CN101177443A - Novel steroid compound and uses thereof - Google Patents
Novel steroid compound and uses thereof Download PDFInfo
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- CN101177443A CN101177443A CNA2006101292765A CN200610129276A CN101177443A CN 101177443 A CN101177443 A CN 101177443A CN A2006101292765 A CNA2006101292765 A CN A2006101292765A CN 200610129276 A CN200610129276 A CN 200610129276A CN 101177443 A CN101177443 A CN 101177443A
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- -1 steroid compound Chemical class 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 87
- 238000002360 preparation method Methods 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims description 41
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 40
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 34
- 230000004224 protection Effects 0.000 claims description 32
- 238000009833 condensation Methods 0.000 claims description 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 24
- 230000005494 condensation Effects 0.000 claims description 23
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 20
- 238000007171 acid catalysis Methods 0.000 claims description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 17
- 229960001145 deflazacort Drugs 0.000 claims description 16
- FBHSPRKOSMHSIF-GRMWVWQJSA-N deflazacort Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(C)=N[C@@]3(C(=O)COC(=O)C)[C@@]1(C)C[C@@H]2O FBHSPRKOSMHSIF-GRMWVWQJSA-N 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 16
- 125000000468 ketone group Chemical group 0.000 claims description 15
- 239000002994 raw material Substances 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 229910021529 ammonia Inorganic materials 0.000 claims description 12
- 150000007524 organic acids Chemical class 0.000 claims description 12
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 12
- 150000003431 steroids Chemical class 0.000 claims description 12
- 239000000463 material Substances 0.000 claims description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 10
- 150000002576 ketones Chemical class 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 8
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 8
- 239000004202 carbamide Substances 0.000 claims description 8
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 8
- 125000006239 protecting group Chemical group 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 238000010511 deprotection reaction Methods 0.000 claims description 7
- 230000001681 protective effect Effects 0.000 claims description 7
- 238000007142 ring opening reaction Methods 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- OWIUPIRUAQMTTK-UHFFFAOYSA-N carbazic acid Chemical class NNC(O)=O OWIUPIRUAQMTTK-UHFFFAOYSA-N 0.000 claims description 6
- 238000006555 catalytic reaction Methods 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- 150000002923 oximes Chemical class 0.000 claims description 6
- 239000000376 reactant Substances 0.000 claims description 6
- 239000001632 sodium acetate Substances 0.000 claims description 6
- 229960004249 sodium acetate Drugs 0.000 claims description 6
- 235000017281 sodium acetate Nutrition 0.000 claims description 6
- 235000019270 ammonium chloride Nutrition 0.000 claims description 5
- 238000010719 annulation reaction Methods 0.000 claims description 5
- 238000010790 dilution Methods 0.000 claims description 5
- 239000012895 dilution Substances 0.000 claims description 5
- 230000007935 neutral effect Effects 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 238000006482 condensation reaction Methods 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- 239000012266 salt solution Substances 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 150000002334 glycols Chemical class 0.000 claims description 3
- 235000019260 propionic acid Nutrition 0.000 claims description 3
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 claims description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 3
- 229910001854 alkali hydroxide Inorganic materials 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 238000003113 dilution method Methods 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 239000007805 chemical reaction reactant Substances 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 7
- 230000008901 benefit Effects 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract 2
- 230000003637 steroidlike Effects 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 150000007659 semicarbazones Chemical class 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- 238000005070 sampling Methods 0.000 description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 125000004494 ethyl ester group Chemical group 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000004593 Epoxy Substances 0.000 description 3
- 150000001540 azides Chemical class 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 3
- 229910003446 platinum oxide Inorganic materials 0.000 description 3
- 229960005205 prednisolone Drugs 0.000 description 3
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[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 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000003999 initiator Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 206010029164 Nephrotic syndrome Diseases 0.000 description 1
- LRJOMUJRLNCICJ-JZYPGELDSA-N Prednisolone acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O LRJOMUJRLNCICJ-JZYPGELDSA-N 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 description 1
- 239000000292 calcium oxide Substances 0.000 description 1
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 238000006392 deoxygenation reaction Methods 0.000 description 1
- FDPIMTJIUBPUKL-UHFFFAOYSA-N dimethylacetone Natural products CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 150000005826 halohydrocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000006192 iodination reaction Methods 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 238000005649 metathesis reaction Methods 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N methyl monoether Natural products COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000002918 oxazolines Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229960002800 prednisolone acetate Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Steroid Compounds (AREA)
Abstract
The invention relates to new steroid compounds and the application, in particular to [17 Alpha, 16 Alpha -d] oxazoline steroid compounds and the preparation method. The new compound (II) and compound (III) from the invention protected by ketol 20, are the important intermediates in synthesizing [17 Alpha, 16 Alpha -d] oxazoline steroid compounds. The invention also provides the application of compound (I), compound (II) and compound (III) in preparing compound (V). The invention has the advantages of high feasibility and strong operability of the process, ability to obtain intermediates through general chemical purification without high risk operation and expensive reagents, and high industrialization factor.
Description
Technical field
The present invention relates to new steroidal compounds and application thereof, especially relate to [17 α, 16 α-d] oxazoline steroidal compounds and preparation method thereof.
Background technology
[17 α, 16 α-d] oxazoline steroidal compounds is a very useful class steroidal active compound, represents medicine that deflazacort is arranged.Deflazacort is a third generation glucocorticoid steroids antiphlogiston, is prednisolone De oxazoline derivative, is mainly used in rheumatoid arthritis, nephrotic syndrome, systemic lupus erythematous, uveitis, sarcoid treatment and organ transplantation.Document Drugs Res.30 (II), Nr, 9 (1980) mention the deflazacort anti-inflammatory activity obviously is better than prednisolone, document Drugs50 (2): 317-313,1995 mention, deflazacort is the same effective with Prednisolone Acetate or six prednisolone in the rheumatic arthritis treatment, and this medicine is suitable with prednisone in children's chronic arthritis treatment.
[17 α, 16 α-d] oxazoline steroidal compounds are obtained by the exploitation of Italian Gruppo Lepetit company the earliest.As far back as the sixties in 20th century, Italy Gruppo Lepetit company is just in that [17 α have done a large amount of synthetic works and pharmacological research on 16 α-d] oxazoline steroidal compounds, and declared a lot of patents, mainly contain: GB1077392, tens of the relevant patent familieses of GB1077393.Main synthetic route is as follows:
This route is with the 3-hydroxyl-11 of A ring filling, 20-diketone-16, and the pregnant steroid of 17-epoxy is an initiator, adopt the synthetic 17-nitrine of azide method-16-hydroxy compound, obtain 16 through the platinum oxide catalytic hydrogenation, 17-oxazole cyclic cpds, then 11-ketone is reduced to the 11-hydroxyl, carries out the transformation of A ring at last.Along with the progress of steroidal synthetic technology, it is to some extent not enough that this operational path seems: azide method explosive at first, and dangerous high, the product complexity, yield is low; Next platinum-oxide catalyst cost costliness; Last bromine legal system is equipped with 1, and 4-diene toxicity is big, and yield is low; This route technology is loaded down with trivial details in a word, and yield is low, and industrial pollution is serious, and operability is relatively poor.
In addition, the eighties in 20th century, U.S. Pat 4431732 is mentioned with 11 β, 21-dihydroxyl-2 '-the pregnant steroid of methyl-5 ' β H--4-alkene [17 α, 16 α-d]-oxazoles-3,20-diketone-21-acetic ester is a raw material, through 1,2 biological dehydrogenation of A ring, obtain deflazacort.The nineties in 20th century, world patent WO97/21722 mentions with 11 β, 21-dihydroxyl-2 '-methyl-5 ' β H-pregnant steroid-1,4-diene [17 α, 16 α-d]-oxazoles-3, the 20-diketone is a raw material, through under alkaline condition, 21 acetic anhydride esterifications obtain deflazacort.Though these two patents are new synthetic routes, also just the route of deflazacort final step has in the end been done some adjustment.
Summary of the invention
At [we utilize the technical superiority of my company for 17 α, 16 α-d] oxazoline steroidal compounds and preparation method thereof problem in history, designed a brand-new He oxazoline steroidal compounds operational path, it is suitable 16 to select, and the pregnant steroid of 17-epoxy is an initiator, through 16, the 17-epoxy addition is cyclized into 16 again, 17-oxazole compound, solved the azide method explosive smoothly, dangerous high, the product complexity, yield is low; And platinum-oxide catalyst cost costliness or the like key issue.Our characteristics of technology are synthetic 20 the ketone group protection methods of novelty that then adopted of: oxazoline steroidal compounds, and behind upward intact 20 ketone group blocking groups, logical again ammonia open loop generates 17-ammonia-16-hydroxyl precursor, and cyclisation obtains in organic acid then.The suitable of blocking group selected for use, guaranteed to be adapted to alkaline environment and promoted the ammonia open loop smoothly, and can remove smoothly under acidic conditions at oxazoline Cheng Huanhou.Under this process advantage is transformed, more synthetic important [17 α, 16 α-d] oxazoline steroidal compounds also becomes very simple such as deflazacort, according to my company's present situation, adopt company's existing intermediate 1,4 through inquiring into us repeatedly, 9-triolefin-16,17-epoxy-3, the pregnant steroid of 20-diketone are that starting raw material synthesizes deflazacort, and this raw material A hexamethylene possesses △
1,4Structure need not to transform once more, comprehensive all technology, and simple in circuits, raw material is easy to get, and does not have expensive raw material, and safety performance and operability are higher, and yield and cost obviously are better than historical deflazacort synthetic method.
The invention provides new compound (II) and compound (III), the contract steroidal of 20 ketone protections of this two class is synthetic [17 α, the important intermediate of 16 α-d] oxazoline steroidal compounds.
Wherein 9,11 ... represent singly-bound or do not exist, X representative=O or OH (when ... representative is not when existing), H (when ... when representing singly-bound), Y represents 20 ketone group protecting groups, it is the protecting group that forms by 20 ketone group protective materials and corresponding catalyst and 20 ketone group condensation reactions of steroide, 20 ketone group protective materials and corresponding catalyst comprise conventional ketone group guard method, such as having: dimethyl ketal protection, hydrochloric acid or p-methyl benzenesulfonic acid catalysis; The protection of glycols ketal, hydrochloric acid or p-methyl benzenesulfonic acid catalysis; N, N-dimethyl hydrazone class condensation protection, acetic acid or toluene catalytically; Urea,amino-condensation protection, sodium-acetate catalysis; Hydrazinecarboxylate class condensation protection, perchloric acid or p-methyl benzenesulfonic acid catalysis; Oximes condensation protection, hydrochloric acid catalysis.
And ring A and B represent following residue:
W
Represent the protecting group of O or following formula oxo base:
N is 2 or 3; R
2Represent alkyl or acyl group.
A and B represents residue (1) when ring, and when W represented O, [17 α, 16 α-d] oxazoline steroidal compounds was even more important synthesizing for new compound (II) and compound (III).
The present invention also provides compound (I), compound (II), the application of compound (III) in preparation compound (V).
Wherein ... represent singly-bound or do not exist, X representative=O or OH (when ... representative is not when existing), H (when ... when representing singly-bound), six carbon of R=are with interior alkyl, and ring A and B represent following residue:
W represents the protecting group of O or following formula oxo base:
N is 2 or 3; R
2Represent alkyl or acyl group.
A and B represents residue (1) when ring, and when W represented O, compound (I), compound (II), the application of compound (III) in preparing compound (V) were particularly important.
New compound provided by the invention (II), by the preparation of condensation ring-opening reaction, process is as follows by compound (I) for its preparation method:
Reactant compound (I) is added in the organic solvent, add 20 ketone group protective materials and corresponding catalyst, reaction changes the feeding ammonia after finishing, and reaction is carried out aftertreatment after finishing, and obtains compound (II).
The organic solvent of condensation ring-opening reaction comprises lower aliphatic alcohols, as methyl alcohol or ethanol; Ketone is as acetone; Amides is as dimethyl formamide; Ethers, as ether, tetrahydrofuran (THF) etc.; Select in these organic solvents one or more for use; Preferred dimethyl formamide, acetone, ether and tetrahydrofuran (THF) and two or more mixed solvents thereof, more preferably dimethyl formamide and tetrahydrofuran (THF).20 ketone group protective materials and corresponding catalyst comprise conventional ketone group guard method, for example: dimethyl ketal protection, hydrochloric acid or p-methyl benzenesulfonic acid catalysis; The protection of glycols ketal, hydrochloric acid or p-methyl benzenesulfonic acid catalysis; N, N-dimethyl hydrazone class condensation protection, acetic acid or toluene catalytically; Urea,amino-condensation protection, sodium-acetate catalysis; Hydrazinecarboxylate class condensation protection, perchloric acid or p-methyl benzenesulfonic acid catalysis; Oximes condensation protection, hydrochloric acid catalysis.The protection of preferred diol class ketal, hydrochloric acid or p-methyl benzenesulfonic acid catalysis; N, N-dimethyl hydrazone class condensation protection, acetic acid or toluene catalytically; Urea,amino-condensation protection, sodium-acetate catalysis; Hydrazinecarboxylate class condensation protection, perchloric acid or p-methyl benzenesulfonic acid catalysis; Oximes condensation protection, hydrochloric acid catalysis.More preferably Urea,amino-condensation protection, sodium-acetate catalysis; Hydrazinecarboxylate class condensation protection, perchloric acid or p-methyl benzenesulfonic acid catalysis; Oximes condensation protection, hydrochloric acid catalysis.The temperature that begins to react is 0～60 ℃, preferred 10～30 ℃.Feeding ammonia afterreaction temperature is 0～40 ℃, preferred 10～30 ℃.Aftertreatment can be diluted in the water, preferably is diluted in the saturated inorganic salt solution preferred sodium-chlor of inorganic salt and ammonium chloride.Aftertreatment can also be diluted in earlier in the water, uses organic solvent to extract then, with organic solvent phase concentration, obtains crystallization; Preferred chloroform of organic solvent and methylene dichloride.Answer a straight-through nitrogen in the condensation reaction before the logical ammonia.
New compound provided by the invention (III), by the cyclization preparation, process is as follows by compound (II) for its preparation method: reactant compound (II) is added in the organic acid, add corresponding organic acid anhydride, after reaction finishes, dilution, regulate PH to neutral, obtain compound (III).
The organic acid of annulation and corresponding organic acid anhydride can be six carbon with interior organic acid and corresponding organic acid anhydride, preferred acetate and diacetyl oxide, propionic acid and propionic anhydride.Temperature of reaction is 0～40 ℃, preferred 10～30 ℃.The reaction dilution process can be diluted in the water, preferably is diluted in the saturated inorganic salt solution preferred sodium-chlor of inorganic salt and ammonium chloride.The dilution back uses mineral alkali to regulate PH to neutral, preferred sodium hydroxide of mineral alkali and potassium hydroxide.
The preparation method of compound provided by the invention (V) is characterized in that being prepared by 20 ketone deprotection reactions by compound (III), and process is as follows:
Reactant compound (III) is added in the organic solvent, and logical nitrogen drips acid, and after reaction finished, dilution obtained compound (V)
The organic solvent of 20 ketone deprotection reactions comprises lower aliphatic alcohols, as methyl alcohol or ethanol; Ketone is as acetone; Halohydrocarbon is as chloroform; Ethers, as ether, tetrahydrofuran (THF) etc.; Select in these organic solvents one or more for use; Preferred acetone, ether, tetrahydrofuran (THF); More preferably acetone, tetrahydrofuran (THF).Acid comprises organic acid and mineral acid, preferred acetic acid, p-methyl benzenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid; More preferably acetic acid, hydrochloric acid.The temperature of reaction is 0～80 ℃, preferred 20～40 ℃.
Above compound (I), compound (II), compound (III) the application route in preparation compound (V) is schematically as follows:
The compound that the present invention also provides (I) is to the preparation method of compound (V), for synthetic [17 α, 16 α-d] oxazoline steroidal compounds is very useful, most important preparation method when the number deflazacort, we select 1,4 in the compound (I) for use, 9-triolefin-16,17-epoxy-3, the pregnant steroid of 20-diketone is a starting raw material, route is as follows:
Compound provided by the invention (I), compound (II), the application of compound (III) in preparation compound (V), new compound (II) and compound (III), and the preparation method of deflazacort have following advantage:
(1) technology is simple and direct, and new compound (II) and the important intermediate of this two class of compound (III) are provided.
(2) feasibility height, strong operability, each goes on foot intermediate and all can obtain by general chemical method purification.
(3) not dangerous too high operation.
(4) do not use too expensive reagent, the industrialization coefficient increases.
Embodiment
Below will the invention will be further described by embodiment, these descriptions are not that content of the present invention is done further to limit.One skilled in the art will understand that to be equal to replacement to what technical characterictic of the present invention was done, or corresponding the improvement, still belong within protection scope of the present invention.
Embodiment one
Condensation, ring-opening reaction
In reaction flask, add 1,4 of 32.4g, 9-triolefin-16,17-epoxy-3, the pregnant steroid of 20-diketone (ZL200210014479.5), the tetrahydrofuran (THF) of 205ml behind the feeding nitrogen replacement air, adds Urea,amino-20.8gH
2NNHCONH
2, the 0.205g tosic acid, temperature control 20-25 ℃ of reaction sampling in 2 hours is carried out tlc analysis to there not being raw material, change the feeding ammonia, temperature stops air guide at 20～25 ℃ after 3 hours, reacted 1 hour, tlc analysis drains ammonia to there not being raw material with air flow nitrogen again, reaction solution is diluted in the saturated sodium-chloride water of 1200ml, stirred 1 hour, left standstill 1 hour, filter, drying obtains 34g compound 16 Alpha-hydroxies-17 alpha-amino group-1,4, the pregnant steroid of 9-triolefin-3-ketone-20-half semicarbazone.
Annulation
16 Alpha-hydroxies-17 alpha-amino group-1 that adds 30g in the anticaustic bottle, 4, the pregnant steroid of 9-triolefin-3-ketone-20-half semicarbazone, acetic anhydride 150ml, acetate 150ml, 10～15 ℃ of reactions of temperature control 2 hours, the flaggy monitoring reaction finishes, with 1800ml times of saturated sodium-chloride water dilute reaction solution, it is neutral that 10% sodium hydroxide solution is regulated the pH value, stirs 1 hour, leaves standstill 1 hour, filter, drying obtains 2 of 29g '-methyl-5 ' β H-pregnant steroid-1,4,9-triolefin-[17 α, 16 α-d]-oxazoles-3-ketone-20-half semicarbazone.
20 ketone deprotection reactions
Adding 27.1g compound 2 in the reaction flask '-methyl-5 ' β H-pregnant steroid-1,4,9-triolefin-[17 α, 16 α-d]-oxazoles-3-ketone-20-half semicarbazone, tetrahydrofuran (THF) 135.5ml, feed nitrogen and discharge oxygen, 20-25 ℃ drips the 67.75ml concentrated hydrochloric acid down, reacted 12 hours, sampling is carried out the flaggy analysis and is determined reaction end, reaction solution is diluted in the saturated sodium-chloride water of 1500ml, separates out material, stirred 1 hour, left standstill 1 hour, filter, be washed to neutrality, dry 20.3g compound 2 '-methyl-5 ' β H-pregnant steroid-1,4,9-triolefin-[17 α, 16 α-d]-oxazoles-3, the 20-diketone.
Above three step process route synoptic diagram is as follows:
Embodiment two
Condensation, ring-opening reaction
In reaction flask, add 16 of 30g, 17-epoxy-11-hydroxyl-1,4-diene pregnant steroid-3,20-diketone (ZL200210014479.5), the dimethyl formamide of 180ml behind the feeding nitrogen replacement air, adds Urea,amino-18gH
2NNHCONH
2, 0.18g tosic acid, 25～30 ℃ of reactions of temperature control 2 hours, sampling is carried out tlc analysis to there not being raw material, changes the feeding ammonia, and temperature is at 10～15 ℃, stop air guide after 5 hours, reacted 1.5 hours again, tlc analysis is to there not being raw material, drain ammonia with air flow nitrogen, reaction solution is diluted in the saturated sodium-chloride water of 800ml, uses 150ml chloroform extraction three times, merge organic phase, be washed to neutrality, concentrating under reduced pressure with ethyl ester displacement 2～3 times, is separated out material during to small volume, 0～5 ℃ of cold putting 1 hour, filter, drying obtains 31.2g compound 11,16 α-two hydroxyls-17 alpha-amino group-1, the pregnant steroid of 4-diene-3-ketone-20-half semicarbazone.
Annulation
Add 11 of 30g in the anticaustic bottle, 16 α-two hydroxyls-17 alpha-amino group-1, the pregnant steroid of 4-diene-3-ketone-20-half semicarbazone, propionic anhydride 150ml, propionic acid 150ml, 10～15 ℃ of reactions of temperature control 2 hours, the flaggy monitoring reaction finishes, with 1500ml times of saturated sodium-chloride water dilute reaction solution, it is neutral that 10% sodium hydroxide solution is regulated the pH value, stirred 1 hour, left standstill 1 hour, filter, dry, obtain the 11-hydroxyl-2 of 29.1g '-ethyl-5 ' β H-pregnant steroid-1,4-diene-[17 α, 16 α-d]-oxazoles-3-ketone-20-half semicarbazone.
20 ketone deprotection reactions
Adding 25g compound 11-hydroxyl-2 in the reaction flask '-ethyl-5 ' β H-pregnant steroid-1,4-diene-[17 α, 16 α-d]-oxazoles-3-ketone-20-half semicarbazone, acetone 125ml feeds nitrogen and discharges oxygen, and 30-35 ℃ drips 30ml40% sulfuric acid down, reacted 10 hours, sampling is carried out the flaggy analysis and is determined reaction end, reaction solution is diluted in the saturated sodium-chloride water of 1500ml, separates out material, stirred 1 hour, left standstill l hour, and filtered, be washed to neutrality, dry 21.2g compound 11-hydroxyl-2 '-ethyl-5 ' β H-pregnant steroid-1,4-diene-[17 α, 16 α-d]-oxazoles-3, the 20-diketone.
Above three step process route synoptic diagram is as follows:
Embodiment three
Synthetic deflazacort:
With obtain 2 among the embodiment one '-methyl-5 ' β H-pregnant steroid-1,4,9-triolefin-[17 α, 16 α-d]-oxazoles-3, the 20-diketone is a raw material.
1) ethylene linkage addition reaction:
With 18.3g 2 '-methyl-5 ' β H-pregnant steroid-1,4,9-triolefin-[17 α, 16 α-d]-oxazoles-3, the 20-diketone, tetrahydrofuran (THF) 183ml adds in the reaction flask, moltenly is cooled to 0 ± 5 ℃ after clear, drips 4.8% high chloro acid solution 110ml fast, add the 22g N-bromosuccinimide afterwards, reacted 30 minutes, sampling is carried out the flaggy analysis and is determined terminal point, adds 30ml saturated sodium sulfite reactant aqueous solution and fades, in 10 ± 2 ℃ stir 30 minutes after, reaction solution poured in the 1200ml saturated sodium-chloride frozen water dilute, stirred 1 hour, left standstill 1 hour, filter, be washed to neutrality, drying, obtain compound 11-hydroxyl-9-bromo-2 of 22g '-methyl-5 ' β H-pregnant steroid-1,4,9-triolefin-[17 α, 16 α-d]-oxazoles-3, the 20-diketone.In the ethyl ester recrystallization obtain 14.6g11-hydroxyl-9-bromo-2 '-methyl-5 ' β H-pregnant steroid-1,4,9-triolefin-[17 α, 16 α-d]-oxazoles-3,20-diketone.
2) debrominate reduction reaction
11-hydroxyl-9-bromo-2 of adding 13.9g in the reaction flask '-methyl-5 ' β H-pregnant steroid-1,4,9-triolefin-[17 α, 16 α-d]-oxazoles-3,20-diketone, DMF111ml, fill the nitrogen deoxygenation, 80～90 ℃ of heating temperature controls splash into reductive agent tributyltin hydride (21ml) fast, and reacting took a sample after 1 hour carries out flaggy analysis confirmation terminal point, be cooled to 30 ℃, pour in the 700ml saturated sodium-chloride and dilute, stirred 1 hour, left standstill 1 hour, filter, be washed to neutrality, drying, obtain the 11-hydroxyl-2 of 11.2g '-methyl-5 ' β H-pregnant steroid-1,4,9-triolefin-[17 α, 16 α-d]-oxazoles-3, the 20-diketone.
3) iodination reaction
Add methyl alcohol 161ml in the reaction flask, calcium oxide 6.4g, in the other volumetric flask with 86ml methanol solution Calcium Chloride Powder Anhydrous 8.6g, molten clear back takes out 1/4, adds in the reaction flask, and surplus person is dissolved iodine grain 15.0g, the 11-hydroxyl-2 of adding 10.73g in the reaction flask '-methyl-5 ' β H-pregnant steroid-1,4,9-triolefin-[17 α, 16 α-d]-oxazoles-3,20-diketone, inflated with nitrogen, temperature control is in 0 ± 5 ℃, drip iodine solution, dripped off in about 4 hours, reacting took a sample after 1 hour again carries out the flaggy analysis, raw material disappears, reaction solution is poured in 2% aqueous ammonium chloride solution of 600ml and diluted, stirred 1 hour, left standstill 1 hour, filter, be washed to neutrality, drying, obtain compound 11-hydroxyl-2 '-methyl-5 ' β H-pregnant steroid-1,4,9-triolefin-[17 α, 16 α-d]-oxazoles-3, the two iodine of 20-diketone-21-, this product instability, drying-free, storage period is unsuitable long, stand-by.
4) replacement(metathesis)reaction
Add DMF11ml in the reaction flask, acetic acid 1ml, Potassium ethanoate 0.8g, adding wet feed compound 11-hydroxyl-2 '-methyl-5 ' β H-pregnant steroid-1,4,9-triolefin-[17 α, 16 α-d]-oxazoles-3, the two iodine of 20-diketone-21-, the chamber is stirred after 1 hour and was warming up to 35 ℃ of restir 1 hour, rise to 60 ± 2 ℃ afterwards again and stirred 2 hours, flaggy analysis confirmation terminal point is carried out in sampling, reduces to room temperature after reacting completely, pour in the 500ml saturated sodium-chloride water and dilute, with 50ml chloroform extraction product three times, merge organic phase, be washed to neutrality after, concentrate, pour ethyl ester during small volume, separate out solid, 0 ± 2 ℃ left standstill 2 hours, filter, a small amount of ethyl ester washing material, drying, 9.1g compound 11-hydroxyl-2 '-methyl-5 ' β H-pregnant steroid-1,4,9-triolefin-[17 α, 16 α-d]-oxazoles-3,20-diketone-21-acetic ester is the deflazacort crude product.Recrystallization in the methyl alcohol obtains 5.56g deflazacort elaboration.Fusing point: 253-256 ℃
Claims (10)
1. a compound (II) and compound (III), its structure is as follows:
Wherein 9,11 ... represent singly-bound or do not exist, X representative=O or OH (when ... representative is not when existing), H (when ... when representing singly-bound), six carbon of R=are with interior alkyl, Y represents 20 ketone group protecting groups, be the protecting group that is formed by 20 ketone group protective materials and corresponding catalyst and 20 ketone group condensation reactions of steroide, 20 ketone group protective materials and corresponding catalyst comprise: dimethyl ketal protection, hydrochloric acid or p-methyl benzenesulfonic acid catalysis; The protection of glycols ketal, hydrochloric acid or p-methyl benzenesulfonic acid catalysis; N, N-dimethyl hydrazone class condensation protection, acetic acid or toluene catalytically; Urea,amino-condensation protection, sodium-acetate catalysis; Hydrazinecarboxylate class condensation protection, perchloric acid or p-methyl benzenesulfonic acid catalysis; Oximes condensation protection, hydrochloric acid catalysis.
And ring A and B represent following residue:
W represents the protecting group of O or following formula oxo base:
N is 2 or 3; R
2Represent alkyl or acyl group.
2. compound (I), compound (II), the application of compound (III) in preparation compound (V).
Wherein 9,11 ... represent singly-bound or do not exist, X representative=O or OH (when ... representative is not when existing), H (when ... when representing singly-bound), six carbon of R=are with interior alkyl, and ring A and B represent following residue:
W represents the protecting group of O or following formula oxo base:
N is 2 or 3; R
2Represent alkyl or acyl group.
3. as described in the claim 2, it is characterized in that the ring A of compound (I) and compound (V) and B represent residue (1), W represents O.
4. the preparation method of compound (II) is characterized in that being prepared by the condensation ring-opening reaction by compound (I),
Described method comprises: the condensation ring-opening reaction
Reactant compound (1) is added in the organic solvent, add 20 ketone group protective materials and corresponding catalyst, reaction changes the feeding ammonia after finishing, and reaction is carried out aftertreatment after finishing, and obtains compound (II).
5. as described in the claim 4, it is characterized in that the preferred Urea,amino-condensation protection of organic solvent of condensation ring-opening reaction, sodium-acetate catalysis; Hydrazinecarboxylate class condensation protection, perchloric acid or p-methyl benzenesulfonic acid catalysis; Oximes condensation protection, hydrochloric acid catalysis.Preferred 10～30 ℃ of the temperature that begins to react feeds preferred 10～30 ℃ of ammonia afterreaction temperature.Aftertreatment preferably is diluted in the saturated inorganic salt solution, preferred sodium-chlor of inorganic salt and ammonium chloride; Answer a straight-through nitrogen in the condensation reaction before the logical ammonia.
6. the preparation method of compound (III) is characterized in that being prepared by cyclization by compound (II), and described method comprises: annulation
Reactant compound (II) is added in the organic acid, add corresponding organic acid anhydride, after reaction finished, dilution was regulated PH to neutral, filters, and obtains compound (III).
7. as described in the claim 6, it is characterized in that organic acid and the corresponding preferred acetate of organic acid anhydride and diacetyl oxide, propionic acid and the propionic anhydride of annulation.Temperature of reaction is preferably 10～30 ℃; The reaction dilution process preferably is diluted in the saturated inorganic salt solution preferred sodium-chlor of inorganic salt and ammonium chloride; Preferred sodium hydroxide of mineral alkali and potassium hydroxide.
8. the preparation method of compound (V) is characterized in that being prepared by 20 ketone deprotection reactions by compound (III), and described method comprises: 20 ketone deprotection reactions
Reactant compound (III) is added in the organic solvent, and logical nitrogen drips acid, and after reaction finished, dilution obtained compound (IV).
9. as described in the claim 8, it is characterized in that the preferred acetone of organic solvent of 20 ketone deprotection reactions, tetrahydrofuran (THF).The preferred acetic acid of acid, hydrochloric acid; Preferred 20～40 ℃ of the temperature of reaction.
10. the preparation method of a deflazacort is characterized in that selecting for use 1,4 in the compound (I), 9-triolefin-16, and 17-epoxy-3, the pregnant steroid of 20-diketone is a starting raw material, route is as follows
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103059096A (en) * | 2013-01-14 | 2013-04-24 | 仙居县圃瑞药业有限公司 | Synthesis method of deflazacort intermediate with [17a,16a-d] oxazoline structure |
| CN106008660A (en) * | 2016-06-20 | 2016-10-12 | 湖南科瑞生物制药股份有限公司 | Method for preparing deflazacort |
| CN107488203A (en) * | 2017-08-30 | 2017-12-19 | 湖南科瑞生物制药股份有限公司 | A kind of preparation method of 16a hydroxy prednisonlones |
| CN112375123A (en) * | 2020-12-10 | 2021-02-19 | 西北农林科技大学 | Oxazolyl steroid derivative, and synthetic method and application thereof |
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| NL128816C (en) * | 1965-04-22 | |||
| DE3173923D1 (en) * | 1980-12-23 | 1986-04-03 | Schering Ag | Process for the preparation of 11-beta, 21-dihydroxy-2'-methyl-5'-beta-h-1,4-pregnadieno-(16,17-d)-oxazole-3,20-dione |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103059096A (en) * | 2013-01-14 | 2013-04-24 | 仙居县圃瑞药业有限公司 | Synthesis method of deflazacort intermediate with [17a,16a-d] oxazoline structure |
| CN106008660A (en) * | 2016-06-20 | 2016-10-12 | 湖南科瑞生物制药股份有限公司 | Method for preparing deflazacort |
| CN106008660B (en) * | 2016-06-20 | 2018-02-23 | 湖南科瑞生物制药股份有限公司 | The preparation method of deflazacort |
| CN107488203A (en) * | 2017-08-30 | 2017-12-19 | 湖南科瑞生物制药股份有限公司 | A kind of preparation method of 16a hydroxy prednisonlones |
| CN107488203B (en) * | 2017-08-30 | 2019-06-04 | 湖南科瑞生物制药股份有限公司 | A kind of preparation method of 16a- hydroxy prednisonlone |
| CN112375123A (en) * | 2020-12-10 | 2021-02-19 | 西北农林科技大学 | Oxazolyl steroid derivative, and synthetic method and application thereof |
| CN112375123B (en) * | 2020-12-10 | 2022-11-01 | 西北农林科技大学 | Oxazolyl steroid derivative, and synthetic method and application thereof |
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