WO2002070567A1 - Compose, procede d'elaboration, et utilisation comme support de reaction en phase solide - Google Patents

Compose, procede d'elaboration, et utilisation comme support de reaction en phase solide Download PDF

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Publication number
WO2002070567A1
WO2002070567A1 PCT/JP2002/002108 JP0202108W WO02070567A1 WO 2002070567 A1 WO2002070567 A1 WO 2002070567A1 JP 0202108 W JP0202108 W JP 0202108W WO 02070567 A1 WO02070567 A1 WO 02070567A1
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Prior art keywords
halogen
compound
alkyl
reaction
formula
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PCT/JP2002/002108
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English (en)
Japanese (ja)
Inventor
Hiroshi Handa
Takashi Takahashi
Hiroshi Ohno
Kuniaki Kawamura
Atsushi Ohtake
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Japan Represented By President Of Tokyo Institute Of Technology
Toray Industries, Inc.
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Priority to JP2002570604A priority Critical patent/JPWO2002070567A1/ja
Publication of WO2002070567A1 publication Critical patent/WO2002070567A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
    • C07C205/35—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/36—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
    • C07C205/37—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F8/00—Chemical modification by after-treatment

Definitions

  • Novel compound its production method and its use as a carrier for solid phase reaction
  • the present invention relates to a novel compound useful as a solid phase reaction carrier, a method for producing the same, and its use as a solid phase applied carrier.
  • an organic compound as a starting material is not directly bonded to a solid support such as a polystyrene resin, but is bonded to a solid support via a linker for solid phase reaction.
  • a solid-phase reaction carrier having a linker As such a solid-phase reaction carrier having a linker, a so-called Wang resin has been widely used since ancient times. This Wang resin is obtained by bonding a 4-hydroxymethyl-1-phenoxymethyl group to a polystyrene resin as a linker, and a starting material to be subjected to the reaction is covalently bonded to a hydroxyl group of the linker.
  • 10-507160 discloses a solid phase reaction linker that is rapidly cleaved under mild conditions and does not generate highly reactive by-products.
  • This linker has a benzene ring similarly to the Wang resin, and has a nitro group on the benzene ring at an ortho position as viewed from a site where the starting material to be subjected to the reaction is bonded.
  • a linker having a sulfoxide group on the benzene ring is known as a solid-state reaction linker usable under acidic conditions (Kiso, Y., Fukui, T., Tanaka, S., K i mura, ⁇ ., Aka ji, ⁇ ⁇ , Tetrahedron Lett., 1994, 35, 3571 -3574) 0 Mr. Kaka Shinano
  • the reaction cannot be carried out under the condition that the sulfoxide group is reduced, and there is a disadvantage that the reaction conditions that can be used are limited.
  • an object of the present invention is to perform a reaction under acidic conditions and under conditions of reducing a sulfoxide group, and to be useful as a solid-phase reaction carrier capable of obtaining a target product only by a cleavage reaction from the solid-phase carrier.
  • the present inventors have found that, as a linker, a nitro group or halogen is not present at a site other than ortho when viewed from a functional group to which a starting material to be subjected to a reaction is bonded without having a sulfoxide group. It has been found that the above object can be achieved by adopting a structure containing a benzene ring, and the present invention has been completed.
  • the present invention provides a compound of the formula (I):
  • R represents a solid support
  • A is - (CH 2) n -, - GH 2 -NH- GO- (GH 2) n -, -GH 2 - 0 - (GH 2) n - or - GO- NH- (CH 2) n - and it is; n is an integer from.
  • R 1 and R 2 Germany respectively Standing hydrogen, 0 ⁇ 1 c ⁇ 8 8 a-alkyl, and is also good Ariru or substituted optionally be substituted, be a good I Ariru (GfCs) alkyl optionally;
  • R 3 and R 4 are each independently Te, hydrogen, halogen, 0 ⁇ 0 8 alkyl or C r G 8 alkoxy,;
  • R 5 is hydrogen, di- Bok port, halogen, C r G 8 alkyl or G r G 8 alkoxy,;
  • R 6 Is nitro or halogen (however, when R 6 is bromine, R 5 is not hydrogen);
  • X 1 is halogen, — SH, — SP, —OH, — OP, one NH 2 , one NH P ( Wherein P is a protecting or activating group, or NR 7 R 8 (where R 7 and R 8 are independently hydrogen, optionally substituted G r C 8 alkyl, optionally substituted Ariru, replacement
  • R-A-Y where Y is hydroxy or halogen, R and A are as defined in the above formula (I) and formula (III):
  • RRR 5 , R 6 and X 1 are reacted with a compound represented by the above formula (I), and if necessary, a chemical reaction is carried out on a solid phase to produce a compound represented by the above formula (I) I will provide a.
  • the present invention provides a solid-phase reaction carrier comprising the compound represented by the above formula (I). Further, the present invention provides a compound represented by the above formula (I), wherein (i) an organic compound is bound by a covalent bond, and ( ⁇ i) a structural change of the organic compound is carried out by a chemical reaction on a solid phase. And (iii) cutting out the organic compound from a solid phase, if desired, to provide a method for producing an organic compound.
  • a solid-phase reaction support that can be used under acidic and reducing conditions Novel compounds have been provided that can be used as bodies.
  • the compound of the present invention is used as a carrier for solid phase reaction, it is possible to carry out the reaction under acidic conditions or reducing conditions that could not be achieved by the conventional solid phase reaction, so that the choice of reaction conditions is widened. The effect is achieved.
  • R represents a solid phase support.
  • the solid support may be made of any material capable of providing a solid phase insoluble in the reaction solvent on which the reaction is performed, and capable of covalently bonding a linker described below.
  • Various synthetic resins can be preferably used. Among them, polystyrene resin and polystyrene-polyethylene glycol (PEG) copolymer resin are preferred. In the latter case, the degree of polymerization of PEG is preferably about 50 to 200.
  • the shape of the solid support is not limited at all, and may be any shape, preferably a bead shape, and the diameter is usually about 1 ⁇ m to 1 mm.
  • A - (GH 2) n - , - GH 2 - NH-C0- (GH 2) n -, - GH 2 - 0- (GH 2) n - or - CO-NH- (GH 2 ) n- .
  • n is an integer of 1 to 8.
  • R 1 and R 2 each independently represent hydrogen, C 2 -Gs alkyl, substituted or unsubstituted or substituted or unsubstituted (G1-G8) alkyl.
  • aryl refers to the remaining atomic group obtained by removing one hydrogen atom from an aromatic hydrocarbon, and preferable examples thereof include phenyl, biphenyl, naphthyl, and anthryl. It is not limited to these.
  • Ariru and ⁇ Li Lumpur (G ⁇ G 8) carbon atoms of Ariru moiety in the alkyl 6-1 2 is preferred. Further, Ariru or Ariru (G r G 8) alkyl may be substituted.
  • examples of the substituent include —C 1 -C 8 alkyl, C i -C 8 alkoxy, nitro, and halogen.
  • the number of carbon atoms is preferably 1 to 4.
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • the number of substituents is not particularly limited, and any number is possible as long as the number is theoretically possible. For example, if aryl is phenyl, the number of substituents is 0-5, if biphenyl is 0-9, if naphthyl is 0-7, if anthranyl, it is 0-9.
  • substituent may be on the aromatic ring, or may be on the alkyl group in the case of aryl (G-Gs) alkyl. Further, Ariru (0 0 8) carbon atoms in the alkyl moiety of the alkyl 1-4 is preferred.
  • R 1 and R 2 are each independently preferably hydrogen, methyl or optionally substituted phenyl.
  • R 3 and R 4 are each independently hydrogen, halogen, G r G 8 alkyl, or G factory G 8 alkoxy.
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • an alkyl group or an alkoxyl group it preferably has 1 to 4 carbon atoms. It is particularly preferred when R 3 and R 4 are both hydrogen.
  • R 5 is hydrogen, nitro, halogen, -G 8 alkyl, or G "G 8 alkoxy.
  • the halogen include fluorine, chlorine, bromine and iodine.
  • the number of carbon atoms is preferably from 1 to 4.
  • R 5 is preferably hydrogen, nitro or halogen, particularly preferably hydrogen or halogen.
  • R 6 is nitro or halogen.
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • R 6 is bromine, the above R 5 is not hydrogen.
  • R 6 is nitro.
  • a preferable example is a compound in which both R 5 and R 6 are halogen.
  • X 1 is halogen, one SH'-SP, one OH, -OP, -NH 2 , one N
  • HP where P is a protecting or activating group or one NR 7 R 8 (where R 7 and R 8 are independently hydrogen, optionally substituted- ⁇ alkyl, substituted which may be Ariru, optionally substituted ⁇ Li Ichiru 0 ⁇ 0 8 alkyl, it represents to) selected from the group consisting of heteroaryl optionally substituted, or X 1 together with ⁇ Represents carbonyl.
  • an ⁇ activating group '' is a group that enhances the reactivity of forming a covalent bond when a second functional group or a reactive group reacts with a specific functional group or a reactive site to form a covalent bond.
  • a hydroxyl group by activating group is activated, - 0 (G 0) CI , -0CH 2 CI, -0 and (C0) Ar (where Ar is an optionally substituted Ariru Represent
  • heteroaryl examples include pyridyl, pyrrolyl, furyl, chenyl and the like.
  • X 1 is preferably halogen, 1 OH, 1 OP, 1 NH 2 , 1 NHP, more preferably —OH or —OP, and particularly preferably —0H. Further, X 1 may represent carbonyl together with R 1, and these cases are also preferable examples.
  • formula (II) the following formula (II):
  • R is a polystyrene resin, A73 ⁇ 4-GH 2 -or -GH 2 CH 2- , and R 1 , R 2 , R 3 , And R 4 are each hydrogen, R 5 is hydrogen or halogen, R 6 is nitro or halogen, and X 1 is 1 OH, —OP.
  • the compound of the present invention represented by the formula (I) is represented by R-A-Y (where Y is hydroxy or halogen, R and A are as defined in the above formula (I)) and the formula (I II):
  • R, A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and X 1 have the same meanings as those of the formula (I)). It can be manufactured by performing a chemical reaction above. The description of each substituent in Formula (III) and preferred examples thereof are the same as those described above for Formula (I).
  • reaction conditions of R-A-Y with the compound represented by the formula (III) are not particularly limited, and are appropriately selected depending on the kind of each substituent. Usually, when Y is hydroxy, the Mitsunobu reaction
  • Y is hydroxy and bonded to the compound represented by the formula (111) by Mitsunobu reaction
  • a combination of a phosphorus compound such as triphenylphosphine or tributylphosphine and an azo compound such as getyl azodicarboxylate-diisopropylcarboxylate can be used.
  • the concentration of the compound of the formula (III) is usually 0.05 to M, preferably 0.1 to 0.3 M, and the reaction ratio of the compound of the formula (I11) to RAY is 1: ⁇ ! ⁇ 20: 1, preferably 2: 1 to 10: 1.
  • the concentration of the phosphorus compound and the azo compound is usually 0.05 to 1,0 M, preferably 0,1!
  • the molar ratio of the phosphorus compound and the azo compound to RA-Y is 1: 1 to 20: 1, preferably 1: 1 to 10: 1.
  • the reaction temperature is from 120 ° C. to 100 ° C., preferably from 0 ° C. to 40 ° C.
  • the reaction time is from 0.1 ”to 48 hours, preferably from 0.5 to 24 hours.
  • the medium is also appropriately selected according to the compound to be used, but usually, tetrahydrofuran or the like can be preferably used.
  • ⁇ is hydroxy and this is converted to trichloride imidate
  • it can be carried out by using trichloroacetonitrile in the presence of a base.
  • preferred examples of the base group include diazabicycloundecene.
  • the reaction temperature is from 1 to 50 ° C., preferably from 110 to 40 ° C.
  • the reaction time is from 0.1 to 48 hours, preferably from 0.5 to 24 hours.
  • the reaction solvent is THF, methylene chloride.
  • concentration of the base is 0.01 to 2 M, preferably 0.03 to 1 M, and the reaction ratio of the base to R-A-Y is 1: 1 to 50: 1, preferably 1 to 1 in molar ratio. : 1 to 30: 1.
  • the concentration of trichloroacetonitrile is 0.01 to 3 M, preferably 0.1%.
  • the molar ratio of trichloroacetonitrile to R-A-Y is 1: "! To 50: 1, preferably 10: 1 to 30: 1.
  • the reaction of the triclomouth imidate with the compound of formula (III) can be achieved in the presence of a Lewis acid.
  • a Lewis acid include a trifluoroporangetyl ether complex.
  • the reaction temperature is -50 to 100 ° C, preferably 0 to 40 ° C, and the reaction time is 0.1 to 48 hours, preferably 0.1 "! To 24 hours.
  • the reaction solvent is methylene chloride or cyclohexane. Preferred is a mixed solvent of xane and methylene monochloride, etc.
  • the concentration of the Lewis acid is 0.005 to 0.3 M, preferably 0.01 to 0.1 M, and the reaction ratio of the Lewis acid to trichloroimide is 0.05: 1 to 20: 1, preferably about 0.1: 1 to 10: 1.
  • a base When Y is a halogen and is bonded to the compound represented by the formula (III) by a nucleophilic substitution reaction, it is preferable to use a base by a conventional method. Examples of a preferable base include cesium carbonate, sodium carbonate, potassium carbonate, and the like. Diazabicycloundecene, potassium t-butoxide, and the like.
  • An additive may be added, and sodium iodide can be preferably used as the additive.
  • the concentration of the base is about 0.01 to 1 M, preferably about 0.1 to 0.3 M, and the reaction ratio of the base to R-AY is 1: 1 to 20: 1 in molar ratio, preferably 2: 1 to 10: Is one.
  • the reaction solvent is appropriately selected according to the reagent to be used, but usually DMF, acetonitrile, THF and the like can be preferably used.
  • the reaction temperature is from 120 to 100 ° C, preferably from 20 to 80 ° C
  • the reaction time is from 1 to 48 hours, preferably from 5 to 24 hours.
  • the concentration of the compound of the formula (III) is 0.01 to 3 M, preferably 0.1 to 1 M, and the reaction ratio of the compound of the formula (II I) to R-A-Y is 1: "!
  • a substituent introduction reaction on the solid phase A desired one of the compounds represented by the formula (I) can also be produced by converting the introduced substituent into another substituent, etc.
  • a reaction for introducing a substituent into an aromatic ring or a substituent Reactions for converting to other substituents are well known in the art, and these can be performed on a solid phase by applying well-known methods.
  • the compound of the present invention can be used as a carrier for solid phase reaction.
  • the resin or the like represented by R above is called a “solid support”, and the structure other than R in the formula (I)
  • the part is called a linker, and the entire compound represented by the formula (I) in which the linker is bound to a solid support is called a solid-phase applied carrier.
  • an organic compound serving as a starting material to be subjected to the reaction is bonded to a portion other than R and A of the compound represented by the formula (I);
  • Structural conversion of the organic compound is performed by a chemical reaction on the solid phase, and then (iii) the organic compound having the desired structural change is cut out from the solid phase.
  • the carrier for solid phase reaction of the present invention exhibits particularly excellent effects when the step (M) includes a chemical reaction under acidic conditions.
  • the acidic condition means that the reaction is carried out on a solid phase. Not all steps of the reaction need to be performed under acidic conditions, meaning that at least one step is performed under acidic conditions.
  • R represents a solid support
  • A is - (CH 2) n -, - GH 2 - NH- GO- (GH 2) n -, - GH 2 -0- (GH 2) n - or - GO- NH- (CH 2) n - and it is;
  • n is 1 foot J an integer of 8;
  • R 1 and R 2 are independently, respectively therewith hydrogen, - G 8 alkyl, optionally substituted good be Ariru or optionally substituted Ariru (0 ⁇ G 8) alkyl;
  • R 3 and R 4 are each independently hydrogen, halogen, G r G 8 alkyl or C-G 8 alkoxy;
  • R 5 is hydrogen, nitro, halogen, G factory G 8 alkyl, or G r G 8 alkoxy;
  • R 6 is nitro or halogen;
  • X 1 is halogen, one SH, -SP, -OH, one OP , -NH 2 , -NH P (where P
  • Organic compounds as a starting material it is preferred to attach the X 1.
  • X 1 forms a ketone or aldehyde together with R 1 or R 1 and R 2
  • this ketone or aldehyde with a starting material.
  • Binding of X 1 and the functional group in the starting material depending on the type of the functional group, leaving at be carried out by a conventional method.
  • the starting material is subjected to a desired structural transformation. This structural change is not limited at all, and may be any such as addition of a structure by condensation or the like, addition or conversion of a substituent, or cleavage of a starting material.
  • a part of the linker is not cleaved under acidic conditions or under the conditions of reducing sulfoxide, so that a part of the linker of the conventional solid-state reaction support is cleaved. Under the conditions, a reaction for structural transformation can be performed.
  • the product is cut out from the solid-phase reaction support, if desired.
  • R 6 is a nitro group
  • this step is carried out by reducing the nitro group and then subjecting it to acidic conditions, or after reducing the nitro group, acylating or sulfonylating the amino group and then subjecting it to acidic conditions. It can be carried out.
  • the reduction of the nitro group can be preferably performed as follows.
  • the reducing agent is preferably a low-valent metal, more preferably tin dichloride dihydrate, and the reaction solvent is preferably DMF, DMAA, N-methylpyrrolidinone, or the like.
  • the reaction temperature is usually from 120 to 80 ° C, preferably from 0 to 40 ° C, and the reaction time is usually from 0.5 to 24 hours, preferably from 1 to 8 hours.
  • the molar ratio of the reducing agent to the dinitro group is usually 1 ::! To 50: 1, preferably 3 ::! ⁇ 20: 1.
  • the concentration of the reducing agent is usually from 0.05 to 1 M, preferably from 0.1 to 0.5 M.
  • the acyl group is not particularly limited. Preferred examples thereof include an acetyl group, a propionyl group, a benzoyl group, a phenylaminocarbonyl group, a propylaminocarbonyl group, and a cyclohexylaminocarbocarbonyl group.
  • the acylation can preferably be performed as follows.
  • the acylation reaction for forming an amide is carried out by condensing various carboxylic acids with an amino group by a conventional method, and a condensing agent is used if necessary.
  • a condensing agent a combination of diisopropylcarbodiimide and N-hydroxybenzotriazole, benzotriazole-1
  • the concentration of the carboxylic acid is 0.05 to 3 M, preferably 0.1 to 1 M, and the reaction ratio of the carboxylic acid to the amino group is 1 ⁇ to 50: 1, preferably 5: 1 to 30: in molar ratio.
  • the concentration of the condensing agent is 0.05-33, preferably 0.1-11, and the reaction ratio of the condensing agent to the amino group is 1: 1-50: 1, preferably 5: 1-30 in molar ratio.
  • the reaction temperature is from 150 to 100 ° C., preferably from 0 to 50 ° C., and the reaction time is from 0.1 to 48 hours, preferably from 1 to 24 hours. , DMF, DMAA, etc.
  • the amide-forming acylation reaction can also be carried out by reacting with sulfonic acid halide in the presence of a base. Usually, diisopropylethylamine, triethylamine, etc. are used. Concentration 0.05 ⁇ 3 M, preferably, 0. "! The molar ratio of the carboxylic acid halide to the amino group is 1: 1 to 50: 1, preferably 5: 1 to 30: 1.
  • the concentration of the base is 0.05 to 3 M, preferably 0.1 to 11, and the molar ratio of the base to the amino group is 1: ⁇ ! To 50: 1, preferably 5: 1 to 30: 1.
  • the reaction temperature is -50 to 100 ° C, preferably 0 to 50 ° C, and the reaction time is 0.1 to 48 hours, preferably 1 to 24 hours.
  • the reaction solvent is not particularly limited, but DMF, DMAA and the like are preferably used.
  • the acylation reaction for forming perylene or thioperia can be carried out by reacting an amino group with various isocyanates or isothiocynates by a conventional method.
  • concentration of the isocyanate or isothiocyanate is 0.05 to 3 M, preferably 0.1 to 1 ⁇
  • the reaction ratio of the isocyanate or isothiocyanate to the amino group is 1: ⁇ ! 5050: 1, preferably 5: 1 to 30: 1.
  • the reaction temperature is between 150 and 100 ° C, preferably between 0 and 50 ° C
  • the reaction time is between 0.1 and 48 hours, preferably between 1 and 24 hours.
  • the reaction solvent is not particularly limited, but methylene chloride and the like are preferably used.
  • the sulfonyl group is not particularly limited, but preferred examples thereof include methanesulfonyl, ethanesulfonyl, phenylsulfonyl, and p-toluenesulfonyl.
  • Sulfonates forming sulfonamides The reaction can be carried out by reacting a lamino group with various sulfonyl chlorides in the presence of a base by a conventional method.
  • the base diisopropylethylamine and the like are preferable.
  • the concentration of the sulfonyl chloride is 0.05 to 3 M, preferably 0.1 to 1 M, and the reaction ratio of the sulfonyl chloride to the amino group is 1: 1 to 50: 1, preferably 5: 1 to 5: 1.
  • the base concentration is 0.05 to 2 M, preferably 0.1 to 1 M, and the reaction ratio of the base to the amino group is 1: 1 to 50: 1, preferably 5: 1 to 30:
  • the reaction temperature is 1 to 100 ° C., preferably 0 to 50 ° C., and the reaction time is 0.1 to 48 hours, preferably 1 to 24 hours.
  • methylene chloride are preferably used.
  • the product is cleaved from the solid-phase reaction carrier under acidic conditions.
  • Acids used under acidic conditions include TFA, acetic acid, hydrochloric acid and the like.
  • the solvent include methylene chloride, THF, water, methanol and the like.
  • an additive may be used, and as the additive, triethylsilane, triisobutyl silane, dimethylsulfide and the like are preferably used.
  • the acidic condition usually 1% to 100% TFA, 1% to "! 00% acetic acid, 1% to saturated hydrochloric acid are preferably used.
  • the reaction temperature is usually 0 to 100 ° C, and preferably ⁇ 0.
  • the reaction time is usually 0.1 to 24 hours, preferably 0. "! ⁇ 2 hours.
  • R 6 is a halogen
  • the product can be cleaved from the solid-phase reaction support by reducing or substituting the halogen with an aryl group and then subjecting the product to acidic conditions.
  • reduction of the halogen or substitution with the aryl group can be preferably carried out as follows.
  • the reduction of halogen can be carried out by a conventional method under conditions using a palladium catalyst.
  • the palladium catalyst is preferably a zero-valent palladium bonded with a suitable ligand, and more preferably tetrakis (triphenylphosphine) palladium.
  • An aqueous sodium carbonate solution is preferably used as the base, and dimethylformamide dimethoxetane is preferably used as the solvent.
  • the concentration of the palladium catalyst is 0.001-1 M, preferably 0.005-0.1 M,
  • the reaction ratio with respect to halogen is 0.001: "! To 5: 1, preferably 0.01: 1 to 2: 1.
  • the concentration of the base is 0.01 to 3 M, preferably 0.1 to 1 M, and the halogen of the base is
  • the reaction ratio with respect to the molar ratio is 1: ⁇ ! To 30: 1, preferably 2: to 10: 1.
  • the reaction temperature is usually 20 to 120 ° C, preferably 70 to 100 ° C.
  • the reaction time is generally 0.5 to 48 hours, preferably 2 to 24 hours.
  • the reaction of substituting a halogen with an aryl group can be carried out by a coupling reaction using a palladium catalyst by a conventional method.
  • the palladium catalyst is preferably a zero-valent palladium bonded with a suitable ligand, more preferably tetrakis (triphenylphosphine) palladium.
  • a suitable ligand more preferably tetrakis (triphenylphosphine) palladium.
  • arylating reagent aryl (trialkyl) tin diaryl boric acid or the like is used, and among them, phenyl boric acid is preferable.
  • As the base an aqueous solution of sodium carbonate or triethylamine is preferably used, and as the solvent, dimethylformamide or the like is preferably used.
  • the concentration of the palladium catalyst is 0.001-1 M, preferably 0.005-0.1 M, and the reaction ratio of the palladium catalyst to halogen is 0.001: 1-5: 1, preferably 0.01: 1-2: 1 in molar ratio. is there.
  • the concentration of the base is 0.01 to 3 M, preferably 0.1 to 1 M, and the reaction ratio of the base to the halogen is 1: 1 to 30: 1, preferably 2: 1 to 10: 1 in molar ratio.
  • the concentration of aryl boric acid is 0.01 to 3 M, preferably 0.2 to 1 M, and the reaction ratio of aryl boric acid to halogen is 1: 1 to 30: 1, preferably 2: "! To 10: 1 in molar ratio.
  • the reaction temperature is usually 20 to 120 ° C., preferably 70 to 100 ° C., and the reaction time is generally 0.5 to 48 hours, preferably 2 to 24 hours. Can be performed in the same manner as described above.
  • the product can be recovered by separating the solid phase and the liquid phase as in the case of the known solid-phase reaction carrier.
  • the recovered product can be further purified by a conventional method, if necessary, to remove the remaining reagents.
  • one advantage of the solid phase reaction is that the product can be obtained only by separating the liquid phase from the solid phase, and as shown in the examples below, the reagents for cutting out by vacuum drying etc.
  • the cut-out can be removed by vacuum drying, for example with trifluoroacetic acid, so that a product with the desired purity can be obtained by simply removing the solvent. It is preferably carried out using an acid.
  • pole-shaped part in the chemical formulas described in the following examples indicates polystyrene.
  • the mixture was filtered, and the resin was washed with THF (5 mU twice), DMF (5 ml, 5 times), THF-H20 (1: 1) (8 m and 3 times), methanol (5 ml, 5 times), THF (5 ml, 5 times), washed with methylene chloride (5 m, 5 times), and dried in vacuo to obtain the target compound (1.25 g).
  • Example 4 one formyl one 2-nitro-phenoxyethanol polystyrene (514 mg, ca 0.28 ⁇ ol) obtained in 1 was suspended in TH F (5 ml), sodium borohydride (145 mg, 3.84 stroke 0
  • the mixture was filtered and the resin was washed with DMF (10 ml, 5 times), methanol (10 m, 5 times), THF (10 ml, 5 times), methylene chloride (10 m, 5 times), and vacuum. Drying was performed to obtain the target compound.
  • Example 3 The 4-formyl-1-2-nitrophenoxethyl polystyrene obtained in Example 3 was suspended in HF (20 ml), and sodium borohydride (750 mg, 19.8 mmol) and methanol (2 ml) were added. Shaking was performed at room temperature for 1 hour. The mixture was filtered, and the resin was treated with methanol (10 ml, 2 times), DMF (10 m, 5 times), methanol (10 ml, 5 times), THF (10 ml, 5 times), methylene chloride (10 ml, 5 times) ) And dried under vacuum to obtain the target compound (2.30 g).
  • the 2-promo 4-formylphenoxicetyl polystyrene (275 mg, ca 0.24 country ol) obtained in Example 5 was suspended in THF (2 ml), and sodium borohydride (47.6 mg, 1.21 mmol), methanol ( 0.2 ml) and shaken at room temperature for 1 hour. The mixture is filtered and the resin is methanol (2 ml, 2 times), DMF (2 m, 5 times), methanol (2 ml, 5 times), THF (2 m, 5 times), methylene chloride (2 m) 5 times) and dried under vacuum to obtain the target compound (281 mg).
  • the 2,6-dibromo-4-formylphenoxicetyl polystyrene (304 mg, ca 0.23 mol) obtained in Example 1 was suspended in THF (2 ml), and sodium borohydride (46 mg, 1.22 mol. ) And methanol (0.2 ml) were added, and the mixture was shaken at room temperature for 45 minutes. The mixture was filtered, and the resin was washed with methanol (2 m twice), DMF (2 ml, 5 times), methanol, THF, methylene chloride, and dried in vacuo to give the target compound (306 mg) .
  • the reaction mixture was filtered, and the resin was washed with DMF (5 x 2 mU), methanol (5 x 2 mU), THF (5 x 2 mU), methylene chloride (5 x 2 mU), and dried in vacuo. went.
  • a 50% trifluoroacetic acid methylene chloride solution (2 ml) was added to the obtained resin, and the mixture was added for 30 minutes. Shake.
  • the reaction mixture was filtered, the resin was washed with methylene chloride (2 ml), combined with the filtrate, and dried under vacuum to obtain N-benzylnaltruindole trifluoroacetate (7.4 mg).
  • Naltrexone was carried on the Wang resin by performing the same operation as in Example 9 except that the solid-phase reaction carrier was replaced with a conventionally widely used Wang resin.
  • indole synthesis was attempted on the solid phase by the same operation as in Example 11, but the excision of naltrexone proceeded and indole synthesis could not be performed on the solid phase.
  • Naltrexone was supported on the photolinker by performing the same operation as in Example 9 except that the photolinker having the above structure was used as the solid phase reaction carrier. Further, when the same operation as in Example 10 was performed to cut out the naltrexone, the naltrexone was cut out from the carrier at the stage when the reduction operation with tin dichloride was performed. This indicates that the photolinker cannot be used for the reaction under such reducing conditions.
  • Example 11 the same operation as in Example 11 was performed on naltrexone supported on the photolinker to synthesize indole on the solid phase. An indole compound was cut out in the liquid. This indicates that the photolinker cannot be subjected to the reaction under such acidic conditions.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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  • Health & Medical Sciences (AREA)
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  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un composé susceptible d'être utilisé comme support de réaction en phase solide dans un environnement acide et sous des conditions qui permettent la réduction des groupes sulfoxyde. A titre d'exemple, ce composé est du type 4-hydroxyméthyl-3-nitrophénoxyéthylpolystyrène.
PCT/JP2002/002108 2001-03-07 2002-03-07 Compose, procede d'elaboration, et utilisation comme support de reaction en phase solide WO2002070567A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0292729A2 (fr) * 1987-05-18 1988-11-30 Bachem Ag Procédé de synthèse de peptides en phase solide
WO1999039207A1 (fr) * 1998-01-29 1999-08-05 Pharmacopeia, Inc. Linker phenoxyalkyle clivable par un acide pour synthese combinatoire

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0292729A2 (fr) * 1987-05-18 1988-11-30 Bachem Ag Procédé de synthèse de peptides en phase solide
WO1999039207A1 (fr) * 1998-01-29 1999-08-05 Pharmacopeia, Inc. Linker phenoxyalkyle clivable par un acide pour synthese combinatoire

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