, cyclohexyl, phenyl, R5, R6 can also form five-membered ring or six membered ring jointly with nitrogen.
In the methods of the invention, R1, R2 all are preferably hydrogen; R3, R4 preferably are selected from oxygen jointly; R5, R6 preferably form six membered ring jointly with nitrogen.
For said synthesis route, its concrete steps are:
(a) 1,1 of 4-diene-androstane compound (II) and 3 or only 3 carry out tetramethyleneimine and replace, generate 5,6-ethylene linkage compound (III) or (IV) or both mixtures;
(b) 1 and 3 bisubstituted compounds (III) or 3 mono-substituted compounds (IV) or both mixtures carry out Mannich reacting generating compound (V);
(c) compound (V) perhaps separates back elimination under acidic conditions and obtains compound (I) without separation.
In the above-mentioned steps, specifically describe as follows:
Step a: to 1,4-diene-androstane compound carries out tetramethyleneimine and replaces, migration of the double bond to 5, in the time of 6, the selective reaction condition can generate 1 and 3 two replacements or only 3 replacements, perhaps obtains both mixtures, two replacements and mono-substituted product can carry out next step reaction, therefore do not need to separate.Compound (II) reacts in alcohols and pyrroles's mixed solvent or single pyrroles's solvent and can obtain compound (III) and (IV), and US3274176 has detailed description to this step reaction.
Step b: be that 1 and 3 bisubstituted compounds (III) or 3 mono-substituted compounds (IV) or both mixtures are dissolved in the alcoholic solvent, add methylphenylamine and formalin, reaction obtains compound (V).
Said alcoholic solvent preferred alcohol.
Step c: be dissolved in the alcoholic solvent after compound (V) do not separated or separate, add acid, eliminate obtaining compound (I).
Step c: perhaps in order to method is alternative down:
The solution decompression evaporate to dryness that contains compound (V) with step (b) obtains after halohydrocarbon or esters solvent dissolving, removes aminated compounds with the dilute acid soln washing; Solvent evaporated is dissolved in acetone or alcoholic solvent with the residue that obtains again, adds acid, eliminates obtaining compound (I).
Said alcoholic solvent particular methanol.
Said acid can be organic acid, also can be mineral acid, preferred hydrochloric acid.
Said halohydrocarbon is preferably methylene dichloride, and esters solvent is preferably ethyl acetate, and said dilute acid soln preferred percent concentration is 0.5～5% sulfuric acid or hydrochloric acid.
A kind of suc as formula (I) 1, the resulting intermediate of synthetic method of 4-diene-6-methylene sterides has following logical formula V:
R1 in the formula, R2 independently are selected from hydrogen, halogen, perhaps alkyl; R3, R4 independently are selected from hydrogen, hydroxyl, and halogen, alkoxyl group, acyl group, hydroxyalkyl, alkoxyalkyl, the hydroxycarbonyl group alkyl, alkoxycarbonyl alkyl, the acetyl oxyalkyl, cyano group, aryloxy, perhaps R3, R4 is selected from oxygen jointly; R5, R6 is selected from lower paraffin hydrocarbons, the hydroxyl lower paraffin hydrocarbons, cyclohexyl, phenyl, R5, R6 can also form five-membered ring or six membered ring jointly with nitrogen.
In the methods of the invention, R1, R2 all are preferably hydrogen; R3, R4 preferably are selected from oxygen jointly; R5, R6 preferably form six membered ring jointly with nitrogen.
Method raw material sources of the present invention cheaply are easy to get, and technological operation is easy to control, the yield height, and cost is low, has bigger suitability for industrialized production to be worth.
Embodiment
The present invention is further detailed explanation below in conjunction with embodiment.
Embodiment 1
1,3-two tetramethyleneimine androstanes-3,5-diene-17-ketone and 3-tetramethyleneimine-androstane-1,3, the preparation of 5-triolefin-17-ketone
Under the argon shield, with 1,4-diene-3,17-diketone-androstane 10.0g are dissolved in 100ml ethanol/methyl alcohol (95:5), add the 6ml tetrahydrofuran (THF) then successively, the 0.2ml Glacial acetic acid, and the 35.4ml Pyrrolidine is heated to 40 ℃, stirring reaction 48 hours.Question response finishes, be concentrated into dried, with isopropyl ether 30ml * 2 carry secretly the distillation 2 times.Add the 20ml dehydrated alcohol then, put into the refrigerator crystallization after stirring, freezing 24 hours.Filter, with refrigerated ethanol 15ml * 2 abundant drip washing, drain, 40 ℃ of vacuum-drying 6h get yellow solid 11.7g, be 1,3-two tetramethyleneimine androstanes-3,5-diene-17-ketone and 3-tetramethyleneimine-androstane-1,3, the mixture of 5-triolefin-17-ketone, both directly carry out next step reaction without separating.
Embodiment 2
6-aminomethyl phenyl amine methylene radical-androstane-1,4-diene-3, the preparation of 17-diketone
Under the argon shield, the solid 5.0g that stirs down embodiment 1 gained is suspended in the 50ml dehydrated alcohol, and then adds 1.41ml methylphenylamine and 5.94ml 40% formalin successively, 20 ℃ of stirring reactions 3.5 hours.After having reacted, 40 ℃ are concentrated into driedly, and residue is with the dissolving of 50ml methylene dichloride, 1% dilute sulphuric acid 50ml washing 3 times, combining water layer is stripped 1 time with methylene dichloride 50ml, merges organic layer, extremely neutral with saturated sodium bicarbonate solution 50ml * 2 washings, anhydrous sodium sulfate drying filters, and 40 ℃ are concentrated into dried, get yellow solid 4.4g, weight yield 88%.
Embodiment 3
6-aminomethyl phenyl amine methylene radical-androstane-1,4-diene-3, the preparation of 17-diketone
Under the argon shield; stirring down will be according to US3274176 does 1,3-two tetramethyleneimine androstanes-3, and 5-diene-17-ketone 5.0g is suspended in the 50ml dehydrated alcohol; and then add 1.41ml methylphenylamine and 5.94ml 40% formalin successively, 15 ℃ of stirring reactions 4 hours.Aftertreatment is the same, gets yellow solid 3.5g, weight yield 70%.
Embodiment 4
6-aminomethyl phenyl amine methylene radical-androstane-1,4-diene-3, the preparation of 17-diketone
Under the argon shield; stirring down will be according to 3-tetramethyleneimine-androstane-1,3 that US3274176 did, and 5-triolefin-17-ketone 5.0g is suspended in the 50ml dehydrated alcohol; and then add 1.41ml methylphenylamine and 5.94ml 40% formalin successively, 20 ℃ of stirring reactions 4.5 hours.After having reacted, 40 ℃ be concentrated into dried, residue 50ml acetic acid ethyl dissolution, 1% dilute hydrochloric acid 50ml washing 3 times, combining water layer is stripped 1 time with ethyl acetate 50ml, merges organic layer, extremely neutral with saturated sodium bicarbonate solution 25ml * 2 washings, anhydrous sodium sulfate drying filters, and 40 ℃ are concentrated into dried, get yellow solid 5.0g, mass yield 100%.
Embodiment 5
6-methylene radical-androstane-1,4-diene-3, the preparation of 17-diketone
Under the argon shield, stir down 6-aminomethyl phenyl amine methylene radical-androstane-1,4-diene-3,17-diketone 1.0g are dissolved in the 20ml anhydrous methanol, and then add the 2ml concentrated hydrochloric acid, 40 ℃ of stirring reactions 24 hours.The raw material primitive reaction finishes, and is cooled to 0 ℃, and temperature control adds saturated sodium bicarbonate solution and transfers pH to neutral below 5 ℃, and then is concentrated into driedly, adds 20ml water, be heated to 40 ℃ after filtered while hot, drain, 80 ℃ of vacuum-dryings of filter cake 8 hours the 0.8g crude product.Crude product obtains white solid 0.7g, mass yield 70% after with acetonitrile refining.
Embodiment 5
6-methylene radical-androstane-1,4-diene-3, the preparation of 17-diketone
Under the argon shield, the solid 5.0g that stirs down embodiment 1 gained is suspended in the 50ml dehydrated alcohol, and then adds 1.41ml methylphenylamine and 5.94ml 40% formalin successively, 20 ℃ of stirring reactions 4 hours.At room temperature drip concentrated hydrochloric acid 15ml, be warming up to 40 ℃ and continued stirring reaction again 24 hours.After the raw material primitive reaction finishes, be cooled to 0 ℃, temperature control adds saturated sodium bicarbonate solution and transfers pH to neutral below 5 ℃, and then is concentrated into driedly, adds 100ml water, be heated to 40 ℃ after filtered while hot, drain, 80 ℃ of vacuum-dryings of filter cake 8 hours the 4.0g crude product.Crude product obtains white solid 3.0g, weight yield 50% after with acetonitrile refining.
Embodiment 6
6-methylene radical-androstane-1,4-diene-3, the preparation of 17-diketone
Under the argon shield; stirring down will be according to US3274176 does 1,3-two tetramethyleneimine androstanes-3, and 5-diene-17-ketone 5.0g is suspended in the 50ml dehydrated alcohol; and then add 1.41ml methylphenylamine and 5.94ml 40% formalin successively, 20 ℃ of stirring reactions 4.5 hours.At room temperature drip concentrated hydrochloric acid 15ml, be warming up to 40 ℃ and continued stirring reaction again 24 hours.Aftertreatment is the same, gets the 3.5g crude product, obtains white solid 2.5g behind the acetonitrile refining, weight yield 50%.
Embodiment 7
6-methylene radical-androstane-1,4-diene-3, the preparation of 17-diketone
Under the argon shield; stirring down will be according to 3-tetramethyleneimine-androstane-1,3 that US3274176 did, and 5-triolefin-17-ketone 5.0g is suspended in the 50ml dehydrated alcohol; and then add 1.41ml methylphenylamine and 5.94ml 40% formalin successively, 20 ℃ of stirring reactions 4.5 hours.At room temperature drip concentrated hydrochloric acid 15ml, be warming up to 40 ℃ and continued stirring reaction again 24 hours.Aftertreatment is the same, gets the 4.1g crude product, obtains white solid 3.2g behind the acetonitrile refining, weight yield 64%.
Claims (20)
1, a kind of synthetic 1, the synthetic method of 4-diene-6-methylene sterides (I) is characterized in that, comprises the steps:
(a) 1,1 of 4-diene-androstane compound (II) and 3 or only 3 carry out tetramethyleneimine and replace, generate 5,6-ethylene linkage compound (III) or (IV) or both mixtures;
(b) 1 and 3 bisubstituted compounds (III) or 3 mono-substituted compounds (IV) or both mixtures carry out Mannich reacting generating compound (V);
(c) compound (V) perhaps separates back elimination under acidic conditions and obtains compound without separation
(I)；
Concrete reaction formula is as follows:
R1 in the formula, R2 independently are selected from hydrogen, halogen, perhaps alkyl; R3, R4 independently are selected from hydrogen, hydroxyl, and halogen, alkoxyl group, acyl group, hydroxyalkyl, alkoxyalkyl, the hydroxycarbonyl group alkyl, alkoxycarbonyl alkyl, the acetyl oxyalkyl, cyano group, aryloxy, perhaps R3, R4 is selected from oxygen jointly; R5, R6 is selected from lower paraffin hydrocarbons, the hydroxyl lower paraffin hydrocarbons, cyclohexyl, phenyl, perhaps R5, R6 and nitrogen form five-membered ring or six membered ring jointly.
2, method according to claim 1 is characterized in that, R5, and R6 is for forming six membered ring jointly with nitrogen.
3, method according to claim 1 is characterized in that, R1 is a hydrogen.
According to claim 1 or 3 described methods, it is characterized in that 4, R2 is a hydrogen.
5, method according to claim 1 is characterized in that, R3, R4 are selected from oxygen jointly.
6, method according to claim 1, it is characterized in that, described step (b) is that 1 and 3 bisubstituted compounds (III) or 3 mono-substituted compounds (IV) or both mixtures are dissolved in the alcoholic solvent, add methylphenylamine and formalin, reaction obtains compound (V).
7, method according to claim 6 is characterized in that, described alcoholic solvent is an ethanol.
8, method according to claim 1 is characterized in that, described step (c) is to be dissolved in the alcoholic solvent after compound (V) is not separated or separates, and adds acid, eliminates obtaining compound (I).
9, method according to claim 8 is characterized in that, described alcoholic solvent is a methyl alcohol.
10, method according to claim 8 is characterized in that, described acid is organic acid or mineral acid.
11, method according to claim 8 is characterized in that, described acid is hydrochloric acid.
12, method according to claim 1 is characterized in that, described step c is in order to method is alternative down:
The solution decompression evaporate to dryness that contains compound (V) with step (b) obtains after halohydrocarbon or esters solvent dissolving, removes aminated compounds with the dilute acid soln washing; Solvent evaporated is dissolved in acetone or alcoholic solvent with the residue that obtains again, adds acid, eliminates obtaining compound (I).
13, method according to claim 12 is characterized in that, described halohydrocarbon is preferably methylene dichloride.
14, method according to claim 12 is characterized in that, esters solvent is preferably ethyl acetate.
15, method according to claim 12 is characterized in that, described dilute acid soln preferred percent concentration is 0.5～5% sulfuric acid or hydrochloric acid.
16, a kind of suc as formula (I) 1, the resulting intermediate of synthetic method of 4-diene-6-methylene sterides has following logical formula V:
R1 in the formula, R2 independently are selected from hydrogen, halogen, perhaps alkyl; R3, R4 independently are selected from hydrogen, hydroxyl, and halogen, alkoxyl group, acyl group, hydroxyalkyl, alkoxyalkyl, the hydroxycarbonyl group alkyl, alkoxycarbonyl alkyl, the acetyl oxyalkyl, cyano group, aryloxy, perhaps R3, R4 is selected from oxygen jointly; R5, R6 is selected from lower paraffin hydrocarbons, the hydroxyl lower paraffin hydrocarbons, cyclohexyl, phenyl, perhaps R5, R6 and nitrogen form five-membered ring or six membered ring jointly.
17, intermediate according to claim 16 is characterized in that, R5, and R6 is for forming six membered ring jointly with nitrogen.
18, intermediate according to claim 16 is characterized in that, R1 is a hydrogen.
According to claim 16 or 18 described intermediates, it is characterized in that 19, R2 is a hydrogen.
20, intermediate according to claim 16 is characterized in that, R3, R4 are selected from oxygen jointly.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100479143A CN101429224B (en) | 2007-11-07 | 2007-11-07 | Synthesis method and intermediate of 1, 4-diene-6-methylene steroid compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100479143A CN101429224B (en) | 2007-11-07 | 2007-11-07 | Synthesis method and intermediate of 1, 4-diene-6-methylene steroid compound |
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| CN101429224B CN101429224B (en) | 2012-05-02 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101704871B (en) * | 2009-12-01 | 2012-05-23 | 北京紫竹药业有限公司 | Steroid compound and use thereof |
| CN106243179A (en) * | 2016-07-31 | 2016-12-21 | 合肥远志医药科技开发有限公司 | A kind of exemestane industrialized preparing process |
| CN107903295A (en) * | 2017-11-15 | 2018-04-13 | 上海交通大学医学院附属仁济医院 | A kind of 4 methylene steroids class compounds and its anticancer usage |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8801697D0 (en) * | 1988-01-26 | 1988-02-24 | Erba Farmitalia | Improvements in synthesis of 6-methylene derivatives of androsta-1 4-diene-3 17-dione |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101704871B (en) * | 2009-12-01 | 2012-05-23 | 北京紫竹药业有限公司 | Steroid compound and use thereof |
| CN106243179A (en) * | 2016-07-31 | 2016-12-21 | 合肥远志医药科技开发有限公司 | A kind of exemestane industrialized preparing process |
| CN107903295A (en) * | 2017-11-15 | 2018-04-13 | 上海交通大学医学院附属仁济医院 | A kind of 4 methylene steroids class compounds and its anticancer usage |
| CN107903295B (en) * | 2017-11-15 | 2019-08-30 | 上海交通大学医学院附属仁济医院 | A kind of 4- methylene steroids class compound and its anticancer usage |
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| CN101429224B (en) | 2012-05-02 |
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