Classifications

• • 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
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/535—Organo-phosphoranes
  • C07F9/5352—Phosphoranes containing the structure P=C-
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C315/00—Preparation of sulfones; Preparation of sulfoxides
  • C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
  • C07D207/48—Sulfur atoms
• • 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
• • 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
  • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
  • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
• • 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
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
  • C07F9/40—Esters thereof
  • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
  • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
• • 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

Definitions

• the present invention provides an optically active compound useful as a raw material for various pharmaceuticals and a method for producing the same.
• the optically active carboxylic acid ester provided by the present invention is extremely important.
• An object of the present invention is to provide an asymmetric synthesis method in which a reaction proceeds in a stereoselective manner, and a large amount of a compound having high optical purity can be easily obtained with an inexpensive reagent.
• R 1 is hydrogen or a hydroxy protecting group
• R 2 ′ is hydrogen or a lower alkyl optionally having substituent (s)
• Q is one CH CHP (R 3 ) 3 or one CHX′X
• R 3 which may have a lower alkyl or substituted group which may have a location substituent Ariru
• X is - P (0) R * R S or a S (0) R ⁇
• R 4 and R 5 is hydrogen, lower alkyl which may have a substituent, lower alkoxy which may have a substituent, aryl or halogen which may have a substituent
• X ' is hydrogen or lower.
• Alkyl; * means an asymmetric carbon atom.
• the present production method comprises the steps of: ! [-(R)
• a compound (I- (R)) or (I- (S)) is subjected to a transesterification reaction, that is, an optionally substituted alcohol such as methanol or ethanol is used as a basic catalyst, for example.
• the compound (BI— (R)) is obtained by reacting in the presence of, sodium alkoxide, pyridine or aluminum alkoxide.
• R 1 has the same meaning as described above, and R 2 represents a lower alkyl which may have a substituent.
• R 1 and R 2 each have the same meaning as described above.
• the free carboxylic acid is preferably combined with a halogenating agent (eg, phosphorus halide such as phosphorus trihalide, phosphorus pentahalide, or thionyl halide).
• a halogenating agent eg, phosphorus halide such as phosphorus trihalide, phosphorus pentahalide, or thionyl halide.
• Is converted to an acid halide by reacting in the presence of a basic substance (eg, an organic base such as pyridine), or is converted to an acid halide in the presence of a basic substance (eg, triethylamine).
• a mixed acid anhydride is obtained by reacting with an ester (eg, methyl chloroformate, ethyl chloroformate, isobutyl isoformate, etc.).
• the compound (la- (R)) is converted from the (3R, 2, R) glutaric acid ester (E- (R)) to the (3S, 2, S) glutaric acid ester.
• the compound (Ia— (S>) can be obtained from (H— (S)), and in the step (b :), ( ⁇ — (il)) gives (Ib- (S)), and (I- (S)) gives (lb- (R)).
• the R-form and the S-form of the compound (I) obtained in each reaction step are both useful, but the (R) -form is more preferable as an intermediate of the HMG-COA reductase inhibitor. . Therefore, in the step (a :), the compound (Ia— (R)) obtained from the (3R, 2, R) glutaric acid ester (I-I (R)) is obtained in the step (b :). The compound (Ib— (R)) obtained from (S, 2 ′S) daltaric acid ester (E— (S)) is used as a useful intermediate.
• the compound (IT) used as a starting material in the present invention is synthesized according to the method described in JP-A-2-250852. That is,
• the hydroxy-protecting group includes ether-forming protecting groups such as methyl, ter-butyl, aryl, benzyl, tetrahydroviranyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl and the like.
• Examples include ester-forming protecting groups such as acetyl and benzoyl, and sulfonate-forming protecting groups such as methylsulfonyl, p-toluenesulfonyl, and phenylsulfonyl.
• ester-forming protecting groups such as acetyl and benzoyl
• sulfonate-forming protecting groups such as methylsulfonyl, p-toluenesulfonyl, and phenylsulfonyl.
• ether-forming protecting groups particularly Tert-butyldimethylsilyl is preferred.
• the ⁇ lower alkyl which may have a substituent '' generally means a linear or branched alkyl having 1 to 6 carbon atoms, for example, methyl, ethyl, n-butyl. N-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isobentyl, neopentyl, tert-pentyl, 2-methylbutyl, n-hexyl and isohexyl, etc. And each may be substituted with halogen or amino.
• “Lower alkoxy optionally having substituent (s)” generally means a linear or branched alkyloxy having 1 to 6 carbon atoms, and the alkyl includes all examples of the lower alkyl. .
• “An optionally substituted aryl” generally refers to an aromatic having 6 to 12 carbon atoms.
• the aryl may be substituted by the above-mentioned alkyl, alkoxy, halogen or amino.
• Nodogen means fluorine, chlorine, bromine and iodine, the best form for carrying out the description
• the reaction solution was poured into a mixture of concentrated hydrochloric acid 15 Oml-water 300 ml-methylene chloride 500 ml while stirring under ice-cooling, and the organic layer was separated. I do.
• the aqueous layer is extracted with 200 ml of methylene chloride, and each organic layer is washed with dilute hydrochloric acid and then with brine.
• the organic layers were combined, dried over magnesium sulfate anhydride, and the solvent was removed to remove the solvent and remove the solvent to obtain a compound of the fergest form ( ⁇ ⁇ (R) -l) 45.07 g (163, 1, yield 99) %).
• IR CCHC1 3 2880, 1730, 1528, 1437, 1250, 1106, 835 cm -1
• the compounds obtained by the method of the present invention are used as side chains of various HMG-COA reductase inhibitors.
• An example is shown below.
• the present invention provides a synthesis method for obtaining various optically active drug materials, more specifically, HMG-CoA reductase inhibitor materials with high optical purity and high yield.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Biochemistry (AREA)
• General Health & Medical Sciences (AREA)
• Molecular Biology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Steroid Compounds (AREA)
• Preparation Of Compounds By Using Micro-Organisms (AREA)
• Pyrrole Compounds (AREA)

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• 1992
  • 1992-05-14 WO PCT/JP1992/000611 patent/WO1992022560A1/ja not_active Ceased
  • 1992-05-14 JP JP50928592A patent/JP3233403B2/ja not_active Expired - Lifetime
  • 1992-05-14 ES ES92910210T patent/ES2110499T3/es not_active Expired - Lifetime
  • 1992-05-14 AT AT92910210T patent/ATE161262T1/de active
  • 1992-05-14 US US07/969,249 patent/US5354879A/en not_active Expired - Lifetime
  • 1992-05-14 DE DE69223603T patent/DE69223603T2/de not_active Expired - Lifetime
  • 1992-05-14 EP EP92910210A patent/EP0554455B1/en not_active Expired - Lifetime
  • 1992-05-14 DK DK92910210.1T patent/DK0554455T3/da active
  • 1992-06-11 TW TW081104572A patent/TW201730B/zh active
• 1993
  • 1993-02-18 KR KR1019930700459A patent/KR100216011B1/ko not_active Expired - Lifetime
• 1998
  • 1998-02-25 GR GR980400381T patent/GR3026204T3/el unknown
• 2001
  • 2001-07-18 JP JP2001218860A patent/JP3635247B2/ja not_active Expired - Lifetime

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