Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
  • C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
  • C07F7/02—Silicon compounds
  • C07F7/08—Compounds having one or more C—Si linkages
  • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
  • C07F7/1804—Compounds having Si-O-C linkages

Definitions

• the present invention relates to novel methods for the separation of the commercially available mixture of gibberellins, and especially gibberellins GA4 and GA7, and to the products made by such separation processes.
• Gibberellins are powerful plant hormones which are responsible for flowering, root growth, stem elongation, fruit size, branching and the like for various fruits and crops.
• the mixture of gibberellins GA4 and GA7 and pure GA3 are the only gibberellins presently commercially produced in quantity from cultures of the fungus Gibberella fuiikoroi. These gibberellins are, therefore, convenient starting materials for the synthesis of less accessible gibberellins and, themselves, are powerful plant hormones which are important for use in agriculture.
• GA7 is obtained from GA3 by a five step reaction sequence which involves selective protection of the 3- ⁇ -hydroxyl group of GA3, preparation of the 13-methanesulfonyl derivative of the 3-acetate, hydrolysis of the acid chloride and reduction of the bridgehead-methanesulfonate, followed by hydrolysis of the resulting acetate.
• GA4 is obtained via Jones oxidation of a GA4/GA7 mixture, followed by Selectride® reduction.
• Another method for obtaining GA4 is selective degradation of GA7 from the mixture of GA4 and GA7, followed by isolation of GA4; but this method literally converts the GA7 into degradation products. None of these methods can provide GA4 and GA7 in large quantities efficiently.
• a process for separating gibberellins from mixtures thereof, and especially GA4 and GA7 from a mixture of GA4 and GA7 which comprises reacting said mixtures with a silylating agent.
• This reaction may be followed, in the case of GA4 and GA7, by selectively hydrolyzing the GA7 silyl ether in the presence of the GA4 silyl ether and separating the GA7 from the GA4 silyl ether.
• the silylating agent in the above process is t-butyldimethylsilyl chloride.
• a gibberellin selected from the group consisting of GA4 and GA7 which is prepared by the above process.
• Ri, R2 and R3 are independently selected from loweralkyl and aryl. Preferred among such compounds are those wherein Ri is t-butyl and R2 and R3 are methyl.
• loweralkyl refers to straight or branched chain alkyl radicals containing from 1 to 7 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
• aryl refers to phenyl, benzyl, diphenylmethyl or triphenylmethyl or substituted phenyl, benzyl, diphenylmethyl or triphenylmethylwherein one or more of the phenyl rings is substitued with loweralkyl, halogen or alkoxy.
• alkoxy refers to R'O- wherein R ! is a loweralkyl group.
• the present invention relates to novel processes for obtaining pure GA4 and GA7 from the readily available mixture of GA4 and GA7.
• the methods of this invention are predicated upon the discovery of the differential reactivities of GA4 and GA7 toward silyl ether formation and subsequent deprotection.
• This selectivity for silylation of GA7 versus GA4 may be attributed to the more accessible steric enviroment of the ring A of GA7 (more planar) than the ring A of GA4.
• Selective reaction was achieved by using slightly more than one equivalent (1.6 eq.) of t-butyldimethylsilyl chloride at room temperature. Increasing the amount of silylating agent in excess of this amount or raising the temperature above room temperature resulted in the formation of the silyl ether of GA4. Under forcing conditiona, such as higher temperature (45°C) and/or excess silylating agent (5 eq.), both GA4 and GA7 can be completely converted to their silyl ethers.
• silylating agents can include alkyl or aryl substituted silylating agents (e.g., R ⁇ R2R3SiX wherein Ri, R2 and R3 are independently selected from loweralkyl and aryl and X is a halogen or -OSO2CF3) such as dimethylphenylsilyl-, triisopropylsilyl-, trimethylsilyl-, t-butyldiphenylsilyl-, triethylsilyl- or triphenylsilyl-halides or triflates.
• alkyl or aryl substituted silylating agents e.g., R ⁇ R2R3SiX wherein Ri, R2 and R3 are independently selected from loweralkyl and aryl and X is a halogen or -OSO2CF3
• alkyl or aryl substituted silylating agents e.g., R ⁇ R2R3SiX wherein Ri, R2 and R3
• Solvents and bases used with these silylating agents include, but are not limited to, aprotic solvents such as tetrahydrofuran (THF), dimethylsulfoxide (DMSO), acetonitrile, DMF or methylene chloride (CH2CI2) and the like, and bases such as imidazole, dimethylaminopyridine (DMAP), triethylamine (TEA), pyridine or carbonates and the like. It has also been discovered that the silyl ether of GA7 formed from the above reaction has completely different physical properties from GA4, such as solubility in organic solvents and in water.
• aprotic solvents such as tetrahydrofuran (THF), dimethylsulfoxide (DMSO), acetonitrile, DMF or methylene chloride (CH2CI2) and the like
• bases such as imidazole, dimethylaminopyridine (DMAP), triethylamine (TEA), pyridine or carbonates and the like.
• the silyl ether of G A7 is much more soluble than GA4 in hexane, ether, and dichloromethane; however, the silyl ether of GA7 is much less soluble than GA4 in acetic acid and water. Based on these differences, the silyl ether of GA7 can be easily separated from GA4 by simple crystallization. The separated silyl ether of GA7 can then be desilylated by simply treating it with a desilylating agents such as tetrabutylammonium fluoride to afford GA7.
• a desilylating agents such as tetrabutylammonium fluoride
• Other useful desilylating agents include K2COj/methanol, H- /methanol (wherein the acidic reagent is an acidic resin such as Dowex® 50W-X8 or Nafion® and the like), KF/crown ether, HF, BF3-Et2 ⁇ , FeC-3/acetic anhydride, acetic acid/water or citric acid/methanol and the like.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Saccharide Compounds (AREA)
• Furan Compounds (AREA)
• Solid-Sorbent Or Filter-Aiding Compositions (AREA)
• Steroid Compounds (AREA)

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• 1992
  • 1992-06-12 JP JP50105793A patent/JP3194581B2/ja not_active Expired - Fee Related
  • 1992-06-12 EP EP92914330A patent/EP0588964B1/en not_active Expired - Lifetime
  • 1992-06-12 AU AU22500/92A patent/AU659661B2/en not_active Ceased
  • 1992-06-12 DE DE69226638T patent/DE69226638T2/de not_active Expired - Fee Related
  • 1992-06-12 AT AT92914330T patent/ATE169620T1/de not_active IP Right Cessation
  • 1992-06-12 US US08/146,108 patent/US5562831A/en not_active Expired - Fee Related
  • 1992-06-12 DK DK92914330T patent/DK0588964T3/da active
  • 1992-06-12 TW TW081104616A patent/TW227001B/zh active
  • 1992-06-12 ES ES92914330T patent/ES2119814T3/es not_active Expired - Lifetime
  • 1992-06-12 WO PCT/US1992/005016 patent/WO1992022544A1/en not_active Ceased
  • 1992-06-15 MX MX9202879A patent/MX9202879A/es active IP Right Grant

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