EP0873352A1 - PROCESS FOR PREPARATION OF 9,11$g(b)-EPOXIDE STEROIDS - Google Patents
PROCESS FOR PREPARATION OF 9,11$g(b)-EPOXIDE STEROIDSInfo
- Publication number
- EP0873352A1 EP0873352A1 EP96944777A EP96944777A EP0873352A1 EP 0873352 A1 EP0873352 A1 EP 0873352A1 EP 96944777 A EP96944777 A EP 96944777A EP 96944777 A EP96944777 A EP 96944777A EP 0873352 A1 EP0873352 A1 EP 0873352A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- temperature
- reaction
- mixture
- bromoformate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title description 2
- ZYSAVXVGWOCMMF-UHFFFAOYSA-N bromo formate Chemical compound BrOC=O ZYSAVXVGWOCMMF-UHFFFAOYSA-N 0.000 claims abstract description 34
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 22
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 18
- 150000003431 steroids Chemical class 0.000 claims abstract description 18
- 239000004593 Epoxy Substances 0.000 claims abstract description 15
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000012320 chlorinating reagent Substances 0.000 claims abstract description 12
- 239000003791 organic solvent mixture Substances 0.000 claims abstract description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 10
- 230000003197 catalytic effect Effects 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 78
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 69
- 239000000203 mixture Substances 0.000 claims description 45
- 238000006243 chemical reaction Methods 0.000 claims description 44
- 150000002118 epoxides Chemical class 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 21
- 239000003795 chemical substances by application Substances 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 5
- QDHHCQZDFGDHMP-UHFFFAOYSA-N Chloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 claims description 3
- 150000005671 trienes Chemical class 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
- 239000000243 solution Substances 0.000 description 30
- 238000004128 high performance liquid chromatography Methods 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 11
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 10
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- 239000000376 reactant Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 229920002554 vinyl polymer Polymers 0.000 description 6
- -1 e.g. Chemical group 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 238000010791 quenching Methods 0.000 description 5
- 230000000171 quenching effect Effects 0.000 description 5
- 239000002002 slurry Substances 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 125000005587 carbonate group Chemical group 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000001475 halogen functional group Chemical group 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 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 group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- RMRFFCXPLWYOOY-UHFFFAOYSA-N allyl radical Chemical compound [CH2]C=C RMRFFCXPLWYOOY-UHFFFAOYSA-N 0.000 description 1
- 239000000538 analytical sample Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 229940092705 beclomethasone Drugs 0.000 description 1
- NBMKJKDGKREAPL-DVTGEIKXSA-N beclomethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O NBMKJKDGKREAPL-DVTGEIKXSA-N 0.000 description 1
- 229960002537 betamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229960002744 mometasone furoate Drugs 0.000 description 1
- WOFMFGQZHJDGCX-ZULDAHANSA-N mometasone furoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(Cl)[C@@]4(C)C=CC(=O)C=C4CC[C@H]3[C@@H]2C[C@H]1C)C(=O)CCl)C(=O)C1=CC=CO1 WOFMFGQZHJDGCX-ZULDAHANSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- HSPSCWZIJWKZKD-UHFFFAOYSA-N n-chloroacetamide Chemical compound CC(=O)NCl HSPSCWZIJWKZKD-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 1
- 150000003128 pregnanes Chemical class 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/008—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21
- C07J7/0085—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21 by an halogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0061—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16
- C07J5/0069—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group
- C07J5/0076—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group by an alkyl group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/001—Oxiranes
- C07J71/0015—Oxiranes at position 9(11)
Definitions
- a translation of East German 268954 Al discloses a process for preparing steroids of the pregnane series which contain a 9 ⁇ - halogen- 1 l ⁇ -formyloxy group. Steroids with these substituents are precursors to the respective 9 ⁇ -halo, 1 l ⁇ -hydroxysteroids.
- processes which produce their precursors in high yield with a minimum of by-products would be a welcome contribution to the art.
- the claimed invention provides just such a contribution.
- the claimed invention is directed to a process for producing 9, l l ⁇ -epoxy steroids from their 9, 1 1 -double bond precursors.
- the use of a minimal amount of DMF and a minimal amount of 70% HCIO 4 when the 9, 1 1 -double bond precursor is reacted with a suitable brominating or chlorinating agent produces the corresponding 9 ⁇ -halo- l l ⁇ -formate steroid with rninirnal formation of dihalo by-products.
- the claimed invention is directed to a process for producing an epoxy steroid of Formula 1.0:
- R 1 is selected from H, -OH, or Cl; and R 2 is selected from hydrogen or lower alkyl; said process comprising: (A) reac :
- R 2 is as defined above; and when R 1 is H then R 3 is H; and when R 1 is -OH then R 3 is a suitably protected -OH group; and when R 1 is Cl then R 3 is Cl; and
- a brominating agent selected from DBH or NBS, in DMF containing a catalytic amount of 70% HCIO4, at a temperature of about 0 to about 40°C; wherein R 2 is is selected from hydrogen or lower alkyl; and R 3 is selected from H, a suitably protected -OH group, or Cl.
- This invention is also directed to a process for producing an epoxy steroid of Formula 1.0
- alkyl - represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms;
- DBH - l 3-dibromo-5,5-dimethylhydantoin;
- DMF - represents dimethylformamide
- lower alkyl - represents straight or branched chain alkyl groups having from 1 to 6 carbon atoms, e.g., methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, n-pentyl, isopentyl, n-hexyl, and 2.3-dimethyl-butyl;
- Meq - represents molar equivalents
- NBS - represents N-bromosuccinimide
- THF - represents tetrahydrofuran.
- R 1 is -OH
- R 2 is lower alkyl with -CH 3 being most preferred.
- R 3 is (a) H when R 1 is H; (b) Cl when R 1 is Cl; and (c) a suitably protected -OH group when R 1 is OH.
- the suitably protected -OH group is obtained using suitable protecting groups known in the art.
- suitable protecting groups are those groups which, under the reaction conditions of the epoxide formation, are easily hydrolyzable to provide an unprotected -OH group for R 1 .
- Suitable protecting groups are disclosed in Green et al.. Protective Groups In Organic Synthesis, Second Edition, John Wiley & Sons Inc., New York, 1991 , the disclosure of which is incorporated herein by reference thereto.
- R 1 is -OH
- suitable R 3 groups include -OC(O)R 4 (an ester) or -OC(O)OR 5 (a carbonate).
- R 5 is selected from Ci to C ⁇ alkyl, aryl (such as phenyl or benzyl), vinyl
- R 3 is -OC(0)OR 5 , more preferably R 3 is -OC(O)OR 5 wherein R 5 is C 1 to C ⁇ alkyl, and most preferably R 3 is -OC(O)OR 5 wherein R 5 is -C 2 H 5 .
- the starting reactant of Formula 2.0 wherein R 3 is H, Cl, or -OC(O)R 4 , wherein R 4 is C i to C ⁇ alkyl or -CF3, and wherein R 3 is -OC(O)OR 5 wherein R 5 is Ci to C ⁇ alkyl, can be made according to the procedures disclosed in International Application No. PCT/US95/06600 filed on May 30, 1995, and U.S. Application Serial No. 08/252,302 filed on June 1 , 1994, the disclosures of each being incorporated herein by reference thereto.
- R 4 is phenyl, benzyl, naphthyl, vinyl or allyl
- R 5 is phenyl, benzyl, vinyl or allyl
- the solvent for these reactions is, for example, methylene chloride in the presence of triethylamine.
- the bond represents the ⁇ or ⁇ configuration.
- the bond represents the ⁇ or ⁇ configuration.
- the reactions of the bromoformate (3.0) or the chloroformate (3.0A) to produce the epoxy steroid (1.0) are preferably conducted under an inert atmosphere, such as nitrogen.
- the compound of Formula 2.0 is reacted with a suitable brominating reagent or chlorinating agent.
- Suitable brominating agents are DBH or NBS, with DBH being preferred.
- Suitable chlorinating agents are N-chloroimides or an N-chloroamides. Examples of chlorinating reagents include: N-chloroacetamide, N-chlorosuccinimide, l ,3-dichloro-5,5-dimethyhydantoin, or
- 1 ,3,5-trichloroisocyanuric acid Preferably, l ,3-dichloro-5,5- dimethyhydantoin or 1 ,3,5-trichloroisocyanuric acid is used.
- a brominating reagent is used.
- the reaction of the compound of Formula 2.0 with the brorninating or chlorinating agent takes place in DMF, to which a catalytic amount of 70% HCIO 4 is added.
- a sufficient amount of the compound of Formula 2.0 and the brominating or chlorinating agent are used to allow the reaction to proceed at a reasonable rate to obtain the desired bromoformate of Formula 3.0 or the desired chloroformate of 3.0A.
- At least about 0.5 molar equivalents (Meq) of the brominating agent, such as DBH, or chlorinating agent is used.
- Meq 0.5 molar equivalents
- DMF is used in an excess relative to the compound of Formula 2.0. Enough DMF is used to function as a solvent and a reactant, and preferably, the minimum required amount is used.
- a volume of DMF is used which is in an excess of about 2 to 20 times the amount of the compound of Formula 2.0, with about 2 to about 5 times being preferred, and about 3 to about 4 times being more preferred, and about 3.5 times being most prefered.
- the 70% HCIO 4 is used in catalytic amounts, and preferably the minimum required amount is used. At least about 0.5 Meq of 70% HCIO 4 is used, with suitable amounts being about 0.5 to about 3.0 Meq, and about 0.5 to about 1.0 Meq being preferred, and about 0.5 to about 0.7 Meq being more preferred, and about 0.6 Meq being most prefered.
- reaction of a compound of Formula 2.0 with the brominating agent or chlorinating is conducted at a temperature of about 0 to about 40°C, with about 5 to about 30°C being preferred, and about 10 to about 25°C being more preferred, and about 10 to about 20°C being most preferred.
- the reaction forming the bromoformate or chloroformate can be monitored by known techniques to determine when the reaction is complete.
- HPLC can be used to monitor the reaction to determine when all of the starting material has been used up.
- the bromoformate of Formula 3.0 or the chloroformate of 3.0A is isolated from the reaction mixture, by techniques well known in the art, before proceeding to the next reaction (epoxide formation).
- the bromoformate or chloroformate can be isolated as a wet cake by quenching the reaction in an excess of water to precipite the bromoformate or chloroformate and then filtering the resulting slurry.
- a Ci to Cg alkanol e.g. , methanol, ethanol, or isopropanol, with methanol being preferred
- alkanol e.g. , methanol
- the quenching solution water and alkanol mixture
- the quenching solution is at least about 5% alkanol, preferably methanol, with about 5 to about 25% being preferrred, and about 10 to about 15% being more preferred, and about 12 to about 14% being still more preferred, and about 13% being most preferred.
- alkanol e.g., methanol
- the quenching solution water and alkanol mixture
- alkanol preferably methanol
- the bromoformate of Formula 3.0 or chloroformate of 3.0A is reacted with a strong base in an organic solvent mixture comprising: (a) THF or CH 2 CI 2 and (b) a C ⁇ to C ⁇ alkanol or acetonitrile.
- Suitable strong bases are those bases which provide -OH ions upon dissociation in aqueous solution.
- the strong base can be an inorganic base, such as NaOH or KOH; or an organic base, such as sodium methoxide, potassium methoxide, sodium butoxide, potassium butoxide. sodium t-butoxide or potassium t- butoxide.
- NaOH is used.
- a sufficient amount of water is used to dissolve the base and provide -OH ions in solution.
- the base is added as an aqueous solution to the reaction mixture, or the base can be added to the reaction mixture to which a sufficient amount of water is added to dissolve the base.
- the base is added as a freshly prepared aqueous solution.
- At least about 7.5 Meq of water is used to provide an aqueous solution of the base, and suitably about 7.5 to about 50 Meq of water are used, with about 7.5 to about 25 being preferred, and about 10 to about 20 Meq being more preferred, and about 14 to about 16 Meq being even more preferred, and about 15 Meq of water being most preferred.
- the base is used in an amount which effectively causes formation of the 9, l l ⁇ -epoxide, and when present, hydrolysis of the R 3 ester or carbonate protecting groups to an R 1 -OH group.
- R 3 is selected from H or Cl
- the base such as NaOH, is used in amounts of about 1.0 to about 4.0 Meq, with about 1.5 to about 2.0 Meq being preferred.
- R 3 is an ester or carbonate protecting group, such as -OC(O)R 4 or -OC(O)OR 5
- the base such as NaOH
- the base is used in amounts of about 2.0 to about 4.0 Meq, with about 2.5 to about 3.5 Meq being preferred, and about 3.0 Meq being most preferred.
- CH2CI2 is preferably used for compounds wherein R 2 is in the ⁇ - or ⁇ - position.
- THF is used it is more preferably used with compounds wherein R 2 is in the ⁇ - position.
- C i to C ⁇ alkanols include but are not limited to: methanol, ethanol or isopropanol.
- methanol is used with the THF or CH 2 C1 2 .
- the CH2CI 2 or THF, preferably CH2CI 2 is used as a solvent in an excess relative to the amount of the compound of Formula 2.0.
- the solvent is used in an excess of at least about 3 times (3X) the amount of the compound of Formula 2.0, with suitable amounts being about 3X to about 20X. and about 4X to about 10X being preferred, and about 5X to about 8X being more preferred, and about 6X to about 7X being most preferred.
- the C i to C 6 alkanol or acetonitrile, preferably methanol, is used in an excess relative to the amount of the compound of Formula 2.0.
- the alkanol or acetonitrile is used in an excess of at least about one time ( IX) the amount of the compound of Formula 2.0, with suitable amounts being about IX to about 20X, and about IX to about 5X being preferred, and about IX to about 3X being more preferred, and about 2X being most preferred.
- the alkanol or acetonitrile is used in an excess of at least about three times (3X) the amount of the compound of Formula 2.0, with suitable amounts being about 3X to about 20X, and about 3X to about 10X being preferred, and about 5X to about 7X being more preferred, and about 6X being most preferred.
- the reaction of the bromoformate of Formula 3.0 or the chloroformate of Formula 3.0A with base to form the epoxide of Formula 1.0 is conducted at a temperature low enough to reduce the formation of unwanted by-products. Generally, a temperature of about + 10 to about -20°C is used, with about 0 to about - 10°C being preferred, and about -2 to about -6°C being more preferred, and about -5°C being most preferred.
- the reaction to form the epoxide can be monitored by known techniques, such as HPLC, to determine when the reaction is complete--i.e., to determine when no more starting reactant is present.
- the reaction can then be quenched, with an organic acid, to a pH of about 3 to about 5. Suitable organic acids include but are not limited to acetic acid, formic acid, and tartaric acid, with acetic acid being preferred.
- the epoxy steroid of Formula 1.0 can be isolated by known techniques. Since the epoxy steroid is normally obtained as a precipitate, it can be isolated by filtration.
- the epoxide can be purified by techniques well known in the art. For example, in a preferred purification method the epoxide of Formula 1.0 is dissolved by heating in a sufficient amount of a mixture of CH 2 CI 2 and methanol. The resulting mixture is then filtered, concentrated, cooled, filtered, washed (preferably with methanol), and dried under vacuum to yield the purified epoxide of Formula 1.0.
- the epoxy steroid obtained can be utilized to produce other known steroids using known techniques.
- the epoxy steroid can be used to produce Betamethasone, Beclomethasone, Dexamethasone or Mometasone Furoate.
- TC is -OC(O)OC 2 H 5
- R 3 is -OC(O)OC 2 H 5
- the 16 ⁇ -methyl-triene-21 -cathylate of Formula 2.1 (about 90% pure) (50 g) was dissolved in DMF ( 175 ml) at room temperature. This mixture was cooled to about 10°C, and then 70% HCIO 4 (6.25 ml) was added to the mixture. This addition was done during a five minute time period to keep the reaction temperature below 20°C. The mixture was cooled to about 10°C and DBH (25.1 g) was added to the mixture. This addition was done over about a 15 minute time period to keep the reaction temperature below 20°C.
- R 3 is -OC(O)OC 2 H 5
- the bromoformate wet cake ( 1 13 g) from Step A was dissolved in a mixture of CH2CI 2 (350 ml) and methanol (325 ml). The resulting mixture was cooled to about -5°C, vacuum degased three times under nitrogen, and kept under nitrogen.
- a NaOH solution was made by dissolving NaOH (15 g) in water (15 ml), and the resulting NaOH solution was cooled to about 5°C.
- the freshly prepared NaOH solution was added to the bromoformate- CH 2 CI2/CH3OH mixture. The addition of the NaOH solution was done slowly over about a one hour time period (0.3ml/minute) while keeping the temperature of the reaction mixture between about -5 and about -3°C.
- the resulting reaction mixture was agitated at about -3 to about -5°C for about two hours. After HPLC indicated the reaction was complete, the reaction mixture was quenched with acetic acid (40 ml). The reaction mixture was concentrated to 250 ml by distillation of the CH 2 CI 2 and vacuum distillation of the CH3OH. Then water (175 ml) was added to the mixture and this mixture was concentrated to 250 ml. This was followed by addition of water (500 ml) and cooling to about 1°C of the resulting slurry. The slurry was agitated for about 30 minutes at about 1°C and then filtered and the wet cake obtained was washed with water.
- the wet cake was dried under vacuum at about 50°C for about 16 hours to provide 41.2 g (purity 90.0% against a standard) of the crude epoxide (Formula 1.1). This represents a 97% molar yield from the triene-21-cathylate (Formula 2.1).
- the crude epoxide (Formula 1.1) (41. lg) was heated in a mixture of CH2CI2 (697 ml) and methanol (205 ml) until dissolved. The resulting solution was filtered and concentrated to a volume of about 164 ml.
- R 3 is -OC(O)OC 2 H 5
- R 3 is -OC(O)OC 2 H 5
- the 16 ⁇ -methyl-triene-21-cathylate of Formula 2.2 (about 86% pure) (10 g) was dissolved in DMF (50 ml) at room temperature. Then 70% HCIO 4 ( 1.25 ml) was added to the mixture. Next, DBH (4.5 g) was added at room temperature over about a 15 minute time period. The resulting mixture was agitated at room temperature for about one hour and monitored by HPLC. When HPLC indicated that the reaction was not complete, about 0.2 g of DBH was added, and agitation was continued for about 30 rninutes. When HPLC indicated the reaction was complete, CH3OH (100 ml) was added to the mixture. The bromoformate of Formula 3.2 was precipitated in water (1000 ml) containing CH 3 OH (100 ml). The mixture was filtered and the wet cake of bromoformate was washed with water.
- R 3 is -OC(O)OC 2 H 5
- the wet cake of bromoformate from Step A was dissolved in a mixture of THF (80 ml) and CH 3 OH (80 ml). The resulting solution is vacuum degassed under nitrogen, kept under a nitrogen atmosphere and cooled to about -3°C.
- a NaOH solution was prepared by dissolving NaOH (1.75 g) in water (7.5 ml) and then cooling the resulting NaOH solution to about 0 to about 5°C.
- the NaOH solution was added to the bromoformate-THF/CH 3 OH solution over about a one hour time period while keeping the temperature of the reaction mixture between about -4.0 and about -2.0°C.
- the crude epoxide (8.05 g) was dissolved by refluxing in a solution of CH 3 OH (60 ml) and CH 2 C1 2 (40 ml). The mixture was agitated for about 30 minutes and then concentrated to about 40 ml (45 ml of solvent was collected). The solution was slowly cooled to room temperature and then cooled to about 0 to about 5°C. The mixture was filtered, the precipitate was washed with cold CH 3 OH (2 X 6 ml), and dried under vacuum.
- the epoxide of Formula 1.2 was obtained as white crystals, 6.6 g, having a purity of 99% and an overall molar yield of 87% (based on the starting triene-21 -cathylate of Formula 2.2).
- R 3 is -OC(O)OC 2 H 5
- R 3 is -OC(O)OC 2 H 5
- the 16 ⁇ -methyl-triene-21-cathylate of Formula 2.2 (86.9% pure) (50 g) was suspended in DMF (175 ml) at room temperature. Then 70% HCIO 4 (6.5 ml) was added at room temperature to the mixture. Next, DBH (25 g) was added at room temperature over about a 10 minute time period. The resulting mixture was agitated at room temperature until HPLC indicated that the reaction was complete (about one hour).
- reaction mixture was diluted with CH 3 OH (150 ml).
- the bromoformate of Formula 3.2 was precipitated, over about a 40 minute time period, in water (4000 ml) that contained CH 3 OH (500 ml) and Na 2 SO 3 (6 g).
- the resulting mixture was agitated at room temperature for about 30 minutes and then cooled to about 4°C and agitated at this temperature for about 30 minutes.
- the bromoformate was collected as a wet cake by filtration, and the wet cake was washed with water (2000 ml) .
- R 3 is -OC(O)OC 2 H 5
- the bromoformate from Step A was dissolved in a mixture of CH 2 C1 2 (300 ml) and CH 3 OH (25 ml). The aqueous layer was separated from the organic layer, and the aqueous layer was extracted with CH 2 CI2 ( 100 ml). The organic layers were combined and CH 3 OH ( 100 ml) was added to the resulting organic solution. The resulting solution was cooled to about -4°C, vacuum degassed four times under nitrogen, and kept under nitrogen.
- a NaOH solution was prepared by dissolving NaOH (15 g) in water (30 ml). The NaOH solution was cooled and was added to the bromoformate-CH 2 Cl 2 /CH 3 ⁇ H solution over about a one hour time period while keeping the temperature of the reaction mixture below -2°C. The reaction mixture was agitated at about -4°C until HPLC indicated that the reaction was complete (about one hour).
- the triene chloride ( 1 g) of Formula 2.3 was dissolved in DMF (3.5 ml), and the resulting solution was cooled to about 13°C.
- 70% Perchloric acid (0.13 ml) was added to the solution followed by the addition of DBH (0.7 g).
- the mixture was agitated at room temperature until HPLC indicated the reaction was complete (about 2 hours).
- CH 3 OH (3.5 ml) was added to the reaction mixture, and the resulting mixture was agitated for about 5 minutes. This resulted in the bromoformate of Formula 3.3 cystallizing out of solution.
- water (70 ml) containing CH3OH (7 ml) was added and the resulting mixture was agitated for about 30 minutes.
- the bromoformate ( 1 g) from Step A was dissolved in a mixture of CH2CI2 ( 10 ml) and CH3OH (5 ml). The solution was cooled to about -5°C, degassed four times under vacuum and kept under nitrogen. A NaOH solution was prepared by dissolving NaOH (0.2 g) in water (1 ml). The NaOH solution was added slowly over about a 30 minute time period to the bromoformate- CH 2 CI2/CH 3 OH solution to keep the reaction mixture at a temperature of about -5 to about -3°C. The reaction was monitored for completion (about one hour) by HPLC. The reaction was quenched with acetic acid (0.5 ml).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US57556295A | 1995-12-20 | 1995-12-20 | |
PCT/US1996/019600 WO1997022616A1 (en) | 1995-12-20 | 1996-12-18 | PROCESS FOR PREPARATION OF 9,11β-EPOXIDE STEROIDS |
US575562 | 2000-05-21 |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0873352A1 true EP0873352A1 (en) | 1998-10-28 |
Family
ID=24300812
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP96944777A Withdrawn EP0873352A1 (en) | 1995-12-20 | 1996-12-18 | PROCESS FOR PREPARATION OF 9,11$g(b)-EPOXIDE STEROIDS |
Country Status (12)
Country | Link |
---|---|
EP (1) | EP0873352A1 (no) |
JP (1) | JP2000502102A (no) |
KR (1) | KR20000064495A (no) |
CN (1) | CN1209138A (no) |
AU (1) | AU1331097A (no) |
BR (1) | BR9612064A (no) |
CZ (1) | CZ191398A3 (no) |
IL (1) | IL125004A0 (no) |
MX (1) | MX9804957A (no) |
NO (1) | NO982877L (no) |
PL (1) | PL327141A1 (no) |
WO (1) | WO1997022616A1 (no) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HUE046243T2 (hu) | 2008-05-28 | 2020-02-28 | Reveragen Biopharma Inc | Nem-hormonális NF-KB szteroid modulátorok betegség kezelésére |
EP2556083A4 (en) | 2010-04-05 | 2013-12-04 | Validus Biopharma Inc | NONHORMONAL STEROID MODULATORS OF NF-KAPPA-B FOR DISEASE TREATMENT |
CN103588853A (zh) * | 2013-11-28 | 2014-02-19 | 浙江省天台县奥锐特药业有限公司 | 制备9,11β-环氧甾族化合物的方法 |
WO2017004205A1 (en) | 2015-06-29 | 2017-01-05 | Reveragen Biopharma, Inc. | NON-HORMONAL STEROID MODULATORS OF NF-κB FOR TREATMENT OF DISEASE |
CN107266519B (zh) * | 2016-04-08 | 2021-06-29 | 天津金耀集团有限公司 | 一种9β,11β-环氧-17α-羟基-16α-甲基-21-氯代-1,4孕甾二烯-3,20-二酮新晶型及其制备方法 |
CN109180767A (zh) * | 2018-09-04 | 2019-01-11 | 浙江仙琚制药股份有限公司 | 一种制备糠酸莫米松的方法 |
US11382922B2 (en) | 2019-03-07 | 2022-07-12 | Reveragen Biopharma, Inc. | Aqueous oral pharmaceutical suspension compositions |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1145170B (de) * | 1959-03-13 | 1963-03-14 | Scherico Ltd | Verfahren zur Herstellung von 9,11-Oxidosteroiden der Androstan- und Pregnanreihe |
GB1244604A (en) * | 1967-08-25 | 1971-09-02 | Organon Labor Ltd | Substituted methylene steroids and their preparation |
GB1416427A (en) * | 1972-01-12 | 1975-12-03 | Akzo Nv | Alkylated pregnanes and process for obtaining same |
DE2617655C2 (de) * | 1976-04-21 | 1984-11-08 | F. Hoffmann-La Roche & Co Ag, Basel | Kortikoide, Verfahren zu deren Herstellung und diese enthaltende pharmazeutische Präparate |
DE3064460D1 (en) * | 1979-01-24 | 1983-09-08 | Akzo Nv | Novel alkylated pregnanes, processes for their preparation and pharmaceutical compositions containing same |
DD268954A1 (de) * | 1983-04-22 | 1989-06-14 | Jenapharm Veb | Verfahren zur herstellung von 9alpha-halogen-11beta-formyloxysteroiden der pregnanreihe |
FR2675146A1 (fr) * | 1991-04-10 | 1992-10-16 | Roussel Uclaf | Nouveaux derives sterouides de la pregna-1,4-diene-3,20-dione, leur preparation, leur application a la preparation de derives 16,17-methylene dioxy substitues et nouveaux intermediaires. |
-
1996
- 1996-12-18 JP JP09522872A patent/JP2000502102A/ja active Pending
- 1996-12-18 CZ CZ981913A patent/CZ191398A3/cs unknown
- 1996-12-18 KR KR1019980704706A patent/KR20000064495A/ko not_active Application Discontinuation
- 1996-12-18 WO PCT/US1996/019600 patent/WO1997022616A1/en not_active Application Discontinuation
- 1996-12-18 EP EP96944777A patent/EP0873352A1/en not_active Withdrawn
- 1996-12-18 AU AU13310/97A patent/AU1331097A/en not_active Abandoned
- 1996-12-18 BR BR9612064A patent/BR9612064A/pt not_active Application Discontinuation
- 1996-12-18 PL PL96327141A patent/PL327141A1/xx unknown
- 1996-12-18 CN CN96180071A patent/CN1209138A/zh active Pending
- 1996-12-18 IL IL12500496A patent/IL125004A0/xx unknown
-
1998
- 1998-06-19 MX MX9804957A patent/MX9804957A/es unknown
- 1998-06-19 NO NO982877A patent/NO982877L/no unknown
Non-Patent Citations (1)
Title |
---|
See references of WO9722616A1 * |
Also Published As
Publication number | Publication date |
---|---|
AU1331097A (en) | 1997-07-14 |
BR9612064A (pt) | 1999-02-23 |
CN1209138A (zh) | 1999-02-24 |
NO982877D0 (no) | 1998-06-19 |
NO982877L (no) | 1998-08-20 |
WO1997022616A1 (en) | 1997-06-26 |
MX9804957A (es) | 1998-09-30 |
PL327141A1 (en) | 1998-11-23 |
JP2000502102A (ja) | 2000-02-22 |
CZ191398A3 (cs) | 1998-11-11 |
KR20000064495A (ko) | 2000-11-06 |
IL125004A0 (en) | 1999-01-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
RU2048472C1 (ru) | СПОСОБ ПОЛУЧЕНИЯ (22R,S)- 16α, 17α -БУTИЛИДEHДИOKCИ- 11β, 21 -ДИГИДPOKCИПPEГHA-1,4-ДИEH-3,20-ДИOHA | |
WO2009083258A2 (en) | Solid and crystalline dutasteride and processes for preparation thereof | |
US6600025B1 (en) | Intermediates, process for preparing macrolide antibiotic agent therefrom | |
JP2018512066A (ja) | デオキシコール酸の作製方法 | |
EP0873352A1 (en) | PROCESS FOR PREPARATION OF 9,11$g(b)-EPOXIDE STEROIDS | |
US20170114088A1 (en) | Process for the preparation of 17-desoxy-corticosteroids | |
EP3854800B1 (en) | High-yield preparation method for novel vascular leakage blocker | |
AU775831B2 (en) | Process for preparing 17alpha-acetoxy-11beta-(4-N,N-(dimethylamino)phenyl)-21- methoxy-19-norpregna-4,9-diene-3,20-dione, intermediates useful in the process, and processes for preparing such intermediates | |
EP0349217A2 (en) | Novel process for the preparation of bronopol | |
EP0739885B1 (en) | Process for producing 3-isoxazolecarboxylic acid | |
EP0257361B1 (en) | 5-fluorouridine derivative and preparation of the same | |
KR910000239B1 (ko) | 메틸 2-테트라데실글리시데이트의 제조방법 | |
JPH0147470B2 (no) | ||
KR860001496B1 (ko) | 20-케토-델타^16-스테로이드류의 신규 제조방법과 이 방법에서 얻는 신규의 중간물류 제조방법 | |
KR100900177B1 (ko) | 트리테르펜 유도체의 제조 방법 | |
CN114478672B (zh) | 一种he3286的合成方法 | |
CA2240407A1 (en) | Process for preparation of 9,11.beta.-epoxide steroids | |
US4477677A (en) | Process for the preparation of 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indoleacetoxyacetic acid | |
US4459415A (en) | Process for the preparation of 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indoleacetoxyacetic acid | |
US7501515B2 (en) | Polymorphic form of 17-β-(N-ter. butyl carbamoyl)-4-aza-5-α-androst-1-en-3-one | |
KR0169558B1 (ko) | 2-아미노-3,5- 디브로모 벤즈알데히드의 제조방법 | |
CN115872923A (zh) | 一种化合物及其制备方法 | |
JP2853929B2 (ja) | 2−クロロ−4,5−ジフルオロ−3−メトキシ安息香酸の製造方法 | |
KR100348100B1 (ko) | 2-[(2,6-디클로로페닐)아미노]페닐아세톡시아세트산의제조방법 | |
KR900007314B1 (ko) | N-(메톡시아세틸)-n-(2,6-디메틸페닐)-3-아미노-옥사조리딘-2-온의 제조방법 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 19980530 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU NL PT SE |
|
AX | Request for extension of the european patent |
Free format text: LT PAYMENT 980530;LV PAYMENT 980530;RO PAYMENT 980530 |
|
17Q | First examination report despatched |
Effective date: 19981015 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN |
|
18W | Application withdrawn |
Withdrawal date: 19990211 |
|
RTI1 | Title (correction) |
Free format text: PROCESS FOR PREPARATION OF 9,11 BETA-EPOXIDE STEROIDS |